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Abstract Background Centre-based child-care has potential to provide multiple health and development benefits to children, families and societies. With rapid urbanisation, increasing numbers of low-income women work with reduced support from extended family, leaving a child-care vacuum in many low- and middle-income countries. We aimed to understand perceptions of, and demand for, centre-based child-care in Dhaka, Bangladesh among poor, urban households, and test the feasibility of delivering sustainable centre-based child-care. Methods We used sequential mixed methods including a household survey (n = 222) and qualitative interviews with care-givers (n = 16), community leaders (n = 5) and policy-makers (n = 5). We co-produced and piloted a centre-based child-care model over ten-months, documenting implementation. A co-design focus group with mothers, parents’ meetings, and qualitative interviews with child-care centre users (n = 5), non-users (n = 3), ex-users (n = 3) and staff (2) were used to refine the model and identify implementation issues. Results We found 24% (95% CI: 16,37%) of care-givers reported turning-down paid work due to lack of child-care and 84% (95% CI:74, 91%) reported wishing to use centre-based child-care and were willing to pay up to 283 Takka (~$3.30) per month. Adjusted odds of reported need for child-care among slum households were 3.8 times those of non-slum households (95% CI: 1.4, 10). Implementation highlighted that poor households needed free child-care with food provided, presenting feasibility challenges. Meta-inference across quantitative and qualitative findings identified the impact of the urban environment on child-care through long working hours, low social capital and fears for child safety. These influences interacted with religious and social norms resulting in caution in using centre-based child-care despite evident need. Conclusion Sustainable provision of centre-based care that focuses on early childhood development requires subsidy and careful design sensitive to the working lives of poor families, particularly women and must respond to the dynamics of the urban environment and community values. We recommend increased research and policy focus on the evaluation and scale-up of quality centre-based child-care, emphasising early-childhood development, to support low-income working families in urban areas.

Abstract Background Understanding of the relationship between multi-drug resistant tuberculosis and mental health is limited. With growing prevalence of multi-drug resistant tuberculosis, addressing mental ill-health has potential to improve treatment outcomes and well-being. In several low and middle-income contexts hospitalisation during treatment is common. Understanding of the impact on mental ill-health are required to inform interventions for patients with multi-drug resistant tuberculosis. Our aim was to identify the prevalence of comorbid depression among in-patients being treated for multi-drug resistant tuberculosis and to explore their experiences of comorbid disease and the care they received in a large specialist chest hospital in Dhaka, Bangladesh. Methods We conducted a quantitative cross-sectional survey among 150 multi-drug resistant tuberculosis in-patients (new cases = 34%, previously treated = 66%) in 2018. A psychiatrist assessed depression was assessed with the Structured Clinical Interview for Depression (SCID DSM-IV). We used multi-level modelling to identify associations with depression. Experience Bangladeshi researchers conducted qualitative interviews with 8 patients, 4 carers, 4 health professionals and reflective notes recorded. Qualitative data was analysed thematically. Results We found 33.8% (95% CI 26.7%; 41.7%) of patients were depressed. While more women were depressed 39.3% (95% CI 27.6%; 52.4%) than men 30.4% (95% CI 22%; 40.5%) this was not significant. After controlling for key variables only having one or more co-morbidity (adjusted odds ratio [AOR] = 2.88 [95% CI 1.13; 7.33]) and being a new rather than previously treated case (AOR = 2.33 [95% CI 1.06; 5.14]) were associated (positively) with depression. Qualitative data highlighted the isolation and despair felt by patients who described a service predominantly focused on providing medicines. Individual, familial, societal and health-care factors influenced resilience, nuanced by gender, socio-economic status and home location. Conclusions Patients with multi-drug resistant tuberculosis are at high risk of depression, particularly those with co- and multi-morbidities. Screening for depression and psycho-social support should be integrated within routine TB services and provided throughout treatment.

