Structural Variants Create New Topological-Associated Domains and Ectopic Retinal Enhancer-Gene Contact in Dominant Retinitis Pigmentosa.

The cause of autosomal-dominant retinitis pigmentosa (adRP), which leads to loss of vision and blindness, was investigated in families lacking a molecular diagnosis. A refined locus for adRP on Chr17q22 (RP17) was delineated through genotyping and genome sequencing, leading to the identification of structural variants (SVs) that segregate with disease. Eight different complex SVs were characterized in 22 adRP-affected families with >300 affected individuals. All RP17 SVs had breakpoints within a genomic region spanning YPEL2 to LINC01476. To investigate the mechanism of disease, we reprogrammed fibroblasts from affected individuals and controls into induced pluripotent stem cells (iPSCs) and differentiated them into photoreceptor precursor cells (PPCs) or retinal organoids (ROs). Hi-C was performed on ROs, and differential expression of regional genes and a retinal enhancer RNA at this locus was assessed by qPCR. The epigenetic landscape of the region, and Hi-C RO data, showed that YPEL2 sits within its own topologically associating domain (TAD), rich in enhancers with binding sites for retinal transcription factors. The Hi-C map of RP17 ROs revealed creation of a neo-TAD with ectopic contacts between GDPD1 and retinal enhancers, and modeling of all RP17 SVs was consistent with neo-TADs leading to ectopic retinal-specific enhancer-GDPD1 accessibility. qPCR confirmed increased expression of GDPD1 and increased expression of the retinal enhancer that enters the neo-TAD. Altered TAD structure resulting in increased retinal expression of GDPD1 is the likely convergent mechanism of disease, consistent with a dominant gain of function. Our study highlights the importance of SVs as a genomic mechanism in unsolved Mendelian diseases.

Development and testing of a bespoke cultural intervention to support healthcare professionals with patients from a diverse background.

OBJECTIVE: Development and test of a culturally sensitive intervention for rheumatology healthcare professionals (HCPs). METHODS: Using a before and after study design, fifteen HCPs were recruited to undertake the bespoke intervention from four NHS sites across England, in areas serving a diverse population. The intervention was evaluated using the validated outcomes: [1] Patient Reported Physician Cultural Competency (PRPCC); and [2] Patient Enablement Instrument (PEI), measuring patients' perceptions of their overall healthcare delivery. Additionally, HCPs completed the Capability COM-B questionnaire (C), Opportunity (O) and Motivation (M) to perform Behaviour (B), measuring behaviour change. RESULTS: 200 patients were recruited before HCPs undertook the intervention (cohort 1), and 200 were recruited after (cohort 2) from fifteen HCPs, after exclusions 178 patients remained in cohort 1 and 186 in cohort 2. Patients identifying as White in both recruited cohorts were 60% compared with 29% and 33% of patients (cohorts 1 and 2 respectively) who identified as of South Asian origin. After the intervention, the COM-B scores indicated HCPs felt more skilled and equipped for consultations. No significant differences were noted in the average overall cultural competency score between the two cohorts in White patients (57.3 vs 56.8, p= 0.8), however, in the South Asian cohort, there was a statistically significant improvement in mean scores (64.1 vs 56.7, p= 0.014). Overall, the enablement score also showed a statistically significant improvement following intervention (7.3 vs 4.3, p< 0.001) in the White patients; and in the South Asian patients (8.0 vs 2.2, p< 0.001). CONCLUSION: This novel study provides evidence for improving cultural competency and patient enablement in rheumatology settings.

Social Empathy and Associated Factors Among Nurses: An Observational Study.

Integral to holistic "big picture" nursing care is an empathy that strives for social justice. Social empathy requires more than technical skills or even interpersonal empathy or other-focus; it also requires a perspective that appreciates the impact of social determinants and seeks action to address them. This study sought to measure social empathy and potentially associated demographic, personal, and work-related factors among nurses. This cross-sectional, observational study used online survey methods to collect data from 614 registered nurses employed in a faith-based health care system in the northwestern United States. Constructs measured included social empathy, social advocacy, self-compassion, emotional exhaustion, and trust/mistrust in God. Parametric statistical tests, including multiple logistic regression, allowed analyses. Findings indicated that social empathy was high in this sample. Younger nurses, those more inclined to advocate, those more self-compassionate, those less burned out, those working part-time (in contrast only with those working overtime), and those with at least a baccalaureate degree in nursing were more socially empathic. Findings highlight further rationale for creating healthy work environments that foster self-compassion and minimize burnout.

