Prediabetes as a risk factor for all-cause and cause-specific mortality: a prospective analysis of 115,919 adults without diabetes in Mexico City.

BACKGROUND: Prediabetes has been associated with increased all-cause and cardiovascular mortality. However, no large-scale studies have been conducted in Mexico or Latin America examining these associations. METHODS: We analyzed data from 115,919 adults without diabetes (diagnosed or undiagnosed) aged 35-84 years who participated in the Mexico City Prospective Study between 1998 and 2004. Participants were followed until January 1st, 2021 for cause-specific mortality. We defined prediabetes according to the American Diabetes Association (ADA, HbA1c 5.7% to 6.4%) and the International Expert Committee (IEC, HbA1c 6.0-6.4%) definitions. Cox regression adjusted for confounders was used to estimate all-cause and cause-specific mortality rate ratios (RR) at ages 35-74 years associated with prediabetes. FINDINGS: During 2,085,392 person-years of follow-up (median in survivors 19 years), there were 6,810 deaths at ages 35-74, including 1,742 from cardiovascular disease, 892 from renal disease and 108 from acute diabetic crises. Of 110,405 participants aged 35-74 years at recruitment, 28,852 (26%) had ADA-defined prediabetes and 7,203 (7%) had IEC-defined prediabetes. Compared with those without prediabetes, individuals with prediabetes had higher risk of all-cause mortality at ages 35-74 years (RR 1.13, 95% CI 1.07-1.19 for ADA-defined prediabetes and RR 1.28, 1.18-1.39 for IEC-defined prediabetes), as well as increased risk of cardiovascular mortality (RR 1.22 [1.10-1.35] and 1.42 [1.22-1.65], respectively), renal mortality (RR 1.35 [1.08-1.68] and 1.69 [1.24-2.31], respectively), and death from an acute diabetic crisis (RR 2.63 [1.76-3.94] and 3.43 [2.09-5.62], respectively). RRs were larger at younger than at older ages, and similar for men compared to women. The absolute excess risk associated with ADA and IEC-defined prediabetes at ages 35-74 accounted for6% and 3% of cardiovascular deaths respectively, 10% and 5% of renal deaths respectively, and 31% and 14% of acute diabetic deaths respectively. INTERPRETATION: Prediabetes is a significant risk factor for all-cause, cardiovascular, renal, and acute diabetic deaths in Mexican adults. Identification and timely management of individuals with prediabetes for targeted risk reduction could contribute to reducing premature mortality from cardiometabolic causes in this population. FUNDING: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, UK Medical Research Council. Instituto Nacional de Geriatría (Mexico City).

Characterising the contribution of rare protein-coding germline variants to prostate cancer risk and severity in 37,184 cases.

The etiology of prostate cancer, the second most common cancer in men globally, has a strong heritable component. While rare coding germline variants in several genes have been identified as risk factors from candidate gene and linkage studies, the exome-wide spectrum of causal rare variants remains to be fully explored. To more comprehensively address their contribution, we analysed data from 37,184 prostate cancer cases and 331,329 male controls from five cohorts with germline exome/genome sequencing and one cohort with imputed array data from a population enriched in low-frequency deleterious variants. Our gene-level collapsing analysis revealed that rare damaging variants in SAMHD1 as well as genes in the DNA damage response pathway (BRCA2, ATM and CHEK2) are associated with the risk of overall prostate cancer. We also found that rare damaging variants in AOX1 and BRCA2 were associated with increased severity of prostate cancer in a case-only analysis of aggressive versus non-aggressive prostate cancer. At the single-variant level, we found rare non-synonymous variants in three genes (HOXB13, CHEK2, BIK) significantly associated with increased risk of overall prostate cancer and in four genes (ANO7, SPDL1, AR, TERT) with decreased risk. Altogether, this study provides deeper insights into the genetic architecture and biological basis of prostate cancer risk and severity.

Human intestinal enteroids platform to assess the infectivity of gastroenteritis viruses in wastewater.

