RESUMEN
How disease-associated mutations impair protein activities in the context of biological networks remains mostly undetermined. Although a few renowned alleles are well characterized, functional information is missing for over 100,000 disease-associated variants. Here we functionally profile several thousand missense mutations across a spectrum of Mendelian disorders using various interaction assays. The majority of disease-associated alleles exhibit wild-type chaperone binding profiles, suggesting they preserve protein folding or stability. While common variants from healthy individuals rarely affect interactions, two-thirds of disease-associated alleles perturb protein-protein interactions, with half corresponding to "edgetic" alleles affecting only a subset of interactions while leaving most other interactions unperturbed. With transcription factors, many alleles that leave protein-protein interactions intact affect DNA binding. Different mutations in the same gene leading to different interaction profiles often result in distinct disease phenotypes. Thus disease-associated alleles that perturb distinct protein activities rather than grossly affecting folding and stability are relatively widespread.
Asunto(s)
Enfermedad/genética , Mutación Missense , Mapas de Interacción de Proteínas , Proteínas/genética , Proteínas/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Sistemas de Lectura Abierta , Pliegue de Proteína , Estabilidad ProteicaRESUMEN
Eco-phylogeographic approaches to comparative population genetic analyses allow for the inclusion of intrinsic influences as drivers of intraspecific genetic structure. This insight into microevolutionary processes, including changes within a species or lineage, provides better mechanistic understanding of species-specific interactions and enables predictions of evolutionary responses to environmental change. In this study, we used single nucleotide polymorphisms (SNPs) identified from reduced representation sequencing to compare neutral population structure, isolation by distance (IBD), genetic diversity and effective population size (Ne) across three closely related and co-distributed saltmarsh sparrow species differing along a specialization gradient-Nelson's (Ammospiza nelsoni subvirgata), saltmarsh (A. caudacuta) and seaside sparrows (A. maritima maritima). Using an eco-phylogeographic lens within a conservation management context, we tested predictions about species' degree of evolutionary history and ecological specialization to tidal marshes, habitat, current distribution and population status on population genetic metrics. Population structure differed among the species consistent with their current distribution and habitat factors, rather than degree of ecological specialization: seaside sparrows were panmictic, saltmarsh sparrows showed hierarchical structure and Nelson's sparrows were differentiated into multiple, genetically distinct populations. Neutral population genetic theory and demographic/evolutionary history predicted patterns of genetic diversity and Ne rather than degree of ecological specialization. Patterns of population variation and evolutionary distinctiveness (Shapely metric) suggest different conservation measures for long-term persistence and evolutionary potential in each species. Our findings contribute to a broader understanding of the complex factors influencing genetic variation, beyond specialist-generalist status and support the role of an eco-phylogeographic approach in population and conservation genetics.
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Gorriones , Animales , Gorriones/genética , Ecosistema , Humedales , Evolución Biológica , Polimorfismo de Nucleótido Simple/genética , Variación Genética/genéticaRESUMEN
Combating the current biodiversity crisis requires the accurate documentation of population responses to human-induced ecological change. However, our ability to pinpoint population responses to human activities is often limited to the analysis of populations studied well after the fact. Museum collections preserve a record of population responses to anthropogenic change that can provide critical baseline data on patterns of genetic diversity, connectivity, and population structure prior to the onset of human perturbation. Here, we leverage a spatially replicated time series of specimens to document population genomic responses to the destruction of nearly 90% of coastal habitats occupied by the Savannah sparrow (Passerculus sandwichensis) in California. We sequenced 219 sparrows collected from 1889 to 2017 across the state of California using an exome capture approach. Spatial-temporal analyses of genetic diversity found that the amount of habitat lost was not predictive of genetic diversity loss. Sparrow populations from southern California historically exhibited lower levels of genetic diversity and experienced the most significant temporal declines in genetic diversity. Despite experiencing the greatest levels of habitat loss, we found that genetic diversity in the San Francisco Bay area remained relatively high. This was potentially related to an observed increase in gene flow into the Bay Area from other populations. While gene flow may have minimized genetic diversity declines, we also found that immigration from inland freshwater-adapted populations into tidal marsh populations led to the erosion of divergence at loci associated with tidal marsh adaptation. Shifting patterns of gene flow through time in response to habitat loss may thus contribute to negative fitness consequences and outbreeding depression. Together, our results underscore the importance of tracing the genomic trajectories of multiple populations over time to address issues of fundamental conservation concern.