TMEM27 expression and clinical characteristics and survival in clear cell renal cell carcinoma.

BACKGROUND: Transmembrane protein 27 (TMEM27/collectrin), a glycoprotein and homolog of angiotensin-converting enzyme 2 (ACE2), is a regulator of renal amino acid uptake in the proximal tubule and may have a protective role in hypertension. Two previous reports have shown that the absence of TMEM27 expression in clear cell renal cell carcinoma (ccRCC) correlates with poorer cancer-related survival. We report our findings of TMEM27 expression in ccRCC and clinical outcomes in an independent third cohort. MATERIAL AND METHODS: We conducted a retrospective analysis to identify all 321 cases of ccRCC diagnosed between 2010 and 2015 at the University of Rochester Medical Center. The intensity of TMEM27 immunostaining on tumor tissue was semi-quantitatively graded on a scale of 0, 0.5, 1, 1.5, 2, 2.5, and 3 by a single pathologist, and correlated with tumor characteristics and survival. RESULTS: There was evidence of metastasis at time of nephrectomy in 36 (11.2%) cases, and at the latest follow-up in 70 (21.8%) cases. As of Spring 2021, 82 (25.5%) had died. TMEM27 staining intensity correlated inversely with various tumor characteristics. Kaplan-Meier survival analysis showed worse overall all-cause mortality (p = 0.02) and disease-free survival (p = 0.028) for tumors without any TMEM27 staining (0) compared to 0.5 or higher by log-rank test. CONCLUSION: The absence of TMEM27 expression is associated with more aggressive tumor characteristics and poorer all-cause mortality and disease-free survival in ccRCC. TMEM27 may be a useful biomarker to assess cancer prognosis. Further studies are needed to better assess if TMEM27 is protective in RCC, and its potential role in active surveillance and prediction of response to target therapy.

Use of Complementary and Alternative Medicine for Prostate Cancer among African Americans, African Immigrants and Caribbean Immigrants.

Black men have the highest rate of prostate cancer (PCa) morbidity and mortality in the US, and often receive delayed and/or poorer-quality treatment. This inequity has led many to turn to complementary and alternative medicine/therapies (CAM). However, little is known about the use of these therapies within the Black community. The purpose of this study was to describe types of CAM therapies used, and the reasons behind their use for overall health and PCa treatment and prevention among three groups of Black males, namely African Americans, Caribbean Immigrants and African Immigrants. This study used a mixed-methods design with a quantitative phase (n = 575) followed by a qualitative phase (n = 61) with participants recruited from various parts of the country. Results revealed differences among subgroups in CAM use for overall health and PCa, as well as differences in the types of CAM therapies used and differences in the reasons behind their use. The findings of this study reveal a prevalence of CAM use for overall health and PCa within three different groups of Black men and identifies the specific CAM used. There were significant differences in the types of CAM used by each subgroup for both overall health and PCa. This study also shows that there is value in looking at Black subgroups distinctively, for their rates of CAM use and reasons for use, are distinctly different.

Stillbirth and infant death: mental health among low-income mothers in Mumbai.

