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Cyclic arginine noncanonical amino acids (ncAAs) are found in several actinobacterial peptide natural products with therapeutically useful antibacterial properties. The preparation of ncAAs like enduracididine and capreomycidine currently takes multiple biosynthetic or chemosynthetic steps, thus limiting the commercial availability and applicability of these cyclic guanidine-containing amino acids. We recently discovered and characterized the biosynthetic pathway of guanitoxin, a potent freshwater cyanobacterial neurotoxin, that contains an arginine-derived cyclic guanidine phosphate within its highly polar structure. The ncAA l-enduracididine is an early intermediate in guanitoxin biosynthesis and is produced by GntC, a unique pyridoxal-5'-phosphate (PLP)-dependent enzyme. GntC catalyzes a cyclodehydration from a stereoselectively γ-hydroxylated l-arginine precursor via a reaction that functionally and mechanistically diverges from previously established actinobacterial cyclic arginine ncAA pathways. Herein, we interrogate l-enduracididine biosynthesis from the cyanobacterium Sphaerospermopsis torques-reginae ITEP-024 using spectroscopy, stable isotope labeling techniques, and X-ray crystallography structure-guided site-directed mutagenesis. GntC initially facilitates the reversible deprotonations of the α- and β-positions of its substrate before catalyzing an irreversible diastereoselective dehydration and subsequent intramolecular cyclization. The comparison of holo- and substrate-bound GntC structures and activity assays on site-specific mutants further identified amino acid residues that contribute to the overall catalytic mechanism. These interdisciplinary efforts at structurally and functionally characterizing GntC enable an improved understanding of how nature divergently produces cyclic arginine ncAAs and generate additional tools for their biocatalytic production and downstream biological applications.