Abstract The epidermal growth factor receptor, EGFR, is frequently activated in lung cancer and glioblastoma by genomic alterations including missense mutations. The different mutation spectra in these diseases are reflected in divergent responses to EGFR inhibition: significant patient benefit in lung cancer, but limited in glioblastoma. Here, we report a comprehensive mutational analysis of EGFR function. We perform saturation mutagenesis of EGFR and assess function of ~22,500 variants in a human EGFR-dependent lung cancer cell line. This approach reveals enrichment of erlotinib-insensitive variants of known and unknown significance in the dimerization, transmembrane, and kinase domains. Multiple EGFR extracellular domain variants, not associated with approved targeted therapies, are sensitive to afatinib and dacomitinib in vitro. Two glioblastoma patients with somatic EGFR G598V dimerization domain mutations show responses to dacomitinib treatment followed by within-pathway resistance mutation in one case. In summary, this comprehensive screen expands the landscape of functional EGFR variants and suggests broader clinical investigation of EGFR inhibition for cancers harboring extracellular domain mutations.

Abstract Background Despite the increased demand for pharmacogenetic (PGx) testing to guide antidepressant use, little is known about how to implement testing in clinical practice. Best–worst scaling (BWS) is a stated preferences technique for determining the relative importance of alternative scenarios and is increasingly being used as a healthcare assessment tool, with potential applications in implementation research. We conducted a BWS experiment to evaluate the relative importance of implementation factors for PGx testing to guide antidepressant use. Methods We surveyed 17 healthcare organizations that either had implemented or were in the process of implementing PGx testing for antidepressants. The survey included a BWS experiment to evaluate the relative importance of Consolidated Framework for Implementation Research (CFIR) constructs from the perspective of implementing sites. Results Participating sites varied on their PGx testing platform and methods for returning recommendations to providers and patients, but they were consistent in ranking several CFIR constructs as most important for implementation: patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and identification of champions. Conclusions This study demonstrates the feasibility of using choice experiments to systematically evaluate the relative importance of implementation determinants from the perspective of implementing organizations. BWS findings can inform other organizations interested in implementing PGx testing for mental health. Further, this study demonstrates the application of BWS to PGx, the findings of which may be used by other organizations to inform implementation of PGx testing for mental health disorders.

Abstract There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best‐worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx‐guided pharmacotherapy for antidepressant management.

Abstract Background Translating pharmacogenetic research findings that have shown clinical efficacy into sustainable, routine clinical care at the institutional level requires strong evidence of improved patient outcomes bolstered by equitable reimbursement and a sound financial analysis. Although extensive research on the clinical value of pharmacogenetics has been completed, adoption into clinical practice lags due to a lack of evidence of clinical effectiveness and limited reimbursement. Methods The Sustainability Working Group within the NHGRI IGNITE I Network conducted an online survey of funded and non-funded IGNITE members to determine which genes they are researching, which have been translated into clinical practice, and how tests are billed. Data from the online surveys was consolidated and analyzed with results being tabulated for key findings. Due to the limited sample size, statistical analysis was forgone and results should be considered directional in nature. Results Fifteen out of twenty (75%) online survey responses were received and analyzed from IGNITE member sites delivering clinical care. Forty different genes were identified as being used for either research or clinical care. Thirty-two different genes were reported as being used clinically, an average of 6.9 genes were reported per site. Twenty-two and twenty-one genes were reported as being billed to third party payers or patients respectively. Although the survey did not ask whether sites submitting for reimbursement received payment, Medicare and Medicaid only reimburse for 6 of the 40 (15%) genes being tested. Of the 40 genes, 18 are rated by CPIC as having A/B level of evidence with the remainder being rated as C/D or having no rating. Approximately 32% more A/B rated genes were being reported clinically than non-A/B. Conclusion Adoption of pharmacogenetic testing continues to lag even at sites where leading experts conduct research and have the capability to report tests clinically. Clinical research that supports CPIC A level of evidence is important for provider and payer support. Adoption of pharmacogentic testing must also be justified financially, reimbursement is one key factor, and more health economic studies are needed in order to capture the value created by preventing drug-gene adverse events, emergency room visits, and hospitalizations.

