Genetic Conditions Research Articles

Non-invasive prenatal screening: Testing motivations and decision making in the low-risk population.

Non-invasive prenatal screening provides a risk assessment for aneuploidies by utilizing cell-free DNA (cfDNA). It is recommended that cell-free DNA screening (cfDNA screening) be offered to all pregnant people regardless of a priori risk for aneuploidy. In the absence of an increased risk, alternative motives for electing cfDNA screening and different levels of informed decision making may arise. Therefore, our study aimed to characterize low-risk patients' motivations for cfDNA screening election, determine how often informed decisions are being made, and compare motivations between informed and uninformed decision makers. A survey that included a modified, validated measure of informed choice (MMIC) and questions to assess patients' motivations for cfDNA screening was offered at four MFM clinics following genetic counseling. It was found that 44% of participants (n = 100) made an uninformed decision about testing. Participants with private insurers were 4.25 times more likely to make an informed decision (95% CI = 1.10-16.37). Informed decision makers scored avoiding invasive procedures higher (p = 0.007) and ranked doing what family/friends desire lower (p = 0.005) than uninformed decision makers. While most participants scored receiving information about genetic conditions highest, 12% of participants reported fetal sex disclosure as a priority. However, this was not found to be associated with uninformed decision making. This study ultimately established that following genetic counseling, a low-risk population shared motivations with high-risk populations which highlights the importance of complete pre-test counseling for all. Future research should investigate the effect of modifying variables, such as socioeconomic status, on the performance of informed choice measures and critically evaluate the parameters that determine informed choice.

Influence of Polygenic Background on the Clinical Presentation of Familial Hypercholesterolemia.

Heterozygous familial hypercholesterolemia (FH) is among the most common genetic conditions worldwide that affects ≈ 1 in 300 individuals. FH is characterized by increased levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of coronary artery disease (CAD), but there is a wide spectrum of severity within the FH population. This variability in expression is incompletely explained by known risk factors. We hypothesized that genome-wide genetic influences, as represented by polygenic risk scores (PRSs) for cardiometabolic traits, would influence the phenotypic severity of FH. We studied individuals with clinically diagnosed FH (n=1123) from the FH Canada National Registry, as well as individuals with genetically identified FH from the UK Biobank (n=723). For all individuals, we used genome-wide gene array data to calculate PRSs for CAD, LDL-C, lipoprotein(a), and other cardiometabolic traits. We compared the distribution of PRSs in individuals with clinically diagnosed FH, genetically diagnosed FH, and non-FH controls and examined the association of the PRSs with the risk of atherosclerotic cardiovascular disease. Individuals with clinically diagnosed FH had higher levels of LDL-C, and the incidence of atherosclerotic cardiovascular disease was higher in individuals with clinically diagnosed compared with genetically identified FH. Individuals with clinically diagnosed FH displayed enrichment for higher PRSs for CAD, LDL-C, and lipoprotein(a) but not for other cardiometabolic risk factors. The CAD PRS was associated with a risk of atherosclerotic cardiovascular disease among individuals with an FH-causing genetic variant. Genetic background, as expressed by genome-wide PRSs for CAD, LDL-C, and lipoprotein(a), influences the phenotypic severity of FH, expanding our understanding of the determinants that contribute to the variable expressivity of FH. A PRS for CAD may aid in risk prediction among individuals with FH.

#1905 Sex differences in primary distal renal tubular acidosis: a single-centre retrospective study

