Sotorasib for Vascular Malformations Associated with KRAS G12C Mutation.

KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).

The tidyomics ecosystem: enhancing omic data analyses.

The growth of omic data presents evolving challenges in data manipulation, analysis and integration. Addressing these challenges, Bioconductor provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming offers a revolutionary data organization and manipulation standard. Here we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analyzing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas, spanning six data frameworks and ten analysis tools.

NK cells with adhesion defects and reduced cytotoxic functions are associated with a poor prognosis in Multiple Myeloma.

The promising results obtained with immunotherapeutic approaches for multiple myeloma (MM) call for a better stratification of patients based on immune components. The most pressing being cytotoxic lymphocytes such as Natural Killer (NK) cells that are mandatory for MM surveillance and therapy. In this study, we performed a single cell RNA sequencing analysis of NK cells from 10 MM patients and 10 age/sex matched healthy donors (HD) that revealed important transcriptomic changes in NK cell landscape affecting both the bone marrow and peripheral blood compartment. The frequency of mature cytotoxic "CD56dim" NK cell subsets was reduced in MM patients at the advantage of late-stage NK cell subsets expressing NFB and IFN-I inflammatory signatures. These NK cell subsets accumulating in MM patients were characterized by a low CD16 and CD226 expression and poor cytotoxic functions. MM CD16/CD226Lo NK cells also had adhesion defects with reduced LFA-1 integrin activation and actin polymerization that may account for their limited effector functions in vitro. Finally, analysis of BM infiltrating NK cells in a retrospective cohort of 177 MM patients from the IFM 2009 trial demonstrated that a high frequency of NK cells and their low CD16 and CD226 expression were associated with a shorter overall survival. Thus, CD16/CD226Lo NK cells with reduced effector functions accumulate along MM development and negatively impact patients' clinical outcome. Given the growing interest in harnessing NK cells to treat myeloma, this improved knowledge around MM-associated NK cell dysfunction will stimulate the development of more efficient immunotherapeutic drugs against MM.

Prioritizing Mental Health within HIV and Tuberculosis Services in PEPFAR.

Underprioritization of mental health is a global problem and threatens the decades-long progress of the US President's Emergency Plan for AIDS Relief (PEPFAR) program. In recent years, mental health has become globally recognized as a part of universal healthcare, making this an opportune moment for the global community to integrate mental health services into routine programming. PEPFAR is well positioned to lead by example. We conceptualized 5 key strategies that might help serve as a framework to support mental health programming as part of PEPFAR's current 5-year strategic plan. PEPFAR and the global community have an opportunity to identify mental health service gaps and interweave global mental health priorities with actions to end the HIV and TB epidemics by 2030.

Use of a carrageenan-based gel had no impact on anal HPVs 16 and 18 viral loads in gay, bisexual, and other men who have sex with men.

The Lubricant Investigation in Men to Inhibit Transmission of human papillomavirus (HPV) Infection randomized control trial in gay, bisexual, and other men who have sex with men (gbMSM) found that carrageenan use neither reduced acquisition of anal HPV infections nor influenced infection clearance. To investigate carrageenan's lack of protective effect, we compared the change in anal HPV16 and HPV18 viral loads following carrageenan use against placebo. We restricted our analysis to participants who completed the first four study visits and had a valid baseline sample (n = 161, 54 HIV-positive). Samples were tested for HPV detection using the linear array PCR assay. HPV16- and/or HPV18-positive samples were tested for viral load using real-time PCR. For participants who tested HPV16- (n = 29) or HPV18-positive (n = 10) at least once across visits 1-4, we compared the change in type-specific viral load between study arms using the Mann-Whitney U test. Although the median net change in HPV16 and HPV18 viral loads across visits 1-4 was higher in the treatment than placebo arm (HPV16: 0.68 vs. 0.18 copies/cell, p = 0.60; HPV18: 18.32 vs. 10.12 copies/cell, p = 0.52), these differences were not statistically significant. Results were similar by HIV status. Carrageenan use did not impact anal HPV16 or HPV18 viral loads, which may further explain its lack of protective effect in gbMSM.