Background Atopic eczema is a common childhood skin problem linked with asthma, food allergy and allergic rhinitis that impairs quality of life. Objectives To determine whether advising parents to apply daily emollients in the first year can prevent eczema and/or other atopic diseases in high-risk children. Design A United Kingdom, multicentre, pragmatic, two-arm, parallel-group randomised controlled prevention trial with follow-up to 5 years. Setting Twelve secondary and four primary care centres. Participants Healthy infants (at least 37 weeks’ gestation) at high risk of developing eczema, screened and consented during the third trimester or post delivery. Interventions Infants were randomised (1 : 1) within 21 days of birth to apply emollient (Doublebase Gel®; Dermal Laboratories Ltd, Hitchin, UK or Diprobase Cream®) daily to the whole body (excluding scalp) for the first year, plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). Families were not blinded to allocation. Main outcome measures Primary outcome was eczema diagnosis in the last year at age 2 years, as defined by the UK Working Party refinement of the Hanifin and Rajka diagnostic criteria, assessed by research nurses blinded to allocation. Secondary outcomes up to age 2 years included other eczema definitions, time to onset and severity of eczema, allergic rhinitis, wheezing, allergic sensitisation, food allergy, safety (skin infections and slippages) and cost-effectiveness. Results One thousand three hundred and ninety-four newborns were randomised between November 2014 and November 2016; 693 emollient and 701 control. Adherence in the emollient group was 88% (466/532), 82% (427/519) and 74% (375/506) at 3, 6 and 12 months. At 2 years, eczema was present in 139/598 (23%) in the emollient group and 150/612 (25%) in controls (adjusted relative risk 0.95, 95% confidence interval 0.78 to 1.16; p = 0.61 and adjusted risk difference −1.2%, 95% confidence interval −5.9% to 3.6%). Other eczema definitions supported the primary analysis. Food allergy (milk, egg, peanut) was present in 41/547 (7.5%) in the emollient group versus 29/568 (5.1%) in controls (adjusted relative risk 1.47, 95% confidence interval 0.93 to 2.33). Mean number of skin infections per child in the first year was 0.23 (standard deviation 0.68) in the emollient group versus 0.15 (standard deviation 0.46) in controls; adjusted incidence rate ratio 1.55, 95% confidence interval 1.15 to 2.09. The adjusted incremental cost per percentage decrease in risk of eczema at 2 years was £5337 (£7281 unadjusted). No difference between the groups in eczema or other atopic diseases was observed during follow-up to age 5 years via parental questionnaires. Limitations Two emollient types were used which could have had different effects. The median time for starting emollients was 11 days after birth. Some contamination occurred in the control group (< 20%). Participating families were unblinded and reported on some outcomes. Conclusions We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children. Emollient use was associated with a higher risk of skin infections and a possible increase in food allergy. Emollient use is unlikely to be considered cost-effective in this context. Future research To pool similar studies in an individual patient data meta-analysis. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information. Plain language summary Eczema is a troublesome itchy skin condition affecting 1 in 5 children and 1 in 10 UK adults. There is no cure and affected children are more likely to develop food allergies. We wanted to see if we could prevent eczema by protecting the skin of babies at higher risk of developing eczema (with an immediate relative with eczema, asthma or hay fever) with moisturisers used to treat dry skin. Previous research suggested that protecting the skin barrier might also prevent food allergy. One thousand three hundred and ninety-four families took part in a study; half of them were asked to apply moisturiser every day to their newborn baby for the first year and half to look after their baby’s skin in the normal way. At the age of 2 years, we did not see any difference in how common eczema was between the two groups: 23% had eczema in the moisturiser group and 25% in the normal care group. It did not matter how we defined eczema – whether examined by a researcher or parent report. We did not find any differences in related conditions like asthma or hay fever either. We found that children using moisturisers had seen their doctor slightly more often for mild skin infections. There was a hint that food allergy might have been increased in the moisturiser group, but there was not enough data to be sure. We followed up the children to age 5 years, but we still did not find any benefits from using moisturisers in early life. Since this study, other similar research has been done using newer types of moisturisers, but their results are the same. This study shows that using daily moisturisers on healthy babies with a high risk of eczema does not prevent eczema. It is one less thing for busy families to worry about. Scientific summary Background Eczema, also known as atopic eczema (AE) or atopic dermatitis, is a common inflammatory skin disease that typically starts in early life. Eczema affects around 20% of children and 10% of adults in developed countries. Although most cases are mild, moderate to severe disease can have a major impact on the quality of life of an affected child and their family. The main symptom of this systemic inflammatory disease is itching which leads to scratching, bleeding, secondary infection as well as sleep loss and the social stigma of a visible skin disease. Genetic factors such as mutations in the gene encoding filaggrin (FLG) – a protein that is important for maintaining skin barrier function – have been shown to be important in increasing eczema risk, severity and persistence. Epidemiological studies showing that eczema is more common in smaller families, migrant populations and in higher socioeconomic status also suggest that the environment is critically important in determining disease expression. Eczema is closely related to other ‘atopic’ conditions including asthma, hay fever and food allergy. Some evidence suggests that the impaired skin barrier caused by eczema in early life is an important route for the development of food allergy as a result of sensitisation through the skin. Treatment of eczema depends on severity: mild eczema can be treated with emollients (moisturisers) and weak topical corticosteroids. Moderate eczema usually needs potent topical corticosteroids and other anti-inflammatory treatments such as topical tacrolimus, whereas severe eczema is treated by ultraviolet light or systemic treatments including ciclosporin, methotrexate, dupilumab and an emerging pipeline of new biologics. While good progress has been made with treatment, prevention of eczema remains challenging. Strategies include avoidance of allergens (foods and house dust mite) during pregnancy and early life, exclusive breastfeeding, or different timing of introducing solids, but these have not shown convincing preventative effects. Probiotics and prebiotics have shown some benefit, but the exact strain or combination and timing of intervention remain unclear. One previously unexplored eczema prevention strategy is enhancement of the skin barrier in early life. The hypothesis is that enhancing the skin barrier could interrupt an early cascade of inflammatory events that can lead to chronic auto-immune eczema and potentially prevent skin sensitisation to common allergens that can lead to food allergy. Two small pilot studies suggested that protecting the skin of babies who had a first-degree relative with eczema, asthma or hay fever with emollients could prevent the development of eczema in the first year of life. We wanted to see whether daily emollient application for the first year of life in such high-risk babies can prevent eczema and other allergic diseases in a sustained and convincing way by means of a definitive pragmatic randomised controlled trial. Objectives The primary objective was to determine whether advising parents to apply emollient daily for the first year of life could prevent eczema at 2 years of age when compared with standard skin-care advice alone in children at high risk of developing eczema. Secondary objectives included evaluating whether prophylactic use of emollients would delay the onset of eczema or reduce eczema severity when compared to standard skin-care advice, whether any preventive effect at age 2 years was sustained up to age 5 years and to determine the safety and cost-effectiveness of such a strategy. We also sought to determine whether emollients could prevent the development of other associated allergic conditions including food allergy, asthma and hay fever up to the age of 5 years. Methods We conducted a multicentre, pragmatic, two-arm parallel group randomised controlled prevention trial which recruited participants from 12 hospitals and 4 general practices in the UK. Participants were infants of at least 37 weeks’ gestation at high risk of developing eczema defined by having at least one first-degree relative with a parental report of doctor-diagnosed eczema, allergic rhinitis or asthma. Mothers had to be 16 years or older, and the consenting adult had to understand English. We excluded babies with a severe widespread skin condition that would make eczema assessment difficult; a serious health issue that would make it difficult for the family to take part in the trial; or a condition that would make the use of emollient inadvisable. Informed consent was obtained from mothers during pregnancy, or mother, father or guardian post delivery. The intervention group was advised to use one of two study emollients (Doublebase Gel® or Diprobase Cream®) at least once daily to the whole body (excluding the scalp) until the child reached 1 year, plus standard skin-care advice (designated the ‘emollient group’). The control group was advised to use standard skin-care advice only. Standard skin-care guidance, in booklet and video format at the time of randomisation, provided advice to use mild cleansers and shampoos specifically formulated for infants, and to avoid soap, bubble bath and baby