Cost-effectiveness of an electronic clinical decision support system for improving quality of antenatal and childbirth care in rural Tanzania: an intervention study

Background: QUALMAT project aimed at improving quality of maternal and newborn care in selected health care facilities in three African countries. An electronic clinical decision support system was implemented to support providers comply with established standards in antenatal and childbirth care. Given that health care resources are limited and interventions differ in their potential impact on health and costs (efficiency), this study aimed at assessing cost-effectiveness of the system in Tanzania. Methods: This was a quantitative pre- and post- intervention study involving 6 health centres in rural Tanzania. Cost information was collected from health provider’s perspective. Outcome information was collected through observation of the process of maternal care. Incremental cost-effectiveness ratios for antenatal and childbirth care were calculated with testing of four models where the system was compared to the conventional paper-based approach to care. One-way sensitivity analysis was conducted to determine whether changes in process quality score and cost would impact on cost-effectiveness ratios. Results: Economic cost of implementation was 167,318 USD, equivalent to 27,886 USD per health center and 43 USD per contact. The system improved antenatal process quality by 4.5% and childbirth care process quality by 23.3% however these improvements were not statistically significant. Base-case incremental cost-effectiveness ratios of the system were 2469 USD and 338 USD per 1% change in process quality for antenatal and childbirth care respectively. Cost-effectiveness of the system was sensitive to assumptions made on costs and outcomes. Conclusions: Although the system managed to marginally improve individual process quality variables, it did not have significant improvement effect on the overall process quality of care in the short-term. A longer duration of usage of the electronic clinical decision support system and retention of staff are critical to the efficiency of the system and can reduce the invested resources. Realization of gains from the system requires effective implementation and an enabling healthcare system. Trial registration: Registered clinical trial at www.clinicaltrials.gov (NCT01409824). Registered May 2009

Nesting doctoral students in collaborative North-South partnerships for health systems research

Background: The European Union (EU) supports North-South Partnerships and collaborative research projects through its Framework Programmes and Horizon 2020. There is limited research on how such projects can be harnessed to provide a structured platform for doctoral level studies as a way of strengthening health system research capacity in sub-Saharan Africa (SSA). Objective: The aim of this study was to explore the challenges of, and facilitating factors for, 'nesting' doctoral students in North South collaborative research projects. The term nesting refers to the embedding of the processes of recruiting, supervising, and coordinating doctoral students in the overall research plan and processes. Design: This cross-sectional qualitative study was undertaken by the EU-funded QUALMAT Project. A questionnaire was implemented with doctoral students, supervisors, and country principal investigators (PIs), and content analysis was undertaken. Results: Completed questionnaires were received from nine doctoral students, six supervisors, and three country PIs (86% responses rate). The doctoral students from SSA described high expectations about the input they would receive (administrative support, equipment, training, supervision). This contrasted with the expectations of the supervisors for proactivity and self-management on the part of the students. The rationale for candidate selection, and understandings of the purpose of the doctoral students in the project were areas of considerable divergence. There were some challenges associated with the use of the country PIs as co-supervisors. Doctoral student progress was at times impeded by delays in the release of funding instalments from the EU. The paper provides a checklist of essential requirements and a set of recommendations for effective nesting of doctoral students in joint North-South projects. Conclusion: There are considerable challenges to the effective nesting of doctoral students within major collaborative research projects. However, ways can be found to overcome them. The nesting process ultimately helped the institutions involved in this example to take better advantage of the opportunities that collaborative projects offer to foster North-South partnerships as a contribution to the strengthening of local research capacity

32‐Channel self‐grounded bow‐tie transceiver array for cardiac MR at 7.0T

Purpose Design, implementation, evaluation, and application of a 32‐channel Self‐Grounded Bow‐Tie (SGBT) transceiver array for cardiac MR (CMR) at 7.0T. Methods The array consists of 32 compact SGBT building blocks. Transmission field (B1+) shimming and radiofrequency safety assessment were performed with numerical simulations and benchmarked against phantom experiments. In vivo B1+ efficiency mapping was conducted with actual flip angle imaging. The array’s applicability for accelerated high spatial resolution 2D FLASH CINE imaging of the heart was examined in a volunteer study (n = 7). Results B1+ shimming provided a uniform field distribution suitable for female and male subjects. Phantom studies demonstrated an excellent agreement between simulated and measured B1+ efficiency maps (7% mean difference). The SGBT array afforded a spatial resolution of (0.8 × 0.8 × 2.5) mm3 for 2D CINE FLASH which is by a factor of 12 superior to standardized cardiovascular MR (CMR) protocols. The density of the SGBT array supports 1D acceleration of up to R = 4 (mean signal‐to‐noise ratio (whole heart) ≥ 16.7, mean contrast‐to‐noise ratio ≥ 13.5) without impairing image quality significantly. Conclusion The compact SGBT building block facilitates a modular high‐density array that supports accelerated and high spatial resolution CMR at 7.0T. The array provides a technological basis for future clinical assessment of parallel transmission techniques.EC/H2020/743077/EU/Thermal Magnetic Resonance: A New Instrument to Define the Role of Temperature in Biological Systems and Disease for Diagnosis and Therapy/ThermalMRBMBF, 01QE1815, Verbundprojekt: Seeing is Believing: Revolution der bildgebenden Diagnostik und Therapiekontrolle des Körperstammes durch superaufgelöste Hochfeld-Magnetresonanztomographie; Teilprojekt: Industrielle Forschung und Entwicklung lokaler Radiofrequenz-Antennen für hochauflösende Hochfeld-MRT des Körperstamme

