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Introduction: Transitional care programs (i.e. interventions delivered both in hospital and in primary care), could increase continuity and consequently quality of care. However, limited studies on the effect of these programs on Adverse Drug Events (ADEs) post-discharge are available. Therefore, the aim of this study was to investigate the effect of a transitional pharmaceutical care program on the occurrence of ADEs 4 weeks post-discharge.Methods: A multicentre prospective before-after study was performed in a general teaching hospital, a university hospital and 49 community pharmacies. The transitional pharmaceutical care program consisted of: teach-back to the patient at discharge, a pharmaceutical discharge letter, a home visit by a community pharmacist and a clinical medication review by both the community and the clinical pharmacist, on top of usual care. Usual care consisted of medication reconciliation at admission and discharge by pharmacy teams. The primary outcome was the proportion of patients who reported at least 1 ADE 4 weeks post-discharge. Multivariable logistic regression was used to adjust for potential confounders.Results: In total, 369 patients were included (control: n = 195, intervention: n = 174). The proportion of patients with at least 1 ADE did not statistically significant differ between the intervention and control group (general teaching hospital: 59% vs. 67%, ORadj 0.70 [95% CI 0.38–1.31], university hospital: 63% vs 50%, OR adj 1.76 [95% CI 0.75–4.13]).Conclusion: The transitional pharmaceutical care program did not decrease the proportion of patients with ADEs after discharge. ADEs after discharge were common and more than 50% of patients reported at least 1 ADE. A process evaluation is needed to gain insight into how a transitional pharmaceutical care program could diminish those ADEs.

This study aimed to determine whether published pharmacokinetic (PK) models can adequately predict the PK profile of imatinib in a new indication, such as coronavirus disease 2019 (COVID-19). Total (bound + unbound) and unbound imatinib plasma concentrations obtained from 134 patients with COVID-19 participating in the CounterCovid study and from an historical dataset of 20 patients with gastrointestinal stromal tumor (GIST) and 85 patients with chronic myeloid leukemia (CML) were compared. Total imatinib area under the concentration time curve (AUC), maximum concentration (C max ) and trough concentration (C trough ) were 2.32-fold (95% confidence interval [CI] 1.34-3.29), 2.31-fold (95% CI 1.33-3.29), and 2.32-fold (95% CI 1.11-3.53) lower, respectively, for patients with CML/GIST compared with patients with COVID-19, whereas unbound concentrations were comparable among groups. Inclusion of alpha1-acid glycoprotein (AAG) concentrations measured in patients with COVID-19 into a previously published model developed to predict free imatinib concentrations in patients with GIST using total imatinib and plasma AAG concentration measurements (AAG-PK-Model) gave an estimated mean (SD) prediction error (PE) of -20% (31%) for total and -7.0% (56%) for unbound concentrations. Further covariate modeling with this combined dataset showed that in addition to AAG; age, bodyweight, albumin, CRP, and intensive care unit admission were predictive of total imatinib oral clearance. In conclusion, high total and unaltered unbound concentrations of imatinib in COVID-19 compared to CML/GIST were a result of variability in acute phase proteins. This is a textbook example of how failure to take into account differences in plasma protein binding and the unbound fraction when interpreting PK of highly protein bound drugs, such as imatinib, could lead to selection of a dose with suboptimal efficacy in patients with COVID-19.

BACKGROUND: Interpatient variability in cytochrome P450 2D6 (CYP2D6) enzyme activity alters the serum concentrations of most psychotropics, which often have narrow therapeutic indices. Therefore, preemptive knowledge of CYP2D6 activity is desired. However, accessible indicators for deficient CYP2D6 activity are necessary because genotyping all patients prescribed CYP2D6 metabolized drugs is often not feasible or cost-effective. METHODS: In this study, the predictive value of the ratio between a CYP2D6 substrate and its metabolite, known as the metabolic ratio (MR), the dose-corrected serum concentration of substrate (CDR), and the dose-corrected sum concentration of substrate and metabolite (Sum CDR) of venlafaxine, risperidone, aripiprazole, and nortriptyline were determined to predict the CYP2D6 poor metabolizer (PM) phenotype. The area-under-the-receiver operator characteristic curve, as well as the sensitivity, specificity, and positive and negative predictive values of the optimal thresholds, were calculated. RESULTS: Although the MR, CDR, and Sum CDR all predicted the CYP2D6 PM phenotype, the predictive value of the MR was most robust for venlafaxine and aripiprazole, and the Sum CDR was inferior for all 3 psychotropics. MRs of venlafaxine, risperidone, and aripiprazole, and CDR of nortriptyline showed an area-under-the-receiver operator characteristics (95% confidence interval) of 97.2% (94.7%-99.6%), 93.0% (88.8%-97.2%), 97.8% (95.4%-100.0%), and 85.6% (78.0%-93.1%), respectively. Thresholds of the log(MR) of ≥0.1 for venlafaxine, ≥0.0 for risperidone, and ≥1.5 for aripiprazole, and log(CDR) ≥0.5 for nortriptyline produced >92% sensitivity and >64% specificity. CONCLUSIONS: If therapeutic drug monitoring is available, the thresholds presented here could serve as a diagnostic tool for the CYP2D6 PM phenotype of psychiatric patients prescribed the aforementioned psychotropic medications.

Background A quality improvement (QI) collaborative approach to enhancing integrated HIV-Tuberculosis (TB) services may be effective in scaling up and improving the quality of service delivery. Little is known of the role of organizational contextual factors (OCFs) in influencing the success of QI collaboratives. This study aims to determine which OCFs were associated with improvement in a QI collaborative intervention to enhance integrated HIV-TB services delivery. Methods This is a nested sub-study embedded in a cluster-randomized controlled trial. Sixteen nurse supervisors (clusters) overseeing 40 clinics were randomized (1:1) to receive QI training and mentorship, or standard of care support (SOC). In the QI arm, eight nurse supervisors and 20 clinics formed a “collaborative” which aimed to improve HIV-TB process indicators, namely HIV testing, TB screening, isoniazid preventive therapy (IPT) initiations, viral load testing, and antiretroviral therapy for TB patients. OCFs measured at baseline were physical infrastructure, key staff, flexibility of clinic hours, monitoring data for improvement (MDI), and leadership support. Surveys were administered to clinic staff at baseline and month 12 to assess perceptions of supportiveness of contexts for change, and clinic organization for delivering integrated HIV-TB services. Linear mixed modelling was used to test for associations between OCFs and HIV-TB process indicators. Results A total of 209 clinic staff participated in the study; 97 (46.4%) and 112 (53.6%) from QI and SOC arms, respectively. There were no differences between the QI and SOC arms scores achieved for physical infrastructure (78.9% vs 64.7%; p = 0.058), key staff (95.8 vs 92; p = 0.270), clinic hours (66.9 vs 65.5; p = 0.900), MDI (63.3 vs 65; p = 0.875, leadership support (46.0 vs 57.4; p = 0.265), and perceptions of supportiveness of contexts for change (76.2 vs 79.7; p = 0.128 and clinic organization for delivering integrated HIV-TB services (74.1 vs 80.1; p = 0.916). IPT initiation was the only indicator that was significantly improved in the parent study. MDI was a significantly associated with increasing IPT initiation rates [beta coefficient (β) = 0.004; p = 0.004]. Discussion MDI is a practice that should be fostered in public health facilities to increase the likelihood of success of future QI collaboratives to improve HIV-TB service delivery. Trial registration Clinicaltrials.gov, NCT02654613. Registered 01 June 2015.

