Endometriosis is a long-term condition where tissue similar to the lining of the uterus grows outside the uterus. It affects about 10% of women of reproductive age. Common symptoms include:
Pelvic pain
Painful periods
Infertility
The exact cause is unknown, diagnosis is often delayed, and current treatments do not always work well. This review explains what is known about its prevalence, risk factors, and how the disease develops.
1. Introduction
Endometriosis was first described in 1860 and is one of the most common gynecological diseases, affecting 6â10% of women of reproductive age. Some women have no symptoms, while others experience:
Chronic pelvic pain
Painful periods
Pain during sex
Infertility
About 50% of women with endometriosis have infertility, and 70â80% experience chronic pain. The disease is also linked to ovarian cancer, autoimmune diseases, and mental health problems.
Diagnosis is often delayed by 7â10 years, which can make symptoms worse. Research shows that genetic, hormonal, and immune system factors all play a role.
2. Epidemiology of Endometriosis
Endometriosis affects 30â50% of women with infertility or chronic pelvic pain. It is most common in women aged 25-34 years. Rates vary between countries because of differences in genetics, healthcare, and diagnosis. Many women remain undiagnosed, so the true number of cases is probably higher.
Endometriosis has major health and financial effects. It can cause
chronic pain
infertility
anxiety
depression.
Medical care and treatment are expensive, and many women miss work because of symptoms, creating additional economic costs.
Studies suggest that endometriosis is becoming more common. Possible reasons include environmental pollution, lifestyle changes, and exposure to certain chemicals. The disease is also linked to a higher risk of ovarian cancer, heart disease, and other chronic illnesses. Changes in the gut and uterine microbiome may also contribute.
3. Risk Factors for EndometriosisFamily history is one of the strongest risk factors. Women with a close relative who has endometriosis are 7-10 times more likely to develop it.
More than 40 genes have been linked to the disease. These genes affect estrogen, inflammation, the immune system, and tissue growth.
Exposure to chemicals such as phthalates, dioxins, and PCBs may increase the risk of endometriosis. These chemicals can affect hormones, increase inflammation, and change the gut microbiome.
Other possible risk factors include alcohol, air pollution, and smoking. Alcohol is generally linked to a higher risk, while evidence for smoking is mixed. Air pollution may increase inflammation and change gene activity.
Diet may affect the risk of endometriosis. Eating a lot of red meat, saturated fat, and refined carbohydrates may increase risk. A diet rich in fruits, vegetables, whole grains, omega-3 fats, and Mediterranean-style foods may lower risk. Low vitamin D levels have also been linked to the disease.
Women with a lower BMI may have a higher risk, although the relationship is not fully understood. Doing at least 3 hours of moderate exercise each week is linked to a 30-40% lower risk, probably because it reduces inflammation and improves hormone balance.
4. Molecular Mechanisms of Endometriosis
This section explains the biological processes that cause and maintain endometriosis.
Endometriosis causes long-term inflammation. High levels of inflammatory substances help abnormal tissue
grow
form new blood vessels
spread
avoid being removed by the immune system
The immune system does not work normally in endometriosis. Some immune cells become overactive, while others become less effective, allowing abnormal tissue to survive and grow outside the uterus.
Changes in DNA methylation can switch genes on or off. These changes affect hormones, inflammation, and tissue growth. They may be caused by environmental factors and could become useful for diagnosis and treatment.
Other changes, including histone modifications and noncoding RNAs, control genes involved in inflammation, cell growth, and tissue invasion, helping the disease progress.
Endometriosis depends on estrogen. High estrogen levels and resistance to progesterone encourage abnormal tissue growth, inflammation, and survival.
Other substances, including
prostaglandins
growth factors
insulin-like growth factors (IGFs)
also increase pain, inflammation, blood vessel growth, and lesion development.
People with endometriosis have increased oxidative stress, meaning harmful molecules (ROS) are higher than the body's antioxidant defenses. This damages cells, increases inflammation, and helps the disease progress. Antioxidants may help reduce symptoms.
Proteins break down surrounding tissue, allowing endometrial-like cells to attach and spread. Lower levels of their natural inhibitors make this process easier.
Changes in cell adhesion and cell cycle proteins help abnormal cells stick to tissues, spread, and multiply more quickly.
5. Diagnosis of Endometriosis
Diagnosis starts by asking about symptoms such as:
Chronic pelvic pain
Painful periods
Pain during sex
Infertility
A pelvic exam may find tenderness or lumps, but it is not always accurate, especially in early disease. Many women wait 7-10 years before receiving a diagnosis because symptoms are often mistaken for other conditions.
Transvaginal ultrasound is the first imaging test used. It is good at finding ovarian cysts (endometriomas) and some deep lesions.
MRI is better for detecting deep endometriosis and is often used before surgery.
CT scans are not usually recommended because they are less accurate.
Laparoscopy is the gold standard for diagnosing endometriosis. It allows doctors to see and sometimes remove endometriosis tissue. A tissue biopsy is often used to confirm the diagnosis.
However, laparoscopy is surgery, so it is invasive and may still miss very small lesions.
Researchers are studying blood tests to diagnose endometriosis without surgery.
CA-125 is the most commonly used marker, but it is not very accurate because it can also be high in other diseases.
Other possible markers include:
CA-199
HE4
microRNAs (miRNAs)
Inflammatory cytokines
VEGF
Using several markers together may improve diagnosis.
Urine and endometrial tissue tests are also being studied. Possible markers include miRNAs, MMP-9, and VEGF.
These tests are less invasive and may help detect endometriosis earlier, but they still need more research.
Doctors currently diagnose endometriosis by combining:
Symptoms
Physical examination
Imaging tests
Laparoscopy when needed
Future research aims to develop better blood tests and AI tools for earlier and more accurate diagnosis without surgery.
6. Management of Endometriosis
Treatment depends on symptoms, disease severity, and whether the patient wants to have children.
Birth control pills are usually the first treatment for pain. They lower estrogen levels, stop ovulation, and reduce the growth of endometrial tissue. Taking them continuously often works better than taking monthly breaks.
Progestins, such as dienogest, reduce estrogen effects, slow tissue growth, and relieve pain.
Possible side effects include:
Weight gain
Mood changes
Irregular bleeding
Lower estrogen levels leading to Menopause-like symptoms
Laparoscopic surgery is the preferred operation. It removes endometriosis tissue, cysts, and scar tissue while preserving healthy tissue.
It can improve pain and fertility, but 20â30% of women develop the disease again within five years.
More extensive surgery, including laparotomy or hysterectomy, is used only for severe cases or women who do not want future pregnancies.
Removing the ovaries is very effective for pain but causes early menopause and may increase long-term health risks.
New treatments are being developed to reduce inflammation by targeting immune molecules such as TNF-α and IL-6.
These treatments are still being studied.
Researchers are developing treatments that target gene activity, blood vessel growth (VEGF), MMPs, and other pathways involved in endometriosis.
These therapies may be more effective and have fewer side effects than current hormone treatments.
Women who want children in the future may choose:
Egg freezing
Embryo freezing
Ovarian tissue preservation
These options may be considered before treatments that could reduce fertility.
Fertility treatment may include:
Healthy lifestyle changes
Fertility medications
In vitro fertilization (IVF)
In some cases, surgery before IVF may improve pregnancy success.
7. Preclinical Models and Clinical Trials
Mice and rats are the most commonly used animal models. Researchers transplant endometrial tissue to study how the disease develops, causes pain and inflammation, and responds to new treatments.
Primates and rabbits are more similar to humans than rodents. Although they are more expensive and take longer to study, they provide important information before treatments are tested in people.
Applying results from animal studies to humans is difficult because animals do not perfectly develop the disease like humans.
Researchers are improving this by using better animal models, finding new biomarkers, and studying new treatment targets such as WNT5A, GBP2, and HCK.
More than 700 clinical drug trials are taking place worldwide.
Most focus on hormone treatments, especially GnRH antagonists, which reduce pain but may lower bone density if used for a long time.
Researchers are also testing nonhormonal treatments, but many have shown only limited success so far.
8. Conclusion and Prospects
Endometriosis is a common long-term disease that greatly affects health and quality of life.
It is influenced by:
Genetics
Environment
Hormones
The immune system
Lifestyle
Diagnosis currently relies on symptoms, imaging, and laparoscopy. Treatment includes hormone therapy, surgery, and newer targeted therapies.
Research also shows that the gut microbiome, chronic inflammation, and environmental chemicals may contribute to the disease.
Important challenges include:
The exact cause is still unknown.
There are no reliable noninvasive diagnostic tests.
Current treatments control symptoms but do not cure the disease.
The disease varies between patients, making personalized treatment difficult.
More research is needed on infertility, chronic pain, and other long-term health problems.
The future of endometriosis treatment is precision medicine, where care is tailored to each patient's symptoms, disease type, and fertility goals.
Physical Activity in Children with Developmental Coordination Disorder
Abstract
This literature review looked at whether physical activity and sports programs help children and teenagers with Developmental Coordination Disorder (DCD) improve their motor skills.
The review included 48 studies published between 2014 and 2022.
Most studies found that physical activity improved motor skills and daily functioning.
However, some programs did not improve balance, possibly because they were too short or poorly designed.
Overall, physical activity is a helpful way to support children with DCD.
Link: https://www.mdpi.com/2035-8377/15/3/51
1. Introduction
Developmental Coordination Disorder (DCD) is a condition that affects a child's movement and coordination. They have difficulty with activities like
walking
writing
balancing
playing sports.
These problems are not caused by intellectual disabilities or other neurological conditions.
DCD can occur along with other conditions such as Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD).
Physical activity programs can improve motor skills, confidence, social skills, and overall well-being in children with DCD.
Many different activities have been used, including
swimming
balance exercises
team sports
trampoline training
therapeutic (horseback) riding.
However, many studies had small sample sizes or short intervention periods, making the results less reliable.
2. Purpose
The purpose of this review was to examine how effective physical activity and sports programs are in improving motor skills in children and adolescents with DCD.
The review only included physical activity interventions, children, and studies that explicitly mentioned DCD.
It excluded electronic games and psychotherapy-only programs.
3. Research Methodology
The review followed typical guidelines for systematic reviews. After selecting studies that met the requirements, 40 research articles were included in the final analysis.
The review included English-language studies published between 2014 and 2022 involving children (ages 4â18) with DCD who participated in physical activity or sports interventions.
The studies were collected from eight databases, including PubMed, Google Scholar, etc. The studies came from 14 countries, mostly Iran and China.
Researchers searched using terms such as DCD, Dyspraxia, Physical Activity, Physical Education, Sport Activity, and Martial Arts.
Three reviewers selected the studies, and two reviewers checked the final articles to ensure they met criteria.
4. Results of the Survey
Taekwondo: Boosts hand-eye coordination after just 12 weeks
Trampoline Training: Enhances balance, coordination, and overall movement skills
Therapeutic Riding: Focuses on improving walking ability and general motor skills
Musical Motor Activities (Dance/Rhythm): Advance basic motor skills and coordination
Mixed Methods (Balance, Ball, Cycling, Treadmill, Physio): Strengthen motor skills, coordination, balance, agility, physical strength, and reaction time
Task-Focused Activities (Balls, Treadmill): Build motor coordination, balance, throwing, and catching; Minimal effect on obstacle avoidance
Aerobic Exercise: Increases endurance, fitness, muscle and bone strength; Reduces fatigue.
These physical programs extend benefits to children with DCD and comorbid conditions like ADHD.
Beyond physical skills, interventions boost self-confidence and increase participation in everyday activities.
5. Case Control
Most physical activity and sports programs improved motor skills and daily functioning in children with DCD.
However, some programs did not improve balance. This may have been because the interventions were too short or poorly designed.
Some improvements may also have been influenced by other treatments (e.g. physical therapy).
Many studies also had small sample sizes, making the results less reliable and harder to apply to larger groups.
Physical activity programs helped children with DCD and other conditions, such as ADHD, ASD, dyslexia, and developmental verbal dyspraxia.
These programs improved motor skills, physical fitness, self-confidence, and participation in everyday activities.
6. Conclusions, Discussion
Overall, the review found that physical activity programs are effective in improving motor skills in children and adolescents with DCD.
Many programs also had additional benefits, including:
Reduced anxiety and depression
Better attention and decision-making
Improved confidence
Better communication skills
Increased participation
Improved quality of life
Some programs, such as horse riding, camp activities, and balance training, also improved emotional, social, and cognitive skills.
The review had some limitations. It only included English-language studies published between 2014 and 2022, and it did not fully examine the risk of bias in each study. Many studies also lacked detailed descriptions of their intervention programs.
6.1. Teaching Instructions and Educational Applications
Schools should place greater emphasis on physical education programs that support children with DCD.
Teachers may also benefit from additional training to better identify and support children with these difficulties.
Activities should be enjoyable and age-appropriate.
6.2. Future Research
Future studies could examine whether combining physical activity with mental imagery techniques leads to even greater improvements in coordination and skills for children with DCD.
Cochlear Implants After Meningitis-Induced Hearing Loss
Abstract
This review summarizes outcomes of cochlear implantation (CI) in patients with hearing loss after meningitis (inflammation surrounding the brain and spinal cord).
Most patients experienced improved hearing after CI. Best results were seen in patients with
no cochlear ossification (where the cochlea's space is replaced with new bone)
complete CI insertion
shorter duration of deafness
no other neurological problems.
Overall, cochlear implantation after meningitis is effective, though early and bilateral implantation is recommended to maximize success.
Link:
https://pmc.ncbi.nlm.nih.gov/articles/PMC7901443/
1. Introduction
Background and Epidemiology
Bacterial meningitis (BM) is a major cause of acquired hearing loss, especially in children (at least 60% of cases). Permanent hearing loss occurs in up to 35% of patients.
Streptococcus pneumoniae and Neisseria meningitidis (both of which are natural bacterium that can be harmlessly carried) are the most common causes.
Hearing loss occurs due to infection spreading to the inner ear, damaging
hair cells (create electrical signals for brain)
cochlea (convert sound into electrical signals)
Labyrinthitis ossificans (LO), where bone fills the cochlea, can develop within 4 weeks and affects up to 90% of patients with severe hearing loss.
2. Diagnosis
Audiological testing within four weeks for bacterial meningitis patients is recommended.
Neurological Complications
BM can also cause epilepsy and neurological/cognitive issues. Patients with
Pre-existing neurological issues
Cognitive or behavioral problems
can have reduced CI performance.
Ossification During Cochlear Implantation
Ossification (conversion to bone tissue) usually occurs in the basal turn of the cochlea (first spiral; where the electrode is inserted).
Previously, ossification was a disqualifier for CI, but improved techniques and designs now allow implantation in these patients.
Risks and Complications of Cochlear Implantation
Cochlear implantation is generally safe but can cause
device failure
infection
nerve injury
cerebrospinal fluid (fluid in the brain and spinal cord that absorbs shock) leaks
CI users may have a higher risk of bacterial meningitis compared to non-users.
3. Materials and Methods
Eligibility Criteria
Population: Children or adults with hearing loss after meningitis.
Intervention: Cochlear implantation; No re-implantation studies.
Search Strategy
Sites were searched using terms for âcochlear implantâ and âmeningitis.â
Study Selection
Two reviewers screened titles, abstracts, and full texts independently. Disagreements were resolved through discussion.
4. Audiological Outcomes
Hearing improved in all studies after cochlear implantation, though methods and follow-up times varied. Seven studies found statistically significant improvements after CI.
