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The objective of this study was to determine whether total serum carotenoids, α-tocopherol, selenium, and obesity were independently associated with oxidized low-density lipoproteins (ox-LDLs) in moderately to severely disabled older women living in the community. Serum ox-LDLs, carotenoids, α-tocopherol, and selenium were measured in a population-based sample of 543 moderately to severely disabled women ≥65 y in the Women's Health and Aging Study I in Baltimore, Maryland. Total serum carotenoids, smoking, overweight (body mass index 25–29.9 kg/m 2), and obesity (body mass index ≥30 mg/kg 2) were significantly associated with the ox-LDL/LDL cholesterol ratio after adjusting for age, C-reactive protein, and chronic diseases. α-Tocopherol and selenium were not significantly associated with the ox-LDL/LDL cholesterol ratio. Older women who are overweight or obese or who have low total serum carotenoids are more likely to have higher lipoprotein oxidation. Weight reduction in overweight/obese women and increased intake of carotenoid-rich foods may potentially reduce lipoprotein oxidation.

Based on results from preclinical and clinical studies, a five-drug combination of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine was identified with treatment shortening potential for drug-susceptible tuberculosis; the Clo-Fast trial aimed to determine the efficacy and safety of this regimen. We compared 3 months of isoniazid, rifapentine, pyrazinamide, ethambutol, and clofazimine, administered with a clofazimine loading dose, to the standard 6 month regimen of isoniazid, rifampicin, pyrazinamide, and ethambutol in drug-susceptible tuberculosis. Clo-Fast was a phase 2c open-label trial recruiting participants at six sites in five countries. Participants aged 18 years or older with pulmonary tuberculosis who were sputum smear positive for acid-fast bacilli or molecular tuberculosis assay positive (with Mycobacterium tuberculosis with sensitivity to rifampicin and isoniazid) were eligible for enrolment. Individuals with HIV infection with a CD4+ cell count ≥100 cells per mm3 could participate. Participants were randomly assigned in a 2:1 ratio (group 1: group 2) or a 2:1:1 ratio (group 1: group 2: group 3), depending on consent to participate in the intensive pharmacokinetic visits required in group 3, using a central web-based system with permuted blocks. The group 1 regimen included 8 weeks of rifapentine–isoniazid–pyrazinamide–ethambutol–clofazimine, with a 2-week 300 mg clofazimine loading dose, followed by 5 weeks of rifapentine–isoniazid–pyrazinamide–clofazimine (13 weeks total). The group 2 control regimen included 8 weeks of isoniazid–rifampicin–pyrazinamide–ethambutol followed by 18 weeks of rifampicin–isoniazid. Group 3 was identical to group 1 over the first 4 weeks of treatment, except that the regimen was administered without a clofazimine loading dose (100 mg daily); after 4 weeks of group 3 treatment, participants transitioned to local standard of care to complete treatment. Group 3 was designed to assess the effect of a 2-week loading dose on clofazimine pharmacokinetics. Randomisation was stratified by HIV status and advanced disease on chest radiograph. The primary efficacy endpoint was time to sputum culture-negative status by 12 weeks. The primary safety endpoint was the proportion of participants experiencing any grade 3 or worse adverse event over 65 weeks. The key secondary endpoint was unfavourable clinical or bacteriological outcomes by week 65. The efficacy analysis population contained participants assigned to groups 1 and 2 who were not late exclusions (no positive culture at screening, entry, or week 1, or if rifampicin resistance or isoniazid resistance was detected at screening or entry); the safety analysis population contained all randomly assigned participants who took at least one dose of treatment. The trial was registered with ClinicalTrials.gov ID: NCT04311502. 104 participants were randomly assigned to group 1 (n=58), group 2 (n=31), and group 3 (n=15). 82 (79%) were male and 74 (71%) had radiographically advanced disease; 30 (29%) were people with HIV. The trial was stopped early for lack of clinical efficacy. For the primary efficacy outcome, 49 (89%) of 55 group 1 participants and 28 (90%) of 31 group 2 participants had stable sputum culture conversion by week 12 (adjusted hazard ratio 1·21 [90% CI 0·82–1·79]; p=0·2089). Adverse events grade 3 or worse occurred in 26 (45%) of 58 group 1 participants and five (16%) of 31 group 2 participants (difference 30%, 90% CI 14–45; p=0·002). The cumulative probability of a week 65 unfavourable outcome was 52% (95% CI 37–69) in group 1 versus 27% (14–50) in group 2 (p=0·049). Although the trial was stopped early, we found that a 3-month regimen containing clofazimine and rifapentine had 12-week culture conversion rates that did not differ statistically from the standard of care. The regimen was associated with an unacceptably high proportion of participants with unfavourable composite clinical outcomes and grade 3 or worse adverse events. US National Institutes of Health Advancing Clinical Therapeutics Globally for HIV/AIDS and Other Infections (ACTG) and the National Institute of Allergy and Infectious Diseases.