Despite being standard of care, gaps in HIV-TB service delivery are present. Quality Improvement methods are effective in uncovering health systems weaknesses that impede efficient delivery of integrated HIV-TB services., Key Findings The quality improvement (QI) intervention was able to guide clinic staff in developing simple but effective change interventions, using resources already available, to improve HIV-TB integrated service delivery.The QI intervention implemented dramatically improved isoniazid preventive therapy initiation rates among eligible HIV patients and resulted in moderate improvements in HIV testing and screening, TB screening, and viral load monitoring. Key Implications Program managers should ensure that all categories of health care workers from all levels of the health care system are included in QI workshops or learning sessions to harness the knowledge and experiences of all role players working within the system.QI implementers should consider adopting a combination approach to improvement interventions, such as QI training combined with mentorship, collaborative learning, and data QI activities.To strengthen and ensure the success of QI interventions, senior-level program managers should consider allocating resources (human, financial, and infrastructure) dedicated to data QI for a sustainable and effective QI program., Introduction: In South Africa, mortality rates among HIV-TB coinfected patients are among the highest in the world. The key to reducing mortality is integrating HIV-TB services, however, a generalizable implementation method and package of tested change ideas to guide the scale-up of integrated HIV-TB services are unavailable. We describe the implementation of a quality improvement (QI) intervention, health systems’ weaknesses, change ideas, and lessons learned in improving integrated HIV-TB services. Methods: Between December 1, 2016, and December 31, 2018, 8 nurse supervisors overseeing 20 primary health care (PHC) clinics formed a learning collaborative to improve a set of HIV-TB process indicators. HIV-TB process indicators comprised: HIV testing services (HTS), TB screening among PHC clinic attendees, isoniazid preventive therapy (IPT) for eligible HIV patients, antiretroviral therapy (ART) for HIV-TB coinfected patients, and viral load (VL) testing at month 12. Routine HIV-TB process data were collected and analyzed. Results: Key change interventions, generated by health care workers, included: patient-flow redesign, daily data quality checks; prior identification of patients eligible for IPT and VL testing. Between baseline and post-QI intervention, IPT initiation rates increased from 15.9% to 76.4% (P=.019), HTS increased from 84.8% to 94.5% (P=.110), TB screening increased from 76.2% to 85.2% (P=.040), and VL testing increased from 61.4% to 74.0% (P=.045). ART initiation decreased from 95.8% to 94.1% (P=.481). Discussion: Although integrating HIV-TB services is standard guidance, existing process gaps to achieve integration can be closed using QI methods. QI interventions can rapidly improve the performance of processes, particularly if baseline performance is low. Improving data quality enhances the success of QI initiatives.

Purpose: Safety, efficacy, and exploratory biomarker analyses were evaluated in patients with advanced HER2-negative germline breast cancer susceptibility gene (gBRCA)-associated breast cancer enrolled in the BROCADE3 trial who received crossover veliparib monotherapy after disease progression on placebo plus carboplatin/paclitaxel. Patients and Methods: Eligible patients (N = 513) were randomized 2:1 to veliparib plus carboplatin/paclitaxel or placebo plus carboplatin/paclitaxel; patients had variable platinum-free intervals (PFI) at progression. In the placebo arm, patients were eligible to receive crossover veliparib monotherapy (300–400 mg twice daily continuous). Antitumor activity and adverse events were assessed during crossover veliparib treatment. BRCA reversion mutations at crossover were analyzed retrospectively using next-generation sequencing on plasma circulating tumor DNA (ctDNA). Results: Seventy-five patients in the placebo plus carboplatin/paclitaxel arm received ≥1 dose of crossover veliparib postprogression (mean treatment duration: 154 days). Eight of 50 (16%) patients with measurable disease had a RECIST v1.1 response. Activity was greater in patients with PFI ≥180 days compared with Conclusions: Crossover veliparib monotherapy demonstrated limited antitumor activity in patients who experienced disease progression on placebo plus carboplatin/paclitaxel. PFI appeared to affect veliparib activity. BRCA reversion mutations may promote cross-resistance and limit veliparib activity following progression on platinum.

Maximal oxygen uptake (VO2max) is a direct measure of human cardiorespiratory fitness and is associated with health. However, the molecular determinants of interindividual differences in baseline (intrinsic) VO2max, and of increases of VO2max in response to exercise training (ΔVO2max), are largely unknown. Here, we measure ~5,000 plasma proteins using an affinity-based platform in over 650 sedentary adults before and after a 20-week endurance-exercise intervention and identify 147 proteins and 102 proteins whose plasma levels are associated with baseline VO2max and ΔVO2max, respectively. Addition of a protein biomarker score derived from these proteins to a score based on clinical traits improves the prediction of an individual’s ΔVO2max. We validate findings in a separate exercise cohort, further link 21 proteins to incident all-cause mortality in a community-based cohort and reproduce the specificity of ~75% of our key findings using antibody-based assays. Taken together, our data shed light on biological pathways relevant to cardiorespiratory fitness and highlight the potential additive value of protein biomarkers in identifying exercise responsiveness in humans. Plasma proteomic profiles from 650 adult humans are measured before and after a 20-week exercise regimen to determine proteins associated with baseline cardiorespiratory fitness and improvements in response to exercise.

Surgery is the only potential curative option of CRLM if resectable. The curative approach in patients over 70 years old is challenging mainly because of comorbidities and other geriatric syndromes. Herein, we report outcomes of older patients with resectable CRLM in our center. We retrospectively analyzed characteristics and outcomes of older patients with CRLM operated at “Centre Hospitalier de l’Université de Montréal” (CHUM) between 2010 and 2019. We identified 210 patients aged ≥70 years with a median age of 76 (range: 70–85). CRLM were synchronous in 56% of patients. Median disease-free survival (DFS) was 41.3 months. Median overall survival (OS) was 62.2 months and estimated 5-year survival rate was 51.5% similar to those of younger counterparts. Patients with metachronous CRLM had a trend to a higher OS compared to those with synchronous disease (67.2 vs. 58.7 months, p = 0.42). Factors associated with lower survival in the multivariate analysis were right-sided tumors and increased Charlson Comorbidity index (CCI). Survival outcomes of patients aged ≥70 years were comparable to those of younger patients and those reported in the literature. Age should not be a limiting factor in the curative management of older patients with resectable CRLM.