Impact of a carrageenan gel on viral load of genital human papillomavirus infections in sexually active women: Findings from the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) trial.

Previous research has shown that women's use of a carrageenan gel reduces the risk of acquiring genital human papillomavirus (HPV) infections but does not help to clear existing ones. Although gel use may not result in complete clearance, it may decrease the viral load of HPV infections. We tested this hypothesis in the Carrageenan-gel Against Transmission of Cervical Human papillomavirus (CATCH) randomized controlled trial. Participants of the CATCH study were selected for viral load testing if they had completed the first four study visits and tested positive for HPV42 or HPV51 in at least one of these visits. HPV42 and HPV51 were chosen as they were among the most abundant low- and high-risk types, respectively, in the study sample. We measured viral load with a type-specific real-time polymerase chain reaction. Results were displayed using summary statistics. Of 461 enrolled participants, 39 were included in the HPV42 analysis set and 56 in the HPV51 analysis set. The median time between visits 1 and 4 was 3.7 months. The viral load (copies/cell) of HPV42 ranged from <0.001 to 13 434.1, and that of HPV51 from <0.001 to 967.1. The net median change in HPV42 viral load over all four visits was -1.04 copies/cell in the carrageenan and -147 copies/cell in the placebo arm (Wilcoxon rank sum test, p = 0.26). There was no net median change in HPV51 viral load over all four visits in either arm (p = 0.45). The use of a carrageenan-based gel is unlikely to reduce the viral load of HPVs 42 or 51.

Tuberculosis Preventive Treatment Update - U.S. President's Emergency Plan for AIDS Relief, 36 Countries, 2016-2023.

Tuberculosis (TB) is the leading cause of death among persons with HIV. In 2022, an estimated 167,000 TB-related deaths occurred globally among persons with HIV. TB preventive treatment (TPT) helps prevent TB disease and is recommended for persons at high risk for developing TB, including those with HIV. TPT, when taken with antiretroviral treatment (ART), can reduce TB-attributable deaths among persons with HIV. In 2018, the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) program committed to offer one course of TPT to all eligible clients receiving ART. This analysis describes trends in TPT initiation and completion among PEPFAR-supported programs in 36 countries in Africa, Central and South America, and Asia during fiscal years (FYs) 2017-2023. Overall, TPT initiation rates peaked in FY19, a possible sign of programmatic saturation. TPT initiation among clients who had been on ART <6 months reached 59%, and overall completion rates up to 87% were reported. Approximately 13 million persons with HIV have completed TPT since FY17, but widespread adoption of shorter regimens, patient-centered approaches, and electronic medical record systems might be needed to ensure full TPT coverage. Through PEPFAR's partnership with national HIV programs, TPT has become the standard of care for persons with HIV.

Characteristics of H3K27M-mutant diffuse gliomas with a non-midline location.

PURPOSE: Diffuse midline gliomas (DMG) with H3K27 alterations (H3K27M-DMG) are a highly aggressive form of brain cancer. In rare cases, H3K27 mutations have been observed in diffuse non-midline gliomas (DNMG). It is currently unclear how these tumors should be classified. Herein, we analyze the characteristics of DNMG with H3K27M mutations. METHODS: We reviewed the clinical, radiological and histological characteristics of all patients with an H3K27M mutated diffuse glioma diagnosed in our institution, between 2016 and 2023, to identify cases with a non-midline location. We then performed a molecular characterization (DNA methylation profiling, whole genome and transcriptome sequencing or targeted sequencing) of patients with an H3K27M-mutant DNMG and reviewed previously reported cases. RESULTS: Among 51 patients (18 children and 33 adults) diagnosed with an H3K27M diffuse glioma, we identified two patients (4%) who had a non-midline location. Including our two patients, 39 patients were reported in the literature with an H3K27M-mutant DNMG. Tumors were most frequently located in the temporal lobe (48%), affected adolescents and adults, and were associated with a poor outcome (median overall survival was 10.3 months (0.1-84)). Median age at diagnosis was 19.1 years. Tumors frequently harbored TP53 mutations (74%), ATRX mutations (71%) and PDGFRA mutations or amplifications (44%). In DNA methylation analysis, H3K27M-mutant DNMG clustered within or close to the reference group of H3K27M-mutant DMG. Compared to their midline counterpart, non-midline gliomas with H3K27M mutations seemed more frequently associated with PDGFRA alterations. CONCLUSION: DNMG with H3K27M mutations share many similarities with their midline counterpart, suggesting that they correspond to a rare anatomical presentation of these tumors. This is of paramount importance, as they may benefit from new therapeutic approaches such as ONC201.