wipes, and was given to both groups. Intervention adherence was measured at 3, 6 and 12 months and defined as satisfactory if emollients were applied at least three to four times per week to most of the child’s body. A similar definition was used to define contamination in the control group. The primary outcome was presence of eczema in the last year when the baby was aged 2 years, defined as meeting the United Kingdom Working Party (UKWP) Diagnostic Criteria for AE for children under 4 years. Secondary outcomes encompassed other ways of defining eczema including any parental report of a clinical diagnosis of eczema up to 2 years, parent completion of UKWP criteria at 1 and 2 years, and presence of visible eczema at 2 years recorded by a nurse masked to treatment allocation. Other eczema secondary outcomes included time to onset of eczema (based on first parent report of clinician diagnosis and first topical corticosteroid or immunosuppressant prescription); severity of eczema measured by trained nurses using the Eczema Area and Severity Index at 2 years and parent-reported Patient-Oriented Eczema Measure at 1 and 2 years. Other secondary outcomes included parent-reported wheezing and allergic rhinitis between 1 and 2 years; allergic sensitisation (masked skin prick tests) to milk, egg, peanut, cat dander, grass pollen or dust mite at 2 years; parent-reported food allergy; parental report of clinical diagnosis of food allergy at 1 and 2 years; and allergy to milk, egg or peanut at 2 years confirmed either by oral food challenge or for cases in which no oral food challenge was done, an expert panel of experienced paediatric allergists masked to treatment allocation. The panel decisions were made using an algorithm, validated using data from a previous trial, which incorporates all available data including skin prick test results, previous reaction history, frequency of food ingestion and allergy tests done outside the trial. The main economic outcome measure was incremental cost per percentage decrease in risk of eczema at 2 years in a cost-effectiveness analysis (CEA). Cost–utility analyses using quality-adjusted life-years (QALYs) derived from the proxy Child Health Utility instrument-9 domains (CHU-9D) for the child was also conducted as a secondary analysis. Safety outcomes were parent-reported skin infections (parents were asked what the doctor called the infection) and emollient-related infant slippages during the intervention period (year 1). Tertiary outcomes at 3, 4 and 5 years were to evaluate if emollients in early life could also prevent later-onset allergic diseases including asthma, hay fever and food allergy, and to see whether any early possible benefits of eczema prevention were sustained. Outcomes included parental-reported presence of eczema; severity of eczema; wheezing; allergic rhinitis; food allergy symptoms and clinical diagnoses of asthma, allergic rhinitis and food allergy. Randomisation (1 : 1) within 21 days of birth was performed using computer-generated pseudo-random code with permuted blocks of randomly varying size and concealed from the trial investigators via a web-based randomisation system. Randomisation was stratified by recruiting centre and number of first-degree relatives with eczema, asthma or hay fever (1, 2 or > 2). Research nurses conducting outcome assessments were masked to participant treatment allocation. Families were not masked to the allocated interventions and were reminded not to reveal allocation to research nurses. The trial was powered to detect a relative reduction of 30% in the primary outcome at the 5% significance level (two-sided) with 90% power assuming that 30% of children in the control group would have eczema and 20% attrition, resulting in a sample size of 1282. The target sample size was reached faster than anticipated at which point the Trial Steering Committee permitted that all pregnant mothers who had already consented to the trial could be randomised on the birth of the baby giving a maximum possible sample size of 1400. We analysed participants as randomised regardless of adherence with allocation using available data (i.e. without imputation for missing data) with sensitivity analyses for missing data. The adjusted relative risk (RR) and risk difference for the primary outcome were estimated using generalised estimating equations with the binomial family and log/identity link respectively, with an exchangeable correlation matrix to account for randomisation stratification by centre and number of immediate family members with atopic disease (one, two, or more than two) included as a covariate. A number of planned subgroup analyses for the primary outcome were conducted including according to FLG genotype, to test the hypothesis that FLG null genotype affects response to intensive emollient use from birth. Results One thousand three hundred and ninety-four newborns were randomised between 19 November 2014 and 18 November 2016; 693 to the emollient group and 701 to the control group. Primary outcome data at 2 years were collected for 1210 infants (87%). Unblinding of research nurses prior to skin examination occurred for 12 infants in the intervention group and 6 in the control group. Adherence in the emollient group was 88% (466/532) at 3 months, 82% (427/519) at 6 months and 74% (375/506) at 12 months. In the control group, contamination due to self-directed use of emollients was reported for 18% (82/457), 17% (62/372) and 15% (49/324) at 3, 6 and 12 months, respectively, for infants who did not have a parental report of a doctor diagnosis of eczema. At age 2 years, eczema was present in 139 (23%) of 598 infants in the emollient group and in 150 (25%) of 612 infants in the control group [adjusted RR 0.95, 95% confidence interval (CI) 0.78 to 1.16; p = 0.61; adjusted risk difference −1.2%, 95% CI −5.9% to 3.6%]. All sensitivity analyses conducted, including using multiple imputation for missing primary outcome data, were consistent with the primary analysis. There was no evidence of an interaction effect with allocated group for the primary eczema outcome in any of the subgroup analyses (including FLG genotype). Other eczema definitions supported the results of the primary analysis. Eczema severity and time to onset of eczema were also similar in the two groups. Mean number of skin infections per child in year 1 was 0.23 [standard deviation (SD) 0.68] in the emollient group versus 0.15 (SD 0.46) in the control group; adjusted incidence rate ratio 1.55 (95% CI 1.15 to 2.09). Infant slippage incidents were reported for 15/584 (2.6%) in the emollient group and 11/584 (1.9%) in the control group. Food allergies to milk, egg or peanut at 2 years were confirmed in 41/547 (7.5%) infants in the emollient group and 29/568 (5.1%) in the control group (adjusted RR 1.47, 95% CI 0.93 to 2.33). The largest difference was in the proportion of infants with confirmed food allergy to egg, with an adjusted RR of 1.56 (95% CI 0.92 to 2.65). Results of other measures of food allergy and food sensitisation were similar. The proportion of infants with allergic rhinitis, wheezing and allergic sensitisation to cat dander, grass pollen and dust mite was similar between groups at 2 years. The differences in quality of life (using CHU-9D for the child and EuroQol-5 Dimensions, five-level version for the main carer) between the two groups were very small. Although the emollient intervention period was the first year of life, parents in the emollient group continued to report more frequent moisturiser application through to 5 years than in the control group. By 5 years, 188/608 (31%) parents in the emollient group had reported a clinical diagnosis of eczema in their child since 12 months, compared with 178/631 (28%) in the control group (adjusted RR 1.10, 95% CI 0.93 to 1.30). A diagnosis of food allergy by 5 years was reported for 92/609 (15%) allocated to emollients and 87/632 (14%) allocated to control (adjusted RR 1.11, 95% CI 0.84 to 1.45). Similarly, the percentage of parents reporting that their child had a clinical diagnosis of asthma or allergic rhinitis by 5 years were similar in the two groups. In the complete-case CEA mean cost was £398.23 (SD 1408.39) per child in the emollient group (n = 598) and £312.16 (SD 1105.04) in the control group (n = 610). When intervention use was combined with other health resource use, the adjusted incremental cost was £87.45 (95% CI −54.31 to 229.27). The adjusted difference in the proportion of children without eczema at 2 years was 0.0164 (95% CI −0.0329 to 0.0656) higher in the emollient group compared to the control group. The adjusted incremental cost per percentage decrease in risk of eczema was £5337 at 2 years. Adjusted QALYs for children were very slightly improved (i.e. higher) in the emollient group at 2 years. Conclusions We found no evidence of a useful preventive effect of emollients for eczema at our primary outcome time of 2 years. The failure to show a reduction in eczema was consistent regardless of how eczema was assessed. Some evidence of an increase in skin infections during the intervention period and a possible increase in food allergy at age 2 years was observed. No benefit was observed for time to onset of eczema or eczema severity, and no benefits were observed for eczema, asthma, hay fever or food allergy in longer-term follow-up to 5 years. Emollient use is unlikely to be considered cost effective in this context. Inclusion of individual patient data from all similar eczema prevention studies in further meta-analysis may provide a clearer assessment of whether emollients can prevent eczema and related diseases and provide more certainty about potential harms. Implications for health care The study does not support the use of emollients to prevent eczema and has found a small signal of possible harms, so this intervention cannot be recommended for health care or public health use. As the study relates to prevention of eczema, emollients should continue to be used as part of standard treatment for eczema. Trial registration This trial is registered as ISRCTN21528841. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 12/67/12) and is published in full in Health Technology Assessment; Vol. 28, No. 29. See the NIHR Funding and Awards website for further award information.

