A quasi-cohort trend analysis of adult obesity in Colombia.

In Colombia, the prevalence of obesity has been increasing in recent years due to changes in dietary and nutritional patterns. While previous studies have focussed on describing obesity and its associated factors, they have mainly used a cross-sectional methodology. Accordingly, this study aims to conduct a descriptive quasi-cohort analysis to capture age-specific cohort trends in body mass index (BMI) according to sex and ethnicity (indigenous, Afro-Colombian, and the remaining population). The study utilised data from the National Survey of the Nutritional Situation in Colombia (ENSIN) conducted in 2005, 2010, and 2015 that included 214,136 individuals aged 20-64 years after screening. Data on ethnicity were only available from the 2010 and 2015 surveys. Overall, the prevalence of obesity increased by 6.1 percentage points (from 15.2% to 21.3%) between 2005 and 2015 (men from 10.4% to 15.7%; women from 18.2% to 25.7%). Among Afro-Colombians, obesity rose 6.6 percentage points (from 19.4% to 26.0%), again more so in women than in men (2015: 35.2% versus 17.8%). Among indigenous people, the proportion increased by 5.3 percentage points (from 13.5% to 18.8%), with women reporting highest rates (2015: 23.7% against 12.6% in men). Age- and cohort-specific results also indicate that recent adult cohorts are experiencing sharp increases in BMI, for example, while 25-29-year-old males born in 1975-1979 had a BMI of 24.2 kg/m2, among 40-44-year-olds of the same cohort, this equalled 26.8 kg/m2. In the case of women, these age differences in BMI among the same cohort are even greater (24.4 and 28.0 kg/m2). In summary, the results of this study indicate that Colombia is still in the early stages of the obesity transition, urging the need to monitor obesity trends in Colombia from both an age and cohort perspective. To achieve this, longitudinal surveys or repeated cross-sectional surveys like the ENSIN could be utilised.

Switching to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat in heavily antiretroviral-experienced, virologically suppressed HIV-infected adults receiving complex regimens.

OBJECTIVES: To evaluate the efficacy and safety of the two-pill regimen bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) plus darunavir/cobicistat as a switching strategy in heavily treatment-experienced people living with HIV (PLWH). METHODS: Multicentre, prospective, single-arm pilot clinical trial. Participants were virologically suppressed adults receiving a stable antiretroviral regimen of at least three pills from at least three drug families due to previous virological failures and/or toxicities with no documented resistance to integrase strand transfer inhibitors or darunavir (≥15 points, Stanford). Clinical and laboratory assessments were performed at 0, 4, 12, 24, 36 and 48 weeks. HIV-1 proviral DNA was amplified and sequenced by Illumina at baseline. Plasma bictegravir concentrations were determined in 22 patients using UHPLC-MS/MS. The primary study endpoint was viral load (VL)< 50 copies/mL at Week 48 (ITT). RESULTS: We enrolled 63 participants (92% men) with median baseline CD4 count of 515 cells/mm3 (IQR: 334.5-734.5), 24 years on ART (IQR: 15.9-27.8). The median number of pills was 4 (range: 3-10). At baseline, proviral DNA was amplified in 39 participants: 33/39 had resistance mutations. Three participants discontinued owing to toxicity. At 48 weeks, 95% had VL < 50 copies/mL by ITT and 100% by PP analysis. A modest increase was observed in the bictegravir plasma concentration, and a significant decrease in estimated glomerular filtration rate was observed only at Week 4, probably related to interaction with renal transporters. CONCLUSIONS: Our data suggest that BIC/FTC/TAF + darunavir/cobicistat is an effective, well-tolerated regimen that may improve convenience and, potentially, long-term success in stable heavily pre-treated PLWH.

Total and Unbound Doravirine Concentrations and Viral Suppression in CSF.

We determined total and unbound concentrations of doravirine (DOR) in cerebrospinal fluid and blood plasma. Total and unbound DOR concentrations in cerebrospinal fluid exceeded the half-maximal effective concentration against wild-type virus (5.1 ng/mL) in all patients, suggesting that DOR may contribute to inhibit viral replication in this compartment.

Chems4EU: chemsex use and its impacts across four European countries in HIV-positive men who have sex with men attending HIV services.

