Relation between Body Composition Trajectories from Childhood to Adolescence and Nonalcoholic Fatty Liver Disease Risk.

NAFLD has become the leading cause of chronic liver disease in children, as a direct consequence of the high prevalence of childhood obesity. This study aimed to characterize body composition trajectories from childhood to adolescence and their association with the risk of developing nonalcoholic fatty liver disease (NAFLD) during adolescence. The participants were part of the 'Chilean Growth and Obesity Cohort Study', comprising 784 children who were followed prospectively from age 3 years. Annual assessments of nutritional status and body composition were conducted, with ultrasound screening for NAFLD during adolescence revealing a 9.8% prevalence. Higher waist circumference measures were associated with NAFLD from age 3 years (p = 0.03), all skin folds from age 4 years (p < 0.01), and DXA body fat measurements from age 12 years (p = 0.01). The fat-free mass index was higher in females (p = 0.006) but not in males (p = 0.211). The second and third tertiles of the fat mass index (FMI) had odds ratios for NAFLD during adolescence of 2.19 (1.48-3.25, 95% CI) and 6.94 (4.79-10.04, 95% CI), respectively. Elevated waist circumference, skin folds, and total body fat were identified as risk factors for future NAFLD development. A higher FMI during childhood was associated with an increased risk of NAFLD during adolescence.

Developing a reporting item checklist for studies of HIV drug resistance prevalence or incidence: a mixed methods study.

BACKGROUND: Adequate surveillance of HIV drug resistance prevalence is challenged by heterogenous and inadequate data reporting. To address this issue, we recently published reporting guidance documentation for studies of HIV drug resistance prevalence and incidence. OBJECTIVES: In this study, we describe the methods used to develop this reporting guidance. DESIGN: We used a mixed-methods sequential explanatory design involving authors and users of studies of HIV drug resistance prevalence. In the quantitative phase, we conducted a cross-sectional electronic survey (n=51). Survey participants rated various reporting items on whether they are essential to report. Validity ratios were computed to determine the items to discuss in the qualitative phase. In the qualitative phase, two focus group discussions (n=9 in total) discussed this draft item checklist, providing a justification and examples for each item. We conducted a descriptive qualitative analysis of the group discussions to identify emergent themes regarding the qualities of an essential reporting item. RESULTS: We identified 38 potential reporting items that better characterise the study participants, improve the interpretability of study results and clarify the methods used for HIV resistance testing. These items were synthesised to create the reporting item checklist. Qualitative insights formed the basis of the explanation, elaboration, and rationale components of the guidance document. CONCLUSIONS: We generated a list of reporting items for studies on the incidence or prevalence of HIV drug resistance along with an explanation of why researchers believe these items are important. Mixed methods allowed for the simultaneous generation and integration of the item list and qualitative insights. The integrated findings were then further developed to become the subsequently published reporting guidance.

Long-term remission of infantile Takayasu arteritis associated with germline CBL syndrome after allogeneic hematopoietic stem cell transplantation: A case report and literature review.

Takayasu arteritis (TA) is a large-vessel vasculitis that rarely presents in infancy. Casitas B-lineage lymphoma (CBL) syndrome is a rare genetic disorder due to heterozygous CBL gene germline pathogenic variants that is characterized by a predisposition to develop juvenile myelomonocytic leukemia (JMML). Vasculitis, including TA, has been reported in several patients. Herein, we describe a patient with CBL syndrome, JMML, and TA, developing long-term remission of this vasculitis after allogeneic hematopoietic stem cell transplant (HSCT), and perform a literature review of CBL syndrome with vasculitis or vasculopathy. We report a female patient with growth delay, developmental issues, and congenital heart disease who was admitted at 14 months of age with massive splenomegaly, lymphadenopathy, fever, and hypertension. Body imaging studies revealed arterial stenosis and wall inflammation of the aorta and multiple thoracic and abdominal branches. Whole exome sequencing revealed a pathogenic variant in CBL with loss of heterozygosity in blood cells, diagnosing CBL syndrome, complicated by JMML and TA. Allogeneic HSCT induced remission of JMML and TA, permitting discontinuation of immunosuppression after 12 months. Six years later, her TA is in complete remission off therapy. A literature review identified 18 additional cases of CBL syndrome with vasculitis or vasculopathy. The pathogenesis of vasculitis in CBL syndrome appears to involve dysregulated T cell function and possibly increased angiogenesis. This case advances the understanding of vascular involvement in CBL syndrome and of the genetic, immune, and vascular interplay in TA, offering insights for treating CBL syndrome and broader TA.

