Maternal iodine status in a multi-ethnic UK birth cohort: Associations with child cognitive and educational development.

BACKGROUND: Maternal iodine requirements increase during pregnancy to supply thyroid hormones critical for fetal neurodevelopment. Iodine insufficiency may result in poorer cognitive or child educational outcomes but current evidence is sparse and inconsistent. OBJECTIVES: To quantify the association between maternal iodine status and child educational outcomes. METHODS: Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6971 mothers at 26-28 weeks' gestation participating in the Born in Bradford cohort. Maternal iodine status was examined in relation to child school achievement (early years foundation stage (EYFS), phonics, and Key Stage 1 (KS1)), other learning outcomes, social and behavioural difficulties, and sensorimotor control in 5745 children aged 4-7 years. RESULTS: Median (interquartile range) UIC was 76 µg/L (46, 120), and I:Cr was 83 µg/g (59, 121). Overall, there was no strong or consistent evidence to support associations between UIC or I:Cr and neurodevelopmental outcomes. For instance, predicted EYFS and phonics scores (primary outcomes) at the 25th vs 75th I:Cr percentiles (99% confidence intervals) were similar, with no evidence of associations: EYFS scores were 32 (99% CI 31, 33) and 33 (99% CI 32, 34), and phonics scores were 34 (99% CI 33, 35) and 35 (99% CI 34, 36), respectively. CONCLUSIONS: In the largest single study of its kind, there was little evidence of detrimental neurodevelopmental outcomes in children born to pregnant women with iodine insufficiency as defined by World Health Organization-outlined thresholds. Alternative functional biomarkers for iodine status in pregnancy and focused assessment of other health outcomes may provide additional insight.

Maternal iodine status, intrauterine growth, birth outcomes and congenital anomalies in a UK birth cohort.

BACKGROUND: Severe iodine insufficiency in pregnancy has significant consequences, but there is inadequate evidence to indicate what constitutes mild or moderate insufficiency, in terms of observed detrimental effects on pregnancy or birth outcomes. A limited number of studies have examined iodine status and birth outcomes, finding inconsistent evidence for specific outcomes. METHODS: Maternal iodine status was estimated from spot urine samples collected at 26-28 weeks' gestation from 6971 mothers in the Born in Bradford birth cohort. Associations with outcomes were examined for both urinary iodine concentration (UIC) and iodine-to-creatinine ratio (I:Cr). Outcomes assessed included customised birthweight (primary outcome), birthweight, small for gestational age (SGA), low birthweight, head circumference and APGAR score. RESULTS: There was a small positive association between I:Cr and birthweight in adjusted analyses. For a typical participant, the predicted birthweight centile at the 25th percentile of I:Cr (59 µg/g) was 2.7 percentage points lower than that at the 75th percentile of I:Cr (121 µg/g) (99% confidence interval (CI) 0.8 to 4.6), birthweight was predicted to be 41 g lower (99% CI 13 to 69) and the predicted probability of SGA was 1.9 percentage points higher (99% CI 0.0 to 3.7). There was no evidence of associations using UIC or other birth outcomes, including stillbirth, preterm birth, ultrasound growth measures or congenital anomalies. CONCLUSION: Lower maternal iodine status was associated with lower birthweight and greater probability of SGA. Whilst small, the effect size for lower iodine on birthweight is comparable to environmental tobacco smoke exposure. Iodine insufficiency is avoidable, and strategies to avoid deficiency in women of reproductive age should be considered. TRIAL REGISTRATION: ClinicalTrials.gov NCT03552341. Registered on June 11, 2018.

Estimating Wildfire Smoke Concentrations during the October 2017 California Fires through BME Space/Time Data Fusion of Observed, Modeled, and Satellite-Derived PM2.5.

Exposure to wildfire smoke causes adverse health outcomes, suggesting the importance of accurately estimating smoke concentrations. Geostatistical methods can combine observed, modeled, and satellite-derived concentrations to produce accurate estimates. Here, we estimate daily average ground-level PM2.5 concentrations at a 1 km resolution during the October 2017 California wildfires, using the Constant Air Quality Model Performance (CAMP) and Bayesian Maximum Entropy (BME) methods to bias-correct and fuse three concentration datasets: permanent and temporary monitoring stations, a chemical transport model (CTM), and satellite-derived estimates. Four BME space/time kriging and data fusion methods were evaluated. All BME methods produce more accurate estimates than the standalone CTM and satellite products. Adding temporary station data increases the R2 by 36%. The data fusion of observations with the CAMP-corrected CTM and satellite-derived concentrations provides the best estimate (R2 = 0.713) in fire-impacted regions, emphasizing the importance of combining multiple datasets. We estimate that approximately 65,000 people were exposed to very unhealthy air (daily average PM2.5 ≥ 150.5 µg/m3).

