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Purpose: Lack of recruitment to clinical academic careers is of concern, and may be linked to lack of awareness and promotion of this pathway in undergraduate medical education. Our study explored undergraduate experiences which support academic career progression and potential barriers to pursuing Specialised Foundation roles in the United Kingdom., Methods: We adopted a constructivist lens and conducted interviews with specialised foundation programme (SFP) doctors and final year students who had applied for SFP positions. We analysed interview transcripts using reflexive thematic analysis., Results: We recognised four key stages which stimulated and supported students in pursuing a clinical academic career: (1) Lighting the inner spark; (2) Igniting the fire; (3) Feeding the fire; and (4) Seeing through the smoke. Although students showed a strong inner drive, meaningful undergraduate experiences and positive interactions with academics were crucial for sparking academic interests. Participants were more often inspired by their extra-curricular activities than core undergraduate education., Conclusions: Early positive experiences are needed for students to overcome stereotypes and consider clinical academic careers. Medical schools should raise awareness of clinical academic careers early on, ensure all students have opportunities to participate in relevant activities with academic teams, and develop medical educators and researchers who can engage and inspire others.

Age is a major risk factor for cancer, but how aging impacts tumor control remains unclear. In this study, we establish that aging of the immune system, regardless of the age of the stroma and tumor, drives lung cancer progression. Hematopoietic aging enhances emergency myelopoiesis, resulting in the local accumulation of myeloid progenitor-like cells in lung tumors. These cells are a major source of interleukin (IL)-1⍺, which drives the enhanced myeloid response. The age-associated decline of DNA methyltransferase 3A enhances IL-1⍺ production, and disrupting IL-1 receptor 1 signaling early during tumor development normalized myelopoiesis and slowed the growth of lung, colonic, and pancreatic tumors. In human tumors, we identified an enrichment for IL-1⍺-expressing monocyte-derived macrophages linked to age, poorer survival, and recurrence, unraveling how aging promotes cancer and offering actionable therapeutic strategies.

Myeloid cells are known to suppress antitumour immunity 1 . However, the molecular drivers of immunosuppressive myeloid cell states are not well defined. Here we used single-cell RNA sequencing of human and mouse non-small cell lung cancer (NSCLC) lesions, and found that in both species the type 2 cytokine interleukin-4 (IL-4) was predicted to be the primary driver of the tumour-infiltrating monocyte-derived macrophage phenotype. Using a panel of conditional knockout mice, we found that only deletion of the IL-4 receptor IL-4Rα in early myeloid progenitors in bone marrow reduced tumour burden, whereas deletion of IL-4Rα in downstream mature myeloid cells had no effect. Mechanistically, IL-4 derived from bone marrow basophils and eosinophils acted on granulocyte-monocyte progenitors to transcriptionally programme the development of immunosuppressive tumour-promoting myeloid cells. Consequentially, depletion of basophils profoundly reduced tumour burden and normalized myelopoiesis. We subsequently initiated a clinical trial of the IL-4Rα blocking antibody dupilumab 2-5 given in conjunction with PD-1/PD-L1 checkpoint blockade in patients with relapsed or refractory NSCLC who had progressed on PD-1/PD-L1 blockade alone (ClinicalTrials.gov identifier NCT05013450 ). Dupilumab supplementation reduced circulating monocytes, expanded tumour-infiltrating CD8 T cells, and in one out of six patients, drove a near-complete clinical response two months after treatment. Our study defines a central role for IL-4 in controlling immunosuppressive myelopoiesis in cancer, identifies a novel combination therapy for immune checkpoint blockade in humans, and highlights cancer as a systemic malady that requires therapeutic strategies beyond the primary disease site., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The career trajectory of medical professionals, particularly in specialized fields like gastroenterology, can significantly impact healthcare and research. This study aimed to analyze career choices among gastroenterology fellows in the US and investigate the factors influencing these choices., Methods: We utilized data from the American Medical Association on internal medicine subspecialty fellows. The study examined career plans of gastroenterology fellows and compared them with those of other subspecialties. A chi-square test was performed to assess differences in career choices and practice settings., Results: Among gastroenterology fellows, 46% opted for private practice, 28% pursued further training, and 26% chose academia. Notably, gastroenterology fellows were more inclined toward private practice than their counterparts in other subspecialties (46.3% vs 38.4%) and were less likely to pursue academic careers (25.6% vs 30.7%)., Conclusion: This study highlights a concerning trend among recent gastroenterology fellowship graduates favoring private practice over academic careers or additional training. To sustain and strengthen academic medicine in gastroenterology, interventions such as scholarships, mentorship programs, and loan repayment initiatives tailored to academic pursuits could play a crucial role., Competing Interests: The authors report no funding or conflicts of interest., (Copyright © 2023 Baylor University Medical Center.)

Although postpartum Ca supplementation strategies are often employed to prevent subclinical hypocalcemia in dairy cows, these strategies have produced a mix of beneficial, neutral, and detrimental results when assessing milk yield and subsequent disease outcomes. Because the mechanisms underlying these differing results are unknown, our objectives were to determine how common postpartum Ca supplementation strategies affect blood Ca concentrations and parathyroid hormone (PTH). We conducted a randomized controlled trial with 74 multiparous dairy cows on a commercial dairy in central New York. Cows were assigned to 1 of 4 supplementation groups immediately after calving: (1) control (CON; no Ca supplementation, n = 15); (2) conventional oral Ca supplementation (BOL-C; 43 g of oral Ca bolus administered immediately after calving and 24 h later, n = 17); (3) delayed oral Ca supplementation (BOL-D; 43 g of oral Ca bolus administered 48 and 72 h after calving, n = 15); or (4) subcutaneous infusion (SQ; 500 mL of 23% Ca borogluconate infused subcutaneously once immediately after calving, n = 15). Blood samples were collected immediately after calving (0 h) and at 8, 16, 24, 32, 40, 48, 56, 64, 72, 80, 88, 96, 120, and 168 h postpartum for a total of 15 blood samples per cow. Cows were excluded if administered Ca, via any route, by farm employees or if they died or were sold within 96 h following parturition, which left 62 cows for analysis. Linear mixed models, accounting for repeated measures, were created to analyze changes in serum total Ca (tCa) and PTH over the first 168 h after parturition and assess differences between supplementation groups. Serum tCa and PTH concentrations were not different at the time of calving among supplementation groups. There was a supplementation group by hour postcalving interaction for mean tCa concentration in which SQ cows had reduced tCa concentrations from 32 to 64 h compared with CON cows, 32 to 96 h compared with BOL-C cows, and 40 to 64 h compared with BOL-D cows. Mean PTH concentration did not differ among supplementation groups across 168 h after enrollment and was 158.1 pmol/L (95% confidence interval [CI] = 148.2 to 168.0) for CON cows, 164.0 pmol/L (95% CI = 154.9 to 173.1) for BOL-C cows, 158.7 pmol/L (95% CI = 149.2 to 168.1) for BOL-D cows, and 153.2 pmol/L (95% CI = 143.6 to 162.8) for SQ cows. Our findings suggest that although serum tCa does not differ between cows that receive conventional or delayed oral Ca bolus supplementation at calving and cows that receive no supplemental Ca, subcutaneous infusion of Ca at calving reduces serum tCa for a substantial period between 32 and 64 h postsupplementation. However, as PTH concentrations did not differ among groups across 168 h postpartum, the mechanism by which tCa is reduced remains unclear., (© 2023.)