Fecal-orally transmitted gastroenteritis viruses, particularly human noroviruses (HuNoVs), are a public health concern. Viral transmission risk through contaminated water results underexplored as they have remained largely unculturable until recently and the robust measuring of gastroenteritis viruses infectivity in a single cell line is challenging. This study primarily aimed to test the feasibility of the human intestinal enteroids (HIE) model to demonstrate the infectivity of multiple gastroenteritis viruses in wastewater. Initially, key factors affecting viral replication in HIE model were assessed, and results demonstrated that the reagent-assisted disruption of 3D HIE represents an efficient alternative to syringe pass-through, and the filtering of HuNoV stool suspensions could be avoided. Moreover, comparable replication yields of clinical strains of HuNoV genogroup I (GI), HuNoV GII, rotavirus (RV), astrovirus (HAstV), and adenoviruses (HAdV) were obtained in single and multiple co-infections. Then, the optimized HIE model was used to demonstrate the infectivity of multiple naturally occurring gastroenteritis viruses from wastewater. Thus, a total of 28 wastewater samples were subjected to (RT)-qPCR for each virus, with subsequent testing on HIE. Among these, 16 samples (57 %) showed replication of HuNoVs (n = 3), RV (n = 5), HAstV (n = 8), and/or HAdV (n = 5). Three samples showed HuNoV replication, and sequences assigned to HuNoV GI.3[P13] and HuNoV GII.4[P16] genotypes. Concurrent replication of multiple gastroenteritis viruses occurred in 4 wastewater samples. By comparing wastewater concentrate and HIE supernatant sequences, diverse HAstV and HAdV genotypes were identified in 4 samples. In summary, we successfully employed HIE to demonstrate the presence of multiple infectious human gastroenteritis viruses, including HuNoV, in naturally contaminated wastewater samples.

The ∆Pv-aCO2/∆Ca-vO2 ratio as a predictor of mortality in patients with severe acute respiratory distress syndrome related to COVID-19.

OBJECTIVE: To evaluate the central venous-to-arterial carbon dioxide difference combined with arterial-to-venous oxygen content difference (∆Pv-aCO2/∆Ca-vO2 ratio) as a predictor of mortality in patients with COVID-19-related severe acute respiratory distress syndrome (ARDS). METHODS: Patients admitted to the intensive care unit with severe ARDS secondary to SARS-CoV-2, and invasive mechanical ventilation were included in this single-center and retrospective cohort study performed between April 18, 2020, and January 18, 2022. The tissue perfusion indexes (lactate, central venous oxygen saturation [ScvO2], and venous-to-arterial carbon dioxide pressure difference [∆Pv-aCO2]), anaerobic metabolism index (∆Pv-aCO2/∆Ca-vO2 ratio), and severity index (Simplified Acute Physiology Score II [SAPSII]) were evaluated to determine its association with the mortality through Cox regression analysis, Kaplan-Meier curve and receiver operating characteristic (ROC) curve. RESULTS: One hundred fifteen patients were included in the study and classified into two groups, the survivor group (n = 54) and the non-survivor group (n = 61). The lactate, ScvO2, ∆Pv-aCO2, and ∆Pv-aCO2/∆Ca-vO2 ratio medians were 1.6 mEq/L, 75%, 5 mmHg, and 1.56 mmHg/mL, respectively. The ∆Pv-aCO2/∆Ca-vO2 ratio (Hazard Ratio (HR) = 1.17, 95% confidence interval (CI) = 1.06-1.29, p = 0.001) was identified as a mortality biomarker for patients with COVID-19-related severe ARDS. The area under the curve for ∆Pv-aCO2/∆Ca-vO2 ratio was 0.691 (95% CI 0.598-0.774, p = 0.0001). The best cut-off point for ∆Pv-aCO2/∆Ca-vO2 ratio was >2.14 mmHg/mL, with a sensitivity of 49.18%, specificity of 85.19%, a positive likelihood of 3.32, and a negative likelihood of 0.6. The Kaplan-Meier curve showed that survival rates were significantly worse in patients with values greater than this cut-off point. CONCLUSIONS: The ∆Pv-aCO2/∆Ca-vO2 ratio could be used as a predictor of mortality in patients with severe ARDS secondary to SARS-CoV-2.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Educational and social inequalities and cause-specific mortality in Mexico City: a prospective study.