Maternal iodine status in a multi-ethnic UK birth cohort: associations with autism spectrum disorder.

BACKGROUND: Maternal iodine requirements increase during pregnancy to supply thyroid hormones essential for fetal brain development. Maternal iodine deficiency can lead to hypothyroxinemia, a reduced fetal supply of thyroid hormones which, in the first trimester, has been linked to an increased risk of autism spectrum disorder (ASD) in the child. No study to date has explored the direct link between maternal iodine deficiency and diagnosis of ASD in offspring. METHODS: Urinary iodine concentrations (UIC) and iodine/creatinine ratios (I:Cr) were measured in 6955 mothers at 26-28 weeks gestation participating in the Born in Bradford (BiB) cohort. Maternal iodine status was examined in relation to the probability of a Read (CTV3) code for autism being present in a child's primary care records through a series of logistic regression models with restricted cubic splines. RESULTS: Median (inter-quartile range) UIC was 76 µg/L (46, 120) and I:Cr was 83 µg/g (59, 121) indicating a deficient population according to WHO guidelines. Ninety two children (1·3%) in our cohort had received a diagnosis of ASD by the census date. Overall, there was no evidence to support an association between I:Cr or UIC and ASD risk in children aged 8-12 years (p = 0·3). CONCLUSIONS: There was no evidence of an increased clinical ASD risk in children born to mothers with mild-to-moderate iodine deficiency at 26 weeks gestation. Alternative functional biomarkers of exposure and a wider range of conditions may provide further insight.

Expansion of IL-23 receptor bearing TNFR2+ T cells is associated with molecular resistance to anti-TNF therapy in Crohn's disease.

OBJECTIVE: Anti-tumour necrosis factor (TNF) antibodies are successfully used for treatment of Crohn's disease. Nevertheless, approximately 40% of patients display failure to anti-TNF therapy. Here, we characterised molecular mechanisms that are associated with endoscopic resistance to anti-TNF therapy. DESIGN: Mucosal and blood cells were isolated from patients with Crohn's disease prior and during anti-TNF therapy. Cytokine profiles, cell surface markers, signalling proteins and cell apoptosis were assessed by microarray, immunohistochemistry, qPCR, ELISA, whole organ cultures and FACS. RESULTS: Responders to anti-TNF therapy displayed a significantly higher expression of TNF receptor 2 (TNFR2) but not IL23R on T cells than non-responders prior to anti-TNF therapy. During anti-TNF therapy, there was a significant upregulation of mucosal IL-23p19, IL23R and IL-17A in anti-TNF non-responders but not in responders. Apoptosis-resistant TNFR2+IL23R+ T cells were significantly expanded in anti-TNF non-responders compared with responders, expressed the gut tropic integrins α4ß7, and exhibited increased expression of IFN-γ, T-bet, IL-17A and RORγt compared with TNFR2+IL23R- cells, indicating a mixed Th1/Th17-like phenotype. Intestinal TNFR2+IL23R+ T cells were activated by IL-23 derived from CD14+ macrophages, which were significantly more present in non-responders prior to anti-TNF treatment. Administration of IL-23 to anti-TNF-treated mucosal organ cultures led to the expansion of CD4+IL23R+TNFR2+ lymphocytes. Functional studies demonstrated that anti-TNF-induced apoptosis in mucosal T cells is abrogated by IL-23. CONCLUSIONS: Expansion of apoptosis-resistant intestinal TNFR2+IL23R+ T cells is associated with resistance to anti-TNF therapy in Crohn's disease. These findings identify IL-23 as a suitable molecular target in patients with Crohn's disease refractory to anti-TNF therapy.

The AP-1 Transcription Factor c-Jun Promotes Arthritis by Regulating Cyclooxygenase-2 and Arginase-1 Expression in Macrophages.

