Pharmacokinetics of a topical application of moxidectin in bare-nosed wombats (Vombatus ursinus).

Sarcoptic mange is a debilitating disease that affects bare-nosed wombats (Vombatus ursinus). One of the drugs currently used for treatment is moxidectin, as it has a relatively high efficacy against endo and ectoparasites and side effects are uncommon in domestic species, thus it is considered a relatively safe drug to use at the recommended doses. Developing further understanding of the pharmacokinetics of moxidectin will aid in developing treatment regimens for sarcoptic mange in wombats. Here we analyzed the pharmacokinetic parameters of using 100 ml of moxidectin (5 g/l) applied topically. We found that mean peak plasma concentration was 0.50 ng/ml and half-life was 8 days. Moxidectin was excreted in scats with the mean peak concentration of 2461.43 ng/g (on a dry matter basis). Our study has provided the pharmacokinetic parameters of a commonly used treatment for sarcoptic mange in wombats. There were no adverse side effects recorded in the wombats after applying moxidectin topically. This study replicated real-world conditions using topical application on free-living wombats. The relatively low plasma concentration suggests the drug is not accumulating in the blood stream and is excreted via scats.

TMEFF1 is a neuron-specific restriction factor for herpes simplex virus.

The brain is highly sensitive to damage caused by infection and inflammation1,2. Herpes simplex virus 1 (HSV-1) is a neurotropic virus and the cause of herpes simplex encephalitis3. It is unknown whether neuron-specific antiviral factors control virus replication to prevent infection and excessive inflammatory responses, hence protecting the brain. Here we identify TMEFF1 as an HSV-1 restriction factor using genome-wide CRISPR screening. TMEFF1 is expressed specifically in neurons of the central nervous system and is not regulated by type I interferon, the best-known innate antiviral system controlling virus infections. Depletion of TMEFF1 in stem-cell-derived human neurons led to elevated viral replication and neuronal death following HSV-1 infection. TMEFF1 blocked the HSV-1 replication cycle at the level of viral entry through interactions with nectin-1 and non-muscle myosin heavy chains IIA and IIB, which are core proteins in virus-cell binding and virus-cell fusion, respectively4-6. Notably, Tmeff1-/- mice exhibited increased susceptibility to HSV-1 infection in the brain but not in the periphery. Within the brain, elevated viral load was observed specifically in neurons. Our study identifies TMEFF1 as a neuron-specific restriction factor essential for prevention of HSV-1 replication in the central nervous system.

Co-shared genomic alterations within tumors from patients with both myeloproliferative neoplasms and lymphoma.

Not available.

Canada's provincial COVID-19 pandemic modelling efforts: A review of mathematical models and their impacts on the responses.

SETTING: Mathematical modelling played an important role in the public health response to COVID-19 in Canada. Variability in epidemic trajectories, modelling approaches, and data infrastructure across provinces provides a unique opportunity to understand the factors that shaped modelling strategies. INTERVENTION: Provinces implemented stringent pandemic interventions to mitigate SARS-CoV-2 transmission, considering evidence from epidemic models. This study aimed to summarize provincial COVID-19 modelling efforts. We identified modelling teams working with provincial decision-makers, through referrals and membership in Canadian modelling networks. Information on models, data sources, and knowledge translation were abstracted using standardized instruments. OUTCOMES: We obtained information from six provinces. For provinces with sustained community transmission, initial modelling efforts focused on projecting epidemic trajectories and healthcare demands, and evaluating impacts of proposed interventions. In provinces with low community transmission, models emphasized quantifying importation risks. Most of the models were compartmental and deterministic, with projection horizons of a few weeks. Models were updated regularly or replaced by new ones, adapting to changing local epidemic dynamics, pathogen characteristics, vaccines, and requests from public health. Surveillance datasets for cases, hospitalizations and deaths, and serological studies were the main data sources for model calibration. Access to data for modelling and the structure for knowledge translation differed markedly between provinces. IMPLICATION: Provincial modelling efforts during the COVID-19 pandemic were tailored to local contexts and modulated by available resources. Strengthening Canadian modelling capacity, developing and sustaining collaborations between modellers and governments, and ensuring earlier access to linked and timely surveillance data could help improve pandemic preparedness.