Abstract Background and Aims The kidney has been described as one of the most estrogen-responsive organs after reproductive ones. Many non-X-linked renal diseases present with sex differences. Although not completely elucidated, an influence of estrogens has been described in several transporters along the renal tubule such as the Na+/phosphate cotransporter (NaPi-IIa) in the proximal tubule, the Na+/K+/2Cl⁻ cotransporter (NKCC) in the thick ascending limb of the loop of Henle, the thiazide-sensitive Na+/Cl⁻ cotransporter (NCC) in the distal convoluted tubule and the epithelial sodium channel (ENaC) expressed by the principal cells of the collecting duct. Our study aimed to investigate possible phenotypic sex differences over the natural history of primary distal renal tubular acidosis (dRTA), a rare genetic condition characterized by impaired urinary acidification in the collecting duct that results in non-anion gap metabolic acidosis, hypokalemia, hypercalciuria, nephrolithiasis and nephrocalcinosis, which can lead to chronic kidney disease (CKD). Method We included a cohort of 31 genetically confirmed dRTA patients (19 women and 12 men) followed at the London Tubular Centre. We retrospectively collected data from 2012 to 2023. Estimated glomerular filtration rate (eGFR) was calculated with the CKD-EPIcr formula. Hypokalemia was defined as serum potassium < 3.5 mmol/L, hypercalciuria was defined as urinary calcium/creatinine (uCa/Cr) > 0.7 mmol/mmol and acidosis was defined as HCO3− ≤ 22 mmol/L. Data were analyzed using non-parametric Mann-Whitney as appropriate (Prism GraphPad 8.0.2). A p value < 0.05 was considered as statistically significant. Results Baseline characteristics and prevalence of different mutations are shown in Table 1. At baseline, both cohorts were young, with preserved kidney function. 60% of women were acidotic compared to 50% of men, and 30% of men were hypokalemic compared to 8% of women. The majority of patients in both cohorts presented with overt hypercalciuria (60% of women vs 90% of men). Prevalence of nephrolithiasis and nephrocalcinosis was similar among women and men. At baseline, no statistically significant difference between sexes was found for serum or urinary parameters. Interestingly, men exhibited a tendency towards higher annual mean slope of eGFR (−3.3 ± 2.5 mL/min/1.73 m2) compared to women (−0.5 ± 1.5 mL/min/1.73 m2) in a statistically significant fashion (Fig. 1a). Although not statically significant, we noticed a tendency towards higher fractional excretion of phosphate (FEPO4) (Fig. 1b) and dyslipidemia in men (Fig. 1c). There was no difference in PTH between the two groups (Fig. 1c). Conclusion Men affected by primary dRTA are at increased risk of CKD progression, tend to have a more severe phenotype at baseline and appear to be more dyslipidemic than women. This is consistent with findings in the literature that report accelerated CKD progression and higher cardiovascular morbidity and mortality in men. To our knowledge, this is the first study reporting sex differences in primary dRTA.

Sudden Cardiac Death, Post-Mortem Investigation: A Proposing Panel of First Line and Second Line Genetic Tests.

Investigating the causes of Sudden cardiac death (SCD) is always difficult; in fact, genetic cardiac conditions associated with SCD could be "silent" even during autopsy investigation. In these cases, it is important to exclude other aetiology and assist to ask for genetic investigations. Herein, the purpose of this review is to collect the most-implicated genes in SCD and generate a panel with indications for first line and second line investigations. A systematic review of genetic disorders that may cause SCD in the general population was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We subsequently listed the genes that may be tested in the case of sudden cardiac death when the autopsy results are negative or with no evidence of acquired cardiac conditions. To make genetic tests more specific and efficient, it is useful and demanded to corroborate autopsy findings with the molecular investigation as evident in the panel proposed. The genes for first line investigations are HCM, MYBPC3, MYH7, TNNT2, TNNI3, while in case of DCM, the most implicated genes are LMNA and TTN, and in second line for these CDM, ACTN2, TPM1, C1QPB could be investigated. In cases of ACM/ARVC, the molecular investigation includes DSP, DSG2, DSC2, RYR2, PKP2. The channelopathies are associated with the following genes: SCN5A, KCNQ1, KCNH2, KCNE1, RYR2. Our work underlines the importance of genetic tests in forensic medicine and clinical pathology; moreover, it could be helpful not only to assist the pathologists to reach a diagnosis, but also to prevent other cases of SCD in the family of the descendant and to standardise the type of analysis performed in similar cases worldwide.

