Multiple Overimputation to Address Missing Data and Measurement Error: Application to HIV Treatment During Pregnancy and Pregnancy Outcomes

Investigations of the association of combination antiretroviral therapy (ART) with pregnancy outcomes often rely on routinely collected clinical data, which are prone to missing data and measurement error. Measurement error in gestational age may bias the relationship between combination ART and gestational age-based outcomes

Relationship Between Venules and Perivascular Spaces in Sporadic Small Vessel Diseases

Background and Purpose— Perivascular spaces (PVS) around venules may help drain interstitial fluid from the brain. We examined relationships between suspected venules and PVS visible on brain magnetic resonance imaging. Methods— We developed a visual venular quantification method to examine the spatial relationship between venules and PVS. We recruited patients with lacunar stroke or minor nondisabling ischemic stroke and performed brain magnetic resonance imaging and retinal imaging. We quantified venules on gradient echo or susceptibility-weighted imaging and PVS on T2-weighted magnetic resonance imaging in the centrum semiovale and then determined overlap between venules and PVS. We assessed associations between venular count and patient demographic characteristics, vascular risk factors, small vessel disease features, retinal vessels, and venous sinus pulsatility. Results— Among 67 patients (69% men, 69.0±9.8 years), only 4.6% (range, 0%–18%) of venules overlapped with PVS. Total venular count increased with total centrum semiovale PVS count in 55 patients after accounting for venule-PVS overlap (β=0.468 [95% CI, 0.187–0.750]) and transverse sinus pulsatility (β=0.547 [95% CI, 0.309–0.786]) and adjusting for age, sex, and systolic blood pressure. Conclusions— Despite increases in both visible PVS and suspected venules, we found minimal spatial overlap between them in patients with sporadic small vessel disease, suggesting that most magnetic resonance imaging-visible centrum semiovale PVS are periarteriolar rather than perivenular

Influence of threshold selection and image sequence in in-vivo segmentation of enlarged perivascular spaces

BACKGROUND: Growing interest surrounds perivascular spaces (PVS) as a clinical biomarker of brain dysfunction given their association with cerebrovascular risk factors and disease. Neuroimaging techniques allowing quick and reliable quantification are being developed, but, in practice, they require optimisation as their limits of validity are usually unspecified.NEW METHOD: We evaluate modifications and alternatives to a state-of-the-art (SOTA) PVS segmentation method that uses a vesselness filter to enhance PVS discrimination, followed by thresholding of its response, applied to brain magnetic resonance images (MRI) from patients with sporadic small vessel disease acquired at 3 T.RESULTS: The method is robust against inter-observer differences in threshold selection, but separate thresholds for each region of interest (i.e., basal ganglia, centrum semiovale, and midbrain) are required. Noise needs to be assessed prior to selecting these thresholds, as effect of noise and imaging artefacts can be mitigated with a careful optimisation of these thresholds. PVS segmentation from T1-weighted images alone, misses small PVS, therefore, underestimates PVS count, may overestimate individual PVS volume especially in the basal ganglia, and is susceptible to the inclusion of calcified vessels and mineral deposits. Visual analyses indicated the incomplete and fragmented detection of long and thin PVS as the primary cause of errors, with the Frangi filter coping better than the Jerman filter.COMPARISON WITH EXISTING METHODS: Limits of validity to a SOTA PVS segmentation method applied to 3 T MRI with confounding pathology are given.CONCLUSIONS: Evidence presented reinforces the STRIVE-2 recommendation of using T2-weighted images for PVS assessment wherever possible. The Frangi filter is recommended for PVS segmentation from MRI, offering robust output against variations in threshold selection and pathology presentation.</p

Magnetic Resonance Imaging Tissue Signatures Associated With White Matter Changes Due to Sporadic Cerebral Small Vessel Disease Indicate That White Matter Hyperintensities Can Regress

