Transportability without positivity: a synthesis of statistical and simulation modeling

When estimating an effect of an action with a randomized or observational study, that study is often not a random sample of the desired target population. Instead, estimates from that study can be transported to the target population. However, transportability methods generally rely on a positivity assumption, such that all relevant covariate patterns in the target population are also observed in the study sample. Strict eligibility criteria, particularly in the context of randomized trials, may lead to violations of this assumption. Two common approaches to address positivity violations are restricting the target population and restricting the relevant covariate set. As neither of these restrictions are ideal, we instead propose a synthesis of statistical and simulation models to address positivity violations. We propose corresponding g-computation and inverse probability weighting estimators. The restriction and synthesis approaches to addressing positivity violations are contrasted with a simulation experiment and an illustrative example in the context of sexually transmitted infection testing uptake. In both cases, the proposed synthesis approach accurately addressed the original research question when paired with a thoughtfully selected simulation model. Neither of the restriction approaches were able to accurately address the motivating question. As public health decisions must often be made with imperfect target population information, model synthesis is a viable approach given a combination of empirical data and external information based on the best available knowledge

Evaluation of Progesterone Agent Utilization and Birth Outcomes in a State Medicaid Plan

An analysis of medication adherence and birth outcomes among members receiving progesterone for the prevention of preterm birth in a state Medicaid program. Data is also used to evaluate the association between member characteristics and medication adherence and birth outcomes as well as whether there was a change in the cost of care

Effectiveness of Ledipasvir/Sofosbuvir and Predictors of Treatment Failure in Members with Hepatitis C Genotype 1: A Retrospective Cohort Study in a Medicaid Population

An evaluation of the effectiveness of HCV genotype 1 treatment with Harvoni® (ledipasvir/sofosbuvir) as measured by a sustained virological response (SVR) of 12 weeks in the MassHealth fee-for-service and Primary Care Clinician plan population. The analysis concluded that treatment was associated with a a high rate of SVR12, which means that Hepatitis C is not detected in the blood after 12 weeks

Cytokine Response Patterns in Severe Pandemic 2009 H1N1 and Seasonal Influenza among Hospitalized Adults

BACKGROUND: Studying cytokine/chemokine responses in severe influenza infections caused by different virus subtypes may improve understanding on pathogenesis. METHODS: Adults hospitalized for laboratory-confirmed seasonal and pandemic 2009 A/H1N1 (pH1N1) influenza were studied. Plasma concentrations of 13 cytokines/chemokines were measured at presentation and then serially, using cytometric-bead-array with flow-cytometry and ELISA. PBMCs from influenza patients were studied for cytokine/chemokine expression using ex-vivo culture (Whole Blood Assay,±PHA/LPS stimulation). Clinical variables were prospectively recorded and analyzed. RESULTS: 63 pH1N1 and 53 seasonal influenza patients were studied. pH1N1 patients were younger (mean±S.D. 42.8±19.2 vs 70.5±16.7 years), and fewer had comorbidities. Respiratory/cardiovascular complications were common in both groups (71.4% vs 81.1%), although severe pneumonia with hypoxemia (54.0% vs 28.3%) and ICU admissions (25.4% vs 1.9%) were more frequent with pH1N1. Hyperactivation of the proinflammatory cytokines IL-6, CXCL8/IL-8, CCL2/MCP-1 and sTNFR-1 was found in pH1N1 pneumonia (2-15 times normal) and in complicated seasonal influenza, but not in milder pH1N1 infections. The adaptive-immunity (Th1/Th17)-related CXCL10/IP-10, CXCL9/MIG and IL-17A however, were markedly suppressed in severe pH1N1 pneumonia (2-27 times lower than seasonal influenza; P-values<0.01). This pattern was further confirmed with serial measurements. Hypercytokinemia tended to be sustained in pH1N1 pneumonia, associated with a slower viral clearance [PCR-negativity: day 3-4, 55% vs 85%; day 6-7, 67% vs 100%]. Elevated proinflammatory cytokines, particularly IL-6, predicted ICU admission (adjusted OR 12.6, 95%CI 2.6-61.5, per log(10)unit increase; P = 0.002), and correlated with fever, tachypnoea, deoxygenation, and length-of-stay (Spearman's rho, P-values<0.01) in influenza infections. PBMCs in seasonal influenza patients were activated and expressed cytokines ex vivo (e.g. IL-6, CXCL8/IL-8, CCL2/MCP-1, CXCL10/IP-10, CXCL9/MIG); their 'responsiveness' to stimuli was shown to change dynamically during the illness course. CONCLUSIONS: A hyperactivated proinflammatory, but suppressed adaptive-immunity (Th1/Th17)-related cytokine response pattern was found in severe pH1N1 pneumonia, different from seasonal influenza. Cytokine/immune-dysregulation may be important in its pathogenesis

