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The COVID-19 pandemic has exacerbated the adverse influence of structural racism and discrimination experienced by historically marginalized communities (e.g., Black, Latino/a/x, Indigenous, and transgender people). Structural racism contributes to trauma-induced health behaviors, increasing exposure to COVID-19 and restricting access to testing and vaccination. This intersection of multiple disadvantages has a negative impact on the mental health of these communities, and interventions addressing collective healing are needed in general and in the context of the COVID-19 pandemic. The Share, Trust, Organize, and Partner COVID-19 California Alliance (STOP COVID-19 CA), a statewide collaborative of 11 universities and 75 community partners, includes several workgroups to address gaps in COVID-19 information, vaccine trial participation, and access. One of these workgroups, the Vaccine Hesitancy Workgroup, adopted an anti-racist community-partnered praxis to implement restorative circles in historically marginalized communities to facilitate collective healing due to structural racism and the COVID-19 pandemic. The project resulted in the development of a multilevel pre-intervention restorative process to build or strengthen community-institutional partnerships when procurement of funds has been sought prior to community partnership. This article discusses this workgroup's role in advancing health justice by providing a community-based mental health intervention to marginalized communities in Southern California while using an antiracist praxis tool to develop a successful community-institutional partnership and to live up to the vision of community-based participatory research.

Abstract Background Surgery is the treatment of choice for patients with basal cell carcinoma (BCC). When surgery is not a choice, only radiotherapy is recommended for patients with high-risk facial BCC. Interferon could be an acceptable therapeutic option for these patients. Objective To evaluate the long-term clinical response to interferon therapy in patients with high-risk facial BCC. Methods Patients with high-risk facial BCC were treated with perilesional injections of alpha-2b+ gamma interferons. Those with incomplete clinical response were reevaluated, their residual tumors excised, and declared cured. Patients treated with interferon and those treated with interferon plus surgery were followed for five years. Time to recurrence and the emergence of a new facial BCC were estimated by Kaplan-Meier survival analysis. Adverse events were documented. Results This study included 195 participants; 143 (73.3%) showed a complete response (95% CI 67.2‒80.1). Patients developed recurrence after a mean of 55 months (95% CI 53.8‒57.4). The estimated rate of recurrence was 12.3% (95% CI 7.4‒17.1). Patients developed a new BCC after a mean of 52.7 months (95% CI 50.4‒54.9). The estimated rate for development of a new BCC was 20.0% (95% CI 14.4‒25.9). Fifteen (7.7%) patients abandoned the study during follow-up. Adverse events were frequent but moderate or mild; fever and local pain were the most frequent. Study limitations Observational cohort design without a control group for comparison. Conclusions Perilesional injections of alpha-2b+ gamma interferons in patients with facial high-risk BCC offer a satisfactory cure rate after five years of follow-up with an acceptable safety profile.

Abstract Background The aim of this study was to assess the impact of immunosuppression management on coronavirus disease 2019 (COVID-19) outcomes. Methods We performed a single-center retrospective study in a cohort of 358 lung transplant recipients (LTx) over the period from March 2020 to April 2022. All included symptomatic patients had at least one positive SARS-CoV-2 rt-PCR. We used a composite primary outcome for COVID-19 including increased need for oxygen since the hospital admission, ICU transfer, and in-hospital mortality. We assessed by univariate and multivariate analyses the risk factors for poor outcomes. Results Overall, we included 91 LTx who contracted COVID-19. The COVID-19 in-hospital mortality rate reached 4.4%. By hierarchical clustering, we found a strong and independent association between the composite poor outcome and the discontinuation of at least one immunosuppressive molecule among tacrolimus, cyclosporine, mycophenolate mofetil, and everolimus. Obesity (OR = 16, 95%CI (1.96; 167), p = 0.01) and chronic renal failure (OR = 4.6, 95%CI (1.4; 18), p = 0.01) were also independently associated with the composite poor outcome. Conversely, full vaccination was protective (OR = 0.23, 95%CI (0.046; 0.89), p = 0.047). Conclusion The administration of immunosuppressive drugs such as tacrolimus, cyclocporine or everolimus can have a protective effect in LTx with COVID-19, probably related to their intrinsic antiviral capacity.