Activation of proinflammatory macrophages is associated with the inflammatory state of rheumatoid arthritis. Their polarization and activation are controlled by transcription factors such as NF-κB and the AP-1 transcription factor member c-Fos. Surprisingly, little is known about the role of the AP-1 transcription factor c-Jun in macrophage activation. In this study, we show that mRNA and protein levels of c-Jun are increased in macrophages following pro- or anti-inflammatory stimulations. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment cluster analyses of microarray data using wild-type and c-Jun-deleted macrophages highlight the central function of c-Jun in macrophages, in particular for immune responses, IL production, and hypoxia pathways. Mice deficient for c-Jun in macrophages show an amelioration of inflammation and bone destruction in the serum-induced arthritis model. In vivo and in vitro gene profiling, together with chromatin immunoprecipitation analysis of macrophages, revealed direct activation of the proinflammatory factor cyclooxygenase-2 and indirect inhibition of the anti-inflammatory factor arginase-1 by c-Jun. Thus, c-Jun regulates the activation state of macrophages and promotes arthritis via differentially regulating cyclooxygenase-2 and arginase-1 levels.

Preclinical Profile of AB-423, an Inhibitor of Hepatitis B Virus Pregenomic RNA Encapsidation.

AB-423 is a member of the sulfamoylbenzamide (SBA) class of hepatitis B virus (HBV) capsid inhibitors in phase 1 clinical trials. In cell culture models, AB-423 showed potent inhibition of HBV replication (50% effective concentration [EC50] = 0.08 to 0.27 µM; EC90 = 0.33 to 1.32 µM) with no significant cytotoxicity (50% cytotoxic concentration > 10 µM). Addition of 40% human serum resulted in a 5-fold increase in the EC50s. AB-423 inhibited HBV genotypes A through D and nucleos(t)ide-resistant variants in vitro Treatment of HepDES19 cells with AB-423 resulted in capsid particles devoid of encapsidated pregenomic RNA and relaxed circular DNA (rcDNA), indicating that it is a class II capsid inhibitor. In a de novo infection model, AB-423 prevented the conversion of encapsidated rcDNA to covalently closed circular DNA, presumably by interfering with the capsid uncoating process. Molecular docking of AB-423 into crystal structures of heteroaryldihydropyrimidines and an SBA and biochemical studies suggest that AB-423 likely also binds to the dimer-dimer interface of core protein. In vitro dual combination studies with AB-423 and anti-HBV agents, such as nucleos(t)ide analogs, RNA interference agents, or interferon alpha, resulted in additive to synergistic antiviral activity. Pharmacokinetic studies with AB-423 in CD-1 mice showed significant systemic exposures and higher levels of accumulation in the liver. A 7-day twice-daily administration of AB-423 in a hydrodynamic injection mouse model of HBV infection resulted in a dose-dependent reduction in serum HBV DNA levels, and combination with entecavir or ARB-1467 resulted in a trend toward antiviral activity greater than that of either agent alone, consistent with the results of the in vitro combination studies. The overall preclinical profile of AB-423 supports its further evaluation for safety, pharmacokinetics, and antiviral activity in patients with chronic hepatitis B.

Deciphering source and sink responses of potato plants (Solanum tuberosum L.) to elevated temperatures.

Potato is an important staple food with increasing popularity worldwide. Elevated temperatures significantly impair tuber yield and quality. Breeding heat-tolerant cultivars is therefore an urgent need to ensure sustainable potato production in the future. An integrated approach combining physiology, biochemistry, and molecular biology was undertaken to contribute to a better understanding of heat effects on source- (leaves) and sink-organs (tubers) in a heat-susceptible cultivar. An experimental set-up was designed allowing tissue-specific heat application. Elevated day and night (29°C/27°C) temperatures impaired photosynthesis and assimilate production. Biomass allocation shifted away from tubers towards leaves indicating reduced sink strength of developing tubers. Reduced sink strength of tubers was paralleled by decreased sucrose synthase activity and expression under elevated temperatures. Heat-mediated inhibition of tuber growth coincided with a decreased expression of the phloem-mobile tuberization signal SP6A in leaves. SP6A expression and photosynthesis were also affected, when only the belowground space was heated, and leaves were kept under control conditions. By contrast, the negative effects on tuber metabolism were attenuated, when only the shoot was subjected to elevated temperatures. This, together with transcriptional changes discussed, indicated a bidirectional communication between leaves and tubers to adjust the source capacity and/or sink strength to environmental conditions.

Sparse regression and marginal testing using cluster prototypes.

