Familial Clustering Research Articles

Healthy individuals genetically at-risk for the development of Pemphigus vulgaris or Alopecia areata share disease-like cytokine dysregulation

Autoimmune diseases (AID) are defined by immune dysregulation characterized by specific humoral and/or cell mediated responses directed against the body’s own tissues. Cytokines in particular play a pivotal role in the pathogenesis of AID, with proinflammatory cytokines contributing to the initiation and propagation of autoimmune inflammation, whereas anti-inflammatory cytokines facilitate regression of inflammation and recovery from acute phases of the disease. Parallel work by our group evaluating a comprehensive set of pro- and anti-inflammatory serum cytokines in Pemphigus vulgaris (PV) as well as Alopecia areata (AA) uncovered a similar pattern of inheritance specific immune dysregulation in these two distinct autoimmune skin diseases. In AA, we found healthy control subjects who are blood related to AA patients exhibit the same cytokine dysregulation in Th1 and Th17 pathways as do patients with AA. In PV, patients as well as individuals who are healthy but yet carry certain PV-associated HLA alleles (termed here as HLA-matched controls) share a similar, but not fully overlapping pattern of cytokine expression that is distinct from control subjects who do not type for these HLA alleles. Specifically, PV patients as well as HLA-matched controls demonstrate immunological activation of several pro-inflammatory-, Th17-, Th2-pathway associated cytokines, and the chemokine IL-8. Thus, in both AA and PV, we reveal cytokine dysregulations that are linked to genetic background. The presence of disease promoting pathways in not only patients, but also genetically related, but healthy control individuals further evokes the novel hypothesis that there may be co-existing disease counteracting immune protective mechanisms at play in thwarting the threat of disease in genetically predisposed individuals who, despite harboring disease associated immune imbalances, remain healthy. Our data underscore the known tendency of AID to cluster in families and support the notion of the shared genetic/common cause hypothesis across multiple AID.

Overlooked and misunderstood: A morpho‐molecular revision of Ditrichaceae s.str. (Dicranidae, Bryophyta), with a focus on the Holarctic species of Ditrichum

AbstractWe revised the Holarctic taxa of Ditrichaceae on the basis of both organellar DNA sequence data and morphological traits. After the removal of phylogenetically discordant elements related to Flexitrichum and Rhamphidium, the remaining representatives of the family cluster into three well‐supported lineages, which are recognized here as the reinstated family Ceratodontaceae and a more restricted Ditrichaceae with two subfamilies. Rhamphidium is segregated into a newly described family, Rhamphidiaceae; Aongstroemia gayana, Dicranella vaginata and Symblepharis krausei are combined under Rhamphidium, and the genus Strombulidens is tentatively moved to Rhamphidiaceae. Ceratodontaceae includes the genera Ceratodon, Cheilothela, Trichodon, and a newly described Pseudaongstroemia, which includes a single species, known earlier as Aongstroemia fuji‐alpina. The genus Trichodon is paraphyletically defined to include T. cylindricus, T. oblongus reinstated at specific rank, and a molecularly distinct lineage, which we were unable to distinguish morphologically from T. cylindricus. The monoicous genera of Ditrichaceae and the autoicous taxa of Ditrichum as previously understood are merged into a single genus, Pleuridium, which is segregated to Ditrichaceae subfam. Pleuridioideae stat. nov. A single genus is also accepted within Ditrichaceae subfam. Ditrichoideae, following the transfer of both Aongstroemia julacea s.str. and A. orientalis to Ditrichum. Ditrichum septentrionale is newly described based on material mostly from North Asia. Two ecologically specialized, putatively only locally distributed taxa are synonymized with more widespread taxa. Ditrichum plumbicola is placed into synonymy with D. lineare and similarly D. cornubicum is tentatively synonymized with D. macrorhynchum. The morphological delimitations of D. lineare, D. pusillum and D. macrorhynchum are clarified and emended.

Genetic Assessment of Living Kidney Transplant Donors: A Survey of Canadian Practices.