RéSUMé: CONTEXTE: La modélisation mathématique a joué un rôle de premier plan dans les ripostes sanitaires à la COVID-19 au Canada. Les différentes trajectoires épidémiques provinciales, leurs approches de modélisation et infrastructures de données représentent une occasion unique de comprendre les facteurs qui ont influencé les stratégies de modélisation provinciales. INTERVENTION: Les provinces ont mis en place des mesures de santé publique strictes afin d'atténuer la transmission du SRAS-CoV-2 en tenant compte des données probantes provenant des modèles épidémiques. Notre étude vise à décrire et résumer les efforts provinciaux de modélisation de la COVID-19. Nous avons identifié les équipes de modélisation travaillant avec les décideurs provinciaux parmi les réseaux Canadiens de modélisation et par référence. Les informations sur les modèles, leurs sources de données et les approches de mobilisation des connaissances ont été obtenues à l'aide d'instruments standardisés. RéSULTATS: Nous avons colligé les informations provenant de six provinces. Pour les provinces qui ont eu de la transmission communautaire soutenue, les efforts de modélisation initiaux se sont concentrés sur la projection des trajectoires épidémiques et des demandes de soins de santé et sur l'évaluation des impacts des interventions proposées. Dans les provinces où la transmission communautaire a été faible, les modèles visaient à quantifier les risques d'importation. La plupart des équipes ont développé des modèles à compartiments déterministes avec des horizons de projection de quelques semaines. Les modèles ont été régulièrement mis à jour ou remplacés par de nouveaux, s'adaptant aux dynamiques locales, à l'arrivée de nouveaux variants, aux vaccins et aux demandes des autorités de santé publique. Les données de surveillance des cas, des hospitalisations et des décès, ainsi que les études sérologiques, ont constitué les principales sources de données pour calibrer les modèles. L'accès aux données pour la modélisation et la structure de mobilisation des connaissances différaient considérablement d'une province à l'autre. IMPLICATION: Les efforts de modélisation provinciaux pendant la pandémie de la COVID-19 ont été adaptés aux contextes locaux et modulés par les ressources disponibles. Le renforcement de la capacité canadienne de modélisation, le développement et le maintien de collaborations entre les modélisateurs et les gouvernements, ainsi qu'un accès rapide et opportun aux données de surveillance individuelles et liées pourraient contribuer à améliorer la préparation aux futures pandémies.

Treatment outcome according to genetic tumour alterations and clinical characteristics in digestive high-grade neuroendocrine neoplasms.

BACKGROUND: Chemotherapy has limited efficacy in advanced digestive high-grade neuroendocrine neoplasms (HG-NEN) and prognosis is dismal. Predictive markers for palliative chemotherapy are lacking, and prognostic markers are limited. METHODS: Digestive HG-NEN patients (n = 229) were prospectively included 2013-2017. Pathological re-assessment revealed 188 neuroendocrine carcinomas (NEC) and 41 neuroendocrine tumours (NET G3). Tumour-DNA was sequenced across 360 cancer-related genes, assessing mutations (mut) and copy number alterations. We linked sequencing results to clinical information and explored potential markers for first-line chemotherapy efficacy and survival. RESULTS: In NEC given cis/carboplatin and etoposide (PE), TP53mut predicted inferior response rate in multivariate analyses (p = 0.009) and no BRAFmut NEC showed response. In overall assessment of PE-treated NEC, no genetic alterations were prognostic for OS. For small-cell NEC, TP53mut were associated with longer OS (p = 0.011) and RB1 deletions predicted lack of immediate-progression (p = 0.003). In non-small cell NEC, APC mut were associated with immediate-progression and shorter PFS (p = 0.008/p = 0.004). For NET G3, ATRXmut, ARID1A- and ERS1 deletions were associated with shorter PFS. CONCLUSION: Correlations between genetic alterations and response/immediate-progression to PE were frequent in NEC but affected PFS or OS only when subdividing for cell-type. The classification of digestive NEC into large- and small-cell seems therefore molecularly and clinically relevant.