From Atherosclerosis to Spontaneous Coronary Artery Dissection: Defining a Clinical and Genetic Risk Spectrum for Myocardial Infarction.

Spontaneous coronary artery dissection (SCAD) has been increasingly recognized as a significant cause of acute myocardial infarction (AMI) in young and middle-aged women and arises through mechanisms independent of atherosclerosis. SCAD has a multifactorial etiology that includes environmental, individual, and genetic factors distinct from those typically associated with coronary artery disease. Here, we summarize the current understanding of the genetic factors contributing to the development of SCAD and highlight those factors which differentiate SCAD from atherosclerotic coronary artery disease. Recent studies have revealed several associated variants with varying effect sizes for SCAD, giving rise to a complex genetic architecture. Associated genes highlight an important role for arterial cells and their extracellular matrix in the pathogenesis of SCAD, as well as notable genetic overlap between SCAD and other systemic arteriopathies such as fibromuscular dysplasia and vascular connective tissue diseases. Further investigation of individual variants (including in the associated gene PHACTR1) along with polygenic score analysis have demonstrated an inverse genetic relationship between SCAD and atherosclerosis as distinct causes of AMI. SCAD represents an increasingly recognized cause of AMI with opposing clinical and genetic risk factors from that of AMI due to atherosclerosis, and it is often associated with complex underlying genetic conditions. Genetic study of SCAD on a larger scale and with more diverse cohorts will not only further our evolving understanding of a newly defined genetic spectrum for AMI, but it will also inform the clinical utility of integrating genetic testing in AMI prevention and management moving forward.

Fibroblasts’ secretome from calcified and non-calcified dermis in Pseudoxanthoma elasticum differently contributes to elastin calcification

Pseudoxanthoma elasticum (PXE) is a rare disease characterized by ectopic calcification, however, despite the widely spread effect of pro/anti-calcifying systemic factors associated with this genetic metabolic condition, it is not known why elastic fibers in the same patient are mainly fragmented or highly mineralized in clinically unaffected (CUS) and affected (CAS) skin, respectively. Cellular morphology and secretome are investigated in vitro in CUS and CAS fibroblasts. Here we show that, compared to CUS, CAS fibroblasts exhibit: a) differently distributed and organized focal adhesions and stress fibers; b) modified cell-matrix interactions (i.e., collagen gel retraction); c) imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases; d) differentially expressed pro- and anti-calcifying proteoglycans and elastic-fibers associated glycoproteins. These data emphasize that in the development of pathologic mineral deposition fibroblasts play an active role altering the stability of elastic fibers and of the extracellular matrix milieu creating a local microenvironment guiding the level of matrix remodeling at an extent that may lead to degradation (in CUS) or to degradation and calcification (in CAS) of the elastic component. In conclusion, this study contributes to a better understanding of the mechanisms of the mineral deposition that can be also associated with several inherited or age-related diseases (e.g., diabetes, atherosclerosis, chronic kidney diseases).

Ranking genotype, environment, management effects on the optimum nitrogen rate for maize: A cropping system modeling analysis

AbstractRanking the contribution of genotype, environment, and management (G × E × M) on maize's economic optimum nitrogen fertilizer rate (EONR) variability could improve understanding and predictability of EONR. We performed a simulation experiment using the Agricultural Production Systems sIMulator model with the objectives to (1) rank the effects of 24 individual G × E × M factors on the magnitude and interannual variability of the EONR across the US Midwest and (2) investigate the impact of G × M factors on the EONR variability under present and future climate scenarios. Results indicate that genetics (27%), management (31%), and environmental conditions (41%) each influence the EONR variability. Within these broad categories, the top three individual factors impacting the EONR were interannual weather variability, crop radiation use efficiency, and the soil inorganic N carryover from the previous year. The G × E × M factors influenced the yield response to N fertilizer in different ways. Soil‐related factors (e.g., organic matter and residual nitrate) influenced grain yields at the low N rates, while management factors (e.g., planting date and density) influenced yield at all N rates. Combining increases in plant density and changes in genetics synergistically increased the EONR by 15% from baseline. Future climate scenarios without adaptation decreased the EONR and yield loss, but crop adaptation was buffered against the negative climate change impacts. We concluded that 59% of the annual EONR variability is manageable (due to genetics and management) and that G × M factors could buffer climate change's negative effects on crop production. Present results can inform experimental research on N fertilizer and N rate decisions.

