Comparing competing risk outcomes within principal strata, with application to studies of mother-to-child transmission of HIV

In randomized trials to prevent breast milk transmission of human immunodeficiency virus (HIV) from mother to infant, investigators are often interested in assessing the effect of a treatment or intervention on the cumulative risk of HIV infection by time (age) t in infants who are alive and uninfected at a certain time point τ0 τ0 within the principal stratum of infants who would be alive and uninfected by τ0 regardless of randomization assignment. Large sample non-parametric bounds and a semi-parametric sensitivity analysis model are developed for drawing inference about this causal effect. A simulation study is presented demonstrating that the proposed methods perform well in finite samples. The proposed methods are applied to a large, recent MTCT trial

Population-average mediation analysis for zero-inflated count outcomes

Mediation analysis is an increasingly popular statistical method for explaining causal pathways to inform intervention. While methods have increased, there is still a dearth of robust mediation methods for count outcomes with excess zeroes. Current mediation methods addressing this issue are computationally intensive, biased, or challenging to interpret. To overcome these limitations, we propose a new mediation methodology for zero-inflated count outcomes using the marginalized zero-inflated Poisson (MZIP) model and the counterfactual approach to mediation. This novel work gives population-average mediation effects whose variance can be estimated rapidly via delta method. This methodology is extended to cases with exposure-mediator interactions. We apply this novel methodology to explore if diabetes diagnosis can explain BMI differences in healthcare utilization and test model performance via simulations comparing the proposed MZIP method to existing zero-inflated and Poisson methods. We find that our proposed method minimizes bias and computation time compared to alternative approaches while allowing for straight-forward interpretations.Comment: 34 pages, 2 figures, 4 tables, 49 pages of Supplemental material, 2 supplemental figure

Receipt of Guideline-Concordant Care Among Older Women With Stage I-III Breast Cancer: A Population-Based Study

Background: This study examined receipt of guideline-concordant care (GCC) according to evidence-based treatment guidelines and quality measures and specific types of treatment among older women with breast cancer. Patients and Methods: A total of 142,433 patients aged ≥66 years diagnosed with stage I–III breast cancer between 2007 and 2011 were identified in the SEER-Medicare linked database. Algorithms considering cancer characteristics and the appropriate course of care as per guidelines versus actual care received determined receipt of GCC. Multivariable logistic regression estimated the likelihood of GCC and specific types of treatment for women aged ≥75 versus 66 to 74 years. Results: Overall, 39.7% of patients received GCC. Patients diagnosed at stage II or III, with certain preexisting conditions, and of nonwhite race were less likely to receive GCC. Patients with hormone-negative tumors, higher grade tumors, and greater access to oncology care resources were more likely to receive GCC. Patients aged ≥75 years were approximately 40% less likely to receive GCC or adjuvant endocrine therapy, 78% less likely to have any surgery, 61% less likely to have chemotherapy, and about half as likely to have radiation therapy than those aged 66 to 74 years. Conclusions: Fewer than half of older women with breast cancer received GCC, with the lowest rates observed among the oldest age groups, racial/ethnic minorities, and women with later-stage cancers. However, patients with more aggressive tumor characteristics and greater access to oncology resources were more likely to receive GCC. Considering that older women have the highest incidence of breast cancer and that many are diagnosed at stages requiring more aggressive treatment, efforts to increase rates of earlier stage diagnosis and the development of less toxic treatments could help improve GCC and survival while preserving quality of life

Surrogates of protection in repeated low-dose challenge experiments

A critical step toward developing a successful vaccine to control the human immunodeficiency virus (HIV) pandemic entails evaluation of vaccine candidates in non-human primates (NHPs). Historically, these studies have usually entailed challenges (i.e., exposures) with very high doses of a simian version of HIV, resulting in infection of all NHPs in the experiment after a single challenge. More recently, researchers have begun to conduct repeated low-dose challenge (RLC) studies in NHPs that are believed to more closely mimic typical exposure in natural human transmission settings. One objective of RLC studies is to assess whether measured immune responses to vaccination can serve as surrogate endpoints for the primary endpoint of interest, namely infection. In this paper, different designs of RLC studies for assessing a binary surrogate of protection are considered

Impact of COVID-19 response on global surgical volumes:an ongoing observational study

Objective: To determine whether location-linked anaesthesiology calculator mobile application (app) data can serve as a qualitative proxy for global surgical case volumes and therefore monitor the impact of the coronavirus disease 2019 (COVID-19) pandemic. Methods: We collected data provided by users of the mobile app "Anesthesiologist" during 1 October 2018-30 June 2020. We analysed these using RStudio and generated 7-day moving-average app use plots. We calculated country-level reductions in app use as a percentage of baseline. We obtained data on COVID-19 case counts from the European Centre for Disease Prevention and Control. We plotted changing app use and COVID-19 case counts for several countries and regions. Findings: A total of 100 099 app users within 214 countries and territories provided data. We observed that app use was reduced during holidays, weekends and at night, correlating with expected fluctuations in surgical volume. We observed that the onset of the pandemic prompted substantial reductions in app use. We noted strong cross-correlation between COVID-19 case count and reductions in app use in low- and middle-income countries, but not in high-income countries. Of the 112 countries and territories with non-zero app use during baseline and during the pandemic, we calculated a median reduction in app use to 73.6% of baseline. Conclusion: App data provide a proxy for surgical case volumes, and can therefore be used as a real-time monitor of the impact of COVID-19 on surgical capacity. We have created a dashboard for ongoing visualization of these data, allowing policy-makers to direct resources to areas of greatest need