Kidney failure is a prevalent condition with tendency for familial clustering in up to 27% of the affected individuals. Living kidney donor (LKD) transplantation is the optimal treatment option; however, in Canada, more than 45% of LKDs are biologically related to their recipients which subjects recipients to worse graft survival and donors to higher future risk of kidney failure. Although not fully understood, this observation could be partially explained by genetic predisposition to kidney diseases. Genetic testing of potential LKDs may improve risk assessment and inform the safety of donation. The strategies to evaluate these donors are still evolving. In Canada, little is known about the practice of assessing for genetic conditions among LKDs. The aim was to examine the Canadian practices regarding LKDs genetic assessment. Questionnaires were sent to 23 Canadian adult transplant centers to examine their protocols for LKDs genetic assessment. The questionnaire comprised of 10 sections and 21 questions including case scenarios of different LKD encounters. Major domains of the survey addressed general demographics, information sharing practices, effect of mode of inheritance on candidacy decision, having a policy for LKD genetic evaluation, and case scenarios covering the following conditions: autosomal dominant polycystic kidney disease (ADPKD), Alport syndrome, Fabry disease, familial focal and segmental glomerulosclerosis (FSGS), atypical hemolytic uremic syndrome (aHUS), autosomal dominant tubulointerstitial kidney disease (ADTKD), sickle cell, and apolipoprotein L1 mutation (APOL1). The questionnaire was sent to the living-donor assessment committee representative (nephrologist) in adult and pediatric kidney transplant centers across Canada. In total, 16 of 23 Canadian centers responded to the survey. Of the 8 surveyed genetic conditions, ADPKD, Alport syndrome, and aHUS were the most frequently encountered. More centers have specific policies for donor evaluation for ADPKD (25%) and aHUS (21.4%) vs none to very few for other genetic conditions. The most cited guidelines are Kidney Disease Improving Global Outcomes (KDIGO), Canadian Society of Nephrology/Canadian Society of Transplantation (CSN/CST), and the Canadian Blood Services' Kidney Paired Donation Protocol. Canadian transplant centers follow a case-by-case approach rather than a standard protocol for genetic assessment of LKDs given that current guideline recommendations are based on expert opinion due to a lack of a reliable body of evidence. With the expected rise in utilization of the increasingly available genetic testing, early multidisciplinary assessment including medical geneticists has the potential to improve personalized management. Studies examining long-term donor and graft outcomes are needed to construct the basis for evidence-based recommendations and inform the safety of donations.

Prevalence and associated risk factors of Helicobacter pylori infection in community households in Lanzhou city.

Helicobacter pylori (H. pylori) infection exhibits a familial clustering phenomenon. To investigate the prevalence of H. pylori infection, identify associated factors, and analyze patterns of transmission within families residing in the community. From July 2021 to September 2021, a total of 191 families (519 people) in two randomly chosen community health service centers in the Chengguan District of Lanzhou in Gansu Province, were recruited to fill out questionnaires and tested for H. pylori infection. Individuals were followed up again from April 2023 and June 2023 to test for H. pylori infection. The relationship between variables and H. pylori infection was analyzed using logistic regression and generalized linear mixed models. In 2021, the individual-based H. pylori infection rate was found to be 47.0% (244/519), which decreased to 38.1% (177/464) in 2023. Additionally, the rate of individual-based H. pylori new infection was 22.8% (55/241). The family-based H. pylori infection rate in 2021 was 76.9% (147/191), which decreased to 67.1% (116/173) in 2023, and the rate of family-based H. pylori new infection was 38.6% (17/44). Individual H. pylori infection was positively correlated with age, body mass index (BMI), eating food that was excessively hot, frequent acid reflux, bloating, and halitosis symptoms, and negatively correlated with family size and nut consumption. New individual H. pylori infection was positively correlated with BMI, other types of family structures, drinking purified water, and frequent heartburn symptoms, while negatively correlated with the use of refrigerators and following a regular eating schedule. A larger living area was an independent protective factor for H. pylori infection in households. Frequently consuming excessively hot food and symptoms of halitosis were independent risk factors for H. pylori infection in individuals; frequent consumption of nuts was an independent protective factor for H. pylori infection. Other types of family structure, drinking purified water, and frequent heartburn symptoms were independent risk factors for new individual H. pylori infection; the use of a refrigerator was an independent protective factor for new H. pylori infections. The household H. pylori infection rate in Lanzhou is relatively high and linked to socio-demographic factors and lifestyles. Eradication efforts and control of related risk factors are recommended in the general population.

PCOS - the many faces of a disorder in women and men.