Longitudinal adaptive behavioral outcomes in Ogden syndrome by seizure status and therapeutic intervention.

Ogden syndrome, also known as NAA10-related neurodevelopmental syndrome, is a rare genetic condition associated with pathogenic variants in the NAA10 N-terminal acetylation family of proteins. The condition was initially described in 2011 and is characterized by a range of neurologic symptoms, including intellectual disability and seizures, as well as developmental delays, psychiatric symptoms, congenital heart abnormalities, hypotonia, and others. Previously published articles have described the etiology and phenotype of Ogden syndrome, mostly with retrospective analyses; herein, we report prospective data concerning its progress over time. The current study involves a total of 58 distinct participants; of these, 43 caregivers were interviewed using the Vineland-3 and answered a survey regarding therapy and other questions, 10 of whom completed the Vineland-3 but did not answer the survey, and 5 participants who answered the survey but have not yet performed the Vineland-3 due to language constraints. The average age at the time of the most recent assessment was 12.4 years, with individuals ranging in age from 11 months to 40.2 years. Using Vineland-3 scores, we show decline in cognitive function over time in individuals with Ogden syndrome (n = 53). Sub-domain analysis found the decline to be present across all modalities. In addition, we describe the nature of seizures in this condition in greater detail, as well as investigate how already-available non-pharmaceutical therapies impact individuals with NAA10-related neurodevelopmental syndrome. Additional investigation between seizure and non-seizure groups showed no significant difference in adaptive behavior outcomes. A therapy investigation showed speech therapy to be the most commonly used therapy by individuals with NAA10-related neurodevelopmental syndrome, followed by occupational and physical therapy, with more severely affected individuals receiving more types of therapy than their less-severe counterparts. Early intervention analysis was only significantly effective for speech therapy, with analyses of all other therapies being non-significant. Our study portrays the decline in cognitive function over time of individuals within our cohort, independent of seizure status, and therapies being received, and highlights the urgent need for the development of effective treatments for Ogden syndrome.

Newborn Screening for Li-Fraumeni Syndrome: Patient Perspectives.

Li-Fraumeni syndrome (LFS) is an inherited cancer predisposition syndrome with an estimated prevalence of 1 in 3,000-5,000 individuals. LFS poses a significant cancer risk throughout the lifespan, with notable cancer susceptibility in childhood. Despite being predominantly inherited, up to 20% of cases arise de novo. Surveillance protocols facilitate the reduction of mortality and morbidity through early cancer detection. While newborn screening (NBS) has proven effective in identifying newborns with rare genetic conditions, even those occurring as rarely as 1 in 185,000, its potential for detecting inherited cancer predispositions remains largely unexplored. This survey-based study investigates perspectives toward NBS for LFS among individuals with and parents of children with LFS receiving care at single comprehensive cancer center in the U.S. All participants unanimously supported NBS for LFS (n = 24). Reasons included empowerment (83.3%), control (66.7%), and peace of mind (54.2%), albeit with concerns about anxiety (62.5%) and devastation (50%) related to receiving positive results. Participants endorsed NBS as beneficial for cancer detection and prevention (91.7%), research efforts (87.5%), and family planning (79.2%) but voiced apprehensions about the financial cost of cancer surveillance (62.5%), emotional burdens (62.5%), and insurance coverage and discrimination (54.2%). Approximately 83% of respondents believed that parental consent should be required to screen newborns for LFS. This study revealed strong support for NBS for LFS despite the recognition of various perceived benefits and risks. These findings underscore the complex interplay between clinical, psychosocial, and ethical factors in considering NBS for LFS from the perspective of the LFS community.

