Ten simple rules for teaching applied programming in an authentic and immersive online environment

From PLOS via Jisc Publications RouterHistory: collection 2021-08, epub 2021-08-05Publication status: Publishe

Inhibition of the glucocorticoid‐activating enzyme 11β‐hydroxysteroid dehydrogenase type 1 drives concurrent 11‐oxygenated androgen excess

Aldo‐keto reductase 1C3 (AKR1C3) is a key enzyme in the activation of both classic and 11‐oxygenated androgens. In adipose tissue, AKR1C3 is co‐expressed with 11β‐hydroxysteroid dehydrogenase type 1 (HSD11B1), which catalyzes not only the local activation of glucocorticoids but also the inactivation of 11‐oxygenated androgens, and thus has the potential to counteract AKR1C3. Using a combination of in vitro assays and in silico modeling we show that HSD11B1 attenuates the biosynthesis of the potent 11‐oxygenated androgen, 11‐ketotestosterone (11KT), by AKR1C3. Employing ex vivo incubations of human female adipose tissue samples we show that inhibition of HSD11B1 results in the increased peripheral biosynthesis of 11KT. Moreover, circulating 11KT increased 2–3 fold in individuals with type 2 diabetes after receiving the selective oral HSD11B1 inhibitor AZD4017 for 35 days, thus confirming that HSD11B1 inhibition results in systemic increases in 11KT concentrations. Our findings show that HSD11B1 protects against excess 11KT production by adipose tissue, a finding of particular significance when considering the evidence for adverse metabolic effects of androgens in women. Therefore, when targeting glucocorticoid activation by HSD11B1 inhibitor treatment in women, the consequently increased generation of 11KT may offset beneficial effects of decreased glucocorticoid activation

Screening for asthma in Cantonese-speaking immigrant children

BACKGROUND: Asthma prevalence among Chinese immigrant children is poorly understood and attempts to screen these children have produced varied outcomes. We sought to learn how to improve screening for asthma in Chinese immigrant children. METHODS: Children (n = 152) were administered the Brief Pediatric Asthma Screen in either Cantonese or English, they then viewed and reacted to a video showing people wheezing and subsequently took a pulmonary function test. RESULTS: The diagnosed asthma prevalence for our study population was 27.0%, with another 5.3% having possible undiagnosed asthma. Very few children had spirometry findings below normal. In multivariate analysis, being native born (p = 0.002) and having a family history of asthma (p = 0.003) were statistically associated with diagnosis of asthma. After viewing the video, 35.6% of respondents indicated that the images differed from their conception of wheezing. Of four translations of the word "wheeze" no single word was chosen by a majority. CONCLUSION: Our findings suggest that asthma diagnoses are higher for Chinese children who were born in the US suggesting that desegregation of data might reveal at risk subpopulations. Care needs to be taken when diagnosing asthma for Cantonese speakers because of the centrality of the word wheeze and the challenges of translation

Investigating the effectiveness and acceptability of oral health and related health behaviour interventions in adults with severe and multiple disadvantage:Protocol for a mixed-methods systematic review

Increasing numbers of people in England experience homelessness, substance use, and repeated offending (known as ‘severe and multiple disadvantage’; SMD). Populations experiencing SMD often have extremely poor oral health, which is closely inter-linked with high levels of substance use, smoking, and poor diet. This study aims to undertake an evidence synthesis to identify the effectiveness, resource requirements, and factors influencing the implementation and acceptability of oral health and related health behaviour interventions in adults experiencing SMD. Two systematic reviews will be conducted using mixed-methods. Review 1 will investigate the effectiveness and resource implications of oral health and related health behaviours (substance use, smoking, diet) interventions; Review 2 will investigate factors influencing the implementation of such interventions. The population includes adults (≥18 years) experiencing SMD. Standard review methods in terms of searches, screening, data extraction, and quality appraisal will be conducted. Narrative syntheses will be conducted. If feasible, a meta-analysis will be conducted for Review 1 and a thematic synthesis for Review 2. Evidence from the two reviews will then be synthesised together. Input from people with experience of SMD will be sought throughout to inform the reviews. An initial logic model will be iteratively refined during the review.</jats:p

Rates of acquisition and clearance of pneumococcal serotypes in the nasopharynges of children in Kilifi District, Kenya.

