Lifelong Impairment Research Articles

IL-1 Blockade Mitigates Autism and Cerebral Palsy Traits in Offspring In-Utero Exposed to Group B Streptococcus Chorioamnionitis.

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders.

Focal cortical dysplasia (type II) detection with multi-modal MRI and a deep-learning framework

Focal cortical dysplasia type II (FCD-II) is a prominent cortical development malformation associated with drug-resistant epileptic seizures that leads to lifelong cognitive impairment. Efficient MRI, followed by its analysis (e.g., cortical abnormality distinction, precise localization assistance, etc.) plays a crucial role in the diagnosis and supervision (e.g., presurgery planning and postoperative care) of FCD-II. Involving machine learning techniques particularly, deep-learning (DL) approaches, could enable more effective analysis techniques. We performed a comprehensive study by choosing six different well-known DL models, three image planes (axial, coronal, and sagittal) of two MRI modalities (T1w and FLAIR), demographic characteristics (age and sex) and clinical characteristics (brain hemisphere and lobes) to identify a suitable DL model for analysing FCD-II. The outcomes show that the DenseNet201 model is more suitable because of its superior classification accuracy, high-precision, F1-score, and large area under the receiver operating characteristic (ROC) curve and precision–recall (PR) curve.

Incidence, aetiology and short term outcomes of extreme hyperbilirubinaemia, in term infants born in the Western health subdistrict of Cape Town, South Africa between 2019 and 2020.

Extreme levels of bilirubin in newborn is a major cause of lifelong neurodevelopmental impairment, which places a financial burden on healthcare resources and caregivers. To determine the incidence, aetiology and short-term outcomes of extreme hyperbilirubinaemia in term infants born in a resource-limited setting. This is a retrospective observational study looking at term neonates with a birth weight ≥2500 g, born in the Western health subdistrict of Cape Town, South Africa, between 1 January 2019 and 31 December 2020, who were exposed to a serum bilirubin level of ≥430 μmol/L in the first week of life and received care in the public health system. Extreme hyperbilirubinaemia occurred in 59 term infants. The incidence was 74 cases per 100 000 (<0.01%) live births equating to 1 case in every 1345 live births. The cause of hyperbilirubinaemia was identified in 51 of the cases (86%), the most common being ABO incompatibility (31/51, 61%), followed by glucose-6-phosphate dehydrogenase deficiency (11/51, 22%). Twelve infants (20 %) underwent an exchange transfusion. Six infants were encephalopathic. Forty-seven infants (80%) were readmitted after initial post-natal discharge, with a mean age of readmission of 113 h old (SD 31 h). The incidence of extreme hyperbilirubinaemia in the Western health subdistrict of Cape Town is higher than in high-income settings. Further work should focus on training of healthcare workers and education of caregivers, for the early detection of significant hyperbilirubinaemia to prevent neurological complications caused by bilirubin toxicity.

Clinical Practice Guideline: The Treatment of Peripheral Nerve Injuries.

Nerve lesions often heal incompletely, leading to lifelong functional impairment and high costs for the health care system. The updated German clinical practice guideline is intended to promote the early recognition of nerve lesions and the timely initiation of proper treatment for optimal restoration of function. The recommendations are based on an assessment of all the evidence revealed by a systematic search of the literature, as well as on the expertise of the multiprofessional guideline group. Only a few publications contain high-quality evidence. This version of the guideline contains a more detailed discussion of war injuries, iatrogenic injuries, MR neurography, and specific treatments than the previous version. As for the different methods of nerve replacement, a comparison of autologous transplantation versus the use of conduits and tubes revealed no significant difference between these two methods on the mBMRC scale, and minimal superiority of autologous transplantation with respect to two-point discrimination. As for the use of nerve transfers when nerve reconstruction is not feasible or unlikely to succeed, nerve transfer yielded slightly better results than proximal reconstruction for elbow flexion, but the difference did not reach statistical significance (mBMRC ≥ 3: RR 1.16, 95% confidence interval [1.02; 1.32]). The treatment of neuromas with targeted muscle reinnervation was superior to the classic approach in decreasing both stump pain (MD 2.0 +/- 2.8) and phantom limb pain (MD 3.4 +/- 4.03). The delayed or improper treatment of peripheral nerve lesions can lead to severe impairment. Timely diagnosis, the use of appropriate treatments in conformity with the guidelines, and interdisciplinary collaboration among specialists are all essential for optimizing the outcome.