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Gorriones , Humedales , Animales , Humanos , Metagenómica , Ecosistema , Gorriones/genética , Agua Dulce , Variación GenéticaRESUMEN
BACKGROUND: Amniocentesis for genetic diagnosis is most commonly done between 15 and 22 weeks of gestation but can be performed at later gestational ages. The safety and genetic diagnostic accuracy of amniocentesis have been well-established through numerous large-scale multicenter studies for procedures before 24 weeks, but comprehensive data on late amniocentesis remain sparse. OBJECTIVE: To evaluate the indications, diagnostic yield, safety, and maternal and fetal outcomes associated with amniocentesis performed at or beyond 24 weeks of gestation. STUDY DESIGN: We conducted an international multicenter retrospective cohort study examining pregnant individuals who underwent amniocentesis for prenatal diagnostic testing at gestational ages between 24w0d and 36w6d. The study, spanning from 2011 to 2022, involved 9 referral centers. We included singleton or twin pregnancies with documented outcomes, excluding cases where other invasive procedures were performed during pregnancy or if amniocentesis was conducted for obstetric indications. We analyzed indications for late amniocentesis, types of genetic tests performed, their results, and the diagnostic yield, along with pregnancy outcomes and postprocedure complications. RESULTS: Of the 752 pregnant individuals included in our study, late amniocentesis was primarily performed for the prenatal diagnosis of structural anomalies (91.6%), followed by suspected fetal infection (2.3%) and high-risk findings from cell-free DNA screening (1.9%). The median gestational age at the time of the procedure was 28w5d, and 98.3% of pregnant individuals received results of genetic testing before birth or pregnancy termination. The diagnostic yield was 22.9%, and a diagnosis was made 2.4 times more often for fetuses with anomalies in multiple organ systems (36.4%) compared to those with anomalies in a single organ system (15.3%). Additionally, the diagnostic yield varied depending on the specific organ system involved, with the highest yield for musculoskeletal anomalies (36.7%) and hydrops fetalis (36.4%) when a single organ system or entity was affected. The most prevalent genetic diagnoses were aneuploidies (46.8%), followed by copy number variants (26.3%) and monogenic disorders (22.2%). The median gestational age at delivery was 38w3d, with an average of 59 days between the procedure and delivery date. The overall complication rate within 2 weeks postprocedure was 1.2%. We found no significant difference in the rate of preterm delivery between pregnant individuals undergoing amniocentesis between 24 and 28 weeks and those between 28 and 32 weeks, reinforcing the procedure's safety across these gestational periods. CONCLUSION: Late amniocentesis, at or after 24 weeks of gestation, especially for pregnancies complicated by multiple congenital anomalies, has a high diagnostic yield and a low complication rate, underscoring its clinical utility. It provides pregnant individuals and their providers with a comprehensive diagnostic evaluation and results before delivery, enabling informed counseling and optimized perinatal and neonatal care planning.
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There is a dearth of data on Se status in very old adults. The aims of this study were to assess Se status and its determinants in 85-year-olds living in the Northeast of England by measuring serum Se and selenoprotein P (SELENOP) concentrations and glutathione peroxidase 3 (GPx3) activity. A secondary aim was to examine the interrelationships between each of the biomarkers. In total, 757 participants (463 women, 293 men) from the Newcastle 85+ Study were included. Biomarker concentrations were compared with selected cut-offs (serum Se: suboptimal 70 µg/l and deficient 45 µg/l; SELENOP: suboptimal 4·5 mg/l and deficient 2·6 mg/l). Determinants were assessed using linear regressions, and interrelationships were assessed using restricted cubic splines. Median (inter-quartile range) concentrations of serum Se, SELENOP and of GPx3 activity were 53·6 (23·6) µg/l, 2·9 (1·9) mg/l and 142·1 (50·7) U/l, respectively. Eighty-two percentage and 83 % of participants had suboptimal serum Se (< 70 µg/l) and SELENOP (< 4·5 mg/l), and 31 % and 40 % of participants had deficient serum Se (< 45 µg/l) and SELENOP (< 2·6 mg/l), respectively. Protein intake was a significant determinant of Se status. Additional determinants of serum Se were sex, waist:hip ratio, self-rated health and disease, while sex, BMI and physical activity were determinants of GPx3 activity. There was a linear association between serum Se and SELENOP, and nonlinear associations between serum Se and GPx3 activity and between SELENOP and GPx3 activity. These findings indicate that most participants had suboptimal Se status to saturate circulating SELENOP.