Contains fulltext : 244635.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To investigate the efficacy of 16-week treatment with etanercept (ETN) in patients with suspected nonradiographic axial spondyloarthritis (SpA). METHODS: Tumor necrosis factor inhibitor-naive patients with inflammatory back pain with at least 2 SpA features and high disease activity (Bath Ankylosing Spondylitis Disease Activity Index score ≥4), without the requirement of a positive finding on magnetic resonance imaging (MRI) of the sacroiliac (SI) joint and/or elevated C-reactive protein (CRP) level, were randomized (1:1) to receive ETN (n = 40) or placebo (n = 40) for 16 weeks and subsequently were followed up for a further 8 weeks (to 24 weeks from baseline) without study medication. The primary end point was the Assessment of SpondyloArthritis international Society 20 (ASAS20) response at 16 weeks. Secondary end points included the Ankylosing Spondylitis Disease Activity Score (ASDAS) and changes in disease parameters, including the Bath Ankylosing Spondylitis Metrology Index (BASMI), CRP level, erythrocyte sedimentation rate (ESR), and Spondyloarthritis Research Consortium of Canada index scores (MRI of the SI joint), after 16 and 24 weeks. RESULTS: Patient characteristics at baseline were comparable between the ETN and placebo groups. At 16 weeks, there was no significant difference in the percentage of patients exhibiting ASAS20 response between the ETN group (6 patients [16.7%]) and the placebo group (4 patients [11.1%]) (relative risk 0.7 [95% confidence interval 0.2-2.2], P = 0.5). Only the ESR showed more improvement in the ETN group compared to the placebo group at 16 weeks (decreases of 2.2 mm/hour and 1.4 mm/hour, respectively), but the difference did not reach statistical significance. Between 16 and 24 weeks, without study medication, the BASMI, CRP level, and ESR had worsened to a greater extent in the ETN group compared to the placebo group, with the difference being significant for the CRP level. CONCLUSION: This study shows that in patients with suspected nonradiographic axial SpA with high disease activity but without the requirement of a positive finding on SI joint MRI and/or elevated CRP level, treatment with ETN is not effective.

Objective: Neurocognitive deficits are at the heart of explanatory models of attention-deficit/hyperactivity disorder (ADHD), and lead to significant impairments in daily life. Determining the dosing effects of methylphenidate (MPH) on a broad range of neurocognitive functions and investigating possible impairing effects of high doses is therefore important. Method: Placebo-controlled trials were included that investigated MPH dosing effects on neurocognitive functions in children and adolescents (aged 5–18 years) diagnosed with ADHD. Effect sizes (standardized mean differences [SMDs]) were calculated for different neurocognitive functions (baseline speed, variability in responding, nonexecutive memory and executive memory, inhibitory control, and cognitive flexibility) and, if available, for ADHD symptoms. Meta-regression analysis were used to investigate linear effects of dose (mg/kg/dose), and separate meta-analyses compared SMDs for 3 MPH dose ranges: low (0.10−0.30 mg/kg/dose), medium (0.31−0.60 mg/kg/dose), and high (0.61−1.00 mg/kg/dose). Results: A total of 31 studies fulfilled inclusion criteria, comprising 804 children with ADHD. Methylphenidate had beneficial effects on all neurocognitive functions (d = 0.20−0.73). Significant linear dosing effects were found for ADHD symptoms and lower-order neurocognitive functions (baseline speed, variability in responding, nonexecutive memory), with greater enhancement of functioning with increasing dose. No dosing effects were found for higher-order neurocognitive functions (executive memory, inhibitory control, and cognitive flexibility). No detrimental effects of MPH were found on any of the investigated functions. Conclusion: Methylphenidate was superior to placebo in improving ADHD symptoms and a broad range of neurocognitive functions; however, effects sizes regarding the effects of dose vary substantially between functions. Our data highlight the importance of considering both neurocognitive and symptomatic aspects of ADHD in clinical practice.

OBJECTIVE To review the outcome of dogs that underwent Zurich cementless total hip arthroplasty (Z-THA) for the repair of acute and chronic capital physeal fractures (CPF) and document the CPF-related hip remodeling. STUDY DESIGN Retrospective study. SAMPLE POPULATION Fifty-three Z-THA in 53 dogs. METHODS Medical records of dogs (2006-2019) that underwent Z-THA for CPF management were reviewed. Dogs were divided into two groups on the basis of the days elapsed between CPF diagnosis and Z-THA, acute (≤30 days) and chronic (>30 days). Hip remodeling variables were determined from preoperative radiographs or intraoperatively. Descriptive statistics were performed, and the complication rates, outcome, and coxofemoral remodeling were recorded. Comparisons of remodeling variables and rates between groups were performed by using Fisher's exact test. RESULTS In total, 23 of 53 (43.4%) cases were acute, and 30 of 53 (56.6%) cases were chronic. There was no difference in the femoral remodeling rates between the acute and chronic groups (P = .184), whereas acetabular remodeling was more prevalent in the chronic group (P

Contains fulltext : 235681.pdf (Publisher’s version ) (Open Access) AIMS: Uterine fibroids are benign tumours that cause various complaints. These complaints may significantly compromise quality of life, necessitating a clinical intervention in 25-50% of the affected women. Hysterectomy, myomectomy or embolization may offer symptomatic relief, but are costly, include a recovery period, can cause serious side-effects, sometimes fail to treat symptoms completely and are not always desired by patients. Ulipristal is a conservative long-term treatment that has a fibroid-volume decreasing effect, acceptable side-effects while preserving fertility and may be an alternative to surgical alternatives. Currently, ulipristal is investigated by the European Medicine Agency and suspended from marketing authorization because it may cause drug-induced liver injury (DILI). However, many drugs can cause severe DILI and prospective studies estimate 14-19 DILI cases/100 000 people. METHODS: This overview will discuss the risk-benefit balance between ulipristal and DILI, describe the safety-efficacy balance of ulipristal and its alternative treatments and the arguments that led to the suspension of its marketing authorization. RESULTS: Ulipristal may be associated with DILI resulting in a risk of severe liver injury in 1.5:100 000 patients and fatal liver injury in 0.1:100 000 patients. This risk needs to be weighed against the higher mortality risk of >1:1000 and higher incidence of severe complications after surgery. CONCLUSION: The DILI risk of ulipristal is considerably lower than that of other medicines that are not suspended, nor need additional safety measures. When evaluating drugs and drug safety, risks that apply to the alternative nonpharmacological treatment options should be taken into consideration.

Background Fluoropyrimidines are used in chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. DPYD*2A polymorphism is one of the most studied variants. The study objective was to document the impact of implementing this test in routine clinical practice. Methods We retrospectively performed chart reviews of all patients who tested positive for a heterozygous or homozygous DPYD*2A mutation in samples obtained from patients throughout the province of Quebec, Canada. Results During a period of 17 months, 2,617 patients were tested: 25 patients tested positive. All were White. Twenty-four of the 25 patients were heterozygous (0.92%), and one was homozygous (0.038%). Data were available for 20 patients: 15 were tested upfront, whereas five were identified after severe toxicities. Of the five patients confirmed after toxicities, all had grade 4 cytopenias, 80% grade ≥3 mucositis, 20% grade 3 rash, and 20% grade 3 diarrhea. Eight patients identified with DPYD*2A mutation prior to treatment received fluoropyrimidine-based chemotherapy at reduced initial doses. The average fluoropyrimidine dose intensity during chemotherapy was 50%. No grade ≥3 toxicities were observed. DPYD*2A test results were available in an average of 6 days, causing no significant delays in treatment initiation. Conclusion Upfront genotyping before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. The administration of chemotherapy at reduced doses appears to be safe in patients heterozygous for DPYD*2A. Implications for Practice Fluoropyrimidines are part of chemotherapy combinations for multiple cancers. Deficient dihydropyrimidine dehydrogenase activity can lead to severe life-threatening toxicities. This retrospective analysis demonstrates that upfront genotyping of DPYD before fluoropyrimidine-based treatment is feasible in clinical practice and can prevent severe toxicities and hospitalizations without delaying treatment initiation. This approach was reported previously, but insufficient data concerning its application in real practice are available. This is likely the first reported experience of systematic DPYD genotyping all over Canada and North America as well.