We discuss 12 misperceptions, misstatements, or mistakes concerning the use of covariates in observational or nonrandomized research. Additionally, we offer advice to help investigators, editors, reviewers, and readers make more informed decisions about conducting and interpreting research where the influence of covariates may be at issue. We primarily address misperceptions in the context of statistical management of the covariates through various forms of modeling, although we also emphasize design and model or variable selection. Other approaches to addressing the effects of covariates, including matching, have logical extensions from what we discuss here but are not dwelled upon heavily. The misperceptions, misstatements, or mistakes we discuss include accurate representation of covariates, effects of measurement error, overreliance on covariate categorization, underestimation of power loss when controlling for covariates, misinterpretation of significance in statistical models, and misconceptions about confounding variables, selecting on a collider, and p value interpretations in covariate-inclusive analyses. This condensed overview serves to correct common errors and improve research quality in general and in nutrition research specifically.

Harmful cyanobacterial blooms (cyanoHABs) cause recurrent toxic events in global watersheds. Although public health agencies monitor the causal toxins of most cyanoHABs and scientists in the field continue developing precise detection and prediction tools, the potent anticholinesterase neurotoxin, guanitoxin, is not presently environmentally monitored. This is largely due to its incompatibility with widely employed analytical methods and instability in the environment, despite guanitoxin being among the most lethal cyanotoxins. Here, we describe the guanitoxin biosynthesis gene cluster and its rigorously characterized nine-step metabolic pathway from l-arginine in the cyanobacterium Sphaerospermopsis torques-reginae ITEP-024. Through environmental sequencing data sets, guanitoxin (gnt) biosynthetic genes are repeatedly detected and expressed in municipal freshwater bodies that have undergone past toxic events. Knowledge of the genetic basis of guanitoxin biosynthesis now allows for environmental, biosynthetic gene monitoring to establish the global scope of this neurotoxic organophosphate.

