Alcohol and mortality in Mexico: prospective study of 150 000 adults.

BACKGROUND: Alcohol consumption is a leading cause of premature death globally, but there is no large-scale prospective evidence from Mexico. METHODS: The Mexico City Prospective Study recruited 150 000 adults aged 35 years or older between 1998 and 2004. Participants were followed up until Oct 1, 2022 for cause-specific mortality. Cox regression in those with no self-reported chronic disease at entry (adjusted for age, sex, district, education, physical activity, smoking, and diabetes) was used to relate baseline-reported alcohol consumption (never, former, occasional [less than monthly], and regular [at least monthly, split into <70, ≥70 to <140, ≥140 to <210, and ≥210 g/week]) to mortality at ages 35-74 from all causes, and from a pre-specified alcohol-related set of underlying causes. Heavy episodic drinking (normally consuming >5 [men] or >4 [women] drinks on a single occasion) and type of preferred drink were also examined. FINDINGS: Among 138 413 participants aged 35-74 years at recruitment, 21 136 (15%) were regular alcohol drinkers (14 863 [33%] men, 6273 [7%] women), of whom 13 383 (63%) favoured spirits and 6580 (31%) favoured beer. During follow-up, there were 13 889 deaths at ages 35-74 years, including 3067 deaths from the pre-specified alcohol-related causes. Overall, J-shaped associations with mortality were observed. Compared with occasional drinkers, those with baseline-reported consumption ≥210 g/week had 43% higher all-cause mortality (rate ratio [RR] 1·43 [95% CI 1·30-1·56]) and nearly three times the mortality from the pre-specified alcohol-related causes (2·77 [2·39-3·20]). Death from liver disease was strongly related to alcohol consumption; the RR comparing regular drinkers of ≥140 g/week with occasional drinkers was 4·03 (3·36-4·83). Compared with occasional light drinking, occasional heavy episodic drinking was associated with 20% higher alcohol-related mortality (1·20 [1·06-1·35]), and regular heavy episodic drinking was associated with 89% higher alcohol-related mortality (1·89 [1·67-2·15]). Drinks with alcohol percentages higher than spirits were associated with the greatest increased mortality risk, even after accounting for the total alcohol consumed. INTERPRETATION: In this Mexican population, higher alcohol consumption, episodic drinking, and very high percentage alcoholic products were all associated with increased 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. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Correction to "Multicomponent Approach for Stable Methylammonium-Free Tin-Lead Perovskite Solar Cells".

[This corrects the article DOI: 10.1021/acsenergylett.3c02426.].

Unstable angina secondary to left main coronary artery vasculitis as a rare initial manifestation of systemic lupus erythematosus. A case report.

We present the case of a woman in her third decade of life, known to have difficult-to-control mixed headaches and polycystic ovary syndrome, under hormonal treatment. Without any other manifestation, the patient debuted with an acute coronary syndrome classified as unstable angina. Electrocardiogram showed anterior and lateral ST segment depression and ST elevation in aVR. Coronary computer tomography and coronary angiography showed evidence of significant obstruction of the left main coronary artery. The patient was diagnosed with systemic lupus erythematosus (SLE), and was classified as vasculitis secondary to SLE as an unusual initial manifestation.

Se presenta el caso de una mujer en la tercera década de la vida, con cefalea mixta de difícil control y síndrome de ovario poliquístico bajo tratamiento hormonal, sin ninguna otra manifestación, la cual debutó con un síndrome coronario agudo tipo angina inestable. El electrocardiograma mostró infradesnivel en cara anterior y lateral, así como supradesnivel del ST en aVR. La angiotomografia de coronarias y la coronariografía mostraron evidencia de obstrucción importante del tronco de la coronaria izquierda. Tras el abordaje se llegó al diagnóstico de vasculitis secundaria a lupus eritematoso sistémico como manifestación inicial poco habitual.

Killip and Kimball classification in the Ultrasound era: Is it time to redefine?