We propose a new approach for sparse regression and marginal testing, for data with correlated features. Our procedure first clusters the features, and then chooses as the cluster prototype the most informative feature in that cluster. Then we apply either sparse regression (lasso) or marginal significance testing to these prototypes. While this kind of strategy is not entirely new, a key feature of our proposal is its use of the post-selection inference theory of Taylor and others (2014, Exact post-selection inference for forward stepwise and least angle regression, Preprint, arXiv:1401.3889) and Lee and others (2014, Exact post-selection inference with the lasso, Preprint, arXiv:1311.6238v5) to compute exact [Formula: see text]-values and confidence intervals that properly account for the selection of prototypes. We also apply the recent "knockoff" idea of Barber and Candès (2014, Controlling the false discovery rate via knockoffs, Preprint, arXiv:1404.5609) to provide exact finite sample control of the FDR of our regression procedure. We illustrate our proposals on both real and simulated data.

Cytosolic glyceraldehyde-3-phosphate dehydrogenases play crucial roles in controlling cold-induced sweetening and apical dominance of potato (Solanum tuberosum L.) tubers.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is an important enzyme that functions in producing energy and supplying intermediates for cellular metabolism. Recent researches indicate that GAPDHs have multiple functions beside glycolysis. However, little information is available for functions of GAPDHs in potato. Here, we identified 4 putative cytosolic GAPDH genes in potato genome and demonstrated that the StGAPC1, StGAPC2, and StGAPC3, which are constitutively expressed in potato tissues and cold inducible in tubers, encode active cytosolic GAPDHs. Cosuppression of these 3 GAPC genes resulted in low tuber GAPDH activity, consequently the accumulation of reducing sugars in cold stored tubers by altering the tuber metabolite pool sizes favoring the sucrose pathway. Furthermore, GAPCs-silenced tubers exhibited a loss of apical dominance dependent on cell death of tuber apical bud meristem (TAB-meristem). It was also confirmed that StGAPC1, StGAPC2, and StGAPC3 interacted with the autophagy-related protein 3 (ATG3), implying that the occurrence of cell death in TAB-meristem could be induced by ATG3 associated events. Collectively, the present research evidences first that the GAPC genes play crucial roles in diverse physiological and developmental processes in potato tubers.

Amylases StAmy23, StBAM1 and StBAM9 regulate cold-induced sweetening of potato tubers in distinct ways.

Cold-induced sweetening (CIS) in potato is detrimental to the quality of processed products. Conversion of starch to reducing sugars (RS) by amylases is considered one of the main pathways in CIS but is not well studied. The amylase genes StAmy23, StBAM1, and StBAM9 were studied for their functions in potato CIS. StAmy23 is localized in the cytoplasm, whereas StBAM1 and StBAM9 are targeted to the plastid stroma and starch granules, respectively. Genetic transformation of these amylases in potatoes by RNA interference showed that ß-amylase activity could be decreased in cold-stored tubers by silencing of StBAM1 and collective silencing of StBAM1 and StBAM9. However, StBAM9 silencing did not decrease ß-amylase activity. Silencing StBAM1 and StBAM9 caused starch accumulation and lower RS, which was more evident in simultaneously silenced lines, suggesting functional redundancy. Soluble starch content increased in RNAi-StBAM1 lines but decreased in RNAi-StBAM9 lines, suggesting that StBAM1 may regulate CIS by hydrolysing soluble starch and StBAM9 by directly acting on starch granules. Moreover, StBAM9 interacted with StBAM1 on the starch granules. StAmy23 silencing resulted in higher phytoglycogen and lower RS accumulation in cold-stored tubers, implying that StAmy23 regulates CIS by degrading cytosolic phytoglycogen. Our findings suggest that StAmy23, StBAM1, and StBAM9 function in potato CIS with varying levels of impact.

Risk Determinants of Acute Mountain Sickness and Summit Success on a 6-Day Ascent of Mount Kilimanjaro (5895 m).