A Multicenter, Retrospective Outcome Analysis of Vancomycin Area Under the Curve versus Trough-Based Dosing Strategies in Patients with Burn OR Inhalational Injuries (MONITOR).

Vancomycin is a glycopeptide antibiotic that requires close therapeutic monitoring. Prolonged exposure to elevated concentrations increases risk for serious adverse effects such as nephrotoxicity. However, sub-therapeutic concentrations may lead to bacterial resistance and clinical failure or death. The most recent Infectious Diseases Society of America (IDSA) publication regarding therapeutic monitoring of vancomycin recommends utilizing area under the curve (AUC)-based monitoring to maximize clinical success. Despite the guideline recommendation for AUC-guided dosing, many institutions still use trough-only monitoring in their practices, including those caring for patients with acute burn injuries. Following burn injury, patients are at a higher risk for infections, multi-organ failure, and pharmacokinetic alterations. The primary objective of this multi-center retrospective study is to determine optimal therapeutic monitoring of vancomycin by comparing clinical success between AUC vs. trough-based monitoring in burn patients. MONITOR was a multicenter, retrospective study of patients with thermal or inhalation injury admitted to one of 13 burn centers from 1/1/17 to 8/31/22 who received vancomycin. Demographic and clinical course data, including acute kidney injury (AKI) incidence and clinical success were obtained. Patients were evaluated for clinical success and grouped according to method of monitoring and adjusting doses: AUC vs. trough-based monitoring. Clinical success was a composite definition and lack of meeting any 1 of 5 criteria: 1) persistent infection, 2) relapse, 3) antibiotic failure (clinical worsening), 4) AKI, 5) death. Five-hundred seventeen vancomycin courses were assessed from 485 patients. There was no difference in the rate of clinical success between AUC monitored and the trough-only monitored groups. Incidence of AKI was higher in the trough-only group; however, was not statistically significant after controlling for renal function on admission, past medical history of chronic kidney disease (CKD), and concomitant nephrotoxins.

Family and parenting factors are associated with emotion regulation neural function in early adolescent girls with elevated internalizing symptoms.

A prominent tripartite model proposes that parent role modeling of emotion regulation, emotion socialization behaviors, and the emotional climate of the family are important for young people's emotional development. However, limited research has examined the neural mechanisms at play. Here, we examined the associations between family and parenting factors, the neural correlates of emotional reactivity and regulation, and internalizing symptoms in early adolescent girls. Sixty-four female adolescents aged 10-12 years with elevated internalizing symptoms completed emotional reactivity, implicit (affect labeling) and explicit (cognitive reappraisal) emotion regulation tasks during functional magnetic resonance imaging. Positive family emotional climate was associated with greater activation in the anterior cingulate and middle temporal cortices during emotional reactivity. Maternal emotion regulation difficulties were associated with increased frontal pole and supramarginal gyrus activation during affect labeling, whereas supportive maternal emotion socialization and positive family emotional climate were associated with activation in prefrontal regions, including inferior frontal and superior frontal gyri, respectively, during cognitive reappraisal. No mediating effects of brain function were observed in the associations between family/parenting factors and adolescent symptoms. These findings highlight the role of family and parenting behaviors in adolescent emotion regulation neurobiology, and contribute to prominent models of adolescent emotional development.

Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain. OBJECTIVE: To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. METHODS: A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined "empiric supplementation" as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D. RESULTS: The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D-containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity. CONCLUSION: The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

Navigating Complexities: Vitamin D, Skin Pigmentation, and Race.