Treatment of congenital Langerhans cell histiocytosis with cobimetinib.

We report a case of congenital multisystem Langerhans cell histiocytosis with cutaneous and hematopoietic involvement. After the failure of first-line (vinblastine and prednisolone) and second-line (vincristine and cytarabine) therapies, treatment with cobimetinib, a mitogen-activated protein kinase (MEK) inhibitor, led to the remission of disease and a sustained response after 11 months of ongoing treatment. Protein kinase inhibitors targeting BRAF or MEK could represent a promising future therapeutic option, also in children with LCH.

Contribution of environmental determinants to the risk of developing type 2 diabetes mellitus in a life-course perspective: a systematic review protocol.

BACKGROUND: Prevention policies against type 2 diabetes mellitus (T2DM) focus solely on individual healthy lifestyle behaviours, while an increasing body of research recognises the involvement of environmental determinants (ED) (cultural norms of land management and planning, local foodscape, built environment, pollution, and neighbourhood deprivation). Precise knowledge of this relationship is essential to proposing a prevention strategy integrating public health and spatial planning. Unfortunately, issues related to the consistency and synthesis of methods, and results in this field of research limit the development of preventive strategies. This systematic review aims to improve knowledge about the relationship between the risk of developing T2DM in adulthood and long-term exposure to its ED during childhood or teenage years. METHODS: This protocol is presented according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) tools. PubMed, Embase, CINAHL, Web of Science, EBSCO, and grey literature from the Laval University Libraries databases will be used for data collection on main concepts such as 'type 2 diabetes mellitus', 'zoning' or 'regional, urban, or rural areas land uses', 'local food landscape', 'built environment', 'pollution', and 'deprivation'. The Covidence application will store the collected data for selection and extraction based on the Population Exposure Comparator Outcome and Study design approach (PECOS). Studies published until December 31, 2023, in English or French, used quantitative data about individuals aged 18 and over that report on T2DM, ED (cultural norms of land management and planning, local foodscape, built environment, and neighbourhood deprivation), and their association (involving only risk estimators) will be included. Then, study quality and risk of bias will be conducted according to the combined criteria and ratings from the ROBINS-E (Risk of Bias in Non-randomised Studies-of Exposures) tools and the 'Effective Public Health Practice Project' (EPHPP). Finally, the analytical synthesis will be produced using the 'Synthesis Without Meta-analysis' (SWiM) guidelines. DISCUSSION: This systematic review will summarise available evidence on ED associated with T2DM. The results will contribute to improving current knowledge and developing more efficient cross-sectoral interventions in land management and public health in this field of research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023392073.

Understanding the barriers and facilitators of urban greenway use among older and disadvantaged adults: A mixed-methods study in Québec city.