Polycystic ovary syndrome (PCOS) is a very common endocrine, metabolic and reproductive disorder. The underlying pathophysiology is not yet fully understood and both genetic and environmental factors contribute to its development. We aimed to explore clinical and genetic aspects of familial clustering in PCOS, shedding light on its reproductive and metabolic consequences in both male and female first-degree relatives of the affected women. Searching the electronic database of PubMed up to October 2023, we synthesized findings from available prospective and retrospective studies and review articles, investigating the familial clustering of PCOS and incorporating data on its metabolic consequences and genetic associations. There is a significant clustering of reproductive and metabolic abnormalities in first-degree relatives of women with PCOS. Genetic studies, including genome-wide association studies (GWAS), reveal a complex molecular etiology, emphasizing polygenic architecture. This is supported by the identification of two distinct PCOS subtypes, termed "reproductive" and "metabolic" which exhibit differential genetic underpinnings. Clinicians should be aware of increased reproductive and metabolic dysfunction both in female and male first-degree relatives of PCOS probands. Current challenges include refining genetic risk scores and understanding the impact of PCOS genetic factors on diverse outcomes, necessitating a sex-specific approach in research and clinical practice. Future directions should address causality, improve diagnostic capability, and unravel the long-term consequences in both genders, emphasizing the importance of proactive clinical assessment in PCOS probands and their families.

Turner syndrome: fertility, familial clustering, and cancer risk.

Is there an increased risk of reproductive or colon cancer in women with Turner syndrome and their family members? Our data suggest that there is an increased risk for sigmoid colon cancer in women with Turner syndrome and an increased prostate cancer risk in second- and third-degree male relatives. Turner syndrome has been associated with lower risk of breast cancer, but increased risk of gonadoblastoma and colon cancer in some, but not all studies. There is also evidence for a genetic predisposition to sex chromosome aneuploidy, which may indicate a predisposition to Turner syndrome and the associated cancer risk in family members. The study was a retrospective case-control study of women with Turner syndrome diagnosed from 1995 to 2021, their relatives, and population subjects from Utah. Women with Turner syndrome were identified using International Classification of Disease (ICD) codes in electronic medical records from two major Utah healthcare systems and reviewed for accuracy. Women with Turner syndrome were linked to genealogy in the Utah Population Database. Cancer diagnoses (breast, ovarian, endometrial, colon, testicular, and prostate) were determined for women with Turner syndrome and their relatives using the Utah Cancer Registry. Live births to women with Turner syndrome were identified by linked birth certificates. The relative risk of cancer in women with Turner syndrome and in relatives was estimated by comparison to population rates matched by age, sex, and birthplace. We identified 289 women with Turner syndrome. Sigmoid colon cancer was increased in women with Turner syndrome (OR [95% CI] 24.2 [2.9, 87.4]; P = 0.0032). There were 233 women with Turner syndrome who had at least three generations of genealogical data. There was an increased risk of Turner syndrome in first- (OR [95% CI] 18.08 [2.19, 65.32]; P = 0.0057) and second-degree relatives (9.62 [1.17, 34.74]; P = 0.019), although numbers were very small. There was an increased risk of prostate cancer in second- (1.8 [1.4, 2.2]; P < 0.001) and third-degree relatives (1.3 [1.1, 1.5]; P < 0.001). There was no increased risk of colon cancer in relatives. Based on the small number of sigmoid colon cancer cases, it is possible that our data have overestimated the colon cancer risk. Limitations include the identification of Turner syndrome by a diagnosis code in one of the two major health systems in Utah. The population is largely northern European with 9.3% of the women self-identified as Hispanic and 2.4% as Native American or multiple races. The results may not be generalizable to other populations. Our data suggest that women with Turner syndrome may need early screening for colon cancer. Additional studies are needed to identify risk factors for sex chromosome aneuploidy and cancer risk in women with Turner syndrome and their male relatives. The work in this publication was supported by R56HD090159 and R01HD099487 (C.K.W.). We also acknowledge partial support for the Utah Population Database through grant P30 CA2014 from the National Cancer Institute. The Utah Cancer Registry is funded by the National Cancer Institute's SEER Program, Contract No. HHSN261201800016I, the US Centers for Disease Control and Prevention's National Program of Cancer Registries, Cooperative Agreement No. NU58DP007131, with additional support from the University of Utah and Huntsman Cancer Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors have no conflicts of interest. N/A.

