Assessing the Knowledge and Comfort Level of US Family Medicine Residents Regarding Consenting and Confidentiality in Adolescent Health Care.

OBJECTIVES: Organizations recommend providing confidential adolescent health care to reduce the consequences of high-risk health behaviors such as substance use, unhealthy eating patterns, and high-risk sexual behaviors. Family physicians are uniquely positioned to provide confidential counseling and care to this vulnerable population but must be trained to provide such care. This study describes the impact of formal and informal training on the knowledge of and comfort level in providing confidential adolescent healthcare among a sample of US Family Medicine residents. METHODS: Electronic surveys were distributed to all Family Medicine residents throughout the United States. We used descriptive statistics and χ2 analysis where appropriate to determine the association between resident-reported receipt of training, confidence, and frequency in providing confidential adolescent health care. RESULTS: A total of 714 Family Medicine residents completed the survey. The majority reported no formal training in residency (50.3%). The receipt of formal and informal training in both medical school and residency was associated with a greater degree of comfort in providing confidential adolescent care and a higher likelihood of providing confidential time alone. Those reporting formal training were more likely to always provide confidential care (P = 0.001). CONCLUSIONS: Training focused on confidential adolescent health care in medical school or residency was associated with a greater degree of comfort and a higher likelihood of providing confidential adolescent health care.

Potency of a small molecule that targets the molluscum contagiosum virus processivity factor increases when conjugated to a tripeptide.

We recently developed compound FC-7269 for targeting the Molluscum contagiosum virus processivity factor (mD4) and demonstrated its ability to inhibit viral processive DNA synthesis in vitro and cellular infection of an mD4-dependent virus (Antiviral Res 211, 2023,105520). However, despite a thorough medicinal chemistry campaign we were unable to generate a potent second analog as a requisite for drug development. We overcame this impasse, by conjugating a short hydrophobic trivaline peptide to FC-7269 to produce FC-TriVal-7269 which significantly increased antiviral potency and reduced cellular toxicity.

Combination of bazedoxifene with chemotherapy and SMAC-mimetics for the treatment of colorectal cancer.

Excessive STAT3 signalling via gp130, the shared receptor subunit for IL-6 and IL-11, contributes to disease progression and poor survival outcomes in patients with colorectal cancer. Here, we provide evidence that bazedoxifene inhibits tumour growth via direct interaction with the gp130 receptor to suppress IL-6 and IL-11-mediated STAT3 signalling. Additionally, bazedoxifene combined with chemotherapy synergistically reduced cell proliferation and induced apoptosis in patient-derived colon cancer organoids. We elucidated that the primary mechanism of anti-tumour activity conferred by bazedoxifene treatment occurs via pro-apoptotic responses in tumour cells. Co-treatment with bazedoxifene and the SMAC-mimetics, LCL161 or Birinapant, that target the IAP family of proteins, demonstrated increased apoptosis and reduced proliferation in colorectal cancer cells. Our findings provide evidence that bazedoxifene treatment could be combined with SMAC-mimetics and chemotherapy to enhance tumour cell apoptosis in colorectal cancer, where gp130 receptor signalling promotes tumour growth and progression.

'Something that helped the whole picture': Experiences of parents offered rapid prenatal exome sequencing in routine clinical care in the English National Health Service.

OBJECTIVES: In October 2020, rapid prenatal exome sequencing (pES) was introduced into routine National Health Service (NHS) care in England. This study aimed to explore parent experiences and their information and support needs from the perspective of parents offered pES and of health professionals involved in its delivery. METHODS: In this qualitative study, semi-structured interviews were conducted with 42 women and 6 male partners and 63 fetal medicine and genetic health professionals. Interviews were transcribed verbatim and analysed using thematic analysis. RESULTS: Overall views about pES were positive and parents were grateful to be offered the test. Highlighted benefits of pES included the value of the additional information for pregnancy management and planning for future pregnancies. An anxious wait for results was common, often associated with the need to make decisions near to 24 weeks in pregnancy when there are legal restrictions for late termination. Descriptions of dealing with uncertainty were also common, even when results had been returned. Many parents described pES results as informing decision-making around whether or not to terminate pregnancy. Some professionals were concerned that a non-informative result could be overly reassuring and highlighted that careful counselling was needed to ensure parents have a good understanding of what the result means for their pregnancy. Emotional support from professionals was valued; however, some parents felt that post-test support was lacking. CONCLUSION: Parents and professionals welcomed the introduction of pES. Results inform parents' decision-making around the termination of pregnancy. When there are no diagnostic findings or uncertain findings from pES, personalised counselling that considers scans and other tests are crucial. Directing parents to reliable online sources of information and providing emotional support throughout could improve their experiences of care.