Urban greenways are multipurpose and multi-user trails that provide a range of socio-ecological and health benefits, including active transportation, social interactions, and increased well-being. However, despite their numerous benefits, barriers exist that limit urban greenway access and use, particularly among older and disadvantaged adults. This study addresses a significant research gap by examining the nuanced factors that influence the choices and experiences of these specific user groups in Québec City, Canada. We use a mixed-methods' approach to explore the facilitators of and barriers to access and use of two urban greenway trails among older and disadvantaged adults. Our methods included a greenway user count, 96 observation time slots, and 15 semi-structured user interviews. The results revealed significant use of greenway trails by older adults for afternoon walks in both seasons studied (autumn and winter). We also observed variations in use patterns, such as higher levels of solitary walking, reduced levels of winter cycling, and the impracticality of the secondary greenway trail owing to snow conditions. In addition, the findings revealed a wide range of factors that influence greenway access and use, categorized as individual or personal, physical or built environment, social environment, and meteorological or climatic dimensions. Future research can build on these insights to design and assess interventions that capitalize on the facilitators and address any barriers, enhancing the value of urban greenways for older and disadvantaged adults.

Empirical sample-specific approaches to define HPV16 and HPV18 seropositivity in unvaccinated, young, sexually active women.

Given low seroconversion rates following human papillomavirus (HPV) infection, fixed external cutoffs may lead to errors in estimating HPV seroprevalence. We evaluated finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) among unvaccinated, sexually active, HPV-exposed women to determine study-specific HPV16 and HPV18 seropositivity thresholds. We included 399 women (aged 18-24 years) enrolled in the HPV Infection and Transmission Among Couples Through Heterosexual Activity (HITCH) cohort study between 2005 and 2011 in Montreal, Canada. Participants' blood samples from up to six visits spanning 2 years were tested by multiplex serology for antibodies [median fluorescence intensity (MFI)] specific to bacterially expressed HPV16 and HPV18 L1 glutathione S-transferase fusion proteins. We applied FMM and GBTM to baseline and longitudinal antibody titer measurements, respectively, to define HPV type-specific seronegative and seropositive distributions. Study-specific thresholds were generated as five standard deviations above the mean seronegative antibody titers, mimicking cutoffs (HPV16: 422 MFI; HPV18: 394 MFI) derived from an external population of sexually inactive, HPV DNA-negative Korean women (aged 15-29 years). Agreement (kappa) of study-specific thresholds was evaluated against external cutoffs. Seroprevalence estimates using FMM (HPV16: 27.5%-43.2%; HPV18: 21.7%-49.5%) and GBTM (HPV16: 11.8%-11.8%; HPV18: 9.9%-13.4%) thresholds exceeded those of external cutoffs (HPV: 10.2%; HPV18: 9.7%). FMM thresholds showed slight-to-moderate agreement with external cutoffs (HPV16: 0.26%-0.46%; HPV18: 0.20%-0.56%), while GBTM thresholds exhibited high agreement (HPV16: 0.92%-0.92%; HPV18: 0.82%-0.99%). Kappa values suggest that GBTM, used for longitudinal serological data, and otherwise FMM, for cross-sectional data, are robust methods for determining the HPV serostatus without prior classification rules.IMPORTANCEWhile human papillomavirus (HPV) seropositivity has been employed as an epidemiologic determinant of the natural history of genital HPV infections, only a fraction of women incidentally infected with HPV respond by developing significant antibody levels. HPV seropositivity is often determined by a dichotomous fixed cutoff based on the seroreactivity of an external population of women presumed as seronegative, given the lack of evidence of HPV exposure. However, considering the variable nature of seroreactivity upon HPV infection, which arguably varies across populations, such externally defined cutoffs may lack specificity to the population of interest, causing inappropriate assessment of HPV seroprevalence and related epidemiologic uses of that information. This study demonstrates that finite mixture modeling (FMM) and group-based trajectory modeling (GBTM) can be used to independently estimate seroprevalence or serve as the basis for defining study-specific seropositivity thresholds without requiring prior subjective assumptions, consequently providing a more apt internally valid discrimination of seropositive from seronegative individuals.

Genetic mapping across autoimmune diseases reveals shared associations and mechanisms.

