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).

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.

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.

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.

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.

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.

Tailoring Single-Mode Random Lasing of Tin Halide Perovskites Integrated in a Vertical Cavity.

The development of random lasing (RL) with predictable and controlled properties is an important step to make these cheap optical sources stable and reliable. However, the design of tailored RL characteristics (emission energy, threshold, number of modes) is only obtained with complex photonic structures, while the simplest optical configurations able to tune the RL are still a challenge. This work demonstrates the tuning of the RL characteristics in spin-coated and inkjet-printed tin-based perovskites integrated into a vertical cavity with low quality factor. When the cavity mode is resonant with the photoluminescence (PL) peak energy, standard vertical lasing is observed. More importantly, single mode RL operation with the lowest threshold and a quality factor as high as 1 000 (twenty times the quality factor of the resonator) is obtained if the cavity mode lies above the PL peak energy due to higher gain. These results can have important technological implications toward the development of low-cost RL sources without chaotic behavior.

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.

Role of Renal Venous Oxygen Pressure for Renal Function Monitoring After Related Living-Donor Kidney Transplantation: Cohort Study.

BACKGROUND: Monitoring of renal function after kidney transplantation (KT) is performed by measuring serum creatinine (SCr), urine volumes (UV), and glomerular filtration rate (GFR). Other methods based on oxygen metabolism, such as the renal venous oxygen pressure (PrvO2), may be useful. The aim of this study was to explore the correlation between PrvO2 and SCr, UV, and GFR 5 days after KT (SCr5, UV5, and GFR5, respectively). METHODS: We conducted a prospective cohort study in adults scheduled for living donor KT. A venous blood sample was taken from the renal vein after declamping the renal artery, and blood gas determinations were made. Correlation analyses between PrvO2 and SCr5, UV5, and GFR5 were done by calculating Spearman's correlation coefficient with generalized linear models (GLM). A Spearman's correlation analysis was performed between the percentage decrease in SCr (%ΔSCr) and PrvO2. A GLM was also performed to determine the association of PrvO2 with slow graft function (SGF). RESULTS: The study included 42 patients, of whom 67% were men. The median age was 31 years (IQR, 27-43.5). PrvO2 was negatively correlated with SCr5 (ρ = -0.53, P = .003), and positively correlated with GFR5 (ρ = 0.49, P = .001) and %ΔSCr (ρ = 0.47, P = .002). A higher PrvO2 was associated with an increase in GFR in univariable (ß = 1.24, 95% CI, 0.56-1.93, P = .001) and multivariable (ß = 1.24, 95% CI, 0.53-1.94, P = .001) analyses. No association was found between PrvO2 and SGF. CONCLUSION: PrvO2 could be used to monitor renal function in the first 5 days after related living-donor KT, given its good correlation with SCr and GFR.

Stefano Marcaccini: a pioneer in isocyanide chemistry.

Stefano Marcaccini was one of the pioneers in the use of isocyanide-based multicomponent reactions in organic synthesis. Throughout his career at the University of Florence he explored many different faces of isocyanide chemistry, especially those geared towards the synthesis of biologically relevant heterocycles. His work inspired many researchers who contributed to other important developments in the field of multicomponent reactions and created a school of synthetic chemists that continues today. In this manuscript we intend to review the articles on isocyanide multicomponent reactions published by Dr. Marcaccini and analyse their influence on the following works by other researchers. With this, we hope to highlight the immense contribution of Stefano Marcaccini to the development of isocyanide chemistry and modern organic synthesis as well as the influence of his research on future generations. We believe that this review will not only be a well-deserved tribute to the figure of Stefano Marcaccini, but will also serve as a useful inspiration for chemists working in this field.

Larvicidal and Adulticidal Activity of Essential Oils from Four Cuban Plants against Three Mosquito Vector Species.