Asunto(s)
Selenio , Masculino , Adulto , Humanos , Femenino , Selenoproteína P/metabolismo , Biomarcadores , Antioxidantes , Inglaterra , Glutatión PeroxidasaRESUMEN
Black men face high rates of police violence, including direct victimization and indirect exposure to or knowledge of harmful policing. This violence can result in death and physical harm, as well as in numerous poor mental health outcomes. There has been little research examining experiences of police violence experienced by Black gay and bisexual men or the effects of police brutality on HIV continuum of care outcomes. To address this important gap, in this exploratory study, we examined the effects of police brutality on engagement in HIV care and adherence to antiretroviral medications. Cross-sectional survey data were collected from 107 Black gay and bisexual men living with HIV. The path analysis showed that men with greater exposure to police violence had increased symptoms of post-traumatic stress disorder and were more likely to have missed HIV care appointments in the past year. Additionally, there was a significant indirect effect of exposure to police violence on missed medication doses via PTSD symptoms.
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Negro o Afroamericano , Infecciones por VIH , Homosexualidad Masculina , Cumplimiento de la Medicación , Policia , Trastornos por Estrés Postraumático , Violencia , Humanos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Estudios Transversales , Adulto , Homosexualidad Masculina/psicología , Homosexualidad Masculina/estadística & datos numéricos , Trastornos por Estrés Postraumático/psicología , Trastornos por Estrés Postraumático/epidemiología , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Persona de Mediana Edad , Violencia/psicología , Minorías Sexuales y de Género/psicología , Minorías Sexuales y de Género/estadística & datos numéricos , Bisexualidad/psicología , Fármacos Anti-VIH/uso terapéutico , Encuestas y Cuestionarios , Víctimas de Crimen/psicologíaRESUMEN
People living with HIV (PLH) who live in rural areas of the United States (US) face more challenges to obtaining medical care and suffer higher mortality rates compared to non-rural PLH. Compared with younger PLH, older PLH (age 50+) also face additional challenges to maintaining their health and wellbeing. Despite the heightened barriers to receiving care and remaining adherent to treatment among older rural PLH, few interventions to increase viral suppression and improve quality of life exist for this population. We pilot-tested four remotely-delivered interventions-group-based social support, group-based stigma-reduction, individual strengths-based case management, and individual technology detailing-aimed to improve care engagement and quality of life in rural older PLH in the southern US. Participants (N = 61, Mage = 58, 75% male) completed surveys and self-collected blood specimens at baseline and 3 months; in between, they were randomized to 0-4 interventions. We assessed feasibility, acceptability, and preliminary impact on medication adherence, viral suppression, quality of life, depressive symptoms, and hypothesized mediating mechanisms. More than 80% participated in assigned intervention(s), and 84% completed the study. Interventions were highly acceptable to participants, with more than 80% reporting they would recommend interventions to peers. More than 80% found the social support and case management interventions to be relevant and enjoyable. We found promising preliminary impact of interventions on quality of life, medication adherence, depressive symptoms, internalized stigma, and loneliness. Remotely-delivered interventions targeting rural older PLH are feasible to conduct and acceptable to participants. Larger scale study of these interventions is warranted.
RESUMEN: A pesar de las múltiples barreras para la adherencia a la medicación y la recepción de atención entre las personas mayores de zonas rurales que viven con el VIH, existen pocas intervenciones para mejorar la supresión viral y la calidad de vida para esta población. Realizamos pruebas piloto de intervenciones realizadas de forma remota (grupos de apoyo social, grupos de reducción del estigma, manejo de casos basado en los puntos fuertes y "technology detailing") entre las personas que viven con el VIH en zonas rurales del sur de Estados Unidos. Los participantes (N = 61, Medad = 58, 75% hombres) completaron encuestas y recolectaron muestras de sangre al inicio y a los 3 meses; en el medio, fueron asignados al azar a 04 intervenciones. Evaluamos la viabilidad, la aceptabilidad y el impacto preliminar. Más del 80% participó en la(s) intervención(es) y el 84% completó el estudio. Las intervenciones fueron muy aceptables para los participantes; más del 80% consideró que las intervenciones de apoyo social y gestión de casos eran relevantes y agradables. Las intervenciones tuvieron un impacto preliminar prometedor sobre la calidad de vida, la adherencia a la medicación, los síntomas depresivos, el estigma y la soledad. Las intervenciones realizadas a distancia dirigidas a las personas que viven con el VIH en zonas rurales de edad avanzada son viables y aceptables, y se justifica un estudio a mayor escala.