Autoimmune and inflammatory diseases are polygenic disorders of the immune system. Many genomic loci harbor risk alleles for several diseases, but the limited resolution of genetic mapping prevents determining whether the same allele is responsible, indicating a shared underlying mechanism. Here, using a collection of 129,058 cases and controls across 6 diseases, we show that ~40% of overlapping associations are due to the same allele. We improve fine-mapping resolution for shared alleles twofold by combining cases and controls across diseases, allowing us to identify more expression quantitative trait loci driven by the shared alleles. The patterns indicate widespread sharing of pathogenic mechanisms but not a single global autoimmune mechanism. Our approach can be applied to any set of traits and is particularly valuable as sample collections become depleted.

Systems Analysis of Immune Changes after B-cell Depletion in Autoimmune Multiple Sclerosis.

Multiple sclerosis (MS) is a complex genetically mediated autoimmune disease of the central nervous system where anti-CD20-mediated B cell depletion is remarkably effective in the treatment of early disease. While previous studies investigated the effect of B cell depletion on select immune cell subsets using flow cytometry-based methods, the therapeutic impact on patient immune landscape is unknown. In this study, we explored how a therapy-driven " in vivo perturbation " modulates the diverse immune landscape by measuring transcriptomic granularity with single-cell RNA sequencing (scRNAseq). We demonstrate that B cell depletion leads to cell type-specific changes in the abundance and function of CSF macrophages and peripheral blood monocytes. Specifically, a CSF-specific macrophage population with an anti-inflammatory transcriptomic signature and peripheral CD16 + monocytes increased in frequency post-B cell depletion. In addition, we observed increases in TNFα messenger RNA and protein in monocytes post-B cell depletion, consistent with the finding that anti-TNFα treatment exacerbates autoimmune activity in MS. In parallel, B cell depletion also induced changes in peripheral CD4 + T cell populations, including increases in the frequency of TIGIT + regulatory T cells and marked decreases in the frequency of myelin peptide loaded-tetramer binding CD4 + T cells. Collectively, this study provides an exhaustive transcriptomic map of immunological changes, revealing different mechanisms of action contributing to the high efficacy in B cell depletion treatment of MS.

Circulating Tumor Reactive KIR+CD8+ T cells Suppress Anti-Tumor Immunity in Patients with Melanoma.

Effective anti-tumor immunity is largely driven by cytotoxic CD8+ T cells that can specifically recognize tumor antigens. However, the factors which ultimately dictate successful tumor rejection remain poorly understood. Here we identify a subpopulation of CD8+ T cells which are tumor antigen-specific in patients with melanoma but resemble KIR+CD8+ T cells with a regulatory function (Tregs). These tumor antigen-specific KIR+CD8+ T cells are detectable in both the tumor and the blood, and higher levels of this population are associated with worse overall survival. Our findings therefore suggest that KIR+CD8+ Tregs are tumor antigen-specific but uniquely suppress anti-tumor immunity in patients with melanoma.

The tidyomics ecosystem: Enhancing omic data analyses.

The growth of omic data presents evolving challenges in data manipulation, analysis, and integration. Addressing these challenges, Bioconductor1 provides an extensive community-driven biological data analysis platform. Meanwhile, tidy R programming2 offers a revolutionary standard for data organisation and manipulation. Here, we present the tidyomics software ecosystem, bridging Bioconductor to the tidy R paradigm. This ecosystem aims to streamline omic analysis, ease learning, and encourage cross-disciplinary collaborations. We demonstrate the effectiveness of tidyomics by analysing 7.5 million peripheral blood mononuclear cells from the Human Cell Atlas3, spanning six data frameworks and ten analysis tools.

Heterogeneities of the perceptual-motor style during locomotion at height.