Lung ultrasound is a tool that is increasingly gaining strength in the initial evaluation of the patient in the emergency department and in critical care areas, making it particularly useful for cardiologists. In patients with ST elevation and acute myocardial infarction it has been observed that 25-45% of patients are wrongly classified as Class I in the Killip and Kimball classification after lung ultrasound (subclinical congestion). The clinical relevance of this finding lies in the fact that the greater the number of B lines, the greater short- and long-term the mortality is. An important advantage is that no prolonged time for learning the technique is required. More studies are needed to evaluate the role and importance of subclinical congestion in patients with acute myocardial infarction. Unfortunately, ultrasound is not widely available in developing countries, so the physical examination will continue to play an important role in the initial evaluation of patients with acute myocardial infraction.

El ultrasonido pulmonar es una herramienta que va cobrando más fuerza en la evaluación inicial del paciente en urgencias y en áreas de cuidados críticos, siendo de especial utilidad para el cardiólogo. Se ha observado que entre el 25 y el 45% de los pacientes con infarto agudo de miocardio con elevación del segmento ST se clasifican erróneamente como Clase 1 en la escala de Killip y Kimball después del ultrasonido pulmonar (congestión subclínica). La relevancia clínica de este hallazgo radica en que cuanto mayor es el número de líneas B, mayor es la mortalidad a corto y largo plazo. Una ventaja importante de esta herramienta es que no se requiere un tiempo prolongado para aprender la técnica. Se necesitan más estudios para evaluar el papel y la importancia de la congestión subclínica en pacientes con infarto agudo de miocardio. Desafortunadamente, el ultrasonido no está ampliamente disponible en los países en desarrollo, por lo que el examen físico seguirá desempeñando un papel importante para la evaluación inicial en pacientes con infarto agudo de miocardio.

Cardiac coherence and medical hypnosis: a feasibility study of a new combined approach for managing preoperative anxiety in patients with breast or gynaecological cancer.

Background: Non-pharmaceutical approaches can help manage preoperative anxiety, but few studies have evaluated psychoeducational programmes, especially for cancer surgery. We assessed the feasibility of the COHErence Cardiaque (COHEC) programme where cardiac coherence and medical hypnosis are combined to manage preoperative anxiety in patients undergoing breast or gynaecological cancer surgical interventions (BGCSI). Methods: Patients undergoing BGCSI were enrolled and followed a daily home programme with cardiac coherence and medical hypnosis sessions, starting 7 days before the procedure. The primary endpoint was optimal patient adherence (i.e. completion of ≥14 sessions). Secondary endpoints were anxiety levels, measured using the Visual Analogue Scale (VAS) and the Amsterdam Preoperative Anxiety and Information Scale (APAIS), satisfaction (EVAN-G), and quality of postoperative recovery (QoR-15). Results: In total, 53 patients [mean age: 55 (34-82) yr] were included; 83.7% had breast cancer and 15.1% had gynaecological cancer. Optimal adherence was achieved by 64.2% (95% confidence interval: 49.8-76.9%) of the intention-to-treat population. Among the 43 patients who completed at least one session, exploratory analysis showed that anxiety on the day before (P=0.02) and the morning of the intervention (P=0.04) was decreased in patients with severe anxiety at baseline (VAS ≥70). The median VAS satisfaction score for the programme was 10 (4-10). Overall, 94% of patients were willing to include the COHEC programme in their daily routine. Conclusions: The implementation of a psychoeducational programme combining cardiac coherence and medical hypnosis is feasible and might potentially help patients undergoing BGCSI to manage preoperative anxiety. A randomised trial is underway to assess the efficacy of the COHEC programme. Clinical trial registration: NCT03981731.

Smoking, all-cause, and cause-specific mortality in individuals with diabetes in Mexico: an analysis of the Mexico city prospective study.