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Infecciones por VIH , Calidad de Vida , Humanos , Masculino , Anciano , Persona de Mediana Edad , Femenino , Estudios de Factibilidad , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , Apoyo Social , Población RuralRESUMEN
This study examined the relationship between exposure to community violence and HIV care engagement among 107 Black gay or bisexual men living with HIV in Chicago. Measures assessed the importance of demographic covariates (age, annual income, health insurance status, and years living with HIV), community violence exposures, mental health, social support, in explaining variations in missed doses of antiretroviral therapy (ART) medication and missed HIV care appointments. Results showed that participants who reported higher rates of exposure to community violence were two times more likely to have missed ART doses and HIV care appointments. Participants who reported depression scores were two times more likely to have greater non-ART adherence. Finally, older participants were more likely to report fewer missed ART doses. More research is needed to clarify the mechanisms between age or depression and ART adherence given community violence exposure. Health care providers should screen for depression when attempting to promote better ART adherence and keeping HIV care appointments for Black gay and bisexual men living with HIV. Younger Black gay and bisexual men living with HIV may be more vulnerable than older men for missed ART doses and may require additional screening and follow-up.
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Bisexualidad , Negro o Afroamericano , Infecciones por VIH , Homosexualidad Masculina , Cumplimiento de la Medicación , Humanos , Masculino , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/psicología , Adulto , Chicago/epidemiología , Negro o Afroamericano/psicología , Negro o Afroamericano/estadística & datos numéricos , Homosexualidad Masculina/psicología , Homosexualidad Masculina/estadística & datos numéricos , Persona de Mediana Edad , Cumplimiento de la Medicación/psicología , Cumplimiento de la Medicación/estadística & datos numéricos , Bisexualidad/psicología , Bisexualidad/estadística & datos numéricos , Depresión/epidemiología , Minorías Sexuales y de Género/psicología , Minorías Sexuales y de Género/estadística & datos numéricos , Apoyo Social , Violencia/estadística & datos numéricos , Violencia/psicología , Fármacos Anti-VIH/uso terapéuticoRESUMEN
Black sexual minority men who have sex with men (MSM) in the United States are at disparate risk for contracting HIV infection, but pre-exposure prophylaxis (PrEP) use is suboptimal. Social network methods were used to recruit a community sample of racial minority MSM and transgender women (TGW) in two Midwestern US cities. 250 PrEP-eligible (HIV-negative) participants completed measures assessing current and intended PrEP use; demographic characteristics; PrEP knowledge, attitudes, norms, stigma, and self-efficacy; and structural barriers to PrEP. Multivariate analyses established predictors of current and intended PrEP use. Only 12% of participants reported currently using PrEP, which was associated with greater PrEP knowledge and not having a main partner, with trends for greater PrEP use by younger participants and those with partners living with HIV. Among participants not currently on PrEP, strength of PrEP use intentions was associated with higher PrEP knowledge, PrEP descriptive social norms, and PrEP use self-efficacy. This study is among few to directly compare Black who have adopted PrEP with those who have not. Its findings underscore the potential benefits of employing social network approaches for strengthening PrEP use peer norms, increasing PrEP knowledge and self-efficacy, and optimizing PrEP uptake among racial minority MSM and TGW.