At the onset of lactation, calcium (Ca) homeostasis is challenged. For the transitioning dairy cow, inadequate responses to this challenge may result in subclinical hypocalcemia at some point in the postpartum period. It has been proposed that dynamics of blood Ca and the timing of subclinical hypocalcemia allow cows to be classified into 4 Ca dynamic groups by assessing serum total Ca concentrations (tCa) at 1 and 4 days in milk (DIM). These differing dynamics are associated with different risks of adverse health events and suboptimal production. Our prospective cohort study aimed to characterize the temporal patterns of milk constituents in cows with differing Ca dynamics to investigate the potential of Fourier-transform infrared spectroscopic (FTIR) analysis of milk as a diagnostic tool for identifying cows with unfavorable Ca dynamics. We sampled the blood of 343 multiparous Holsteins on a single dairy in Cayuga County, New York, at 1 and 4 DIM and classified these cows into Ca dynamic groups using threshold concentrations of tCa (1 DIM: tCa <1.98 mmol/L; 4 DIM: tCa <2.22 mmol/L) derived from receiver operating characteristic curve analysis based on epidemiologically relevant health and production outcomes. We also collected proportional milk samples from each of these cows from 3 to 10 DIM for FTIR analysis of milk constituents. Through this analysis we estimated the milk constituent levels of anhydrous lactose (g/100 g of milk and g/milking), true protein (g/100 g of milk and g/milking), fat (g/100 g of milk and g/milking), milk urea nitrogen (mg/100 g of milk), fatty acid (FA) groups including de novo, mixed origin, and preformed FA measured in grams/100 g of milk, by relative percentage, and grams/milking, as well as energy-related metabolites including ketone bodies and milk-predicted blood nonesterified FA. Individual milk constituents were compared among groups at each time point and over the entire sample period using linear regression models. Overall, we found differences among the constituent profiles of Ca dynamic groups at approximately every time point and over the entire sample period. The 2 at-risk groups of cows did not differ from each other at more than one time point for any constituent, however prominent differences existed between the milk of normocalcemic cows and the milk of the other Ca dynamic groups with respect to FA. Over the entire sample period, lactose and protein yield (g/milking) were lower in the milk of at-risk cows than in the milk of the other Ca dynamic groups. In addition, milk yield per milking followed patterns consistent with previous Ca dynamic group research. Though our use of a single farm does limit the general applicability of these findings, our conclusions provide evidence that FTIR may be a useful method for discriminating between cows with different Ca dynamics at time points that may be relevant in the optimization of management or development of clinical intervention strategies., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Background: Four decades into the HIV epidemic, CNS infection remains a leading cause of preventable HIV-related deaths in routine care. The Driving Reduced AIDS-associated Meningo-encephalitis Mortality (DREAMM) project aimed to develop, implement, and evaluate pragmatic implementation interventions and strategies to reduce mortality from HIV-related CNS infection., Methods: DREAMM took place in five public hospitals in Cameroon, Malawi, and Tanzania. The main intervention was a stepwise algorithm for HIV-related CNS infections including bedside rapid diagnostic testing and implementation of WHO cryptococcal meningitis guidelines. A health system strengthening approach for hospitals was adopted to deliver quality care through a co-designed education programme, optimised clinical and laboratory pathways, and communities of practice. DREAMM was led and driven by local leadership and divided into three phases: observation (including situational analyses of routine care), training, and implementation. Consecutive adults (aged ≥18 years) living with HIV presenting with a first episode of suspected CNS infection were eligible for recruitment. The primary endpoint was the comparison of 2-week all-cause mortality between observation and implementation phases. This study completed follow-up in September, 2021. The project was registered on ClinicalTrials.gov, NCT03226379., Findings: From November, 2016 to April, 2019, 139 eligible participants were enrolled in the observation phase. From Jan 9, 2018, to March 25, 2021, 362 participants were enrolled into the implementation phase. 216 (76%) of 286 participants had advanced HIV disease (209 participants had missing CD4 cell count), and 340 (69%) of 494 participants had exposure to antiretroviral therapy (ART; one participant had missing ART data). In the implementation phase 269 (76%) of 356 participants had a probable CNS infection, 203 (76%) of whom received a confirmed microbiological or radiological diagnosis of CNS infection using existing diagnostic tests and medicines. 63 (49%) of 129 participants died at 2 weeks in the observation phase compared with 63 (24%) of 266 in the implementation phase; and all-cause mortality was lower in the implementation phase when adjusted for site, sex, age, ART exposure (adjusted risk difference -23%, 95% CI -33 to -13; p<0·001). At 10 weeks, 71 (55%) died in the observation phase compared with 103 (39%) in the implementation phase (-13%, -24 to -3; p=0·01)., Interpretation: DREAMM substantially reduced mortality from HIV-associated CNS infection in resource-limited settings in Africa. DREAMM scale-up is urgently required to reduce deaths in public hospitals and help meet Sustainable Development Goals., Funding: European and Developing Countries Clinical Trials Partnership, French Agency for Research on AIDS and Viral Hepatitis., Translations: For the French and Portuguese translations of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests AL, DSL, and JB all received support for this project from European and Developing Countries Clinical Trials Partnership (EDCTP), paid to their institutions. AL has received grants from EDCTP, the National Institute for Health and Care Research, and the National Institutes of Health, and consultancy fees from Unitaid to advise on the Unitaid-CHAI Advanced HIV Disease programme, all paid to St George's University of London; AL is also the Chair and Lead of the End AIDS Action Group, which encompasses the work of the Cryptococcal Meningitis Action gorup, an unfunded role. RR received a grant from The National Institute of Allergy and Infectious Diseases, paid to their institution. OL receives consulting fees and payments or honoraria of less than US$1000 per year from Gilead Sciences; and is part of the advisory board for Mundipharma. THa received an investigator award from Gilead Sciences and has received payments or honoraria from Gilead Sciences and Pfizer for speaking fees. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background and Objectives: In patrilocal societies, married women typically co-reside with their parents-in-law, who may act in their son's reproductive interests. These relationships may shape maternal mental health and autonomy. Few studies have examined these dynamics from an evolutionary perspective. Theoretically, marital kin may increase their fitness by increasing maternal investment or by reducing paternity uncertainty. We explored how co-residence with parents-in-law and husband is associated with maternal outcomes to evaluate whether marital kin provide support or constraint., Methodology: We analysed data from 444 households in rural lowland Nepal. Maternal mental health was assessed by General Health Questionnaire. Logistic regression models investigated whether, relative to mothers living with both husband and parents-in-law, those co-resident with other combinations of relatives had poorer mental health and lower household economic autonomy (decision-making, bargaining power), adjusting for socio-economic confounders., Results: Co-residence with husband only, or neither husband nor parents-in-law, was associated with higher odds of mothers reporting feeling worthless and losing sleep but also earning income and making household expenditure decisions. Husband co-residence was associated with overall maternal distress but also with less unpaid care work and greater decision-making responsibility. There were no differences in maternal outcomes for mothers living with parents-in-law only, relative to those living with both husbands and parents-in-law., Conclusions and Implications: Co-residence of parents-in-law and husbands was associated with contrasting patterns of maternal mental health and economic autonomy. We suggest that different marital kin place different economic demands on mothers, while restricting their autonomy in different ways as forms of 'mate-guarding'., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Cows undergo immense physiological stress to produce milk during early lactation. Monitoring early lactation milk through Fourier-transform infrared (FTIR) spectroscopy might offer an understanding of which cows transition successfully. Daily patterns of milk constituents in early lactation have yet to be reported continuously, and the study objective was to initially describe these patterns for cows of varying parity groups from 3 through 10 d postpartum, piloted on a single dairy. We enrolled 1,024 Holstein cows from a commercial dairy farm in Cayuga County, New York, in an observational study, with a total of 306 parity 1 cows, 274 parity 2 cows, and 444 parity ≥3 cows. Cows were sampled once daily, Monday through Friday, via proportional milk samplers, and milk was stored at 4°C until analysis using FTIR. Estimated constituents included anhydrous lactose, true protein, and fat (g/100 g of milk); relative % (rel%) of total fatty acids (FA) and concentration (g/100 g of milk) of de novo, mixed, and preformed FA; individual fatty acids C16:0, C18:0, and C18:1 cis-9 (g/100 g of milk); milk urea nitrogen (MUN; mg/100 g of milk); and milk acetone (mACE), milk β-hydroxybutyrate (mBHB), and milk-predicted blood nonesterified fatty acids (mpbNEFA) (all expressed in mmol/L). Differences between parity groups were assessed using repeated-measures ANOVA. Milk yield per milking differed over time between 3 and 10 DIM and averaged 8.7, 13.3, and 13.3 kg for parity 1, 2, and ≥3 cows, respectively. Parity differences were found for % anhydrous lactose, % fat, and preformed FA (g/100 g of milk). Parity differed across DIM for % true protein, de novo FA (rel% and g/100 g of milk), mixed FA (rel% and g/100 g of milk), preformed FA rel%, C16:0, C18:0, C18:1 cis-9, MUN, mACE, mBHB, and mpbNEFA. Parity 1 cows had less true protein and greater fat percentages than parity 2 and ≥3 cows (% true protein: 3.52, 3.76, 3.81; % fat: 5.55, 4.69, 4.95, for parity 1, 2, ≥3, respectively). De novo and mixed FA rel% were reduced and preformed FA rel% were increased in primiparous compared with parity 2 and ≥3 cows. The increase in preformed FA rel% in primiparous cows agreed with milk markers of energy deficit, such that mpbNEFA, mBHB, and mACE were greatest in parity 1 cows followed by parity ≥3 cows, with parity 2 cows having the lowest concentrations. When measuring milk constituents with FTIR, these results suggest it is critical to account for parity for the majority of estimated milk constituents. We acknowledge the limitation that this study was conducted on a single farm; however, if FTIR technology is to be used as a method of identifying cows maladapted to lactation, understanding variations in early lactation milk constituents is a crucial first step in the practical adoption of this technology., (The Authors. Published by Elsevier Inc. and Fass Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