OBJECTIVE: This study investigated whether improvements in working memory, reaction time, lapses of attention, interference control, academic motivation, and perceived competence mediated effects of methylphenidate on math performance.METHOD: Sixty-three children (ADHD diagnosis; methylphenidate treatment; age 8-13; IQ > 70) were randomly allocated to a 7-day methylphenidate or placebo treatment in this double-blind placebo-controlled crossover study and compared with 67 controls. Data were collected at schools and analyzed using mixed-model analysis. Methylphenidate was hypothesized to improve all measures; all measures were evaluated as potential mediators of methylphenidate-related math improvements.RESULTS: Controls mostly outperformed the ADHD group. Methylphenidate did not affect measures of cognitive functioning ( p = .082-.641) or academic motivation ( p = .199-.865). Methylphenidate improved parent ratings of their child's self-perceived competence ( p < .01), which mediated methylphenidate efficacy on math productivity.CONCLUSION: These results question the necessity of improvements in specific cognitive and motivational deficits associated with ADHD for medication-related academic improvement. They also stimulate further study of perceived competence as a mediator.

Investigator-initiated clinical trials are crucial for improving quality of care for children and pregnant women as they are often excluded from industry-initiated trials. However, trials have become increasingly time-consuming and costly since the EU Clinical Trial Directive entered into force in 2001. This directive made compliance with ICH-Good Clinical Practice Guidelines (ethical and quality standard for conducting human subject research) mandatory for all clinical trials, regardless of its risk-classification. By discussing two investigator-initiated, ‘low-risk’ drug trials, we aim to illustrate that compliance with all GCP requirements makes trials very laborious and expensive, while a clear rationale is missing. This discourages clinical researchers to start and carry out investigator-initiated research. However, the forthcoming EU Clinical Trial Regulation (No 536/2014) seems to provide a solution as it allows for less stringent rules for low-risk trials. We want to raise awareness for these developments in both the clinical research community and the European and national regulatory authorities. Implementation of this forthcoming Regulation regulatory policies should be done in such a way that investigator-initiated trials evaluating standard care interventions will become more feasible. This will allow us to obtain evidence on optimal and safe treatments, especially for groups that are underrepresented in medical research. What is Known• Investigator-initiated trials are indispensable for improving care for children and pregnant women as they are often excluded from industry-initiated trials• Trials have become increasingly time-consuming and costly because of mandatory compliance with ICH-GCP guidelines What is New• The forthcoming EU Clinical Trial Regulation allows less stringent rules for low-risk trials• The national legislator and regulatory authorities should recognize the importance of this opportunity and implement the Regulation in such a way that investigator-initiated trials will become more feasible

Background Despite policies and guidelines recommending integration of health services in South Africa, provision of maternal and child health services remains fragmented. This study evaluated a rapid, scaleable, quality improvement (QI) intervention to improve integration of maternal and child health and HIV services at a primary health level, in KwaZulu-Natal, South Africa. Methods A three-month intervention comprised of six QI mentoring visits, learning sessions with clinic staff to share learnings, and a self-administered checklist aimed to assist health workers monitor and implement an integrated package of health services for mothers and children. The study evaluated 27 clinics in four sub-districts using a stepped-wedge design. Each sub-district received the intervention sequentially in a randomly selected order. Five waves of data collection were conducted in all participating clinics between December 2016–February 2017. A multi-level, mixed effects logistic regression was used to account for random cluster fixed time and group effects using Stata V13.1. Results Improvements in some growth monitoring indicators were achieved in intervention clinics compared to control clinics, including measuring the length of the baby (77% vs 63%; p = 0.001) and health workers asking mothers about the child’s feeding (74% vs 67%; p = 0.003), but the proportion of mothers who received feeding advice remained unchanged (38% vs 35%; p = 0.48). Significantly more mothers in the intervention group were asked about their baby’s health (44% vs 36%; p = 0.001), and completeness of record keeping improved (40% vs 26%; I = p = 0.009) and family planning (33.5% vs 19.5%; p Conclusion This robust evaluation shows significant improvements in coverage of some services, but the QI intervention was unable to achieve the substantial changes required to provide a comprehensive package of services to all mothers and children. We suggest the QI process be adapted to complex under-resourced health systems, building on the strengths of this approach, to provide workable health systems strengthening solutions for scalable implementation. Trial registration ClinicalTrials.gov NCT04278612. Date of Registration: February 19, 2020. Retrospectively registered.

Background: Adequate pre-hospital trauma triage is crucial to enable optimal care in inclusive trauma systems. Transport of children in need of specialised trauma care to lower-level trauma centres is associated with adverse patient outcomes. We aimed to evaluate the diagnostic accuracy of paediatric field triage based on patient destination and triage tools. Methods: We did a multisite observational study (P2-T2) of all children (aged

This study was conducted to assess raw milk bacterial loads and micro-organisms associated with milk handling practices and raw milk chain in the North-western region of Rwanda. A multistage sampling method was used to collect sixty-seven raw milk samples that were analyzed for milk quality at four stages of the raw milk chain: dairy farmers, milk hawkers, milk collection centres (MCC) and milk kiosks. Total bacterial counts (TBC) at different stages of the chain were determined and microorganisms were isolated. A questionnaire was distributed to gather information on factors and milk handling practices that influence milk quality at farm level. The study revealed a TBC mean values of 1.2 × 106 CFU/ml (dairy farmers), 2.6 × 107 CFU/ml (milk hawkers), 1.5 × 106 CFU/ml (MCC) and 6.9 × 106 CFU/ml (kiosks/restaurants). The prevalent micro-organisms were: Escherichia coli (E. coli), 26.9%; Salmonella spp., 16.4%; Streptococcus spp., 16.4%; coagulase- negative staphylococci (CNS), 14.9%. Bacterial load was highly associated with containers used for milk transport, cleaning time of milk containers and source of water used to clean containers. It is, therefore, highly recommended that all concerned parties in the raw milk value chain improve their milk handling and storage practices. Key words: Bacterial contamination, milk handling, milk quality, north-western Rwanda, raw milk.

Background When gastric pull-up is unsuccessful or unsuitable for total esophageal reconstruction, a supercharged pedicled jejunum can be used to reestablish gastrointestinal continuity. The authors reviewed their technique and outcomes of the supercharged pedicled jejunum for total esophageal reconstruction. Methods A retrospective review of a prospectively maintained database was performed of 100 patients who underwent supercharged pedicled jejunum for total esophageal reconstruction between 2000 and 2017 at the Texas Medical Center. Patient characteristics, technical details, and outcomes were analyzed. Results Mean patient age was 59.5 ± 11.4 years. Forty-two patients (42 percent) had surgical complications (18 percent at the recipient site, 13 percent at the donor site, and 11 percent at both). Medical complications occurred in 28 patients (28 percent). A major surgical complication occurred in 20 patients (20 percent). The average length of stay was 15 days (range, 6 to 152 days). At last follow-up, 20 patients (20 percent) had metastatic disease and six (6 percent) had local recurrence. Fifty-four patients (54 percent) died during the follow-up period. Of 79 patients with follow-up longer than 6 months, 68 (86 percent) tolerated a solid or soft oral diet, with a 16 percent tube feed-dependence rate. Overall survival at 1, 3, and 5 years was 78.8, 53.7, and 33.1 percent, respectively. The median survival time was 38.7 months. Conclusions The authors present their experience with 100 supercharged pedicled jejunums for total esophageal reconstruction. Functional outcomes are comparable to, or better than, other salvage modalities. With careful multidisciplinary planning and meticulous, well-orchestrated surgical technique, swallowing function can be restored to provide quality of life in patients with few remaining surgical options.