Background White matter hyperintensities (WMHs) might regress and progress contemporaneously, but we know little about underlying mechanisms. We examined WMH change and underlying quantitative magnetic resonance imaging tissue measures over 1 year in patients with minor ischemic stroke with sporadic cerebral small vessel disease. Methods and Results We defined areas of stable normal‐appearing white matter, stable WMHs, progressing and regressing WMHs based on baseline and 1‐year brain magnetic resonance imaging. In these areas we assessed tissue characteristics with quantitative T1, fractional anisotropy (FA), mean diffusivity (MD), and neurite orientation dispersion and density imaging (baseline only). We compared tissue signatures cross‐sectionally between areas, and longitudinally within each area. WMH change masks were available for N=197. Participants' mean age was 65.61 years (SD, 11.10), 59% had a lacunar infarct, and 68% were men. FA and MD were available for N=195, quantitative T1 for N=182, and neurite orientation dispersion and density imaging for N=174. Cross‐sectionally, all 4 tissue classes differed for FA, MD, T1, and Neurite Density Index. Longitudinally, in regressing WMHs, FA increased with little change in MD and T1 (difference estimate, 0.011 [95% CI, 0.006–0.017]; −0.002 [95% CI, −0.008 to 0.003] and −0.003 [95% CI, −0.009 to 0.004]); in progressing and stable WMHs, FA decreased (−0.022 [95% CI, −0.027 to −0.017] and −0.009 [95% CI, −0.011 to −0.006]), whereas MD and T1 increased (progressing WMHs, 0.057 [95% CI, 0.050–0.063], 0.058 [95% CI, 0.050 –0.066]; stable WMHs, 0.054 [95% CI, 0.045–0.063], 0.049 [95% CI, 0.039–0.058]); and in stable normal‐appearing white matter, MD increased (0.004 [95% CI, 0.003–0.005]), whereas FA and T1 slightly decreased and increased (−0.002 [95% CI, −0.004 to −0.000] and 0.005 [95% CI, 0.001–0.009]). Conclusions Quantitative magnetic resonance imaging shows that WMHs that regress have less abnormal microstructure at baseline than stable WMHs and follow trajectories indicating tissue improvement compared with stable and progressing WMHs

Protocol-driven primary care and community linkages to improve population health in rural Zambia: the Better Health Outcomes through Mentoring and Assessment (BHOMA) project

Abstract Introduction Zambia’s under-resourced public health system will not be able to deliver on its health-related Millennium Development Goals without a substantial acceleration in mortality reduction. Reducing mortality will depend not only upon increasing access to health care but also upon improving the quality of care that is delivered. Our project proposes to improve the quality of clinical care and to improve utilization of that care, through a targeted quality improvement (QI) intervention delivered at the facility and community level. Description of implementation The project is being carried out 42 primary health care facilities that serve a largely rural population of more than 450,000 in Zambia’s Lusaka Province. We have deployed six QI teams to implement consensus clinical protocols, forms, and systems at each site. The QI teams define new clinical quality expectations and provide tools needed to deliver on those expectations. They also monitor the care that is provided and mentor facility staff to improve care quality. We also engage community health workers to actively refer and follow up patients. Evaluation design Project implementation occurs over a period of four years in a stepped expansion to six randomly selected new facilities every three months. Three annual household surveys will determine population estimates of age-standardized mortality and under-5 mortality in each community before, during, and after implementation. Surveys will also provide measures of childhood vaccine coverage, pregnancy care utilization, and general adult health. Health facility surveys will assess coverage of primary health interventions and measures of health system effectiveness. Discussion The patient-provider interaction is an important interface where the community and the health system meet. Our project aims to reduce population mortality by substantially improving this interaction. Our success will hinge upon the ability of mentoring and continuous QI to improve clinical service delivery. It will also be critical that once the quality of services improves, increasing proportions of the population will recognize their value and begin to utilize them

Protocol-driven primary care and community linkages to improve population health in rural Zambia: the Better Health Outcomes through Mentoring and Assessment (BHOMA) project.

INTRODUCTION: Zambia's under-resourced public health system will not be able to deliver on its health-related Millennium Development Goals without a substantial acceleration in mortality reduction. Reducing mortality will depend not only upon increasing access to health care but also upon improving the quality of care that is delivered. Our project proposes to improve the quality of clinical care and to improve utilization of that care, through a targeted quality improvement (QI) intervention delivered at the facility and community level. DESCRIPTION OF IMPLEMENTATION: The project is being carried out 42 primary health care facilities that serve a largely rural population of more than 450,000 in Zambia's Lusaka Province. We have deployed six QI teams to implement consensus clinical protocols, forms, and systems at each site. The QI teams define new clinical quality expectations and provide tools needed to deliver on those expectations. They also monitor the care that is provided and mentor facility staff to improve care quality. We also engage community health workers to actively refer and follow up patients. EVALUATION DESIGN: Project implementation occurs over a period of four years in a stepped expansion to six randomly selected new facilities every three months. Three annual household surveys will determine population estimates of age-standardized mortality and under-5 mortality in each community before, during, and after implementation. Surveys will also provide measures of childhood vaccine coverage, pregnancy care utilization, and general adult health. Health facility surveys will assess coverage of primary health interventions and measures of health system effectiveness. DISCUSSION: The patient-provider interaction is an important interface where the community and the health system meet. Our project aims to reduce population mortality by substantially improving this interaction. Our success will hinge upon the ability of mentoring and continuous QI to improve clinical service delivery. It will also be critical that once the quality of services improves, increasing proportions of the population will recognize their value and begin to utilize them

A risk score to identify HIV-infected women most likely to become lost to follow-up in the postpartum period