Marriage during childhood and adolescence adversely affects maternal and child health and well-being, making it a critical global health issue. Analysis of factors associated with women marrying ≥18 years has limited utility in societies where the norm is to marry substantially earlier. This paper investigated how much education Nepali women needed to delay marriage across the range of ages from 15 to ≥18 years. Data on 6,406 women aged 23-30 years were analysed from the Low Birth Weight South Asia Trial on the early-marrying and low-educated Maithili-speaking Madhesi population in Terai, Nepal. Multivariable logistic regression models assessed the associations of women's education with marrying aged ≥15, ≥16, ≥17 and ≥18 years. Cox proportional hazards regression models quantified the hazard of marrying. Models adjusted for caste affiliation. Women married at median age of 15 years and three-quarters were uneducated. Women's primary and lower-secondary education were weakly associated with delaying marriage, whether the cut-off to define early marriage was 15, 16, 17 or 18 years, with stronger associations for secondary education. Caste associations were weak. Overall, models explained relatively little of the variance in the likelihood of marriage at different ages. The joint effects of lower-secondary and higher caste affiliation and of secondary/higher education and mid and higher caste affiliation reduced the hazard of marrying. In early-marrying and low-educated societies, changing caste-based norms are unlikely to delay women's marriage. Research on broader risk factors and norms that are more relevant for delaying marriage in these contexts is needed. Gradual increases in women's median marriage age and increased secondary education may, over time, reduce child and adolescent marriage.

In this study, 10 essential oils (EOs), from nine plants ( Cinnamomum camphora , Curcuma longa , Citrus aurantium , Morinda citrifolia , Petroselinum crispum , Plectranthus amboinicus , Pittosporum senacia , Syzygium coriaceum , and Syzygium samarangense ) were assessed for their antimicrobial, antiaging and antiproliferative properties. While only S. coriaceum , P. amboinicus (MIC: 0.50 mg/mL) and M. citrifolia (MIC: 2 mg/mL) EOs showed activity against Cutibacterium acnes , all EOs except S. samarangense EO demonstrated activity against Mycobacterium smegmatis (MIC: 0.125-0.50 mg/mL). The EOs were either fungistatic or fungicidal against one or both tested Candida species with minimum inhibitory/fungicidal concentrations of 0.016-32 mg/mL. The EOs also inhibited one or both key enzymes involved in skin aging, elastase and collagenase (IC 50 : 89.22-459.2 µg/mL; 0.17-0.18 mg/mL, respectively). Turmerone, previously identified in the C. longa EO, showed the highest binding affinity with the enzymes (binding energy: -5.11 and -6.64 kcal/mol). Only C. aurantium leaf, C. longa , P. amboinicus , P. senacia , S. coriaceum , and S. samarangense EOs were cytotoxic to the human malignant melanoma cells, UCT-MEL1 (IC 50 : 88.91-277.25 µg/mL). All the EOs, except M. citrifolia EO, were also cytotoxic to the human keratinocytes non-tumorigenic cells, HaCat (IC 50 : 33.73-250.90 µg/mL). Altogether, some interesting therapeutic properties of the EOs of pharmacological/cosmeceutical interests were observed, which warrants further investigations.