Can Hemorrhagic Stroke Genetics Help Forensic Diagnosis in Pediatric Age (

When stroke occurs in pediatric age, it might be mistakenly interpreted as non-accidental head injury (NAHI). In these situations, a multidisciplinary approach is fundamental, including a thorough personal and familial history, along with accurate physical examination and additional investigations. Especially when the clinical picture is uncertain, it is important to remember that certain genetic conditions can cause bleeding inside the brain, which may resemble NAHI. Pediatric strokes occurring around the time of birth can also be an initial sign of undiagnosed genetic disorders. Hence, it is crucial to conduct a thorough evaluation, including genetic testing, when there is a suspicion of NAHI but the symptoms are unclear. In these cases, a characteristic set of symptoms is often observed. This study aims to summarize some of the genetic causes of hemorrhagic stroke in the pediatric population, thus mimicking non-accidental head injury, considering elements that can be useful in characterizing pathologies. A systematic review of genetic disorders that may cause ICH in children was carried out according to the Preferred Reporting Item for Systematic Review (PRISMA) standards. We selected 10 articles regarding the main genetic diseases in stroke; we additionally selected 11 papers concerning patients with pediatric stroke and genetic diseases, or studies outlining the characteristics of stroke in these patients. The disorders we identified were Moyamoya disease (MMD), COL4A1, COL4A2 pathogenic variant, Ehlers-Danlos syndrome (E-D), neurofibromatosis type 1 (Nf1), sickle cell disease (SCD), cerebral cavernous malformations (CCM), hereditary hemorrhagic telangiectasia (HHT) and Marfan syndrome. In conclusion, this paper provides a comprehensive overview of the genetic disorders that could be tested in children when there is a suspicion of NAHI but an unclear picture.

Chimeric Cell Therapies as a Novel Approach for Duchenne Muscular Dystrophy (DMD) and Muscle Regeneration.

Chimerism-based strategies represent a pioneering concept which has led to groundbreaking advancements in regenerative medicine and transplantation. This new approach offers therapeutic potential for the treatment of various diseases, including inherited disorders. The ongoing studies on chimeric cells prompted the development of Dystrophin-Expressing Chimeric (DEC) cells which were introduced as a potential therapy for Duchenne Muscular Dystrophy (DMD). DMD is a genetic condition that leads to premature death in adolescent boys and remains incurable with current methods. DEC therapy, created via the fusion of human myoblasts derived from normal and DMD-affected donors, has proven to be safe and efficacious when tested in experimental models of DMD after systemic-intraosseous administration. These studies confirmed increased dystrophin expression, which correlated with functional and morphological improvements in DMD-affected muscles, including cardiac, respiratory, and skeletal muscles. Furthermore, the application of DEC therapy in a clinical study confirmed its long-term safety and efficacy in DMD patients. This review summarizes the development of chimeric cell technology tested in preclinical models and clinical studies, highlighting the potential of DEC therapy in muscle regeneration and repair, and introduces chimeric cell-based therapies as a promising, novel approach for muscle regeneration and the treatment of DMD and other neuromuscular disorders.

The effect of fixation type on periprosthetic fractures in high-risk patients who have osteoporosis undergoing total joint arthroplasty