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure.

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here, we investigate the effect of lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that lenacapavir's potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.

Assembling a global health image: Ethical and pragmatic tensions through the lenses of photographers.

BACKGROUND: Recently, global health has been confronting its visual culture, historically modulated by colonialism, racism and abusive representation. There have been international calls to promote ethicality of visual practices. However, despite this focus on the history and the institutional use of global health images, little is known about how in practice contemporary images are created in communities, and how consent to be in photographs is obtained. METHODS: We conducted semi-structured interviews with 29 global health photographers about the ethical and practical challenges they experience in creating global health images, and thematically analysed the findings. FINDINGS: The following themes were identified: (1) global health photography is undergoing a marketing transformation and images are being increasingly moderated; (2) photographers routinely negotiate stereotypical and abusive tropes purposefully sought by organisations; (3) local scenes are modified, enhanced and staged to achieve a desired marketing effect; (4) 'empowerment' is becoming an increasingly prominent dehumanising visual trope; (5) consent to be photographed can be jeopardised by power imbalances, illiteracy, fears and trust; (6) organisations sometimes problematically recycle images. INTERPRETATION/DISCUSSION: This research has identified practical and ethical issues experienced by global health photographers, suggesting that the production cycle of global health images can be easily abused. The detected themes raise questions of responsibility and accountability, and require further transdisciplinary discussion, especially if promoting ethical photojournalism is the goal for 21st century global health.

Ethical preparedness in genomic medicine: how NHS clinical scientists navigate ethical issues.

Much has been published about the ethical issues encountered by clinicians in genetics/genomics, but those experienced by clinical laboratory scientists are less well described. Clinical laboratory scientists now frequently face navigating ethical problems in their work, but how they should be best supported to do this is underexplored. This lack of attention is also reflected in the ethics tools available to clinical laboratory scientists such as guidance and deliberative ethics forums, developed primarily to manage issues arising within the clinic.We explore what ethical issues are being experienced by clinical scientists, how they think such issues could be best analysed and managed, and whether their practice might be enhanced by more situated approaches to ethics deliberation and practice such as ethical preparedness. From thematic analysis of cases presented by clinical scientists at a specially convened meeting of the UK Genethics Forum, we derived three main ethical themes: (1) the redistribution of labour and responsibilities resulting from the practice of genomic medicine; (2) the interpretation and certainty of results and (3) the proposal that better standardisation and consistency of ethical approaches (for example, more guidelines and policy) could resolve some of the challenges arising.We argue that although standardisation is important for promoting shared understandings of good (including ethical) practice, supplementary approaches to enhance and sustain ethical preparedness will be important to help clinical scientists and others in the recently expanded genetic/genomic medicine environment foster quality ethical thinking.

BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome.

INTRODUCTION: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome. METHODS: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein. RESULTS: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures. CONCLUSION: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

Getting rights right: implementing 'Martha's Rule'.

The UK government has recently committed to adopting a new policy-dubbed 'Martha's Rule'-which has been characterised as providing patients the right to rapidly access a second clinical opinion in urgent or contested cases. Support for the rule emerged following the death of Martha Mills in 2021, after doctors failed to admit her to intensive care despite concerns raised by her parents. We argue that framing this issue in terms of patient rights is not productive, and should be avoided. Insofar as the ultimate goal of Martha's Rule is the provision of a clinical service that protects patient safety, an approach that focuses on the obligations of the health system-rather than the individual rights of patients-will better serve this goal. We outline an alternative approach that situates rapid clinical review as part of a suite of services aimed at enhancing and protecting patient care. This approach would make greater progress towards addressing the difficult systemic issues that Martha's Rule does not, while also better engaging with the constraints of clinical practice.

Spliceosome malfunction causes neurodevelopmental disorders with overlapping features.

Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.

Specialist healthcare services for concussion/mild traumatic brain injury in England: a consensus statement using modified Delphi methodology.