OBJECTIVE: The aims of this study were to assess incidence of acute mountain sickness (AMS) and summit success on a 6-day ascent profile of Mt. Kilimanjaro and evaluate potential risk factors for these outcomes. METHODS: All trekkers through a single Australian tour company between August 2012 and July 2014 were included. Participants ascended via the Rongai route and attempted the summit on day 6. Daily assessments were made using the self-reported Lake Louise score (LLS) questionnaire. Two different AMS diagnostic criteria (LLS ≥ 3 and LLS ≥ 5) were used for data analysis. Risk factors for development of AMS and summit success were analyzed. RESULTS: Over the 24-month period a total of 175 participants undertook the trek. Incidence of AMS was 52.6% (LLS ≥ 3) and 22.9% (LLS ≥ 5). Summit success was 88%. Age, sex, body mass index, and acetazolamide use were not associated with risk of AMS development. Age ≥ 40 years (P = .0002) and female sex (P = .0004) were both significantly associated with reduced summit success rate. CONCLUSIONS: Our cohort found a lower incidence of AMS and better summit success on a 6-day ascent of Mt Kilimanjaro than previously described in other groups on 4- and 5-day ascents. Female sex and age ≥ 40 years both predicted failure to summit, but did not increase risk of developing AMS. AMS is a common cause of morbidity on Mt. Kilimanjaro, and although the risk can be mitigated by a slower ascent, there is an ongoing need for education of individual trekkers, tour companies, and local authorities.

Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat.

When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats.

Placement, support, and retention of health professionals: national, cross-sectional findings from medical and dental community service officers in South Africa.

BACKGROUND: In South Africa, community service following medical training serves as a mechanism for equitable distribution of health professionals and their professional development. Community service officers are required to contribute a year towards serving in a public health facility while receiving supervision and remuneration. Although the South African community service programme has been in effect since 1998, little is known about how placement and practical support occur, or how community service may impact future retention of health professionals. METHODS: National, cross-sectional data were collected from community service officers who served during 2009 using a structured self-report questionnaire. A Supervision Satisfaction Scale (SSS) was created by summing scores of five questions rated on a three-point Likert scale (orientation, clinical advising, ongoing mentorship, accessibility of clinic leadership, and handling of community service officers' concerns). Research endpoints were guided by community service programmatic goals and analysed as dichotomous outcomes. Bivariate and multivariate logistical regressions were conducted using Stata 12. RESULTS: The sample population comprised 685 doctors and dentists (response rate 44%). Rural placement was more likely among unmarried, male, and black practitioners. Rates of self-reported professional development were high (470 out of 539 responses; 87%). Participants with higher scores on the SSS were more likely to report professional development. Although few participants planned to continue work in rural, underserved communities (n = 171 out of 657 responses, 25%), those serving in a rural facility during the community service year had higher intentions of continuing rural work. Those reporting professional development during the community service year were twice as likely to report intentions to remain in rural, underserved communities. CONCLUSIONS: Despite challenges in equitable distribution of practitioners, participant satisfaction with the compulsory community service programme appears to be high among those who responded to a 2009 questionnaire. These data offer a starting point for designing programmes and policies that better meet the health needs of the South African population through more appropriate human resource management. An emphasis on professional development and supervision is crucial if South Africa is to build practitioner skills, equitably distribute health professionals, and retain the medical workforce in rural, underserved areas.

African leaders' views on critical human resource issues for the implementation of family medicine in Africa.

BACKGROUND: The World Health Organisation has advocated for comprehensive primary care teams, which include family physicians. However, despite (or because of) severe doctor shortages in Africa, there is insufficient clarity on the role of the family physician in the primary health care team. Instead there is a trend towards task shifting without thought for teamwork, which runs the risk of dangerous oversimplification. It is not clear how African leaders understand the challenges of implementing family medicine, especially in human resource terms. This study, therefore, sought to explore the views of academic and government leaders on critical human resource issues for implementation of family medicine in Africa. METHOD: In this qualitative study, key academic and government leaders were purposively selected from sixteen African countries. In-depth interviews were conducted using an interview guide. All interviews were audio-recorded, transcribed and thematically analysed. RESULTS: There were 27 interviews conducted with 16 government and 11 academic leaders in nine Sub-Saharan African countries: Botswana, Democratic Republic of Congo, Ghana, Kenya, Malawi, Nigeria, Rwanda, South Africa and Uganda. Respondents spoke about: educating doctors in family medicine suited to Africa, including procedural skills and holistic care, to address the difficulty of recruiting and retaining doctors in rural and underserved areas; planning for primary health care teams, including family physicians; new supervisory models in primary health care; and general human resource management issues. CONCLUSIONS: Important milestones in African health care fail to specifically address the human resource issues of integrated primary health care teamwork that includes family physicians. Leaders interviewed in this study, however, proposed organising the district health system with a strong embrace of family medicine in Africa, especially with regard to providing clinical leadership in team-based primary health care. Whilst these leaders focussed positively on entry and workforce issues, in terms of the 2006 World Health Report on human resources for health, they did not substantially address retention of family physicians. Family physicians need to respond to the challenge by respondents to articulate human resource policies appropriate to Africa, including the organisational development of the primary health care team with more sophisticated skills and teamwork.