OBJECTIVE: Evidence from low- and middle-income countries regarding the effect of smoking in people with diabetes is lacking. Here, we report the association of smoking with mortality in a large cohort of Mexican adults with diabetes. METHODS: Participants with diabetes mellitus (self-reported diagnosis, use of antidiabetic medications or HbA1c ≥ 6.5%) aged 35-74 years when recruited into the Mexico City Prospective Study were included. Cox regression confounder-adjusted mortality rate ratios (RRs) associated with baseline smoking status were estimated. RESULTS: Among 15,975 women and 8225 men aged 35-74 years with diabetes but no other comorbidities at recruitment, 2498 (16%) women and 2875 (35%) men reported former smoking and 2753 (17%) women, and 3796 (46%) men reported current smoking. During a median of 17 years of follow-up there were 5087 deaths at ages 35-74 years. Compared with never smoking, all-cause mortality RR was 1.08 (95%CI 1.01-1.17) for former smoking, 1.11 (95%CI 1.03-1.20) for current smoking, 1.09 (95%CI 0.99-1.20) for non-daily smoking, 1.06 (95%CI 0.96-1.16) for smoking < 10 cigarettes/day (median during follow-up 4 cigarettes/day), and 1.28 (95% CI 1.14-1.43) for smoking ≥ 10 cigarettes/day (median during follow-up 15 cigarettes/day). Mortality risk among daily smokers was greatest for COPD, lung cancer, cardiovascular diseases, and acute diabetic complications. CONCLUSION: In this cohort of Mexican adults with diabetes, low-intensity daily smoking was associated with increased mortality, despite observing smoking patterns which are different from other populations, and over 5% of total deaths were associated with smoking.

Development of Resorbable Phosphate-Based Glass Microspheres as MRI Contrast Media Agents.

In this research, resorbable phosphate-based glass (PBG) compositions were developed using varying modifier oxides including iron (Fe2O3), copper (CuO), and manganese (MnO2), and then processed via a rapid single-stage flame spheroidisation process to manufacture dense (i.e., solid) and highly porous microspheres. Solid (63-200 µm) and porous (100-200 µm) microspheres were produced and characterised via SEM, XRD, and EDX to investigate their surface topography, structural properties, and elemental distribution. Complementary NMR investigations revealed the formation of Q2, Q1, and Q0 phosphate species within the porous and solid microspheres, and degradation studies performed to evaluate mass loss, particle size, and pH changes over 28 days showed no significant differences among the microspheres (63-71 µm) investigated. The microspheres produced were then investigated using clinical (1.5 T) and preclinical (7 T) MRI systems to determine the R1 and R2 relaxation rates. Among the compositions investigated, manganese-based porous and solid microspheres revealed enhanced levels of R2 (9.7-10.5 s-1 for 1.5 T; 17.1-18.9 s-1 for 7 T) and R1 (3.4-3.9 s-1 for 1.5 T; 2.2-2.3 s-1 for 7 T) when compared to the copper and iron-based microsphere samples. This was suggested to be due to paramagnetic ions present in the Mn-based microspheres. It is also suggested that the porosity in the resorbable PBG porous microspheres could be further explored for loading with drugs or other biologics. This would further advance these materials as MRI theranostic agents and generate new opportunities for MRI contrast-enhancement oral-delivery applications.

Denovo glomerulonephritis associated with IgA anti-GBM alloantibodies after kidney transplantation in Alport syndrome: A case report with diagnostic implications.

Alport syndrome (AS) is a hereditary disorder caused by pathogenic variants in COL4A3, COL4A4, or COL4A5 genes expressing α3, α4, and α5 chains of basement membrane type IV collagen (COL4). The triple-helical α3α4α5(IV) protomer is a major component of the mature glomerular basement membrane (GBM) whose defective formation in AS leads to structural GBM disruption and kidney dysfunction, often resulting in kidney replacement therapy. A genetically intact renal graft exposes the immune system to a non-tolerized α3α4α5(IV) component and an alloimmune response eventually ensues. So far, only IgG alloantibodies reacting against COL4 have been reported in AS alloimmune responses. Here, we report alloimmune glomerulonephritis mediated by IgA antibodies against the non-collagenous C-terminal domain 1 of the α5(IV) chain in a patient with autosomal recessive AS following a second kidney transplantation. The patient presented a not previously described biallelic variant in the COL4A4 gene. Immunological, diagnostic, and clinical implications are discussed.

Stable Oxygen Incorporation in Superconducting TaN: An Experimental and Theoretical Assessment.