CAP (Categorized Auditory Performance): Measures everyday listening ability; Average post-CI was >5 (speech without lip-reading)
Open-set speech perception: Measures understanding random words without clues; Scores dropped from 84% to 0%
Full electrode insertion: Measures full wire placement; Improved
Neurological/developmental issues: Led to slower/reduced improvements
Shorter duration of deafness: Quicker surgery led to better hearing results.
Post-2001 CI technology: Modern implants with thinner wires and smarter chips; Improved outcomes.
Surgical Complications and Reimplantation
Minor
Otitis media (28 cases; Middle ear infection)
Mastoiditis (2 cases; Infection of mastoid bone in ear)
CI Reimplantation (15 cases; Often due to infection or trauma)
Educational and Occupational Outcomes
Children with cochlear ossification more often required special schooling. With 5â10 years of CI use, most children could attend mainstream education, with some reaching higher education / full-time work.
5. Conclusion
Overall Success: Cochlear implants (CIs) give meningitis patients good, usable hearing and speech understanding.
Key Risk: Meningitis can cause bone growth (ossification) in the ear, making CI implantation difficult. Pre-surgery scans can sometimes miss this bone growth.
Best Strategy: Doctors recommend fast, bilateral (both ears) surgery before bones can grow.
Patients get the best hearing results when:
There's no bone growth inside the cochlea.
The entire implant wire fits inside the ear.
There's a short period of deafness before getting the implant.
Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) are conditions in children that cause a sudden onset of
obsessive-compulsive symptoms
motor and vocal tics
other behavioral changes
after a strep infection.
PANDAS is an autoimmune disease (the bodyâs immune response to the infection may mistakenly attack healthy tissues).
One common explanation is molecular mimicry, meaning the bacteria resembles the bodyâs own cells. Therefore, the immune system reacts against both.
Diagnosis is mainly based on medical history and physical examination.
If left untreated, there's a chance symptoms (obsessive-compulsive behaviors and tics) will continue into adulthood.
1. Introduction
PANDAS stands for "pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections." It is marked by sudden and severe changes in behavior, personality, and movement in children who have had a streptococcal infection (strep throat, sinus infections, or scarlet fever).
Herpes simplex virus: Causes cold sores around the mouth or blisters on the genitals
Varicella-zoster virus: Causes chickenpox in children
can trigger similar inflammatory reactions and neuropsychiatric symptoms. These are grouped under a broader condition called Pediatric Acute-onset Neuropsychiatric Syndrome (PANS).
PANDAS was first identified in 1990 when researchers observed sudden
obsessive-compulsive symptoms
motor and vocal tics
behavioral problems
in children with beta-hemolytic streptococcal infections.
Several risk factors may increase the chance of developing PANDAS, including repeated group A strep infections and a family history of autoimmune conditions. The condition is more common in boys and usually affects children 3-12 years old.
PANDAS is considered a rare disorder. Because many of its symptoms overlap with other conditions, it is often difficult to diagnose.
2. Methods
For this review, researchers searched medical journal databases for studies published 1996-2020.
Only articles relevant to these topics were included. Studies written in languages other than English, letters to editors, conference presentations, editorials, comments, opinion papers, and articles without free access, were excluded.
3. Results
PANDAS pathogenesis
PANDAS is considered an autoimmune disorder triggered by strep infection. The main mechanism is believed to be "molecular mimicry."
This is when antibodies produced against strep bacteria mistakenly attack brain tissue, especially the basal ganglia (involved in movement control), causing neuropsychiatric symptoms.
Several autoantibodies, including those targeting
Dopamine receptors: Capture dopamine (control your mood, motivation, and body movements)
Lysoganglioside: Fat molecule found in cell membranes (too much leads to brain issues)
Tubulin: Links together to give cell shape and structure
CaMKII: Enzyme that turns on when calcium levels rise; Important for learning and memory creation
may play a role. Animal studies showed they can cause obsessive behaviors similar to PANDAS symptoms.
Researchers have investigated biomarkers, but results remain inconsistent. The Cunningham Panel (a test designed to measure these antibodies) has limited reliability too.
Recent studies suggest that these levels increase during acute episodes of PANDAS (and decrease as symptoms improve).
Clinical Picture
PANDAS symptoms usually begin 4â6 weeks after a strep infection and often resemble OCD or Tourette Syndrome. Symptoms appear suddenly and can rapidly become severe within 2â3 days.
Psychological symptoms may include:
Obsessive-compulsive behaviors
Anxiety and panic attacks
Mood swings and irritability
Emotional regression
Depression or hallucinations
Physical symptoms may include:
Motor and vocal tics
Abnormal movements
Sensitivity to light, sound, or touch
Poor handwriting and motor skills
Hyperactivity and concentration problems
Sleep disturbances
Frequent urination or bedwetting
These symptoms can significantly affect daily life.
Diagnosis
PANDAS is diagnosed mainly through medical history and physical examination.
Diagnostic Criteria include:
OCD symptoms, ADHD-like symptoms, or tics
Neurological symptoms (hyperactivity, anxiety, mood changes, bedwetting, or involuntary movements)
Symptom onset between ages 3â12
Evidence of a recent strep infection
Sudden onset or rapid worsening of symptoms
PANDAS is a diagnosis of exclusion (other disorders must first be ruled out).
Paraclinical investigation
There is no specific mark diagnosing PANDAS. Recommended tests are only to prove strep exposure:
Complete Blood Count: Measures types and amounts of cells in blood
Erythrocyte Sedimentation Rate: Rate red blood cells settle to the bottom of a test tube in an hour (sees if they're inflamed)
C-Reactive Protein: Specific protein that increases due to inflammation
Metabolic panel and urine analysis
Throat swab and anti-streptococcal antibody tests
Differential diagnosis
PANDAS should be differentiated from:
Sydenhamâs chorea: Uncontrollable movements after a strep infection (but no OCD symptoms)
Tourette Syndrome: Sudden, repetitive movements or sounds called tics
Obsessive-Compulsive Disorder: Unwanted thoughts and repetitive behaviors to soothe those thoughts
Autoimmune encephalitis: Immune system mistakenly attacks the brain, causing sudden swelling, confusion, and memory issues
CNS vasculitis: Inflammation damages the blood vessels inside the brain and spine
Neuropsychiatric lupus: Lupus attacks the nervous system, causing mental health changes, headaches, or seizures
Treatment
Treatment focuses on both the infection and psychiatric symptoms.
Strep infections are treated with antibiotics. Some may also improve neuropsychiatric symptoms.
Psychiatric symptoms are commonly treated with:
Cognitive behavioral therapy
SSRIs (a type of antidepressants)
Severe cases may require immunomodulatory therapies, including:
Corticosteroids: Medications that reduce swelling and calm the immune system
Intravenous immunoglobulin (IVIG): Donated healthy antibodies neutralize antibodies that are attacking the nervous system
Plasmapheresis (Plasma Exchange): Filtering by removing the liquid plasma containing the self-attacking antibodies
Rituximab or Mycophenolate: Drugs that stop specific immune cells responsible for attacks on the brain
However, evidence for these treatments remains controversial, and more research is needed.
Prognosis
Some children recover fully, while others continue to experience symptoms after future strep infections.
Untreated PANDAS may increase the risk of OCD symptoms and tics continuing into adulthood and may negatively affect quality of life.
4. Conclusions
Although PANDAS has been researched for over 20 years, clearer diagnostic criteria, reliable markers, and better treatment guidelines are still needed.
PET Scans, Deep Brain Stimulation & Psychiatric Disorders
Abstract
Background
Deep brain stimulation (DBS) is a treatment for psychiatric disorders that donât respond to regular medications.
PET imaging (being injected with a tracer and seeing the cells that are attracted to it) helps plan, guide, and monitor DBS.
This review looks at how PET can show brain changes and predict response to DBS.
Methods
Writers searched PubMed, Web of Science, and Scopus for studies using PET to study DBS effects in psychiatric disorders. Information was collected on study design, PET results, and clinical outcomes.
Results
Out of 149 articles, 27 studies were included: depression (11), OCD (8), substance use disorder (3), anorexia nervosa (3), schizophrenia (1). PET tracers used included
FDG (sees which cells are hungriest for glucose)
15O-water (sees which organ parts are getting oxygenated blood)
11C-raclopride (shows where dopamine is going)
PET showed brain changes after DBS that often matched improvements in symptoms. Different DBS targets produced unique PET patterns.
Conclusions
PET can show how DBS changes brain activity, helping doctors select patients, predict outcomes, and monitor long-term effects.
About 1 in 4 adults in the U.S. have a mental illness. Serious cases like OCD, depression, or schizophrenia affect daily life. It's not uncommon for them to not fully respond to therapy or medication. Around 10% of OCD patients and 30% of depression or schizophrenia patients are treatment-resistant.
DBS, which is already used for Parkinsonâs and epilepsy, involves placing electrodes in the brain to control activity. DBS may help psychiatric patients who donât respond to normal treatments. Other brain stimulation methods have mixed success.
This review examines whether PET can predict or track DBS effects in psychiatric disorders.
Materials and Methods
PubMed, Web of Science, and Scopus articles up to July 15, 2025 were searched. Specifically, studies that
Used DBS in human psychiatric patients
Used PET to track brain changes
Were original peer-reviewed studies
Weren't animal studies
Weren't reviews
Had less than 3 subjects
Weren't in English papers
Had no baseline PET scans.
Results
Study Characteristics
Disorders Treated:
Depression: 12 studies
OCD: 8 studies
Substance use disorder: 3 studies
Anorexia nervosa: 3 studies
Schizophrenia: 1 study
PET tracers used:
FDG (21 studies)
15O-water (5 studies)
15O-CO2 (1 study)
11C-raclopride (1 study)
PET showed molecular brain changes after DBS that often matched clinical improvement.
_____
Treatment-Resistant Depression
Twelve studies looked at DBS for treatment-resistant depression (TRD).
DBS targeted three main areas:
Nucleus accumbens (NAcc; center that relies on dopamine) - 4 studies
Medial forebrain bundle (MFB; fibers that transfer emotional signals) - 2 studies
SGC/SCC DBS:
SGC/SCC is overactive in depression.
DBS reduced activity and increased dorsolateral prefrontal activity (better memory, control, and emotional regulation) in responders.
Reductions in PET signal matched clinical improvements.
NAcc DBS:
NAcc is involved in reward and motivation.
PET showed increased activity in NAcc, with decreased activity in caudate (in charge of learning and reward), and thalamus (in charge of sensory and motor signals).
Anterior limb of internal capsule (ALIC; Links emotions and thinking) - 3 studies
Subthalamic nucleus (STN; Controls movement) - 1 study
VC/VS DBS:
Increased metabolism in ventral striatum (which produces dopamine) and substantia nigra (receives dopamine for reward).
Clinical improvement matched PET changes.
ALIC DBS:
Reduced frontal (holds back impulses) and limbic (relating to anxiety) metabolism, with symptom improvement.
Variability in patient responses, but strongest responders showed largest metabolic changes.
STN DBS:
DBS-on reduced metabolism in anterior cingulate (monitors behavior) and medial frontal cortex (decision-making).
Clinical improvements matched PET reductions.
_____
Substance Use Disorder
DBS reduced craving, depression, and compulsivity.
PET showed increased metabolism in 3 of 4 brain lobes in patients who remained abstinent.
PET changes matched long-term abstinence and clinical improvement in heroin and opioid-dependent patients.
_____
Anorexia Nervosa
NAcc DBS: Reduced frontal hypermetabolism (after 3â6 months) in
Hippocampus (long-term memories)
Amygdala (fear, anxiety, aggression)
Subcallosal gyrus (emotions, depression, reward)
SCC DBS:
3 patients maintained BMI gains; PET showed increased activity in posterior cortices (handle sensory input and recognition).
BMI increased from 13.8 to 17.3 at 12 months
Improvements seen in comorbid depression, anxiety, and emotion regulation.
_____
Schizophrenia
One study (6 imaging-completed patients) examined DBS targeting NAcc or SGC.
NAcc DBS: Increased metabolism in prefrontal cortex (handles logic, planning, and social behavior).
SGC DBS: Decreased metabolism in some regions.
5/6 patients met response criteria (symptom reductions of 37-86%).
DBS may restore impaired brain circuits in schizophrenia.
_____
Quality Assessment
6 studies (22%) low risk of bias; 21 studies (78%) had some concerns.
Discussion
This review of 27 PET studies shows DBS changes brain metabolism in treatment-refractory psychiatric disorders.
Depression:
DBS modulates the cortico-striato-thalamo-cortical (CSTC) circuit (in charge of movement, habits, and thoughts).
PET shows reduced SCC hyperactivity (linked to deep sadness).
PET shows increased activity in dorsal limbic (manages logic and emotion) and cortical areas (manages high-level thinking).
NAcc and MFB DBS also regulate mood and reward circuits.
OCD: DBS alters
CSTC circuits, reducing hyperactivity in
orbitofrontal (manages rewards and decision-making)
anterior cingulate (manages error detection and emotional regulation)
medial prefrontal regions (manages self-reflection)
Substance use disorder: PET reductions in NAcc activity link to decreased alcohol use, and frontal hypermetabolism appears in abstinent patients.
Anorexia nervosa: DBS changes
fronto-limbic (logic and emotion) metabolism
parietal (sensory processing) metabolism
Schizophrenia: DBS may restore metabolism in
prefrontal (handles planning) regions
subcortical (basic urges and reflexes) regions
Limitations:
Small sample sizes (3-65 patients),
Short follow-up (max 12 months).
PET protocols and outcome measures varied.
Most studies used FDG PET, limiting insights into other neurotransmitter systems.
Long-term DBS effects and potential stimulation tolerance remain unclear.
Future directions:
Standardized protocols and endpoints.
Compare different DBS targets with PET.
Use other PET tracers to study neurotransmitter activity.
Conclusion
PET scans help doctors see how brain surgery (DBS) works at a molecular level to treat mental illness. Using these scans as biomarkers can help pick the right patients and track their long-term recovery.
Abstract
Background
Dissociation, when experiences feel disconnected or fragmented, is common but not well studied in epilepsy. Itâs rarely assessed in epilepsy care, even though it can affect treatment and diagnosis.
Objective
This review looks at known information about dissociation in epilepsy (symptoms, causes, brain mechanisms, and ways to measure it), connecting psychiatry and neurology.
Method
Reviewing studies that examined dissociation in epilepsy.
Results
Dissociation happens both during and between seizures but is often overlooked. Evidence suggests that epilepsy and dissociation influence each other, sharing networks and risk factors.
Factors like
seizure trauma
chronic stress
social challenges
may also contribute. Brain imaging and stimulation studies hint at complex interactions between epilepsy and dissociation across seizure states.
Conclusions
Dissociation is clinically important but not well integrated into epilepsy care. Better assessment tools and research could improve understanding and treatment. Recognizing the link between epilepsy and dissociation can give a better picture of interactions.
1. Introduction
Dissociation means experiences feel fragmented or disconnected. While usually discussed in psychiatry, people with epilepsy can also experience it, both during and between seizures. Some seizure types (e.g. absence seizures) look very similar to dissociative experiences.
Anxiety and depression are commonly treated in epilepsy, but dissociation is rarely addressed. This makes diagnosis harder, especially when dissociative seizures are present. One challenge is that neurology and psychiatry use different terms, tools, and treatments, so integrated care is difficult.
This review looks at how dissociation appears in epilepsy, influences, the brain's involvement, and how it can be measured.