IntroductionMinimizing the burden of periprosthetic fractures (PFF) following total joint arthroplasty (TJA) with regard to morbidity and mortality remains an outcome of interest. Patient and surgical risk factors, including osteoporosis and fixation type, have not truly been optimized in patients undergoing TJA as a means to reduce the risk of PFF. As such, we examined: (1) What percentage of patients who underwent THA and total knee arthroplasty (TKA) met the criteria for osteoporosis screening? (2) How did the 5-year rate of PFF and fragility fracture differ in the high-risk and low-risk groups for osteoporosis between the cemented and cementless cohorts? (3) What percentage of the aforementioned patients received a dual x-ray absorptiometry (DEXA) scan before THA or TKA? MethodsWe queried an all-payer, national database from April 1, 2016 to December 31, 2021, to identify high-risk and low-risk patients who underwent TJA with a cementless or cemented fixation. High-risk patients met at least one of the following criteria: men at least 70 years old, women at least 65 years old, or patients at least 60 years old who have the following: tobacco use, alcohol abuse, body mass index <18.5, prior fragility fracture, chronic systemic corticosteroids, or genetic condition affecting sex hormones or bone mineral density. Exclusion criteria were a diagnosis of malignancy, high-energy events (motor vehicle collision), those who underwent TJA indicated for fracture, patients less than 50 years old, those who had a prior diagnosis of or treatment for osteoporosis, and a minimum follow-up of less than 2 years. ResultsThere were 384,783 patients (67.1 %) who underwent cementless TKA and 67,774 patients (11.8 %) who underwent cementless TKA who were considered high risk. Additionally, there were 62,505 patients (10.9 %) who underwent cemented THA and 58,667 patients (10.2 %) who underwent cementless THA and were considered high risk. The cementless cohort had a 5-year periprosthetic fracture risk following TKA of 7.8 % (95 % CI, 5.56 to 10.98) in comparison to 4.30 % in the cemented cohort (85 % CI, 3.98 to 4.65), P < 0.0001. The high-risk cementless cohort had a 5-year periprosthetic fracture risk following THA of 7.9 % (95 % confidence interval (CI), 6.87 to 9.19) in comparison to 7.78 % in the cemented cohort (85 % CI, 6.77 to 8.94), P < 0.0001. ConclusionThere is an increased risk of PFF at 5 years following TKA in patients at high risk for osteoporosis undergoing cementless fixation in comparison to cemented fixation. There is an increased risk of PFF at 5 years following THA in patients at high risk for osteoporosis for both cementless fixation and cemented fixation, but no clinically meaningful difference between the two groups. Addressing the shortcomings of the underutilization of bone density scans and better selecting appropriate patients for TJA based on bone quality and fracture risk can help expedite the process of improving the current state of practice.

The presence and clinical significance of autoantibodies in amyotrophic lateral sclerosis: a narrative review.

Amyotrophic lateral sclerosis (ALS) is a debilitating and rapidly fatal neurodegenerative disease, which is characterized by the selective loss of the upper and lower motor neurons. The pathogenesis of ALS remains to be elucidated and has been connected to genetic, environmental and immune conditions. Evidence from clinical and experimental studies has suggested that the immune system played an important role in ALS pathophysiology. Autoantibodies are essential components of the immune system. Several autoantibodies directed at antigens associated with ALS pathogenesis have been identified in the serum and/or cerebrospinal fluid of ALS patients. The aim of this review is to summarize the presence and clinical significance of autoantibodies in ALS.

Samobójstwa wśród młodzieży jako problem kryminologiczny

Suicide is the subject of interest in many scientific disciplines, such as psychology, sociology, law, theology. A serious social problem is the growing number of young people who, in an act of desperation, lack of ability to cope with school and family problems, peer exclusion and low stress resistance, decide to take their own lives. Suicide in this aspect should be considered as a major social crisis of the 21st century. In criminological literature, it is seen as a type of voluntary death and an act of discontinuation of life. Suicide among young people is often preceded by a suicide attempt, which is a “call for help”, an attempt to draw attention to themselves, but above all an act of despair and rebellion against the reality they have to face. Suicidal risk factors intersect and complement each other. These include both those related to the suicidal person, as well as his or her personality traits, cognitive styles, genetic or biological conditions. An important role is played by those linked to the immediate environment, the family, the social group and the media. The aim of this article is to characterise the phenomenon of suicides in Poland with special attention to data on children and adolescents based on the statistics of the Police Headquarters. In addition, the authors attempt to provide a psychological portrait of the person who decides to commit suicide and to draw attention to suicide risk factors among adolescents.