BACKGROUND: Social inequalities in adult mortality have been reported across diverse populations, but there is no large-scale prospective evidence from Mexico. We aimed to quantify social, including educational, inequalities in mortality among adults in Mexico City. METHODS: The Mexico City Prospective Study recruited 150 000 adults aged 35 years and older from two districts of Mexico City between 1998 and 2004. Participants were followed up until Jan 1, 2021 for cause-specific mortality. Cox regression analysis yielded rate ratios (RRs) for death at ages 35-74 years associated with education and examined, in exploratory analyses, the mediating effects of lifestyle and related risk factors. FINDINGS: Among 143 478 participants aged 35-74 years, there was a strong inverse association of education with premature death. Compared with participants with tertiary education, after adjustment for age and sex, those with no education had about twice the mortality rate (RR 1·84; 95% CI 1·71-1·98), equivalent to approximately 6 years lower life expectancy, with an RR of 1·78 (1·67-1·90) among participants with incomplete primary, 1·62 (1·53-1·72) with complete primary, and 1·34 (1·25-1·42) with secondary education. Education was most strongly associated with death from renal disease and acute diabetic crises (RR 3·65; 95% CI 3·05-4·38 for no education vs tertiary education) and from infectious diseases (2·67; 2·00-3·56), but there was an apparent higher rate of death from all specific causes studied with lower education, with the exception of cancer for which there was little association. Lifestyle factors (ie, smoking, alcohol drinking, and leisure time physical activity) and related physiological correlates (ie, adiposity, diabetes, and blood pressure) accounted for about four-fifths of the association of education with premature mortality. INTERPRETATION: In this Mexican population there were marked educational inequalities in premature adult mortality, which appeared to largely be accounted for by lifestyle and related risk factors. Effective interventions to reduce these risk factors could reduce inequalities and have a major impact on premature mortality. FUNDING: Wellcome Trust, the Mexican Health Ministry, the National Council of Science and Technology for Mexico, Cancer Research UK, British Heart Foundation, and the UK Medical Research Council Population Health Research Unit.

A Spontaneous Melanoma Mouse Model Applicable for a Longitudinal Chemotherapy and Immunotherapy Study.

Mouse models that reflect human disorders provide invaluable tools for the translation of basic science discoveries to clinical therapies. However, many of these in vivo therapeutic studies are short term and do not accurately mimic patient conditions. In this study, we used a fully immunocompetent, transgenic mouse model, TGS, in which the spontaneous development of metastatic melanoma is driven by the ectopic expression of a normal neuronal receptor, mGluR1, as a model to assess longitudinal treatment response (up to 8 months) with an inhibitor of glutamatergic signaling, troriluzole, which is a prodrug of riluzole, plus an antibody against PD-1, an immune checkpoint inhibitor. Our results reveal a sex-biased treatment response that led to improved survival in troriluzole and/or anti-PD-1-treated male mice that correlated with differential CD8+ T cells and CD11b+ myeloid cell populations in the tumor-stromal interface, supporting the notion that this model is a responsive and tractable system for evaluating therapeutic regimens for melanoma in an immunocompetent setting.

Craniofacial fibrous dysplasia and aneurismal bone cyst in a patient with McCune-Albright syndrome. A case report and review of the literature.

McCune-Albright syndrome (MAS) is a rare heterogeneous genetic disorder that is characterized by a triad of polyostotic fibrous dysplasia (FD), café au lait spots (CAL), and multiple hyperfunctional endocrinopathies. In general, it is diagnosed clinically. From the triads, 2 of the findings are enough to make the diagnosis. Craniofacial fibrous dysplasia is a term that is used to describe the fibrous dysplasia, which was localized at the craniofacial skeleton and is common in MAS patients. Aneurysmal bone cyst (ABC) is a rare non-neoplastic bone lesion that involves mostly the long bones and vertebrae and may occur very rarely in the craniofacial bones. ABCs may occur as secondary bony pathologies in association with various benign and malignant bone tumors and with fibrous dysplasia. Secondary ABC occurring in craniofacial FD is extremely rare. We present the case of a 21-year-old patient treated at our center for a right orbital aneurysmal bone cyst associated with MAS and provide a review of the relevant literature.