Cord blood transfusions in extremely low gestational age neonates to reduce severe retinopathy of prematurity: results of a prespecified interim analysis of the randomized BORN trial

BackgroundPreterm infants are at high risk for retinopathy of prematurity (ROP), with potential life-long visual impairment. Low fetal hemoglobin (HbF) levels predict ROP. It is unknown if preventing the HbF decrease also reduces ROP.MethodsBORN is an ongoing multicenter double-blinded randomized controlled trial investigating whether transfusing HbF-enriched cord blood-red blood cells (CB-RBCs) instead of adult donor-RBC units (A-RBCs) reduces the incidence of severe ROP (NCT05100212). Neonates born between 24 and 27 + 6 weeks of gestation are enrolled and randomized 1:1 to receive adult donor-RBCs (A-RBCs, arm A) or allogeneic CB-RBCs (arm B) from birth to the postmenstrual age (PMA) of 31 + 6 weeks. Primary outcome is the rate of severe ROP at 40 weeks of PMA or discharge, with a sample size of 146 patients. A prespecified interim analysis was scheduled after the first 58 patients were enrolled, with the main purpose to evaluate the safety of CB-RBC transfusions.ResultsResults in the intention-to-treat and per-protocol analysis are reported. Twenty-eight patients were in arm A and 30 in arm B. Overall, 104 A-RBC units and 49 CB-RBC units were transfused, with a high rate of protocol deviations. A total of 336 adverse events were recorded, with similar incidence and severity in the two arms. By per-protocol analysis, patients receiving A-RBCs or both RBC types experienced more adverse events than non-transfused patients or those transfused exclusively with CB-RBCs, and suffered from more severe forms of bradycardia, pulmonary hypertension, and hemodynamically significant patent ductus arteriosus. Serum potassium, lactate, and pH were similar after CB-RBCs or A-RBCs. Fourteen patients died and 44 were evaluated for ROP. Ten of them developed severe ROP, with no differences between arms. At per-protocol analysis each A-RBC transfusion carried a relative risk for severe ROP of 1.66 (95% CI 1.06–2.20) in comparison with CB-RBCs. The area under the curve of HbF suggested that HbF decrement before 30 weeks PMA is critical for severe ROP development. Subsequent CB-RBC transfusions do not lessen the ROP risk.ConclusionsThe interim analysis shows that CB-RBC transfusion strategy in preterm neonates is safe and, if early adopted, might protect them from severe ROP.Trial registrationProspectively registered at ClinicalTrials.gov on October 29, 2021. Identifier number NCT05100212.

Assessment of Gross Motor Skills in Ponseti-treated Children With Idiopathic Clubfoot at 3 Years Old: Insights from the Peabody Developmental Motor Scale 2.