INTRODUCTION: Chemsex in a European context is the use of any of the following drugs to facilitate sex: crystal methamphetamine, mephedrone and gamma-hydroxybutyrate (GHB)/gamma-butyrolactone (GBL) and, to a lesser extent, cocaine and ketamine. This study describes the prevalence of self-reported recreational drug use and chemsex in HIV-positive men who have sex with men (MSM) accessing HIV services in four countries. It also examines the problematic impacts and harms of chemsex and access to chemsex-related services. METHODS: This is a cross-sectional multi-centre questionnaire study of HIV-positive MSM accessing nine HIV services in the UK, Spain, Greece and Italy. RESULTS: In all, 1589 HIV-positive MSM attending HIV services in four countries completed the questionnaire. The median age of participants was 38 years (interquartile range: 32-46 years) and 1525 (96.0%) were taking antiretroviral therapy (ART). In the previous 12 months, 709 (44.6%) had used recreational drugs, 382 (24.0%) reported chemsex and 104 (6.5%) reported injection of chemsex-associated drugs ('slamsex'). Of the 382 engaging in chemsex, 155 (40.6%) reported unwanted side effects as a result of chemsex and 81 (21.2%) as a result of withdrawal from chemsex. The reported negative impacts from chemsex were on work (25.1%, 96), friends/family (24.3%, 93) and relationships (28.3%, 108). Fifty-seven (14.9%) accessed chemsex-related services in the past year, 38 of whom (67%) felt the service met their needs. DISCUSSION: A quarter of participants self-reported chemsex in the past 12 months. There were high rates of harms from chemsex across all countries, including negative impacts on work, friends/family and relationships. Although a minority of those engaging in chemsex accessed support, most found this useful.

Reduction of chronic malnutrition for infants in Bogotá, Colombia.

BACKGROUND: According to the 2015 National Survey of the Nutritional Situation in Colombia the prevalence of stunting in children under 5 years of age was 10.8%. In terms of region, Bogotá, presented the highest prevalence rate (13%), a figure that exceeded national records. With the collaboration of local and national government, and nongovernmental it was decided to develop a pilot study involving a public health intervention with residents of Bogotá under 1 year of age with nutritional classification by anthropometry compatible with stunting risk or stunting. METHODS: Pre-experimental, before and after study that sought to determine the magnitude of the change in nutritional status through a 10 months public health nutrition intervention in children under one-year-old residing in 3 prioritized territories of Bogotá. RESULTS: The intervention comprised 1126 children living in the following territories in Bogotá: Kennedy, San Cristóbal, and Engativá. A total of 43.3% children presented delay in height for age, and 56.7% presented risk of short stature. In the final measurement, data were obtained from 686 children, identifying that 17% of the children progressed from stunting to a stunting risk and that 4.5% recovered their growth trajectory, achieving an adequate length for their age. CONCLUSION: That children classified as at risk or stunting at the beginning of the intervention showed an increased probability of approaching or being in the appropriate growth trajectory according to the length-for-age indicator after the intervention.

Total and Unbound Bictegravir Concentrations and Viral Suppression in Cerebrospinal Fluid of Human Immunodeficiency Virus-Infected Patients (Spanish HIV/AIDS Research Network, PreEC/RIS 56).

We determined total and unbound concentrations of bictegravir (BIC) in cerebrospinal fluid (CSF) in 15 asymptomatic, virologically suppressed patients. The median plasma and CSF total BIC concentrations were 1837.1 ng/mL (interquartile range [IQR], 1237.2-2586.7) and 6.9 (IQR, 4.8-10.9), respectively. Median unbound BIC concentration was 2.48 ng/mL (IQR, 1.6-3.7). Total and unbound BIC CSF concentrations were above the half-maximal effective concentration value in all patients, and all subjects had human immunodeficiency virus viral suppression in plasma and CSF. Bictegravir may contribute to inhibit viral replication in this compartment.

Earliness per se×temperature interaction: consequences on leaf, spikelet, and floret development in wheat.

Wheat adaptation can be fine-tuned by earliness per se (Eps) genes. Although the effects of Eps genes are often assumed to act independently of the environment, previous studies have shown that they exhibit temperature sensitivity. The number of leaves and phyllochron are considered determinants of flowering time and the numerical components of yield include spikelets per spike and fertile floret number within spikelets. We studied the dynamics of leaf, spikelet, and floret development in near isogenic lines with either late or early alleles of Eps-D1 under seven temperature regimes. Leaf appearance dynamics were modulated by temperature, and Eps alleles had a greater effect on the period from flag leaf to heading than phyllochron. In addition, the effects of the Eps alleles on spikelets per spike were minor, and more related to spikelet plastochron than the duration of the early reproductive phase. However, fertile floret number was affected by the interaction between Eps alleles and temperature. So, at 9 °C, Eps-early alleles had more fertile florets than Eps-late alleles, at intermediate temperatures there was no significant difference, and at 18 °C (the highest temperature) the effect was reversed, with lines carrying the late allele producing more fertile florets. These effects were mediated through changes in floret survival; there were no clear effects on the maximum number of floret primordia.