Vitamin D plays a critical role in many physiological functions, including calcium metabolism and musculoskeletal health. This commentary aims to explore the intricate relationships among skin complexion, race, and 25-hydroxyvitamin D (25[OH]D) levels, focusing on challenges the Endocrine Society encountered during clinical practice guideline development. Given that increased melanin content reduces 25(OH)D production in the skin in response to UV light, the guideline development panel addressed the potential role for 25(OH)D screening in individuals with dark skin complexion. The panel discovered that no randomized clinical trials have directly assessed vitamin D related patient-important outcomes based on participants' skin pigmentation, although race and ethnicity often served as presumed proxies for skin pigmentation in the literature. In their deliberations, guideline panel members and selected Endocrine Society leaders underscored the critical need to distinguish between skin pigmentation as a biological variable and race and ethnicity as socially determined constructs. This differentiation is vital to maximize scientific rigor and, thus, the validity of resulting recommendations. Lessons learned from the guideline development process emphasize the necessity of clarity when incorporating race and ethnicity into clinical guidelines. Such clarity is an essential step toward improving health outcomes and ensuring equitable healthcare practices.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D.

CONTEXT: Low vitamin D status is common and is associated with various common medical conditions. OBJECTIVE: To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. METHODS: We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. RESULTS: Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. CONCLUSION: The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals' and providers' values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Relative importance of intensity and spectrum of artificial light at night in disrupting behavior of a nocturnal rodent.

The influence of light spectral properties on circadian rhythms is of substantial interest to laboratory-based investigation of the circadian system and to field-based understanding of the effects of artificial light at night. The trade-offs between intensity and spectrum regarding masking behaviors are largely unknown, even for well-studied organisms. We used a custom LED illumination system to document the response of wild-type house mice (Mus musculus) to 1-h nocturnal exposure of all combinations of four intensity levels (0.01, 0.5, 5 and 50 lx) and three correlated color temperatures (CCT; 1750, 1950 and 3000 K). Higher intensities of light (50 lx) suppressed cage activity substantially, and consistently more for the higher CCT light (91% for 3000 K, 53% for 1750 K). At the lowest intensity (0.01 lx), mean activity was increased, with the greatest increases for the lowest CCT (12.3% increase at 1750 K, 3% increase at 3000 K). Multiple linear regression confirmed the influence of both CCT and intensity on changes in activity, with the scaled effect size of intensity 3.6 times greater than that of CCT. Activity suppression was significantly lower for male than for female mice. Assessment of light-evoked cFos expression in the suprachiasmatic nucleus at 50 lx showed no significant difference between high and low CCT exposure. The significant differences by spectral composition illustrate a need to account for light spectrum in circadian studies of behavior, and confirm that spectral controls can mitigate some, but certainly not all, of the effects of light pollution on species in the wild.

Stimulus-related modulation in the 1/f spectral slope suggests an impaired inhibition during a working memory task in people with multiple sclerosis.

BACKGROUND: An imbalance of excitatory and inhibitory synaptic transmission in multiple sclerosis (MS) may lead to cognitive impairment, such as impaired working memory. The 1/f slope of electroencephalography/magnetoencephalography (EEG/MEG) power spectra is shown to be a non-invasive proxy of excitation/inhibition balance. A flatter slope is associated with higher excitation/lower inhibition. OBJECTIVES: To assess the 1/f slope modulation induced by stimulus and its association with behavioral and cognitive measures. METHODS: We analyzed MEG recordings of 38 healthy controls (HCs) and 79 people with multiple sclerosis (pwMS) while performing an n-back task including target and distractor stimuli. Target trials require an answer, while distractor trials do not. We computed the 1/f spectral slope through the fitting oscillations and one over f (FOOOF) algorithm within the time windows 1 second before and after each stimulus presentation. RESULTS: We observed a flatter 1/f slope after distractor stimuli in pwMS compared to HCs. The 1/f slope was significantly steeper after stimulus for both HCs and pwMS and was significantly correlated with reaction times. This modulation in 1/f slope was significantly correlated with visuospatial memory assessed by the BVMT-R test. CONCLUSION: Our results suggest possible inhibitory mechanism deficits in pwMS during a working memory task.

Correction: P-NGAL Day 1 predicts early but not one year graft function following deceased donor kidney transplantation-The CONTEXT study.

[This corrects the article DOI: 10.1371/journal.pone.0212676.].

HSV-1 employs UL56 to antagonize expression and function of cGAMP channels.