Índices de oxigenación como marcadores pronósticos en neumonía grave por SARS-CoV-2 / Oxygenation indices as prognostic marker in severe pneumonia due to SARS-CoV-2 / Índices de oxigenação como marcadores prognósticos na pneumonia grave por SARS-CoV-2

Resumen: Introducción: a través de los índices de oxigenación valoramos la función del sistema respiratorio de oxigenación y ventilación. Objetivo: determinar el valor de los índices de oxigenación como factor de pronóstico para el desenlace en neumonía grave por SARS-CoV-2. Material y métodos: estudio retrospectivo, longitudinal, descriptivo, analítico. Se incluyeron pacientes > 18 años con diagnóstico de neumonía por SARS-CoV-2 entre el 01 junio y el 31 de diciembre de 2020. Se clasificó a los pacientes de acuerdo al desenlace: sobreviviente o no sobreviviente. Se empleó estadística descriptiva y pruebas paramétricas y no paramétricas de acuerdo al caso, se construyeron curvas ROC (Receiver Operating Characteristic Curve) para determinar los puntos de corte de los gases arteriales con la mejor sensibilidad y especificidad y se determinó el área bajo la curva (ABC) para el desenlace fatal. Resultados: se incluyeron 175 pacientes, 70.3% correspondió al sexo masculino, la media de edad fue de 56 años (rango intercuartil 45-64). El grupo de sobrevivientes incluyó 51 pacientes y el grupo de no sobrevivientes 124 pacientes. Al analizar los gases arteriales al momento de ingresar a la unidad de cuidados intensivos sobresale la PaO2/FiO2 de 100 mmHg y el índice respiratorio (IR) > 2.4 con un ABC de 0.694 y 0.722 respectivamente. A las 96 horas de ingreso destaca PaO2/FiO2 de 145 mmHg, el IR >3 y la PaO2/PAO2 de 0.22 con un ABC de 0.846, 0.840 y 0.842 respectivamente. Conclusión: los gases arteriales medidos a las 96 horas de ingreso a la UCI son marcadores pronósticos para el desenlace fatal en la neumonía grave por SARS-CoV-2.

Abstract: Introduction: oxygenation indices we assess the function of the respiratory system of oxygenation and ventilation. Objective: to determine the value of arterial gases as a prognostic factor for the outcome of patients with severe SARS-CoV-2 pneumonia. Material and methods: retrospective, longitudinal, descriptive, analytical study. We included patients > 18 years with a diagnosis of SARS-CoV-2 pneumonia between 1 June and 31 December 2020. Patients were classified according to outcome: survivor or non-survivor. Descriptive statistics and parametric and non-parametric tests were used according to the case, ROC (Receiver Operating Characteristic Curve) curves were constructed to determine the cut-off points of arterial gases with the best sensitivity and specificity and the area under the curve (AUC) for the fatal outcome was determined. Results: we included 175 patients, 70.3% corresponded to the male sex, the mean age was 56 years (interquartile range 45-64). The survivor group included 51 patients and the non-survivor group 124 patients. When analyzing arterial gases at the time of admission to the ICU, paO2/FiO2 of 100 mmHg and respiratory index (RI) > 2.4 with ABC 0.694 and 0.722 respectively. At 96 hours of admission, PaO2/FiO2 of 145 mmHg stands out, the RI > 3 and the DA-aO2 of 0.22 with ABC 0.846, 0.840 and 0.842 respectively. Conclusion: arterial blood gases measured at 96 hours of ICU admission are prognostic markers for fatal outcome in severe SARS-CoV-2 pneumonia.