Dissociation is complex, varying in intensity and duration. Essentially, it's a disruption in normal experience, including changes in self-perception, memory, control, and emotion.
Itâs important to distinguish dissociation from loss of consciousness. Reduced awareness during a seizure is a change in consciousness level. Dissociation affects the content of consciousness itself. People may be fully awake but feel/experience:
disconnected
depersonalization (detachment from self)
derealization (detachment from the world)
altered sense of self.
Dissociation can occur:
During seizures with impaired awareness (both level and content change)
During seizures with preserved awareness (content change only)
Between seizures when fully awake (content change only)
2. Search strategy and methodology
Articles about dissociation, depersonalization, derealization, and epilepsy were searched on PubMed, MEDLINE, and Embase, covering all publications up to December 31, 2024.
After removing duplicates, two authors independently screened titles and abstracts for relevance and resolved disagreements through discussion. Studies that:
Were empirical (clinical, neurophysiological, or imaging-based), case series, or theoretical
Focused on epilepsy and depersonalization, derealization, altered agency, body-awareness changes
Focused on fragmented experience during or between seizures
were included.
Full texts were reviewed, and had reference lists checked and included relevant studies known to the authors. There were 20 studies directly addressing dissociation in epilepsy.
This was not a systematic review, but all included studies were relevant to dissociation in epilepsy.
3. Dissociation: what and why?
3.1 What is dissociation?
DSM-5 defines dissociation as a âdisruption of normally integrated functions of consciousness, memory, identity, and perception of the environment.â More broadly, dissociation is when experiences, thoughts, or sense of self feel disconnected.
Symptoms are varied and can be grouped as:
Detachment symptoms: Feeling separated from the body, self, or world (e.g., depersonalization, derealization)
Compartmentalization symptoms: Mental or behavioral processes feel split off from normal, like involuntary thoughts or actions
Dissociation can range from normal daydreaming to severe impairments / disorders. It can be a long-term trait or a temporary state triggered by situations. Dissociation occurs in many conditions, not just dissociative or trauma-related disorders.
3.2 Why does dissociation occur?
Two main models explain dissociation:
Post-traumatic model (PTM): Dissociation arises as a coping mechanism after trauma
Sociocognitive model (SCM): Dissociation is shaped by expectations, learning, and attention
These models offer complementary explanations for why dissociation happens.
3.2.1 The post-traumatic model (PTM)
The PTM sees dissociation as a defense mechanism against trauma. It helps people cope by separating overwhelming experiences, emotions, and memories from awareness.
Structural dissociation theory suggests that personality develops from separate systems in infancy. Trauma can prevent full integration, causing lasting divisions in personality.
Evidence supports PTM because trauma often correlates with dissociation.
In epilepsy, PTM is relevant because some seizures can feel traumatic (especially if they are life-threatening) and meet DSM-5 trauma criteria.
3.2.2 The sociocognitive model (SCM)
SCM suggests dissociation isnât always trauma-related. Instead, itâs shaped by cognitive, social, and cultural factors (e.g. media, therapy, and societal ideas about self and consciousness).
This model is flexible but harder to test scientifically. It's also likely that sociocultural factors alone arenât enough.
3.2.3 Integrative and transtheoretical approaches
Dissociation is complex and canât be fully explained by one model. Newer theories combine factors like:
Blurring of sleep-wake experiences
Emotional regulation issues
Impaired self-monitoring and cognition
Trauma may trigger or worsen dissociation, but sleep disruption, emotional dysregulation, and self-monitoring deficits are immediate causes.
3.2.4 The role of sleep in dissociation
Sleep is closely linked to dissociation.
Nightmares
Hypnopompic hallucinations (occuring after waking)
Hypnagogic hallucinations (when falling asleep)
Vivid dreams
Insomnia (can't fall asleep / keep waking up)
Hypersomnia (excessive sleepiness)
are strongly associated with dissociative symptoms.
Sleep disturbances may both cause and result from dissociation. Sleep is also important in epilepsy, suggesting a shared pathway between epilepsy and dissociation.
3.3 How do we measure dissociation?
Dissociation is complex, so measurement tools need to capture its many symptoms. Currently, no tool is specifically validated for epilepsy. Bodily dissociation is also rarely assessed.
4. Dissociation in epilepsy
People with epilepsy can show dissociative symptoms both between seizures and during seizures. Some seizures resemble dissociative experiences, and patients may meet criteria for dissociative disorders. Functional seizures (psychogenic ones that aren't epilepsy-related) are more common in epilepsy than the general population, suggesting overlap with dissociation.
4.1 Phenomenology of dissociation in epilepsy
4.1.1 Dissociation-like symptoms during seizures
Some epileptic seizures involve dissociative experiences (altered perception or self-awareness), similar to dissociative disorders.
Despite similarities, epileptic seizures and dissociative seizures are different in brain mechanisms. However, overlapping experiences make diagnosis tricky, especially when a patient has both types. Dissociative seizures occur independently of epileptic activity and are interictal (between seizures).
Phenomenological Overlaps between Ictal/Postictal Symptoms and Dissociative Symptoms:
Ictal dissociative experiences occur during epileptic seizures.
Dissociative seizures are psychogenic events not caused by epilepsy.
Both epileptic and dissociative seizures involve altered consciousness.
During seizures, common experiences include unusual sensations, distorted thoughts, strong emotions, and a sense of detachment.
Brain areas involved may vary:
Frontal lobe is connected to depersonalization
Temporal lobe lobe is connected to derealization
Lateral prefrontal lobe is connected to disturbed agency
Parietal lobe is connected to body image/self-location distortions
These experiences show the complexity of dissociation during seizures.
4.1.2 Phenomenology of Dissociation During Interictal Periods
People with epilepsy report
higher dissociation than healthy controls
lower than dissociative disorder patients.
Seizure onset side may affect dissociation, but findings are inconsistent.
4.1.3 Postictal States
After seizures, cognitive, emotional, and perceptual changes often occur.
Postictal dissociative symptoms (e.g., disorientation, emotional detachment) are under-studied.
4.2 Determinants of Dissociation in Epilepsy
Epilepsy and dissociation influence each other, sharing mechanisms and risk factors.
4.2.1 Dissociation as a Consequence of Epilepsy
More frequent seizures and shorter epilepsy duration can lead to higher dissociation.
Younger age and lower education may contribute.
Seizures can be traumatic, potentially causing post-seizure PTSD.
Chronic stress, stigma, and isolation can also increase dissociation.
4.2.2 Shared Neurobiology and Risk Factors
Both epilepsy and dissociation are network disorders (not reliant on the presence of the trigger), making patients predisposed to large-scale connectivity disruptions.
Additionally, seizures can worsen dissociation, and dissociation can affect seizures.
Sleep disruption and trauma contributes to both.
5. Neurophysiological Basis of Dissociation in Epilepsy
Trauma-related dissociation involves limbic system regulation. The limbic system, which manages long-term memory and emotional regulation, makes this affect self-awareness.
Epilepsy-related dissociation involves similar networks but is usually temporary and during seizures or interictal periods. Meanwhile, trauma-related dissociation is often chronic and adaptive.
Brain regions linked to dissociation in epilepsy include the
Insula: Processes internal body state
Precuneus: Self-awareness, mental imagery, and personal memory retrieval
Cingulate cortex: Emotional regulation, error detection, and memory
Prefrontal cortex: Planning and decision-making
Parietal lobes: Processes sensory information
Supplementary motor area: Planning and coordinating complex movements
Mesial temporal structures: Memory and emotion
Dissociation can appear ictal or interictal, with different brain mechanisms involved.
5.1 Dissociation during seizures: intracranial evidence
Posteromedial cortex: Seizures here can cause feeling like an outside observer to oneâs thoughts.
Precuneus and posterior cingulate cortex (PCC): These are linked to body perception changes and altered consciousness.
Prefrontal cortex : Stimulation of this area can trigger loss of control over thoughts.
Insula: Integrates bodily, emotional, and cognitive signals to form the sense of self.
5.2 Interictal dissociation
Symptoms between seizures may result from disruptions in networks controlling perception, emotion, and self-awareness.
PFC connectivity is especially important; TLE patients with dissociative seizures often show executive function deficits.
Recurrent seizures may gradually disrupt memory, perception, and self-related networks.
6. Conclusion and perspectives
Dissociation is common in epilepsy but underrecognized.
It occurs during and between seizures.
It likely arises from shared brain networks, seizure-related trauma, and psychosocial stress.
Research is limited. Future work should integrate psychiatric and neurological perspectives to improve understanding and care, psychoeducation, therapy, or neuromodulation.
7. Statements and declarations
No specific funding received.
No new data created.
Authors contributed to writing, review, and conceptualization.
JAK Inhibitors' Effectiveness for Rheumatoid Arthritis
Abstract
Rheumatoid arthritis (RA) is a chronic autoimmune disease. It causes
joint inflammation
pain
progressive damage.
Standard treatments include
conventional synthetic DMARDs (csDMARDs; suppresses the immune system broadly)
biologic DMARDs (bDMARDs; suppresses only specific pathways of the immune system)
but these therapies may have limited effectiveness and require injections.
Janus kinase inhibitors (JAKis) are newer targeted synthetic DMARDs that work by blocking inflammatory signaling pathways.
This review summarizes evidence from clinical trials and guidelines on approved JAK inhibitors, including
baricitinib / Olumiant
tofacitinib / Xeljanz
upadacitinib / Rinvoq
peficitinib / Smyraf
filgotinib / Jyseleca
Studies show that JAK inhibitors improve symptoms, reduce disease activity, and slow joint damage compared with placebo and methotrexate.
However, safety concerns have been reported in some patients:
cardiovascular events
herpes zoster
possible malignancy
Overall, JAK inhibitors are effective treatment options for RA but require careful patient selection and monitoring.
Introduction and background
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes joint inflammation and progressive joint damage. It can also affect other organs and be disabling.
In 2020, about 17.6 million people worldwide were living with RA. The disease develops when immune cells release inflammatory cytokines (which tell the immune system how to react) such as IL-6 and TNF, leading to persistent inflammation and destruction.
Treatment aims to reduce disease activity or achieve remission.
First-line therapy usually includes csDMARDs such as
If these treatments are not effective, patients may receive biologic DMARDs or JAK inhibitors.
Janus kinase inhibitors
JAK inhibitors are oral medications that reduce inflammation by blocking the JAK-STAT signaling pathway, which regulates immune responses.
They inhibit JAK enzymes (JAK1, JAK2, JAK3, and TYK2), preventing activation of inflammatory cytokines such as IL-6 and interferons. By targeting multiple cytokine pathways, they provide broader immune suppression than some biologic drugs.
The first JAK inhibitor approved for RA was Xeljanz in 2012, followed by Olumiant and Rinvoq in the United States. Jyseleca and Smyraf were later approved in other regions.
JAK inhibitors are now recommended in treatment guidelines as targeted synthetic DMARDs and are increasingly used in RA management.
Methods
This review includes peer-reviewed studies, clinical trials, regulatory documents, and international guidelines on JAK inhibitors (JAKis) in RA. Studies involved adults diagnosed with RA. Both randomized controlled trials and observational studies were included to evaluate efficacy, safety, and real-world outcomes.
The review focused only on approved JAK inhibitors for RA, not investigational JAK inhibitors.
Non-English papers, conference abstracts without full texts, preclinical studies, and articles without original data were also excluded.
JAKis vs Placebo in RA
JAK inhibitors work much better than no treatment or placebos.
Early trials of Xeljanz showed higher ACR20 (measures if RA has improved by at least) response rates (about 60â66%) compared with placebo (around 27%).
Similarly, trials of Olumiant showed ACR20 responses of about 70% compared with 40% with placebo
Studies consistently show strong benefits across different JAK drugs.
JAKis vs MTX in RA
Methotrexate is usually the first treatment doctors try.
Xeljanz may work better for symptom relief and disease control.
They may also slow joint damage more.
JAKis vs Adalimumab in RA
Adalimumab is also a common drug for RA, though it's a biologic.
Olumiant improved more outcomes than Adalimumab.
Rinvoq also shows similar or slightly better responses.
Some show faster improvement and less joint damage over time.
Adverse effects of JAKis
JAK inhibitors (JAKis) can cause both common and serious side effects. Common adverse effects include
nausea
headache
upper respiratory infections.
More serious but less frequent complications include
heart attacks
stroke
venous thromboembolism (VTE; blood clots)
malignancy
serious infections.
Neurological symptoms and weight gain have also been reported in some patients.
Certain groups may be at higher risk of complications, including patients over 65 years old, smokers, and those with at risk of cardiovascular disease or cancer. Therefore, careful patient selection and monitoring are important when prescribing JAK inhibitors.
Major Adverse Cardiovascular Effects
Major adverse cardiovascular events (MACE), including heart attacks, stroke, and cardiovascular death, have been reported with JAK inhibitor therapy. Some studies show higher rates of MACE with Xeljanz compared with tumor necrosis factor inhibitors (TNFi; cleans out excess inflammatory proteins in blood), particularly in patients with high cardiovascular risk.
However, randomized trials in broader patient populations generally show low absolute event rates.
Overall, cardiovascular risk appears to be higher mainly in patients with pre-existing cardiovascular risk factors.
Herpes Zoster
An increased risk of herpes zoster (shingles) is a well-established adverse effect of JAK inhibitors. Studies show that the risk is about two to four times higher than other treatments (placebo, methotrexate, or TNF inhibitors).
The risk varies depending on the specific drug and dose but is consistently higher than the background risk in RA patients. Vaccination and careful monitoring are recommended before starting therapy.
Malignancy
JAK inhibitors may be associated with a small increase in malignancy risk compared with TNFis, although randomized trials show low overall incidence rates.
The risk appears to increase with longer treatment duration and is more noticeable in higher-risk groups, such as older patients and smokers. Lung cancer and non-melanoma skin cancer have been reported most frequently.
Venous Thromboembolism
Some studies show a slightly increased risk of blood clots, including deep vein thrombosis (blood clot in a deep vein) and pulmonary embolism (a blood clot breaking free and getting stuck in the lung), in patients taking JAK inhibitors compared with TNF inhibitors. However, the overall event rate remains low.
Because of this potential risk, clinicians should assess individual patient risk factors before starting treatment.
JAKi Drug Interactions
JAK inhibitors may interact with
certain antibiotics
antifungals
drugs affecting liver enzymes
St. Johnâs Wort
grapefruit.
Patients should be advised about these interactions to avoid reduced drug effectiveness or increased side effects.
Conclusions
JAK inhibitors are effective treatments for rheumatoid arthritis, offering oral administration, rapid onset, and broad anti-inflammatory effects. They can decrease disease activity and physical function and may outperform some conventional and biologic therapies.
However, safety concerns (including cardiovascular events, shingles, malignancy, and blood clots) require careful patient selection and monitoring.
Continued long-term studies are needed to better understand their overall benefit-risk profile.
Gene-Environment Interactions in Pediatric Pulmonology
Abstract (Summary)
Genes and environmental exposures both affect lung disease in children. However, their combined effects are rarely used in clinical practice.
Geneâenvironment (GxE) interactions happen when genes change how an exposure affects disease risk. Studying these interactions can help identify high-risk groups and explain differences between studies.
This review explains the basic idea of GxE interactions and briefly summarizes findings in asthma, cystic fibrosis, and bronchopulmonary dysplasia.
These interactions may influence lung health from early life into adulthood. Understanding both genetic risk and environmental exposure together may improve prevention/treatment.