Water quality trends of streams in Puerto Rico: Evaluating 50 years of the Clean Water Act.

Water quality regulations entail a substantial commitment of resources from governments and private entities. It is important to continually evaluate the effectiveness of these regulations to ensure they are having the intended impact. In this paper, we evaluated nutrient data as indicators of primary productivity and dissolved oxygen (DO) concentrations and pH as response variables to assess historical water quality trends from 55 stations of Puerto Rico. The stations were divided into impaired versus non-impaired categories based on their historical total phosphorus (TP) mean concentration. Mean TP and total nitrogen (TN) concentrations were significantly higher in the impaired stations relative to the non-impaired stations. In contrast, DO mean concentrations and mean pH values were significantly lower in the impaired stations. A generalized additive mixed model was used to demonstrate temporal trends. A significant decrease in TP and TN concentrations was observed with time at the impaired stations. This was accompanied by significant increases in DO concentrations and pH. The non-impaired stations showed a marginal (statistically nonsignificant) decreasing trend with time. The large reductions in nutrient concentrations observed at the impaired stations seem to be related to the closure of several primary wastewater treatment plants (WWTPs) across the island. The conversion of abandoned crop agricultural lands into secondary forest in recent decades has resulted in small but significant decreases in TN (not TP) in receiving streams. We conclude that the Clean Water Act has promoted improvements in water quality in Puerto Rico by advancing upgrades in sanitary infrastructure and the regulation of point sources of pollution.

Key Grazing Behaviours of Beef Cattle Identify Specific Genotypes of the Glutamate Metabotropic Receptor 5 Gene (GRM5).

Genotype-phenotype associations between the bovine genome and grazing behaviours measured over time and across contexts have been reported in the past decade, with these suggesting the potential for genetic control over grazing personalities in beef cattle. From the large array of metrics used to describe grazing personality behaviours (GP-behaviours), it is still unclear which ones are linked to specific genes. Our prior observational study has reported associations and trends towards associations between genotypes of the glutamate metabotropic receptor 5 gene (GRM5) and four GP-behaviours, yet the unbalanced representation of GRM5 genotypes occurring in observational studies may have limited the ability to detect associations. Here, we applied a subsampling technique to create a genotypically-balanced dataset in a quasi-manipulative experiment with free ranging cows grazing in steep and rugged terrain of New Zealand's South Island. Using quadratic discriminant analysis, two combinations of eleven GP-behaviours (and a total of fifteen behaviours) were selected to build an exploration model and an elevation model, respectively. Both models achieved ∼ 86% accuracy in correctly discriminating cows' GRM5 genotypes with the training dataset, and the exploration model achieved 85% correct genotype prediction of cows from a testing dataset. Our study suggests a potential pleiotropic effect, with GRM5 controlling multiple grazing behaviours, and with implications for the grazing of steep and rugged grasslands. The study highlights the importance of grazing behavioural genetics in cattle and the potential use of GRM5 markers to select individuals with desired grazing personalities and built herds that collectively utilize steep and rugged rangelands sustainably.

Evaluating fluvoxamine for the outpatient treatment of COVID-19: A systematic review and meta-analysis.

This systematic review and meta-analysis of randomised controlled trials (RCTs) aimed to evaluate the efficacy, safety, and tolerability of fluvoxamine for the outpatient management of COVID-19. We conducted this review in accordance with the PRISMA 2020 guidelines. Literature searches were conducted in MEDLINE, EMBASE, International Pharmaceutical Abstracts, CINAHL, Web of Science, and CENTRAL up to 14 September 2023. Outcomes included incidence of hospitalisation, healthcare utilization (emergency room visits and/or hospitalisation), mortality, supplemental oxygen and mechanical ventilation requirements, serious adverse events (SAEs) and non-adherence. Fluvoxamine 100 mg twice a day was associated with reductions in the risk of hospitalisation (risk ratio [RR] 0.75, 95% confidence interval [CI] 0.58-0.97; I 2  = 0%) and reductions in the risk of healthcare utilization (RR 0.68, 95% CI 0.53-0.86; I 2  = 0%). While no increased SAEs were observed, fluvoxamine 100 mg twice a day was associated with higher treatment non-adherence compared to placebo (RR 1.61, 95% CI 1.22-2.14; I 2  = 53%). In subgroup analyses, fluvoxamine reduced healthcare utilization in outpatients with BMI ≥30 kg/m2 , but not in those with lower BMIs. While fluvoxamine offers potential benefits in reducing healthcare utilization, its efficacy may be most pronounced in high-risk patient populations. The observed non-adherence rates highlight the need for better patient education and counselling. Future investigations should reassess trial endpoints to include outcomes relating to post-COVID sequelaes. Registration: This review was prospectively registered on PROSPERO (CRD42023463829).