Understanding rodent-ectoparasite interactions and the factors driving them is important in understanding the epidemiology of diseases involving an arthropod vector. Fleas are the primary vector for Yersinia pestis, the bacteria that causes plague and monitoring of flea population is essential for planning the potential mitigation measures to prevent the disease outbreak. In this study, we investigated flea abundance, community structure and the potential factors driving flea infestation in areas with frequent (persistent) and non-frequent plague (non-persistent) outbreaks. We collected fleas from captured rodents in two villages with both forest and farm habitats. We found 352 fleas belonging to 5 species with Dinopsyllus lypusus the most abundant overall (57.10%) and Ctenophthalmus spp. the lowest (1.70%). There were no significant differences of flea abundance between study localities, habitats and seasons (p > 0.05) but, flea infestation was significantly positively associated with the persistent locality and with the short rain season (p

Abstract The energy-energy correlator (EEC) is an observable of wide interest for collider physics and Standard Model measurements, due to both its simple theoretical description in terms of the energy-momentum tensor and its novel features for experimental studies. Significant progress has been made in both applications and higher-order perturbative predictions for the EEC. Here, we analyze the nature of the asymptotic perturbative series for the EEC by determining its analytic form in Borel space under the bubble-sum approximation. This result provides information on the leading and subleading nonperturbative power corrections through renormalon poles. We improve the perturbative convergence of the MS ¯ $$ \overline{\textrm{MS}} $$ series for the EEC by removing its leading renormalon using an MSR scheme, which is independent of the bubble-sum approximation. Using the leading MSR scheme power correction determined by fits to thrust, we find good agreement with EEC OPAL data already at O $$ \mathcal{O} $$ ( α s 2 $$ {\alpha}_s^2 $$ ).

