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We have been able to induce a series of lactonisation reactions of unsaturated acids using a carbocationic intermediate formed in situ. The transformation generates five and six membered lactone rings AND forms a new exocyclic C–C bond at the same time, thus removing the need for further derivatisation of typical lactonisation products (such as from iodo lactonisation). The reaction is operationally straightforward, does not employ any metals and utilises readily accessible alcohol and unsaturated acid substrates. [ABSTRACT FROM AUTHOR]

Single‐domain antibodies (sdAbs), such as VHHs, are increasingly being developed for gastrointestinal (GI) applications against pathogens to strengthen gut health. However, what constitutes a suitable developability profile for applying these proteins in a gastrointestinal setting remains poorly explored. Here, we describe an in vitro methodology for the identification of sdAb derivatives, more specifically divalent VHH constructs, that display extraordinary developability properties for oral delivery and functionality in the GI environment. We showcase this by developing a heterodivalent VHH construct that cross‐inhibits the toxic activity of the glycosyltransferase domains (GTDs) from three different toxinotypes of cytotoxin B (TcdB) from lineages of Clostridium difficile. We show that the VHH construct possesses high stability and binding activity under gastric conditions, in the presence of bile salts, and at high temperatures. We suggest that the incorporation of early developability assessment could significantly aid in the efficient discovery of VHHs and related constructs fit for oral delivery and GI applications. [ABSTRACT FROM AUTHOR]

Background Infectious conjunctivitis affects 1 in 8 children annually, resulting in high ophthalmic antibiotic prescribing and absenteeism from childcare and school. We aimed to quantify the cost-effectiveness and annual savings of 3 evidence-based approaches to conjunctivitis management and return to childcare and school compared to usual care. Methods Using a decision analytic model from a societal perspective over a 1-year time horizon, we conducted a cost-effectiveness analysis of 3 management strategies for children aged 6 months to 17 years with non-severe conjunctivitis compared to usual care in the United States. Strategies accounted for rate of transmission. Strategies included (1) refraining from prescribing ophthalmic antibiotics for non-severe conjunctivitis, (2) allowing children without systemic symptoms to attend childcare and school, (3) and the combined approach of refraining from prescribing ophthalmic antibiotics and allowing children without systemic symptoms to attend childcare and school. Results The estimated annual expenditure for pediatric conjunctivitis was $1.95 billion. Usual care was the most expensive ($212.73/episode), followed by refraining from ophthalmic antibiotic prescribing ($199.92) and allowing children without systemic symptoms to attend childcare and school ($140.18). The combined approach was the least costly ($127.38). Disutility was similar between approaches (quality-adjusted life days 0.271 vs 0.274). Refraining from antibiotic prescribing and the combination approach were dominant compared to usual care. The combined approach resulted in an estimated $783 million annual savings and 1.6 million ophthalmic antibiotic courses averted. Conclusions Conjunctivitis poses an economic burden that could be reduced by refraining from ophthalmic antibiotic use and allowing children without systemic symptoms to remain at school or childcare. [ABSTRACT FROM AUTHOR]

The assessment of epigenetic profiles in sperm is sensitive to somatic cell contamination, which can influence methylation signals at gene promoters. This contamination is particularly problematic in the assessment of DNA methylation in samples with low sperm counts, where fractional amounts of somatic cell DNA can lead to significant shifts in measured methylation state. In this study, a new method of detecting possible somatic cell contamination is proposed through two multi-region bioinformatic models: a traditional differential methylation analysis and a machine learning logistic regression model. These models were trained on publicly available sperm (n = 489) and blood (n = 1029) DNA methylation array data and tested on a contamination set, wherein the sperm of four donors with normal sperm counts were run on a 450k methylation array with four permutations each, including pure blood, half blood and half sperm by DNA concentration, half blood and half sperm by cell count, and pure sperm (n = 16). The DMR and logistic regression model classified the contamination testing set with 100% and 94% accuracy, respectively. These new methods of detecting the effects of somatic cell contamination allow for more accurate differentiation between epigenetic profiles that contain a biological somatic-like shift and those that have somatic-like signatures because of contamination. [ABSTRACT FROM AUTHOR]