BACKGROUND: To understand and model the impact of pneumococcal conjugate vaccines at the population level, we need to know the transmission dynamics of individual pneumococcal serotypes. We estimated serotype-specific clearance and acquisition rates of nasopharyngeal colonization among Kenyan children. METHODS: Children aged 3-59 months who were identified as carriers in a cross-sectional survey were followed-up approximately 1, 2, 4, 8, 16, and 32 days later and monthly thereafter until culture of 2 consecutive swabs yielded an alternative serotype or no pneumococcus. Serotype-specific clearance rates were estimated by exponential regression of interval-censored carriage durations. Duration was estimated as the reciprocal of the clearance rate, and acquisition rates were estimated on the basis of prevalence and duration, assuming an equilibrium state. RESULTS: Of 2840 children sampled between October 2006 and December 2008, 1868 were carriers. The clearance rate was 0.032 episodes/day (95% confidence interval [CI], .030-.034), for a carriage duration of 31.3 days, and the rate varied by serotype (P< .0005). Carriage durations for the 28 serotypes with ≥ 10 carriers ranged from 6.7 to 50 days. Clearance rates increased with year of age, adjusted for serotype (hazard ratio, 1.21; 95% CI, 1.15-1.27). The acquisition rate was 0.061 episodes/day (95% CI, .055-.067), which did not vary with age. Serotype-specific acquisition rates varied from 0.0002 to 0.0022 episodes/day. Serotype-specific acquisition rates correlated with prevalence (r=0.91; P< .00005) and with acquisition rates measured in a separate study involving 1404 newborns in Kilifi (r=0.87; P< .00005). CONCLUSIONS: The large sample size and short swabbing intervals provide a precise description of the prevalence, duration, and acquisition of carriage of 28 pneumococcal serotypes. In Kilifi, young children experience approximately 8 episodes of carriage per year. The declining prevalence with age is attributable to increasing clearance rates

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer.

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM -/- patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Multiple populations in globular clusters. Lessons learned from the Milky Way globular clusters

Recent progress in studies of globular clusters has shown that they are not simple stellar populations, being rather made of multiple generations. Evidence stems both from photometry and spectroscopy. A new paradigm is then arising for the formation of massive star clusters, which includes several episodes of star formation. While this provides an explanation for several features of globular clusters, including the second parameter problem, it also opens new perspectives about the relation between globular clusters and the halo of our Galaxy, and by extension of all populations with a high specific frequency of globular clusters, such as, e.g., giant elliptical galaxies. We review progress in this area, focusing on the most recent studies. Several points remain to be properly understood, in particular those concerning the nature of the polluters producing the abundance pattern in the clusters and the typical timescale, the range of cluster masses where this phenomenon is active, and the relation between globular clusters and other satellites of our Galaxy.Comment: In press (The Astronomy and Astrophysics Review

Association of prolactin receptor (PRLR) variants with prolactinomas

Prolactinomas are the most frequent type of pituitary tumors, which represent 10–20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P 1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms

Peer navigation improves diagnostic follow-up after breast cancer screening among Korean American women: results of a randomized trial

To test an intervention to increase adherence to diagnostic follow-up tests among Asian American women. Korean American women who were referred for a diagnostic follow-up test (mainly diagnostic mammograms) and who had missed their follow-up appointment were eligible to participate in the study. Women from two clinics (n&nbsp;=&nbsp;176) were randomly allocated to a usual care control arm or a peer navigator intervention arm. A 20-min telephone survey was administered to women in both study arms six&nbsp;months after they were identified to assess demographic and socio-economic characteristics and the primary outcome, self-reported completion of the recommended follow-up exam. Among women who completed the survey at six-month follow-up, self-reported completion of follow-up procedures was 97% in the intervention arm and 67% in the control arm (p&nbsp;&lt;&nbsp;0.001). Based on an intent-to-treat analysis of all women who were randomized and an assumption of no completion of follow-up exam for women with missing outcome data, self-reported completion of follow-up was 61% in the intervention arm and 46% in the usual care control arm (p&nbsp;&lt;&nbsp;0.069). Our results suggest that a peer navigator intervention to assist Korean American women to obtain follow-up diagnostic tests after an abnormal breast cancer screening test is efficacious