Regularization Paths for Conditional Logistic Regression: The clogitL1 Package.

We apply the cyclic coordinate descent algorithm of Friedman, Hastie, and Tibshirani (2010) to the fitting of a conditional logistic regression model with lasso [Formula: see text] and elastic net penalties. The sequential strong rules of Tibshirani, Bien, Hastie, Friedman, Taylor, Simon, and Tibshirani (2012) are also used in the algorithm and it is shown that these offer a considerable speed up over the standard coordinate descent algorithm with warm starts. Once implemented, the algorithm is used in simulation studies to compare the variable selection and prediction performance of the conditional logistic regression model against that of its unconditional (standard) counterpart. We find that the conditional model performs admirably on datasets drawn from a suitable conditional distribution, outperforming its unconditional counterpart at variable selection. The conditional model is also fit to a small real world dataset, demonstrating how we obtain regularization paths for the parameters of the model and how we apply cross validation for this method where natural unconditional prediction rules are hard to come by.

Peer review for social accountability of health sciences education: a model from South Africa.

BACKGROUND: The Collaboration for Health Equity in Education and Research (CHEER) is unique in the composition of its members who represent all the Faculties of Health Sciences in South Africa. Over the past 10 years, CHEER has conducted 18 peer reviews involving all the institutions. In August 2012, CHEER embarked on its pilot peer review on Social Accountability in Health Sciences in South Africa. This paper shares the lessons learned and insights from the pilot process. METHODS: A descriptive study design, using qualitative methods, which focused primarily on semi-structured interviews and focus group discussions, supplemented with supporting documentation, was employed. The protocol was developed by CHEER members and ethics approval was obtained. RESULTS: Arising from our pilot peer review, reviewers identified several key components of the review process that should be noted for future reviews on social accountability. These relate to: (a) The composition of the review team; (b) the review process; (c) data collection and analysis; and (d) the reporting process. DISCUSSION: Peer review is a useful way of building consensus and a common set of values that become more explicit through the process. We found that six criteria, namely, values, reference population, partnerships, student profile, graduate outcomes and impact, provide the basis for establishing standards for reflecting social accountability. The peer review is a process of institutional self-review supported by 'a panel of critical friends' and is useful when considered as part of the process of preparation for the formal accreditation review at Health Sciences educational institutions.

NLRP3 Inhibition Leads to Impaired Mucosal Fibroblast Function in Patients with Inflammatory Bowel Diseases.

BACKGROUND AND AIMS: Inflammatory bowel diseases (IBD) are characterized by mucosal inflammation and sequential fibrosis formation, but the exact role of the hyperactive NLRP3 inflammasome in these processes is unclear. Thus, we studied the expression and function of the NLRP3 inflammasome in the context of inflammation and fibrosis in IBD. METHODS: We analysed intestinal NLRP3 expression in mucosal immune cells and fibroblasts from IBD patients and NLRP3-associated gene expression via single-cell RNA sequencing and microarray analyses. Furthermore, cytokine secretion of NLRP3 inhibitor treated blood and mucosal cells, as well as proliferation, collagen production, and cell death of NLRP3 inhibitor treated intestinal fibroblasts from IBD patients were studied. RESULTS: We found increased NLRP3 expression in the inflamed mucosa of IBD patients and NLRP3 inhibition led to reduced IL-1ß and IL-18 production in blood cells and diminished the bioactive form of mucosal IL-1ß. Single cell analysis identified overlapping expression patterns of NLRP3 and IL-1ß in classically activated intestinal macrophages and we also detected NLRP3 expression in CD163+ macrophages. In addition, NLRP3 expression was also found in intestinal fibroblasts from IBD patients. Inhibition of NLRP3 led to reduced proliferation of intestinal fibroblasts, which was associated with a marked decrease in production of collagen type I and type VI in IBD patients. Moreover, NLRP3 inhibition in intestinal fibroblasts induced autophagy, a cellular process involved in collagen degradation. CONCLUSIONS: In the presented study, we demonstrate that inhibiting NLRP3 might pave the way for novel therapeutic approaches in IBD, especially to prevent the severe complication of intestinal fibrosis formation.