Abstract Background Oxidative modifications have been observed in lipids and proteins in lipoproteins isolated from women with preeclampsia. Thus, newborns could also be susceptible to this damage directly through their mothers. In this study, we evaluated the oxidative profile of LDL-c and HDL-c lipoproteins isolated from the umbilical cord from newborns born to women with preeclampsia. Methods Thirty newborns born to women with preeclampsia and thirty newborns born to women with healthy pregnancies were included. Lipid-damage biomarkers, including conjugated dienes, lipohydroperoxides and malondialdehyde, were measured. The reduction of nitroblue tetrazolium, formation of dityrosines, and carbonylation of proteins were assessed as indicators of protein damage. The protective activity of paraoxonase-I on HDL-c particles was evaluated. The total antioxidant capacity and lipid profiles were quantified in plasma. Data were analysed using Student’s t-tests and Pearson correlation coefficients. Results Compared with the control group, the preeclampsia group had an increase in the percentage of lipid damage in both lipoproteins. There was an increase of 23.3 and 19.9% for conjugated dienes, 82.4 and 21.1% for lipohydroperoxides, and 103.8 and 51.5% for malondialdehyde in LDL-c and HDL-c, respectively. However, these infants did not show evident damage in protein oxidation. The activity of the enzyme paraoxonase-I was decreased by 36.2%; by contrast, the total antioxidant capacity was increased by 40% (protein) and 28.8% (non-protein). Conclusions The oxidative modifications that occur in HDL-c and LDL-c isolated from newborns from women with preeclampsia are mainly caused by lipoperoxidation processes related to evident paraoxonase-I inactivation. The absence of protein damage is likely linked to an increase in total antioxidant capacity. Therefore, antioxidant support could be helpful in reducing oxidative stress in mother/newborn dyads.

Poor adherence to medication regimens and medical record inconsistencies result in incomplete knowledge of medication therapy in polypharmacy patients. By quantitatively identifying medications in the blood of patients and reconciling detected medications with the medical record, we have defined the severity of this knowledge gap and created a path toward optimizing medication therapy.We validated a liquid chromatography-tandem mass spectrometry assay to detect and/or quantify 38 medications across a broad range of chronic diseases to obtain a comprehensive survey of patient adherence, medical record accuracy, and exposure variability in two patient populations. In a retrospectively tested 821-patient cohort representing U.S. adults, we found that 46% of medications assessed were detected in patients as prescribed in the medical record. Of the remaining medications, 23% were detected, but not listed in the medical record while 30% were prescribed to patients, but not detected in blood. To determine how often each detected medication fell within literature-derived reference ranges when taken as prescribed, we prospectively enrolled a cohort of 151 treatment-regimen adherent patients. In this cohort, we found that 53% of medications that were taken as prescribed, as determined using patient self-reporting, were not within the blood reference range. Of the medications not in range, 83% were below and 17% above the lower and upper range limits, respectively. Only 32% of out-of-range medications could be attributed to short oral half-lives, leaving extensive exposure variability to result from patient behavior, undefined drug interactions, genetics, and other characteristics that can affect medication exposure.This is the first study to assess compliance, medical record accuracy, and exposure as determinants of real-world treatment and response. Variation in medication detection and exposure is greater than previously demonstrated, illustrating the scope of current therapy issues and opening avenues that warrant further investigation to optimize medication therapy.

Reducing the scale of biochemical reactions is becoming commonplace. Examples include the screening of large libraries of chemical compounds or gene sequences. These applications demand the ability to transfer sub-microliter volumes of fluid. To this end, we have modified a Hamilton® MICROLAB® 2200 with high-speed solenoids and a liquid pressurization system to modulate volume delivery down to the nanoliter level. Additional modifications include the use of sapphire-tipped dispensing nozzles and a high-resolution substage to assist in the construction of DNA microarrays. Techniques for characterizing the dispensed volume are presented.

Abstract Background RAF family activating fusions have been described as a potentially targetable molecular finding in a subset of soft tissue sarcomas. To further expand upon the landscape of this genetic feature, we describe a novel MTAP-RAF1 activating fusion identified in a S100 positive soft tissue sarcoma. Case presentation A 51 year old man underwent excision of a soft tissue mass in his foot. Pathology revealed a spindle cell neoplasm with S100 positivity, ultimately classified as a soft tissue sarcoma, not otherwise specified. Comprehensive molecular profiling was performed to help establish the diagnosis and revealed a novel MTAP-RAF1 fusion that includes the tyrosine kinase domain of RAF1. Conclusions Our report adds to the spectrum of fusion-driven RAF activation observed in soft tissue sarcomas and lends additional evidence that RAF activation plays an important role in some soft tissue sarcomas. Identification of novel fusions involving the MAPK/ERK pathway in sarcomas may provide new avenues for precision medicine strategies involving targeted kinase inhibitors.