Experimental and computational biophysics to identify vasodilator drugs targeted at TRPV2 using agonists based on the probenecid scaffold

TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca2+ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

Genetic Predisposition to Hypertension in West Africa: Insights from Regional Studies

Hypertension is a major public health concern in West Africa, with prevalence rates higher than the global average. This review explores the genetic predisposition to hypertension in the region by synthesizing findings from regional studies. While environmental factors like diet, obesity, and urbanization significantly contribute to hypertension, genetic factors play a critical role in the susceptibility to this condition. West African populations, known for a high prevalence of salt sensitivity, demonstrate familial clustering of hypertension, suggesting strong genetic underpinnings. Key genetic markers identified include variants in the renin-angiotensin-aldosterone system (RAAS), sodium-handling genes, and genes affecting vascular tone. These genetic predispositions, in interaction with environmental factors such as high sodium intake and obesity, exacerbate hypertension risk. The review underscores the importance of understanding these genetic factors to develop targeted prevention and treatment strategies, which can lead to more personalized healthcare approaches for managing hypertension in West Africa. Keywords: Hypertension, Genetic predisposition, West Africa, Salt sensitivity.

Beyond here and there? A description and typology of multi-transnational extended family configurations of refugees

The number of persons forcibly displaced across international borders increased significantly over the last decade and forced migrants’ spatial family configurations have diversified and are likely to show different patterns compared to what research has found for, e.g. labour migrants. This paper examines and disentangles the diversity of spatial family arrangements across countries of nuclear and extended family members of female and male forced migrants surveyed in Germany. Moreover, I propose a typology of refugees’ family configurations based on the whereabouts of the partner, children, parents, and siblings. The empirical analyses employ representative survey data of recent refugees from Eritrea and Syria collected in Germany in 2020. This dataset allows to account for the whereabouts of members of the nuclear as well as extended family. Descriptive statistics show the prevalence and distributions of locations of specific family members and cluster analysis is conducted to identify and propose a typology of spatial configurations of refugee families. Finally, multinomial logistic regressions are used to test associations between the obtained clusters and gender, country of origin and the financial situation, controlling for other characteristics. The findings indicate that multi-transnational family constellations beyond origin and destination countries are a common pattern among refugees, especially when considering nuclear as well as extended family members. Furthermore, different types of spatial family arrangements are related to gender and country of origin as well as family financial resources.

NCMP-22. CO-OCCURRENCE OF MULTIPLE SCLEROSIS AND HODGKIN LYMPHOMA. IS THERE A COMMON PATHOPHYSIOLOGY?

Abstract BACKGROUND Multiple sclerosis (MS) and Hodgkin lymphoma (HL) share common epidemiology, genetics and immunological factors. Both affect immune activation, cell proliferation and lymphocyte-mediated immunity. However, occurrence of these two distinct clinical conditions is rare. We present a case of a woman with transverse myelitis fulfilling criteria for MS with synchronous HL. CASE REPORT A 37-year-old woman presented to the emergency room with bilateral leg weakness, numbness and urinary retention. A contrasted MRI of the brain and thoracic spine showed non-specific, non-enhancing white-matter lesions in the brain, and patchy areas of peripheral contrast-enhancement with T2-hyperintensity in the thoracic cord. Treatment with steroid infusion resulted in mild improvements of leg weakness and numbness. Cerebrospinal fluid (CSF) demonstrated oligoclonal bands (OCB) and increased IgG index. Serum was positive for JCV antibody. Due to the atypical MRI findings, namely the peripheral nature of thoracic contrast-enhancement, we were concerned for other inflammatory or autoimmune etiologies. A computed tomography of the chest, abdomen and pelvis revealed a large mediastinal mass and enlarged lymph nodes. A biopsy revealed classic HL. Three-months later, a follow-up MRI brain showed worsening contrast-enhanced lesions. A repeat CSF study revealed normal OCBs and IgG index. CSF was negative for malignant cells and JC virus DNA. To rule out a rare possibility of central nervous system HL, a biopsy of an enhancing brain lesion was obtained, which showed focal gliosis and focal perivascular lymphocytic infiltrates. No malignant cells were observed. She was diagnosed with multiple sclerosis and started systemic chemotherapy (doxorubicin, bleomycin, dacarbazine and vinblastine) for HL. CONCLUSIONS We report a case of an atypical transverse myelitis with HL. Although familial genetic clustering has been described, other potential common risk-factors between MS and HL are Epstein-Barr Virus infection and immunologic overlap, particularly in the context of lymphocyte-mediated immunity.