Impact of wildfires on ozone exceptional events in the Western u.s.

Wildfires generate substantial emissions of nitrogen oxides (NOx) and volatile organic compounds (VOCs). As such, wildfires contribute to elevated ozone (O3) in the atmosphere. However, there is a large amount of variability in the emissions of O3 precursors and the amount of O3 produced between fires. There is also significant interannual variability as seen in median O3, organic carbon and satellite derived carbon monoxide mixing ratios in the western U.S. To better understand O3 produced from wildfires, we developed a statistical model that estimates the maximum daily 8 h average (MDA8) O3 as a function of several meteorological and temporal variables for three urban areas in the western U.S.: Salt Lake City, UT; Boise, ID; and Reno, NV. The model is developed using data from June-September 2000-2012. For these three locations, the statistical model can explain 60, 52, and 27% of the variability in daily MDA8. The Statistical Model Residual (SMR) can give information on additional sources of O3 that are not explained by the usual meteorological pattern. Several possible O3 sources can explain high SMR values on any given day. We examine several cases with high SMR that are due to wildfire influence. The first case considered is for Reno in June 2008 when the MDA8 reached 82 ppbv. The wildfire influence for this episode is supported by PM concentrations, the known location of wildfires at the time and simulations with the Weather and Research Forecasting Model with Chemistry (WRF-Chem) which indicates transport to Reno from large fires burning in California. The contribution to the MDA8 in Reno from the California wildfires is estimated to be 26 ppbv, based on the SMR, and 60 ppbv, based on WRF-Chem. The WRF-Chem model also indicates an important role for peroxyacetyl nitrate (PAN) in producing O3 during transport from the California wildfires. We hypothesize that enhancements in PAN due to wildfire emissions may lead to regional enhancements in O3 during high fire years. The second case is for the Salt Lake City (SLC) region for August 2012. During this period the MDA8 reached 83 ppbv and the SMR suggests a wildfire contribution of 19 ppbv to the MDA8. The wildfire influence is supported by PM2.5 data, the known location of wildfires at the time, HYSPLIT dispersion modeling that indicates transport from fires in Idaho, and results from the CMAQ model that confirm the fire impacts. Concentrations of PM2.5 and O3 are enhanced during this period, but overall there is a poor relationship between them, which is consistent with the complexities in the secondary production of O3. A third case looks at high MDA8 in Boise, ID, during July 2012 and reaches similar conclusions. These results support the use of statistical modeling as a tool to quantify the influence from wildfires on urban O3 concentrations.

Verbal Autopsy to Assess Postdischarge Mortality in Children With Suspected Sepsis in Uganda.

BACKGROUND: Reducing child mortality in low-income countries is constrained by a lack of vital statistics. In the absence of such data, verbal autopsies provide an acceptable method to determining attributable causes of death. The objective was to assess potential causes of pediatric postdischarge mortality in children younger than age 5 years (under-5) originally admitted for suspected sepsis using verbal autopsies. METHODS: Secondary analysis of verbal autopsy data from children admitted to 6 hospitals across Uganda from July 2017 to March 2020. Structured verbal autopsy interviews were conducted for all deaths within 6 months after discharge. Two physicians independently classified a primary cause of death, up to 4 alternative causes, and up to 5 contributing conditions using the Start-Up Mortality List, with discordance resolved by consensus. RESULTS: Verbal autopsies were completed for 361 (98.6%) of the 366 (5.9%) children who died among 6191 discharges (median admission age: 5.4 months [interquartile range, 1.8-16.7]; median time to mortality: 28 days [interquartile range, 9-74]). Most deaths (62.3%) occurred in the community. Leading primary causes of death, assigned in 356 (98.6%) of cases, were pneumonia (26.2%), sepsis (22.1%), malaria (8.5%), and diarrhea (7.9%). Common contributors to death were malnutrition (50.5%) and anemia (25.7%). Reviewers were less confident in their causes of death for neonates than older children (P < .05). CONCLUSIONS: Postdischarge mortality frequently occurred in the community in children admitted for suspected sepsis in Uganda. Analyses of the probable causes for these deaths using verbal autopsies suggest potential areas for interventions, focused on early detection of infections, as well as prevention and treatment of underlying contributors such as malnutrition and anemia.