Abstract Background Almost three quarters of non-communicable disease (NCD) deaths, and 82% of premature NCD deaths, occur in low- and middle-income countries. Bangladesh has an estimated 7 million hypertensives and 10 million diabetics, and primary care is struggling to respond. Our aim was to develop and support implementation of a diabetes and hypertension case management package, and assess its appropriateness, feasibility and acceptability in two NCD clinics within two primary-care centres in Bangladesh. Methods We used a convergent mixed methods design. We first assessed the level of appropriate hypertension and cardiovascular disease patient management, based on a composite outcome indicator using data from patients’ treatment cards. Appropriate management was primarily informed by International Diabetes Federation (IDF) and World Health Organisation (WHO) guidelines. We then performed qualitative in-depth interviews with doctors and patients to explain these quantitative findings and to understand the challenges to achieving appropriate patient management in the NCD clinics. Results Eighty-one newly diagnosed patients were recruited. Over 3 months, 53.1% (95% CI 42.3% to 63.6%) of patients were appropriately managed. We found incomplete diagnosis (especially missing hypertension diagnosis alongside diabetes) and non-provision of follow-up appointments were the main causes of the relatively low level of appropriate management. We conducted interviews with 11 patients and 8 health professionals and found a shortage of human resources, reporting materials, available drugs and diagnostic equipment. This undermined patients’ willingness to attend clinics and doctors’ willingness to offer follow-ups. Hands-on skill-building training was valuable in increasing doctors’ competence for appropriate management, but was seen as a novel training method and faced constraints to implementation. Conclusions A clinical guide, skill-based training and recording package can be implemented in routine primary care and can lead to appropriate management of around half of diabetic and hypertensive patients in a low-income country. However, considerable health systems challenges must be addressed before more patients can be managed appropriately.

Abstract Background Oxidative stress causes biochemical changes in lipids and proteins; these changes can induce damage to the vascular endothelium and create maternal complications that are characteristic of preeclampsia. In this study, we evaluated the oxidative profile of lipoproteins isolated from women with preeclampsia. Methods Thirty women diagnosed with preeclampsia and thirty women without preeclampsia were included in the study. Lipid-damage biomarkers, including conjugated dienes, lipohydroperoxides and malondialdehyde, were measured. The reduction of nitroblue tetrazolium, the formation of dityrosines, and the carbonylation of proteins were assessed as indicators of protein damage. The protective activity of HDL-c was evaluated by the paraoxonase-I activity present on the HDL-c particles. Serum lipid profiles were also quantified in both groups. Data were analysed using Student’s t test and the Pearson correlation coefficient. Results Our results demonstrated in PE women evident oxidative changes in the lipids and proteins in HDL-c and LDL-c particles and the activity of the antioxidant enzyme PON-I decreased 59.9%. HDL-c exhibited self-defence, as demonstrated by the negative correlation between paraoxonase-I activity and the formation of lipohydroperoxides in HDL-c (r = −0.3755, p

A 1-D ice cover model was developed to predict and constrain drivers of long-term ice thickness trends in chemically stratified lakes of Taylor Valley, Antarctica. The model is driven by surface radiative heat fluxes and heat fluxes from the underlying water column. The model successfully reproduced 16 a (between 1996 and 2012) of ice thickness changes for the west lobe of Lake Bonney (average ice thickness = 3.53 m) and Lake Fryxell (average ice thickness = 4.22 m). Long-term ice thickness trends require coupling with the thermal structure of the water column. The heat stored within the temperature maximum of lakes exceeding a liquid water column depth of 20 m can either impede or facilitate ice thickness change depending on the predominant climatic trend (cooling or warming). As such, shallow (