SARS-CoV-2 mutations that cause resistance to monoclonal antibody (mAb) therapy have been reported. However, it remains unclear whether in vivo emergence of SARS-CoV-2 resistance mutations alters viral replication dynamics or therapeutic efficacy in the immune-competent population. As part of the ACTIV-2/A5401 randomized clinical trial (NCT04518410), non-hospitalized participants with symptomatic SARS-CoV-2 infection were given bamlanivimab (700 mg or 7,000 mg) or placebo treatment. Here¸ we report that treatment-emergent resistance mutations [detected through targeted Spike (S) gene next-generation sequencing] were significantly more likely to be detected after bamlanivimab 700 mg treatment compared with the placebo group (7% of 111 vs 0% of 112 participants, P  = 0.003). No treatment-emergent resistance mutations among the 48 participants who received 7,000 mg bamlanivimab were recorded. Participants in which emerging mAb resistant virus mutations were identified showed significantly higher pretreatment nasopharyngeal and anterior nasal viral loads. Daily respiratory tract viral sampling through study day 14 showed the dynamic nature of in vivo SARS-CoV-2 infection and indicated a rapid and sustained viral rebound after the emergence of resistance mutations. Participants with emerging bamlanivimab resistance often accumulated additional polymorphisms found in current variants of concern/interest that are associated with immune escape. These results highlight the potential for rapid emergence of resistance during mAb monotherapy treatment that results in prolonged high-level respiratory tract viral loads. Assessment of viral resistance should be prioritized during the development and clinical implementation of antiviral treatments for COVID-19. This Article reports the emergence of SARS-CoV-2 escape mutations during bamlanivimab therapy in the setting of a phase II clinical trial.

This cohort study of US adults with untreated COVID-19 examines the types and length of symptoms experienced following symptom recurrence.

Aims : To characterize the relationship between advanced glycation end products (AGEs) and circulating receptors for AGEs (RAGE) with cardiovascular disease mortality. Methods : The relationships between serum AGEs, total RAGE (sRAGE), and endogenous secretory RAGE (esRAGE), and mortality were characterized in 559 community-dwelling women, ‡ 65 years, in Baltimore, Maryland. Results : During 4.5 years of follow-up, 123 (22%) women died, of whom 54 died with cardiovascular disease. The measure of serum AGEs was carboxymethyl-lysine (CML), a dominant AGE. Serum CML predicted cardiovascular disease mortality (Hazards Ratio [HR] for highest vs lower three quartiles, 1.94, 95% Confidence Interval [CI] 1.08–3.48, p=0.026), after adjusting for age, race, body mass index, and renal insufficiency. Serum sRAGE (ng/mL) and esRAGE (ng/mL) predicted cardiovascular disease mortality (HR per 1 Standard Deviation [SD] 1.27, 95% CI 0.98–1.65, p=0.07; HR 1.28, 95% CI 1.02–1.63, p=0.03), after adjusting for the same covariates. Among non-diabetic women, serum CML, sRAGE, and esRAGE, respectively, predicted cardiovascular disease mortality (HR for highest vs lower three quartiles, 2.29, 95% CI 1.21–4.34, p=0.01; HR per 1 SD, 1.24, 95% CI0.92–1.65, p=0.16; HR per 1 SD 1.45, 95% CI 1.08–1.93, p=0.01), after adjusting for the same covariates. Conclusions : High circulating AGEs and RAGE predict cardiovascular disease mortality among older community-dwelling women. AGEs are a potential target for interventions, as serum AGEs can be lowered by change in dietary pattern and pharmacological treatment.