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure. Here, we tested the efficacy of a novel synaptogenic small molecule, SPG302 - a 3rd-generation benzothiazole derivative that increases the density of axospinous glutamatergic synapses - in 3xTg-AD mice. Daily dosing of 3xTg-AD mice with SPG302 at 3 and 30 mg/kg (i.p.) for 4 weeks restored hippocampal synaptic density and improved cognitive function in hippocampal-dependent tasks. Mushroom and stubby spine profiles were increased by SPG302, and associated with enhanced expression of key postsynaptic proteins - including postsynaptic density protein 95 (PSD95), drebrin, and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) - and increased colocalization of PSD95 with synaptophysin. Notably, SPG302 proved efficacious in this model without modifying Aβ and tau pathology. Thus, our study provides preclinical support for the idea that compounds capable of restoring synaptic density offer a viable strategy to reverse cognitive decline in AD.

Transient myeloproliferative disorder (TMD) is a pre-leukemic condition that occurs only in neonates with Trisomy 21 (T21), and is attributed to a genetic interaction between the third copy of chromosome 21 (HSA21) and a mutation in the transcription factor GATA1 that results in a truncated protein (GATA1s). We generated a euploid iPSC line with a GATA1s mutation that is isogenic to a previously published pair of T21 lines with and without a GATA1 mutation. The line was characterized for pluripotency, differentiation potential, and genomic stability. This line is a valuable isogenic control for studying the T21 hematopoietic phenotype.

The CHOPWT17_TPM1KOc28 iPSC line was generated to interrogate the functions of Tropomyosin 1 (TPM1) in primary human cell development. This line was reprogrammed from a previously published wild type control iPSC line.

Beginning in March 2020, to reduce COVID-19 transmission, the US President’s Emergency Plan for AIDS Relief supporting voluntary medical male circumcision (VMMC) services was delayed in 15 sub-Saharan African countries. We reviewed performance indicators to compare the number of VMMCs performed in 2020 with those performed in previous years. In all countries, the annual number of VMMCs performed decreased 32.5% (from 3,898,960 in 2019 to 2,631,951 in 2020). That reduction is largely attributed to national and local COVID-19 mitigation measures instituted by ministries of health. Overall, 66.7% of the VMMC global annual target was met in 2020, compared with 102.0% in 2019. Countries were not uniformly affected; South Africa achieved only 30.7% of its annual target in 2020, but Rwanda achieved 123.0%. Continued disruption to the VMMC program may lead to reduced circumcision coverage and potentially increased HIV-susceptible populations. Strategies for modifying VMMC services provide lessons for adapting healthcare systems during a global pandemic.