OBJECTIVE: To establish a consensus on the structure and process of healthcare services for patients with concussion in England to facilitate better healthcare quality and patient outcome. DESIGN: This consensus study followed the modified Delphi methodology with five phases: participant identification, item development, two rounds of voting and a meeting to finalise the consensus statements. The predefined threshold for agreement was set at ≥70%. SETTING: Specialist outpatient services. PARTICIPANTS: Members of the UK Head Injury Network were invited to participate. The network consists of clinical specialists in head injury practising in emergency medicine, neurology, neuropsychology, neurosurgery, paediatric medicine, rehabilitation medicine and sports and exercise medicine in England. PRIMARY OUTCOME MEASURE: A consensus statement on the structure and process of specialist outpatient care for patients with concussion in England. RESULTS: 55 items were voted on in the first round. 29 items were removed following the first voting round and 3 items were removed following the second voting round. Items were modified where appropriate. A final 18 statements reached consensus covering 3 main topics in specialist healthcare services for concussion; care pathway to structured follow-up, prognosis and measures of recovery, and provision of outpatient clinics. CONCLUSIONS: This work presents statements on how the healthcare services for patients with concussion in England could be redesigned to meet their health needs. Future work will seek to implement these into the clinical pathway.

Ethical issues in Nipah virus control and research: addressing a neglected disease.

Nipah virus is a priority pathogen that is receiving increasing attention among scientists and in work on epidemic preparedness. Despite this trend, there has been almost no bioethical work examining ethical considerations surrounding the epidemiology, prevention, and treatment of Nipah virus or research that has already begun into animal and human vaccines. In this paper, we advance the case for further work on Nipah virus disease in public health ethics due to the distinct issues it raises concerning communication about the modes of transmission, the burdens of public health surveillance, the recent use of stringent public health measures during epidemics, and social or religious norms intersecting with preventive measures. We also advance the case for further work on Nipah virus disease in research ethics, given ethical issues surrounding potential vaccine trials for a high-fatality disease with sporadic spillover events, the different local contexts where trials may occur, and the potential use of unproven therapeutics during outbreaks. Further bioethics work may help to ensure that research and public health interventions for Nipah virus disease are ethically acceptable and more likely to be effective.

Factors associated with low school readiness, a linked health and education data study in Wales, UK.

BACKGROUND: School readiness is a measure of a child's cognitive, social, and emotional readiness to begin formal schooling. Children with low school readiness need additional support from schools for learning, developing required social and academic skills, and catching-up with their school-ready peers. This study aims to identify the most significant risk factors associated with low school readiness using linked routine data for children in Wales. METHOD: This was a longitudinal cohort study using linked data. The cohort comprises of children who completed the Foundation Phase assessment between 2012 and 2018. Individuals were identified by linking Welsh Demographic Service and Pre16 Education Attainment datasets. School readiness was assessed via the binary outcome of the Foundation Phase assessment (achieved/not achieved). This study used multivariable logistic regression model and a decision tree to identify and weight the most important risk factors associated with low school readiness. RESULTS: In order of importance, logistic regression identified maternal learning difficulties (adjusted odds ratio 5.35(95% confidence interval 3.97-7.22)), childhood epilepsy (2.95(2.39-3.66)), very low birth weight (2.24(1.86-2.70), being a boy (2.11(2.04-2.19)), being on free school meals (1.85(1.78-1.93)), living in the most deprived areas (1.67(1.57-1.77)), maternal death (1.47(1.09-1.98)), and maternal diabetes (1.46(1.23-1.78)) as factors associated with low school readiness. Using a decision tree, eligibility for free school meals, being a boy, absence/low attendance at school, being born late in the academic year, being a low birthweight child, and not being breastfed were factors which were associated with low school readiness. CONCLUSION: This work suggests that public health interventions focusing on children who are: boys, living in deprived areas, have poor early years attendance, have parents with learning difficulties, have parents with an illness or have illnesses themselves, would make the most difference to school readiness in the population.

The challenges and potential solutions of achieving meaningful consent amongst research participants in northern Thailand: a qualitative study.