BACKGROUND: India has the highest number of stillbirths and the highest neonatal death rate in the world. In the context of its pronatalist society, women who experience perinatal loss often encounter significant social repercussions on top of grief. Furthermore, even when pregnancy outcomes were favorable, adverse life circumstances put some women at risk for postnatal depression. Therefore, perinatal loss and postnatal depression take a heavy toll on women's mental health. The purpose of this study is to assess mental health among a sample of Mumbai slum-dwelling women with a history of recent childbirth, stillbirth, or infant death, who are at risk for perinatal grief, postnatal depression, or mental health sequelae. METHODS: We conducted a mixed method, cross-sectional study. A focus group discussion informed the development of a comprehensive survey using mainly internationally validated scales. After rigorous forward and back-translation, surveys were administered as face-to-face structured interviews due to low literacy and research naiveté among our respondents. Interviews were conducted by culturally, linguistically, gender-matched, trained research assistants. RESULTS: Of our reproductive age (N = 260) participants, 105 had experienced stillbirth, 69 had a history of infant death, and 25 had experienced both types of loss. Nearly half of the sample met criteria for postnatal depression, and 20% of these women also met criteria for perinatal grief. Anxiety and depression varied by subgroup, and was highest among women desiring an intervention. CONCLUSIONS: Understanding factors contributing to women's suffering related to reproductive challenges in this pronatalist context is critically important for women's wellbeing.

Lipopolysaccharide binding protein is associated with CVD risk in older adults.

BACKGROUND: Intestinal (i.e., "gut") permeability may be related to cardiovascular disease (CVD) risk, but biomarkers for gut permeability are limited and associations with CVD risk are unknown-particularly among older adults. AIMS: This cross-sectional study aimed to determine if serum biomarkers related to gut permeability [intestinal fatty acid-binding protein (iFABP)] and bacterial toxin clearing [cluster of differentiation 14 (CD14), lipopolysaccharide binding protein (LBP)] are associated with CVD risk among older adults. METHODS: Older adults (n = 74, 69.6 ± 6.5-years-old) were stratified by CVD risk category. One-way ANOVAs determined differences in each biomarker by risk category, and associations with risk score were evaluated with Pearson correlations. RESULTS: LBP (p = 0.007), but not iFABP and CD14, was significantly different between CVD risk categories. Post-hoc tests indicated LBP was higher in moderate risk and high-moderate risk compared to the high risk category (p < 0.005). Evaluation of LBP and individual components in the risk score demonstrated a moderate, negative correlation of LBP with age and systolic blood pressure (r = - 0.335 and r = - 0.297) and a small positive correlation between LBP and total cholesterol and LDL cholesterol (r = 0.204 and r = 0.220). DISCUSSION/CONCLUSION: Lower risk for CVD was associated with higher circulating concentrations of LBP, lower iFABP, and lower systemic inflammation in older adults. Further, there were small positive relationships between total and LDL cholesterol and circulating levels of LBP. These data suggest LBP may be a key component in reducing CVD risk in older adults.

Improving consultations for persistent musculoskeletal low back pain in orthopaedic spine settings: an intervention development.

BACKGROUND: There is a need to improve consultations between patients with persistent musculoskeletal low back pain and orthopaedic spine clinicians when surgery is not indicated. Poor communication and lack of education about self- management in these consultations have been shown to be associated with increased distress and higher subsequent health care seeking. AIM: To develop a standardised intervention to improve spine care consultations for patients for whom surgery is not beneficial. METHOD: The intervention was developed in six stages. The first three stages included: interviews with patients, an interactive workshop with clinicians from a mix of disciplines, and interviews with spine clinicians about their perspective of the recommendations, their perceived difficulties and potential improvements. Information from these stages was synthesised by an expert panel, creating a draft intervention structure and content. The main features of the intervention and the materials developed were then reviewed by patients and spine clinicians. Finally, the research team incorporated the recommended amendments to produce the intervention. RESULTS: In total, 36 patients and 79 clinicians contributed to the development of the intervention. The final intervention includes three components: a pre-consultation letter with information suggesting that surgery is one possible intervention amongst many, introducing the staff, and alerting patients to bring with them a potted history of interventions tried previously. The intervention includes short online training sessions to improve clinicians' communication skills, during the consultation, in reference to listening skills, validation of patients' pain, and use of appropriate language. Clinicians are also supplied with a list of evidence-based sources for advice and further information to share with patients. Finally, post consultation, a follow up letter includes a short summary of the patients' clinical journey, the results of their examination and tests, and a reminder of recommendations for self-management. CONCLUSION: The intervention includes aspects around patient education and enhanced clinician skills. It was developed with input from a multitude of stakeholders and is based on patients' perceptions of what they would find reassuring and empowering when surgery is excluded. The intervention has the potential to improve the patients care journey and might lead to changes in practice in spine clinicians.