Mosquitoes are one of the main vectors of many important diseases and their degree of resistance to chemical insecticides has increased. Nowadays, it has become crucial to identify novel plant larvicides with an eco-friendly impact. The components of essential oils from Croton linearis Jacq. (EO-Cl), Lantana involucrata L. (EO-Li), Ocimum sanctum var. cubensis M. Gómez. (EO-Os), and Zanthoxylum pistaciifolium Griseb. (syn. Zanthoxylum flavum subsp. pistaciifolium (Griseb.) Reynel (EO-Zp) were determined using gas chromatography-mass spectrometry (GC-MS) analysis. Larvicidal and adulticidal bioassays against Aedes aegypti, Anopheles albitarsis and Culex quinquefasciatus, were performed according to the World Health Organization standard methods. A high diversity of compounds was identified in the four oils, with a total of 152 compounds (33-70 components). EO-Cl, EO-Li, and EO-Os were classified as active against both insect forms, larvae and adults. Lantana involucrata showed the best results, with LC50 values from 33.8 to 41.7 mg/L. In most of the cases, it was not possible to associate the main compounds with the measured activity, supporting the hypothesis about probable synergistic interactions among major and minor compounds. The results indicate EO-Cl, EO-Os, and EO-Li as good eco-friendly insecticides with potential.

Culture of Human Rotaviruses in Relevant Models Shows Differences in Culture-Adapted and Nonculture-Adapted Strains.

Rotavirus (RV) is the leading cause of acute gastroenteritis (AGE) in children under 5 years old worldwide, and several studies have demonstrated that histo-blood group antigens (HBGAs) play a role in its infection process. In the present study, human stool filtrates from patients diagnosed with RV diarrhea (genotyped as P[8]) were used to infect differentiated Caco-2 cells (dCaco-2) to determine whether such viral strains of clinical origin had the ability to replicate in cell cultures displaying HBGAs. The cell culture-adapted human RV Wa model strain (P[8] genotype) was used as a control. A time-course analysis of infection was conducted in dCaco-2 at 1, 24, 48, 72, and 96 h. The replication of two selected clinical isolates and Wa was further assayed in MA104, undifferentiated Caco-2 (uCaco-2), HT29, and HT29-M6 cells, as well as in monolayers of differentiated human intestinal enteroids (HIEs). The results showed that the culture-adapted Wa strain replicated more efficiently in MA104 cells than other utilized cell types. In contrast, clinical virus isolates replicated more efficiently in dCaco-2 cells and HIEs. Furthermore, through surface plasmon resonance analysis of the interaction between the RV spike protein (VP8*) and its glycan receptor (the H antigen), the V7 RV clinical isolate showed 45 times better affinity compared to VP8* from the Wa strain. These findings support the hypothesis that the differences in virus tropism between clinical virus isolates and RV Wa could be a consequence of the different HBGA contents on the surface of the cell lines employed. dCaco-2, HT29, and HT29M6 cells and HIEs display HBGAs on their surfaces, whereas MA104 and uCaco-2 cells do not. These results indicate the relevance of using non-cell culture-adapted human RV to investigate the replication of rotavirus in relevant infection models.

[Vitamin D in a pediatric population after the end of home lockdown: a prospective study]. / Vitamina D en pediatría tras el fin del confinamiento domiciliario: estudio prospectivo.

Home confinement during the onset of the SARS-CoV-2 pandemic decreased sunlight exposure, the main source of vitamin D in the body. OBJECTIVE: To evaluate the impact of SARS-CoV-2 confinement on 25-hydroxyvitamin D (25-OH-VD) levels in a pediatric population. PATIENTS AND METHODS: Observational study in a Spanish pediatric population between June and October 2020. 25-OH- VD levels were measured by electrochemiluminescence and several related variables were collected (anthropometry, sex, skin phototype, date, calcium level, inorganic phosphorus, parathormone, and alkaline phosphatase). The child's companion answered a survey that included the following aspects: access to open air in the house where the confinement took place, hours of sunlight per day received by the child after the end of the confinement, regular use of sunscreen with outdoor exposure, skin phototype of the child, type of milk the child usually drinks, 25-OH-VD supplementation intake, and if so, dosage and adherence to treatment. RESULTS: 123 children participated, mean age 8.15 years (95%CI 7.52-8.79), and 56.1% were female. The median 25-OH-VD was 27.70 ng/ml (RIC 22.7533.60), and 14% presented 25-OH-VD insufficiency (< 20 ng/ml). 25-OH-VD levels presented an ascending correlation slope as the date moved away from the end of confinement (Rho 0.467; p < 0.001), being related to sunshine hours (Rho 0.368; p < 0.001). 25-OH-VD levels were higher in patients with photoprotection (median 29.9 vs 23.5 ng/ml, p = 0.005), with differences according to skin phototype (p = 0.032), but were not related to age, weight z-score, height z-score, body mass index z-score, or the presence of a balcony or garden at home. CONCLUSION: The rate of 25-OH-VD insufficiency at the end of confinement was not higher than in previous studies. 25-OH-VD levels increased progressively in relation to the hours of sunlight exposure and to the summer months. Interestingly, 25-OH-VD levels were higher in children using phot.