Congenital talipes equinovarus, or clubfoot, can lead to lifelong functional impairments, including diminished gross motor skills (GMS), if left untreated. The Ponseti method corrects idiopathic clubfoot through casting and bracing. Given the importance of GMS in childhood development, this technique must be optimized to support childhood and long-term health outcomes. This study examined immediate posttreatment GMS in 3-year-old children treated with Ponseti, hypothesizing that they would perform on par with their nonclubfoot peers. Data from 45 children (33 to 46mo of age) treated for idiopathic clubfoot were analyzed. The Peabody Developmental Motor Scales, 2nd edition, was used to assess GMS, and logistic regression identified factors influencing Gross Motor Quotient (GMQ) scores. Approximately half (n=22) of the patients exhibited below-average GMS (11th to 25th percentile), with 11 scoring below the 10th percentile. Initial deformity severity, gender, and cast numbers did not impact GMQ. Repeat percutaneous tenotomy was associated with lower GMQs. Brace compliance significantly reduced odds of low GMQs by up to 80%. Age at testing and additional surgery were also linked to below-average and poor GMQs. GMS appeared to be impaired in almost half of the 3-year-old patients treated for idiopathic clubfoot, so our hypothesis was disproven. Repeat percutaneous tenotomy was associated with lower GMS, necessitating future recognition of patients who might be at risk of relapse. Brace noncompliance emerged as a significant risk factor, emphasizing early identification of these patients and education for their parents. This study offers a benchmark for clinicians and parents, but research on long-term outcomes is needed. Level II, prospective cohort study.

Study Protocol: Pegasus: psychotherapy incorporating horses for ‘therapy-resistant’ adolescents with autism spectrum disorders, a study with series of randomised, baseline controlled n-of-1 trials

BackgroundFor people with autism spectrum disorder (ASD), daily life can be highly stressful with many unpredictable events that can evoke emotion dysregulation (ED): a strong difficulty with appropriately negative affect regulation. For some of the patients with ASD, treatment as usual does not prove to be effective for ED. They may be at risk of life-long impairment, development of other disorders and loss of motivation for most regular forms of therapy. A highly promising method that may prove effective for therapy-resistant individuals with ASD is Psychotherapy incorporating horses (PIH). PIH uses the interactions of the horse and the patients on the ground and does not include horseriding. While often met with prejudgment and scepticism, reports from parents and therapists as well as a recent systematic review suggest that PIH may have beneficial effects on youths with ASD. Therefore, we examine clinical outcomes both in the short and in the long terms of PIH offered to adolescents with ASD and severe ED despite regular therapy.MethodsA total of 35 adolescents aged 11–18 years with ASD will receive PIH during 15 sessions once a week with randomization to five different groups differentiating in baseline phase from 2 to 6 weeks. PIH uses horses to promote social awareness and self-awareness as well as relationship management and self-management. The primary outcome is the response to treatment on the Emotion Dysregulation Index (EDI). The secondary outcome measures include ASD symptom severity, quality of life, self-esteem, global and family functioning, and goal attainment. Assessments take place at the baseline (T0), at the end of baseline phase A (T1), after completion of intervention phase B (T2), after the end of post-measurement phase C (T3) and after one year (T4). Qualitative interviews of participants, parents and therapists will be held to reveal facilitators and barriers of PIH and a cost-effectiveness study will be performed.DiscussionThis study aims at contributing to clinical practice for adolescents with ASD and persistent emotion regulation problems despite 1.5 year of treatment by offering Psychotherapy incorporating horses in a study with series of randomised, baseline controlled n-of-1 trials.Trial registrationwww.ClinicalTrials.gov NCT05200351, December 10th 2021.

Treatment, Education, and Prognosis of Slow Learners (Borderline Intelligence).

Borderline intelligence has been excluded from formal diagnostic systems and not included in disability diagnoses, leaving gaps in treatment, education, and social welfare despite various functional impairments. Therefore, we aimed to shed light on ways to enhance the intelligence and functioning of individuals with borderline intelligence by reviewing research on its progression, education, and treatment. Ten studies that met the inclusion and exclusion criteria were included in the final literature review and analyzed according to detailed topics (participant characteristics, design, and results). Borderline intelligence is associated with various comorbid conditions, such as anxiety, depression, attention deficit/hyperactivity disorder, and addictive disorders, which negatively impact its course and prognosis. Individuals with borderline intelligence often face challenges in academics, employment, interpersonal relationships, and health owing to lifelong cognitive impairments. The treatment of borderline intelligence necessitates addressing environmental factors, such as neglect and abuse, as well as treating comorbid mental disorders, which are crucial for prognosis. Tailoring treatment programs for cognitive profile characteristics have been proposed, and studies have reported the effectiveness of pharmacotherapy, working memory training, and intensive rehabilitation training. Therefore, early intervention during childhood brain development is necessary. Risk factors, such as lack of parental education, and their impact on treatment outcomes have also been reported. Extensive research is needed on education, treatment, and prognosis related to borderline intelligence. Active intervention for children with borderline intelligence is essential to improve their functioning and quality of life.