Chatbots to Support People With Dementia and Their Caregivers: Systematic Review of Functions and Quality.

BACKGROUND: Over the past decade, there has been an increase in the use of information technologies to educate and support people with dementia and their family caregivers. At the same time, chatbot technologies have become increasingly popular for use by the public and have been identified as having benefits for health care delivery. However, little is known about how chatbot technologies may benefit people with dementia and their caregivers. OBJECTIVE: This study aims to identify the types of current commercially available chatbots that are designed for use by people with dementia and their caregivers and to assess their quality in terms of features and content. METHODS: Chatbots were identified through a systematic search on Google Play Store, Apple App Store, Alexa Skills, and the internet. An evidence-based assessment tool was used to evaluate the features and content of the identified apps. The assessment was conducted through interrater agreement among 4 separate reviewers. RESULTS: Of the 505 initial chatbots identified, 6 were included in the review. The chatbots assessed varied significantly in terms of content and scope. Although the chatbots were generally found to be easy to use, some limitations were noted regarding their performance and programmed content for dialog. CONCLUSIONS: Although chatbot technologies are well established and commonly used by the public, their development for people with dementia and their caregivers is in its infancy. Given the successful use of chatbots in other health care settings and for other applications, there are opportunities to integrate this technology into dementia care. However, more evidence-based chatbots that have undergone end user evaluation are needed to evaluate their potential to adequately educate and support these populations.

Dedication in a Difficult Context: Faith-Based Nursing in Haiti.

ABSTRACT: Haitian nurses live in a precarious environment, with healthcare disparity and low wages. In the presence of significant politico-social-economic disparities, adverse effects of natural disasters, deleterious infrastructure, challenged self-boundaries, and the burden of caring for high-need patients, the authors sought a better understanding of nurses' perspective of the situation. During qualitative interviews, Haitian nurses in two faith-based hospitals (N = 17) reported feeling powerless yet exhibited resilience and dedication to nursing as a calling. These conditions cry out for support of nurses' self-care needs. Future interventions may help nurses identify better resources to care for themselves and guide their practice.

Renal dysfunction, rod-cone dystrophy, and sensorineural hearing loss caused by a mutation in RRM2B.

More than two decades ago, a recessive syndromic phenotype affecting kidneys, eyes, and ears, was first described in the endogamous Afrikaner population of South Africa. Using whole-exome sequencing of DNA from two affected siblings (and their carrier parents), we identified the novel RRM2B c.786G>T variant as a plausible disease-causing mutation. The RRM2B gene is involved in mitochondrial integrity, and the observed change was not previously reported in any genomic database. The subsequent screening revealed the variant in two newly presenting unrelated patients, as well as two patients in our registry with rod-cone dystrophy, hearing loss, and Fanconi-type renal disease. All patients with the c.786G>T variant share an identical 1.5 Mb haplotype around this gene, suggesting a founder effect in the Afrikaner population. We present ultrastructural evidence of mitochondrial impairment in one patient, to support our thesis that this RRM2B variant is associated with the renal, ophthalmological, and auditory phenotype.

The impact of the c.5603A>T hypomorphic variant on founder mutation screening of ABCA4 for Stargardt disease in South Africa.

Purpose: Seven founder mutations in ABCA4 underlie a large proportion of Stargardt disease in the South African Caucasian population of Afrikaner descent. The Quick 7 assay was locally developed to test for these specific mutations and is available through the National Health Laboratory Service. However, in 2017 it was suggested that one of these mutations, c.2588G>C (p.Gly863Ala), is only pathogenic when present in cis with the c.5603A>T (p.Asn1868Ile) hypomorphic variant. Several patients and family members have been screened and have had their results delivered; thus, a retrospective analysis for the presence of c.5603A>T in all resolved ABCA4 cases was warranted. Methods: In this study, probands with biallelic mutations in ABCA4 and all families carrying the c.2588G>C variant were genotyped for c.5603A>T with restriction fragment length polymorphism analysis. Cosegregation analysis was performed to ascertain the phase of causative mutations. Results: The downgraded c.2588G>C variant was present in 26 families, of whom 24 (92.31%) also carried the hypomorphic variant (cis phase confirmation was possible in 12 families). Two families (7.69%) carried the downgraded variant without the hypomorphic variant; however, in these cases the second disease-causing variant had not been identified. These two families remained in research mode; therefore, family follow-up was not immediately required. Additionally, the hypomorphic variant occurred in cis with two of the other Quick 7 mutations. Conclusions: This study adds to the evidence of the pathogenicity downgrade of c.2588G>C, as it results in disease when in cis with c.5603A>T in this cohort. This work highlights the value of a close link between research and diagnostic laboratories, in keeping abreast of the functionality of variants. It is recommended that the Quick 7 assay be expanded to include c.5603A>T, and that only the complex c.[2588G>C;5603A>T] allele be reported as pathogenic. Confirmation of cis or trans configuration of alleles by the inclusion of familial samples is strongly recommended.