Resumo: Introdução: através dos índices de oxigenação avaliamos a função do sistema respiratório de oxigenação e ventilação. Objetivo: determinar o valor dos índices de oxigenação como fator prognóstico para o desfecho em pneumonia grave por SARS-CoV-2. Material e métodos: estudo retrospectivo, longitudinal, descritivo, analítico. Icluíram-se pacientes com mais de 18 anos de idade diagnosticados com pneumonia por SARS-CoV-2 entre 1º de junho e 31 de dezembro de 2020. Os pacientes foram classificados de acordo com o desfecho: sobreviventes ou não sobreviventes. Foram usadas estatística descritiva e testes paramétricos e não paramétricos de acordo com o caso, foram construídas curvas ROC (Receiver Operating Characteristic Curve) para determinar os pontos de corte da gasometria arterial com melhor sensibilidade e especificidade e determinou-se a área sob a curva (ABC) para o desfecho fatal. Resultados: incluíram-se 175 pacientes, 70.3% eram do sexo masculino, a média de idade foi de 56 anos (rango interquartil 45-64). O grupo sobrevivente incluiu 51 pacientes e o grupo não sobrevivente 124 pacientes. Na análise dos gases arteriais no momento da admissão na UTI, destacam-se a PaO2/FiO2 de 100 mmHg e o índice respiratório (IR) > 2.4 com AUC 0.694 e 0.722 respectivamente. Às 96 horas de internamento destaca-se PaO2/FiO2 145 mmHg, IR > 3 e PaO2/PAO2 de 0.22 com ABC 0.846, 0.840 e 0.842 respetivamente. Conclusão: os gases sanguíneos arteriais medidos 96 horas após a admissão na UTI são marcadores prognósticos para desfecho fatal em pneumonia grave por SARS-CoV-2.

Chemical Composition and In Vitro and In Silico Antileishmanial Evaluation of the Essential Oil from Croton linearis Jacq. Stems.

Croton linearis Jacq. is an aromatic shrub that has been utilized in traditional medicine in the Bahamas, Jamaica, and Cuba. Recent studies have revealed the antiprotozoal potential of its leaves. The present work is aimed to identify the volatile constituents of essential oil from the stems of C. linearis (CLS-EO) and evaluate its in vitro antileishmanial activity. In addition, an in silico study of the molecular interactions was performed using molecular docking. A gas chromatographic-mass spectrometric analysis of CLS-EO identified 1,8-cineole (27.8%), α-pinene (11.1%), cis-sabinene (8.1%), p-cymene (5.7%), α-terpineol (4.4%), epi-γ-eudesmol (4.2%), linalool (3.9%), and terpinen-4-ol (2.6%) as major constituents. The evaluation of antileishmanial activity showed that CLS-EO has good activity on both parasite forms (IC50Promastigote = 21.4 ± 0.1 µg/mL; IC50Amastigote = 18.9 ± 0.3 µg/mL), with a CC50 of 49.0 ± 5.0 µg/mL on peritoneal macrophages from BALB/c mice (selectivity index = 2 and 3 using the promastigote and amastigote results). Molecular docking showed good binding of epi-γ-eudesmol with different target enzymes of Leishmania. This study is the first report of the chemical composition and anti-Leishmania evaluation of CLS-EO. These findings provide support for further studies of the antileishmanial effect of this product.

Transvascular Balloon Occlusion: A Novel Bailout Strategy in Large Left Main Perforations.

Several complications have been reported in rotational atherectomy, and these complications are closely associated with cardiac tamponade, emergent surgery, and death. Here we describe a case of left main coronary artery, bullet-like perforation treated with a novel approach-transvascular balloon occlusion. (Level of Difficulty: Advanced.).

Arsenicism by Chronic Exposure to Mine Tailings in Peru: An Analysis of 17 Cases with Lesions on Skin and/or Annexes.

Objective: To characterize the epidemiology and clinical manifestations of arsenicism from chronic exposure to mine tailings in people with lesions on their skin and/or annexes in two mining districts in the highlands of Peru. Materials and Methods: In this case series study, we included 17 people that presented arsenical lesions in skin and annexes which were identified in two prior studies. We evaluated age, occupation, place of exposure, time of exposure, time of disease, manifestations on skin and annexes, location of lesions, severity, and 24-hour urine clearance of arsenic. Results: The average time of exposure was 16.5 ± 14.7 years, and the average length of disease was 9.8 ± 8.1 years. In this study, 70.6% were men, 41.2% were farmers and 17.6% were underage. The most frequent main manifestations in skin and annexes were plantar keratosis (23.5%), palmar (11.8%), palmoplantar (11.8%) and thoracic keratosis (5.9%). Other manifestations were palmoplantar keratosis with thoracic hyperpigmentation (17.6%), Mees' lines (17.6%) and hyper/hypopigmentation in thorax and back (11.8%). With relation to the severity of lesions, 35.3% were grade 1 (mild), 29.4 % were grade 0 (asymptomatic), 29.4 % were grade 2 (moderate), and 5.9% were grade 3 (severe). The median of 24-hour urine clearance of arsenic was 55 µg/L/24 hours. No cases of skin cancer were presented. Conclusion: The studied cases of arsenicism with lesions on skin and/or annexes by exposure to mine tailings present with differential characteristics in comparison to other forms of arsenicism such as less severity, lower urine clearance of arsenic, and absence of skin cancer cases.