Intersection Control Evaluation for Highway Safety Analysis

Road traffic accidents take more lives than a combination of other accidents and natural disasters. An article published on September 9, 2023, in the Nepali Times, reported that between April 2022 and April 2023, a total of 2,320 individuals lost their lives, with 28,856 sustaining injuries, many resulting in lifelong impairment. Traffic studies have revealed that Intersection Control Evaluation (ICE) facilitates strategic decision-making through the use of factual information, data, and metrics. The primary objective of this research on intersection control evaluation is to explore how the screening process and the selection of alternative intersections in ICE contribute to the reduction of accidents at intersections. A focused examination of the literature assessing the methodology's effectiveness in maintaining intersection safety suggests that intersection control evaluation aids in strategy selection during expansion and signal usage at major intersections. Subsequent discussions utilized various spreadsheet tools and online forums. The findings indicate that ICE serves as an effective framework for screening intersection alternatives and identifying optimal solutions. Results show that tools such as 'Capacity Analysis for Planning of Junctions' (CAP-X) effectively evaluate intersection types. Additionally, 'Safety Performance of Intersection Control Evaluations' (SPICE) is employed for safety analysis at grade intersections. Cost analysis, based on results obtained from the Life Cycle Cost Estimation Tool (LCCET) spreadsheet, demonstrated the cost-effectiveness of this approach.In light of the results and discussions, intersection control evaluation should play a crucial role in implementing safer, more balanced, and cost-effective solutions at road intersections.

Decreasing Perioperative Opiate Use During Pancreaticoduodenectomy Using Transversus Abdominus Plane Blocks: A Review of the Literature.

Pancreatoduodenectomy is a highly complex surgical procedure associated with high postoperative morbidity and mortality. Treatment of postoperative pain is crucial to preventing chronic pain and further complications. Opioids are the leading treatment modality for acute postoperative pain for all surgical procedures in the US, contributing to the opioid epidemic, a crisis causing death and lifelong impairment in many patients. Multimodal analgesia techniques, such as the transversus abdominis plane (TAP) block, are suggested to reduce perioperative opioid usage. This exploratory literature review aims to investigate the use of TAP block in postoperative pain and opioid use in patients undergoing pancreatoduodenectomy. A search strategy developed from Cochrane best practice recommendations was applied to a comprehensive search of PubMed, Scopus, and PsycINFO databases, yielding three articles of relevance in patients having pancreatic surgery. Previous research demonstrates TAP block efficacy in decreasing opiate consumption after major abdominal surgery; however, there is a paucity of data regarding opioid consumption in pancreatoduodenectomy patients. Research in relation to TAP block analgesia is varied given the variety of approaches, techniques, and timing of the TAP block procedure. Future research should seek to elucidate the role of TAP blocks in reducing postoperative pain and opioid consumption in pancreatoduodenectomy patients.

Drowning and Nonfatal Drowning in Children and Adolescents: A Subsequent Retrospective Data Analysis.