Background and Objectives: Evolutionary research on the sex ratio at birth (SRB) has focused on explaining variability within and between populations, and whether parental fitness is maximized by producing daughters or sons. We tested predictors of SRB in a low-income setting, to understand whether girls differ from boys in their likelihood of being born into families with the capacity to invest in them, which has implications for their future health and fitness., Methodology: We used data from a cluster randomized control trial from lowland rural Nepal (16 115 mother-child dyads). We applied principal component analysis to extract two composite indices reflecting maternal socio-economic and reproductive (parity, age) capital. We fitted mixed-effects logistic regression models to estimate odds ratios of having a girl in association with these individual factors and indices., Results: The SRB was 112. Compared to the global reference SRB (105), there were seven missing girls per 100 boys. Uneducated, early-marrying, poorer and shorter mothers were more likely to give birth to girls. Analysing composite maternal indices, lower socio-economic and reproductive capital were independently associated with a greater likelihood of having a girl., Conclusions and Implications: In this population, girls start life facing composite disadvantages, being more likely than boys to be born to mothers with lower socio-economic status and reproductive capital. Both physiological and behavioural mechanisms may contribute to these epidemiological associations. Differential early exposure by sex to maternal factors may underpin intergenerational cycles of gender inequality, mediated by developmental trajectory, education and socio-economic status., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Background and Objectives: Women's nutritional status is important for their health and reproductive fitness. In a population where early marriage is common, we investigated how women's nutritional status is associated with their age at marriage (marking a geographical transfer between households), and at first pregnancy., Methodology: We used data from a cluster-randomized control trial from lowland Nepal ( n  = 4071). Outcomes including body mass index (BMI) were measured in early pregnancy and trial endpoint, after delivery. We fitted mixed-effects linear and logistic regression models to estimate associations of age at marriage and age at pregnancy with outcomes, and with odds of chronic energy deficiency (CED, BMI <18.5 kg/m 2 ), at both timepoints., Results: BMI in early pregnancy averaged 20.9 kg/m 2 , with CED prevalence of 12.5%. In 750 women measured twice, BMI declined 1.2 (95% confidence interval 1.1, 1.3) kg/m 2 between early pregnancy and endpoint, when CED prevalence was 35.5%. Early pregnancy was associated in dose-response manner with poorer nutritional status. Early marriage was independently associated with poorer nutritional status among those pregnant ≤15 years, but with better nutritional status among those pregnant ≥19 years., Conclusions and Implications: The primary determinant of nutritional status was age at pregnancy, but this association also varied by marriage age. Our results suggest that natal households may marry their daughters earlier if food insecure, but that their nutritional status can improve in the marital household if pregnancy is delayed. Marriage age therefore determines which household funds adolescent weight gain, with implications for Darwinian fitness of the members of both households., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Foundation for Evolution, Medicine, and Public Health.)

Objectives: By convention, women's early marriage is considered a sociocultural decision sensitive to factors acting during adolescence such as poverty, early menarche, and less education. Few studies have examined broader risk factors in the natal household prior to marriage. We investigated whether biosocial markers of parental investment through the daughters' life-course were associated with early marriage risk in rural India. We used an evolutionary perspective to interpret our findings., Materials and Methods: A prospective cohort recruited mothers at preconception. Children were followed from birth to age 21 years. Multivariable logistic regression models estimated odds ratios of marrying early (<19 years) associated first with wealth, age at menarche and education, and then with broader markers of maternal phenotype, natal household characteristics, and girls' growth trajectories. Models adjusted for confounders., Results: Of 305 girls, 71 (23%) had married early. Early married girls showed different patterns of growth compared to unmarried girls. Neither poverty nor early menarche predicted early marriage. Girls' non-completion of lower secondary school predicted early marriage, explaining 19% of the variance. Independent of girls' lower schooling, nuclear household, low paternal education, shorter gestation, and girls' poor infant weight gain were associated with marrying early, explaining in combination 35% of the variance., Discussion: Early marriage reflects "future discounting," where reduced parental investment in daughters' somatic and educational capital from early in her life favors an earlier transition to the life-course stage when reproduction can occur. Interventions initiated in adolescence may occur too late in the life-course to effectively delay women's marriage., (© 2021 The Authors. American Journal of Physical Anthropology published by Wiley Periodicals LLC.)

Background: Women's early marriage (<18 years) is a critical global health issue affecting 650 million women worldwide. It is associated with a range of adverse maternal physical and mental health outcomes, including early childbearing, child undernutrition and morbidity. Poverty is widely asserted to be the key risk factor driving early marriage. However, most studies do not measure wealth in the natal household, but instead, use marital household wealth as a proxy for natal wealth. Further research is required to understand the key drivers of early marriage., Methods: We investigated whether natal household poverty was associated with marrying early, independently of women's lower educational attainment and broader markers of household disadvantage. Data on natal household wealth (material asset score) for 2,432 women aged 18-39 years was used from the cluster-randomized Low Birth Weight South Asia Trial in lowland rural Nepal. Different early marriage definitions (<15, <16, <17 and <18 years) were used because most of our population marries below the conventional 18-year cut-off. Logistic mixed-effects models were fitted to estimate the probabilities, derived from adjusted Odds Ratios, of (a) marrying at different early ages for the full sample and for the uneducated women, and (b) being uneducated in the first place., Results: Women married at median age 15 years (interquartile range 3), and only 18% married ≥18 years. Two-thirds of the women were entirely uneducated. We found that, rather than poverty, women's lower education was the primary factor associated with early marriage, regardless of how 'early' is defined. Neither poverty nor other markers of household disadvantage were associated with early marriage at any age in the uneducated women. However, poverty was associated with women being uneducated., Conclusion: When assets are measured in the natal household in this population, there is no support for the conventional hypothesis that household poverty is associated with daughters' early marriage, but it is associated with not going to school. We propose that improving access to free education would both reduce early marriage and have broader benefits for maternal and child health and gender equality., Competing Interests: The authors declare that they have no competing interests., (© 2021 Marphatia et al.)

Objectives: Evolutionary perspectives on human childbirth have primarily focused on characteristics of our species in general, rather than variability within and between contemporary populations. We use an evolutionary framework to explore how physical and demographic characteristics of mothers shape the risks of childbirth complications in rural lowland Nepal, where childbearing typically commences in adolescence and chronic undernutrition is widespread, though maternal overweight is increasing in association with nutrition transition., Methods: We conducted secondary analyses of data from a cluster-randomized trial. Women aged 14-35 years were categorized by age, number of previous pregnancies, height, body mass index (BMI), husband's education, and household wealth. Multivariable logistic regression models tested whether these characteristics independently predicted risks of episiotomy and cesarean section (CS, n = 14 261), and obstructed labor (OL, n = 5185)., Results: Risks were greatest among first-time adolescent mothers, though associations with age varied by outcome. Independent of age and parity, short stature and high BMI increased risks of CS and OL, whereas associations were weaker for episiotomy. Male offspring had increased risk of CS and OL but not episiotomy. Wealth was not associated with OL, but lower wealth and lower husband's education were associated with lower likelihood of episiotomy and CS., Conclusions: At the individual level, the risk childbirth complications is shaped by trade-offs between fertility, growth, and survival. Some biological markers of disadvantage (early childbearing, short stature) increased the risk, whereas low socio-economic status was associated with lower risk, indicating reduced access to relevant facilities. Independent of these associations, maternal age showed complex effects., (© 2021 The Authors. American Journal of Human Biology published by Wiley Periodicals LLC.)

Eight prenylated xanthones including four new analogues were extracted and purified from the leaves of Garcinia xipshuanbannaensis . Multiple techniques including UV, 1D and 2D NMR, and HRESIMS were used to determine the structures of the isolated xanthones. These xanthones were evaluated for their cytotoxicity toward human cancer cells, and compound 4 exhibited activity against HeLa cells. A cytotoxic mechanism examination revealed the active compound induced cell apoptosis by arresting the cell cycle, increasing the levels of ROS, and inhibiting the expression of p-STAT3 in HeLa cells. In in vivo zebrafish experiments, compound 4 was found to block tumor proliferation and migration and have antiangiogenetic activity, and thus seems worthy of further laboratory evaluation.