Inhibitory Effect on Nitric Oxide Release in LPS-Stimulated Macrophages and Free Radical Scavenging Activity of Croton linearis Jacq. Leaves.

Oxidative stress is an important component of many diseases including cancer, along with inflammatory and neurodegenerative processes. Natural antioxidants have emerged as promising substances to protect the human body against reactive oxygen and nitrogen species. The present study evaluates the inhibition of nitric oxide (NO) production in LPS-stimulated RAW 264.7 murine macrophages and the free radical scavenging activity of Croton linearis Jacq. leaves. UPLC-QTOF-MS analysis identified 18 compounds: nine alkaloids with a morphinane, benzylisoquinoline or aporphine nucleus, and nine O-glycosylated-flavonoids with quercetin, kaempferol and isorhamnetin as the aglycones. The crude extract (IC50 21.59 µg/mL) and the n-hexane fraction (IC50 4.88 µg/mL) significantly reduced the NO production in LPS-stimulated macrophages but with relatively high cytotoxicity (CC50 75.30 and CC50 70.12 µg/mL, respectively), while the ethyl acetate fraction also showed good activity (IC50 40.03 µg/mL) without affecting the RAW 264.7 cell viability. On the other hand, the crude extract, as well as the dichloromethane and ethyl acetate fractions, showed better DPPH and ABTS free radical scavenging activities. Considering the chemical composition and the activity observed for Croton linearis leaves, they may be considered a good source of antioxidants to combat oxidative damage-related diseases.

Boosting Protein Encapsulation through Lewis-Acid-Mediated Metal-Organic Framework Mineralization: Toward Effective Intracellular Delivery.

Encapsulation of biomolecules using metal-organic frameworks (MOFs) to form stable biocomposites has been demonstrated to be a valuable strategy for their preservation and controlled release, which has been however restricted to specific electrostatic surface conditions. We present a Lewis-acid-mediated general in situ strategy that promotes the spontaneous MOF growth on a broad variety of proteins, for the first time, regardless of their surface nature. We demonstrate that MOFs based on cations exhibiting considerable inherent acidity such as MIL-100(Fe) enable efficient biomolecule encapsulation, including elusive alkaline proteins previously inaccessible by the well-developed in situ azolate-based MOF encapsulation. Specifically, we prove the MIL-100(Fe) scaffold for the encapsulation of a group of proteins exhibiting very different isoelectric points (5 < pI < 11), allowing triggered release under biocompatible conditions and retaining their activity after exposure to denaturing environments. Finally, we demonstrate the potential of the myoglobin-carrying biocomposite to facilitate the delivery of O2 into hypoxic human lung carcinoma A549 cells, overcoming hypoxia-associated chemoresistance.

Replication of Human Norovirus in Mice after Antibiotic-Mediated Intestinal Bacteria Depletion.

Human noroviruses (HuNoVs) are the main cause of acute gastroenteritis causing more than 50,000 deaths per year. Recent evidence shows that the gut microbiota plays a key role in enteric virus infectivity. In this context, we tested whether microbiota depletion or microbiota replacement with that of human individuals susceptible to HuNoVs infection could favor viral replication in mice. Four groups of mice (n = 5) were used, including a control group and three groups that were treated with antibiotics to eliminate the autochthonous intestinal microbiota. Two of the antibiotic-treated groups received fecal microbiota transplantation from a pool of feces from infants (age 1-3 months) or an auto-transplantation with mouse feces that obtained prior antibiotic treatment. The inoculation of the different mouse groups with a HuNoVs strain (GII.4 Sydney [P16] genotype) showed that the virus replicated more efficiently in animals only treated with antibiotics but not subject to microbiota transplantation. Viral replication in animals receiving fecal microbiota from newborn infants was intermediate, whereas virus excretion in feces from auto-transplanted mice was as low as in the control mice. The analysis of the fecal microbiota by 16S rDNA NGS showed deep variations in the composition in the different mice groups. Furthermore, differences were observed in the gene expression of relevant immunological mediators, such as IL4, CXCL15, IL13, TNFα and TLR2, at the small intestine. Our results suggest that microbiota depletion eliminates bacteria that restrict HuNoVs infectivity and that the mechanism(s) could involve immune mediators.