Fatal and nonfatal drowning are among the leading causes of death and lifelong severe neurological impairment among children and adolescents. This study aimed to complement research from Leipzig 1994-2008 to seek trends within risk factors, treatments, and outcomes throughout the last decade. We retrospectively investigated data of 47 inpatients aged 0-18 admitted to Leipzig University Department of Pediatrics who matched ICD-10 code T75.1 from 2008 to 2020 and compared them to a preceding study at the same institution. We also examined the prognostic value of parameters regarding the patients' outcomes. There were three median incidents per annum. The median age was 2.75 years; 76% of incidents happened in males. An accumulation was seen during the summer months and weekends. Most drowning incidents occurred in private ponds or pools (48.9%). Thirty-nine children were discharged without resulting morbidity, four showed neurological impairment, and three died. Risk factors concerning age, sex, and incident characteristics were confirmed. Special supervision needs still apply to 1-3-year-old male children or children with pre-existing health conditions around private pools and ponds. Hospitalization duration shortened, and morbidity and lethality decreased since the previous study. There was structural improvement in primary care and medical documentation. Parameters suggesting good outcomes include a submersion time < 5 min, GCS > 3 points, spontaneous movement upon admission, remaining pupillary light response, the absence of cardiovascular arrest, body temperature ≥ 32 °C, pH > 7, blood glucose < 15 mmol/L, lactate < 14 mmol/L, base excess ≥ -15 mmol/L, and the absence of ARDS. Clear legislation can contribute to improved private home water safety. Further studies should include a broad in- and outpatient spectrum and standardized incident documentation presupposing Utstein-style reporting. Regular reinvestigation of consistent geographical regions facilitates process evaluations of drowning epidemiology and therapy evolution.

Yoga in Stress Alleviation: a Therapeutic and Psychodynamic Approach

Yoga has been an increasing topic of interest over the past few years. Alleviation of stress, which is the main purpose of yoga, can be interpreted from different contexts based on one’s level of contemplation and basis of understanding. Today, it is effectively prescribed and implemented as an alternate to medicine therapy. Based on the acute beneficial effects that yoga ought to enjoy, it is often considered by chiropractors, physiotherapists, clinicians as an integral constituent of their medical treatment. Yogasanas and exercise postures in inclusion to pranayama, are widely adopted today as remediations for various symptoms, which if left derelicted, can manifest to life-long impairments. The therapeutic standpoint of Yoga mainly lays stress on the clinical implications and practicality of yoga today. On the contrary, the psychodynamic approach mainly emphasizes on the behavioral regulations and apprehensions of their general mechanisms. The review primarily depicts the portrayal of Yoga from times of its inception, modern day understanding of yoga from the global perspectives, and its relationship with stress. The ultimate objective of this review is to enumerate the impacts of yoga from both the therapeutic and psychodynamic standpoints thereby justifying the validity of yoga as a patent restorer of physiological homeostasis.

The Impact of Oxidative Stress on the Epigenetics of Fetal Alcohol Spectrum Disorders.

Fetal alcohol spectrum disorders (FASD) represent a continuum of lifelong impairments resulting from prenatal exposure to alcohol, with significant global impact. The "spectrum" of disorders includes a continuum of physical, cognitive, behavioral, and developmental impairments which can have profound and lasting effects on individuals throughout their lives, impacting their health, social interactions, psychological well-being, and every aspect of their lives. This narrative paper explores the intricate relationship between oxidative stress and epigenetics in FASD pathogenesis and its therapeutic implications. Oxidative stress, induced by alcohol metabolism, disrupts cellular components, particularly in the vulnerable fetal brain, leading to aberrant development. Furthermore, oxidative stress is implicated in epigenetic changes, including alterations in DNA methylation, histone modifications, and microRNA expression, which influence gene regulation in FASD patients. Moreover, mitochondrial dysfunction and neuroinflammation contribute to epigenetic changes associated with FASD. Understanding these mechanisms holds promise for targeted therapeutic interventions. This includes antioxidant supplementation and lifestyle modifications to mitigate FASD-related impairments. While preclinical studies show promise, further clinical trials are needed to validate these interventions' efficacy in improving clinical outcomes for individuals affected by FASD. This comprehensive understanding of the role of oxidative stress in epigenetics in FASD underscores the importance of multidisciplinary approaches for diagnosis, management, and prevention strategies. Continued research in this field is crucial for advancing our knowledge and developing effective interventions to address this significant public health concern.