The Vaupés River stands out as one of the few within the Amazon basin due to its numerous rapids. These riverine fast-flowing sections not only provide habitat to highly specialized fishes but also function as natural barriers hindering the movement of fish along its course. During a fish-collecting expedition in the lower Vaupés River basin in Colombia, 95 species were registered belonging to 30 families and seven orders. Despite recent inventories in the region, our comprehensive sampling efforts particularly focused on the rapids and associated rheophilic fauna, allowing us to contribute the first records of four fish species in Colombia (Myloplus lucienae Andrade, Ota, Bastos & Jégu, 2016, Tometes makue Jégu, Santos & Jégu, 2002, also first record of the genus, Leptodoras praelongus (Myers & Weitzman, 1956), and Eigenmannia matintapereira Peixoto, Dutra & Wosiacki, 2015) and six presumably undescribed species (i.e., Jupiaba sp., Moenkhausia sp., Phenacogaster sp., Bunocephalus sp., Hemiancistrus sp., and Archolaemus sp.). In this study, a commented list of the ichthyofauna of these environments is presented, as well as a photographic catalog of fish species integrated into the CaVFish Project – Colombia.

Abstract 5q-spinal muscular atrophy (SMA) is a neuromuscular disorder (NMD) that has become one of the first 5% treatable rare diseases. The efficacy of new SMA therapies is creating a dynamic SMA patient landscape, where disease progression and scoliosis development play a central role, however, remain difficult to anticipate. New approaches to anticipate disease progression and associated sequelae will be needed to continuously provide these patients the best standard of care. Here we developed an interpretable machine learning (ML) model that can function as an assistive tool in the anticipation of SMA-associated scoliosis based on disease progression markers. We collected longitudinal data from 86 genetically confirmed SMA patients. We selected six features routinely assessed over time to train a random forest classifier. The model achieved a mean accuracy of 0.77 (SD 0.2) and an average ROC AUC of 0.85 (SD 0.17). For class 1 ‘scoliosis’ the average precision was 0.84 (SD 0.11), recall 0.89 (SD 0.22), F1-score of 0.85 (SD 0.17), respectively. Our trained model could predict scoliosis using selected disease progression markers and was consistent with the radiological measurements. During post validation, the model could predict scoliosis in patients who were unseen during training. We also demonstrate that rare disease data sets can be wrangled to build predictive ML models. Interpretable ML models can function as assistive tools in a changing disease landscape and have the potential to democratize expertise that is otherwise clustered at specialized centers.

Abstract Pneumolysin (PLY) is a cholesterol-dependent cytolysin (CDC) from Streptococcus pneumoniae, the main cause for bacterial pneumonia. Liberation of PLY during infection leads to compromised immune system and cytolytic cell death. Here, we report discovery, development, and validation of targeted small molecule inhibitors of PLY (pore-blockers, PB). PB-1 is a virtual screening hit inhibiting PLY-mediated hemolysis. Structural optimization provides PB-2 with improved efficacy. Cryo-electron tomography reveals that PB-2 blocks PLY-binding to cholesterol-containing membranes and subsequent pore formation. Scaffold-hopping delivers PB-3 with superior chemical stability and solubility. PB-3, formed in a protein-templated reaction, binds to Cys428 adjacent to the cholesterol recognition domain of PLY with a K D of 256 nM and a residence time of 2000 s. It acts as anti-virulence factor preventing human lung epithelial cells from PLY-mediated cytolysis and cell death during infection with Streptococcus pneumoniae and is active against the homologous Cys-containing CDC perfringolysin (PFO) as well.

Abstract Background Loss of AZGP1 expression is a biomarker associated with progression to castration resistance, development of metastasis, and poor disease-specific survival in prostate cancer. However, high expression of AZGP1 cells in prostate cancer has been reported to increase proliferation and invasion. The exact role of AZGP1 in prostate cancer progression remains elusive. Method AZGP1 knockout and overexpressing prostate cancer cells were generated using a lentiviral system. The effects of AZGP1 under- or over-expression in prostate cancer cells were evaluated by in vitro cell proliferation, migration, and invasion assays. Heterozygous AZGP1± mice were obtained from European Mouse Mutant Archive (EMMA), and prostate tissues from homozygous knockout male mice were collected at 2, 6 and 10 months for histological analysis. In vivo xenografts generated from AZGP1 under- or over-expressing prostate cancer cells were used to determine the role of AZGP1 in prostate cancer tumor growth, and subsequent proteomics analysis was conducted to elucidate the mechanisms of AZGP1 action in prostate cancer progression. AZGP1 expression and microvessel density were measured in human prostate cancer samples on a tissue microarray of 215 independent patient samples. Result Neither the knockout nor overexpression of AZGP1 exhibited significant effects on prostate cancer cell proliferation, clonal growth, migration, or invasion in vitro. The prostates of AZGP1−/− mice initially appeared to have grossly normal morphology; however, we observed fibrosis in the periglandular stroma and higher blood vessel density in the mouse prostate by 6 months. In PC3 and DU145 mouse xenografts, over-expression of AZGP1 did not affect tumor growth. Instead, these tumors displayed decreased microvessel density compared to xenografts derived from PC3 and DU145 control cells, suggesting that AZGP1 functions to inhibit angiogenesis in prostate cancer. Proteomics profiling further indicated that, compared to control xenografts, AZGP1 overexpressing PC3 xenografts are enriched with angiogenesis pathway proteins, including YWHAZ, EPHA2, SERPINE1, and PDCD6, MMP9, GPX1, HSPB1, COL18A1, RNH1, and ANXA1. In vitro functional studies show that AZGP1 inhibits human umbilical vein endothelial cell proliferation, migration, tubular formation and branching. Additionally, tumor microarray analysis shows that AZGP1 expression is negatively correlated with blood vessel density in human prostate cancer tissues. Conclusion AZGP1 is a negative regulator of angiogenesis, such that loss of AZGP1 promotes angiogenesis in prostate cancer. AZGP1 likely exerts heterotypical effects on cells in the tumor microenvironment, such as stromal and endothelial cells. This study sheds light on the anti-angiogenic characteristics of AZGP1 in the prostate and provides a rationale to target AZGP1 to inhibit prostate cancer progression.