Oxide formation in superconducting TaN thin films is analyzed through experimental measurements and computational simulations. TaN was synthesized in an ultrahigh vacuum (UHV) system by reactive pulsed laser deposition and characterized in situ by X-ray photoelectron spectroscopy; it was also characterized ex situ by X-ray diffraction, transmission electron microscopy, and the four-point probe method. Despite being grown in an UHV chamber with a base pressure of 5 × 10-9 Torr, TaN contains a significant amount of oxygen (up to 20 at. %) attributed to residual gases containing O atoms. Several TaN1-x O x models, with different amounts of O atoms incorporated into N sites, were simulated using ab initio calculations to assess the feasibility of oxide formation. Thermodynamic stability analysis reveals that TaN1-x O x stability increases with oxygen addition, indicating that its incorporation is thermodynamically favorable. The oxygen-impurified TaN exhibits a face-centered cubic structure and is a superconductor (R = 0 Ω) at 2.99 K. The results discussed here highlight the importance of considering stable oxygen impurities when studying superconductivity in TaN films. The formation of TaN1-x O x regions in the compound may be key to understanding the variation in critical temperature reported in the literature.

Clinical-epidemiological characterization of patients with long COVID in Mexico.

BACKGROUND: Long COVID is defined as the persistence of COVID-19 symptoms four weeks after having undergone acute infection, according to the most recent CDC definition. It is estimated that there are 65 million people affected by this entity, although other figures speak of 200 million. OBJECTIVE: To characterize the population affected by long COVID in Mexico. MATERIAL AND METHODS: Patients older than 18 years who agreed to answer an online survey and who met the criteria for long COVID were included. RESULTS: Data from 203 subjects were included, with 138 (68.0%) being found to be females, and average age to be 41.8 years; 29.6% had severe disease, and 70.4%, mild to moderate disease; 89.7% had received prior COVID-19 vaccination: 6.9% had received one dose; 31.5%, two doses; and 51.2%, three or more doses. The main risk factors were diabetes, overweight or obesity, and hypertension. The most commonly reported symptom was fatigue, followed by other neuropsychiatric manifestations. CONCLUSION: It is important for the population affected by long COVID to be characterized in order to generate diagnostic and treatment protocols.

ANTECEDENTES: El COVID persistente se define como la persistencia de síntomas de COVID-19 después de cuatro semanas de cursar con un cuadro agudo, según la definición más reciente de los Centers for Disease Control and Prevention. Se estima que existen 65 millones de personas afectadas por esta entidad, aunque algunos reportes indican 200 millones. OBJETIVO: Caracterizar a la población afectada por COVID persistente en México. MATERIAL Y MÉTODOS: Se incluyeron pacientes mayores de 18 años que consintieron responder a una encuesta en línea y que cumplían los criterios de COVID persistente. RESULTADOS: Se incluyeron los datos de 203 sujetos. Se identificó que 138 (68.0 %) contestaron ser del sexo femenino, con una media de edad de 41.8 años; 29.6 % presentó enfermedad grave y 70.4 %, enfermedad leve a moderada; 89.7 % había recibido vacunas previas para COVID-19: 6.9 %, una dosis; 31.5 %, dos dosis; y 51.2 %, tres o más dosis. Los principales factores de riesgo fueron diabetes, sobrepeso u obesidad e hipertensión arterial sistémica. El principal síntoma reportado fue fatiga, seguido de otras manifestaciones neuropsiquiátricas. CONCLUSIÓN: Es importante caracterizar a la población para generar protocolos de diagnóstico y tratamiento.

Synthesis of Hybrid Tin-Based Perovskite Microcrystals for LED Applications.

Considerable focus on tin-based perovskites lies on substitution to leadhalide perovskites for the fabrication of eco-friendly optoelectronic devices. The major concern related to tin-based perovskite devices are mainly the stability and the efficiency. However, thinking on the final commercialization scope, other considerations such as precursor stability and cost are major factors to carry about. In this regard, this work presents a robust and facile synthesis of 2D A2SnX4 (A = 4-fluorophenethylammonium(4-FPEA); X = I, Br, I/Br) and 3D FASnI3 perovskite microcrystals following a developed synthesis strategy with low-cost starting materials. In this developed methodology, acetic acid is used as a solvent, which helps to protect from water by making a hydrophobic network over the perovskite surface, and hence provides sufficient ambient and long-term inert atmosphere stability of the microcrystals. Further, the microcrystals are recrystallized in thin films for LED application, allowing the fabrication of orange, near-infrared and purered emitting LEDs. The two-step recrystallized devices show better performance and stability in comparison to the reference devices made by using commercial precursors. Importantly, the developed synthesis methodology is defined as a generic method for the preparation of varieties of hybrid tin-based perovskites microcrystals and application in optoelectronic devices.