Link: https://pubmed.ncbi.nlm.nih.gov/41772910/
1. Introduction
Most pediatric lung diseases are influenced by both genes and the environment. Only a few of these factors are used in treatment.
For example, doctors often focus on tobacco smoke exposure for most disorders, and CFTR gene-targeted treatments for cystic fibrosis.
However, most lung diseases are more complex.
Children often run around, breathing in large amounts of air daily and exposing the lungs to many environmental substances. Lung development also depends on genetic control.
Because the lungs have large reserve capacity, small genetic or environmental effects may not cause immediate disease.
Instead, they may slowly affect lung growth over time. These small effects are difficult to detect in research. Studying GxE interactions may help reveal them.
A GxE interaction occurs when the effect of an exposure depends on genetics. Looking at genetically high-risk groups can make these effects easier to see.
This review introduces basic GxE concepts and summarizes examples in pediatric lung disease.
2. Interpreting GxE Interactions
A GxE interaction means an exposure affects people differently depending on their genes.
Interactions can be measured in two ways:
Multiplicative scale: relative risk between groups.
Additive scale: absolute risk differences.
An exposure may show an interaction on one scale but not the other, so studies should state which scale they use.
Statistical models usually include:
a genetic effect
an exposure effect
a GxE interaction term
Results also depend on the reference level used for exposure. For example, using zero pollution as a reference is unrealistic. Using an average exposure level is often more meaningful.
Clear reporting of the scale and reference values helped researchers interpret results.
2.2. The Implications of GxE Interactions
Environmental exposures do not affect everyone the same way. Some people are genetically more vulnerable. If studies average everyone together, these differences can be hidden.
Identifying genetically high-risk groups can help researchers find who is most likely to benefit from prevention or treatment.
One study found that prematurely born children with higher genetic risk for COPD had a much greater chance of poor lung function by age 6 (in comparison to other prematurely born children). Because risk is higher in this group, studies focusing on them may need smaller sample sizes to detect effects.
GxE interactions can also explain why different studies sometimes show different results.
Previous Challenges:
Differing Exposures: A genetic effect may appear strong in one population but weak in another if environmental exposures differ.
Measurements: Poor measurements can weaken evidence for interactions.
Overall, GxE models help show where risk is concentrated and where interventions may have the greatest benefit.
2.3. Statistical Approaches to GxE
Testing GxE interactions can be difficult because genetic studies test many variants and environmental exposures are often measured with error. This makes detecting interactions harder.
One simple approach is to
add an interaction term (value for situations where effect of one variable depends on another)
in a regression model (tool to understand and quantify relationship between two variables).
This tests whether the effect of an exposure differs by genotype. However, this may lack statistical power.
In genome-wide studies, testing GxE interactions for millions of variants reduces power. Researchers use several strategies to improve detection:
Joint tests: combine genetic and interaction effects.
Two-stage approaches: select variants by likelihood and then test interactions.
Polygenic risk score models: combine multiple variants into one score and test its interaction with exposure.
Study design can also help. For example:
Case-only studies should ook at exposure differences among cases.
Family-based studies should compare inherited and non-inherited genes (mutations not found in egg/sperm) within families.
Researchers should combine genetics with epigenetic (an environment affecting how a gene is expressed) or gene-expression data.
Overall, no single method works best in all situations. Clear reporting of methods and assumptions is important for reliable results.
3. Known GxE Interactions in Pediatric Pulmonology
3.1. Asthma
Asthma (where your airway gets inflamed in response to different triggers) is the most studied pediatric disease for GxE interactions. This is partly because asthma varies widely between patients.
One important factor is timing of exposure. Environmental exposures can have different effects depending on timing (before birth, in infancy, or later in childhood).
Genetic risk can also matter more during certain developmental periods. The most studied exposures are:
Tobacco smoke
Air pollution
Microbial exposure (direct contact with bacteria, viruses, fungi)
Genes related to immune response often modify the effects of these exposures.
A few interactions appear repeatedly in studies. For example:
Variants in the 17q21 (long arm of chromosome 17) region interact with early viral infections to increase asthma risk.
Glutathione pathway genes may change how tobacco smoke and air pollution affect the lungs.
CD14 and other immune genes may interact with microbial exposure.
Epigenetic research shows that environmental exposures can change gene activity, which may influence asthma risk later in life.
Overall, asthma studies show that exposure timing and accurate measurement are critical for understanding GxE interactions.
3.2. Cystic Fibrosis
Cystic fibrosis (CF; where there's buildup of mucus in the lungs) is caused by mutations in a single gene (CFTR), but disease severity varies widely. This suggests that other genes and environmental factors influence outcomes.
TGFB1: Children with certain TGFB1 variants experience a decline in lung function when exposed to smoke.
MBL2: MBL2 variants increase risk of chronic infections. Patients may decline faster if they develop Pseudomonas (bacteria in soil/debris) infections.
GSTM1: GSTM1 is related to oxidative stress, and variants may also worsen lung disease under higher environmental stress.
New CFTR modulator therapies have improved outcomes. However, environmental exposures and genetic modifiers may still affect how well these treatments work.
Future research will need to consider genes, environment, and treatments together.
3.3. Lifelong GxE Effects: From BPD to COPD
GxE interactions can affect lung health across the entire lifespan.
Premature infants may experience exposures such as:
High oxygen levels
Mechanical ventilation
Early infections
These exposures can interact with genetics to increase risk of bronchopulmonary dysplasia (BPD; lung disease in premature infants).
Even if breathing improves later, children with BPD often have lower lung reserve, making them more vulnerable to later exposures.
This can increase the risk of chronic obstructive pulmonary disease (COPD; irreversible lung disease causing inflammation) in adulthood.
Genetic variation may partly explain why outcomes differ between similar patients.
Variants near IL18R1/IL18RAP influence lung disease risk.
Polygenic risk scores for COPD can also predict poorer lung function in children, especially premature births.
Overall, these findings suggest that genetic risk can affect lung health differently at different life stages depending on environmental exposures.
4. Conclusion and Future Directions
Pediatric lung diseases are influenced by both genetics and environmental exposures, especially when they interact.
Across diseases like asthma, cystic fibrosis, BPD, and COPD, GxE interactions help explain differences in risk and disease severity.
Future progress will require:
Clear reporting of statistical methods in GxE studies
Better measurement of environmental exposures
Integration of genetic and biological data
Most importantly, research should aim to translate findings into practice, such as identifying high-risk children and designing prevention or treatment strategies.
Abstract
Introduction: Photobiomodulation (PBM; using light to heal/protect tissues) is a possible treatment for chronic pain. However, its effectiveness and safety are still debated.
Results: Fourteen studies were included. They involved patients with
fibromyalgia (the brain processing pain signals differently, causing pain and fatigue)
peripheral neuropathy (nerve damage that causes numbess, tingling, and weakness)
orofacial pain (chronic pain in the mouth, jaw, or face)
musculoskeletal pain (chronic pain in the bones, joints, muscles, or connective tissue)
Most studies showed that PBM reduced pain, especially in fibromyalgia and neuropathy. Some studies also reported better function and improved quality of life. Few adverse events were reported, suggesting PBM is safe. However, differences in treatment make it hard to standardize results.
Conclusion: PBM appears to reduce chronic pain and has a good safety profile, especially in cases that are hard to treat with standard therapies. However, differences in protocols and follow-ups prevent strong clinical recommendations.
Introduction
Chronic pain is pain that lasts longer than normal healing or ongoing disease processes. About 20% of adults experience pain at some point, and around 10% develop chronic pain each year.
Risk factors include
Older age
Female sex
Poor sleep
Mood disorders
Obesity
Fatigue
Cognitive problems
According to ICD-11 (a disease standardization tool), chronic primary pain is considered a disease on its own. Chronic secondary pain happens because of another condition.
Chronic primary pain involves changes in how the nervous system processes pain. There is increased sensitivity and changes in central pain pathways. This means pain can continue even without active tissue damage, also known as nociplastic pain. Because of this, treatments that act on both peripheral and central pathways, such as PBM, may be helpful.
PBM
PBM uses red or near-infrared light to stimulate cells. This helps them reduce inflammation, change pain signaling, and help tissue repair.
Works at both peripheral and central levels.
Stimulates the mitochondria, which is involved with ATP/energy production, and using that energy to boost tissue regeneration.
Improves blood flow and lymphatic circulation, helping remove inflammatory substances (which decreases swelling and nerve sensitivity).
Reduces the activity of pain fibers
Increases inhibitory neuromodulators like serotonin (which is pro-inflammatory)
These effects may
Decrease allodynia (pain from something that shouldn't hurt at all)
Decrease hyperalgesia (extreme pain from something that should only be a bit painful)
Improve muscle function
Improve joint function
Reduce pain intensity, and decrease the need for pain medication
This review analyzes current evidence on PBM for chronic pain.
Methods
Eligibility criteria: Followed the PICO framework (population, intervention, comparison, outcome).
1. Population: Adults (18+) with chronic pain lasting at least three months. Conditions included
Fibromyalgia
Headaches
Temporomandibular disorders (jawbone to skull)
Neuropathic pain (nervous system-related)
Chronic neck or shoulder pain
Post-COVID-19 pain
2. Intervention: Studies using photobiomodulation (PBM) with laser or LED devices to reduce pain and improve function. Studies had to report parameters about the light:
Wavelength
Frequency
Dose
Session duration
Total number of sessions
3. Comparison: Sham or placebo PBM, no treatment, standard care, or other stimulation protocols.
4. Outcomes: The primary outcome was pain reduction. Secondary outcomes included function, quality of life, psychological factors, and adverse events.
Study design: Only randomized controlled trials (RCTs) published in peer-reviewed journals were included. Everything else (e.g. non-randomized studies, case reports, reviews) were excluded.
Information sources: Medical journal sites (PubMed, Embase, Scopus, LILACS, and MEDLINE) were searched. The search included studies published between September 1, 2015 and September 1, 2025. Articles in English, Spanish, and Portuguese were considered.
Study selection:
All records were imported into Rayyan (AI that ranks studies to help identify what's relevant) to remove duplicates and screen studies.
Two independent reviewers screened titles and abstracts, then reviewed full texts. Disagreements were resolved by discussion or a third reviewer.
Data extraction
Two reviewers independently extracted data using a standardized form. The following information was collected: Author, year, country, study design, and sample size.
When necessary, study authors were contacted to obtain missing data.
Risk of Bias:
Risk of bias was assessed using the RoB 2.0 tool (Cochrane). This tool evaluates:
Randomization process
Deviations from intended interventions
Missing data
Outcome measurement
Data synthesis
A narrative synthesis (method for summarizing findings from diverse studies) was performed. Studies were compared based on:
PBM protocol
Comparator group
Outcomes
Results
The database search identified 6,611 studies.
After removing 450 duplicates, 6,161 records were screened.
After title and abstract screening, 5,732 studies were excluded.
415 were excluded due to inappropriate design, population, or intervention.
14 studies met the inclusion criteria and were included in the review.
Study selection and characteristics
14 studies were included. They covered different chronic pain conditions.
Five studies: fibromyalgia
Two studies: temporomandibular disorders
Two studies: chemotherapy-induced peripheral neuropathy
Two studies: diabetic neuropathy
One study: post-COVID-19 orofacial pain with tension-type headache
One study: chronic neck/shoulder pain
One study: neuropathic pain related to leprosy
PBM protocols varied widely.
Devices included laser systems, whole-body PBM, cluster diodes, and LED systems.
Wavelengths ranged from 660 to 905 nm.
Session frequency ranged from daily to once weekly.
Treatment duration ranged from 3 days to 12 weeks.
Comparators included:
Placebo PBM (8 studies)
No intervention (1 study)
Standard Medication (1 study)
Exercise (2 studies)
Placebo + Exercise (1 study)
Primary Outcome (Pain)
Most studies reported pain reduction with PBM.
Some trials showed significant improvements compared to other groups.
Others showed improvements but no significant difference between groups.
PBM tended to reduce pain intensity, especially fibromyalgia and neuropathic pain.
Secondary Outcomes
Better walking
Better work performance
Better sleep
Improved jaw function in TMD
Reduced anxiety and depression
Better overall health-related quality of life
However, not all studies found differences between PBM and placebo (particularly for neck/shoulder pain).
Bias
Three had some concerns of bias, while two were rated as high risk of bias.
The most common issue was unclear reporting of the randomization process.
Some studies did not clearly report adherence to the intervention protocol.
One study did not clearly report participants dropping out.
Safety and adverse events
Safety findings were consistent.
Thirteen of the fourteen studies reported no adverse events.
One study reported mild and temporary effects (warmth, discomfort, and tingling). These resolved without treatment.
No serious adverse events or treatment-related dropouts were reported.
Overall, PBM appears to be safe for chronic pain management.
Limitations
Although the findings are promising, several limitations must be considered.
There were many differences in devices, wavelengths, treatment schedules, and outcome measures.
Many trials had small sample sizes, short follow-up periods, and incomplete reporting of treatment and adverse events.
Additionally, studies with negative results are less likely to be published.
Because of major differences, specific numbers could not be quantitatively combined.
Discussion
This review analyzed fourteen randomized controlled trials investigating PBM in different chronic pain conditions.
In fact, pain reduction exceeded the commonly accepted threshold for clinical relevance.
Overall, PBM showed meaningful pain reduction compared with placebo or standard care. However, the consistency of results varied depending on condition, design, and assessment tools.
Examples include improvements in:
Post-COVID-19 orofacial pain
Fibromyalgia
Diabetic neuropathy
Chemotherapy-induced neuropathy
Positive results across different conditions suggest that PBM likely works through general pain mechanisms rather than disease-specific mechanisms.
Central vs Peripheral vs Musculoskeletal Conditions
In fibromyalgia (a central nervous system disorder), studies frequently reported pain reduction, increased pain threshold, and improved quality of life.
Similar improvements were observed in peripheral disorders (diabetic neuropathy and chemotherapy-induced neuropathy).
This supports the idea that PBM may act on both peripheral and central pain pathways.
In contrast, findings were more variable in musculoskeletal conditions. Some studies showed improvements within groups but not significant differences compared with outside groups.
This variability may reflect differences in underlying mechanisms.
One consistent strength across studies was safety. No serious adverse events were reported. Minor effects were rare and similar to placebo.
This supports PBM as a low-risk option, especially for patients with multiple disorders or limited medication tolerance.
In summary, current evidence suggests that PBM is a promising non-pharmacological treatment for chronic pain.
However, variability in protocols and short follow-up periods limit the development of clear clinical guidelines.
Future research should include:
Larger, multicenter trials
Standardized PBM parameters
Longer follow-up periods
These steps will help clarify optimal protocols and strengthen the clinical application of photobiomodulation for chronic pain.
Gene Therapy's Potential as a Hearing Loss Treatment
Abstract
Hearing loss (HL) is a common health problem around the world that affects quality of life.
About 1 in 500 babies are born with hearing loss before they learn to speak. Many of these cases are caused by genetic factors. Early diagnosis and treatment can help children develop speech more normally.
Current treatments include hearing aids and cochlear implants (CI; implants that directly contact the auditory nerve past the cochlea to let the patient hear). These treatments improve hearing, but they do not restore it fully.
Gene therapy (correcting, replacing, or inactivating faulty genes) is a new treatment approach that aims to fix the root genetic cause of hearing loss. Because many different genes can cause hearing loss, gene therapy is challenging but promising.
