Vaccine Effectiveness during Outbreak of COVID-19 Alpha (B.1.1.7) Variant in Men's Correctional Facility, United States.

In April 2021, a COVID-19 outbreak occurred at a correctional facility in rural Virginia, USA. Eighty-four infections were identified among 854 incarcerated persons by facilitywide testing with reverse transcription quantitative PCR (qRT-PCR). We used whole-genome sequencing to link all infections to 2 employees infected with the B.1.1.7α (UK) variant. The relative risk comparing unvaccinated to fully vaccinated persons (mRNA-1273 [Moderna, https://www.modernatx.com]) was 7.8 (95% CI 4.8-12.7), corresponding to a vaccine effectiveness of 87.1% (95% CI 79.0%-92.1%). Average qRT-PCR cycle threshold values were lower, suggesting higher viral loads, among unvaccinated infected than vaccinated cases for the nucleocapsid, envelope, and spike genes. Vaccination was highly effective at preventing SARS-CoV-2 infection in this high-risk setting. This approach can be applied to similar settings to estimate vaccine effectiveness as variants emerge to guide public health strategies during the ongoing pandemic.

How Should the World Pay for a Coronavirus Disease (COVID-19) Vaccine?

The potential health and economic value of a vaccine for coronavirus disease (COVID-19) is self-evident given nearly 2 million deaths, "collateral" loss of life as other conditions go untreated, and massive economic damage. Results from the first licensed products are very encouraging; however, there are important reasons why we will likely need second and third generation vaccines. Dedicated incentives and funding focused explicitly on nurturing and advancing competing second and third generation vaccines are essential. This article proposes a collaborative, market-based financing mechanism for the world to incentivize and pay for the development of, and provide equitable access to, second and third generation COVID-19 vaccines. Specifically, we propose consideration of a Benefit-Based Advance Market Commitment (BBAMC). The BBAMC uses health technology assessment to determine value-based prices to guarantee overall market revenues, not revenue for any specific product or company. The poorest countries would not pay a value-based price but a discounted "tail-price." Innovators must agree to supply them at this tail price or to facilitate technology transfer to local licensees at low or zero cost to enable them to supply at this price. We expect these purchases to be paid for in full or large part by global donors. The BBAMC therefore sets prices in relation to value, protects intellectual property rights, encourages competition, and ensures all populations get access to vaccines, subject to agreed priority allocation rules.

Sexually Transmitted Disease Partner Services Costs, Other Resources, and Strategies Across Jurisdictions to Address Unique Epidemic Characteristics and Increased Incidence.

BACKGROUND: Sexually transmitted disease (STD) partner services (PS) are a core component of STD programs. Data on costs are needed to support PS programming. METHODS: In Washington State STD PS programs, disease intervention specialists (DIS) conduct telephone-based interviews and occasional field visits, offer expedited partner therapy to heterosexuals with gonorrhea or chlamydia, and promote human immunodeficiency virus (HIV) testing, preexposure prophylaxis, and HIV care. We conducted activity-based microcosting of PS, including: observational and self-reported time studies and interviews. We analyzed cost, surveillance, and service delivery data to determine costs per program outcomes. RESULTS: In King, Pierce, and Spokane counties, respectively, DIS allocated 6.5, 6.4, and 28.8 hours per syphilis case and 1.5, 1.6, and 2.9 hours per gonorrhea/chlamydia case, on average. In 2016, each full-time DIS investigated 270, 268, and 61 syphilis and 1177, 1105, and 769 gonorrhea/chlamydia cases. Greater than 80% of syphilis cases in King and Pierce were among men who have sex with men versus 38% in Spokane. Disease intervention specialists spent 12% to 39% of their time actively interviewing cases and notifying partners (clients), and the remaining time locating clients, coordinating and verifying care, and managing case reports. Time spent on expedited partner therapy, HIV testing, and referrals to HIV treatment or preexposure prophylaxis, was minimal (<5 minutes per interview) at locations with resources outside PS staff. Program cost-per-interview ranged from US $527 to US $2210 for syphilis, US $219 to US $484 for gonorrhea, and US $164 to US $547 for chlamydia. DISCUSSION: The STD PS resource needs depended on epidemic characteristics and program models. Integrating HIV prevention objectives minimally impacted PS-specific program costs. Results can inform program planning, future budget impact, and cost-effectiveness analyses.