In a recent review, we summarized the characteristics of perceptual-motor style in humans. Style can vary from individual to individual, task to task and pathology to pathology, as sensorimotor transformations demonstrate considerable adaptability and plasticity. Although the behavioral evidence for individual styles is substantial, much remains to be done to understand the neural and mechanical substrates of inter-individual differences in sensorimotor performance. In this study, we aimed to investigate the modulation of perceptual-motor style during locomotion at height in 16 persons with no history of fear of heights or acrophobia. We used an inexpensive virtual reality (VR) video game. In this VR game, Richie's Plank, the person progresses on a narrow plank placed between two buildings at the height of the 30th floor. Our first finding was that the static markers (head, trunk and limb configurations relative to the gravitational vertical) and some dynamic markers (jerk, root mean square, sample entropy and two-thirds power law at head, trunk and limb level) we had previously identified to define perceptual motor style during locomotion could account for fear modulation during VR play. Our second surprising result was the heterogeneity of this modulation in the 16 young, healthy individuals exposed to moving at a height. Finally, 56% of participants showed a persistent change in at least one variable of their skeletal configuration and 61% in one variable of their dynamic control during ground locomotion after exposure to height.

Evaluación de amigdalectomias y adenoidectomias realizadas en el Hospital Regional Honorio Delgado de Arequipa entre 1975 a 1994

Se realiza el presente trabajo de investigación para determinar la tendencia de este tipo de intervenciones quirúrgicas en nuestro medio, comparandolas con las obtenidas en otros lugares, ademas sus indicaciones, técnicas quirúrgicas, epidemiología y complicaciones. Se seleccionaron a todos los pacientes sometidos a amigdalectomía, adenoidectomía y adenoamigdalectomía en el Servicio de Otorrinolaringología del H.R.H.D.A entre los años 1975 a 1994. El presente trabajo de investigación es un estudio de corte transversal, descriptivo y retrospectivo. El grupo etáreo que fue intervenido quirúrgicamente con mayor frecuencia está comprendido entre 10 a 19 años(37.50 por ciento), la mayoría amigdalectomizados(42.55 por ciento), seguido del de 0 a 9 años(29.69 por ciento), la mayor parte adenoamigdalectomizados(70 por ciento); del total de operados el sexo femenino fue el más prevalente(54.69 por ciento). Los sintomas más comunes en amigdalectomizados correspondió a la odinofagía(63.15 por ciento), disfagia(35.08 por ciento), sensación febril(36.84 por ciento), artralgiamialgia(31.57 por ciento), rinorrea(29.82 por ciento), halitosis(17.54 por ciento) y eliminación de caseum(14.03 por ciento); en adenoidectomizados: dificultad respiratoria nasal(70.58 por ciento), respiración bucal(70.58 por ciento) y rinorrea(64.70 por ciento). Los signos clínicos más frecuentemente encontrados en amigdalectomizados son la hipertrofia amigdalina(80.70 por ciento), congestión de amígdalas(47.37 por ciento), caseum(42.10 por ciento), congestión de pilares(38.59 por ciento) y adenopatía(35.08 por ciento); en adenoidectomizados: masa adenoidea(70.58 por ciento), adenopatía(41.17 por ciento) y rinitis(41.17 por ciento). Las indicaciones quirúrgicas prevalentes fueron en amigdalectomias: amigdalitis recurrente(47.36 por ciento), amigdalitis crónica(14.03 por ciento), obstrucción respiratoria o alteración de la deglución(5.26 por ciento); en adenoidectomías: obstrucción nasal crónica por adenoides(88.24 por ciento). La técnica quirúrgica más empleada en amigdalectomías es la disección extracapsular y lazo(91.23 por ciento) y en adenoidectomías la exéresis con adenótomo(52.94 por ciento). El total de complicaciones postoperatorias fue de 14.06 por ciento. En amigdalectomía la hemorragia(6.38 por ciento) e inflamación del paladar blando y úvula(4.26 por ciento), en adenoidectomías la fiebre(14.29 por ciento) y en la mixta la inflamación del paladar blando(10 por ciento)