This review discusses gene therapy strategies, delivery methods, types of carriers (vectors), routes of administration, and the main challenges that still need to be solved.
Introduction
Hearing loss is one of the most common sensory disorders.
The prelingual type (before speech develops) affects about 1 in 500 people. According to the World Health Organization (WHO), the number of people with some degree of hearing loss may reach 2.5 billion in the next 25 years. More than half of congenital (present at birth) hearing loss cases are genetic.
Hearing loss can be classified in many ways:
Where it happens in the ear
When it starts
How severe it is
Worsening or improving over time
Whether it affects one or both ears
Cause (genetic or environmental)
Currently, there is no complete cure.
Hearing aids and cochlear implants help patients hear better, but hearing is still not fully restored to the level of a hearing person. Many patients still have trouble recognizing tones and understanding speech clearly.
In recent years, researchers have focused on gene therapy as a possible long-term solution. This review explains recent progress in understanding hearing loss genetics and gene therapy approaches.
Evolution of the Genetic Landscape in HL
Research into the genetic causes of hearing loss began in 1995. Since then, many genes have been discovered due to better genetic testing technologies.
Genes Refuted and Added
Some genes were later removed from the hearing loss list because studies did not support their role. For example:
GJB6 was refuted for autosomal recessive non-syndromic hearing loss (ARNSHL).
HARS was refuted for Usher syndrome.
MYO1A was refuted for autosomal dominant non-syndromic hearing loss (ADNSHL).
At the same time, new genes have been confirmed to be linked to inherited hearing loss.
Functions of Genes Involved in Hearing
The hearing system in mice is very similar to humans. Because of this, animal models help scientists understand how hearing works and how gene mutations cause hearing loss.
Genes involved in hearing can be grouped based on their function, such as:
Hair cell structure (In the inner ear; Bend at mechnical sounds)
Ion transport (Used by hair cells)
Synapse function (Convert hair cell bending into a chemical signal)
Cell development
Gene Therapy
Better understanding of hearing genetics has led to attempts to correct gene defects. Successful therapy depends on:
Choosing the right strategy
Using the best delivery method
Selecting a safe and effective vector
Treating at the correct time
This section explains gene therapy strategies, delivery vehicles, routes, and challenges.
Vehicles
1. Viral Vectors
Viruses are commonly used to deliver genes into cells. Types studied for hearing loss include:
Lentiviruses (Insert their genetic code into DNA)
Adenoviruses (AdVs; Gives a boost of genetic information temporarily without permanent DNA changes)
Adeno-associated viruses (AAVs; Small viruses that put new genes into cells without causing dsiease)
Herpes simplex viruses (Large viruses that hide in the nervous system)
Among these, AAVs are the safest and least likely to cause immune reactions. There are 12 natural AAV types, and many modified versions have been created to improve their ability to enter specific cells.
2. Non-Viral Vectors
Non-viral methods are safer because they do not insert into human DNA and cause less immune reaction.
However, they are usually less efficient than viral vectors.
Routes of Gene Therapy Delivery
Gene therapy can reach the inner ear in different ways:
Through the eardrum (trans- or intra-tympanic / outermembrane)
Through the stapes bone (stapedotomy / making a hole in a bone)
Through the round window membrane (RWM)
Through the oval window (OW)
Through the utricle (going through a fluid-filled organ)
Through the endolymphatic sac (going through the pouch that regulates fluid pressure)
Through cochleostomy (direct opening into the cochlea/ making a hole into the cochlea)
Through canalostomy (posterior semicircular canal / making a hole in a canal for balance)
Cochleostomy and RWM are common methods for reaching inner hair cells. However, cochleostomy has a higher surgical risk. Combining RWM and canalostomy may improve gene delivery efficiency.
Treatment Approaches
Most gene therapy studies focus on hearing loss. There are two main approaches:
Gene-dependent approach â fixes or replaces the faulty gene
Gene-independent approach â improves or regenerates hair cells (regardless of the specific gene defect)
1. Gene Replacement (Gene-Dependent)
Gene replacement is the most common strategy. It is mainly used when both copies of a gene do not work properly. A healthy copy of the gene (cDNA) is delivered into cells, usually using AAV.
Examples:
In one study, AAV8 carrying the VGLUT3 gene (helps release glutamate, which helps stimulate neurons) was injected into newborn mice. Hearing improved for up to 3 months.
Another study used AAV to deliver the ESP8 gene through the RWM in mice. Hair cell growth improved depending on the dose given.
2. Gene Suppression (Gene-Dependent)
Gene suppression is used when a mutant gene produces a harmful protein that interferes with a healthy one. The goal is to silence the mutant gene.
This can be done using:
Antisense oligonucleotides (ASOs; binds to and blocks genetic instructions)
Small interfering RNAs (siRNAs; destroys harmful genetic messages)
MicroRNAs (miRNAs; can quiet down genetic signals)
ASO-29 improved hearing in animal models for several months after injection.
In cases involving the GJB2 gene (seals nearby cells together in the inner ear), siRNA was used to reduce mutant gene expression to about 30%.
3. Gene Editing (Gene-Dependent)
Gene editing directly changes the DNA sequence. It can remove harmful mutations or correct faulty ones.
CRISPR/Cas9 is the most widely used because it is easier to design and more efficient. It was tested in mice with a TMC1 mutation (DFNA36; leads to autosomal dominant hearing loss). Initial results showed limited improvement. Later, a modified version of Cas9 prevented deafness for up to one year in treated mice.
Gene-Independent Approach
Instead of fixing a gene, this approach focuses on regenerating hair cells.
The gene Atoh1 helps hair cells develop. Studies showed that increasing Atoh1 expression can turn supporting cells into hair cells. However, other factors are also needed for full recovery.
Stem cells are another option. Mesenchymal stem cells (MSCs; assist tissue repair and immune regulation) from bone marrow or fat tissue can be transplanted into the inner ear. In animal studies, this revealed stem cells helped repair damaged sensory cells.
Protective Local Treatments (Gene-Independent Approach)
Some studies focus on protecting inner ear neurons instead of directly fixing the gene defect. The goal is to stop nerve damage from cochlear implants (CI).
Neurotrophin-3 (NT-3) is a growth factor that helps protect cochlear neurons. It supports normal nerve connections and keeps synapses healthy after birth. In noise-exposed mice, NT-3 was delivered through the round window membrane (RWM) using a slow-release gel. This helped regenerate synapses and protected nerve fibers.
Gene Therapy Trials on Humans
In recent years, some human clinical trials have started. Most of them target common hearing loss genes, certain syndromes, or aim to regenerate hair cells.
The first human clinical trial began in 2014. It included 22 adults aged 18â75 with severe hearing loss. Researchers used an adenovirus (Ad5) carrying the Hath1 gene to stimulate hair cell regeneration. The results showed only slight improvement.
Another study included adults aged 18â80 with mild to moderate hearing loss . Patients received a gamma secretase inhibitor (GSI; prevents the cleavage of certain proteins) through intratympanic injection. This drug increases Atoh1 expression, which helps hair cells develop. Hearing thresholds did not significantly improve.
The study concluded that the treatment was safe but did not show strong benefit.
The OTOF Gene
Special attention has been given to the OTOF gene, which causes auditory neuropathy spectrum disorder (ANSD; hearing disorder) and DFNB9 (a type of inherited hearing loss).
One study in China included six children with severe hearing loss caused by OTOF mutations (protein used for transmitting sound signals to the auditory nerve). They received a single injection of AAV1-hOTOF through the RWM.
After 26 weeks, there were no serious side effects but mild changes in lymphocytes (a type of white blood cell) and cholesterol. Five children showed hearing improvement by 40â57 dB.
Another study treated two children with OTOF-related hearing loss.
A 5-year-old received injection in one ear (the other ear already had CI). An 8-year-old received injections in both ears.
Both children showed hearing improvement. The 5-year-old reached near-normal hearing levels after three months without a hearing aid.
In general, children seem to benefit more from gene therapy. This may be because early childhood is a critical period for language development and brain plasticity (ability for the brain to reorganize itself).
Challenges for Gene Therapy
1. Animal Models Do Not Fully Match Humans
Mice have a similar inner ear structure to humans, but their hearing develops after birth. In humans, hearing is already developed at birth. Some genes (like Atoh1 and Pax genes) are important during early development. If they are missing during pregnancy, damage may be permanent and cannot be fixed. Also, viruses may behave differently in humans and mice, making results harder to translate. Additionally, mice cochleae are fully surrounded by bone.
2. Genetic Diversity and Timing
There are many different genes that cause hearing loss. The best timing of treatment depends on the gene, the type of protein, and the target cells. Because of this, it is difficult to create one universal therapy.
3. The Blood-Labyrinth Barrier (BLB)
The BLB protects the inner ear by controlling what enters from the blood. It keeps the inner ear stable and protected from infection. However, this can also limit drug delivery (though some substances can temporarily increase its permeability).
4. Low Cargo Capacity of AAV
AAV can only carry small genes. Larger genes require special strategies (dual or triple AAV systems).
There is also a small risk that viral DNA could insert into the genome and cause unwanted effects, such as cancer. Improving DNA repair mechanisms may reduce this risk.
5. Risks of Gene Editing (PE and DAP)
Advanced gene editing methods like prime editing (PE; does DNA substitutions, insertions, or deletions) and Drive and Process (DAP; having the cell follow tRNA's commands to read instructions) may accidentally edit unintended genes. This could affect other gene functions.
6. Risk of Structural Damage During Injection
Injection into the inner ear may damage hair cells due to pressure changes.
The RWM method is less invasive because it uses a natural opening. Meanwhile, cochleostomy requires drilling into the cochlea and carries more surgical risk.
7. Inner Ear-Brain Connection
The inner ear is connected to the brain This means viral material could potentially spread beyond the ear.
If viral particles enter the bloodstream, the immune system may react and reduce treatment effectiveness.
In one clinical trial, inserted DNA was detected in the blood shortly after injection but disappeared within days. No serious side effects were observed.
8. Uncertain Long-Term Effects
Most animal studies follow treated mice for only a few weeks. About half of studies showed reduced benefit after two months.
This may mean repeated doses are needed. Long-term safety are still unclear, so this could be dangerous.
9. Lack of Reinnervation
Some studies regenerate hair cells, but these new cells may not connect properly to spiral ganglion neurons (which help transmit their information to the brainstem). Without proper nerve connections, the new hair cells can't function fully.
10. Ethical Considerations
Gene therapy during pregnancy is controversial. It may prevent severe diseases, but it also raises safety and ethical concerns.
Long-term monitoring would be necessary. Some experts support its use in severe or lethal conditions. Careful riskâbenefit analysis is required.
11. Cost and Access Barrier
Gene therapy is expensive due to research, manufacturing, and clinical trials.
Unlike the retina (which needs small drug doses), the ear may require repeated doses. This increases cost, which decreases accessibility.
Conclusion
Because many cases are caused by single-gene defects, hearing loss is a good candidate for gene therapy. Gene therapy alone or combined with CI offers hope for clearer hearing. Many studies show promising results, especially in children.
However, challenges like delivery methods, long-term effectiveness, safety, cost, and ethical concerns remain.
More research is needed to improve and refine these therapies before they become widely available.
Non-Surgical Treatments for Intermittent Exotropia: A Systematic & Network Analysis
Objective
To compare how well different non-surgical treatments work for intermittent exotropia (IXT).
Methods
Randomized Controlled Trials (RCTs) were searched in different medical journal sites (PubMed, EMbase, and the Cochrane Library) up to June 2024. Data was analyzed using network meta-analysis in R software (a freely available programming language).
Results
11 RCTs with 1,411 patients were included. Treatments were
Overminus lenses (OML; Glasses with a stronger prescription to force the eyes to work harder to see clearly)
Conventional prisms (CP; Glasses that bend light before they hit the eye, making the image appear to where the misaligned eye is looking)
Part-time occlusion (PTO; Eyepatching the stronger eye to make the weaker eye work harder)
Binocular vision training (BVT; Brain exercises for better eye-brain coordination)
OML was the most effective treatment.
It improved distance deviation (deviation when looking at a nearby object).
However, it did not significantly reduce distance deviation (deviation when looking at a distant object).
PTO, BVT, and CP showed no significant benefit.
OML ranked highest overall.
None of the treatments improved near stereoacuity (depth perception).
Conclusion
OML is the most effective non-surgical treatment for IXT. None of the treatments improve near stereoacuity. Treatment should be chosen based on patient condition, effectiveness, and cost.
Introduction
Intermittent exotropia (IXT) is the most common type of strabismus. When to treat children with IXT is unclear. Treatment is usually considered when eye misalignment is seen for more than half of waking time. Such a time is considered a long period, which is when exotropia may harm binocular vision (eyes working together). Treatment may also be needed for social concerns or loss of stereopsis (depth perception).
IXT can be treated surgically or non-surgically. Non-surgical treatments are often used in
Younger children
Patients with small deviation angles
Good control
Those delaying surgery
These treatments aim to reduce eye deviation, improve eye coordination, and strengthen binocular control.
Common non-surgical treatments include overminus lenses (OML), part-time occlusion (PTO), prism therapy, and binocular vision training (BVT). Because it is unclear which treatment works best and when to use them, a clear comparison of their effectiveness is needed.
Previous meta-analyses used simple comparisons and could not rank treatments. Network meta-analysis allows both direct and indirect comparisons, and can rank multiple treatments. Therefore, this study uses network meta-analysis to compare commonly used non-surgical treatments for IXT.
Materials and methods
Search strategy: Multiple databases were searched from their start dates to March 2024. Search terms covered IXT, non-surgical treatments, patching, overminus lenses, prisms, and vision therapy.
Reference (bibliographies at the ends of reports), conference abstracts (summaries presented at conferences), and relevant professional websites were also searched. Experts in pediatric ophthalmology were contacted to identify unpublished or ongoing studies.
Inclusion Criteria:
Participants diagnosed with intermittent exotropia
Non-surgical treatments
Studies with matched control groups (age, sex, and deviation/control)
Control at distance (primary), near, deviation angle, or near stereoacuity (secondary)
Randomized controlled trials
Exclusion Criteria:
Non-original studies (case reports, reviews, meta-analyses, letters, conference papers)
Duplicates
Unclear IXT type
Insufficient data for analysis
Previous treatment before enrollment
Study selection and data extraction
Two researchers screened studies and extracted data. Disagreements were resolved by a third researcher. Duplicates were removed using EndNote 20. Titles and abstracts were screened first, followed by full-text review.
Quality assessment
Study quality was assessed using the Cochrane risk-of-bias tool. Items included:
Randomization
Allocation Concealment (concealing info so that professionals will choose a random participant (not one they think will do well))
Blinding
Data completeness
Reporting bias
Disagreements were resolved by a third reviewer.
Evidence Quality Assessment
Evidence quality was assessed using the CINeMA online tool (which grades quality of research). Six domains were evaluated:
Study bias (bias due to how a study was done)
Reporting bias (bias from researchers focusing on good things)
Indirectness (answering a related question but not the asked one)
Imprecision (study being too small)
Heterogeneity (studies with drastically different results)
Inconsistency
Statistical analysis
All outcomes were continuous variables and were analyzed using the mean difference (the mean of one group subtracted by the mean of the other). This was one used 95% confidence intervals.
Stata 17 (software that crunches these numbers) and R software helped generate
Network plots (comparisons between two different things)
Forest plots (comparisons between many things)
Network diversity and treatment co-occurrence were evaluated. Diversity was measured using the Probability of Interspecific Encounter (PIE; high value means highly diverse, and vice-versa), with values above 0.75 indicating high diversity.