Checklist for studies of HIV drug resistance prevalence or incidence: rationale and recommended use.

HIV drug resistance (HIVDR) is a major challenge to the effectiveness of antiretroviral therapy. Global efforts in addressing HIVDR require clear, transparent, and replicable reporting in HIVDR studies. We describe the rationale and recommended use of a checklist that should be included in reports of HIVDR incidence and prevalence. After preliminary consultations with experts on HIVDR and establishing the need for guidance on HIVDR reporting, we used a sequential, explanatory, mixed methods approach to create the checklist; together with the accompanying articles, the checklist was reviewed by the authors and validated externally. The checklist for studies on HIVDR prevalence or incidence (CEDRIC-HIV) includes 15 recommended items that would enhance transparency and facilitate interpretation, comparability, and replicability of HIVDR studies. CEDRIC-HIV will help authors of HIVDR studies prepare research reports and assist reviewers and editors in assessments of completeness of reporting. The checklist will also facilitate statistical pooling and interpretation of HIVDR data.

Quality Variations in Thyrotropin Alfa.

Thyrotropin alfa is a heterodimeric glycoprotein containing human thyroid stimulating hormone (TSH). It is used as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy. Inter-lot variability in the Fourier transform near-infrared spectra of 30 samples obtained from four separate lots of Thyrogen® was detected in the Drug Quality Study (DQS). The vials fell into two distinct groups (rtst = 0.90, rlim= 0.98, p=0.02). In addition, one vial of the 30 (3%) appeared 4.7 multidimensional SDs from all of the other vials, suggesting that it also represents a different material.

Evaluating the Efficacy and Safety of Laparoscopic Heller Myotomy in Treating Achalasia

Introduction: Laparoscopic Heller myotomy (LHM) is widely recognized as the standard surgical treatment for esophageal achalasia. However, there is a lack of local data regarding the clinical characteristics of patients and the outcomes of this intervention. Methodology: This retrospective study analyzed patients who underwent LHM over an eight-year period. Demographic, operative, and postoperative variables were assessed. The Eckardt score was used to compare symptoms before and after the intervention. Continuous variables were presented as means. Results: Among the 39 patients assessed, 27 met the inclusion criteria. Of these, 51% were male, with an average age of 48 years. The average lower esophageal sphincter pressure was 36 mmHg. The mean operative time and bleeding were 133 minutes and 34 mL, respectively. The average length of the myotomy was 8.3 cm. Partial fundoplication was performed in all cases, and intraoperative endoscopy was conducted in 88% of the cases. Two intraoperative mucosal perforations occurred. The average length of hospital stay was 2.7 days. There was one medical complication but no mortality. Dysphagia significantly improved by 95%, and the mean Eckardt score decreased from 7.7 to 1.2 after surgery (p < 0.001). The average follow-up period was 24 months. Conclusion: LHM with partial fundoplication proves to be an effective and safe procedure for treating achalasia. It results in the resolution of dysphagia in 95% of cases and carries minimal morbidity. Therefore, LHM should be considered the definitive treatment of choice for achalasia.

Introducción: la miotomía de Heller laparoscópica (MHL) se considera el tratamiento quirúrgico estándar en acalasia esofágica. A nivel local se desconocen las características clínicas de los pacientes y los resultados de la intervención. Metodología: estudio retrospectivo que incluye pacientes llevados a MHL durante un periodo de 8 años. Se analizaron variables demográficas, operatorias y posoperatorias. Mediante el puntaje de Eckardt se compararon síntomas antes y después de la intervención. Las variables continuas se expresan en promedios. Resultados: 27 de 39 pacientes cumplieron los criterios de inclusión. El 51% fueron hombres y el promedio de edad fue de 48 años. La presión promedio del esfínter esofágico inferior fue de 36 mm Hg. El promedio de tiempo operatorio y sangrado fue de 133 minutos y 34 mL, respectivamente. La longitud promedio de la miotomía fue de 8,3 cm. Se adicionó funduplicatura parcial en todos los casos y en el 88% se realizó una endoscopia intraoperatoria. Se presentaron 2 perforaciones intraoperatorias de la mucosa. El promedio de estancia hospitalaria fue 2,7 días. Hubo una complicación médica y ninguna mortalidad. La disfagia mejoró en el 95% y el promedio del puntaje de Eckardt disminuyó de 7,7 a 1,2 luego de cirugía (p < 0,001). El seguimiento fue de 24 meses en promedio. Conclusión: la MHL con funduplicatura parcial es un procedimiento efectivo y seguro para el tratamiento de la acalasia. Se asocia a resolución de la disfagia en el 95% de los casos, su morbilidad es mínima y debe considerarse el tratamiento definitivo de elección.