Primary hyperoxaluria (PH) is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis and eventually kidney failure; the subsequent storage of oxalate can cause life-threatening systemic disease. Diagnosis of PH is often delayed or missed owing to its rarity, variable clinical expression and other diagnostic challenges. Management of patients with PH and kidney failure is also extremely challenging. However, in the past few years, several new developments, including new outcome data from patients with infantile oxalosis, from transplanted patients with type 1 PH (PH1) and from patients with the rarer PH types 2 and 3, have emerged. In addition, two promising therapies based on RNA interference have been introduced. These developments warrant an update of existing guidelines on PH, based on new evidence and on a broad consensus. In response to this need, a consensus development core group, comprising (paediatric) nephrologists, (paediatric) urologists, biochemists and geneticists from OxalEurope and the European Rare Kidney Disease Reference Network (ERKNet), formulated and graded statements relating to the management of PH on the basis of existing evidence. Consensus was reached following review of the recommendations by representatives of OxalEurope, ESPN, ERKNet and ERA, resulting in 48 practical statements relating to the diagnosis and management of PH, including consideration of conventional therapy (conservative therapy, dialysis and transplantation), new therapies and recommendations for patient follow-up.Primary hyperoxaluria is an inherited disorder that results from the overproduction of endogenous oxalate, leading to recurrent kidney stones, nephrocalcinosis, kidney failure and life-threatening systemic disease. This Consensus Statement from ERKNet and OxalEurope provides recommendations for the management of primary hyperoxaluria, including consideration of conventional therapies, new therapies and recommendations for patient follow-up.

Background The Breastfeeding Self-Efficacy Scale and its short-form were developed in Canada and have been used internationally among numerous maternal populations. However, the psychometric properties of the scales have not been reviewed to confirm their appropriateness in measuring breastfeeding self-efficacy in culturally diverse populations. The purpose of this research was to critically appraise and synthesize the psychometric properties of the scales via systematic review. Methods The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Three databases (EMBASE, MEDLINE, and PsycINFO) were searched from 1999 (original publication of the Scale) until April 27, 2022. The search was updated on April 1, 2023. Studies that assessed the psychometric properties of the BSES or BSES-SF were included. Two researchers independently extracted data and completed the quality appraisals. Results Forty-one studies evaluated the psychometrics of the BSES ( n  = 5 studies) or BSES-SF ( n  = 36 studies) among demographically or culturally diverse populations. All versions of the instrument demonstrated good reliability, with Cronbach's alphas ranging from .72 to .97. Construct validity was supported by statistically significant differences in mean scores among women with and without previous breastfeeding experience and by correlations between the scales and theoretically related constructs. Predictive validity was demonstrated by statistically significant lower scores among women who ultimately discontinued breastfeeding compared to those who did not. Conclusion The BSES and BSES-SF appear to be valid and reliable measures of breastfeeding self-efficacy that may be used globally to (1) assess women who may be at risk of negative breastfeeding outcomes (e.g., initiation, duration and exclusivity), (2) individualize breastfeeding support, and (3) evaluate the effectiveness of breastfeeding interventions.