A national postgraduate nurse practitioner and physician assistant fellowship in cystic fibrosis: An innovative approach to the provider shortage in complex and rare disease.

Cystic fibrosis (CF) is a complex life-limiting genetic condition that affects the respiratory, digestive, reproductive system, and sweat glands. Advances in treatment have led to improved survival and quality of life. Today, most persons with CF live to adulthood but require highly specialized care at accredited CF Care Centers. The growing and aging CF population combined with the provider workforce shortage have increased the demand for qualified CF providers. Nurse practitioners (NPs) and physician assistants (PAs) have been providing CF care for decades, but most learned on the job. The Leadership and Education for Advanced Practice Provider (LEAPP) fellowship in CF care aims to address the provider gap, ease transition to practice, and ensure access to specialized care. Unlike other institutional based joint NP/PA fellowships, LEAPP was designed to train providers at various locations across the national CF care center network. The program is innovative in several ways: (1) LEAPP employs a flipped classroom that pairs an online curriculum with case-based virtual discussion with content experts from the CF care network; (2) fellows receive mentored clinical training at their home CF center; (3) LEAPP partnered with a university-based team to ensure best practices and evaluation for adult learners; and (4) LEAPP promotes organizational enculturation through program components of professional mentoring, quality improvement, and leadership. This innovative approach may be suitable for other complex conditions that require highly specialized care, such as sickle cell disease, spina bifida, and solid organ transplant.

Hypertrophic cardiomyopathy and competitive sports: let 'em play?

Hypertrophic cardiomyopathy (HCM) is one of the most common cardiovascular genetic conditions. Although most patients with HCM typically do well clinically, there is a small but real incidence of sudden cardiac death. A diagnosis of HCM was previously a reason for complete exclusion in sports, particularly competitive sports.However, many of these recommendations are based on expert consensus, and much data has been published in the last decade furthering the scientific knowledge in this area, and allowing athletes who may have been previously excluded the potential to participate in strenuous activities and competitive sports. With recent publications on participation in sports with HCM, as well as an emphasis on shared decision-making, more athletes with HCM are participating in competitive sports, even at a professional level. Even contact sports in the presence of an implantable cardioverter-defibrillator are no longer mutually exclusive in the current era. Previous guidelines were likely overly restrictive for patients with HCM. Although there is a risk of sudden death that cannot be ignored, the potential for shared decision making as well as medical guidance are entering a new era in all aspects of medicine, particularly in sports participation.

Antitrypsin deficiency: still more to learn about the lung after 60 years.

The past 60 years have seen multiple publications related to lung disease in α1-antitrypsin deficiency largely reflecting the pathophysiology, biochemical effect and outcomes of augmentation therapy. However, the complexity of disease phenotype and the impact of the natural history presents problems of patient management, study design and hence interpretation of outcome. Although many national and some international registries exist, the lack of consistent in-depth assessment and importantly, the impact of augmentation therapy likely influences our perception of the true natural history. Development of new therapeutic strategies, and even assessment of the role and efficacy of augmentation, remain a challenge as powering such studies for conventional COPD outcomes is impractical due to relative rarity of the genetic condition and the presence of clinical phenotypic variation. The current review approaches these issues, discusses the nature and complexity of assessing patient variability, and provides guidance on further studies required to address them.

Collateral Child and Parent Effects of Behavioral Sleep Interventions for Children with Rare Genetic Neurodevelopmental Conditions

Abstract Objectives This study, following Woodford et al. (2024), investigated the collateral child and parent effects of function-based behavioral sleep interventions for 21 children with rare genetic neurodevelopmental conditions (RGNC). Methods Measures completed by parents at pre- and post-intervention assessed change in children’s internalizing and externalizing symptoms, health-related quality of life, behavioral strengths and difficulties, as well as parental sleep, relationship quality, and mental health symptoms. Data were analysed using modified Brinley plots and effect size estimates. Results Results demonstrate modest collateral benefits across child emotional and behavioral difficulties and health-related quality of life, and maternal anxiety and stress symptoms and sleep quality. There was minimal improvement in parent ratings of child externalizing symptoms and physical health-related quality of life, parent relationship satisfaction and all paternal outcome measures. There was no statistically significant relationship between changes in collateral outcomes and sleep problem severity. Conclusions Findings underscore the diverse potential benefits of improved sleep and highlight the need for further prioritisation of sleep services and research in RGNC.