الملخص: أهداف البحث: تحديد النتائج التوليدية للنساء في زواج ''رحالة العمل'' (عندما يكون أحد الزوجين في منزل الأسرة بينما يسافر الآخر للعمل في مدينة أو دولة أخرى) مقارنة بالنساء في الزيجات العادية، وكذلك تأثير العيش مع آخرين على النتائج التوليدية بين النساء في زواج ''رحالة العمل''. طرق البحث: تم إجراء دراسة مقارنة مستقبلية، متعددة المراكز، بين مراجعات عيادة متابعة الحمل في زواج ''رحالة العمل'' (160 امرأة) والزواج العادي (160 امرأة). بعد أخذ الموافقة، تم متابعة المراجعات ومراقبتهن من بداية متابعتهن في العيادة حتى ستة أسابيع بعد الولادة. قياس النتيجة الأولية: النتائج التوليدية (الإجهاض، دخول المستشفى المرتبط بمرض ما قبل الولادة، عمر الحمل عند الولادة، ارتفاع ضغط الدم الناجم عن الحمل، سكري الحمل، ووزن الولادة). قياس النتيجة الثانوية: تأثير العيش مع آخرين على نتائج التوليد. تم تحليل البيانات باستخدام مربع كاي أو اختبار تي حسب الاقتضاء. النتائج: كان الشريك المتنقل هو الزوج (151؛ 94.4٪) بسبب نقل العمل (76؛ 47.5٪) أو العمل الجديد (60؛ 37.5٪). كان هناك ارتباط ذو دلالة إحصائية بين زواج ''رحالة العمل'' وكل من التأخير قبل الحمل الأول (27 مقابل 15)؛ متوسط عمر الحمل الأعلى (22.19 ± 7.7 مقابل 19.86 ± 6.93)؛ دخول المستشفى المرتبط بمرض ما قبل الولادة (39 مقابل 19)؛ الولادة المبكرة (54 مقابل 11)؛ وانخفاض الوزن عند الولادة (26 مقابل 8). كان متوسط عمر الحمل عند الولادة (35.10 ± 2.53 مقابل 38.00 ± 2.38) ووزن الولادة (2445.0 ± 749.37 مقابل 3146.4 ± 1645.79) أقل وذات دلالة إحصائية بين النساء في زواج ''رحالة العمل'' اللاتي يعشن وحدهن مقارنة مع اللاتي يعشن مع آخرين. الاستنتاجات: ارتبط زواج ''رحالة العمل'' بنتائج توليدية ضائرة ولكن يبدو أن العيش مع آخرين يساهم في تقليل هذه النتائج الضائرة. Abstract: Objectives: The study aims to determine obstetric outcomes for women in commuter marriages (CoMs) compared to women in non-CoMs, as well as the influence of living-in-companions on the obstetric outcomes. Methods: A prospective, multicentre, comparative study was conducted among antenatal clinic attendees in CoMs (160 women) and non-CoMs (160 women). Following consent, participants were recruited and monitored from antenatal booking until six weeks postpartum. The primary outcome measure was the obstetric outcomes (miscarriages, antenatal illness-associated hospital admissions, gestational ages at delivery, pregnancy-induced hypertension, gestational diabetes, and birth weights), while the secondary outcome measure was the influence of living-in-companions on the obstetric outcomes, which was measured by comparing the outcomes in women with those without living-in-companions. Data analysis was conducted using chi-square and t-tests, as applicable; a p

Abstract Transverse-momentum-dependent parton distributions (TMDs) can be calculated from first principles by computing a related set of Euclidean lattice observables and connecting them via a factorization formula. This work focuses on the leading-power factorization formula connecting the lattice quasi-TMD and continuum Collins TMD for gluons. We calculate the one-loop gluon matching coefficient, which is known to be independent of spin and exhibits no mixing with quarks. We demonstrate that this coefficient satisfies Casimir scaling with respect to the quark matching coefficient at one-loop order. Our result facilitates reliable lattice QCD calculations of gluon TMDs.

Trisomy 21 (T21), or Down Syndrome (DS), is a common chromosomal disorder resulting from a third copy of chromosome 21 (HSA21). Transient myeloproliferative disorder (TMD) is a pre-leukemic condition that occurs only in neonates with DS and is characterized by a mutation in the transcription factor GATA1 that results in a truncated protein (GATA1s). We generated a pair of isogenic T21 lines derived from a patient with TMD that differ only in GATA1 status. The iPSC lines were characterized for pluripotency, differentiation potential, and genomic stability. These lines are a valuable resource for studying T21 hematopoietic diseases.

Background: Regular class observations are common ways of monitoring what happens inside classrooms during the teaching and learning processes. From the start of 2020, the Ugandan Education System introduced a new curriculum focusing on active learning methods which foster learner-centered approaches, including Problem-Based Learning (PBL). However, this new curriculum is now only emphasized in the lower classes (grades eight and nine), and teachers of the upper classes are still at liberty to use methods of their choice. This study documented the effect of problem-based learning on Ugandan secondary school physics classroom practices using a Reformed Teaching Observation Protocol (RTOP). Methods: The study followed a quantitative approach with a quasi-experimental design employing cross-sectional survey techniques. The study was carried in 19 secondary schools, both government and private, in Mitooma District, southwestern Uganda. The participants were 419 13 th-grade physics students of 2020/2021 school year together with 22 teachers. Professional training in implementing and assessing PBL lessons were offered to some teachers (experimental group), who were compared to those who did not receive the training (control group). The standard and validated international RTOP was used to observe 152 physics lessons. Microsoft Excel 2016 was used to compute descriptive analysis, while IBM SPSS 25 was used to compute inferential statistics. Results: The results indicated that teachers in the experimental group effectively taught their classes using PBL and learners were more active compared to the control group. Female teachers showed a statistically significant difference compared to their male teachers in reformed teaching of physics, while no significance was found between government and private schools. Conclusion: Giving teachers professional training is key to effective classroom practices. We recommend teachers to use PBL in teaching, policymakers train teachers on its implementations, and researchers investigate its effect on other subjects with RTOP or other standard observation protocols.