Dynamics of floret initiation/death determining spike fertility in wheat as affected by Ppd genes under field conditions.

As wheat yield is linearly related to grain number, understanding the physiological determinants of the number of fertile florets based on floret development dynamics due to the role of the particular genes is relevant. The effects of photoperiod genes on dynamics of floret development are largely ignored. Field experiments were carried out to (i) characterize the dynamics of floret primordia initiation and degeneration and (ii) to determine which are the most critical traits of such dynamics in establishing genotypic differences in the number of fertile florets at anthesis in near isogenic lines (NILs) carrying photoperiod-insensitive alleles. Results varied in magnitude between the two growing seasons, but in general introgression of Ppd-1a alleles reduced the number of fertile florets. The actual effect was affected not only by the genome and the doses but also by the source of the alleles. Differences in the number of fertile florets were mainly explained by differences in the floret generation/degeneration dynamics, and in most cases associated with floret survival. Manipulating photoperiod insensitivity, unquestionably useful for changing flowering time, may reduce spike fertility but much less than proportionally to the change in duration of development, as the insensitivity alleles did increase the rate of floret development.

Dynamics of leaf and spikelet primordia initiation in wheat as affected by Ppd-1a alleles under field conditions.

Wheat adaptation is affected by Ppd genes, but the role of these alleles in the rates of leaf and spikelet initiation has not been properly analysed. Twelve near isogenic lines (NILs) combining Ppd-1a alleles from different donors introgressed in A, B, and/or D genomes were tested under field conditions during two growing seasons together with the wild type, Paragon. Leaf initiation rate was unaffected by Ppd-1a alleles so the final leaf number (FLN) was reduced in parallel with reductions in the duration of the vegetative phase. Spikelet primordia initiation was accelerated and consequently the effect on spikelets per spike was less than proportional to the effect on the duration of spikelet initiation. The magnitude of these effects on spikelet plastochron depended on the doses of Ppd-1 homoeoalleles and the specific insensitivity alleles carried. Double ridge was consistently later than floral initiation, but the difference between them was not affected by Ppd-1a alleles. These findings have potential for selecting the best combinations from the Ppd-1 homoeoallelic series for manipulating adaptation taking into consideration particular effects on spikelet number.

CD66b+/CD68+ circulating extracellular vesicles, lactate dehydrogenase and neutrophil-to-lymphocyte ratio can differentiate coronavirus disease 2019 severity during and after infection.

Coronavirus disease 2019 (COVID-19) has been a major public health burden. We hypothesised that circulating extracellular vesicles (cEVs), key players in health and disease, could trace the cell changes during COVID-19 infection and recovery. Therefore, we studied the temporal trend of cEV and inflammatory marker levels in plasma samples of COVID-19 patients that were collected within 24 h of patient admission (baseline, n = 80) and after hospital discharge at day-90 post-admission (n = 59). Inflammatory markers were measured by standard biochemical methods. cEVs were quantitatively and phenotypically characterized by high-sensitivity nano flow cytometry. In patients recovered from COVID-19 lower levels of inflammatory markers were detected. cEVs from vascular (endothelial cells) and blood (platelets, distinct immune subsets) cells were significantly reduced at day-90 compared to admission levels, a pattern also observed for cEVs from progenitor, perivascular and epithelial cells. The best discriminatory power for COVID-19 severity was found for inflammatory markers lactate dehydrogenase and neutrophil-to-lymphocyte ratio and for granulocyte/macrophage-released CD66b+/CD68+-cEVs. Albeit inflammatory markers were good indicators of systemic inflammatory response and discriminators of COVID-19 remission, they do not completely reveal cell stress and organ damage states. cEVs reaching baseline pre-infection levels at 90 days post-infection in recovered patients discriminate parental cells affected by disease.

Corrigendum to "O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis" [JHEP Reports 6 [2024] 100878].

[This corrects the article DOI: 10.1016/j.jhepr.2023.100878.].

O-GlcNAc transferase acts as a critical nutritional node for the control of liver homeostasis.