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Negro o Afroamericano , Infecciones por VIH , Conocimientos, Actitudes y Práctica en Salud , Homosexualidad Masculina , Profilaxis Pre-Exposición , Personas Transgénero , Humanos , Masculino , Profilaxis Pre-Exposición/estadística & datos numéricos , Adulto , Personas Transgénero/estadística & datos numéricos , Personas Transgénero/psicología , Homosexualidad Masculina/estadística & datos numéricos , Homosexualidad Masculina/psicología , Homosexualidad Masculina/etnología , Infecciones por VIH/prevención & control , Infecciones por VIH/etnología , Negro o Afroamericano/estadística & datos numéricos , Negro o Afroamericano/psicología , Femenino , Medio Oeste de Estados Unidos , Persona de Mediana Edad , Adulto Joven , Fármacos Anti-VIH/uso terapéutico , Estigma Social , Minorías Sexuales y de Género/estadística & datos numéricos , Minorías Sexuales y de Género/psicología , Parejas Sexuales/psicología , Adolescente , AutoeficaciaRESUMEN
The goal of this study was to examine the effects of racial discrimination, depression, and Black LGBTQ community support on HIV care outcomes among a sample of Black sexually minoritized men living with HIV. We conducted a cross-sectional survey with 107 Black sexually minoritized men living with HIV in Chicago. A path model was used to test associations between racial discrimination, Black LGBTQ community support, depressive symptoms, and missed antiretroviral medication doses and HIV care appointments. Results of the path model showed that men who had experienced more racism had more depressive symptoms and subsequently, missed more doses of HIV antiretroviral medication and had missed more HIV care appointments. Greater Black LGBTQ community support was associated with fewer missed HIV care appointments in the past year. This research shows that anti-Black racism may be a pervasive and harmful determinant of HIV inequities and a critical driver of racial disparities in ART adherence and HIV care engagement experienced by Black SMM. Black LGBTQ community support may buffer against the effects of racial discrimination on HIV care outcomes by providing safe, inclusive, supportive spaces for Black SMM.
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Infecciones por VIH , Racismo , Masculino , Humanos , Infecciones por VIH/tratamiento farmacológico , Negro o Afroamericano , Estudios Transversales , Conducta SexualRESUMEN
Previous research has demonstrated associations between experiences of microaggressions and negative mental and physical health outcomes, and national organizations such as the Centers for Disease Control and Prevention have acknowledged racism as a public health issue. Individuals with multiple marginalized identities, such as young Black men who have sex with men and transgender women, are commonly affected by discrimination and stigma, contributing to health disparities. One possible path by which microaggressions are linked to negative health outcomes for these groups is their impact on individuals' decisions to conceal their sexual identity, in some cases leading to increased stress and use of maladaptive coping strategies. We surveyed 280 young Black male (86%) and transgender or non-binary (14%) individuals between the ages of 16-25 years old (M = 21.68, SD = 2.73) who reported being recently sexually active with men about their experiences with intersectional microaggressions, concealment of their sexual identity, psychological distress, and substance use before and during sexual activity. Structural equation modeling revealed that experiences of microaggressions were associated with greater sexual identity concealment, and concealment partially mediated the relationship between microaggressions and psychological distress. While microaggressions were associated with greater substance use, sexual identity concealment did not mediate this relationship. Findings have implications for addressing health disparities among this population.
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Minorías Sexuales y de Género , Trastornos Relacionados con Sustancias , Personas Transgénero , Masculino , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Homosexualidad Masculina/psicología , Personas Transgénero/psicología , Salud Mental , Microagresión , Conducta SexualRESUMEN
BACKGROUND: Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. METHODS: A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN. Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. RESULTS: Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. CONCLUSIONS: These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.