Exploring Patients' Experiences of Internet-Based Self-Management Support for Low Back Pain in Primary Care.

OBJECTIVE: We explored patients' experiences of using Internet-based self-management support for low back pain (LBP) in primary care, with and without physiotherapist telephone guidance. DESIGN: Exploratory descriptive qualitative study using thematic analysis, nested within a randomized feasibility trial. METHODS: Patients with LBP who participated in a feasibility trial of the SupportBack Internet intervention (ISRCTN: 31034004) were invited to take part in semistructured telephone interviews after the three-month intervention period (a convenience sample from within the trial population). Fifteen participants took part (age range = 36-87 years, 66.7% female, characteristics representative of the trial population). Data were analyzed thematically. RESULTS: Analysis resulted in the development of six themes (subthemes in parentheses): Perceptions of SupportBack's design (Clarity and ease of use, Variety and range of information provided, Need for specificity and flexibility), Engaging with the SupportBack intervention, Promoting positive thought processes (Reassurance, Awareness of self-management), Managing behavior with SupportBack (Motivation and goal setting, Using activity as a pain management strategy, Preferences for walking or gentle back exercises), Feeling supported by telephone physiotherapists (Provision of reassurances and clarity, Physiotherapists are motivating), Severity and comorbidity as barriers (Preexisting condition or severity acting as a barrier, Less useful for mild low back pain). CONCLUSIONS: The Internet intervention SupportBack appeared to feasibly support self-management of LBP. Reassurance and ongoing support to implement behavioral changes were central to reported benefits. The addition of physiotherapist telephone support further enhanced the patient experience and the potential utility of the intervention.

Limited pharmaceuticalisation: a qualitative case study of physiotherapist prescribing practices in an NHS Trust in England following the expansion of non-medical prescribing in the UK.

Over the last quarter century, non-medical prescribing in the UK has grown significantly; eight non-medical professional groups now have authority to prescribe a wide range of medicines, suggesting it could be a potent driver of pharmaceuticalisation. In this article, we present data from a case study of physiotherapists' prescribing practices. UK physiotherapists have had legal rights to prescribe medicines since 2005, but relatively little is known about the contribution they make to expanding patient access to medicines. We approached our study through a lens of governmentality to capture the mentalities and micro-practices governing physiotherapist non-medical prescribing. Ethnographic methods were used to gather data from an outpatient orthopaedic service in an NHS Trust in England employing physiotherapist prescribers. From the data, we identified a grid of intelligibility - an organising framework formulated by powerful discourses and technologies of government through which physiotherapist prescribing was acted into being. A primary effect of this grid was the constitution of new physiotherapist subjectivities, mostly as non-prescribers of medicines contrary to policy intentions, underpinned by a familiar and enduring template of medical professionalism.

Age-related deficits in bilateral motor synergies and force coordination.