Background & Aims: O-GlcNAcylation is a reversible post-translational modification controlled by the activity of two enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA). In the liver, O-GlcNAcylation has emerged as an important regulatory mechanism underlying normal liver physiology and metabolic disease. Methods: To address whether OGT acts as a critical hepatic nutritional node, mice with a constitutive hepatocyte-specific deletion of OGT (OGTLKO) were generated and challenged with different carbohydrate- and lipid-containing diets. Results: Analyses of 4-week-old OGTLKO mice revealed significant oxidative and endoplasmic reticulum stress, and DNA damage, together with inflammation and fibrosis, in the liver. Susceptibility to oxidative and endoplasmic reticulum stress-induced apoptosis was also elevated in OGTLKO hepatocytes. Although OGT expression was partially recovered in the liver of 8-week-old OGTLKO mice, hepatic injury and fibrosis were not rescued but rather worsened with time. Interestingly, weaning of OGTLKO mice on a ketogenic diet (low carbohydrate, high fat) fully prevented the hepatic alterations induced by OGT deletion, indicating that reduced carbohydrate intake protects an OGT-deficient liver. Conclusions: These findings pinpoint OGT as a key mediator of hepatocyte homeostasis and survival upon carbohydrate intake and validate OGTLKO mice as a valuable model for assessing therapeutical approaches of advanced liver fibrosis. Impact and Implications: Our study shows that hepatocyte-specific deletion of O-GlcNAc transferase (OGT) leads to severe liver injury, reinforcing the importance of O-GlcNAcylation and OGT for hepatocyte homeostasis and survival. Our study also validates the Ogt liver-deficient mouse as a valuable model for the study of advanced liver fibrosis. Importantly, as the severe hepatic fibrosis of Ogt liver-deficient mice could be fully prevented upon feeding on a ketogenic diet (i.e. very-low-carbohydrate, high-fat diet) this work underlines the potential interest of nutritional intervention as antifibrogenic strategies.

Evaluation of factors associated with recruitment rates in early phase clinical trials based on the European Clinical Trials Register data.

Effective participant recruitment is a critical challenge in clinical trials. Inadequate enrollment of participants can precipitate delays, escalated costs, and compromise scientific integrity. Despite its relevance, particularly during the early phases, it persists as an obstacle in the field of clinical research. The primary aim of this study was to analyze the recruitment rates of early-phase clinical trials and evaluate their potential associations with key trial characteristics. Using a descriptive and statistical analysis, a research study was conducted based on the early-phase trials registered at the European Clinical Trials Register (EU-CTR), spanning the timeframe from January 2017 to December 2021. Among the 194 trials examined, we found median recruitment rates of 68%. A more detailed exploration revealed a greater level of success in terms of recruitment achievement in pediatric trials when compared to trials involving adults, non-oncologic trials, or those also developed in non-European countries. It is important to underscore that only 69 trials out of the total managed to conclude recruitment, with the most prevalent reason for premature cessation being the presence of efficacy and safety issues or sponsor's strategy. This number can be greatly improved. Despite certain disparities observed in the information within EU-CTR, we have successfully determined the recruitment rates of the studies and established associations with some of the clinical trial characteristics analyzed. Owing to the inherent constraints of this study, further research is warranted to gain a comprehensive understanding of the intricate interplay between trial characteristics and their impact on recruitment rates in early-phase studies.

Membrane transporters in cell physiology, cancer metabolism and drug response.

By controlling the passage of small molecules across lipid bilayers, membrane transporters influence not only the uptake and efflux of nutrients, but also the metabolic state of the cell. With more than 450 members, the Solute Carriers (SLCs) are the largest transporter super-family, clustering into families with different substrate specificities and regulatory properties. Cells of different types are, therefore, able to tailor their transporter expression signatures depending on their metabolic requirements, and the physiological importance of these proteins is illustrated by their mis-regulation in a number of disease states. In cancer, transporter expression is heterogeneous, and the SLC family has been shown to facilitate the accumulation of biomass, influence redox homeostasis, and also mediate metabolic crosstalk with other cell types within the tumour microenvironment. This Review explores the roles of membrane transporters in physiological and malignant settings, and how these roles can affect drug response, through either indirect modulation of sensitivity or the direct transport of small-molecule therapeutic compounds into cells.

Academia and industry agreement on a feasibility tool for first-time-in-human clinical trial units.