Las prácticas funerarias del IV y III milenio cal ac se caracterizan en la mayor parte de la Península Ibérica por la generalización de la arquitectura megalítica, en paralelo a las importantes transformaciones sociales que tienen lugar a lo largo de la denominada Edad del Cobre. Al mismo tiempo, proliferan enterramientos colectivos en cuevas naturales en zonas montañosas del área meridional de Iberia, muchos de los cuales parecen compartir usos similares a los propios de cámaras ortostáticas. En este trabajo presentaremos el sorprendente caso del yacimiento de Peñacalera, en Obejo, provincia de Córdoba, una pequeña cavidad funeraria situada en un prominente afloramiento rocoso situado en el macizo de Sierra Morena descubierta en 2014. El contexto funerario comprende los restos óseos de al menos cinco individuos, asociados a elementos de ajuar como vasos cerámicos, y elementos de naturaleza orgánica en un notable estado de conservación, especialmente placas de corcho de alcornoque y algunos fragmentos textiles. El análisis de las dataciones radiocarbónicas efectuadas apunta a dos fases de uso diferenciadas, una en el tercer cuarto del iv y otra a mediados del III milenio cal AC.

Criminality in the business environment has become a topic that currently generates much academic discussion, especially if the classic formulas for determining authorship and participation are adequate to respond to these new criminal phenomena. Various ideas for solutions have been proposed, but none of them has been free of criticism. In this context, we sought to analyze the formulas provided in the Colombian penal code to determine whether they are prepared to curb this new scourge. Based on a descriptive model of doctrinal and legal review, the results show that they must undergo a process of modernization to adapt to the new scenarios of criminality in the business context.

Abstract Introduction Computed tomography (CT) is routinely employed on the evaluation of dyspnea, yet limited data exist on its assessment of diaphragmatic muscle. This study aimed to determine the capability of CT in identifying structural changes in the diaphragm among patients with ultrasound-confirmed diaphragmatic dysfunction. Methods Diaphragmatic ultrasounds conducted between 2018 and 2021 at our center in Marseille, France, were retrospectively collected. Diaphragmatic pillars were measured on CT scans at the L1 level and the celiac artery. Additionally, the difference in height between the two diaphragmatic domes in both diaphragmatic dysfunction cases and controls was measured and compared. Results A total of 65 patients were included, comprising 24 with diaphragmatic paralysis, 13 with diaphragmatic weakness, and 28 controls. In the case group (paralysis and weakness) with left dysfunctions (n = 24), the CT thickness of the pillars at the level of L1 and the celiac artery was significantly thinner compared with controls (2.0 mm vs. 7.4 mm and 1.8 mm vs. 3.1 mm, p