Describing Engagement in the HIV Care Cascade: A Methodological Study.

Introduction: Engagement in the HIV care cascade is required for people living with HIV (PLWH) to achieve an undetectable viral load. However, varying definitions of engagement exist, contributing to heterogeneity in research regarding how many individuals are actively participating and benefitting from care. A standardized definition is needed to enhance comparability and pooling of data from engagement studies. Objectives: The objective of this paper was to describe the various definitions for engagement used in HIV clinical trials. Methods: Articles were retrieved from CASCADE, a database of 298 clinical trials conducted to improve the HIV care cascade (https://hivcarecascade.com/), curated by income level, vulnerable population, who delivered the intervention, the setting in which it was delivered, the intervention type, and the level of pragmatism of the intervention. Studies with engagement listed as an outcome were selected from this database. Results: 13 studies were eligible, of which five did not provide an explicit definition for engagement. The remaining studies used one or more of the following: appointment adherence (n=6), laboratory testing (n=2), adherence to antiretroviral therapy (n=2), time specification (n=5), intervention adherence (n=5), and quality of interaction (n=1). Conclusion: This paper highlights the existing diversity in definitions for engagement in the HIV care cascade and categorize these definitions into appointment adherence, laboratory testing, adherence to antiretroviral therapy, time specification, intervention adherence, and quality of interaction. We recommend consensus on how to describe and measure engagement.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.

Measures of Retention in HIV Care: A Study Within a Review.

People living with HIV (PLHIV) need lifelong medical care. However, retention in HIV care is not measured uniformly, making it challenging to compare or pool data. The objective of this study within a review (SWAR) is to describe the assortment of definitions used for retention in HIV care in randomized controlled trials (RCTs). We conducted a SWAR, drawing data from an overview of systematic reviews on interventions to improve the HIV care cascade. Ethics review was not required for this analysis of secondary data. We identified RCTs of interventions used to improve retention in care for PLHIV, including all age groups and extracted the definitions used and their characteristics. We identified 50 trials that measured retention published between 2007 and 2021 and provided 59 definitions for retention in care. The definitions consisted of nine different characteristics with follow-up time (n = 47), and clinical visits (n = 36) most used. The definitions of retention in HIV care are highly heterogeneous. In this study, we present the pros and cons of characteristics used to measure retention in HIV care.

Efficacy and safety of selective serotonin reuptake inhibitors in COVID-19 management: a systematic review and meta-analysis.

BACKGROUND: The efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of acute COVID-19 is still under investigation, with conflicting results reported from randomized controlled trials (RCTs). Different dosing regimens may have contributed to the contradictory findings. OBJECTIVES: To evaluate the efficacy and safety of SSRIs and the effect of different dosing regimens on the treatment of acute COVID-19. DATA SOURCES: Seven databases were searched from January 2020 to December 2022. Trial registries, previous reviews, and preprint servers were hand-searched. STUDY ELIGIBILITY CRITERIA: RCTs and observational studies with no language restrictions. PARTICIPANTS: COVID-19 inpatients/outpatients. INTERVENTIONS: SSRIs prescribed after diagnosis were compared against a placebo or standard of care. ASSESSMENT OF RISK OF BIAS: Risk of bias was rated using the revised Cochrane Risk of Bias Tool for Randomized Trials version 2.0 and Risk of Bias in Non-Randomized Studies of Interventions. METHODS OF DATA SYNTHESIS: Outcomes were mortality, hospitalization, composite of hospitalization/emergency room visits, hypoxemia, requirement for supplemental oxygen, ventilator support, and serious adverse events. RCT data were pooled in random-effects meta-analyses. Observational findings were narratively described. Subgroup analyses were performed on the basis of SSRI dose, and sensitivity analyses were performed excluding studies with a high risk of bias. The Grading of Recommendations, Assessment, Development and Evaluations framework was used to assess the quality of evidence. RESULTS: Six RCTs (N = 4197) and five observational studies (N = 1156) were included. Meta-analyses associated fluvoxamine with reduced mortality (risk ratio, 0.72; 95% CI, 0.63-0.82) and hospitalization (risk ratio, 0.79; 95% CI, 0.64-0.99) on the basis of moderate quality of evidence. Medium-dose fluvoxamine (100 mg twice a day) was associated with reduced mortality, hospitalization, and composite of hospitalization/emergency room visits, but low-dose fluvoxamine (50 mg twice a day) was not. Fluvoxamine was not associated with increased serious adverse events. Observational studies support the use of fluvoxamine and highlight fluoxetine as a possible alternative to SSRIs for the treatment of COVID-19. DISCUSSION: Fluvoxamine remains a candidate pharmacotherapy for treating COVID-19 in outpatients. Medium-dose fluvoxamine may be preferable over low-dose fluvoxamine.