Immunogenicity of a Rotavirus VP8* Multivalent Subunit Vaccine in Mice.

Rotavirus remains a significant public health threat, especially in low-income countries, where it is the leading cause of severe acute childhood gastroenteritis, contributing to over 128,500 deaths annually. Although the introduction of the Rotarix and RotaTeq vaccines in 2006 marked a milestone in reducing mortality rates, approximately 83,158 preventable deaths persisted, showing ongoing challenges in vaccine accessibility and effectiveness. To address these issues, a novel subcutaneous vaccine formulation targeting multiple rotavirus genotypes has been developed. This vaccine consists of nine VP8* proteins from nine distinct rotavirus genotypes and sub-genotypes (P[4], P[6], P[8]LI, P[8]LIII, P[8]LIV, P[9], P[11], P[14], and P[25]) expressed in E. coli. Two groups of mice were immunized either with a single immunogen, the VP8* from the rotavirus Wa strain (P[8]LI), or with the nonavalent formulation. Preliminary results from mouse immunization studies showed promising outcomes, eliciting antibody responses against six of the nine immunogens. Notably, significantly higher antibody titers against VP8* P[8]LI were observed in the group immunized with the nonavalent vaccine compared to mice specifically immunized against this genotype alone. Overall, the development of parenteral vaccines targeting multiple rotavirus genotypes represents a promising strategy in mitigating the global burden of rotavirus-related morbidity and mortality, offering new avenues for disease prevention and control.

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.

White adipose tissue uptake on 18F FDG PET/CT: A case report.

Three distinct types of adipose tissue have been characterized: brown, white, and beige. Brown adipose tissue (BAT) is typically found in specific regions including the anterior cervical, supraclavicular, axillary, and paravertebral areas. White adipose tissue (WAT) predominantly resides in subcutaneous layers, intramuscular spaces and among visceral organs, while beige adipose tissue is a subtype of WAT and is found interspersed within WAT deposits. BAT displays metabolic activity detectable on PET/CT scans, in contrast to WAT, which typically exhibits minimal to no uptake. Beige adipose tissue has been observed metabolically active in mice under certain conditions. Alterations in adipose tissue biodistribution are uncommon and have been linked to high-dose corticosteroid use. We present a rare case illustrating abnormal FDG uptake in WAT associated with high-dose corticosteroid therapy.

Synthesis of fucosyllactose using α-L-fucosidases GH29 from infant gut microbial metagenome.

Fucosyl-oligosaccharides (FUS) provide many health benefits to breastfed infants, but they are almost completely absent from bovine milk, which is the basis of infant formula. Therefore, there is a growing interest in the development of enzymatic transfucosylation strategies for the production of FUS. In this work, the α-L-fucosidases Fuc2358 and Fuc5372, previously isolated from the intestinal bacterial metagenome of breastfed infants, were used to synthesize fucosyllactose (FL) by transfucosylation reactions using p-nitrophenyl-α-L-fucopyranoside (pNP-Fuc) as donor and lactose as acceptor. Fuc2358 efficiently synthesized the major fucosylated human milk oligosaccharide (HMO) 2'-fucosyllactose (2'FL) with a 35% yield. Fuc2358 also produced the non-HMO FL isomer 3'-fucosyllactose (3'FL) and traces of non-reducing 1-fucosyllactose (1FL). Fuc5372 showed a lower transfucosylation activity compared to Fuc2358, producing several FL isomers, including 2'FL, 3'FL, and 1FL, with a higher proportion of 3'FL. Site-directed mutagenesis using rational design was performed to increase FUS yields in both α-L-fucosidases, based on structural models and sequence identity analysis. Mutants Fuc2358-F184H, Fuc2358-K286R, and Fuc5372-R230K showed a significantly higher ratio between 2'FL yields and hydrolyzed pNP-Fuc than their respective wild-type enzymes after 4 h of transfucosylation. The results with the Fuc2358-F184W and Fuc5372-W151F mutants showed that the residues F184 of Fuc2358 and W151 of Fuc5372 could have an effect on transfucosylation regioselectivity. Interestingly, phenylalanine increases the selectivity for α-1,2 linkages and tryptophan for α-1,3 linkages. These results give insight into the functionality of the active site amino acids in the transfucosylation activity of the GH29 α-L-fucosidases Fuc2358 and Fuc5372. KEY POINTS: Two α-L-fucosidases from infant gut bacterial microbiomes can fucosylate glycans Transfucosylation efficacy improved by tailored point-mutations in the active site F184 of Fuc2358 and W151 of Fuc5372 seem to steer transglycosylation regioselectivity.