Subventricular zone stem cell niche injury is associated with intestinal perforation in preterm infants and predicts future motor impairment

Brain injury is highly associated with preterm birth. Complications of prematurity, including spontaneous or necrotizing enterocolitis (NEC)-associated intestinal perforations, are linked to lifelong neurologic impairment, yet the mechanisms are poorly understood. Early diagnosis of preterm brain injuries remains a significant challenge. Here, we identified subventricular zone echogenicity (SVE) on cranial ultrasound in preterm infants following intestinal perforations. The development of SVE was significantly associated with motor impairment at 2 years. SVE was replicated in a neonatal mouse model of intestinal perforation. Examination of the murine echogenic subventricular zone (SVZ) revealed NLRP3-inflammasome assembly in multiciliated FoxJ1+ ependymal cells and a loss of the ependymal border in this postnatal stem cell niche. These data suggest a mechanism of preterm brain injury localized to the SVZ that has not been adequately considered. Ultrasound detection of SVE may serve as an early biomarker for neurodevelopmental impairment after inflammatory disease in preterm infants.

The potential role of artificial intelligence in the clinical management of Hansen's disease (leprosy).

Missed and delayed diagnoses of Hansen's disease (HD) are making the battle against it even more complex, increasing its transmission and significantly impacting those affected and their families. This strains public health systems and raises the risk of lifelong impairments and disabilities. Worryingly, the three countries most affected by HD witnessed a growth in new cases in 2022, jeopardizing the World Health Organization's targets to interrupt transmission. Artificial intelligence (AI) can help address these challenges by offering the potential for rapid case detection, customized treatment, and solutions for accessibility challenges-especially in regions with a shortage of trained healthcare professionals. This perspective article explores how AI can significantly impact the clinical management of HD, focusing on therapeutic strategies. AI can help classify cases, ensure multidrug therapy compliance, monitor geographical treatment coverage, and detect adverse drug reactions and antimicrobial resistance. In addition, AI can assist in the early detection of nerve damage, which aids in disability prevention and planning rehabilitation. Incorporating AI into mental health counseling is also a promising contribution to combating the stigma associated with HD. By revolutionizing therapeutic approaches, AI offers a holistic solution to reduce the burden of HD and improve patient outcomes.

A Single Case Study in Management of Pakshaghat with Ayurveda

In the Sharira, Vata is seen as the controller of all things. Vatavyadhi is the term for the influence of vitiated vata on the Dusyas, which permeate the whole body or a portion of it and give rise to various sorts of illness. One of the significant illnesses that fits this description is pakshaghata, also referred to as hemiplegia. One Vataj Nanatmaja Vyadhi who is regarded as a Mahavatavyadhi is Pakshaghata. There is a correlation between pakshaghata and hemiplegia, a condition caused by a cerebrovascular accident or stroke. Hemiplegia, which results in both mental and physical instability. In the world’s population, there are around 9 instances per 1000 people. A stroke is described as an abrupt onset of vascular mechanism-related neurologic impairment. 15% are initial hemorrhages, and 85% are ischemic. The World Health Organization estimates that 15 million stroke victims globally experience a stroke each year, of whom 5 million die and another 5 million become permanently incapacitated. According to current scientific theory, brain injuries that are too severe for treatment to reverse can result in lifelong neurological impairment. As a result, the prognosis for the illness is dismal, leaving the crippled individual dependent. The current research aims to provide baseline data for student physicians to cope with this terrible condition by identifying the etiopathogenesis, clinical aspects, and therapy of the disease from Ayurvedic classics.

Speculum-free portable preterm imaging system.