Access to lifelong combination antiretroviral therapy (cART) is expanding among HIV-infected pregnant and breastfeeding women throughout sub-Saharan Africa. For this strategy to meaningfully improve maternal HIV outcomes, retention in HIV care is essential. We developed a risk score to identify women with high likelihood of loss to follow-up (LTFU) at 6 months postpartum from HIV care, using data from public health facilities in Lusaka, Zambia. LTFU was defined as not presenting for HIV care within 60 days of the last scheduled appointment. We used logistic regression to assess demographic, obstetric, and HIV predictors of LTFU and to develop a simple risk score. Sensitivity and specificity were assessed at each risk score cut-point. Among 2,029 pregnant women initiating cART between 2009 and 2011, 507 (25%) were LTFU by 6 months postpartum. Parity, education, employment status, WHO clinical stage, duration of cART during pregnancy, and number of antenatal care visits were associated with LTFU (p-value<0.10). A risk score cut-point of 11 (42nd percentile) had 85% sensitivity (95% CI 82%, 88%) and 22% specificity (95% CI 20%, 24%) to detect women LTFU and would exclude 20% of women from a retention intervention. A risk score cut-point of 18 (69th percentile) identified the 23% of women with the highest probability of LTFU and had sensitivity 32% (95% CI 28%, 36%) and specificity 80% (95% CI 78%, 82%). A risk score approach may be useful to triage a subset of women most likely to be LTFU for targeted retention interventions

Effect of Pembrolizumab Plus Neoadjuvant Chemotherapy on Pathologic Complete Response in Women With Early-Stage Breast Cancer: An Analysis of the Ongoing Phase 2 Adaptively Randomized I-SPY2 Trial.

Importance: Approximately 25% of patients with early-stage breast cancer who receive (neo)adjuvant chemotherapy experience a recurrence within 5 years. Improvements in therapy are greatly needed. Objective: To determine if pembrolizumab plus neoadjuvant chemotherapy (NACT) in early-stage breast cancer is likely to be successful in a 300-patient, confirmatory randomized phase 3 neoadjuvant clinical trial. Design, Setting, and Participants: The I-SPY2 study is an ongoing open-label, multicenter, adaptively randomized phase 2 platform trial for high-risk, stage II/III breast cancer, evaluating multiple investigational arms in parallel. Standard NACT serves as the common control arm; investigational agent(s) are added to this backbone. Patients with ERBB2 (formerly HER2)-negative breast cancer were eligible for randomization to pembrolizumab between November 2015 and November 2016. Interventions: Participants were randomized to receive taxane- and anthracycline-based NACT with or without pembrolizumab, followed by definitive surgery. Main Outcomes and Measures: The primary end point was pathologic complete response (pCR). Secondary end points were residual cancer burden (RCB) and 3-year event-free and distant recurrence-free survival. Investigational arms graduated when demonstrating an 85% predictive probability of success in a hypothetical confirmatory phase 3 trial. Results: Of the 250 women included in the final analysis, 181 were randomized to the standard NACT control group (median [range] age, 47 [24.77] years). Sixty-nine women (median [range] age, 50 [27-71] years) were randomized to 4 cycles of pembrolizumab in combination with weekly paclitaxel followed by AC; 40 hormone receptor (HR)-positive and 29 triple-negative. Pembrolizumab graduated in all 3 biomarker signatures studied. Final estimated pCR rates, evaluated in March 2017, were 44% vs 17%, 30% vs 13%, and 60% vs 22% for pembrolizumab vs control in the ERBB2-negative, HR-positive/ERBB2-negative, and triple-negative cohorts, respectively. Pembrolizumab shifted the RCB distribution to a lower disease burden for each cohort evaluated. Adverse events included immune-related endocrinopathies, notably thyroid abnormalities (13.0%) and adrenal insufficiency (8.7%). Achieving a pCR appeared predictive of long-term outcome, where patients with pCR following pembrolizumab plus chemotherapy had high event-free survival rates (93% at 3 years with 2.8 years\u27 median follow-up). Conclusions and Relevance: When added to standard neoadjuvant chemotherapy, pembrolizumab more than doubled the estimated pCR rates for both HR-positive/ERBB2-negative and triple-negative breast cancer, indicating that checkpoint blockade in women with early-stage, high-risk, ERBB2-negative breast cancer is highly likely to succeed in a phase 3 trial. Pembrolizumab was the first of 10 agents to graduate in the HR-positive/ERBB2-negative signature. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379

What Will It Take to Eliminate Pediatric HIV? Reaching WHO Target Rates of Mother-to-Child HIV Transmission in Zimbabwe: A Model-Based Analysis

Using a simulation model, Andrea Ciaranello and colleagues find that the latest WHO PMTCT (prevention of mother to child transmission of HIV) guidelines plus better access to PMTCT programs, better retention of women in care, and better adherence to drugs are needed to eliminate pediatric HIV in Zimbabwe