Abstract Accurate diagnosis of primary hyperoxaluria (PH) has important therapeutic consequences. Since biochemical assessment can be unreliable, genetic testing is a crucial diagnostic tool for patients with PH to define the disease type. Patients with PH type 1 (PH1) have a worse prognosis than those with other PH types, despite the same extent of oxalate excretion. The relation between genotype and clinical phenotype in PH1 is extremely heterogeneous with respect to age of first symptoms and development of kidney failure. Some mutations are significantly linked to pyridoxine-sensitivity in PH1, such as homozygosity for p.G170R and p.F152I combined with a common polymorphism. Although patients with these mutations display on average better outcomes, they may also present with CKD stage 5 in infancy. In vitro studies suggest pyridoxine-sensitivity for some other mutations, but confirmatory clinical data are lacking (p.G47R, p.G161R, p.I56N/major allele) or scarce (p.I244T). These studies also suggest that other vitamin B6 derivatives than pyridoxine may be more effective and should be a focus for clinical testing. PH patients displaying the same mutation, even within one family, may have completely different clinical outcomes. This discordance may be caused by environmental or genetic factors that are unrelated to the effect of the causative mutation(s). No relation between genotype and clinical or biochemical phenotypes have been found so far in PH types 2 and 3. This manuscript reviews the current knowledge on the genetic background of the three types of primary hyperoxaluria and its impact on clinical management, including prenatal diagnosis.

Connecting chemical properties to various wine characteristics is of great interest to the science of olfaction as well as the wine industry. We explored whether Bordeaux wine chemical identities and vintages (harvest year) can be inferred from a common and affordable chemical analysis, namely, a combination of gas chromatography (GC) and electron ionization mass spectrometry. Using 12 vintages (within the 1990–2007 range) from 7 estates of the Bordeaux region, we report that, remarkably, nonlinear dimensionality reduction techniques applied to raw gas chromatograms recover the geography of the Bordeaux region. Using machine learning, we found that we can not only recover the estate perfectly from gas chromatograms, but also the vintage with up to 50% accuracy. Interestingly, we observed that the entire chromatogram is informative with respect to geographic location and age, thus suggesting that the chemical identity of a wine is not defined by just a few molecules but is distributed over a large chemical spectrum. This study demonstrates the remarkable potential of GC analysis to explore fundamental questions about the origin and age of wine. © 2023, The Author(s).

Behavioral plasticity, the alteration of behavior in response to stimuli, is becoming increasingly important in the context of human‐induced rapid environmental change. Theoretical and empirical studies suggest that the expression and magnitude of behavioral plasticity are likely facilitated or constrained primarily by two factors: environmental variation and endogenous traits such as body size. The contextual role of these factors on behavioral plasticity, however, is poorly understood; there are relatively few studies that have compared the magnitude and potential drivers of behavioral plasticity at different levels (i.e., population and individual) across species, especially in free‐ranging animals with diverse behavioral traits such as large mammals. Here, we quantify and test potential hypotheses for the mechanisms underpinning behavioral plasticity at the individual and population level in response to variation in summer temperatures for 1068 animal‐years in 17 populations across nine species of large mammals. All populations displayed behavioral plasticity in response to increased temperatures, modifying their relative selection for heat‐relieving habitat attributes (e.g., elevation) and heat‐generating behavior (i.e., movement speed). We found strong support for the hypothesis that the variability of the physical environment is an important driver of behavioral plasticity—both mean population behavioral plasticity and variation among individuals within each population in plasticity were lower with increased heterogeneity of habitat attributes such as tree cover. Yet, the variability in environmental conditions (i.e., the magnitude of the temperature increase) had no effect on behavioral plasticity within and among populations. We did not detect an effect of endogenous traits on the expression of behavioral plasticity; however, we note that data availability limited our tests of this hypothesis to a select few endogenous traits (body size, feeding guild, and sex of the tracked individuals) that predominantly vary at the species level, for which we had one to three replicate populations per species. Our results provide an integrative and generalizable understanding of the expression of behavioral plasticity among populations of large mammals in temperate environments and emphasize the important but nuanced role of environmental variation in determining the scope of behavioral plasticity in these populations.