We develop an epidemionomic model that jointly analyzes the health and economic responses to the COVID-19 crisis and to the related containment and public health policy measures implemented in Luxembourg. The model has been used to produce nowcasts and forecasts at various stages of the crisis. We focus here on two key moments in time, namely the deconfinement period following the first lockdown, and the onset of the second wave. In May 2020, we predicted a high risk of a second wave that was mainly explained by the resumption of social life, low participation in large-scale testing, and reduction in teleworking practices. Simulations conducted 5 months later reveal that managing the second wave with moderately coercive measures has been epidemiologically and economically effective. Assuming a massive third (or fourth) wave will not materialize in 2021, the real GDP loss due to the second wave will be smaller than 0.4 percentage points in 2020 and 2021.

Background: During cocaine withdrawal, transient depressive symptoms that do not meet the criteria for depression, but promote relapse, are frequently observed. Their temporality could evoke a role of dopamine, especially since the underlying mechanism of these depressive symptoms is not well understood. We hypothesized that variation in the dopaminergic activity profile, modeled from clinical markers, could be implicated in the development of depressive symptoms during cocaine withdrawal.Methods: We compared patients reporting depressive symptoms (RDS+) or not (RDS–) during cocaine withdrawal. We evaluated dopaminergic activity through indirect clinical markers based on the known dopaminergic behaviors. A combined criterion was constructed for hyper and hypo dopaminergic models according to the O'Brien method and illustrated by the Hedges' effect-size and forest-plot graph. A multidimensional factorial analysis was carried out to determine which parameters discriminate RDS+/RDS– patients.Results: 313 patients were included, and 77% reported depressive symptoms during cocaine withdrawal. Hyperdopaminergic variables used to discriminate the two groups had a large overall effect size (−0.669) and included psychotic symptoms (−0.524), hallucinations (−0.548), and delusions (−0.528). The overall effect of the hypodopaminergic component was considerable (−0.604) with a large effect size for the severity of dependence (−0.616), withdrawal symptoms (−0.578), and anhedonia (−0.528). The combined model including hyperdopaminergic and hypodopaminergic components had the largest effect size (−0.785).Conclusion: The dopaminergic activities profile, assessed by indirect clinical markers, seems to characterize patients with depressive symptoms very well during cocaine withdrawal. RDS+ patients reported moreover higher levels of psychotic symptoms and more severe cocaine use disorder than RDS–.

Purpose The coronavirus disease 2019 (COVID-19) pandemic resulted in accelerated market access to remdesivir worldwide. Therefore, data about complications experienced during use of the drug are limited. This is the first published case series (1 case report exists) to describe remdesivir infiltration in 3 patients with COVID-19. Summary In the first case, a 91-year-old woman experienced remdesivir infiltration resulting in edema, hematoma at the area of infiltration; on palpation, the affected area felt cooler than the surrounding areas. Swelling was still present after 6 weeks. In the second case, remdesivir infiltration occurred in a 72-year-old male, resulting in edema, hematoma, and pain at the area of infiltration. The hematoma lasted for 7 days. The third case concerned a 67-year-old woman, in whom remdesivir infiltration led to edema and a small hematoma. The hematoma regressed to a negligible size within 3 days. However, a week after infiltration, redness had reappeared. In 2 cases, the patient was immediately treated with hyaluronidase injections, but no specific treatments were provided in the other case. Conclusion Based on the product information provided by remdesivir’s manufacturer, we believe symptoms and signs observed in the 3 cases may have resulted from the low pH (~4) of the nonbuffered remdesivir solution, although the patients were not formally assessed for caustic injury. Previous experience with other noncytotoxic medications suggests that infusion-specific factors (eg, volume of leaked fluid) and patient-specific factors (eg, advanced age) may have a role in the outcome of remdesivir infiltration. The possibility of symptoms caused by cyclodextrins in the formulation or by intrinsic toxicity of remdesivir warrants exploration.

Background: Acute care services are currently overstretched in many high income countries. Overcrowding also plays a major role in acute care in the Netherlands. In a region of the Netherlands, the general practice cooperative (GPC) and ambulance service have begun to integrate their care, and the rapid and complete transfer of information between these two care organisations is now the basis for delivering appropriate care. The primary aim of this mixed-methods study is to evaluate the Netherlands Triage System (NTS) merger project and answering the question: What is the added value of implementing a digital NTS merger in terms of healthcare use and healthcare costs? A secondary question is: What are the experiences of patients and care professionals in different acute healthcare organisations following implementation of the digital NTS merger? Methods: Patients who made an acute care request during the 12 months before the NTS merge intervention (control period) were compared with matched patients in the 12 months following the start of the NTS merge. Outcomes included difference in healthcare use 30 days after an acute event and patient’ and care professional’ experiences during the intervention period. To assess healthcare costs, we used reference prices updated to 2021. Results: Compared to patients in the control period, patients in the intervention period were hospitalized less often (52.9% vs 64.4%, p = 0.061) and had fewer emergency department (ED) visits (58.7% vs 69.3%, p = 0.074) in the 30 days following the acute care request. The ED costs were significantly lower during the intervention period compared to the control period (p = 0.042). Furthermore, patients in the intervention period were very satisfied overall with the acute care network (4.63 of 5) and care professionals were fairly satisfied with the cooperation to date (2.73 of 4). Conclusion: The Triple Aim for acute care can be met using relatively simple interventions, but medical data merging is a prerequisite for achieving more robust results covering on the various aspects of the Triple Aim. These successes should be communicated so that a common language can be developed that will support the successful further implementation of larger scale initiatives.