Snakebite envenoming is a neglected tropical disease that causes substantial mortality and morbidity globally. The venom of African spitting cobras often causes permanent injury via tissue-destructive dermonecrosis at the bite site, which is ineffectively treated by current antivenoms. To address this therapeutic gap, we identified the etiological venom toxins in Naja nigricollis venom responsible for causing local dermonecrosis. While cytotoxic three-finger toxins were primarily responsible for causing spitting cobra cytotoxicity in cultured keratinocytes, their potentiation by phospholipases A2 toxins was essential to cause dermonecrosis in vivo. This evidence of probable toxin synergism suggests that a single toxin-family inhibiting drug could prevent local envenoming. We show that local injection with the repurposed phospholipase A2-inhibiting drug varespladib significantly prevents local tissue damage caused by several spitting cobra venoms in murine models of envenoming. Our findings therefore provide a therapeutic strategy that may effectively prevent life-changing morbidity caused by snakebite in rural Africa. [ABSTRACT FROM AUTHOR]

Rationale: Standing from a sitting position is an important activity of daily living. The five-repetition sit-to-stand test (5STS) is a simple physical performance test that measures the fastest time taken to stand five times from a chair with arms folded. It can be measured in most healthcare settings and at home, where traditional field walking tests may not be possible. The 5STS has been validated in community-dwelling older adults and people with chronic obstructive pulmonary disease, but data in idiopathic pulmonary fibrosis (IPF) are limited. Objectives: The aims of this cohort study were to establish the construct validity, responsiveness to pulmonary rehabilitation (PR), and minimal important difference (MID) of the 5STS in IPF. Methods: In 149 people with IPF, we compared the 5STS with measures of lung function, exercise capacity, quadriceps strength, breathlessness, and health-related quality of life. Responsiveness and effect sizes were determined by measuring the 5STS before and after PR. The MID was estimated using anchor- and distribution-based methods. Results: The 5STS correlated significantly with incremental shuttle walk test (ISW) (r = −0.55), isometric quadriceps maximum voluntary contraction (QMVC) (r = −0.45), Medical Research Council dyspnea scale score (r = 0.40), Chronic Respiratory Questionnaire–Total (r = −0.21), and King's Brief Interstitial Lung Disease Questionnaire–Total (r = −0.21) but not forced vital capacity percentage predicted or quadriceps one-repetition maximum (1RM). There was a significant but very weak correlation between change in 5STS and changes in Medical Research Council (r = 0.18), ISW (r = −0.21), and Chronic Respiratory Questionnaire–Total (r = −0.26) but no significant correlation with change in 1RM (r = −0.12) or QMVC (r = −0.18). 5STS time improved with PR (median [25th percentile, 75th percentile] change, −1.97 [−3.47, −0.62] s; P < 0.001). The effect size for the 5STS was 0.66 and higher than quadriceps 1RM, QMVC, and ISW. The mean (range) MID estimate was −1.93 (−1.85 to −2.10) seconds. Conclusions: In people with IPF, the 5STS is a valid physical performance measure that is responsive to exercise-based interventions and suitable for use in most healthcare settings. [ABSTRACT FROM AUTHOR]

Evidence-based guidelines for implementation and measurement of antibiotic stewardship interventions in inpatient populations including long-term care were prepared by a multidisciplinary expert panel of the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. The panel included clinicians and investigators representing internal medicine, emergency medicine, microbiology, critical care, surgery, epidemiology, pharmacy, and adult and pediatric infectious diseases specialties. These recommendations address the best approaches for antibiotic stewardship programs to influence the optimal use of antibiotics.