Putting the PASS in Class: Peer Mentors’ Identities in Science Workshops on Campus and Online

In this paper, we analyse the introduction of peer mentors into timetabled classes to understand how in-class mentoring supports students’ learning. The peer mentors in this study are high-achieving students who previously completed the same course and who were hired and trained to facilitate Peer Assisted Study Sessions (PASS). PASS gives students the opportunity to deepen their understanding through revision and active learning and are typically held outside of class time. In contrast, our trial embedded peer mentors into classes for a large (~250 students) first-year workshop-based course. We employed a participatory action research methodology to facilitate the peer mentors’ co-creation of the research process. Data sources include peer mentors’ journal entries, student cohort data, and a focus group with teaching staff. We found that during face-to-face workshops, peer mentors role-modelled ideal student behaviour (e.g., asking questions) rather than acting as additional teachers, and this helped students to better understand how to interact effectively in class. The identity of embedded peer mentors is neither that of teachers nor of students, and it instead spans aspects of both as described using a three-part schema comprising (i) identity, (ii) associated roles, and (iii) associated practices. As we moved classes online mid-semester in response to the COVID-19 pandemic, mentors’ identities remained stable, but mentors adjusted their associated roles and practices, including through the technical aspects of their engagement with students. This study highlights the benefits of embedding mentors in classrooms on campus and online

Trial Protocol: Randomised controlled trial of the effects of very low calorie diet, modest dietary restriction, and sequential behavioural programme on hunger, urges to smoke, abstinence and weight gain in overweight smokers stopping smoking

Background\ud Weight gain accompanies smoking cessation, but dieting during quitting is controversial as hunger may increase urges to smoke. This is a feasibility trial for the investigation of a very low calorie diet (VLCD), individual modest energy restriction, and usual advice on hunger, ketosis, urges to smoke, abstinence and weight gain in overweight smokers trying to quit. \ud \ud Methods\ud This is a 3 armed, unblinded, randomized controlled trial in overweight (BMI > 25 kg/$m^2$), daily smokers (CO > 10 ppm); with at least 30 participants in each group. Each group receives identical behavioural support and NRT patches (25 mg(8 weeks),15 mg(2 weeks),10 mg(2 weeks)). The VLCD group receive a 429-559 kcal/day liquid formula beginning 1 week before quitting and continuing for 4 weeks afterwards. The modest energy restricted group (termed individual dietary and activity planning(IDAP)) engage in goal-setting and receive an energy prescription based on individual basal metabolic rate(BMR) aiming for daily reduction of 600 kcal. The control group receive usual dietary advice that accompanies smoking cessation i.e. avoiding feeling hungry but eating healthy snacks. After this, the VLCD participants receive IDAP to provide support for changing eating habits in the longer term; the IDAP group continues receiving this support. The control group receive IDAP 8 weeks after quitting. This allows us to compare IDAP following a successful quit attempt with dieting concurrently during quitting. It also aims to prevent attrition in the unblinded, control group by meeting their need for weight management. Follow-up occurs at 6 and 12 months. \ud \ud Outcome measures include participant acceptability, measured qualitatively by semi-structured interviewing and quantitatively by recruitment and attrition rates. Feasibility of running the trial within primary care is measured by interview and questionnaire of the treatment providers. Adherence to the VLCD is verified by the presence of urinary ketones measured weekly. Daily urges to smoke, hunger and withdrawal are measured using the Mood and Physical Symptoms Scale-Combined (MPSS-C) and a Hunger Craving Score (HCS). 24 hour, 7 day point prevalence and 4-week prolonged abstinence (Russell Standard) is confirmed by CO < 10 ppm. Weight, waist and hip circumference and percentage body fat are measured at each visit. \ud \ud Trial Registration\ud Current controlled trials ISRCTN83865809\ud \u