Juvenile myelomonocytic leukemia (JMML) is an uncommon myeloproliferative neoplasm driven by Ras pathway mutations and hyperactive Ras/MAPK signaling. Outcomes for many children with JMML remain dismal with current standard-of-care cytoreductive chemotherapy and hematopoietic stem cell transplantation. We used patient-derived induced pluripotent stem cells (iPSCs) to characterize the signaling profiles and potential therapeutic vulnerabilities of PTPN11-mutant and CBL-mutant JMML. We assessed whether MEK, JAK, and PI3K/mTOR kinase inhibitors (i) could inhibit myeloproliferation and aberrant signaling in iPSC-derived hematopoietic progenitors with PTPN11 E76K or CBL Y371H mutations. We detected constitutive Ras/MAPK and PI3K/mTOR signaling in PTPN11 and CBL iPSC-derived myeloid cells. Activated signaling and growth of PTPN11 iPSCs were preferentially inhibited in vitro by the MEKi PD0325901 and trametinib. Conversely, JAK/STAT signaling was selectively activated in CBL iPSCs and abrogated by the JAKi momelotinib and ruxolitinib. The PI3Kδi idelalisib and mTORi rapamycin inhibited signaling and myeloproliferation in both PTPN11 and CBL iPSCs. These findings demonstrate differential sensitivity of PTPN11 iPSCs to MEKi and of CBL iPSCs to JAKi, but similar sensitivity to PI3Ki and mTORi. Clinical investigation of mutation-specific kinase inhibitor therapies in children with JMML may be warranted.

Abstract Transverse-momentum-dependent parton distribution functions (TMDs) can be studied from first principles by a perturbative matching onto lattice-calculable quantities: so-called lattice TMDs, which are a class of equal-time correlators that includes quasi-TMDs and TMDs in the Lorentz-invariant approach. We introduce a general correlator that includes as special cases these two Lattice TMDs and continuum TMDs, like the Collins scheme. Then, to facilitate the derivation of a factorization relation between lattice and continuum TMDs, we construct a new scheme, the Large Rapidity (LR) scheme, intermediate between the Collins and quasi-TMDs. The LR and Collins schemes differ only by an order of limits, and can be matched onto one another by a multiplicative kernel. We show that this same matching also holds between quasi and Collins TMDs, which enables us to prove a factorization relation between these quantities to all orders in α s . Our results imply that there is no mixing between various quark flavors or gluons when matching Collins and quasi TMDs, making the lattice calculation of individual flavors and gluon TMDs easier than anticipated. We cross-check these results explicitly at one loop and discuss implications for other physical-to-lattice scheme factorizations.

Background: Attitude is a learning scale that informs which approach should be used to call students to school. It can be seen a supporting tool that informs teachers, policymakers, and researchers of the needs for raising interest in learning a certain subject, such as physics. This study aimed at determining the effect of problem-based learning on students’ attitude towards learning physics. Methods: The study followed a quantitative approach with a quasi-experimental design employing cross-sectional survey techniques. The participants of the study were 419 13 th-grade physics students of the 2020/2021 school year in both Ugandan government and private secondary schools. Among these students, one group was taught using problem-based learning instruction while another group was taught using traditional instruction for 12 weeks. Data were collected using a standardized tool called Views About Science Survey. Using Microsoft Excel 2016 and Statistical Package for Social Scientist version 23.0, descriptive and inferential statistics were used to determine a significant difference between experiment and control groups. Results: It was found that both problem-based learning and traditional instructions caused a statistically significant positive effect on students’ attitudes towards physics. However, the experimental group gained more positive attitude than the control group as they were more inclined towards the expert-like attitude (thinking like a scientist in a domain) than their counterparts due to the problem-based learning approach they learned in. Conclusions: Therefore, it was concluded that problem-based learning is a more effective method of teaching physics than traditional methods. Hence, we suggest that secondary school teachers need to adopt the use of problem-based learning in the teaching of science concepts, especially physics.

This article provides guidelines for blood product transfusions in neonates and infants based on current evidence. The guidelines recommend specific transfusion volumes for different blood products and address concerns about transfusion-associated necrotizing enterocolitis (NEC) and the use of plasma for volume expansion. The authors conducted a survey and found that the majority of providers in their neonatal network were familiar with and following the guidelines. Future trials are expected to further refine transfusion recommendations for specific patient populations. [Extracted from the article]