Preterm birth is defined as a birth before 37 weeks of gestation and is one of the leading contributors to infant mortality rates globally. Premature birth can lead to life-long developmental impairment for the child. Unfortunately, there is a significant lack of tools to diagnose preterm birth risk, which limits patient care and the development of new therapies. To develop a speculum-free, portable preterm imaging system (PPRIM) for cervical imaging; testing of the PPRIM system to resolve polarization properties of birefringent samples; and testing of the PPRIM under an IRB on healthy, non-pregnant volunteers for visualization and polarization analysis of cervical images. The PPRIM can perform Mueller-matrix imaging to characterize the remodeling of the uterine cervix during pregnancy. The PPRIM is built with a polarized imaging probe and a flexible insertable sheath made with a compatible flexible rubber-like material to maximize comfort and ease of use. The PPRIM device is developed to meet specific design specifications as a speculum-free, portable, and comfortable imaging system with polarized imaging capabilities. This system comprises a main imaging component and a flexible silicone inserter. The inserter is designed to maximize comfort and usability for the patient. The PPRIM shows high-resolution imaging capabilities at the 20mm working distance and 25mm circular field of view. The PPRIM demonstrates the ability to resolve birefringent sample orientation and full field capture of a healthy, non-pregnant cervix. The development of the PPRIM aims to improve access to the standard of care for women's reproductive health using polarized Mueller-matrix imaging of the cervix and reduce infant and maternal mortality rates and better quality of life.

Genetic Vulnerability to Social Anxiety Disorder.

Most anxiety disorders 'run within families': people suffering from an anxiety disorder often have family members who are highly anxious as well. In this chapter, we explore recent work devoted to unraveling the complex interplay between genes and environment in the development of anxiety. We review studies focusing on the genetic vulnerability to develop social anxiety disorder (SAD), as SAD is one of the most prevalent anxiety disorders, with an early onset, a chronic course, and associated with significant life-long impairments. More insight into the development of SAD is thus of uttermost importance.First, we will discuss family studies, twin studies, and large-sized population-based registry studies and explain what these studies can reveal about the genetic vulnerability to develop anxiety. Next, we describe the endophenotype approach; in this context, we will summarize results from the Leiden Family Lab study on Social Anxiety Disorder. Subsequently, we review the relationship between the heritable trait 'behavioral inhibition' and the development of SAD, and highlight the relevance of this work for the development and improvement of preventative and therapeutic interventions for socially anxious youth.

Identifying Pregnancies at Higher Risk for HPA-1a Alloimmunization and Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT): An International, Prospective, Natural History Study