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Síndrome de Birt-Hogg-Dubé , Carcinoma de Células Renales , Pólipos del Colon , Neoplasias Renales , Humanos , Masculino , Femenino , Anciano , Síndrome de Birt-Hogg-Dubé/genética , Síndrome de Birt-Hogg-Dubé/patología , Penetrancia , Proteínas Proto-Oncogénicas/genética , Proteínas Supresoras de Tumor/genética , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genéticaRESUMEN
OBJECTIVE: This guideline provides recommendations for the prevention of Rh D alloimmunization (isoimmunization) in pregnancy, including parental testing, routine postpartum and antepartum prophylaxis, and other clinical indications for prophylaxis. Prevention of red cell alloimmunization in pregnancy with atypical antigens (other than the D antigen), for which immunoprophylaxis is not currently available, is not addressed in this guideline. TARGET POPULATION: All Rh D-negative pregnant individuals at risk for Rh D alloimmunization due to potential exposure to a paternally derived fetal Rh D antigen. OUTCOMES: Routine postpartum and antepartum Rh D immunoprophylaxis reduces the risk of Rh D alloimmunization at 6 months postpartum and in a subsequent pregnancy. BENEFITS, HARMS, AND COSTS: This guideline details the population of pregnant individuals who may benefit from Rho(D) immune globulin (RhIG) immunoprophylaxis. Thus, those for whom the intervention is not required may avoid adverse effects, while those who are at risk of alloimmunization may mitigate this risk for themselves and/or their fetus. EVIDENCE: For recommendations regarding use of RhIG, Medline and Medline in Process via Ovid and Embase Classic + Embase via Ovid were searched using both the trials and observational studies search strategies with study design filters. For trials, the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Database of Abstracts of Reviews of Effects via Ovid were also searched. All databases were searched from January 2000 to November 26, 2019. Studies published before 2000 were captured from the grey literature of national obstetrics and gynaecology specialty societies, luminary specialty journals, and bibliographic searching. A formal process for the systematic review was undertaken for this update, as described in the systematic review manuscript published separately. VALIDATION METHODS: The authors rated the quality of evidence and strength of recommendations using the SOGC's modified GRADE approach. See Appendix A (Tables A1 for definitions and A2 for interpretations of strong and conditional [weak] recommendations). INTENDED AUDIENCE: The intended users of this guideline include prenatal care providers such as obstetricians, midwives, family physicians, emergency room physicians, and residents, as well as registered nurses and nurse practitioners. TWEETABLE ABSTRACT: An updated Canadian guideline for prevention of Rh D alloimmunization addresses D variants, cffDNA for fetal Rh type, and updates recommendations on timing of RhIG administration. SUMMARY STATEMENTS: RECOMMENDATIONS.
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Isoinmunización Rh , Globulina Inmune rho(D) , Humanos , Isoinmunización Rh/prevención & control , Femenino , Embarazo , Globulina Inmune rho(D)/uso terapéutico , Globulina Inmune rho(D)/administración & dosificación , Sistema del Grupo Sanguíneo Rh-Hr/inmunologíaRESUMEN
INTRODUCTION: This study aimed to assess prevalence of back pain among older people living with HIV (PLH) in rural areas of the United States (US); compare the presence of comorbidities, socioeconomic factors, and sociodemographic factors among older PLH in rural areas of the US with and without back pain; and examine the associations between back pain, depression, and QOL among older PLH in rural areas of the US. METHODS: Cross-sectional data was collected among US rural dwelling PLH of at least 50 years of age. Multiple logistic regression was performed to examine the association between back pain and depression. Multiple linear regression was performed to assess the association between back pain and QOL. RESULTS: A total of 38.8% (n = 164) of participants self-reported back pain. PLH with back pain were more likely to have depression (60.87%, n = 98). PLH with back pain had lower mean QOL scores (53.01 ± 18.39). Back pain was associated with greater odds of having depression (OR 1.61 [CI 0.99-2.61], p = .054) and was significantly associated with lower QOL (p < .001). CONCLUSIONS: Prevention strategies to reduce back pain and poor HIV outcomes among PLH living in rural areas of the US are needed.
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Glucocorticoids are commonly used for neurological disorders, but they can have significant adverse effects, including adrenal insufficiency, hyperglycaemia, osteoporosis and increased infection risk. Long-term use of corticosteroids requires the prescriber to plan risk mitigation, including monitoring and often coprescribing. This article highlights the potential risks of corticosteroid prescribing and draws together up-to-date guidance with multispecialty input to clarify ways of reducing those risks. We discuss home blood glucose monitoring and consider a steroid safety checklist to promote safer steroid prescribing.