Brain Iron and Metabolic Abnormalities in C19orf12 Mutation Carriers: A 7.0 Tesla MRI Study in Mitochondrial Membrane Protein–Associated Neurodegeneration

Background Mitochondrial membrane protein‐associated neurodegeneration is an autosomal‐recessive disorder caused by C19orf12 mutations and characterized by iron deposits in the basal ganglia. Objectives The aim of this study was to quantify iron concentrations in deep gray matter structures using quantitative susceptibility mapping MRI and to characterize metabolic abnormalities in the pyramidal pathway using 1H MR spectroscopy in clinically manifesting membrane protein‐associated neurodegeneration patients and asymptomatic C19orf12 gene mutation heterozygous carriers. Methods We present data of 4 clinically affected membrane protein‐associated neurodegeneration patients (mean age: 21.0 ± 2.9 years) and 9 heterozygous gene mutation carriers (mean age: 50.4 ± 9.8 years), compared to age‐matched healthy controls. MRI assessments were performed on a 7.0 Tesla whole‐body system, consisting of whole‐brain gradient‐echo scans and short echo time, single‐volume MR spectroscopy in the white matter of the precentral/postcentral gyrus. Quantitative susceptibility mapping, a surrogate marker for iron concentration, was performed using a state‐of‐the‐art multiscale dipole inversion approach with focus on the globus pallidus, thalamus, putamen, caudate nucleus, and SN. Results and Conclusion In membrane protein‐associated neurodegeneration patients, magnetic susceptibilities were 2 to 3 times higher in the globus pallidus (P = 0.02) and SN (P = 0.02) compared to controls. In addition, significantly higher magnetic susceptibility was observed in the caudate nucleus (P = 0.02). Non‐manifesting heterozygous mutation carriers exhibited significantly increased magnetic susceptibility (relative to controls) in the putamen (P = 0.003) and caudate nucleus (P = 0.001), which may be an endophenotypic marker of genetic heterozygosity. MR spectroscopy revealed significantly increased levels of glutamate, taurine, and the combined concentration of glutamate and glutamine in membrane protein‐associated neurodegeneration, which may be a correlate of corticospinal pathway dysfunction frequently observed in membrane protein‐associated neurodegeneration patients

The Human Minor Histocompatibility Antigen1 Is a RhoGAP

The human minor Histocompatibility Antigen HMHA-1 is a major target of immune responses after allogeneic stem cell transplantation applied for the treatment of leukemia and solid tumors. The restriction of its expression to hematopoietic cells and many solid tumors raised questions regarding its cellular functions. Sequence analysis of the HMHA-1 encoding HMHA1 protein revealed the presence of a possible C-terminal RhoGTPase Activating Protein (GAP) domain and an N-terminal BAR domain. Rho-family GTPases, including Rac1, Cdc42, and RhoA are key regulators of the actin cytoskeleton and control cell spreading and migration. RhoGTPase activity is under tight control as aberrant signaling can lead to pathology, including inflammation and cancer. Whereas Guanine nucleotide Exchange Factors (GEFs) mediate the exchange of GDP for GTP resulting in RhoGTPase activation, GAPs catalyze the low intrinsic GTPase activity of active RhoGTPases, resulting in inactivation. Here we identify the HMHA1 protein as a novel RhoGAP. We show that HMHA1 constructs, lacking the N-terminal region, negatively regulate the actin cytoskeleton as well as cell spreading. Furthermore, we show that HMHA1 regulates RhoGTPase activity in vitro and in vivo. Finally, we demonstrate that the HMHA1 N-terminal BAR domain is auto-inhibitory as HMHA1 mutants lacking this region, but not full-length HMHA1, showed GAP activity towards RhoGTPases. In conclusion, this study shows that HMHA1 acts as a RhoGAP to regulate GTPase activity, cytoskeletal remodeling and cell spreading, which are crucial functions in normal hematopoietic and cancer cells

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570