Background: Veliparib (Vel) is a potent PARP1/2 inhibitor with demonstrated antitumor activity when administered alone or combined with carboplatin and paclitaxel (C/P). The phase 3 randomized, double-blind, multicenter BROCADE3 study (NCT02163694) evaluated the efficacy and safety of Vel + C/P treatment compared with placebo (Pbo) + C/P treatment in patients (pts) with germline BRCA1/2 mutations and HER2-negative metastatic or locally advanced breast cancer (BC). Vel + C/P significantly prolonged progression-free survival (PFS) compared with Pbo + C/P treatment (14.5 months [mo] vs 12.6 mo, hazard ratio [HR]=0.71 [95% CI: 0.57, 0.88]; P=0.002). Previous studies have identified increased acute hematologic toxicity in response to chemotherapy in pts with BC carrying BRCA1 mutations compared with BRCA2 mutations or wildtype BRCA1/2. Herein we report a subgroup analysis of the efficacy and safety of Vel + C/P treatment in pts with BRCA1- or BRCA2-positive BC. Methods: Pts ≥18 years of age who received ≤2 prior lines of cytotoxic chemotherapy for metastatic disease were randomized 2:1 to receive Vel + C/P or Pbo + C/P: Vel (120 mg PO BID) or Pbo on days -2 to 5, C (AUC 6 IV) on day 1, and P (80 mg/m2 IV) on days 1, 8, and 15 in 21-day cycles. Pts who discontinued C/P in the absence of disease progression could continue receiving Vel or Pbo monotherapy (300-400 mg BID continuous). Subgroup analysis of PFS stratified by BRCA1/2 status was preplanned. The primary endpoint was investigator-assessed PFS. Adverse events (AEs) were graded according to NCI CTCAE version 4.0. Ten pts with both BRCA1 and BRCA2 mutations were excluded from the analyses presented here. Results: In the intent-to-treat population, 256 pts had BRCA1 mutations and 243 pts had BRCA2 mutations. The proportion of as-treated pts with BRCA1 or BRCA2 mutations was comparable between the Vel + C/P (51.4% BRCA1, 48.6% BRCA2) and Pbo + C/P (50.9% BRCA1, 49.1% BRCA2) study arms. Investigator-assessed PFS for the Vel + C/P and Pbo + C/P arms was 14.2 mo vs 12.6 mo, respectively, in the BRCA1 subgroup (HR=0.75 [95% CI: 0.55, 1.03]; P=0.073) and 14.6 mo vs 12.6 mo, respectively, in the BRCA2 subgroup (HR=0.69 [95% CI: 0.50, 0.95]; P=0.021). Safety data in the as-treated population are presented in the Table. Regarding any grade AEs, thrombocytopenia and anemia were slightly more frequent in pts in the BRCA1 subgroup compared with the BRCA2 subgroup, whereas pts in the BRCA2 subgroup experienced slightly more frequent nausea, fatigue, and neuropathy. Conclusions: Globally, there was no clinically relevant difference in toxicity between BRCA1 and BRCA2 subgroups. Comparisons between treatment arms were generally consistent with findings in the overall study population, with more frequent thrombocytopenia and anemia of any grade reported in the Vel + C/P arm within both the BRCA1 and BRCA2 subgroups. Vel + C/P treatment improved PFS similarly in both BRCA1 and BRCA2 subgroups over C/P alone. BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)Any grade AE [≥50% of pts], n (%)Any event167 (99.4)85 (100)158 (99.4)82 (100)Neutropenia151 (89.9)78 (91.8)140 (88.1)74 (90.2)Thrombocytopenia140 (83.3)66 (77.6)124 (78.0)54 (65.9)Anemia139 (82.7)64 (75.3)122 (76.7)52 (63.4)Nausea118 (70.2)49 (57.6)119 (74.8)58 (70.7)Alopecia89 (53.0)43 (50.6)89 (56.0)41 (50.0)Fatigue79 (47.0)37 (43.5)87 (54.7)48 (58.5)Peripheral sensory neuropathy69 (41.1)37 (43.5)82 (51.6)49 (59.8)Any grade ≥3 AE [≥30% of pts], n (%)Any event164 (97.6)82 (96.5)152 (95.6)77 (93.9)Anemia73 (43.5)31 (36.5)67 (42.1)35 (42.7)Leukopenia54 (32.1)20 (23.5)44 (27.7)25 (30.5)Neutropenia136 (81.0)72 (84.7)131 (82.4)67 (81.7)Thrombocytopenia72 (42.9)30 (35.3)59 (37.1)18 (22.0)Serious AEs, n (%)58 (34.5)26 (30.6)56 (35.2)22 (26.8)AEs of special interest, n (%)Infections within 14 days of neutropenia64 (38.1)34 (40.0)59 (37.1)25 (30.5)Hemorrhages within 14 days of thrombocytopenia14 (8.3)5 (5.9)17 (10.7)7 (8.5)Any AE leading to study drug discontinuation not due to disease progression, n (%)16 (9.5)5 (5.9)15 (9.4)4 (4.9)Any AE leading to study drug interruption, n (%)153 (91.1)77 (90.6)139 (87.4)67 (81.7)Any AE leading to study drug reduction, n (%)28 (16.7)6 (7.1)27 (17.0)7 (8.5)Any AE leading to death with reasonable possibility related to study drug, n (%)0 (0)0 (0)0 (0)0 (0)AE, adverse event; BRCA, breast cancer susceptibility gene; C/P, carboplatin plus paclitaxel; Pbo, placebo; pts, patients; Vel, veliparib. Citation Format: Hans Wildiers, Jean-Pierre Ayoub, Michael Friedlander, Bella Kaufman, Banu K. Arun, Hyo S. Han, Shannon L. Puhalla, David Maag, Dai Feng, Christine K. Ratajczak, Bruce A. Bach, Véronique Diéras. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-03.

Background: Globally, amidst increased utilization of facility-based maternal care services, there is continued need to better understand women’s experience of care in places of birth. Quantitative surveys may not sufficiently characterize satisfaction with maternal healthcare (MHC) in local context, limiting their interpretation and applicability. The purpose of this study is to untangle how contextual and cultural expectations shape women’s care experience and what women mean by satisfaction in two Ethiopian regions. Methods: Health center and hospital childbirth care registries were used to identify and interview 41 women who had delivered a live newborn within a six-month period. We used a semi-structured interview guide informed by the Donabedian framework to elicit women’s experiences with MHC and delivery, any prior delivery experiences, and recommendations to improve MHC. We used an inductive analytical approach to compare and contrast MHC processes, experiences, and satisfaction. Results: Maternal and newborn survival and safety were central to women’s descriptions of their MHC experiences. Women nearly exclusively described healthy and safe deliveries with healthy outcomes as ‘satisfactory’. The texture behind this ‘satisfaction’, however, was shaped by what mothers bring to their delivery experiences, creating expectations from events including past births, experiences with antenatal care, and social and community influences. Secondary to the absence of adverse outcomes, health provider’s interpersonal behaviors (e.g., supportive communication and behavioral demonstrations of commitment to their births) and the facility’s amenities (e.g., bathing, cleaning, water, coffee, etc) enhanced women’s experiences. Finally, at the social and community levels, we found that family support and material resources may significantly buffer against negative experiences and facilitate women’s overall satisfaction, even in the context of poor-quality facilities and limited resources. Conclusion: Our findings highlight the importance of understanding contextual factors including past experiences, expectations, and social support that influence perceived quality of MHC and the agency a woman has to negotiate her care experience. Our finding that newborn and maternal survival primarily drove women’s satisfaction suggests that quantitative assessments conducted shortly following delivery may be overly influenced by these outcomes and not fully capture the complexity of women’s care experience.