Multiancestry exome sequencing reveals INHBE mutations associated with favorable fat distribution and protection from diabetes.

Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10-09), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin ßE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.

Decúbito prono prolongado: una estrategia no ventilatoria en neumonía grave por SARS-CoV-2 / Prono position: a non-ventilatory strategy in patients with severe pneumonia due to SARS-CoV-2 / Posição prona prolongada: uma estratégia não ventilatória em pneumonia grave devido a SARS-CoV-2

Resumen: Introducción: La neumonía grave por SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) ocasiona hipoxemia severa, por lo anterior, las guías para el manejo de pacientes adultos críticamente enfermos con COVID-19 recomiendan el uso de la posición decúbito prono para mejorar la oxigenación. Material y métodos: Estudio de cohorte, prospectivo, descriptivo y analítico. Pacientes ingresados a la unidad de cuidados intensivos en el periodo comprendido entre el 18 de abril de 2020 y el 18 de agosto de 2021 con ventilación mecánica invasiva (VMI) secundaria a neumonía grave por SARS-CoV-2 confirmados. Resultados: En el periodo comprendido se incluyeron 110 pacientes que cumplieron con los criterios de inclusión. Del total, 88 pacientes se incluyeron en el grupo de mejoría sostenida al retiro del prono y 22 en el grupo de mejoría no sostenida al retiro del prono. Se observó que la disminución del porcentaje de la PaO2/FiO2 al retiro del prono es útil para predecir mortalidad con ABC de 0.740 con IC95% de (0.646-0.834) y p = 0.001. Conclusión: La disminución > 50% de la PaO2/FiO2 al retiro de la posición decúbito prono prolongado o mejoría no sostenida es un predictor de mortalidad en los pacientes con neumonía grave por SARS-CoV-2.

Abstract: Introduction: Severe pneumonia due to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) causes severe hypoxemia, therefore, the guidelines for the management of critically ill adult patients with COVID-19 recommend the use of the prone position to improve oxygenation. Material and methods: A prospective, descriptive and analytical cohort study. Patients admitted to the intensive care unit in the period from April 18, 2020 to August 18, 2021 with confirmed IMV secondary to severe SARS-CoV-2 pneumonia. Results: In the period covered, 110 patients who met the inclusion criteria were included. Of the total, 88 patients were included in the group with sustained improvement at prone withdrawal and 22 in the group with non-sustained improvement at prone withdrawal. It was observed that the% Decrease in PaO2/FiO2 upon prone removal is useful to predict mortality with AUC of 0.740 with 95% CI of (0.646-0.834) and p = 0.001. Conclusion: A > 50% decrease in PaO2/FiO2 upon removal from prolonged prone position or unsustained improvement is a predictor of mortality in patients with severe SARS-CoV-2 pneumonia.

Resumo: Introdução: A pneumonia grave por SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) causa hipoxemia grave, portanto, as diretrizes para o manejo de pacientes adultos criticamente doentes com COVID-19 recomendam o uso da posição prona para melhorar a oxigenação. Material e métodos: Estudo de coorte, prospectivo, descritivo e analítico. Pacientes admitidos na unidade de terapia intensiva no período entre 18 de abril de 2020 e 18 de agosto de 2021 com VMI secundária a pneumonia grave por SARS-CoV-2 confirmadas. Resultados: No período abrangido, incluíram-se 110 pacientes que atenderam aos critérios de inclusão. Do total, 88 pacientes foram incluídos no grupo melhora sustentada na retirada da posição prona e 22 no grupo melhora não sustentada na retirada da posição prona. Observou-se que a % de diminuição da PaO2/FiO2 na retirada da pronação é útil para predizer mortalidade com ABC de 0.740 com IC de 95% de (0.646-0.834) e p = 0.001. Conclusão: Uma diminuição > 50% na PaO2/FiO2 após a retirada da posição prona prolongada ou melhora não sustentada é um preditor de mortalidade em pacientes com pneumonia grave por SARS-CoV-2.