BACKGROUND: Ageing may cause impairments in executing bilateral movement control. This study investigated age-related changes in interlimb force coordination across multiple trials by quantifying bilateral motor synergies based on the uncontrolled manifold hypothesis. Participants completed the trials with and without visual feedback. METHODS: Twenty healthy individuals (10 older adults and 10 young adults) performed 12 isometric force control trials for the two vision conditions at 5% of maximal voluntary contraction. All dependent variables were analyzed in two-way mixed model (Group × Vision Condition; 2 × 2) ANOVAs with repeated measures on the last factor. RESULTS: The analyses revealed that older adults had greater mean force produced by two hands in both vision conditions (i.e., yes and no visual feedback). Across both vision conditions, the older adult group showed greater asymmetrical force variability (i.e., standard deviation of non-dominant hand > standard deviation of dominant hand) and revealed more positive correlation coefficients between forces produced by two hands as compared with the young adult group. Finally, an index of bilateral motor synergies was significantly greater in young adults than older adults when visual feedback was available. CONCLUSION: The current findings indicate that deficits in interlimb force coordination across multiple trials appeared in older adults.

Distinct roles for the IIId2 sub-domain in pestivirus and picornavirus internal ribosome entry sites.

Viral internal ribosomes entry site (IRES) elements coordinate the recruitment of the host translation machinery to direct the initiation of viral protein synthesis. Within hepatitis C virus (HCV)-like IRES elements, the sub-domain IIId(1) is crucial for recruiting the 40S ribosomal subunit. However, some HCV-like IRES elements possess an additional sub-domain, termed IIId2, whose function remains unclear. Herein, we show that IIId2 sub-domains from divergent viruses have different functions. The IIId2 sub-domain present in Seneca valley virus (SVV), a picornavirus, is dispensable for IRES activity, while the IIId2 sub-domains of two pestiviruses, classical swine fever virus (CSFV) and border disease virus (BDV), are required for 80S ribosomes assembly and IRES activity. Unlike in SVV, the deletion of IIId2 from the CSFV and BDV IRES elements impairs initiation of translation by inhibiting the assembly of 80S ribosomes. Consequently, this negatively affects the replication of CSFV and BDV. Finally, we show that the SVV IIId2 sub-domain is required for efficient viral RNA synthesis and growth of SVV, but not for IRES function. This study sheds light on the molecular evolution of viruses by clearly demonstrating that conserved RNA structures, within distantly related RNA viruses, have acquired different roles in the virus life cycles.

Update on Inherited Retinal Disease in South Africa: Encouraging Diversity in Molecular Genetics.

There is a glaring disparity in the populations included in genetic research; the majority of work involves European-derived cohorts, while other global populations - including Africans - are underrepresented. This is also true for the study of inherited retinal diseases. Being the most ancient of extant populations, African samples carry more variation than others, making them valuable for novel gene and variant discovery. The inclusion of diverse populations in research is essential to gain a more comprehensive understanding of genetic variation and molecular mechanisms of disease.

Type I and III IFNs Produced by Plasmacytoid Dendritic Cells in Response to a Member of the Flaviviridae Suppress Cellular Immune Responses.

The pestivirus noncytopathic bovine viral diarrhea virus (BVDV) can suppress IFN production in the majority of cell types in vitro. However, IFN is detectable in serum during acute infection in vivo for ∼5-7 d, which correlates with a period of leucopoenia and immunosuppression. In this study, we demonstrate that a highly enriched population of bovine plasmacytoid dendritic cells (DCs) produced IFN in response to BVDV in vitro. We further show that the majority of the IFN produced in response to infection both in vitro and in vivo is type III IFN and acid labile. Further, we show IL-28B (IFN-λ3) mRNA is induced in this cell population in vitro. Supernatant from plasmacytoid DCs harvested postinfection with BVDV or recombinant bovine IFN-α or human IL-28B significantly reduced CD4(+) T cell proliferation induced by tubercle bacillus Ag 85-stimulated monocyte-derived DCs. Furthermore, these IFNs induced IFN-stimulated gene expression predominantly in monocyte-derived DCs. IFN-treated immature DCs derived from murine bone marrow also had a reduced capacity to stimulate T cell proliferative responses to tubercle bacillus Ag 85. Immature DCs derived from either source had a reduced capacity for Ag uptake following IFN treatment that is dose dependent. Immunosuppression is a feature of a number of pestivirus infections; our studies suggest type III IFN production plays a key role in the pathogenesis of this family of viruses. Overall, in a natural host, we have demonstrated a link between the induction of type I and III IFN after acute viral infection and transient immunosuppression.