Relationship of ethnicity and CD4 Count with glucose metabolism among HIV patients on Highly-Active Antiretroviral Therapy (HAART)

Background HIV patients on HAART are prone to metabolic abnormalities, including insulin resistance, lipodystrophy and diabetes. This study purports to investigate the relationship of ethnicity and CD4+ T cell count attained after stable highly-active antiretroviral treatment (HAART) with glucose metabolism in hyperrtriglyceridemic HIV patients without a history of diabetes. Methods Demographic, anthropometric, clinical, endocrinologic, energy expenditure and metabolic measures were obtained in 199 multiethnic, healthy but hypertriglyceridemic HIV-infected patients [46% Hispanic, 17% African-American, 37% Non-Hispanic White (NHW)] on stable HAART without a history of diabetes. The relationship of glucose and insulin responses to ethnicity, CD4 strata (low (\u3c300/cc) or moderate-to-high (≥ 300/cc)), and their interaction was determined. Results African-Americans had significantly greater impairment of glucose tolerance (P \u3c 0.05) and HbA1c levels (P \u3c .001) than either Hispanics or NHWs. In multivariate models, after adjusting for confounders (age, sex, HIV/HAART duration, smoking, obesity, glucose, insulin and lipids), African-Americans and Hispanics had significantly higher HbA1c and 2-hour glucose levels than NHW’s. Demonstrating a significant interaction between ethnicity and CD4 count (P = 0.023), African Americans with CD4 \u3c300/cc and Hispanics with CD4 ≥300/cc had the most impaired glucose response following oral glucose challenge. Conclusions Among hypertriglyceridemic HIV patients on HAART, African-Americans and Hispanics are at increased risk of developing diabetes. Ethnicity also interacts with CD4+ T cell count attained on stable HAART to affect post-challenge glycemic response

Feasibility of a mHealth Approach to Nutrition Counseling in an Appalachian State

Abstract: West Virginia is a rural state with an aging population that may experience barriers to accessing nutritional and lifestyle counseling. This study examined feasibility of an online personalized nutrition tracking application, Good Measures (GM), with patients at seven health care clinics throughout the state. Fourteen healthcare providers and 64 patients 18 years or older with a Body Mass Index (BMI) greater than or equal to 30 and access to the Internet were recruited for this 12-week feasibility study. Patient participants logged meals and exercise into the GM application via smart phone, tablet, or computer and virtually engaged with a Registered Dietitian Nutritionist (RDN) in one-on-one sessions. The primary endpoint was to examine feasibility of the program by usage of the application and feedback questions regarding the benefits and challenges of the application. Participants were predominately white (92%) and female (76%). Minimal improvements in weight and systolic blood pressure were found. Participant attitude survey data declined from 4-weeks to 12-weeks of the intervention. Interestingly though, patients in a rural clinic had lesser declines in attitudes than peri-urban participants. Qualitative feedback data identified participants predominately had a positive overall feeling toward the approach. Participants expressed favorability of RDN access, the variety of foods, but did give suggestions for in-person meetings and more updating of the application. Implementing a technology approach to nutrition in rural areas of West Virginia using a mobile application with RDN access may be one strategy to address public health issues such as obesity

Quality Improvement Intervention for Reduction of Redundant Testing

Laboratory data are critical to analyzing and improving clinical quality. In the setting of residual use of creatine kinase M and B isoenzyme testing for myocardial infarction, we assessed disease outcomes of discordant creatine kinase M and B isoenzyme +/troponin I (−) test pairs in order to address anticipated clinician concerns about potential loss of case-finding sensitivity following proposed discontinuation of routine creatine kinase and creatine kinase M and B isoenzyme testing. Time-sequenced interventions were introduced. The main outcome was the percentage of cardiac marker studies performed within guidelines. Nonguideline orders dominated at baseline. Creatine kinase M and B isoenzyme testing in 7496 order sets failed to detect additional myocardial infarctions but was associated with 42 potentially preventable admissions/quarter. Interruptive computerized soft stops improved guideline compliance from 32.3% to 58% (P \u3c .001) in services not receiving peer leader intervention and to \u3e80% (P \u3c .001) with peer leadership that featured dashboard feedback about test order performance. This successful experience was recapitulated in interrupted time series within 2 additional services within facility 1 and then in 2 external hospitals (including a critical access facility). Improvements have been sustained postintervention. Laboratory cost savings at the academic facility were estimated to be ≥US$635 000 per year. National collaborative data indicated that facility 1 improved its order patterns from fourth to first quartile compared to peer norms and imply that nonguideline orders persist elsewhere. This example illustrates how pathologists can provide leadership in assisting clinicians in changing laboratory ordering practices. We found that clinicians respond to local laboratory data about their own test performance and that evidence suggesting harm is more compelling to clinicians than evidence of cost savings. Our experience indicates that interventions done at an academic facility can be readily instituted by private practitioners at external facilities. The intervention data also supplement existing literature that electronic order interruptions are more successful when combined with modalities that rely on peer education combined with dashboard feedback about laboratory order performance. The findings may have implications for the role of the pathology laboratory in the ongoing pivot from quantity-based to value-based health care

Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells

It has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions

Natural Killer Cell Signal Integration Balances Synapse Symmetry and Migration

Imaging immune surveillance by natural killer (NK) cells has revealed that integration of activating and inhibitory signals determines whether or not NK cells stop to kill the target cell or retain a migratory configuration