Effects of Face Masks on Physiological Parameters and Voice Production during Cycling Activity.

This study investigates the effects of face masks on physiological and voice parameters, focusing on cyclists that perform incremental sports activity. Three healthy male subjects were monitored in a climatic chamber wearing three types of masks with different acoustic properties, breathing resistance, and air filtration performance. Masks A and B were surgical masks made of hydrophobic fabric and three layers of non-woven fabric of 100% polypropylene, respectively. Mask S was a multilayer cloth mask designed for sports activity. Mask B and Mask S behave similarly and show lower sound attenuation and sound transmission loss and lower breathing resistance than Mask A, although Mask A exhibits slightly higher filtration efficiency. Similar cheek temperatures were observed for Masks A and B, while a significantly higher temperature was measured with Mask S at incremental physical activity. No differences were found between the masks and the no-mask condition for voice monitoring. Overall, Mask B and Mask S are suitable for sports activities without adverse effects on voice production while ensuring good breathing resistance and filtration efficiency. These outcomes support choosing appropriate masks for sports activities, showing the best trade-off between breathing resistance and filtration efficiency, sound attenuation, and sound transmission loss.

An all-in-one point-of-care testing device for multiplexed detection of respiratory infections.

The impact of the COVID-19 pandemic has reinforced the need for rapid, cost-effective, and reliable point-of-care testing (POCT) devices for massive population screening. The co-circulation of SARS-CoV-2 with several seasonal respiratory viruses highlights the need for multiplexed biosensing approaches. Herein, we present a fast and robust all-in-one POCT device for parallel viral antigen and serological analysis. The biosensing approach consists of a functionalized polycarbonate disc-shaped surface with microfluidic structures, where specific bioreagents are immobilized in microarray format, and a portable optoelectronic analyzer. The biosensor quantifies the concentration of viral antigens and specific immunoglobulins G and M for SARS-CoV-2, influenza A/B, adenovirus, and respiratory syncytial virus, using 30 µL of a sample. The semi-automated analysis of 6 samples is performed in 30 min. Validation studies performed with 135 serum samples and 147 nasopharyngeal specimens reveal high diagnostic sensitivity (98-100%) and specificity (84-98%), achieving an excellent agreement (κ = 0.937) with commercial immunoassays, which complies with the World Health Organization criteria for POC COVID-19 diagnostic tests. The versatility of the POCT device paves the way for the detection of other pathogens and analytes in the incoming post-pandemic world, integrating specific bioreagents against different variants of concerns and interests.

Factors Indicating Surgical Excision in Classical Type of Lobular Neoplasia of the Breast.

Purpose: Classical type of lobular neoplasia (LN) encompassing both atypical lobular hyperplasia and classical lobular carcinoma in situ of the breast is a lesion with uncertain malignant potential and has been the topic of several studies with conflicting outcome results. The aim of our study was to clarify outcome-relevant factors and treatment options of classical LN. Methods: We performed a pathological re-evaluation of the preoperative biopsy specimens and a retrospective clinical and radiological data analysis of 160 patients with LN from the Breast Center Zurich. Open surgery was performed in 65 patients, vacuum-assisted biopsy (VAB) in 79 patients, and surveillance after breast core needle biopsy (CNB) in 16 patients. Results: The upgrade rate into ductal carcinoma in situ/invasive cancer was the highest in case of imaging/histology discordance (40%). If the number of foci in the biopsy specimen was ≥3, the upgrade rate in the consecutive surgical specimens was increased (p = 0.01). The association of classical LN with histological microcalcification correlated with shortened disease-free survival (p < 0.01), whereas other factors showed no impact on follow-up. Conclusions: Surveillance or subsequent VAB after CNB of LN is sufficient in most cases. Careful consideration of individual radiological and histological factors is required to identify patients with a high risk of upgrade into malignancy. In those cases, surgical excision is indicated.