Previous systematic literature reviews of rotavirus genotype circulation in Europe and the Middle East are limited because they do not include country-specific prevalence data. This study documents country-specific evidence on the prevalence of rotavirus genotypes in Europe and the Middle East to enable more precise epidemiological modeling and contribute to the evidence-base about circulating rotavirus genotypes in the post-vaccination era. This study systematically searched PubMed, Embase and Scopus for all empirical epidemiological studies that presented genotype-specific surveillance data for countries in Europe and the Middle East published between 2006 and 2021. The STROBE checklist was used to assess the quality of included studies. Proportional meta-analysis was conducted using the generic inverse variance method with arcsine transformation and generalized linear-mixed models to summarize genotype prevalence. Our analysis estimated the genotype prevalence by country across three date categories corresponding with rotavirus seasons: 2006–2010, 2011–2015, 2016–2021. A total of 7601 deduplicated papers were identified of which 88 studies were included in the final review. Rotavirus genotypes exhibited significant variability across regions and time periods, with G1P[8], G2P[4], G3P[8], G4P[8], G9P[8], and, to a lesser extent G12P[8], being the most prevalent genotypes through different regions and time-periods. Uncommon genotypes included G3P[9] in Poland, G2P[6] in Iraq, G4P[4] in Qatar, and G9P[4] as reported by the European Rotavirus Network. There was high genotype diversity with routinely identified genotypes being G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]; there was high variability across time periods and regions. Continued surveillance at the national and regional levels is relevant to support further research and inform public health decision-making.

Imbalances in proteolytic activity have been linked to the development of inflammatory bowel diseases (IBD) and experimental colitis. Proteases in the intestine play important roles in maintaining homeostasis, but exposure of mucosal tissues to excess proteolytic activity can promote pathology through protease-activated receptors (PARs). Previous research implicates microbial proteases in IBD, but the underlying pathways and specific interactions between microbes and PARs remain unclear. In this study, we investigated the role of microbial proteolytic activation of the external domain of PAR2 in intestinal injury using mice expressing PAR2 with a mutated N-terminal external domain that is resistant to canonical activation by proteolytic cleavage. Our findings demonstrate the key role of proteolytic cleavage of the PAR2 external domain in promoting intestinal permeability and inflammation during colitis. In wild-type mice expressing protease-sensitive PAR2, excessive inflammation leads to the expansion of bacterial taxa that cleave the external domain of PAR2, exacerbating colitis severity. In contrast, mice expressing mutated protease-resistant PAR2 exhibit attenuated colitis severity and do not experience the same proteolytic bacterial expansion. Colonization of wild-type mice with proteolytic PAR2-activating Enterococcus and Staphylococcus worsens colitis severity. Our study identifies a previously unknown interaction between proteolytic bacterial communities, which are shaped by inflammation, and the external domain of PAR2 in colitis. The findings should encourage new therapeutic developments for IBD by targeting excessive PAR2 cleavage by bacterial proteases.

ABSTRACTThe aim of this study was to analyse the role of the 5Cs of Positive Youth Development (PYD) in the relationship between physical activity (PA) and health-related quality of life (HRQoL), in a sample of adolescents enrolled at public secondary schools in both rural and urban environments in Huelva (Spain). The sample comprised 418 adolescents (Mean age = 14.40; SD = 1.20; 53% boys). A cross-sectional design was employed. PA (PAQ-A), Adherence to the Mediterranean Diet (KIDMED), PYD and HRQoL (KIDSCREEN-27) were assessed using self-report questionnaires. The results indicated that adolescents from rural environments were more physically active and achieved higher scores in PYD and HRQoL dimensions compared to those from urban environments. Mediation analyses demonstrated that the competence dimension of PYD positively mediated the relationship between PA and HRQoL. Consequently, this study highlights the importance of implementing PA interventions considering PYD and its positive impact on HRQoL.

Outdoor recreation benefits local economies, environmental education, and public health and wellbeing, but it can also adversely affect local ecosystems. Human presence in natural areas alters feeding and reproductive behaviors, physiology, and population structure in many wildlife species, often resulting in cascading effects through entire ecological communities. As outdoor recreation gains popularity, existing trails are becoming overcrowded and new trails are being built to accommodate increasing use. Many recreation impact studies have investigated effects of the presence or absence of humans while few have investigated recreation effects on wildlife using a gradient of disturbance intensity. We used camera traps to quantify trail use by humans and mid- to large-sized mammals in an area of intense outdoor recreation–the Upper East River Valley, Colorado, USA. We selected five trails with different types and intensities of human use and deployed six cameras on each trail for five weeks during a COVID-enhanced 2020 summer tourism season. We used occupancy models to estimate detectability and habitat use of the three most common mammal species in the study area and determined which human activities affect the habitat use patterns of each species. Human activities affected each species differently. Mule deer (Odocoileus hemionus) tended to use areas with more vehicles, more predators, and greater distances from the trailhead, and they were more likely to be detected where there were more bikers. Coyotes (Canis latrans) and red foxes (Vulpes vulpes) were most likely to use areas where their prey species occurred, and foxes were more likely to be detected where the vegetation was shorter. Humans and their recreational activities differentially influence different species. More generally, these results reinforce that it is unlikely that a single management policy is suitable for all species and management should thus be tailored for each target species.