BACKGROUND: Achieving meaningful consent can be challenging, particularly in contexts of diminished literacy, yet is a vital part of participant protection in global health research. METHOD: We explored the challenges and potential solutions of achieving meaningful consent through a qualitative study in a predominantly hill tribe ethnic minority population in northern Thailand, a culturally distinctive population with low literacy. Semi-structured interviews were conducted with 37 respondents who had participated in scrub typhus clinical research, their family members, researchers and other key informants. A thematic analysis was conducted. RESULTS: Our analysis identified four interrelated themes surrounding participants' ability to give consent: varying degrees of research understanding, limitations of using informal translators, issues impacting decisions to join research, and voluntariness of consent. Suggestions for achieving more meaningful consent included the use of formal translators and community engagement with research populations. CONCLUSIONS: Participant's agency in decision making to join research should be supported, but research information needs to be communicated to potential participants in a way that they can understand. We found that improved understanding about the study and its potential benefits and harms goes beyond literacy or translation and requires attention to social and cultural factors.

Structures of the interleukin 11 signalling complex reveal gp130 dynamics and the inhibitory mechanism of a cytokine variant.

Interleukin (IL-)11, an IL-6 family cytokine, has pivotal roles in autoimmune diseases, fibrotic complications, and solid cancers. Despite intense therapeutic targeting efforts, structural understanding of IL-11 signalling and mechanistic insights into current inhibitors are lacking. Here we present cryo-EM and crystal structures of the human IL-11 signalling complex, including the complex containing the complete extracellular domains of the shared IL-6 family ß-receptor, gp130. We show that complex formation requires conformational reorganisation of IL-11 and that the membrane-proximal domains of gp130 are dynamic. We demonstrate that the cytokine mutant, IL-11 Mutein, competitively inhibits signalling in human cell lines. Structural shifts in IL-11 Mutein underlie inhibition by altering cytokine binding interactions at all three receptor-engaging sites and abrogating the final gp130 binding step. Our results reveal the structural basis of IL-11 signalling, define the molecular mechanisms of an inhibitor, and advance understanding of gp130-containing receptor complexes, with potential applications in therapeutic development.

Examining weight stigmatization toward obese individuals among nutrition and dietetic students using the attribution theory.

Background: Despite the increasing prevalence of obesity in the United States, negative attitudes toward obese individuals are widespread. Health-care providers, including dietetics and nutritionists, are not exempt from showing bias toward obese individuals, which may lead to subsequent psychological and health problems. Objectives: The purpose of this study was to measure the extent of weight bias among dietetics and nutrition students and investigate its determinants. Materials and Methods: A cross-sectional survey (316) was conducted among undergraduate dietetics and nutrition students at a large Midwestern University to assess weight bias using the Fat Phobia Scale. Eating competence was measured using the ecSI 2.0 and body dissatisfaction using the Stunkard Figure Rating Scale. Other variables included experience with obesity, media exposure to health and nutrition information, and demographic characteristics. Results: About 36% of the participants had weight bias, 64% were unsatisfied with their body image and none of the participants had eating competence. Media exposure to health information, body dissatisfaction, and eating competence was related to fat phobia (P < 0.05). Conclusion: These findings highlight that weight bias is an apparent issue among students enrolling in health-related programs. Considering their future role in clinical and community settings, this issue should be addressed properly.

Chimeric Viruses Containing Select Agents: The Biology Behind Their Creation, Attenuation, and Exclusion From Regulation.

The US Centers for Disease Control and Prevention (CDC), as part of the Federal Select Agent Program, and under the purview of 42 CFR §73.3, has the ability to regulate chimeric viruses that contain portions of pathogens that are part of the select agents and toxins list. In addition, the CDC is responsible for excluding pathogens from regulation, including chimeric viruses, that are sufficiently attenuated. Since 2003, the CDC has excluded over 20 chimeric viruses that contain portions of select agents. But in late 2021, the CDC proposed a regulatory first-the addition of a chimeric virus to the select agents and toxins list. To better understand the importance and applicability of this action, we surveyed the landscape of previous exclusions from select agent regulation. First, we reviewed the exclusion criteria used by the Intragovernmental Select Agents and Toxins Technical Advisory Committee in their advisement of the Federal Select Agent Program. We then reviewed the literature on chimeric viruses that contain portions of select agents and that have been excluded from regulation due to sufficient attenuation, focusing on chimeric alphaviruses and chimeric avian influenza viruses. By analyzing biological commonalities and patterns in the structure and methodology of the development of previously excluded chimeric viruses, we provide insight into how the CDC has used exclusion criteria in the past to regulate chimeric viruses. We conclude by contrasting previous exclusions with the recent addition of SARS-CoV-1/SARS-CoV-2 chimeric viruses to the select agents and toxins list, demonstrating that this addition strays from established, effective regulatory processes, and is thus a regulatory misstep.