The impact of COVID-19 pandemic on the psychological well-being among health care workers: A 6-month cohort longitudinal survey study.

Introduction: Health care workers (HCW) have been identified as a risk group to suffer psychological burden derived from Coronavirus Disease 19 (COVID-19) pandemic. In addition, possible gender differences in the emotional reactions derived from COVID-19 pandemic have been suggested in this population. The aims of the study were to explore the impact of COVID-19 as well as possible gender differences on mental health status and suicidality in a cohort of HCW. Materials and methods: One thousand four hundred and thirty-two HCW responded to an online survey including sociodemographic, clinical, and psychometric tests in May 2020 while 251 HCW answered in November 2020. Mental health status was measured by General Health Questionnaire 28 (GHQ-28) in both time periods. Results: HCW informed of a worsening in somatic symptomatology over the follow up period. Gender differences were found in all GHQ-28 dimensions as well in the total score of the questionnaire. Post hoc analyses displayed significant interaction between the time and gender in somatic and anxiety dimensions as well as in GHQ-28 total score. Stress produced by COVID-19 spreading and the feeling of being overwhelmed at work resulted the main predictors of psychological distress although each domain is characterized by a specific set of predictors. Conclusions: Somatic reactions represent the most sensitive dimension over the follow-up period. Moreover, women are characterized by a greater psychological distress at the beginning, although these differences tend to disappear over time. Finally, a complex network of factors predicted different dimensions of psychological distress, showing the complexity of prevention in high-risk populations facing major disasters.

Introducción: Los trabajadores sanitarios (TS) han sido identificados como un grupo vulnerable de sufrir consecuencias emocionales derivadas de la pandemia causada por la COVID-19. Además, se han sugerido posibles diferencias de género en las reacciones emocionales derivadas del afrontamiento de la pandemia. Los objetivos del estudio fueron explorar el impacto de la COVID-19, así como posibles diferencias de género en las reacciones emociones derivadas de la COVID-19 en una cohorte de TS. Materiales y métodos: Un total de 1.432 TS respondieron a una encuesta en línea que incluía preguntas referidas a datos sociodemográficos, clínicos y psicométricos en mayo de 2020, mientras que 251 TS respondieron en noviembre de 2020. El estado de salud mental se midió mediante el Cuestionario de Salud General 28 (General Health Questionnaire 28 [GHQ-28]) en ambos periodos de tiempo. Resultados: Los TS informaron de un empeoramiento de la sintomatología somática. Se encontraron diferencias de género en todas las dimensiones del GHQ-28. Los análisis post hoc mostraron una interacción significativa entre el tiempo y el género en las dimensiones somáticas y de ansiedad, así como en la puntuación total del GHQ-28. El estrés producido por ser fuente de infección y la sensación de agobio en el trabajo resultaron ser los principales predictores del malestar psicológico, aunque cada dominio se caracteriza por un conjunto específico de predictores. Conclusiones: Las reacciones somáticas representan la dimensión más sensible. Además, las mujeres se caracterizan por un mayor malestar psicológico al principio, aunque estas diferencias tienden a desaparecer con el tiempo. Por último, una compleja red de factores predijo las diferentes dimensiones de la angustia psicológica.