Guiding phosphorus stewardship for multiple ecosystem services

The essential role of phosphorus (P) for agriculture and its impact on water quality has received decades of research attention. However, the benefits of sustainable P use and management for society due to its downstream impacts on multiple ecosystem services are rarely acknowledged. We propose a conceptual framework—the “phosphorus-ecosystem services cascade” (PESC)—to integrate the key ecosystem processes and functions that moderate the relationship between P released to the environment from human actions and ecosystem services at distinct spatial and temporal scales. Indirect pathways in the cascade via soil and aquatic processes link anthropogenic P to biodiversity and multiple services, including recreation, drinking water provision, and fisheries. As anthropogenic P cascades through catchments, it often shifts from a subsidy to a stressor of ecosystem services. Phosphorus stewardship can have emergent ecosystem service co-benefits due to synergies with other societal or management goals (e.g., recycling of livestock manures and organic wastes could impact soil carbon storage). Applying the PESC framework, we identify key research priorities to align P stewardship with the management of multiple ecosystem services, such as incorporating additional services into agri-environmental P indices, assessing how widespread recycling of organic P sources could differentially impact agricultural yields and water quality, and accounting for shifting baselines in P stewardship due to climate change. Ultimately, P impacts depend on site-specific agricultural and biogeophysical contexts, so greater precision in targeting stewardship strategies to specific locations would help to optimize for ecosystem services and to more effectively internalize the downstream costs of farm nutrient management

Fecal Viral Concentration and Diarrhea in Norovirus Gastroenteritis

Fecal viral concentrations of 40 patients infected with norovirus genogroup GII.4 correlated with diarrhea duration and frequency of vomiting. Higher viral concentration and older age were independently associated with prolonged diarrhea (>4 days). These findings provide information on the pathogenesis and transmission of norovirus infections

‘It Takes Two Hands to Clap’: How Gaddi Shepherds in the Indian Himalayas Negotiate Access to Grazing

This article examines the effects of state intervention on the workings of informal institutions that coordinate the communal use and management of natural resources. Specifically it focuses on the case of the nomadic Gaddi shepherds and official attempts to regulate their access to grazing pastures in the Indian Himalayas. It is often predicted that the increased presence of the modern state critically undermines locally appropriate and community-based resource management arrangements. Drawing on the work of Pauline Peters and Francis Cleaver, I identify key instances of socially embedded ‘common’ management institutions and explain the evolution of these arrangements through dynamic interactions between individuals, communities and the agents of the state. Through describing the ‘living space’ of Gaddi shepherds across the annual cycle of nomadic migration with their flocks I explore the ways in which they have been able to creatively reinterpret external interventions, and suggest how contemporary arrangements for accessing pasture at different moments of the annual cycle involve complex combinations of the formal and the informal, the ‘traditional’ and the ‘modern’

The occurrence of tarsal injuries in male mice of C57BL/6N substrains in multiple international mouse facilities.

Dislocation in hindlimb tarsals are being observed at a low, but persistent frequency in group-housed adult male mice from C57BL/6N substrains. Clinical signs included a sudden onset of mild to severe unilateral or bilateral tarsal abduction, swelling, abnormal hindlimb morphology and lameness. Contraction of digits and gait abnormalities were noted in multiple cases. Radiographical and histological examination revealed caudal dislocation of the calcaneus and partial dislocation of the calcaneoquartal (calcaneus-tarsal bone IV) joint. The detection, frequency, and cause of this pathology in five large mouse production and phenotyping centres (MRC Harwell, UK; The Jackson Laboratory, USA; The Centre for Phenogenomics, Canada; German Mouse Clinic, Germany; Baylor College of Medicine, USA) are discussed