In the present study, an immunological arabinan, LCP70-2A, was isolated from Ligusticum chuanxiong for the first time. The absolute molecular weight of LCP70-2A was determined to be 6.46 × 10 4  g/mol using the HPSEC-MALLS-RID method. The absolute configuration of arabinose in LCP70-2A was determined to be L-configuration. Physicochemical characterization revealed that LCP70-2A was a homogeneous polysaccharide and had a backbone of (1 → 5)-linked α-L-Araf with terminal α-L-arabinose residues at position O-2 and O-3. Molecular conformation analysis showed that LCP70-2A was a branching polysaccharide with a compact coil chain conformation in 0.1 M NaCl solution. In addition, in vitro cell assays showed that LCP70-2A can activate macrophages by enhancing the phagocytosis and potentiating the secretion of immunoregulatory factors including NO, TNF-α, IL-6, and IL-1β. Furthermore, LCP70-2A was proved to promote the production of ROS and NO using the zebrafish model, suggesting that LCP70-2A can be further developed as a candidate supplement for immunological enhancement., Competing Interests: Declaration of competing interest The authors have no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

This paper explores the purposeful use of conceptual and methodological tools provided by Cultural Historical Activity Theory (CHAT) to transform learning cultures and practices within and across diverse clinical learning environments. We describe how Change Laboratory methodology helped clinicians and others who support student, intern, and resident education to make changes collaboratively. A case study in undergraduate medical education shows how this created new forms of medical student placement and a postgraduate study shows how it addressed supervisors' undermining behaviour towards Obstetrics and Gynaecology residents. This empirical work illustrates ways of modifying the classical Change Laboratory process to fit local contexts, resources, and needs. We conclude with lessons learned and future directions for practitioner-researchers who wish to broaden the range of methodological tools they use to transform clinical learning environments.

Objectives: In many South Asian communities, the majority of women are married during adolescence and reproduce before 20 years. Early reproduction may adversely affect maternal nutrition and linear growth, however whether early marriage has similar effects is unknown. Shorter women might also be preferentially chosen for earlier marriage. We hypothesized that early marriage and early pregnancy may each be associated with women's shorter height, independent of any selection effects., Materials and Methods: We analyzed cross-sectional data on 7,146 women aged 20-30 years from rural lowland Nepal. Linear regression models tested associations of early marriage and early reproduction with height, adjusting for women's education and husbands' characteristics (education and wealth) that might index preferential selection of short young women for marriage., Results: Median ages at marriage and first pregnancy were 15 and 18 years, respectively, with 20% pregnant <16 years. Both early marriage and early pregnancy were independently associated with shorter stature, accounting for a decrement of 1.4 cm, which decreased to 1 cm after adjusting for women's education. Effects of early marriage and reproduction persisted after adjusting for the tendency of poorer and less educated men to marry young and short women, indicating a role for social selection., Discussion: The decrements in height associated with early marriage and reproduction are indicative of broader adverse effects on maternal metabolism during a "critical period" of growth and maturation in the life-course of women. Although the magnitudes of effect are relatively small, they affect large numbers of women in this population., (© 2020 Wiley Periodicals LLC.)

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), known to cause the disease COVID-19, was declared a pandemic in early 2020. The objective of this review was to collate information regarding the potential of plants and natural products to inhibit coronavirus and targets associated with infection in humans and to highlight known drugs, which may have potential activity against SARS-CoV-2. Due to the similarity in the RNA genome, main proteases, and primary host receptor between SARS-CoV and SARS-CoV-2, a review was conducted on plants and secondary metabolites, which have shown activity against SARS-CoV. Numerous scientific reports on the potential of plants and secondary metabolites against SARS-CoV infection were found, providing important information on their possible activity against SARS-CoV-2. Based on current literature, 83 compounds have been identified with the potential to inhibit COVID-19. The most prominent selectivity was found for the alkaloid, lycorine, the lignan, savinin, and the abietane terpenoid, 8-beta-hydroxyabieta-9(11),13-dien-12-one with selectivity index values greater than 945, 667, and 510, respectively. Plants and their secondary metabolites, with activity against targets associated with the SARS-CoV infection, could provide valuable leads for the development into drugs for the novel SARS-CoV-2. The prospects of using computational methods to screen secondary metabolites against SARS-CoV targets are briefly discussed, and the drawbacks have been highlighted. Finally, we discuss plants traditionally used in Southern Africa for symptoms associated with respiratory viral infections and influenza, such as coughs, fever, and colds. However, only a few of these plants have been screened against SARS-CoV. Natural products hold a prominent role in discovering novel therapeutics to mitigate the current COVID-19 pandemic; however, further investigations regarding in vitro , in vivo , pre-clinical, and clinical phases are still required., (Copyright © 2020 Verma, Twilley, Esmear, Oosthuizen, Reid, Nel and Lall.)

Violating expectancies during exposure therapy is proposed to promote inhibitory learning and improved treatment outcomes. Because people tend to overestimate how distressing emotionally challenging situations will be, violating expectations of distress may be an intuitive way to promote treatment outcome during exposure-based cognitive-behavioral therapy (CBT). This study evaluated overpredictions of distress during exposure tasks in 33 youth with obsessive-compulsive disorder (OCD; ages 8-17) participating in CBT. Youth with more variable prediction accuracy and a higher proportion of overpredictions experienced more rapid symptom reduction, b = -0.29, p = .002. Underpredictions were less common toward the end of therapy as youth experienced less severe OCD, b = 0.12, p= .001. Findings suggest that although youth often accurately predict the intensity of exposure, overpredictions are common as well. The frequency of these overpredictions promoted treatment outcome, supporting expectancy violations as one indicator of inhibitory learning during exposure therapy.

Several papers have primarily considered a female disadvantage in mortality as something to explain, considering a male disadvantage to be a "natural condition". Even if, due to biological reasons, shorter life expectancy among males has been demonstrated, other factors need to be involved to explain firstly the increasing, and then the decreasing, of the male relative disadvantage over the past century. The principal aim of this paper is to provide a clearer picture of the major age-class and cause-of-death contributions to male excess mortality in England and Wales from 1881 to 2011. Results indicate a clear shift in contributions to the male disadvantage from differences occurring during the first year of life to those occurring in ageing people, and from tuberculosis, respiratory diseases, external causes and perinatal and congenital conditions to neoplasms and circulatory diseases. In contrast, the narrowing of the gap since 1981 seems to be most closely related to the decrease in the male disadvantage in respiratory diseases and to the simultaneous increasing in the female disadvantage in old-age diseases. The most important novelty of this research relates to the method: instead of using ratios to investigate gender differences in health, we use decomposition methods., Competing Interests: None., (© 2020 The Authors.)

As active commuting levels continue to decline among primary schoolchildren, evidence about which built environmental characteristics influence walking or cycling to school remains inconclusive and is strongly context-dependent. This study aimed to identify the objective built environmental drivers of, and barriers to, active commuting to school for a multi-ethnic sample of 1,889 healthy primary schoolchildren (aged 5-11) in London, UK. Using cross-sectional multilevel ordered logistic regression modelling, supported by the spatial exploration of built environmental characteristics through cartography, the objective built environment was shown to be strongly implicated in children's commuting behaviour. In line with earlier research, proximity to school emerged as the prime variable associated with the choice for active commuting. However, other elements of the urban form were also significantly associated with children's use of active or passive modes of transport. High levels of accidents, crime and air pollution along the route to school were independently correlated with a lower likelihood of children walking or cycling to school. Higher average and minimum walkability and higher average densities of convenience stores along the way were independently linked to higher odds of active commuting. The significance of the relations for crime, air pollution and walkability disappeared in the fully-adjusted model including all built environmental variables. In contrast, relationships with proximity, traffic danger and the food environment were maintained in this comprehensive model. Black children, pupils with obesity, younger participants and those from high socioeconomic families were less likely to actively commute to school. There is thus a particular need to ensure that roads with high volumes of actively commuting children are kept safe and clean, and children's exposure to unhealthy food options along the way is limited. Moreover, as short commuting distances are strongly correlated with walking or cycling, providing high-quality education near residential areas might incite active transport to school., Competing Interests: The authors have declared that no competing interests exist.