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Glucocorticoides , Neurología , Humanos , Insuficiencia Suprarrenal/tratamiento farmacológico , Insuficiencia Suprarrenal/inducido químicamente , Glucocorticoides/uso terapéutico , Glucocorticoides/efectos adversos , Enfermedades del Sistema Nervioso/tratamiento farmacológico , Neurología/métodosRESUMEN
Chronotype is linked to adverse health measures and may have important associations with obstructive sleep apnea and blood pressure, but data are limited. This study aimed to determine the separate and combined associations of chronotype with obstructive sleep apnea and blood pressure in a middle-aged community population. Adults (n = 811) from the Raine Study (female = 59.2%; age mean [range] = 56.6 [42.1-76.6] years) were assessed for chronotype (Morningness-Eveningness Questionnaire), blood pressure and hypertension (doctor diagnosed or systolic blood pressure ≥ 140 mmHg and/or diastolic ≥ 90 mmHg), and obstructive sleep apnea at different in-laboratory apnea-hypopnea index thresholds (5, 10, 15 events per hr). Linear and logistic regression models examined relationships between chronotype and the presence and severity of obstructive sleep apnea, blood pressure, hypertension, and blood pressure stratified by obstructive sleep apnea severity at above-mentioned apnea-hypopnea index thresholds. Covariates included age, sex, body mass index, alcohol consumption, smoking, physical activity, sleep duration, anti-hypertensive medication, insomnia, and depressive symptoms. Most participants were categorised as morning (40%) or intermediate (43%), with 17% meeting criteria for evening chronotypes. Participants with apnea-hypopnea index ≥ 15 events per hr and morning chronotype had higher systolic (9.9 mmHg, p < 0.001) and a trend for higher diastolic blood pressure (3.4 mmHg, p = 0.07) compared with those with an evening chronotype, and higher systolic blood pressure compared with those with an intermediate chronotype (4.8 mmHg, p = 0.03). Across chronotype categories, no differences in systolic or diastolic blood pressure or odds of hypertension were found at apnea-hypopnea index thresholds of ≥ 5 or ≥ 10 events per hr. Among participants with apnea-hypopnea index ≥ 15 events per hr, systolic blood pressure is higher in those with a morning chronotype than evening and intermediate chronotypes. Assessment for morning chronotype may improve risk stratification for hypertension in patients with obstructive sleep apnea.
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Hipertensión , Apnea Obstructiva del Sueño , Adulto , Persona de Mediana Edad , Humanos , Femenino , Presión Sanguínea/fisiología , Cronotipo , Estudios Transversales , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Hipertensión/complicaciones , Hipertensión/epidemiología , Sueño/fisiologíaRESUMEN
Intersectional stigma and discrimination have increasingly been recognized as impediments to the health and well-being of young Black sexual minority men (YBSMM) and transgender women (TW). However, little research has examined the relationship between intersectional discrimination and HIV pre-exposure prophylaxis (PrEP) outcomes. This study with 283 YBSMM and TW examines the relationship between intersectional discrimination and current PrEP use and likelihood of future PrEP use. Path models were used to test associations between intersectional discrimination, resilience and social support, and PrEP use and intentions. Individuals with higher levels of anticipated discrimination were less likely to be current PrEP users (OR = 0.59, p = .013), and higher levels of daily discrimination were associated with increased likelihood of using PrEP in the future (B = 0.48 (0.16), p = .002). Greater discrimination was associated with higher levels of resilience, social support, and connection to the Black LGBTQ community. Social support mediated the effect of day-to-day discrimination on likelihood of future PrEP use. Additionally, there was a significant and negative indirect effect of PrEP social concerns on current PrEP use via Black LGBTQ community connectedness. The results of this study highlight the complexity of the relationships between discrimination, resilience, and health outcomes.