Heterogeneity analysis
Heterogeneity was assessed using
chi-square test (math to see if a result is real or lucky)
IÂČ statistic (measures inconsistency in percentage)
Inconsistency Examination
Consistency between direct and indirect evidence was assessed using node-splitting analysis (seeing if both types of evidence actually agree). Publication bias was not assessed due to the small number of studies in each comparison.
Results
The screening process and results
A total of 373 studies were identified.
After removing duplicates and irrelevant articles, 11 studies were included.
Nine studies were included in the network meta-analysis.
Two were included only in the systematic review due to incompatible outcome measures.
Eye Control When Looking at Distant Objects
Only overminus lenses (OML) showed significant improvement in distance control.
No treatment significantly reduced distance deviation compared with observation.
OML, BVT, and PTO all showed improved distance control compared with observation.
Eye Control When Looking at Nearby Objects
Only overminus lenses (OML) showed significant improvement in near control.
OML significantly reduced near deviation.
BVT performed better than conventional prisms (CP) for near deviation.
BVT and PTO ranked next for improving control and reducing deviation.
Depth Perception When Looking at Nearby Objects
None of the non-surgical treatments improved near stereopsis compared with observation.
CP ranked highest for near stereopsis, although no treatment showed a significant effect.
OML ranked as the most effective treatment overall.
Stability & Quality
An analysis based on occlusion time was performed after excluding one study. Treatment rankings remained largely unchanged.
No significant inconsistency was found between direct and indirect comparisons.
Using the CINeMA method, evidence quality ranged from moderate to very low.
Distant-Object Eye Control: OML and PTO compared with observation showed moderate-quality evidence. However, BVT and CP showed low-quality evidence.
Nearby-Object Eye Control: OML showed moderate-quality evidence, while PTO, BVT, and CP showed low-quality evidence.
Nearby-Object Depth Perception: Most comparisons showed low or very low-quality evidence.
Discussion
This study is the first network meta-analysis comparing four non-surgical treatments for intermittent exotropia (IXT).
OML was the most effective treatment for improving control, then BVT and PTO, with CP ranking last.
None of the treatments significantly improved near stereopsis.
Because OML likely works by increasing convergence (signalling them to pull inward, rather than letting them stray).
Previous studies also support its effectiveness. However, OML has two main concerns:
Control may worsen after stopping treatment.
Long-term use may cause myopic progression.
Several limitations should be noted.
For this study, final control scores alone were not used. This was because the differences between groups might influence the values.
The number of included studies was small
The treatment protocols varied.
Future studies should explore long-term treatment effects and combination therapies to better guide non-surgical management of IXT.
Scalp biopsy (in which a piece of skin is taken from the scalp) and trichoscopy (in which a magnifying glass is used on the scalp) are commonly used to diagnose alopecia. However, trichoscopy alone may not always provide enough information.
New non-invasive imaging techniques can visualize structures beneath the scalp and assess hair shafts. These techniques include
High Frequency Ultrasound (HFU) - Sees 10mm into the scalp; Reveals deep inflammation, scarring, etc.
Ultra High Frequency Ultrasound (UHFU) - Similar to HFU; Sees 3mm into the scalp; Reveals hair follicles, blood vessels, and hair shafts before emergence
Reflectance Confocal Microscopy (RCM) - Horizontal imaging of the skin; Sees 0.2mm into the scalp; Reveals individual cells
Optical Coherence Tomography (OCT) - Uses light instead of sound waves; Sees 2mm into the scalp; Reveals skin thickness
This review summarizes the main findings of these techniques in scarring and non-scarring alopecia. This is hoped to improve diagnosis, understanding of the mechanisms of alopecia, and monitoring patients.
Imaging Modalities in Trichology
The diagnosis of alopecia is mainly based on medical history, physical examination, trichoscopy, and sometimes biopsy. There is growing interest in non-invasive imaging methods because they guide treatment decisions and reduce the need for biopsies.
High-frequency ultrasound (HFUS), reflectance confocal microscopy (RCM), and optical coherence tomography (OCT) have shown increasing usefulness in recent years.
This review summarizes the available evidence on their role in both scarring and non-scarring alopecia.
(An electronic literature search was conducted in PubMed up to March 2024 using the terms âhigh-frequency ultrasound,â âreflectance confocal microscopy,â âoptical coherence tomography,â âalopecia,â and âhair.â)
Ultrasound
HFUS is widely used in dermatology and works by emitting high-frequency sound waves (>15 MHz) into the skin and recording their echoes. Frequencies of 15â20 MHz allow visualization of skin structures up to 10 mm deep.
Ultra-high-frequency ultrasound (UHFUS), using frequencies above 50 MHz (up to 70 MHz), provides higher resolution, reaching 30 ÎŒm. Color Doppler can also be used to assess blood flow.
In trichology, normal hair follicles appear as oblique hypoechoic bands (darker structures; can also represent under-the-skin fat) in the dermis. Anagen follicles are found in the deep dermis (middler layer of the skin) or upper hypodermis (lower layer of the skin), while telogen follicles (hair follicles that are no longer growing) are limited to the upper dermis. Hair shafts appear as trilaminar hyperechoic structures (white structures).
Compared with trichoscopy, HFUS shows a similar number of follicular units, although follicles appear wider. With UHFUS, hair shafts can be visualized within the follicle before emerging at the surface.
Non-Scarring Alopecia
In androgenetic alopecia (AGA; male/female pattern baldness), affected follicles often show reduced echogenicity (ability to reflect ultrasound waves), possibly related to inflammation. Studies have reported
shallower follicles
loss of the normal trilaminar hair shaft pattern (three distinct lines representing the cuticle, cortex, and medulla; healthy and thick scalp hair)
areas without follicles in patients with AGA
In alopecia areata (AA), ultrasound may reveal empty follicles and increased perifollicular echogenicity (ability to reflect ultrasound waves in the surrounding area) in the subcutaneous tissue, which can help assess disease severity.
Recent studies have described distinct ultrasound features according to disease phase
Widened, water drop-shaped follicles = Active AA
Fewer, poorly defined follicles = Inactive AA
Follicles of varying width and shape = Regrowth.
Overall, follicles in AA tend to be wider and more echogenic than in other conditions, while AGA shows the narrowest follicles.
Scarring Alopecia
Early studies using HFUS showed that
Increased Stiffness Related to Fibrosis (scar tissue).
HFUS has been studied in patients with
Lichen Planopilaris (LPP) - The immune system attacks hair follicles, irresversibly destructing them
Discoid Lupus Erythematosus (DLE) - Circular hair loss patches; Leads to permanent bald spots if not treated early
Frontal Fibrosing Alopecia (FFA) - Similar to LPP; Linear and band-like recession of the hairline
No Alopecia
Active disease showed abnormal follicular morphology (abnormal physical structure), while inactive disease showed a marked reduction in follicle number. Skin and follicular echogenicity were higher than in controls, likely due to fibrosis.
Importantly, the absence of follicular openings on trichoscopy did not always mean complete follicular loss on ultrasound, suggesting HFUS can help determine when scarring is complete.
UHFUS studies in FFA have described
Perifollicular Hypoechogenicity
Poorly Defined Distal Follicles (widened lower end of a hair follicle)
Hyperechoic bands in the subcutaneous tissue
These findings correlate with
Perifollicular Inflammation
Follicular Destruction
Fibrous Septa (connective tissue that separates groups of hair follicles)
Other studies have shown increased vessel diameter and blood flow in the frontal hairline compared with alopecic areas and controls, reflecting active inflammation and fibrosis.
Increased vessel diameter in clinically unaffected scalp may indicate subclinical inflammation (inflammation you can't see/feel) and predict disease progression.
In dissecting cellulitis (the scalp develops interconnected lumps and sores), ultrasound findings resemble those of
Hidradenitis Suppurativa (recurring nodules and lesions in areas with hair follicles)
Dilated Follicles
Pseudocysts (round pockets with no clean lining)
Hypoechoic Collections
Dermal and Subcutaneous Tunnels (caused by inflammation burrowing through skin layers)
Fibrosis
Variable peripheral hypervascularization (extra blood flow surrounding the area) on Doppler imaging
Reflectance Confocal Microscopy
RCM is a non-invasive optical imaging technique that uses low-power laser light to produce high-resolution, histology-like images.
Its main advantage is excellent cellular detail, while its limitation is shallow penetration, reaching only the superficial dermis. Because of this, RCM is considered an intermediate tool (bridges the gaps) between trichoscopy and biopsy. Normal hair follicles appear as well-organized structures with small basal cells (lowest layer of the epidermis / highest layer of skin).
Non-Scarring Alopecia
RCM studies have shown similar hair shaft structure in healthy individuals, alopecia areata (AA), and androgenetic alopecia (AGA), although AGA shows greater variability in shaft thickness. Reported RCM features of non-scarring alopecia include
Visible Dermal Papillae (bottom of the hair root; blood vessels; tells the hair to grow)
Follicular Miniaturization
Follicular Keratinization (follicle producing keratin; can block the follicle opening).
Retrospective studies comparing scarring and non-scarring alopecias identified significant differences between the two groups, although no clear RCM features reliably distinguished AGA from AA. In AA, inflammatory cells were often observed in the epidermis and around follicles, consistent with its autoimmune nature.
In tinea capitis, RCM can detect small, rounded hyperreflective structures near the hair shaft, corresponding to fungal conidia (fungal spores).
Distinct RCM features have also been described in chemotherapy-induced alopecia (with chemotherapy treating cancer), varying according to disease stage.
Scarring Alopecia
In scarring alopecias, RCM commonly shows inflammatory cells in the epidermis, dermis, and around adnexal structures. Key features include epidermal inflammation, absence of follicular miniaturization, and absence of follicular keratinization.
Active inflammation at the follicular epithelium (lining of the hair follicle) or dermoepidermal junction (border between epidermis and dermis), along with blurred dermal papillae, helps distinguish scarring from non-scarring alopecia.
Another important finding is dermal sclerosis, seen as thickened fibers arranged around follicles. Although typical of scarring alopecia, similar changes may appear in advanced non-scarring alopecia due to chronic inflammation or sun damage.
In LPP and FFA,
Early lesions show inflammatory cells near the follicular infundibulum (top of the hair follicle; exit tunnel for hair and oil), consistent with early histopathological changes.
Long-standing lesions show dilated blood vessels, thickened dermal fibers, and marked perifollicular fibrosis.
In LPP and DLE,
several RCM features have shown good correlation with histopathology.
In LPP, inflammation mainly affects the epidermis and follicular epithelium, with diffuse interface changes.
In DLE, changes are more focal, involving the dermoepidermal junction. These findings were reported in a small study of patients with histologically confirmed LPP and DLE.
DLE can be particularly challenging to diagnose, and RCM may be especially helpful. An observational study in patients with DLE found that interface dermatitis (skin inflammation) and infundibular dilation (stretched-out hair pore) showed the strongest agreement with histopathology. Combining RCM with selected trichoscopic findings further improved diagnostic accuracy.
RCM findings have also been described in other scarring conditions. In coup de saber morphea, RCM showed hyperreflective areas, gland atrophy, loss of sebaceous glands, and reduced follicles, helping differentiate early inflammatory from late sclerotic stages (hardened scar).
In folliculitis decalvans (pus-filled spots that often lead to tufting (many hairs growing out of one pore)), RCM revealed
Reflective tubular and rounded structures
Interfollicular hyperkeratosis (thick buildup between the hairs)
correlating with trichoscopic findings (findings seen under the magnifier) such as
Tufted hairs
Pustules
Scaling
Optical Coherence Tomography
OCT is a non-invasive imaging technique that uses near-infrared light to produce high-resolution cross-sectional images of the skin up to 2â3 mm deep.
In trichology, it shows the scalp surface as bright and hair shafts as dark hollow structures with reflective rings. OCT offers high resolution but limited penetration, preventing full visualization of subcutaneous tissue.
Non-Scarring Alopecias
OCT evaluates hair structure using two main parameters:
Cross-Section (CS; slice view of hair shaft that measures thickness)
Form Factor (FF; describes the shape of hair).
In healthy individuals, CS and FF show minimal variation, while greater variability has been observed in patients undergoing chemotherapy and in alopecia areata (AA).
Studies in patients receiving chemotherapy showed a reduction in hair diameter and CS, while no significant changes were observed in patients treated with tamoxifen (breast cancer drug; sometimes used to treat FFA). In AA, OCT demonstrated smaller CS values in active lesions compared with unaffected areas, indicating structural changes limited to active disease.
OCT has also been used to monitor treatment response in AA. In patients with patchy AA treated with platelet-rich plasma (where blood is spun to concentrate growth factors), an increase in follicle number and length was observed, while no improvement was seen in universal AA. Other studies have shown that OCT can detect growing follicles below the surface that are not clinically visible.
Scarring Alopecias
OCT studies have shown increased epidermal thickness and reduced follicle density in scarring alopecias compared with non-scarring alopecias and healthy scalp. Although based on small cohorts, these findings may be useful for diagnosis and monitoring.
In frontal fibrosing alopecia (FFA), OCT has demonstrated increased epidermal thickness in active hairline areas and thinning in scarred zones. These changes reflect
Inflammation
Edema (swelling) in active disease
Atrophy in scarred areas
Progressive disease is also associated with
Reduced superficial vascular flow (blood vessels at the surface; destroyed by scar tissue)
Increased deeper flow due to vessel obliteration in scarred skin (due to surface vessels not being there, the body compensates by pumping blood through vessels under the scar)
Conclusions
Histopathology remains the gold standard for diagnosing hair disorders, but it is invasive and may not represent the entire disease process. Trichoscopy allows detailed surface evaluation but cannot assess deeper follicular structures. New non-invasive imaging techniques complement these methods by visualizing deeper anatomy and enabling disease monitoring over time.
However, widespread adoption is limited by factors such as
Cost
Required expertise
Technical challenges of the scalp
Small study sizes
Limited correlation with histopathology.
Understanding the strengths and limitations of each imaging modality is essential to optimize their use in trichology.
Nemluvio / Nemolizumab Medication and Atopic Dermatitis / Eczema
Abstract
Purpose
Atopic dermatitis (AD) is an immune-mediated condition that causes dry and itchy skin. It Current treatments for moderate-to-severe AD (steroids, biologics, etc) often have limited long-term effectiveness and safety concerns.
Interleukin-31 (IL-31) is an important molecule in AD that causes itch, skin barrier damage, inflammation, and thickening. Nemolizumab, a monoclonal antibody that blocks the IL-31 receptor (IL-31RA), is a new targeted therapy for AD.
Materials and Methods
This summarizes what is known about IL-31âs role in AD and highlights recent clinical trial results on nemolizumabâs effectiveness and safety.
Results
Clinical trials show that nemolizumab significantly reduces itch and disease severity in moderate-to-severe AD. Most side effects were mild and non-serious.
Conclusions
IL-31 is a key player in AD development. Clinical evidence supports nemolizumab as an effective and safe treatment option that blocks IL-31 for patients with moderate-to-severe AD.
Introduction
Atopic dermatitis (AD), or eczema, is the most common long-term inflammatory skin disease worldwide, affecting both children and adults. It often starts in early childhood and is linked to other allergic conditions (asthma, hay fever, and food allergies). However, some people develop AD later in life or continue to have symptoms into adulthood. Genetics, family history, and environmental factors (urban living and dry climates) play major roles in its development.