Background and significance Fetal and neonatal alloimmune thrombocytopenia (FNAIT) results from parental incompatibility of human platelet antigen (HPA) and subsequent maternal sensitization. When this occurs, fetal platelet production is impaired and platelet destruction accelerated. FNAIT is the platelet counterpart of Rhesus disease (RhD); however, FNAIT is rarer, more often occurs in first pregnancies, and alloimmunization may be detected as early as the 2nd trimester. Clinical presentation of FNAIT ranges from no/mild symptoms to severe thrombocytopenia and intracranial hemorrhage, which can take place in the second trimester and cause death or lifelong neurological impairment. Severe FNAIT outcomes impose substantial emotional and financial burden on affected families and healthcare systems. Among pregnant HPA-1a-negative women bearing an HPA-1a-positive fetus at risk of alloimmunization, ~27% carry the HLA-DRB3*01:01 gene variant, increasing sensitization risk ~25 fold and thus leading to much higher FNAIT risk. Screening for FNAIT in pregnancy is not routinely performed, unlike in RhD, resulting in failure to identify at-risk pregnancies prior to birth. To prevent severe FNAIT outcomes, we believe at-risk pregnancies must be identified very early in the second trimester, and prophylactic interventions started immediately. Current management of women with existing alloimmunization due to a prior FNAIT-affected pregnancy involves months of weekly antenatal intravenous immunoglobulin with or without steroid administration. Although fetal platelet counts often improve, this therapy is very burdensome to patients. Most data on FNAIT prevalence and risk are from Caucasian populations; studies in non-Caucasian populations have been too small to be informative. This is the first epidemiological study that seeks to identify HPA-1a-based FNAIT in a racially and ethnically diverse international population of pregnant women. Data to be tracked are: frequency of DRB3*0101 in HPA-1bb women; anti-HPA-1a alloimmunization; pregnancy outcomes; and neonatal thrombocytopenia. These data will provide a contemporary control population preceding future single-arm studies of a novel human anti-HPA-1a monoclonal antibody, RLYB212, in prophylaxis of maternal HPA-1a alloimmunization and FNAIT. The virtual elimination of RhD by screening of all pregnancies and administration of prophylaxis in at-risk cases remains one of the most significant medical advances ever achieved and provides a roadmap for FNAIT. Study design and methods Prospective, non-interventional, natural-history study assessing HPA-1a alloimmunization in pregnant women, conducted across multiple European centers in Norway, Netherlands, UK, and Germany, and in the USA. It will provide insights into anti-HPA-1a-mediated FNAIT risk and frequency among Caucasian and non-Caucasian pregnant women. Up to 30,000 women will be screened at gestational weeks 10-14 to enable early identification and follow-up of those women at higher alloimmunization risk, so that in the future, prophylaxis of the higher-risk women could be initiated. Informed consent will be requested for blood-sample collection at the 10-14 week visit for evaluation of FNAIT risk. Inclusion criteria Pregnant women aged ≥18 years Exclusion criteria Prior history of FNAIT or known HPA-1a alloimmunization Statistical methods Demographic, baseline characteristics and discrete variables will be summarized Primary objective To inform frequency of higher FNAIT risk among pregnant women of diverse racial and ethnic characteristics (all comers). (Figure) Secondary objectives Frequency of HPA-1a maternal alloimmunization at Weeks 10-14 postpartum in pregnant women at higher FNAIT risk and outcomes such as: - Spontaneous abortion: non-deliberate fetal death prior to 19 weeks of gestation - Elective abortion: deliberate termination of pregnancy at any time in gestation - Stillbirth: non-deliberate fetal death after 19 weeks of gestation - Premature birth: live birth prior to 37 completed weeks of gestation - Live births: ≥37 completed weeks of gestation Neonatal and severe neonatal thrombocytopenia: platelet count &amp;lt;150 × 10 9/L and &amp;lt;50 × 10 9/L, respectively, within 72 hours of birth Current status Enrolment for clinical-trial NCT05345561 is ongoing and expected to continue for ~3 years.

Single-fraction Radiation Treatment Dose Response in a Genetically Engineered Mouse Model of Medulloblastoma.

Medulloblastoma is the most common malignant brain tumor of children. Although standard of care radiotherapy for pediatric medulloblastoma (PM) can lead to long-term remission or cure in many patients, it can also cause life-long cognitive impairment and other adverse effects. The pathophysiological mechanisms involved in radiation-induced cerebral damage are incompletely understood, and their elucidation may lead to interventions that mitigate radiation toxicity. To explore the mechanisms of radiation-induced cerebral damage, transgenic mouse models of PM and non-tumor-bearing controls were exposed to radiation doses that ranged from 0 to 30 Gy. Between 0-20 Gy, a significant dose-dependent reduction in tumor-associated hydrocephalus and increase in overall survival were observed. However, at 30 Gy, hydrocephalus incidence increased and median overall survival fell to near-untreated levels. Immunohistochemistry revealed that both tumor-bearing and non-tumor-bearing mice treated with 30 Gy of radiation had significantly more reactive astrocytes and microvascular damage compared to untreated controls. This effect was persistent across mice that were given 1 and 2 weeks of recovery time after irradiation. Our data suggest that radiation therapy promotes neural death by inducing long-term neuroinflammation in PM, suggesting radiation delivery methods that limit inflammation may be effective at widening the therapeutic window of radiation therapy in PM patients.