Background: Early childbirth is associated with adverse maternal and child health outcomes. In South Asia, where women generally marry before having children, public health efforts need to focus on delaying marriage. Female education is widely considered the primary means to achieve this. However, it remains unclear how much education is required to delay marriage to the universal minimum age of 18 years, or what predicts marriage age in women lacking any education. This is crucial to address in the Terai region of Nepal which has the highest proportion of children out of school and where girls marry and have their first pregnancy early. Methods: We analyzed data from 6,406 women aged 23-30 years from a cluster-randomized trial in lowland Terai Nepal. Using Kaplan-Meier survival analysis, multivariable logistic and Cox proportional hazards regression models, we investigated associations between women's education level and age at marriage and first pregnancy, and the interval between these events. Among the uneducated women, we investigated associations of husband's education level with the same outcomes. Results: Compared to uneducated women, educated women had a greater probability of delaying marriage until the age of 18 years and of pregnancy until 20 years. Women needed to complete grade 9, and ideally 11, to substantially increase their odds of marrying after 18 years. Delaying first pregnancy to 20 years was largely due to marrying later; education had little extra effect. The association of marriage with first pregnancy age worked independently of education. However, later-marrying women, who generally had completed more education, had their first pregnancy sooner after marriage than earlier marrying women. Most uneducated women, regardless of their husbands' level of education, still married under the legal age of marriage. Conclusion: Delaying marriage to majority age requires greater efforts to ensure girls get to school in the first place, and complete secondary education. Since currently only 36% of girls in the Terai attend secondary school, parallel efforts to delay marriage are crucial to prevent early childbearing. Sexual and reproductive health programmes in school and in women's groups for married and uneducated adolescents may help prepare for marriage and pregnancy., (Copyright © 2020 Marphatia, Saville, Amable, Manandhar, Cortina-Borja, Wells and Reid.)

•Over-age attendance is increasing but remains under-studied in South Asia.•Children fall behind by entering pre-primary or primary late, and by repeating a grade during/after primary school.•Rural location, thin and uneducated mothers predicted late pre-primary entry.•Educational research and interventions need to focus on the earlier time-point of pre-primary.•Improving maternal nutrition and education may ensure timely progression of children in school., Competing Interests: None., (© 2019 The Authors.)

Although obsessive-compulsive disorder (OCD) has often been characterized as an internalizing disorder, some children with OCD exhibit externalizing behaviors that are specific to their OCD. This study sought to demonstrate that parents perceive both internalizing and externalizing behaviors in childhood OCD by examining the factor structure of the Child Obsessive-Compulsive Externalizing/Internalizing Scale (COCEIS), a parent-report questionnaire intended to measure these constructs. This study also investigated clinical correlates of internalizing and externalizing factors in the COCEIS. A factor analysis of questionnaire responses from 122 parents of youth with OCD revealed both externalizing and internalizing factors in the COCEIS. Externalizing behaviors in childhood OCD were associated with other, co-occurring externalizing behavior problems, while both factors were positively correlated with OCD severity and co-occurring internalizing symptoms. They were positively associated with each other at a trend level, and neither showed a significant relationship with insight. Sixty-two percent of parents endorsed "often" or "always" to at least one externalizing item, though modal responses to items suggested that each individual feature captured by the COCEIS may be relatively uncommon. Mean responses were significantly greater for internalizing items. This study provides evidence for distinct but related externalizing and internalizing behaviors specific to childhood OCD. Treatment for children with OCD presenting with more externalizing behaviors may require a greater emphasis on behavioral parent training and motivational enhancement.

Verbascoside is found in many medicinal plant families such as Verbenaceae. Important biological activities have been ascribed to verbascoside. Investigated in this study is the potential of verbascoside as an adjuvant during tuberculosis treatment. The present study reports on the in vitro metabolism in human hepatic microsomes and cytosol incubations as well as the presence and quantity of verbascoside within Lippia scaberrima . Additionally, studied are the inhibitory properties on human hepatic CYP enzymes together with antioxidant and cytotoxic properties. The results yielded no metabolites in the hydrolysis or cytochrome P450 (CYP) oxidation incubations. However, five different methylated conjugates of verbascoside could be found in S-adenosylmethionine incubation, three different sulphate conjugates with 3'-phosphoadenosine 5'-phosphosulfate (PAPS) incubation with human liver samples, and very low levels of glucuronide metabolites after incubation with recombinant human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A7, UGT1A8, and UGT1A10. Additionally, verbascoside showed weak inhibitory potency against CYP1A2 and CYP1B1 with IC 50 values of 83 µM and 86 µM, respectively. Potent antioxidant and low cytotoxic potential were observed. Based on these data, verbascoside does not possess any clinically relevant CYP-mediated interaction potential, but it has effective biological activity. Therefore, verbascoside could be considered as a lead compound for further drug development and as an adjuvant during tuberculosis treatment.

Background: Body Mass Index (BMI) is a common outcome when assessing associations between childhood overweight and obesity and physical activity patterns. However, the fat and fat-free components of BMI, measured by the Fat Mass Index (FMI) and Fat-Free Mass Index (FFMI), may show contrasting associations with physical activity, while ethnic groups may vary in both physical activity patterns and body composition. Body composition must therefore be evaluated when assessing the associations between childhood overweight and obesity and physical activity in multi-ethnic populations., Methods: This cross-sectional study investigated associations of BMI, FMI and FFMI z-scores with extracurricular physical activity for 2171 London primary schoolchildren (aged 5-11 years) of black, South Asian and white/other ethnicity. Multilevel mixed-effects ordered logistic modelling was used, adjusting for age, sex and family and neighbourhood socioeconomic status as potential confounders., Results: Controlling for ethnicity and individual, family and neighbourhood socioeconomic confounders, actively commuting children had significantly lower Odds Ratios for being in high BMI (Odds Ratio (OR) = 0.678; 95 % Confidence Interval (CI) = 0.531 - 0.865; p - value = 0.002) and FMI z-score groups (OR = 0.679; 95 % CI = 0.499 - 0.922; p = 0.013), but not FFMI z-score groups, than passive commuters. Children doing sports less than once a week had lower Odds Ratios for being in high BMI (OR = 0.435; 95 % CI = 0.236 - 0.802; p = 0.008) and FFMI (OR = 0.455; 95 % CI = 0.214 - 0.969; p = .041) z-score categories compared to daily active children. Differences in FMI between groups did not reach the significance threshold. A trend towards statistical significance was obtained whereby children's complete inactivity was associated with higher odds for being in higher BMI (OR = 2.222 : 95 % CI = 0.977 - 5.052; p = .057) and FMI z-score groups (OR = 2.485 : 95 % CI = 0.961 - 6.429; p = .060). FFMI z-scores did not show a similar trend with complete inactivity., Conclusions: Active commuting was objectively associated with lower adiposity, while more frequent extracurricular sports participation was correlated with greater fat-free mass accretion. These relationships were independent of ethnicity and individual, family or neighbourhood socioeconomic confounding factors.