Introduction : Tuberculosis (TB) remains the most common cause of death among people living with HIV. Integrating HIV and TB services reduces mortality but is sub‐optimally implemented. Quality improvement (QI) methods offer a low‐cost and easily implementable approach to strengthening healthcare delivery systems. This trial assessed a QI intervention on key process indicators for delivering integrated HIV‐TB care in rural South African primary healthcare (PHC) clinics. Methods Sixteen nurse supervisors, (each with a cluster of clinics) overseeing 40 PHC clinics, were randomized 1:1 to the intervention or the standard of care (SOC) groups. The QI intervention comprised three key components: clinical and QI skills training, on‐site mentorship of nurse supervisors and clinic staff, and data quality improvement activities to enhance accuracy and completeness of routine clinic data. The SOC comprised monthly supervision and data feedback meetings. From 01 December 2016 to 31 December 2018, data were collected monthly by a team of study‐appointed data capturers from all study clinics. This study's outcomes were HIV testing services (HTS), TB screening, antiretroviral therapy (ART) initiation, isoniazid preventive therapy (IPT) initiation and viral load (VL) testing. Results The QI group (eight clusters) comprised 244 clinic staff who attended to 13,347 patients during the trial compared to the SOC group (eight clusters) with 217 clinic staff who attended to 8141 patients. QI mentors completed 85% (510/600) of expected QI mentorship visits to QI clinics. HTS was 19% higher [94.5% vs. 79.6%; relative risk (RR)=1.19; 95% CI: 1.02–1.38; p=0.029] and IPT initiation was 66% higher (61.2 vs. 36.8; RR=1.66; 95% CI: 1.02–2.72; p=0·044), in the QI group compared to SOC group. The percentage of patients screened for TB (83.4% vs. 79.3%; RR=1.05; p=0.448), initiated on ART (91.7 vs. 95.5; RR=0.96; p=0.172) and VL testing (72.2% vs. 72.8%; RR=0.99; p=0.879) was similar in both groups. Conclusions QI improved HIV testing and IPT initiation compared to SOC. TB screening, ART initiation and VL testing remained similar. Incorporating QI methods into routine supervision and support activities may strengthen integrated HIV‐TB service delivery and increase the success of future QI scale‐up activities.

Reliable methods to quantify dynamic signaling changes across diverse pathways are needed to better understand the effects of disease and drug treatment in cells and tissues but are presently lacking. Here, we present SigPath, a targeted mass spectrometry (MS) assay that measures 284 phosphosites in 200 phosphoproteins of biological interest. SigPath probes a broad swath of signaling biology with high throughput and quantitative precision. We applied the assay to investigate changes in phospho‐signaling in drug‐treated cancer cell lines, breast cancer preclinical models, and human medulloblastoma tumors. In addition to validating previous findings, SigPath detected and quantified a large number of differentially regulated phosphosites newly associated with disease models and human tumors at baseline or with drug perturbation. Our results highlight the potential of SigPath to monitor phosphoproteomic signaling events and to nominate mechanistic hypotheses regarding oncogenesis, response, and resistance to therapy., SigPath is a targeted, quantitative mass spectrometry assay that measures 284 phosphosites spanning 200 phosphoproteins with high throughput and quantitative precision across a broad swath of signaling biology of known interest.

Background The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. Methods This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1–9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020–001236–10). Findings Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56–73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76–1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27–0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26–1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63–1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3–13) in the imatinib group compared with 12 days (6–20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. Interpretation The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings.&nbsp

The aim of this review was to summarise the available HBM data in DRC in order to provide recommendations for developing the HBM field. We performed a systematic search of PubMed/MedLine, EMBASE, and ISI Web of Science for papers on exposure levels to chemicals in DR C (2009-2019). A total of 12 papers were found: 9 in Kinshasa (75.0%) and 3 in Katanga (25.0%). Globally, the results reveal concern about exposure levels to environmental chemicals, mostly heavy metals. Some studies connected HBM data to negative health effects (preeclampsia, birth defects, children's temperament difficulties, holoprosencephaly) demonstrating the importance of regulation in occupational and environmental settings. The recommendations of this review include expanding HBM studies as well as the number of environmental chemicals; and establishment of a national HBM laboratory for developing and/or enhancing the capacity of DRC to undertake a national policy-related HBM.

Viruses modulate mitochondrial processes during infection to increase biosynthetic precursors and energy output, fueling virus replication. In a surprising fashion, although it triggers mitochondrial fragmentation, the prevalent pathogen human cytomegalovirus (HCMV) increases mitochondrial metabolism through a yet-unknown mechanism. Here, we integrate molecular virology, metabolic assays, quantitative proteomics, and superresolution confocal microscopy to define this mechanism. We establish that the previously uncharacterized viral protein pUL13 is required for productive HCMV replication, targets the mitochondria, and functions to increase oxidative phosphorylation during infection. We demonstrate that pUL13 forms temporally tuned interactions with the mitochondrial contact site and cristae organizing system (MICOS) complex, a critical regulator of cristae architecture and electron transport chain (ETC) function. Stimulated emission depletion superresolution microscopy shows that expression of pUL13 alters cristae architecture. Indeed, using live-cell Seahorse assays, we establish that pUL13 alone is sufficient to increase cellular respiration, not requiring the presence of other viral proteins. Our findings address the outstanding question of how HCMV targets mitochondria to increase bioenergetic output and expands the knowledge of the intricate connection between mitochondrial architecture and ETC function.

BACKGROUND: In 2016, the response to a yellow fever outbreak in Angola and the Democratic Republic of Congo led to a global shortage of yellow fever vaccine. As a result, a fractional dose of the 17DD yellow fever vaccine (containing one fifth [0.1 ml] of the standard dose) was offered to 7.6 million children 2 years of age or older and nonpregnant adults in a preemptive campaign in Kinshasa. The goal of this study was to assess the immune response to the fractional dose in a large-scale campaign. METHODS: We recruited participants in four age strata at six vaccination sites. We assessed neutralizing antibody titers against yellow fever virus in blood samples obtained before vaccination and at 1 month and 1 year after vaccination, using a plaque reduction neutralization test with a 50% cutoff (PRNT(50)). Participants with a PRNT(50) titer of 10 or higher were considered to be seropositive. Those with a baseline titer of less than 10 who became seropositive at follow-up were classified as having undergone seroconversion. Participants who were seropositive at baseline and who had an increase in the titer by a factor of 4 or more at follow-up were classified as having an immune response. RESULTS: Among 716 participants who completed the 1-month follow-up, 705 (98%; 95% confidence interval [CI], 97 to 99) were seropositive after vaccination. Among 493 participants who were seronegative at baseline, 482 (98%; 95% CI, 96 to 99) underwent seroconversion. Among 223 participants who were seropositive at baseline, 148 (66%; 95% CI, 60 to 72) had an immune response. Lower baseline titers were associated with a higher probability of having an immune response (P

OBJECTIVE To evaluate safety of stylet-in and stylet-out techniques for collection of CSF from the cisterna magna and to assess whether there were differences between techniques with regard to contamination of samples, sample quality, and efficiency of collection. ANIMALS 10 adult purpose-bred research Beagles. PROCEDURES A prospective crossover study was conducted. Preanesthetic physical and neurologic examinations and hematologic analyses were performed. Dogs were anesthetized, and collection of CSF samples from the cisterna magna by use of a stylet-in or stylet-out technique was performed. Two weeks later, samples were collected with the other sample collection technique. Samples of CSF were processed within 1 hour after collection. RESULTS Cellular debris was detected in higher numbers in stylet-in samples, although this did not affect sample quality. The stylet-out technique was performed more rapidly. No adverse effects were detected for either technique. CONCLUSIONS AND CLINICAL RELEVANCE Both techniques could be safely performed in healthy anesthetized dogs. The stylet-out technique was performed more rapidly and yielded a sample with less cellular debris. Both techniques can be used in clinical practice to yield CSF samples with good diagnostic quality.