First-time-in-human (FTIH) trials are designed to generate information on the safety, tolerability, as well as the pharmacokinetic and pharmacodynamics profile of new drugs. To ensure the safety of participants, these trials need to be conducted at specifically equipped phase I clinical trial units (CTUs). In accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) and the European Union (EU) regulatory guidelines, one of the aims of the European Regime Accelerator for Tuberculosis (ERA4TB) project is to collaboratively create a feasibility tool, through a partnership between public and private entities, for the validation of CTUs selected to conduct FTIH trials. A feasibility form, encompassing nine sections, was created to gather information on the unit in relation to key attributes of FTIH trials. Collaboratively, industry and academic partners defined the minimal criteria to ensure the adherence of CTUs to the principles of ICH GCP and regulations outlined by the European Medicines Agency (EMA) for the execution of FTIH trials. Subsequently, all CTUs available for the project were assessed for FTIH trial eligibility. The introduction of the certification procedure through the feasibility tool within ERA4TB resulted in the accreditation of the five academic CTUs, which are now prepared to carry out FTIH trials as part of the Consortium. The developed feasibility tool aims to establish open and widely used minimum requirements for the validation of academic CTUs as FTIH units, marking it as the inaugural tool for CTU validation resulting from the collaboration between industry and academia within the ERA4TB project. The established partnership has enabled an innovative and novel way of working.

Short-term Neuropsychiatric and Body Weight Changes in Patients Switching From EVG/Cobi/FTC/TAF to BIC/FTC/TAF (PreEC/RIS69).

BACKGROUND: We report NP, clinical and laboratory changes in patients switching from EVG/Cobi/FTC/TAF to BIC/FTC/TAF in clinical practice. METHODS: A group of subjects switching from EVG/Cobi/FTC/TAF to BIC/F/TAF was prospectively followed. A validated sleep quality questionnaire (Pittsburgh Sleep Quality Index), as well as the Hospital Anxiety and Depression Scale (HADS), were administered after 4 weeks from the treatment switch. Adverse events, side effects and discontinuation were recorded at weeks 4 and 24. Pretreatment switch and week 24 body weight and laboratory data were compared. RESULTS: A total of 96 virologically suppressed patients (86% male) were included. All patients received EVG/Cobi/FTC/TAF at least 1 year before the treatment switch. Median (IQR) nadir CD4 was 367 (263). The most common comorbidities were dyslipidemia, HTA and diabetes, 26%, 14% and 7%, respectively. Depression was reported by 8%. Five patients discontinued BIC/FTC/TAF before week 4 due to intolerance (2 insomnia, 1 headache and 2 GI symptoms). No changes in sleep quality, anxiety and depression outcomes were observed at week 4 (p = 0.1, p = 0.1 and p = 0.3, respectively). After 6 months, the median body weight change was statistically significant (0.6 kg, p = 0.003). All patients maintained HIV suppression. CONCLUSION: Except in a few cases, sleep quality, anxiety and depression symptoms remain stable in HIV virologically suppressed patients on EVG/Cobi/FTC/TAF who switch to BIC/F/TAF. NPAEs are mild and tend to occur in those with previous neuropsychiatric symptoms. Weight gain tends to be small but statistically significant. Long-term follow-up in "real-life" cohorts would be needed to confirm these findings.

Nitrogen influenced biomolecular changes on Physalis L. species studied using 2DCOS spectral analysis coupled with chemometric and Receiver operation characteristics analysis.

The determination of the molecular composition of plant leaves is essential to assist in nutritional management, whether for cultivated or non-cultivated species. In this sense, the study aimed to apply FTIR technique in combination with chemometrics and ROC analysis for the evaluation of changes in compositional of plant leaves of Physalis angulata and Physalis peruviana due to nitrogen fertilization treatments. Both species were grown under different doses of nitrogen (0, 200, 400, and 600 Kg ha-1) and leaf samples were evaluated using ATR-FTIR. Our results demonstrate that the spectra of both species were influenced by the nitrogen doses. The computed band area from the lipid/amide, lipid/carbohydrates, degree of esterification and calcium oxalate shows nitrogen fertilization due to 400 Kg ha-1 of N treatment is more effective for a better quality of yield. 2D correlation spectral analysis (2DCOS) reveals cellulose and pectin begins changes followed by amide of proteins due to nitrogen treatment in P. peruviana samples. The P. angulata plants shows hemicellulose changes predominating followed by proteins and polysaccharides. The obtained principle component analysis plot and loading values show the Physalis species samples distinctly separated from control with protein and carbohydrates are predominant in influencing separation among them. Receiver operation characteristic analysis shows a higher value of area under the curve reflecting better reliability of the experiments carried out. Hierarchical cluster analysis shows closed separation for a similar group on dissimilarity scale. Thus the use of 2DCOS coupled with chemometrics helps to identify changes in the composition of leaves of physalis species due to nitrogen doses, constituting a fast and precise measuring for the suitable management of this fertilization.