Active centromeres are defined by the presence of nucleosomes containing CENP-A, a histone H3 variant, which alone is sufficient to direct kinetochore assembly. Once assembled at a location, CENP-A chromatin and kinetochores are maintained at that location through a positive feedback loop where kinetochore proteins recruited by CENP-A promote deposition of new CENP-A following replication. Although CENP-A chromatin itself is a heritable entity, it is normally associated with specific sequences. Intrinsic properties of centromeric DNA may favor the assembly of CENP-A rather than H3 nucleosomes. Here we investigate histone dynamics on centromere DNA. We show that during S phase, histone H3 is deposited as a placeholder at fission yeast centromeres and is subsequently evicted in G2, when we detect deposition of the majority of new CENP-A Cnp1 . We also find that centromere DNA has an innate property of driving high rates of turnover of H3-containing nucleosomes, resulting in low nucleosome occupancy. When placed at an ectopic chromosomal location in the absence of any CENP-A Cnp1 assembly, centromere DNA appears to retain its ability to impose S phase deposition and G2 eviction of H3, suggesting that features within centromere DNA program H3 dynamics. Because RNA polymerase II (RNAPII) occupancy on this centromere DNA coincides with H3 eviction in G2, we propose a model in which RNAPII-coupled chromatin remodeling promotes replacement of H3 with CENP-A Cnp1 nucleosomes., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Interprofessional education (IPE) is time consuming to develop and sustain and presents many logistical and practical challenges to curriculum developers. Drawing on findings from an evaluation study of an IPE pilot, this paper brings new insights into both positive implications and potentially negative consequences of delivering large scale IPE., Objective: The aim of the study was to evaluate a large scale IPE pilot delivered to students in the first year of their training., Design and Setting: The IPE pilot took place on campus and was focused on patient safety (human factors)., Participants: The study involved 630 first year undergraduates across 10 programmes at a UK university., Methods: A mixed methods evaluation was conducted comprising a paper-based survey circulated at the end of the taught session followed by uni-professional focus groups (n = 4). Questionnaire data was subject to descriptive statistical analysis and key themes were generated from the focus group data., Results: Three overarching themes emerged from analysis of the qualitative data: Understanding differences in roles, Learning about stereotypes and Unintended perpetuation of stereotypes., Conclusions: IPE is an important part of the training of all health and social care professionals and the study revealed many benefits of this approach. However, we should be sensitive to the possibility of inadvertently perpetuating negative stereotypes as a consequence of IPE activities. Our work highlights the need for caution when considering the planning and executing IPE activities., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Sleep is known to play an active role in consolidating new vocabulary in adults; however, the mechanisms by which sleep promotes vocabulary consolidation in childhood are less well understood. Furthermore, there has been no investigation into whether previously reported differences in sleep architecture might account for variability in vocabulary consolidation in children with dyslexia. Twenty-three children with dyslexia and 29 age-matched typically developing peers were exposed to 16 novel spoken words. Typically developing children showed overnight improvements in novel word recall; the size of the improvement correlated positively with slow wave activity, similar to previous findings with adults. Children with dyslexia showed poorer recall of the novel words overall, but nevertheless showed overnight improvements similar to age-matched peers. However, comparisons with younger children matched on initial levels of novel word recall pointed to reduced consolidation in dyslexics after 1 week. Crucially, there were no significant correlations between overnight consolidation and sleep parameters in the dyslexic group. This suggests a reduced role of sleep in vocabulary consolidation in dyslexia, possibly as a consequence of lower levels of learning prior to sleep, and highlights how models of sleep-associated memory consolidation can be usefully informed by data from typical and atypical development., (© 2017 John Wiley & Sons Ltd.)

Exposure therapy is a highly effective, evidence-based treatment technique for children and adolescents with anxiety disorders. Regardless, therapists in the community are reported to use exposure relatively rarely compared with other approaches. The goal of the present study was to identify how practicing clinicians treat youth with anxiety disorders across the United States and what factors contribute to their use of exposure therapy. Recruited from public directories, 257 private practice therapists who treat anxious youth were surveyed. Non-exposure cognitive-behavioral techniques like cognitive restructuring and relaxation techniques were used significantly more frequently than exposure. Providers with more training in exposure therapy and fewer negative beliefs about this approach reported using exposure significantly more in the treatment of youth with social anxiety, obsessive-compulsive, and panic disorders. Self-identification as an anxiety disorder specialist significantly predicted exposure use for youth with posttraumatic stress disorder. Most therapists in private practice have minimal training in exposure therapy, perceive a lack of training options, and believe there would be a benefit to acquiring more training. The implications of these findings are discussed, including how to optimally design training opportunities in exposure therapy., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Testicular germ cell tumours are the commonest tumours of young men and are broadly managed either as pure seminomas or as 'nonseminomas'. The management of Stage 1 nonseminomatous germ cell tumours (NSGCTs), beyond surgical removal of the primary tumour at orchidectomy, is somewhat controversial. Cancer-specific survival rates in these patients are in the order of 99% regardless of whether surveillance, retroperitoneal lymph node dissection, or adjuvant chemotherapy is employed. However, the toxicities of these treatment modalities differ. Undertreating those destined to relapse exposes them to the potentially significant toxicities of 3-4 cycles of bleomycin, etoposide, and cisplatin (BEP) chemotherapy. Conversely, giving adjuvant chemotherapy to all patients following orchidectomy results in overtreatment of a significant proportion. Therefore, the challenge lies in delineating the patient population who require adjuvant chemotherapy and in determining how much chemotherapy to give to adequately reduce relapse risk. This chapter reviews the factors to be considered when adopting a risk-adapted strategy for giving adjuvant chemotherapy in Stage 1B NSGCT sand discusses the data regarding the number of BEP cycles to administer.

Context: For medical education researchers, a key concern may be the practicalities of gaining ethical approval where this is a national or local requirement. However, in qualitative studies, where the dynamics of human interaction pervade, ethical considerations are an ongoing process which continues long after approval has been granted. Responding to ethical dilemmas arising 'in the moment' requires a reflexive approach whereby the researcher questions his/her own motivations, assumptions and interests. Drawing on empirical studies and their experiences in academic and clinical research practice, the authors share their reflections on adhering to ethical principles throughout the research process to illustrate the complexities and nuances involved., Objectives and Findings: These reflections offer critical insights into dilemmas arising in view of the ethical principles driving good conduct, and through domains which distinguish between procedural ethics, situational ethics, ethical relationships and ethical issues in exiting the study. The accounts consider integrity and altruism in research, gatekeeping and negotiating access, consent and confidentiality, power dynamics and role conflict, and challenges in dissemination of findings. The experiences are based on a range of examples of research in a UK context from managing difficult conversations in the classroom to video-ethnography in the operating theatre., Discussion and Conclusions: These critical reflections make visible the challenges encountered and decisions that must be taken in the moment and on reflection after the event. Through sharing our experiences and debating the decisions we made, we offer insights into reflexivity in qualitative research which will be of value to others.