A deep catalogue of protein-coding variation in 983,578 individuals.

Rare coding variants that substantially affect function provide insights into the biology of a gene1-3. However, ascertaining the frequency of such variants requires large sample sizes4-8. Here we present a catalogue of human protein-coding variation, derived from exome sequencing of 983,578 individuals across diverse populations. In total, 23% of the Regeneron Genetics Center Million Exome (RGC-ME) data come from individuals of African, East Asian, Indigenous American, Middle Eastern and South Asian ancestry. The catalogue includes more than 10.4 million missense and 1.1 million predicted loss-of-function (pLOF) variants. We identify individuals with rare biallelic pLOF variants in 4,848 genes, 1,751 of which have not been previously reported. From precise quantitative estimates of selection against heterozygous loss of function (LOF), we identify 3,988 LOF-intolerant genes, including 86 that were previously assessed as tolerant and 1,153 that lack established disease annotation. We also define regions of missense depletion at high resolution. Notably, 1,482 genes have regions that are depleted of missense variants despite being tolerant of pLOF variants. Finally, we estimate that 3% of individuals have a clinically actionable genetic variant, and that 11,773 variants reported in ClinVar with unknown significance are likely to be deleterious cryptic splice sites. To facilitate variant interpretation and genetics-informed precision medicine, we make this resource of coding variation from the RGC-ME dataset publicly accessible through a variant allele frequency browser.

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).

Elucidation of the Pyridine Ring-Opening Mechanism of 2,2'-Bipyridine or 1,10-Phenanthroline Ligands at Re(I) Carbonyl Complexes.

The cleavage of the C-N bonds of aromatic heterocycles, such as pyridines or quinolines, is a crucial step in the hydrodenitrogenation (HDN) industrial processes of fuels in order to minimize the emission of nitrogen oxides into the atmosphere. Due to the harsh conditions under which these reactions take place (high temperature and H2 pressure), the mechanism by which they occur is only partially understood, and any study at the molecular level that reveals new mechanistic possibilities in this area is of great interest. Herein, we unravel the pyridine ring-opening mechanism of 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) ligands coordinated to the cis-{Re(CO)2(N-RIm)(PMe3)} (N-RIm= N-alkylimidazole) fragment under mild conditions. Computational calculations show that deprotonation of the pyridine ring, once dearomatized, is crucial to induce ring contraction, triggering extrusion of the nitrogen atom from the ring and cleavage of the C-N bond. It is noteworthy that different products (regioisomers) are obtained depending on whether the ligand used is bipy or phen due to the additional rigidity and stability conferred by the central ring of the phen ligand, an issue also addressed and clarified computationally. Strong support for the proposed mechanism is provided by the characterization and isolation, including three single-crystal X-ray diffraction structures, of several of the proposed reaction intermediates.

Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease.

Obesity is a major risk factor for many common diseases and has a substantial heritable component. To identify new genetic determinants, we performed exome-sequence analyses for adult body mass index (BMI) in up to 587,027 individuals. We identified rare loss-of-function variants in two genes (BSN and APBA1) with effects substantially larger than those of well-established obesity genes such as MC4R. In contrast to most other obesity-related genes, rare variants in BSN and APBA1 were not associated with normal variation in childhood adiposity. Furthermore, BSN protein-truncating variants (PTVs) magnified the influence of common genetic variants associated with BMI, with a common variant polygenic score exhibiting an effect twice as large in BSN PTV carriers than in noncarriers. Finally, we explored the plasma proteomic signatures of BSN PTV carriers as well as the functional consequences of BSN deletion in human induced pluripotent stem cell-derived hypothalamic neurons. Collectively, our findings implicate degenerative processes in synaptic function in the etiology of adult-onset obesity.

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.