Representing and Quantifying Conformational Changes of Kinases and Phosphatases Using the TSR-Based Algorithm

Protein kinases and phosphatases are key signaling proteins and are important drug targets. An explosion in the number of publicly available 3D structures of proteins has been seen in recent years. Three-dimensional structures of kinase and phosphatase have not been systematically investigated. This is due to the difficulty of designing structure-based descriptors that are capable of quantifying conformational changes. We have developed a triangular spatial relationship (TSR)-based algorithm that enables a unique representation of a protein’s 3D structure using a vector of integers (keys). The main objective of this study is to provide structural insight into conformational changes. We also aim to link TSR-based structural descriptors to their functions. The 3D structures of 2527 kinases and 505 phosphatases are studied. This study results in several major findings as follows: (i) The clustering method yields functionally coherent clusters of kinase and phosphatase families and their superfamilies. (ii) Specific TSR keys are identified as structural signatures for different types of kinases and phosphatases. (iii) TSR keys can identify different conformations of the well-known DFG motif of kinases. (iv) A significant number of phosphatases have their own distinct DFG motifs. The TSR keys from kinases and phosphatases agree with each other. TSR keys are successfully used to represent and quantify conformational changes of CDK2 upon the binding of cyclin or phosphorylation. TSR keys are effective when used as features for unsupervised machine learning and for key searches. If discriminative TSR keys are identified, they can be mapped back to atomic details within the amino acids involved. In conclusion, this study presents an advanced computational methodology with significant advantages in not only representing and quantifying conformational changes of protein structures but also having the capability of directly linking protein structures to their functions.

Intergenerational transmission of childhood trauma in youths with mood disorders and their parents

ObjectiveChildhood trauma is a significant environmental stressor linked to mood disorder. It can affect not only the individuals directly involved but also the next generation through the intergenerational transmission of trauma. This study aimed to investigate, for the first time, the co-occurrence of childhood trauma in youths with mood disorders and their parents. MethodsWe assessed 443 individuals, 100 youths with DSM-5 mood disorders, 100 youths healthy controls (HCs), 92 s' parents and 161 adult HCs. History of childhood trauma was obtained using the Childhood Trauma Questionnaire (CTQ). The distribution patterns of childhood trauma subtypes was estimated through a multivariate model. Intraclass correlations (ICC) were calculated to account for the familial clustering of the sample. ResultsWe found significantly higher scores for Patients as compared to Young-HC in all the subtypes of childhood trauma (p < 0.05). Considering Parents and Adult-HC groups, Physical abuse (p = 0.001) and Emotional neglect showed higher scores in Parents (p < 0.001). Regarding the familial clustering of the sample, emotional (p < 0.001) and sexual abuse (p = 0.001), and emotional (p = 0.3) and physical neglect (p = 0.003) showed statistical significance, but only emotional abuse reveled a medium level ICC (0.25). ConclusionsOur study highlights the effect of intergenerational transmission of childhood trauma on the diagnosis of mood disorders in youths. Our findings underscore the significance of systematically assessing childhood trauma, in particular emotional abuse, in youths with mood disorders and their parents. Additionally, there is urgent need for evidence-based preventive measures aimed at promoting positive parenting strategies and emotionally supportive environments for children.

Characterisation of patients diagnosed with pernicious anaemia: A first step towards James Lind Alliance Priority Setting Partnership driven research