AD is marked by severe itching, dry skin, and a relapsing course. It has a major impact on sleep, mental health, and daily life.
The disease arises from several interacting factors
Genetic defects that weaken the skin barrier
Immune system overactivation
Nerve hypersensitivity
Changes in the skinâs microbiome
One key molecule involved is interleukin-31 (IL-31), a cytokine that triggers itch, inflammation, and barrier damage.
For mild-to-moderate AD, topical treatments are standard (normally creams, ointments, etc).
For more severe cases, traditional immunosuppressants often have limited benefits and long-term safety issues. Recent biologic and small-molecule treatments
Dupilumab / Dupixent
Tralokinumab / Adbry
JAK inhibitors (where JAKs help inhibit the pathway that leads to inflammation and immune responses))
have improved outcomes, but some patients still do not respond well.
It's possible to develop antibodies to counteract against dupilumab.
Because itching is one of the most distressing symptoms, new therapies are focusing on breaking the itch-scratch cycle.
Nemolizumab, an injectable antibody that blocks the IL-31 receptor (IL-31RA), directly targets the main pathway behind AD itch. Approved in Japan in 2022 and more recently by the FDA and EMA, it is used for moderate-to-severe AD not controlled by topical therapy. This review explores IL-31âs role in AD and summarizes the latest findings on nemolizumabâs clinical benefits and safety.
The Role of IL-31 in AD
In AD, the skin barrier becomes weak due to genetic mutations and reduced skin lipids such as ceramides (a fat that locks in moisture). This allows allergens to enter the skin and trigger immune responses dominated by cytokines (proteins secreted by immune cells) like IL-4, IL-13, and IL-31.
IL-31, produced mainly by Th2 immune cells, is a major cause of itching in AD. It acts on receptors found on skin cells, nerves, and immune cells, activating pathways that drive inflammation and itch.
IL-31 directly stimulates sensory nerves to cause itch independently of histamine, explaining why antihistamines often donât work well in AD. Higher IL-31 levels in the blood are linked to more severe itching and inflammation. It also makes nerve endings more sensitive, worsening chronic itch.
Beyond itch, IL-31 disrupts the skin barrier by reducing proteins (filaggrin and claudin-1 which help the skin barrier) and by promoting the release of inflammatory molecules.
Scratching and skin infections (especially with Staphylococcus aureus) further increase IL-31 receptor expression, worsening inflammation.
IL-31 attracts more immune cells to the skin and stimulates them to release additional inflammatory and fibrotic (scar tissue) factors, contributing to both acute inflammation and chronic skin thickening.
Overall, IL-31 is a key link between itching, inflammation, and skin barrier damage in AD. Targeting the IL-31/IL-31RA pathway, which is what nemolizumab does, offers a promising way to control both itch and underlying disease activity.
Clinical Efficacy in Atopic Dermatitis (AD)
Nemolizumabâs effectiveness in treating moderate-to-severe AD has been tested in several clinical trials. Overall, results show that nemolizumab quickly and consistently reduces itch and improves skin symptoms, with good long-term safety.
Phase II Trials' Main Findings:
Adults receiving nemolizumab every 4 weeks had much greater itch reduction than those on placebo
Improvements began as early as week 1
Itch and skin improvements were maintained or further increased over time
Improved sleep and quality of life scores
Takeaway: Nemolizumab provides fast, dose-dependent, and lasting improvements in itch, skin inflammation, sleep, and quality of life.
Phase III Trials' Main Findings
In the Japanese phase III trial, improvements were noticeable within 2 days of the first injection.
In the self-injection study, patients could safely and effectively self-administer nemolizumab after week 12.
In the pediatric phase III trial, children (6â12 years) showed significantly better itch reduction than placebo (visible effects within 2 days).
In the global phase III trials, 1,700+ adolescents achieved clear/almost clear skin and benefits appeared within the first week.
Summary
Across all phase II and III trials, nemolizumab:
Rapidly reduces itch (often within days)
Improves skin inflammation and quality of life
Maintains effectiveness over long-term use
Shows consistent results regardless of age
Has mostly mild side effects
These findings support nemolizumab as a strong and well-tolerated treatment option for moderate-to-severe AD.
Safety
Nemolizumab has been consistently well tolerated in patients with atopic dermatitis (AD).
Most adverse events (AEs) were mild to moderate and rarely led to treatment discontinuation. The most commonly reported AEs included
Nasopharyngitis (inflammation of the nasal passages and the back of the throat)
AD exacerbations
Upper respiratory tract inflammation
Elevated blood creatine phosphokinase (which converts creatine into phosphocreatine, an energy reserve for muscle cells)
Importantly, AD worsening did not correlate with reduced itch improvement (though the reason for the worsening remains unclear).
Injection-site reactions occurred infrequently and decreased with continued treatment.
An increase in asthma attacks was observed among patients with preexisting asthma, but they were typically mild and may reflect other factors.
Real-World Evidence
Real-world studies support the clinical effectiveness and favorable safety of nemolizumab in AD. Data shows rapid improvements in itching and eczema severity, consistent with clinical trial results.
Findings suggest that patients with AD that isn't triggered by allergies may respond more robustly than those with externally-caused disease.
Interestingly, improvement has been seen without consistent changes in biomarkers such as IgE (an immune system antibody). This is despite the fact that lower IgE levels have been associated with better outcomes.
Larger studies with longer follow-up are needed to better define treatment outcomes across diverse populations and care settings.
Conclusion
IL-31 is central in the pathogenesis of AD, driving itching, inflammation, and barrier dysfunction. Clinical data from phase II and III trials consistently demonstrate that nemolizumab provides rapid and sustained reductions in itch and severity.
Its favorable and durable safety profile supports nemolizumab as a promising addition to moderate-to-severe AD treatments. Future, long-term, and real-world will be crucial to further define its position and potential.
Quality of Life and Food Allergen Oral Immunotherapy
Abstract (Summary)
Background
Food allergen oral immunotherapy (OIT) is a treatment in which people with food allergies are given small doses that slowly increase over time, and is done to build tolerance to that substance.
Itâs unclear how much food allergen OIT improves health-related quality of life (HRQL).
Methods
Researchers searched major databases for randomized OIT trials that measured HRQL. They compared results between OIT and control groups using.
Results
Ten studies (nine on peanut, one on baked milk; 1,330 participants) were analyzed. There was no meaningful difference in HRQL between OIT and control groupsâacross parent, child, or teen reports.
12 months after completing OIT, childrenâs parentâreported HRQL improved.
No difference was found in the baked milk OIT study.
Conclusion
OIT showed improvements in quality of life after treatment was finished. Evidence during active treatment remains limited.
Food allergy is a growing public health issue that affects all ages and often reduces quality of life.
Avoiding allergens can increase anxiety. Many patients say that improving quality of life is more important to them than being âcured.â
OIT works by exposing patients to increasing doses of an allergen to help them tolerate it better.
Desensitization (fewer reactions while on OIT)
Remission (sustained tolerance even after stopping OIT).
HRQL
Measures how health affects overall wellbeing.
Assessed using questionnaires (Food Allergy Quality of Life Questionnaire (FAQLQ) and the Pediatric Quality of Life Inventory (PedsQL)).
Evaluate physical, emotional, and social wellbeing and are adapted for different ages.
Parents report for younger children.
Older kids and teens self-report.
Earlier reviews on OIT and HRQL found mixed results. Differences in how studies measured HRQL or whose reports they used (parent-report vs. self-report) may explain the inconsistency. Also, past reviews didnât state outcomes (desensitization or remission).
Therefore, this updated meta-analysis aimed to find out:
Does OIT improve overall HRQL during or after treatment?
How does OIT affect specific areas of HRQL (physical, emotional, social)?
Do certain groups (by age, allergy type, or treatment outcome) benefit more from OIT?
Methods
This review followed PRISMA reporting standards.
2.1 Search Strategy and Eligibility
Researchers searched MEDLINE, Embase, CENTRAL, and Google Scholar (Jul 2023) for randomized trials comparing OIT with any control group (placebo or allergen avoidance).
Only studies that measured HRQL using a validated tool were included.
Observational studies, reviews, conference abstracts, and nonâfood allergy studies were excluded.
Two reviewers independently screened all titles, abstracts, and full texts using Covidence software, resolving disagreements with a senior reviewer.
2.2 Data Extraction
Data was collected on study design, OIT protocol, control group, HRQL tools used, and main HRQL findings.
If necessary, authors were contacted for missing summary data.
2.3 Risk of Bias
Study quality was rated using the RoB 2.0 tool (which looks at randomization, missing data, outcome measurement, and selective reporting).
Two reviewers rated each study, with a third resolving any disagreements.
If studies had multiple HRQL perspectives, each was assessed separately.
2.4 Data Synthesis and Analysis
Results were grouped by:
Treatment vs. postâtreatment followâup
Reporter (parent, child, teen, adult)
Allergen type
HRQL changes were compared between OIT and control using Hedgesâ g (a standardized effect size).
When enough studies were available, results were combined.
2.5 Sensitivity Analyses
Extra checks were done to make sure results werenât skewed (by study design differences, bias levels, or a single outlier study).
2.6 Ethics
Because only published, deâidentified data were used, no ethics approval was needed.
Results
3.1 Included Trials
10 eligible trials (11 publications) were included:
9 peanut OIT studies in children
1 baked milk OIT study (children, teens, and adults)
Total: 1,330 participants
Most trials compared OIT with placebo, and all HRQL measurements were through validated questionnaires.
3.2 Risk of Bias
3 trials: low risk of bias
6 trials: some concerns (mostly missing HRQL data)
1 trial: high risk (missing data mainly in the OIT group)
Some bias was possible due to selective HRQL reporting.
3.3 Peanut OIT During Treatment
Across all peanut OIT trials, no clear improvement in HRQL was seen during treatment.
3.4 Peanut OIT After Treatment
At 12 months postâOIT, parentâreported HRQL significantly improved.
Improvements were strongest for food anxiety and social/dietary restriction subscales.
At 4 years postâOIT, HRQL was even better compared to placebo.
Quality of life benefits appear after OIT ends, not during active treatment.
3.5 Baked Milk OIT
Parent reports showed no difference, and child selfâreports suggested a possible worsening, but results were uncertain.
3.6 Subgroup Effects
Age and treatment outcomes were the only factors linked to HRQL differences:
Older children (5+ years) showed more improvement.
Participants who achieved remission reported better HRQL than those who stayed allergic.
3.7 Sensitivity Analyses
Results stayed consistent after checking for differences in bias, study design, and dosing. This means no single study changed the overall conclusions.
Discussion
Peanut OIT improved quality of life only after treatment ended, especially 12 months later.
No HRQL difference was seen between OIT and control groups during treatment.
This pattern makes sense: once patients are desensitized or reach sustained unresponsiveness, they can live with less fear and dietary restriction, which boosts their wellbeing.
The fact that HRQL doesnât improve until after OIT may be important for doctors and patients to discuss. Setting realistic expectations could prevent disappointment or treatment dropout.
Limits:
Most studies focus on children with peanut allergy, not adults or other foods.
Adults with food allergies report poor HRQL and few treatment options, so future studies should expand to these groups.
Studies varied in design
There were only two long-term trials were available.
Future research should also look beyond randomized controlled trials.
Conclusion
OIT improves quality of life mainly after treatment, especially for patients who achieve sustained unresponsiveness or desensitization.
During active treatment, there was no clear benefit.
For clinicians and patients, expectations should focus on long-term gains rather than short-term relief.
More research across different ages, allergens, and treatment outcomes is needed to guide future use and approval of OIT.
Abstract
Hypothyroidism (an underactive thyroid) is a condition where the thyroid gland does not produce enough thyroid hormones.
Symptoms include
Fatigue
Weight gain
Cold intolerance
Dry skin and hair
Muscle aches and weakness
Depression
Slow heart rate
Puffiness in the face
Congenital hypothyroidism (CH) is the most common hormone disorder in newborns.
Since newborn screening began about 50 years ago, treatment and outcomes have greatly improved. In countries with screening programs, most babies with CH show few or no symptoms.
Today, doctors focus on genetic testing to find the cause and may reassess thyroid function after 6 months if only a small dose of medicine is needed.
This review explains how CH is diagnosed, managed, and treated to achieve the best results.
Introduction
Hypothyroidism happens when the body doesnât make enough thyroid hormone (TH), which affects growth, brain development, and metabolism. When this hormone shortage starts at birth, itâs called congenital hypothyroidism (CH).
CH can occur for different reasons, such as problems with
The thyroid gland itself
Brain hormones
Tissues not responding correctly to thyroid hormones
Screening helps detect cases early, leading to much better outcomes. However, only about 30% of countries offer CH screening.
Recent genetic and environmental studies are helping doctors understand different types and causes of CH more precisely. Treatment in children can still be tricky (deciding the right starting dose, medication form, and when to stop treatment).
This review focuses on improving the diagnosis, care, and treatment of children with congenital hypothyroidism.
Background: Anatomy, Embryogenesis, and Function
The thyroid gland is a small, two-lobed organ in the neck. It has two main cell types:
Follicular cells, which make thyroid hormones
Parafollicular cells, which make calcitonin (a hormone that helps control calcium levels)
Most thyroid tissue is made of follicular cells arranged in small round structures called follicles.
Development (Embryogenesis):
The thyroid starts to form 3 weeks after conception as a small thickening in the fetus's throat.
It reaches to its final spot (in front of the windpipe) by day 50.
The thyroid starts making hormones between weeks 10-12 of pregnancy, once iodine is incorporated into the hormones.
Function: Make thyroid hormones (TH), which help with growth, metabolism, and brain development.
Early in pregnancy, the fetus relies on the motherâs thyroid hormones because its own thyroid hasnât started working yet.
Around 20 weeks, the thyroid starts to function, and hormone levels gradually rise with gestational age. Premature babies usually have lower thyroid hormone levels than full-term babies because of this reason.
If the fetus's thyroid doesnât form properly, maternal thyroid hormones can still protect brain development before birth.
However, if both mother and baby are hypothyroid, this can cause lasting problems with brain development, even if treatment begins right after birth.Mothers with hypothyroidism during early pregnancy can also have children with mild learning difficulties.
At birth
Sudden drop in temperature from the womb to the outside world causes a spike in thyroid hormone within 30 minutes, leading to a rise in thyroid hormones.
In full-term babies, FT4 levels drop back to normal within 4â6 weeks.
In preterm or low-birth-weight infants, this spike is smaller or may not happen at all.
Epidemiology
Congenital hypothyroidism (CH) is the most common hormone disorder in newborns.
Before newborn screening began in 1974, CH occurred in about 1 in 7,000 births.
With improved screening and iodine nutrition, the rate increased to 1 in 3,500.
This rise is likely due to:
Lower cut-off values in screening, which detect more mild cases
Better detection in high-risk babies (multiple births, premature, or low-birth-weight infants)
Advances in neonatal care allowing more preterm babies to survive
Ethnic and environmental factors affecting thyroid function
Milder cases where the gland is present but underactive have increased.
CH is:
Twice as common in girls as in boys
More common in Hispanic than in African or African-American infants
More frequent in babies with Down syndrome
Aetiology and Pathogenesis
In healthy people, the hypothalamicâpituitaryâthyroid (HPT) axis keeps thyroid hormone (FT4) levels stable. In congenital hypothyroidism (CH), the thyroid gland doesnât make enough hormone, so the body increases TSH to try to compensate.