Pronostico desfavorable de linfoma t/nk: reporte de casos

El linfoma de células T/NK tiene una frecuencia de presentación inusual, caracterizado por una progresión rápida y de mal pronóstico. Ocurrencia aludida a regiones de Asia y Latinoamérica por la fuerte incidencia de infección por el virus de Epstein- Barr. Su presentación puede ser nasal o en otra localización. Los esquemas de tratamiento suelen conllevar respuestas insuficientes, empero protocolos con base en L-Asparaginasa reflejarían mejores resultados. El presente reporte corresponde a 4 casos de este tipo de linfoma, 2 de tipo nasal y 2 de diversa presentación. Todos evolucionaron desfavorablemente, en parte por el mal pronóstico atribuido y también por el diagnóstico suscitado en etapas avanzadas de enfermedad concatenadas a dificultades económicas para sostener el tratamiento, factores intervinientes en nuestro medio.

NK/T cell lymphoma is an unusual neoplasm, characterized by fast progression and poor prognosis. It is present in regions of Asia and Latin America associated to a high incidence of Epstein-Barr virus infection. Its presentation can be nasal or in another location. Treatment schemes usually lead to insufficient responses, however protocols based on L-Asparaginase would reflect better results. This report concerns 4 cases of this lymphoma, 2 nasal type and 2 of a different presentation. Patients responses were unfavorable, partly due to the poor prognosis att r ibuted and also due to the diagnosis raised in advanced stages of the disease as well as to economic difficulties to sustain treatment, intervening factors in our country.

Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2.

In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19, which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation.

Participant experiences of intervention to detect and manage familial hypercholesterolaemia in Australian general practice: A qualitative descriptive study.

BACKGROUND AND OBJECTIVES: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting. METHOD: Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study. RESULTS: Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing. DISCUSSION: Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

A specialized tyrosine-based endocytosis signal in MR1 controls antigen presentation to MAIT cells.

MR1 is a highly conserved microbial immune-detection system in mammals. It captures vitamin B-related metabolite antigens from diverse microbes and presents them at the cell surface to stimulate MR1-restricted lymphocytes including mucosal-associated invariant T (MAIT) cells. MR1 presentation and MAIT cell recognition mediate homeostasis through host defense and tissue repair. The cellular mechanisms regulating MR1 cell surface expression are critical to its function and MAIT cell recognition, yet they are poorly defined. Here, we report that human MR1 is equipped with a tyrosine-based motif in its cytoplasmic domain that mediates low affinity binding with the endocytic adaptor protein 2 (AP2) complex. This interaction controls the kinetics of MR1 internalization from the cell surface and minimizes recycling. We propose MR1 uses AP2 endocytosis to define the duration of antigen presentation to MAIT cells and the detection of a microbial metabolic signature by the immune system.

The glutamate metabotropic receptor 5 (GRM5) gene is associated with beef cattle home range and movement tortuosity.

BACKGROUND: The grazing behaviour of herbivores and their grazing personalities might in part be determined genetically, but there are few studies in beef cattle illustrating this. In this study, we investigated for first time the genetic variation within a candidate 'grazing gene', the glutamate metabotropic receptor 5 gene (GRM5), and tested associations between variation in that gene and variation in grazing personality behaviours (GP-behaviours) displayed by free-ranging cows during winter grazing in the steep and rugged rangelands of New Zealand. Mature beef cows (n = 303, from 3 to 10 years of age) were tracked with global positioning system (GPS) and, with 5-minutes (min) relocation frequency, various GP-behaviours were calculated. These included horizontal and vertical distances travelled, mean elevation, elevation range, elevation gain, slope, home range and movement tortuosity, variously calculated using daily relocation trajectories with repeated measurements (i.e., 7 to 24 days (d)) and satellite-derived digital elevation models (DEM). The different GP-behaviours were fitted into mixed models to ascertain their associations with variant sequences and genotypes of GRM5. RESULTS: We discovered three GRM5 variants (A, B and C) and identified the six possible genotypes in the cattle studied. The mixed models revealed that A was significantly associated with elevation range, home range and movement tortuosity. Similarly, GRM5 genotypes were associated (P < 0.05) to home range and movement tortuosity, while trends suggesting association (P <  0.1) were also revealed for elevation range and horizontal distance travelled. Most GP-behaviour models were improved by correcting for cow age-class as a fixed factor. The analysis of GP-behaviours averaged per cow age-class suggests that grazing personality is fully established as beef cows reached 4 years of age. Home range and movement tortuosity were not only associated with GRM5 variation, but also negatively correlated with each other (r = - 0.27, P < 0.001). CONCLUSIONS: There seems to be a genetically determined trade-off between home range and movement tortuosity that may be useful in beef cattle breeding programmes aiming to improve the grazing distribution and utilisation of steep and rugged rangelands.