Pernicious anaemia (PA) is characterised by vitamin B12 deficiency due to autoimmune-mediated loss of gastric parietal cells and intrinsic factor, a specific transporter for the intestinal uptake of vitamin B12. PA is typically managed with lifelong intramuscular hydroxocobalamin injections every 2-3 months. However, this regimen lacks robust scientific validation and fails to account for varied symptomatic responses among patients, with many requiring more frequent injections(1).The Pernicious Anaemia Society (PAS) is a patient-driven charity that identified 10 research priorities for PA through a James-Lind Alliance Priority Setting Partnership(2). PAS members were surveyed to build a PA Research Repository, exploring diagnostics, treatment, family histories, and comorbidities. This project aims to better understand and manage the condition by addressing these priorities and characterising a cohort of patients.An online survey was designed using SurveyMonkey comprising 21 questions to collect data on demographics, mode and timing of PA diagnosis, diagnosed comorbidities, family history of PA or other autoimmune conditions, and management (type, regime and patient satisfaction). All questions were compulsory. The survey was sent to 3,482 PAS members (April-September 2022) via the PAS newsletter, email, and website. Chi-square tests were used to investigate associations between gender and survey responses. The study protocol and procedures received a Favourable Ethical Opinion.Completed surveys were received from 1,191 PAS members (34% response rate). Among these, 971 (81%) had a confirmed PA diagnoses, and the cohort was predominantly UK-based (92%) females (81%) aged 23-90 years, with a wide age of onset (10 to 80 years, mean 49 years). Diagnoses were typically based on low serum B12 (40%), positive intrinsic factor (31%), and/or parietal cell autoantibodies (13%), with 7% diagnosed via the now obsolete Schilling test. Diagnostic delays were common, 39% of participants reported waiting ≥3 years for a diagnosis. Over half (59%) reported other micronutrient deficiencies upon diagnosis. Half reported additional autoimmune diseases, with one-third having family with PA or other autoimmune conditions. Treatment primarily involved hydroxocobalamin intramuscular injections (77%), with 48% following the recommended guidelines and 52% injecting more frequently. Females had higher prevalence rates of Hashimoto’s disease (27% vs 7%), asthma (33% vs 20%), and iron deficiency (49% vs 35%) (all p &lt; 0.05).This survey has established the first-ever PA research repository of over 1,000 participants offering initial insight into the complexities of PA, from varied age-of-onset and familial clustering to diagnostic challenges and treatment variability. These results support the need for improved diagnostic and treatment strategies, supporting the research recommendations made in the recent vitamin B12 deficiency NICE guidelines(3). It also highlights the potential of collaborative research with a patient-driven charity. Collaborative efforts aim to advance patient-centred PA research, improve treatment evaluation, and develop evidence-based approaches to managing this complex condition.

System-wide health needs segmentation: innovating integrated care for complex needs households

Abstract Background Health needs segmentation is increasingly used in healthcare delivery and health policy planning to cater for diverse population groups and develop effective and equitable health policies. But existing models often lack a systemic approach, focusing instead on single conditions or settings. This leads to fragmentation, gaps and inefficiencies in service provision and inequities in health outcomes, particularly when addressing complexity, and specifically for children, as adversity clusters in families. Aims To develop a household health needs segmentation model to identify those households with children with high levels of complex cross-sectoral needs, to plan for integrated care services. Methods Data linkage of primary, secondary, mental, community and social care services, mortality records, residential information, and small-area multiple deprivation measures was used to design a rule-based model to identifying households with children with the most complex needs in the UK region of Cheshire and Merseyside (C&amp;M), with large variation in demography, (human) geography, and deprivation. Results Of 2,645,329 individuals in C&amp;M (97% of the registered population in 2021), 1,022,840 lived in 266,939 households with children aged 0-16: 21,527 households had complex needs. This 8% of families accounted for an estimated 34% of health and social care costs for families, £362 million in total, 42% of which spent on children in care of local authorities. Implications The model identified a specific group of families with complex service use patterns, high mental and physical comorbidity and socioeconomic vulnerabilities. These exhibit potential for improved outcomes through better integration of services and targeting of community building and family support resources. Conclusions Our model represents a significant innovation in health needs segmentation. By using whole system linked data, it provides a pragmatic way of profiling complexity for proactive care. Key messages • Complex health and social problems in children cluster in families with adults also having complex needs, so we need to transform fragmented services to support the whole family to improve outcomes. • Household level segmentation using cross-sectoral, whole system data is an innovation to identify households with complex needs with respect to their locality to improve integration of support.