This study investigates the time course of incorporation of waking life experiences into daydreams. Thirty-one participants kept a diary for 10 days, reporting major daily activities (MDAs), personally significant events (PSEs) and major concerns (MCs). They were then cued for daydream, Rapid Eye Movement (REM) and N2 dream reports in the sleep laboratory. There was a higher incorporation into daydreams of MCs from the previous two days (day-residue effect), but no day-residue effect for MDAs or PSEs, supporting a function for daydreams of processing current concerns. A day-residue effect for PSEs and the delayed incorporation of PSEs from 5 to 7 days before the dream (the dream-lag effect) have previously been found for REM dreams. Delayed incorporation was not found in this study for daydreams. Daydreams might thus differ in function from REM sleep dreams. However, the REM dream-lag effect was not replicated here, possibly due to design differences from previous studies., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Exposure and response prevention (ERP) is an effective treatment for individuals with obsessive-compulsive disorder (OCD), yet a substantial number of individuals with OCD do not fully respond to this intervention. Based on emerging experimental and clinical research on acceptance, this study sought to explore whether willingness to experience unpleasant thoughts, emotions, and bodily sensations during ERP was associated with improved treatment response., Methods: Two hundred eighty-eight adults with OCD receiving residential ERP provided self-rated willingness and other exposure-related variables during each daily coached ERP session. Obsessive-compulsive and depressive symptom severity was assessed every week. Multilevel modeling was used to study the impact of willingness on treatment outcome during the first 6 weeks of residential care., Results: Data indicated that individuals with higher willingness during ERP reported faster symptom reduction during residential treatment, even when controlling for length of stay, psychopharmacological intervention, depression, adherence, and rituals performed during ERP. These results appear to have both statistical and clinical significance., Conclusions: Willingness to fully experience unpleasant and unwanted thoughts, emotions, and bodily sensations during exposures appears to be a marker of successful exposure therapy in adults with OCD. Future research should examine how willingness may enhance extinction learning during ERP., (© 2017 Wiley Periodicals, Inc.)

In many traditional societies, women's age at marriage acts simultaneously as a gateway to new family roles and the likelihood of producing offspring. However, inadequate attention has previously been given to the broader health and social implications of variability in women's marriage age for public health. Biomedical scientists have primarily been concerned with whether the onset of reproduction occurs before the woman is adequately able to nurture her offspring and maintain her own health. Social scientists have argued that early marriage prevents women from attaining their rightful education, accessing employment and training opportunities, developing social relationships with peers, and participating in civic life. The aim of this review article is to provide comprehensive research evidence on why women's marriage age, independent of age at first childbirth, is a crucial issue for public health. It focuses on data from four South Asian countries, Bangladesh, India, Nepal, and Pakistan, in which marriage is near universal and where a large proportion of women still marry below the United Nations prescribed minimum marriage age of 18 years. Using an integrative perspective, we provide a comprehensive synthesis of the physiological, bio-demographic, and socio-environmental drivers of variable marriage age. We describe the adverse health consequences to mothers and to their offspring of an early age at marriage and of childbearing, which include malnutrition and high rates of morbidity and mortality. We also highlight the complex association of marriage age, educational attainment, and low societal status of women, all of which generate major public health impact. Studies consistently find a public health dividend of increased girls' education for maternal and child nutritional status and health outcomes. Paradoxically, recent relative increases in girls' educational attainment across South Asia have had limited success in delaying marriage age. This evidence suggests that in order for public health initiatives to maximize the health of women and their offspring, they must first address the factors that shape the age at which women marry.

This study investigated the prevalence of common barriers to the use of exposure therapy (ET) in the treatment of youth with anxiety disorders, specifically examining both logistical limitations and negative beliefs about ET. Results from 230 practicing clinicians who treat youth with anxiety disorders found that the top three barriers were session length (56%), lack of training (48%), and concern about parent reaction (47%). Endorsement of barriers to ET was associated with less ET utilization and less optimal implementation of ET. Results suggest that several barriers, especially logistical limitations, must be addressed in order to improve the dissemination of ET.

Background: This study follows on from a study that investigated how to develop effective final year medical student assistantship placements, using multidisciplinary clinical teams in planning and delivery., Aims: This study assessed the effects on objective structured clinical examination (OSCE) performance of the in-course enhanced "super-assistantship" placement introduced to a randomly selected sample of 2013-14 final year medical students at Leeds medical school., Methods: Quantitative data analysis was used to compare the global grades of OSCE stations between students who undertook this placement against those who did not., Results: There was a small overall improvement in the "super-assistantship" student scores across the whole assessment (effect size = 0.085). "Pre-op Capacity", "Admissions Prescribing" and "Hip Pain" stations had small-medium effect sizes (0.226, 0.215, and 0.214) in favor of the intervention group. Other stations had small effect sizes (0.107-0.191), mostly in favor of the intervention group., Conclusions: The "super-assistantship" experience characterized by increasing student responsibility on placement can help to improve competence and confidence in clinical decision-making "in a simulated environment". The clinical environment and multidisciplinary team must be ready and supported to provide these opportunities effectively. Further in-course opportunities for increasing final year student responsibility should be developed.

Objective: To describe the experiences of emergency department (ED) use among a population of Rhode Island Medicaid patients with chronic pain and a recent history of frequent ED use, who were eligible to participate in the Rhode Island Medicaid Pain Management program., Methods:  Qualitative interviews were conducted with twenty-four patients who were either enrolled, or eligible to be enrolled, in a pain management program that is part of a state-funded initiative to reduce ED overuse., Results: Four main themes describe the experiences of these patients seeking ED care: (1) patients perceive that they use the ED appropriately; (2) frustrations in communication with ED providers; (3) helplessness; (4) changes in beliefs and behaviors with care coordination., Conclusions: Patients enrolled, or eligible to be enrolled, in the Rhode Island Medicaid Pain Management program believe they use the ED for true emergencies, but feel helpless and unable to communicate effectively with ED providers. [Full article available at http://rimed.org/rimedicaljournal-2017-02.asp].

Attention-deficit/hyperactivity disorder (ADHD) has been found to be highly comorbid in children and adolescents with obsessive-compulsive disorder (OCD). Some have proposed, however, that obsessive anxiety may cause inattention and executive dysfunction, leading to inappropriate ADHD diagnoses in those with OCD. If this were the case, these symptoms would be expected to decrease following successful OCD treatment. The present study tested this hypothesis and evaluated whether ADHD symptoms at baseline predicted OCD treatment response. Obsessive-compulsive and ADHD symptoms were assessed in 50 youth enrolled in a randomized controlled trial investigating selective serotonin reuptake inhibitor and cognitive behavioral treatment. Repeated-measures analysis of variance (RMANOVA) revealed that ADHD symptoms at baseline do not significantly predict treatment outcome. A multivariate RMANOVA found that OCD treatment response moderated change in inattention; participants who showed greater reduction in OCD severity experienced greater reduction in ADHD-inattentive symptoms, while those with less substantial reduction in obsessions and compulsions showed less change. These findings suggest that children and adolescents with OCD and inattention may experience meaningful improvements in attention problems following OCD treatment. Thus, in many youth with OCD, inattention may be inherently tied to obsessions and compulsions. Clinicians may consider addressing OCD in treatment before targeting inattentive-type ADHD., Competing Interests: Conflict of Interest: All other authors have no conflicts of interest to report.