DNA sensing is important for antiviral immunity. The DNA sensor cGAS synthesizes 2'3'-cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which induces innate immunity. cGAMP not only activates STING in the cell where it is produced but cGAMP also transfers to other cells. Transporters, channels, and pores (including SLC19A1, SLC46A2, P2X7, ABCC1, and volume-regulated anion channels (VRACs)) release cGAMP into the extracellular space and/or import cGAMP. We report that infection with multiple human viruses depletes some of these cGAMP conduits. This includes herpes simplex virus 1 (HSV-1) that targets SLC46A2, P2X7, and the VRAC subunits LRRC8A and LRRC8C for degradation. The HSV-1 protein UL56 is necessary and sufficient for these effects that are mediated at least partially by proteasomal turnover. UL56 thereby inhibits cGAMP uptake via VRAC, SLC46A2, and P2X7. Taken together, HSV-1 antagonizes intercellular cGAMP transfer. We propose that this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.

Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. METHODS: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. RESULTS: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. CONCLUSIONS: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

Carrying SNP rs17506395 (T > G) in TP63 gene and CCR5Δ32 mutation associated with the occurrence of breast cancer in Burkina Faso.

Genetic alterations in the TP63 (GenBank: NC_000003.12, ID: 8626) and CCR5 (receptor 5 chemokine co-receptor) (GenBank: NC_000003.12, ID: 1234) genes may increase the risk of developing breast cancer. The aim of this study was to investigate the probable involvement of polymorphisms rs17506395 in the TP63 (tumour protein 63) gene and the CCR5Δ32 mutation in the occurrence of breast cancer in Burkina Faso. This case-control study included 72 patients and 72 controls. Genotyping of SNP rs17506395 (TP63) was performed by polymerase chain reaction-restriction fragment length polymorphism, and genotyping of the CCR5Δ32 mutation was performed by allele-specific oligonucleotide polymerase chain reaction. For SNP rs17506395 (TP63), the genotypic frequencies of wild-type homozygotes (TT) and heterozygotes (TG) were, respectively, 27.72 and 72.22% in cases and 36.11 and 63.89% in controls. No mutated homozygotes (GG) were observed. For the CCR5Δ32 mutation, the genotypic frequencies of wild-type homozygotes (WT/WT) and heterozygotes (WT/Δ32) were 87.5 and 13.5%, respectively, in the cases and 89.29 and 10.71%, respectively, in the controls. No mutated homozygotes (Δ32/Δ32) were observed. None of the polymorphisms rs17506395 of the TP63 gene (OR = 1.47, 95% CI = 0.69-3.17, P = 0.284) and the CCR5Δ32 mutation (OR = 1.32, 95% CI = 0.46-3.77; P = 0.79) were associated with the occurrence of breast cancer in this study.

Development of a closed-tube, calcein-based loop-mediated isothermal amplification assay to detect Salmonella spp. in raw meat samples.

Foodborne pathogens compromise food safety and public health, and Salmonella spp. are among the major pathogenic bacteria that cause outbreaks worldwide. Proper surveillance through timely and cost-effective detection methods across the food animal production chain is crucial to prevent Salmonella outbreaks and agricultural losses. Traditional culture methods are labor- and resource-intensive, with lengthy turnaround times. Meanwhile, conventional molecular tools, such as PCR and qPCR, are expensive and require technical skills and equipment. Loop-mediated isothermal amplification (LAMP) is a simple, rapid, inexpensive, highly sensitive, and specific molecular assay that does not require expensive equipment. Hence, this study developed and optimized a closed-tube, calcein-based LAMP assay to detect Salmonella using the invA gene and performed evaluation and validation against conventional PCR. The LAMP assay showed high specificity and sensitivity. It showed 10-fold higher sensitivity than conventional PCR, at <1 ng/µL DNA concentrations. Meanwhile, for CFU/mL, LAMP assay showed 1000-fold higher sensitivity than conventional PCR at 4.8 × 103 cells/mL than 4.8 × 107 cells/mL, respectively. For parallel testing of 341 raw meat samples, after conventional culture enrichment (until Rappaport-Vassiliadis broth), the optimized LAMP assay showed 100% detection on all samples while conventional PCR showed 100%, 99.04%, and 96.64% for raw chicken, beef, and pork samples, respectively. Meanwhile, a shortened enrichment protocol involving 3-h incubation in buffered peptone water only, showed lower accuracy in tandem with the optimized LAMP assay ranging from 55 to 75% positivity rates among samples. These suggest that the optimized LAMP assay possesses higher sensitivity over conventional PCR for invA gene detection when coupled with conventional enrichment culture methods. Hence, this assay has potential as a powerful complementary or alternative Salmonella detection method to increase surveillance capacity and protect consumer food safety and public health worldwide.