Participation rate and yield of indirect cascade genetic screening for familial hypercholesterolemia using a web-based communication platform (CATCH): a randomized multicenter implementation trial

Abstract Introduction Cascade genetic screening for familial hypercholesterolemia (FH) is poorly performed when direct contact with relatives by health professionals is not allowed. We aimed to compare the effectiveness of implementing a web-based communication platform in a large-scale cascade genetic screening program for FH, while maintaining the confidentiality of indirect family contacts. Methods The CATCH study is a prospective randomized open-label multicenter implementation trial that promotes family cascade genetic screening in Swiss adults older than 16 years with a newly diagnosed pathogenic variant for FH. Each family was randomly assigned to a multigenerational indirect cascade genetic screening (1:1) either via the possibility to use of a web-based platform designed to send pre-prepared text messages or emails, and allowing to connect to a specialized clinical center, or a cascade genetic screening via the local recommended procedure. The primary outcome was the 6-month participation rate of relatives, defined as the number of genetic tests performed within 6 months after referral, over the number of eligible relatives for screening, i.e. living first-degree relatives aged 5 years or older. The secondary outcome was the 6-month yield of positive genetic tests, defined as the number of positive tests over the number of eligible relatives. Both outcome estimates were obtained after accounting for family clusters. Results Between 11/20 and 12/23, we enrolled 221 adults with a phenotype of FH for genetic testing, with 87 of them having confirmed genetic FH, corresponding to a total of 401 eligible relatives for cascade screening, with 102 relatives eventually undergoing genetic testing. Among the 87 index cases with genetic FH, 44 were randomly assigned to the web-based platform screening, and 43 were assigned to the local procedure screening. The 6-month participation rate of relatives was 71 of the 218 eligible relatives (29% [95% CI 21–38]) for the web-based platform screening, and 31 of the 183 eligible relatives (14% [95% CI 8–23]) for the local procedure screening (odds ratio (OR) 2.46 [95% CI 1.22–4.98]), p=0.012) (Figure). Similarly, the yield of detection of positive relatives was higher for the web-based platform screening, (16% [95% CI 11–23]) compared to the local procedure screening (7% [95% CI 4–13]), with OR of 2.43 [95% CI 1.11–5.30], p=0.026. Among the 55 positive relatives identified with genetic FH within 6-months, 13.0% were younger than 18 years, 25.5% were current smokers, and 56.0% were not using any lipid-lowering drugs. Conclusions The effectiveness of cascade genetic screening for FH was approximately doubled by integrating a web-based platform that facilitates family communication and access to specialized clinical centers. Modern communication technology is well suited to be integrated in large-scale indirect genetic screening programs to increase the early identification of patients at high cardiovascular risk.

Adverse Childhood Experiences and Socioemotional Outcomes of Children Born Very Preterm

ObjectiveTo examine whether adverse childhood experiences (ACEs) confer risk for socio-emotional problems in children born very preterm (VPT) Study designAs part of a longitudinal study, 96 infants born VPT at 23-30 weeks of gestation were recruited from a level III neonatal intensive care unit and underwent follow-up at ages 2 and 5 years. Eighty-three full-term (FT, 37-41 weeks gestation) children were recruited from an adjoining obstetric service and the local community. ACEs were assessed with the Child Life Events Scale at age 2 and Preschool Age Psychiatric Assessment at age 5. At age 5, internalizing, externalizing, and Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms were assessed with the Child Behavior Checklist and Conner’s Rating Scale-Revised, respectively. Covariates including socioeconomic disadvantage, maternal distress, and parent ADHD symptoms were assessed at the 2- and/or 5-year follow-up. Mediation and moderation analysis, accounting for family clustering, examined associations between birth group, ACEs, and socio-emotional outcomes. ResultsAfter covariate adjustment, children born VPT experienced more ACEs (p<0.001), particularly medical ACEs (p<0.01), and had worse ADHD and internalizing outcomes (p<.05) than FT children. ACEs mediated the association between birth group and ADHD outcomes (95% CIs: 0.11 – 4.08). There was no evidence of mediation for internalizing outcomes. Higher parent ADHD symptoms (p<.001) and maternal distress (p<.05) were associated with poorer internalizing outcomes. ConclusionsScreening for childhood ACEs should be embedded in the follow-up care of children born VPT and their families. Strategies to screen for and address parent psychosocial functioning may be important to support children’s socio-emotional development.