Clinical Profile and Risk Factors of Cerebral Venous Sinus Thrombosis

Background: Cerebral venous sinus thrombosis (CVST) is a rare but serious neurovascular disorder that can lead to life-threatening complications such as hemorrhage and cerebral edema. This condition presents with a wide array of symptoms due to the formation of blood clots in the cerebral venous sinuses, impairing the drainage of deoxygenated blood and cerebrospinal fluid from the brain. Objective: The aim of this study was to elucidate the clinical profile and risk factors associated with CVST, enhancing the understanding of its epidemiology and facilitating better diagnostic and therapeutic strategies. Methods: This prospective cross-sectional study was conducted at the Department of Neurology, Jinnah Postgraduate Medical Centre, Karachi, Pakistan. A total of 135 participants diagnosed with CVST were enrolled through non-probability consecutive sampling. Participants underwent comprehensive physical and neurological examinations using a structured Clinical Patient Assessment Form. Diagnostic imaging included MRI, MRV, CT, and CT venography, although the principal diagnostic tools were CT and MRV. Data collection focused on demographics, clinical manifestations, and risk factors, with all information analyzed using SPSS version 25. Results: The study population predominantly consisted of females (74.8%) with the age group of 31-40 years being the most common (31.1%). Headache was the most frequently reported symptom (90.4%), followed by hemiparesis (53.3%) and seizures (40%). Significant risk factors included postpartum status (50.4%), iron deficiency anemia (25.9%), and genetic prothrombotic conditions (9.6%). Imaging studies revealed that the transverse sinus was the most affected site (74.1%). Conclusion: CVST exhibits a diverse range of clinical presentations and is associated with multiple demographic and physiological risk factors. Early diagnosis and management are crucial to prevent severe outcomes. This study highlights the importance of considering a detailed clinical and risk factor profile in patients presenting with neurological symptoms to aid in timely and accurate diagnosis of CVST.

Behavioral Sleep Interventions for Children with Rare Genetic Neurodevelopmental Conditions: A Retrospective Analysis of Overall Outcomes for 26 Cases

Abstract Objectives Sleep difficulties are highly prevalent among children with rare genetic neurodevelopmental conditions (RGNC) such as Angelman and Smith-Magenis syndromes. Behavioral interventions are commonly used in the treatment of sleep difficulties in children; however, research is limited in children with RGNC. This study evaluated the overall effectiveness and acceptability of function-based behavioral sleep interventions for children with RGNC. Methods Data was collated from a series of experimental single-case research studies with 26 children (18 months to 19 years of age) with a range of RGNC, who received a behavioral sleep intervention. Intervention strategies included circadian (e.g., sleep/wake rescheduling), antecedent (e.g., sleep hygiene), and/or consequence (e.g., positive reinforcement of sleep-conducive behavior and modified extinction) modifications implemented by parents. Clinicians provided support for parents mostly via telehealth methods. Overall outcomes were examined using modified Brinley plots and effect size estimates. The effect of age, gender, and a range of psychological variables on intervention response was also examined. Results Improvements in sleep problem severity were observed for 24/26 participants, and gains were maintained at long-term follow-up for 13/16. Interestingly, 50% of the children achieved clinically significant change with less restrictive strategies (e.g., circadian, antecedent and positive reinforcement strategies), suggesting extinction procedures may be used as the last option in a sequence of interventions. Parents generally perceived interventions to be acceptable. There was minimal evidence of any differential response to intervention as a function of age, gender, or psychological variables. Conclusions Results suggest function-based behavioral interventions offer an effective and socially valid method for treating sleep disturbance in children with RGNC.