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Infecciones por VIH , Profilaxis Pre-Exposición , Minorías Sexuales y de Género , Transexualidad , Masculino , Humanos , Femenino , Homosexualidad Masculina , Infecciones por VIH/epidemiología , Infecciones por VIH/prevención & control , Estigma Social , Profilaxis Pre-Exposición/métodos , Apoyo SocialRESUMEN
BACKGROUND: Obstructive sleep apnoea (OSA) and perioperative respiratory adverse events are significant risks for anaesthesia in children undergoing adenotonsillectomy. Upper airway collapse is a crucial feature of OSA that contributes to respiratory adverse events. A measure of upper airway collapsibility to identify undiagnosed OSA can help guide perioperative management. We investigated the utility of pharyngeal closing pressure (PCLOSE) for predicting OSA and respiratory adverse events. METHODS: Children scheduled for elective adenotonsillectomy underwent in-laboratory polysomnography 2-12 weeks before surgery. PCLOSE measurements were obtained while the child was anaesthetised and breathing spontaneously just before surgery. Logistic regression was used to assess the predictive performance of PCLOSE for detecting OSA and perioperative respiratory adverse events after adjusting for potential covariates. RESULTS: In 52 children (age, mean [standard deviation] 5.7 [1.8] yr; 20 [38%] females), airway collapse during PCLOSE was observed in 42 (81%). Of these, 19 of 42 (45%) patients did not have OSA, 15 (36%) had mild OSA, and eight (19%) had moderate-to-severe OSA. All 10 children with no evidence of airway collapse during the PCLOSE measurements did not have OSA. PCLOSE predicted moderate-to-severe OSA (odds ratio [OR] 1.71; 95% confidence interval [CI]: 1.2-2.8; P=0.011). All children with moderate-to-severe OSA could be identified at a PCLOSE threshold of -4.0 cm H2O (100% sensitivity), and most with no or mild OSA were ruled out (64.7% specificity; receiver operating characteristic/area under the curve=0.857). However, there was no significant association between respiratory adverse events and PCLOSE (OR 1.0; 95% CI: 0.8-1.1; P=0.641). CONCLUSIONS: Measurement of PCLOSE after induction of anaesthesia can reliably identify moderate or severe OSA but not perioperative respiratory adverse events in children before adenotonsillectomy. CLINICAL TRIAL REGISTRATION: ANZCTR ACTRN 12617001503314.
Asunto(s)
Apnea Obstructiva del Sueño , Tonsilectomía , Femenino , Humanos , Niño , Masculino , Apnea Obstructiva del Sueño/diagnóstico , Faringe , Respiración , Polisomnografía , Tonsilectomía/efectos adversosRESUMEN
BACKGROUND: Secreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape. METHODS: We describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants. RESULTS: From the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup. CONCLUSION: Common phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of 'myopathy'.
Asunto(s)
Fracturas por Compresión , Osteogénesis Imperfecta , Escoliosis , Fracturas de la Columna Vertebral , Colágeno Tipo I/genética , Humanos , Mutación , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/patología , Osteonectina/genética , FenotipoRESUMEN
AIM: The primary aim of this study was to review the diagnosis, management and outcome of Candida meningitis/ventriculitis in our hospital over a ten-year period. MATERIALS AND METHODS: We retrospectively reviewed all culture and 18s rRNA nucleic acid positive CSF specimens processed between 1st January 2010 and 31st December 2020. Patient records were subsequently reviewed to assess the significance of the isolate. RESULTS: Of 851 culture-positive cerebrospinal fluid (CSF) specimens, Candida spp. were isolated from 29 (3.4%), representing infection in 12 patients. One culture-negative specimen was positive for Candida on 18s rRNA testing. Of the 13 patients, eight were male; 61.5% and the median age was 47 years; range: 20-70. The median interval from admission to onset of infection and culture positivity was 24 days (range: 1-63 days). All patients had a central nervous system (CNS) device in situ (external ventricular drain: 11; ventriculoperitoneal shunt: 1; lumbar drain: 1). Four were colonised with Candida spp. before meningitis/ventriculitis diagnosis, from wounds (n = 3), respiratory (n = 3), and urine (n = 1) specimens. On culture, the most common species was Candida albicans (n = 8), followed by C. parapsilosis (n = 2), C. tropicalis (n = 1), and C. dubliniensis (n = 1). The median number of follow-up CSFs per patient was nine (range; 3-22), with a median of 6 days to CSF sterility (range 3-10 days). Treatment included; liposomal amphotericin B (n = 5), fluconazole (n = 2), liposomal amphotericin B, and flucytosine (n = 2), liposomal amphotericin B, fluconazole and flucytosine (n = 3), and intra-ventricular amphotericin B (n = 1). Median treatment duration was 25 days (range 11-76) and CNS device removal occurred in 12 patients. The median length-of-stay (LOS) was 58 days (range 24-406). On discharge, moderate to severe disability (Modified Rankin Scale [mRS] 3-5) was evident in eight patients. Two patients died and one was lost to follow-up. CONCLUSION: Meningitis/ventriculitis due to Candida spp. is an uncommon but challenging infection, usually associated with a device, increased morbidity, LOS, and necessitating prolonged treatment. Neurosurgeons need to be aware of these issues in managing and in communicating with such complex patients.