Investigation of a family cluster poisoning incident caused by Galerina sulciceps mushroom

Mushroom poisoning is the most important cause of death in food-borne poisoning in China, mainly caused by amanitin, which is caused by rapid progression, complex mechanism and latency. Early identification, diagnosis and treatment are important to improve the prognosis of fatal mushroom poisoning. This article analyzes the clinical characteristics, identification process and treatment of 14 patients with amanitin-containing Galerina sulciceps mushroom poisoning in a family, so as to improve the identification ability of the first physician in recognizing and managing early-stage mushroom poisoning, and to increase the cure rate through early bundle therapy of mushroom poisoning.

Unmet Financial Needs of People with Psychotic Disorders-A Cross-Sectional Study in People with Psychotic Disorders, Parents, Siblings, and Controls.

Background. Psychotic disorders have a strong negative impact on people's lives, including their financial situation. This study aimed to examine differences in unmet financial needs between people with psychotic disorders, parents, siblings, and controls. Secondly, we aimed to examine whether family clustering contributes to unmet financial needs. Lastly, we aimed to examine to what extent demographic, economic, psychiatric, functional, and cognitive characteristics and substance use predict unmet financial needs in people with psychosis. Methods. Data from the first assessment of people with psychosis (n = 956), siblings (n = 889), parents (n = 858), and controls (n = 496) included in the Genetic Risk and Outcome of Psychosis study were used. Group differences were assessed with Kruskal-Wallis tests (aim 1), while a mixed-effects logistic regression analysis and explorative and confirmative ordinal logistic regression analyses were conducted for aims 2 and 3, respectively. Results. Twenty-four percent of people with psychotic disorders reported unmet financial needs. These levels of unmet financial needs were significantly higher than levels for siblings, parents, and controls. We found a negligible influence of (direct) familial clustering on unmet financial needs. Lastly, cannabis and tobacco use significantly and consistently predicted higher levels of unmet financial needs of people with psychosis. Conclusions. Relatively high levels of unmet financial needs occurred in a heterogeneous group of people with psychosis, especially when people used cannabis or tobacco. Unmet financial needs can have detrimental consequences for mental health, stigmatization, leisure time activities, and social engagement. Thus, it is pivotal to recognize unmet financial needs, especially combined with substance use, as a crucial stressor for people with psychosis.

Borane-Mediated Polyhedral Expansion to Access Metal-Free Neutral and Cationic Derivatives of closo-Heptaboranes.

Boranes with closed polyhedral structures feature peculiar bonding and structural characteristics, rendering them widely applicable in diverse research areas ranging from basic functionalization reactions to applications such as medicine, nanomaterials, molecular electronics, and neutron capture therapy. Among the closed borane family, the neutral and cationic heptaborane B7 clusters have been missing in contemporary boron cluster chemistry to date. Herein, we report a polyhedral expansion protocol to construct a neutral derivative of closo-heptaborane (B7) from closo-hexaborane (B6) mediated by borane. Conversion of the neutral derivative of closo-heptaborane to a cationic derivative is also demonstrated. X-ray crystallographic and spectroscopic analyses with the aid of quantum chemical calculations reveal that both neutral and cationic derivatives of closo-heptaborane exhibit a pentagonal-bipyramidal geometry and involve the delocalized σ skeletal electrons, leading to three-dimensional aromaticity. Moreover, the B7 core of the former undergoes a complexation reaction with silver tetrafluoroborate, representing the first experimental demonstration of the nucleophilic nature of the closo-heptaborane.

Statistics to prioritize rare variants in family-based sequencing studies with disease subtypes.

Family-based sequencing studies are increasingly used to find rare genetic variants of high risk for disease traits with familial clustering. In some studies, families with multiple disease subtypes are collected and the exomes of affected relatives are sequenced for shared rare variants (RVs). Since different families can harbor different causal variants and each family harbors many RVs, tests to detect causal variants can have low power in this study design. Our goal is rather to prioritize shared variants for further investigation by, for example, pathway analyses or functional studies. The transmission-disequilibrium test prioritizes variants based on departures from Mendelian transmission in parent-child trios. Extending this idea to families, we propose methods to prioritize RVs shared in affected relatives with two disease subtypes, with one subtype more heritable than the other. Global approaches condition on a variant being observed in the study and assume a known probability of carrying a causal variant. In contrast, local approaches condition on a variant being observed in specific families to eliminate the carrier probability. Our simulation results indicate that global approaches are robust to misspecification of the carrier probability and prioritize more effectively than local approaches even when the carrier probability is misspecified.