By the end of October 2022, the US HL-LHC Accelerator Upgrade Project (AUP) had completed fabrication of ten MQXFA magnets and tested eight of them. The MQXFA magnets are the low-beta quadrupole magnets to be used in the Q1 and Q3 Inner Triplet elements of the High Luminosity LHC. This AUP effort is shared by BNL, Fermilab, and LBNL, with strand verification tests at NHMFL. An important step of the AUP QA plan is the testing of MQXFA magnets in a vertical cryostat at BNL. The acceptance criteria that could be tested at BNL were all met by the first four production magnets (MQXFA03-MQXFA06). Subsequently, two magnets (MQXFA07 and MQXFA08) did not meet some of the criteria and were disassembled. Lessons learned during the disassembly of MQXFA07 caused a revision to the assembly specifications that were used for MQXFA10 and subsequent magnets. In this article, we present a summary of: 1) the fabrication and test data for all the MQXFA magnets; 2) the analysis of MQXFA07/A08 test results with characterization of the limiting mechanism; 3) the outcome of the investigation, including the lessons learned during MQXFA07 disassembly; and 4) the finite element analysis correlating observations with test performance.

Languages have constructions that convey the logical concepts of negation, conjunction, and disjunction. These constructions are often logically ambiguous. A disjunction can be exclusive (XOR) or inclusive (IOR), and a negative conjunction/disjunction can be an alternative denial (NAND) or joint denial (NOR). Previous studies have suggested that there is substantial crosslinguistic variation in the interpretation of logical constructions and that languages fall into two groups. The first group including English interprets a negative conjunction as alternative denial (NAND) and a negative disjunction as joint denial (NOR). The second group including Hungarian and Chinese has the opposite interpretation pattern. However, there have been few crosslinguistic studies on the adult interpretation of logical constructions. Using an card selection task, we tested speakers of English, Hungarian, Spanish, and Chinese on different logical constructions. We found that speakers of these languages showed consistency in their interpretations of these constructions in the question environment.

BackgroundWe sought to describe trends in extracorporeal membrane oxygenation (ECMO) use, and define the impact on PGD incidence and early mortality in lung transplantation.MethodsPatients were enrolled from August 2011 to June 2018 at 10 transplant centers in the multi-center Lung Transplant Outcomes Group prospective cohort study. PGD was defined as Grade 3 at 48 or 72 hours, based on the 2016 PGD ISHLT guidelines. Logistic regression and survival models were used to contrast between group effects for event (i.e., PGD and Death) and time-to-event (i.e., death, extubation, discharge) outcomes respectively. Both modeling frameworks accommodate the inclusion of potential confounders.ResultsA total of 1,528 subjects were enrolled with a 25.7% incidence of PGD. Annual PGD incidence (14.3%-38.2%, p = .0002), median LAS (38.0-47.7 p = .009) and the use of ECMO salvage for PGD (5.7%-20.9%, p = .007) increased over the course of the study. PGD was associated with increased 1 year mortality (OR 1.7 [95% C.I. 1.2, 2.3], p = .0001). Bridging strategies were not associated with increased mortality compared to non-bridged patients (p = .66); however, salvage ECMO for PGD was significantly associated with increased mortality (OR 1.9 [1.3, 2.7], p = .0007). Restricted mean survival time comparison at 1-year demonstrated 84.1 days lost in venoarterial salvaged recipients with PGD when compared to those without PGD (ratio 1.3 [1.1, 1.5]) and 27.2 days for venovenous with PGD (ratio 1.1 [1.0, 1.4]).ConclusionsPGD incidence continues to rise in modern transplant practice paralleled by significant increases in recipient severity of illness. Bridging strategies have increased but did not affect PGD incidence or mortality. PGD remains highly associated with mortality and is increasingly treated with salvage ECMO.

El Paisaje Cultural Cafetero de Colombia (PCCC) fue reconocido en el año 2011 por la Unesco como patrimonio de la humanidad, lo cual ha significado para los municipios involucrados un amplio reconocimiento internacional y una importante responsabilidad en diferentes niveles, debido a que la gestión, protección y sostenibilidad de este valioso patrimonio mundial demanda una serie de recursos humanos, técnicos y económicos que deben ser entregados a través de ejercicios de colaboración y concurrencia entre la nación y las entidades locales. A partir de un enfoque metodológico mixto, el artículo analiza diversos elementos de las finanzas públicas con el fin de dar luces frente a la necesidad de cooperación entre las distintas entidades responsables del PCCC. Para ello, el texto se divide en cuatro componentes: contexto general del PCCC, finanzas públicas de los municipios, análisis de la dependencia fiscal y conclusiones generales.