The main types of CH are primary (thyroid problem) and central (brain-related; rarer).
The most common cause of primary CH is thyroid dysgenesis (unformed or abnormally formed thyroid) like
Athyreosis - Absence of thyroid tissue
Ectopic thyroid - Gland formed in the wrong place (base of the tongue or under it)
Hypoplasia or hemi-thyroid - Small or one-lobe thyroid
The exact cause of thyroid dysgenesis is often unknown, but some cases are linked to mutations in genes that control thyroid development (TSHR, NKX2.1, PAX8, and FOXE1).
Only about 5â10% of cases are genetic, and family cases are rare.
In many other cases, the thyroid gland is present but underactive (thyroid dyshormonogenesis). It happens when thereâs a defect in one of the steps needed to make thyroid hormone.
Itâs usually inherited (recessive) and often caused by TPO gene mutations.
These children usually have a goiter (enlarged thyroid).
A rare example is Pendred syndrome, which causes both CH and hearing loss.
Other genes involved include DUOX2, DUOXA2, PENDRIN, and SLC26A7.
Tests such as thyroid scans and perchlorate tests help doctors identify the exact type of defect. In general:
Low iodine uptake means problem with iodine transport (like NIS/SLC5A5 defect)
Positive perchlorate test means problem in hormone formation (like TPO, DUOX2, or PENDRIN defect)
Negative test means problem in thyroglobulin or iodine recycling (like DEHAL1 defect)
Recently, new combinations of hypothyroidism-type and mutations have been found.
CH can also have multiple genetic or environmental causes acting together. This may explain why symptoms and severity vary so much, even within families.
Clinical
The symptoms of CH result from the lack of thyroid hormone, which affects nearly every system in the body.
Thyroid hormones normally:
Increase heart rate and cardiac output
Help the kidneys, intestines, and metabolism function normally
Support growth, body temperature, and especially brain development
At birth, babies are still protected for about two weeks by thyroid hormones passed from the mother. Because of this, only a few (about 1â4%) show clear signs right away.
Typical features of newborns with CH:
Born late and with higher birth weight
Large posterior fontanelle (soft spot on the head)
Prolonged jaundice
Dry, mottled skin
Large anterior fontanelle
Umbilical hernia
Constipation and poor feeding
Low muscle tone, lethargy, cold body temperature, slow heartbeat
Puffy face, large tongue (macroglossia)
Hoarse cry, slow growth, and developmental delay
Goiter (enlarged thyroid) usually occurs in dyshormonogenesis, but itâs rare in newborns and often appears later in childhood.
Symptoms tend to be more severe in babies with thyroid dysgenesis (missing or abnormal thyroid).
Children with CH also have a higher risk of other birth defects, especially heart problems. Other associated anomalies can affect the kidneys, digestive system, bones, or muscles (mainly seen in thyroid agenesis or dyshormonogenesis).
Finally, studies show that neurological disorders are more common in children with CH than in healthy peers.
Newborn Screening
The main goal of CH screening is to prevent intellectual disability caused by untreated CH.
Screening began in 1974 and is now used in many parts of the world (North America, Europe, Japan, and Australia).
Some areas of the world still do not have CH screening programs. Expanding these programs can save lives and improve quality of life for affected children.
Combined T4 + TSH testing (the most accurate approach)
Only a few countries have programs that can also detect central hypothyroidism (brain-related).
When to screen:
Between 48 and 72 hours after birth (after the first day but before hospital discharge).
Testing too early (before 24 hours) can give false positive results because TSH is naturally high right after birth.
The test should be done before any blood transfusion, since this can affect results.
Special cases:
Preterm or critically ill infants should have screening done within 7 days of life and again at 2â4 weeks because their levels can rise later.
Screening should also be repeated in twins/triplets/etc, low-birth-weight babies, sick newborns, and babies with Down syndrome.
Diagnosis
If the screening test is abnormal, blood tests should be done to confirm the diagnosis:
FT4 (free thyroxine)
FT3 (free triiodothyronine)
TSH (thyroid-stimulating hormone)
Typical results for CH show low FT4 and high TSH.
Even if screening results are normal, these tests should be performed immediately if a baby shows other symptoms.
Interpreting results:
TSH 6â20 mIU/L, normal FT4 = possible subclinical CH. Doctors can start immediate treatment or repeat tests after 1â2 weeks.
TSH >20 mIU/L or low FT4 = start immediate treatment.
Further tests help find the cause:
Thyroglobulin levels = high in dyshormonogenesis; absent in athyreosis
Anti-thyroid antibodies = determine if it's due to maternal autoimmune antibodies
Thyroid ultrasound = shows gland size and shape but may miss ectopic thyroid tissue.
Thyroid scintigraphy = shows how well the thyroid takes up iodine (uses technetium (Tc-99) or iodine (I-123)).
Perchlorate discharge test = shows defects in iodine organification (how iodine is used).
Other investigations:
Knee or heel x-rays â check for delayed bone growth, showing CH started before birth.
Heart and kidney ultrasounds â checks for associated birth defects.
At diagnosis, itâs important that parents receive clear written information about CH and how to manage it.
Genetic
Advances in genetic testing have greatly improved the understanding of CH. These technologies have identified new genes linked to CH and new thyroid abnormalities caused by known mutations. Knowing the exact genetic cause can help guide diagnosis, treatment, and long-term care.
Genetic testing is especially recommended for:
Children with dyshormonogenesis
Families with more than one affected member (familial dysgenesis)
In some cases, genetic counseling should also be offered when CH occurs along with:
Hearing loss or family history of deafness
Neurological problems
Heart, kidney, or lung defects
Cleft palate
Albright hereditary osteodystrophy (bone and hormone condition)
Testing is usually done using
Array CGH (Array Comparative Genomic Hybridization) - Looking at chromosomes to see if any DNA is missing or duplicated
NGS gene panels - Reading DNA to see if any set are known to cause a specific disease
WES (Whole-exome sequencing) - Reading the exome (protein-coding regions) to see any disease-causing changes (instead of just reading a few genes like NGS gene analysis)
In children whose thyroid gland is present but hormone levels are very abnormal (TSH ℠80 mIU/L or FT4 †5 pmol/L), a genetic cause is more likely to be found.
Environmental factors, such as iodine intake, can also affect how a gene mutation appears or how severe the symptoms are. More research in this area may explain why the same mutation causes different symptoms in different people.
Treatment and Management
Treatment has been known for many years, but new therapies and genetic insights continue to emerge.
The main goal is to start treatment early (first 2 weeks after birth) to ensure normal growth and brain development.
Medication
The standard treatment is L-thyroxine (L-T4), a synthetic thyroid hormone. The starting dose is 10â15 ÎŒg/kg/day, but may be higher depending on severity. For babies with heart problems, doctors may begin with about half the usual dose and increase it gradually.
Tablets are the most common form and can be crushed. They can be mixed with water (not in a full milk bottle).
Liquid and soft capsule forms are also available and may be absorbed better, especially in babies or children with feeding issues.
Soy, iron, or calcium can reduce absorption and aren't recommended to consume alongside the medication.
Rarely, it's given intravenously. In those cases, the dose should be about 80% of the oral dose.
Follow-up and Monitoring
TSH and FT4 are rechecked in 1â2 weeks, then every 2 weeks until normal levels are reached.
Afterwards, checks will take place:
Every 1â3 months during the first year
Every 2â4 months between ages 1â3
Every 3â6 months until growth is complete
TSH should stay within the normal range for age.
FT4 may be in the upper half of the normal range (only if TSH is normal).
Overtreatment:
The dose is reduced only if TSH is suppressed or symptoms of hyperthyroidism appear.
Too much hormone can cause premature skull bone closure (craniosynostosis) in infants.
Neurodevelopment
Children who start treatment early generally have normal intelligence and school performance.
Mild issues (regarding motor coordination, memory, or attention problems) may occur.
Some children may also have mild hearing loss, particularly at high frequencies.
Itâs important to monitor psychomotor development, school progress, and hearing.
If learning or developmental delays are noted, other causes should be investigated.
Transient Form of Congenital Hypothyroidism
Although congenital hypothyroidism (CH) due to thyroid dysgenesis is typically permanent, 35% of patients with a gland in its original location present do not require lifelong treatment.
If permanent hypothyroidism has not been confirmed, it is advisable to discontinue therapy around 3 years of age.
The standard approach involves withdrawing L-thyroxine for 4 weeks and then re-evaluating thyroid function:
If TSH and FT4 are normal, transient CH (not needing lifelong treatment) is confirmed.
If TSH is mildly elevated (<10 mU/L), testing should be repeated after 4â8 weeks. If TSH >10 mU/L and/or FT4 is low, permanent CH is confirmed, and treatment should be resumed.
The prevalence of iodine-related transient CH has declined with salt iodization programs.
Transient CH is common in premature infants, who are at particular risk of iodine deficiency because of the low iodine content in preterm formulas and parenteral nutrition.
At diagnosis, it is impossible to distinguish transient from permanent CH, but some clues that suggest transient disease are
Low L-thyroxine requirement
Low initial TSH
In children with a thyroid gland in the correct place and L-T4 <2â3 ”g/kg/day, thyroid function re-evaluation may be appropriate as early as 6 months of age.
Conclusions and Future Perspectives
Congenital hypothyroidism treatment is driven by advances in newborn screening and genetic discoveries.
A key unresolved issue is the global implementation of newborn screening. Extending screening programs to underserved regions where birth rates are high is crucial.
Genetic analysis represents another major area of progress.
The integration of epigenetic studies (where DNA stays the same but the expression of it changes) and research on environmental factors (iodine exposure especially) may explain expressivity of CH.
Finally, prospective and caseâcontrol studies are needed to establish evidence-based criteria for when and how to discontinue therapy in transient CH.
Overall, there's lots of promise for achieving individualized management and improving the long-term outcomes of children with congenital hypothyroidism.
Abstract
Magnetic Particle Imaging (MPI) is a new medical imaging technique that has developed rapidly over the last 20 years.
It detects special magnetic nanoparticles (SPIONs) using changing magnetic fields.
By detecting SPIONs, MPI can
Visualize blood flow
Detect diseases
Guide medical procedures.
MPI is very sensitive, can create 3D images in real time, and doesnât use harmful radiation.
Thanks to its high sensitivity, MPI can be used for many purposes, including heart and blood vessel imaging, stroke detection, and tracking cells in the body.
MPI works by detecting SPIONs using static and changing magnetic fields. This provides high sensitivity, background-free imaging, and no harmful radiation.
MPI can also distinguish between different types of particles or conditions. Human-scale scanners for imaging the brain and legs have recently been developed, and a clinically approved tracer (made of SPIONs; marks so scanners know where to look / what to measure) is now available in some regions.
Instrumentation Developments
MPI uses three key magnetic fields to detect and map SPIONs:
Drive Field (DF): fast; low-strength; it defines where the scanner pays attention
Selection Field (SF): static magnetic gradient; created by coils; makes the SPIONs wiggle which makes them more detectable
Focus Field (FF): slower; high-strength; moves or expands imaging region (field of view; FOV)
Two main encoding designs are used: field-free point (FFP) and field-free line (FFL) systems.
Field-Free Point (FFP) Systems: Scans point-by-point
Field-Free Line (FFL) Systems: Scans line-by-line
Hybrid Imaging Approaches
MPI doesnât show anatomical detail.
To overcome this, it's being combined with MRI, CT, and ultrasound technology.
For context:
Magnetic Resonance Imaging (MRI): Details soft tissue using strong magnets and radio waves
Computed Tomography (CT): Details bone and structure using X-rays
MRI and CT systems combining with MPI can merge functional and structural information.
Fiducial markers (markers that show up clearly in both systems) help line up images so everything matches.
Dual-use tracers (nanoparticles that can be seen by multiple imaging methods) also help align images.
MPI and ultrasound combinations are being studied for targeted thermal therapies (treatments where a specific area is heated up; ultrasounds would help focus sound waves and destroy tumors).
Magnetic Particle Spectroscopy (MPS)
Related to MPI
Works without a gradient field
Some are simpler and more flexible
Some are limited by power and size.
Algorithmic Developments
Two main approaches in MPI progress are:
1. System matrix-based reconstruction - describes how nanoparticles respond to magnetic fields.
Measured, providing accurate calibration of a specific scanner setup
Modeled, allowing more general use across different systems
2. X-space reconstruction - converts measured MPI signal into image space using FFP or FFL. Signal blurring can occur due to particle relaxation effects.
Field of View (FOV) and Stitching Techniques
FOV Patching or partial-FOV (pFOV) Reconstruction - Scanners move the FOV and then combine multiple FOVs into one image
SM-based reconstruction requires multiple system matrices (for multi-contrast).
X-space reconstruction has differences extracted from the signal characteristics (for multi-contrast).
MPIâs magnetic fields can be used to control and move magnetic objects. Specialized algorithms now enable precise movement using the selection field.
Nanoparticular Tracer System Developments
The unique nonlinear magnetic behavior of SPIONs is what makes MPI possible.
The structure and coating of SPIONs determine
The signal quality in MPI
How the particles circulate
How the particles clear in the body
SPIONs are removed by the reticuloendothelial system, leading to accumulation in the liver and spleen. However, their blood half-life is short.
To address this limitation, red blood cell-loaded SPIONs have been developed.
RBC-loaded SPIONs circulate much longer.
RBC-loaded SPIONs can monitor blood flow or brain perfusion.
SPIONs have also been explored for cell labeling, enabling the tracking of specific cells (tumor cells and mesenchymal stem cells have been tested).
SPIONs are often internalized by other cells.
Cells have a process called endocytosis, where they swallow particles.
SPIONs are small and compatible, and recognized as edible.
When SPIONs are internalized by cells, they can't interact with anything outside.
For targeted imaging, coated SPIONs are used. Coated SPIONs can bind to glioblastoma (brain tumor) cells, supporting both diagnostic imaging and targeted hyperthermia therapy.
Particle Design and Optimization
An early clinical tracer named Resovist had a much wider size distribution, with only about 3% of particles in the optimal range.
Resotran was reintroduced as a clinically approved tracer.
It performs well, but specialized preclinical tracers still provide better MPI signal quality.
Next-Generation Tracer Concepts
Superferromagnetic iron oxide nanoparticle chains (SFMIOs): provide 10x higher spatial resolution and signal-to-noise ratio.
Genetically engineered magnetosomes: biologically produced nanoparticles with improved magnetic properties.
SMART rhesins: microspheres filled with SPIONs for high-viscosity environments.
Application Developments
MPI is a new medical imaging technique with strong potential. It can capture images very quickly, making it useful for real-time imaging.
The first MPI experiment on a live animal showed a beating mouse heart. Unlike MRI, MPI doesnât need patients to hold their breath or use radiation. Itâs been tested for procedures like stent placement, angioplasty, and aneurysm treatments.
MPI signals directly reflect how many magnetic particles are there, allowing accurate measurement of blood vessels and blood flow. It has been used to study
Kidney function
Stroke
Internal bleeding
Changes in blood flow
Certain cells' changes over time
Researchers are also exploring MPI for cancer detection, locating lymph nodes in breast cancer or help surgeons find tumor edges.
Outlook and Clinical Perspective
With the arrival of human-scale scanners and clinically approved tracers, the first human MPI studies are within reach.
For MPI to become part of clinical practice, it must demonstrate clear clinical benefits and answer specific medical questions.
Regulatory approval and clinical validation must progress.