Large-Area, Flexible, Lead-Free Sn-Perovskite Solar Modules.

For the first time, large-area, flexible organic-inorganic tin perovskite solar modules are fabricated by means of an industry-compatible and scalable blade-coating technique. An 8-cell interconnected mini module with dimensions of 25 cm2 (active area = 8 × 1.5 cm2) reached 5.7% power conversion efficiency under 1000 W/m2 (AM 1.5G) and 9.4% under 2000 lx (white-LED).

Research design and baseline participant characteristics of the Resilient, Empowered, Active Living with Diabetes - Telehealth (REAL-T) Study: A randomized controlled trial for young adults with type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is a chronic condition affecting nearly 1.9 million people in the United States. Young adults (YAs) with T1D face unique challenges in managing their condition, experiencing poorer health and well-being than other age groups. The current study is evaluating the Resilient, Empowered, Active Living (REAL) intervention, previously shown to improve glucose levels and quality of life among YAs with diabetes, using telehealth delivery (REAL-T) to expand reach and accessibility. This paper reports on the methodology and baseline participant characteristics of the REAL-T study. METHODS: REAL-T is a two-arm randomized controlled trial that recruited 18-30 year olds with T1D via clinics and social media advertising. Data collection, which was adapted to be fully remote due to COVID-19, occurs every three months for one year. Participants receive either usual care or a 6-month telehealth occupational therapy intervention. The primary outcome is glycated hemoglobin (A1c); secondary outcomes include diabetes distress, quality of life, and continuous glucose monitor-derived measures. RESULTS: The study enrolled a diverse sample of 209 YAs with T1D. Analysis of baseline data indicates equivalence between the intervention and control groups. Study participants have notably higher diabetes distress and poorer mental well-being than similar populations. CONCLUSION: The REAL-T study successfully adapted to remote implementation during the COVID-19 pandemic. By examining long-term outcomes, mediating pathways, and cost-effectiveness, the study will contribute knowledge of the impact of tailored interventions for YAs with T1D, designed to reduce disparities and improve health and well-being in this population.

Alternative protein encapsulation with MOFs: overcoming the elusive mineralization of HKUST-1 in water.

Protein encapsulation by in situ formation of MOFs is a valuable strategy to immobilise and protect these bioentities. However the required biocompatible conditions limits the scope of MOFs under investigation, particularly in the case of hydrolytically unstable MOFs such as HKUST-1. We report alternative synthetic procedures to obtain protein@HKUST-1 biocomposites from related Cu-BTC dense biocomposites. pH dependent dense phase precursors are first obtained and their transformations into HKUST-1 are characterized. Encapsulation efficiency is affected by the protein's nature, and can be modulated by the sequential or simultaneous addition of MOF precursors.

Genotyping, sequencing and analysis of 140,000 adults from Mexico City.

The Mexico City Prospective Study is a prospective cohort of more than 150,000 adults recruited two decades ago from the urban districts of Coyoacán and Iztapalapa in Mexico City1. Here we generated genotype and exome-sequencing data for all individuals and whole-genome sequencing data for 9,950 selected individuals. We describe high levels of relatedness and substantial heterogeneity in ancestry composition across individuals. Most sequenced individuals had admixed Indigenous American, European and African ancestry, with extensive admixture from Indigenous populations in central, southern and southeastern Mexico. Indigenous Mexican segments of the genome had lower levels of coding variation but an excess of homozygous loss-of-function variants compared with segments of African and European origin. We estimated ancestry-specific allele frequencies at 142 million genomic variants, with an effective sample size of 91,856 for Indigenous Mexican ancestry at exome variants, all available through a public browser. Using whole-genome sequencing, we developed an imputation reference panel that outperforms existing panels at common variants in individuals with high proportions of central, southern and southeastern Indigenous Mexican ancestry. Our work illustrates the value of genetic studies in diverse populations and provides foundational imputation and allele frequency resources for future genetic studies in Mexico and in the United States, where the Hispanic/Latino population is predominantly of Mexican descent.