Supplemental Digital Content is Available in the Text., Background: There have been a range of quality improvement (QI) and quality assurance initiatives in low- and middle-income countries to improve antiretroviral therapy (ART) treatment outcomes for people living with HIV. To date, these initiatives have not been systematically assessed and little is known about how effective, cost-effective, or sustainable these strategies are in improving clinical outcomes. Methods: We conducted a systematic review adhering to PRISMA guidelines (PROSPERO ID: CRD42017071848), searching PubMed, MEDLINE, Embase, Web of Science, and the Cochrane database of controlled trials for articles reporting on the effectiveness of QI and quality assurance initiatives in HIV programs in low- and middle-income countries in relation to ART uptake, retention in care, adherence, viral load suppression, mortality, and other outcomes including cost-effectiveness and long-term sustainability. Results: One thousand eight hundred sixty articles were found, of which 29 were included. QI approaches were categorized as follows: (1) health system approaches using QI methods; (2) QI learning networks including collaboratives; (3) standard-based methods that use QI tools to improve performance gaps; and (4) campaigns using QI methods. The greatest improvements were seen in ART uptake [median increase of 14.0%; interquartile range (IQR) −9.0 to 29.3], adherence [median increase of 22.0% (IQR −7.0 to 25.0)], and viral load suppression [median increase 26.0% (IQR −8.0 to 26.0)]. Conclusions: QI interventions can be effective in improving clinical outcomes; however, there was significant variability, making it challenging to identify which aspects of interventions lead to clinical improvements. Standardizing reporting and assessment of QI initiatives is needed, supported by national quality policies and directorates, and robust research.

OBJECTIVE To describe the signalment, clinical signs, biological behavior, and outcome for cats with apocrine gland anal sac adenocarcinoma (AGASACA) that underwent surgical excision. DESIGN Retrospective case series. ANIMALS 30 client-owned cats. PROCEDURES Databases of 13 Veterinary Society of Surgical Oncology member–affiliated institutions were searched for records of cats with a histologic diagnosis of AGASACA that underwent tumor excision. For each cat, information regarding signalment, clinical signs, diagnostic test results, treatment, and outcome was extracted from the medical record. The Kaplan-Meier method was used to determine median time to local recurrence (TLR), disease-free interval (DFI), and survival time. Cox regression was used to identify factors associated with TLR, DFI, and survival time. RESULTS Perineal ulceration or discharge was the most common clinical sign in affected cats. Eleven cats developed local recurrence at a median of 96 days after AGASACA excision. Incomplete tumor margins and a high nuclear pleomorphic score were risk factors for local recurrence. Nuclear pleomorphic score was negatively associated with DFI. Local recurrence and a high nuclear pleomorphic score were risk factors for death. Median DFI and survival time were 234 and 260 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that, in cats, perineal ulceration or discharge should raise suspicion of AGASACA and prompt rectal and anal sac examinations. Local recurrence was the most common life-limiting event in cats that underwent surgery for treatment of AGASACA, suggesting that wide margins should be obtained whenever possible during AGASACA excision. Efficacy of chemotherapy and radiation therapy for treatment of cats with AGASACA requires further investigation. (J Am Vet Med Assoc 2019;254:716–722)

Objective To determine the influence of 3 fixation systems on complications rate after tibial plateau leveling osteotomy (TPLO) in dogs >45.4 kg. Study design Retrospective case series. Sample population Dogs (N = 287, 342 stifles) >45.4 kg with cranial cruciate ligament tear treated with TPLO. Methods The medical records of dogs treated with TPLO were reviewed for fixation and postoperative complications, with a follow-up of at least 6 weeks. A random effects logistic regression model was used to evaluate the association between the type of TPLO fixation system and complications. Results The fixation systems included a 3.5-mm broad TPLO plate alone (8P; 78.4%), a 3.5-mm broad TPLO plate with SOP (String of Pearls) plate (8AP; 14.9%), and a 3.5-mm standard TPLO plate (6P; 6.7%). Among the included stifles, 214 (62.6%) fixation systems were classified as locking, and 128 (37.4%) were classified as nonlocking. The fixation system was predictive of complications. The 8P had the lowest odds ratio for complication among the 3 fixation systems. Odds of developing complications were higher with the 8AP fixation system than with the 8P fixation system. Locking fixation eliminated the association between weight and complication rate. Conclusion Fixation of a TPLO with the 8AP increased the risk of complications compared with the 8P in this population of large dogs. Clinical significance Locking fixation of TPLO with a 3.5-mm broad TPLO plate alone should be considered in large dogs because it may reduce complications.

Background: Depressive symptoms and impaired physical functioning are prevalent among older adults. Supplementation with vitamin D might improve both conditions, particularly in persons with low vitamin D status. \ud Objective: The D-Vitaal study primarily aimed to investigate the effect of vitamin D supplementation on depressive symptoms, functional limitations and physical performance in a high-risk older population with low vitamin D status. Secondary aims included examining the effect of vitamin D supplementation on anxiety symptoms, cognitive functioning, mobility, hand grip strength and health-related quality of life.\ud Design: This study was a randomized placebo-controlled trial with 155 participants aged 60-80 years who had clinically relevant depressive symptoms, ≥1 functional limitation and serum 25-hydroxyvitamin D (25(OH)D) concentrations of 15-50/70 nmol/L (depending on season). Participants received 1200 IU/day vitamin D3 (n=76) or placebo tablets (n=77) for 12 months. Serum 25(OH)D was measured at baseline and 6 months; outcomes were assessed at baseline, 6 and 12 months. Linear mixed models analyses were conducted according to the intention-to-treat principle to assess the effect of the intervention.\ud Results: The supplementation increased serum 25(OH)D concentrations in the intervention group to a mean of 85 nmol/L (SD: 16) against 43 nmol/L (SD: 18) in the placebo group after 6 months (P

The invasive, locally aggressive nature of feline injection-site sarcomas (FISSs) poses a unique challenge for surgeons to obtain complete margins with surgical excision. Optical coherence tomography (OCT), an imaging technology that uses light waves to generate real-time views of tissue architecture, provides an emerging solution to this dilemma by allowing fast, high-resolution scanning of surgical margins. The purpose of this study was to use OCT to assess surgical margins of FISS and to evaluate the diagnostic accuracy of OCT for detecting residual cancer using six evaluators of varying experience. Five FISSs were imaged with OCT to create a training set of OCT images that were compared with histopathology. Next, 25 FISSs were imaged with OCT prior to histopathology. Six evaluators of varying experience participated in a training session on OCT imaging after which each of the evaluators was given a dataset that included OCT images and videos to score on a scale from cancerous to non-cancerous. Diagnostic accuracy statistics were calculated. The overall sensitivity and specificity for classification of OCT images by evaluators were 78.9% and 77.6%, respectively. Correct classification rate of OCT images was associated with experience, while individual sensitivities and specificities had more variation between experience groups. This study demonstrates the ability of evaluators to correctly classify OCT images with overall low levels of experience and training and also illustrates areas where increased training can improve accuracy of evaluators in interpretation of OCT surgical margin images.