[Health status and quality of life in ß-thalassemia adults in Marseille, France]. / État de santé et qualité de vie des patients ß-thalassémiques adultes à Marseille, France.

INTRODUCTION: The life expectancy of ß-thalassemia patients has increased over the last 20 years. In this study, we evaluated the current health status and quality of life of these patients managed in a reference center in Marseille. METHODS: This is a single-center, descriptive study conducted between June and August 2019 in patients over 18 years of age with ß-thalassemia major or intermedia. Clinical and paraclinical data were collected retrospectively and the SF-36 health survey questionnaire was proposed to each patient. RESULTS: 43 of 64 selected patients were included and divided into 2 groups: 35 patients with transfusion-dependent ß-thalassemia and 8 patients with non-transfusion-dependent ß-thalassemia. Liver iron overload is the most frequent complication, present in 80% of transfusion-dependent and 62.5% of non-transfusion-dependent patients. Cardiac iron overload is present only in the transfusion dependent ß-thalassemia group (20%). Hypogonadotropic hypogonadism remains the most common endocrine disorder (41.9%) followed by osteoporosis (37.2%). Among the 31 patients who completed the SF-36 questionnaire, physical and mental quality of life scores were lowered in transfusion dependent (respectively 42.7 and 46.8) as in non-transfusion-dependent patients (respectively 43.8 and 28.9). CONCLUSION: Despite an improvement in medical care, our patients with ß-thalassemia show an alteration in their quality of life that will need to be characterized in the entire French cohort.

Pituitary Adenoma in the Philippines: A Scoping Review on the Treatment Gaps, Challenges, and Current State of Care.

BACKGROUND: Pituitary adenomas are benign brain tumors that impose a heavy burden on patients worldwide. The local burden of disease is yet to be established due to scarcity of data. In line with this, this study aims to present the challenges and gaps in the treatment of pituitary adenomas in the Philippines. METHODS: A scoping review of available relevant literature on epidemiology, clinical experience with treatment, health financing, and healthcare delivery system based on the Preferred Reporting Items for Systematic reviews and Meta-analysis guidelines extension for Scoping Reviews was conducted. RESULTS: The scarcity of updated local clinical data, inequity of distribution of resources, inadequate government support, and lack of affordable diagnostic testing, medications, and neurosurgical procedures are the factors that hinder provision of adequate care of pituitary adenomas in the Philippines. CONCLUSION: There are notable treatment gaps in the management of pituitary adenomas in the Philippines, which may be addressed by strengthening universal healthcare. Strategies to address these gaps were proposed, including improving public-private insurance coverage, increasing manpower, enhancing accessibility to resources, and spreading more awareness.

SAM68 directs STING signaling to apoptosis in macrophages.

DNA is a danger signal sensed by cGAS to engage signaling through STING to activate innate immune functions. The best-studied downstream responses to STING activation include expression of type I interferon and inflammatory genes, but STING also activates other pathways, including apoptosis. Here, we report that STING-dependent induction of apoptosis in macrophages occurs through the intrinsic mitochondrial pathway and is mediated via IRF3 but acts independently of gene transcription. By intersecting four mass spectrometry datasets, we identify SAM68 as crucial for the induction of apoptosis downstream of STING activation. SAM68 is essential for the full activation of apoptosis. Still, it is not required for STING-mediated activation of IFN expression or activation of NF-κB. Mechanistic studies reveal that protein trafficking is required and involves SAM68 recruitment to STING upon activation, with the two proteins associating at the Golgi or a post-Golgi compartment. Collectively, our work identifies SAM68 as a STING-interacting protein enabling induction of apoptosis through this DNA-activated innate immune pathway.