Randomization-based analysis of covariance for inference in the sequential parallel comparison design.

The sequential parallel comparison design (SPCD), with sequence groups P:P, P:T, and T:T, together with the exclusion of the second-period information from placebo responders in the first period, can serve usefully for studies with highly favorable placebo response, for example, psychiatric clinical trials. This paper presents a methodology for the first-period treatment difference in the overall population and the second-period treatment difference in the placebo nonresponders for the first period, as well as other available sources of information that could be of potential interest. Without any assumptions, a hypothesis testing method is proposed based on the randomization distribution of comparisons using the covariance structure for the randomized population under the null hypothesis to control type I error. Randomization-based analysis of covariance (ANCOVA) is introduced to adjust for baseline and for the observations that serve as baselines for the second period. Related methods are proposed for the study population as a simple random sample of an almost infinite population. The statistical properties of the proposed methods are described with simulation studies; and the use of the methods is illustrated for an example based on the data from the ADAPT-A clinical trial.

Sequential parallel comparison design with binary and time-to-event outcomes.

Sequential parallel comparison design (SPCD) has been proposed to increase the likelihood of success of clinical trials especially trials with possibly high placebo effect. Sequential parallel comparison design is conducted with 2 stages. Participants are randomized between active therapy and placebo in stage 1. Then, stage 1 placebo nonresponders are rerandomized between active therapy and placebo. Data from the 2 stages are pooled to yield a single P value. We consider SPCD with binary and with time-to-event outcomes. For time-to-event outcomes, response is defined as a favorable event prior to the end of follow-up for a given stage of SPCD. We show that for these cases, the usual test statistics from stages 1 and 2 are asymptotically normal and uncorrelated under the null hypothesis, leading to a straightforward combined testing procedure. In addition, we show that the estimators of the treatment effects from the 2 stages are asymptotically normal and uncorrelated under the null and alternative hypothesis, yielding confidence interval procedures with correct coverage. Simulations and real data analysis demonstrate the utility of the binary and time-to-event SPCD.

Prevalence of Pre-antiretroviral-Treatment Drug Resistance by Gender, Age, and Other Factors in HIV-Infected Individuals Initiating Therapy in Kenya, 2013-2014.

Background: Pre-antiretroviral-treatment drug resistance (PDR) is a predictor of human immunodeficiency virus (HIV) treatment failure. We determined PDR prevalence and correlates in a Kenyan cohort. Methods: We conducted a cross-sectional analysis of antiretroviral (ARV) treatment-eligible HIV-infected participants. PDR was defined as ≥2% mutant frequency in a participant's HIV quasispecies at pol codons K103N, Y181C, G190A, M184 V, or K65R by oligonucleotide ligation assay and Illumina sequencing. PDR prevalence was calculated by demographics and codon, stratifying by prior ARV experience. Poisson regression was used to estimate prevalence ratios. Results: PDR prevalences (95% confidence interval [CI]) in 815 ARV-naive adults, 136 ARV-experienced adults, and 36 predominantly ARV-naive children were 9.4% (7.5%-11.7%), 12.5% (7.5%-19.3%), and 2.8% (0.1%-14.5%), respectively. Median mutant frequency within an individual's HIV quasispecies was 67%. PDR prevalence in ARV-naive women 18-24 years old was 21.9% (9.3%-40.0%). Only age in females associated with PDR: A 5-year age decrease was associated with adjusted PDR prevalence ratio 1.20 (95% CI, 1.06-1.36; P = .004). Conclusions: The high PDR prevalence may warrant resistance testing and/or alternative ARVs in high HIV prevalence settings, with attention to young women, likely to have recent infection and higher rates of resistance. Clinical Trials Registration: NCT01898754.

My femme friendship.

This autoethnographic study of femme friendship explores the connection and relationship between two femme lesbians-my femme friend Amber and myself. The shared experience of invisibility and the related perils and privileges that come with passing as straight enact a bond unlike any either of us have previously experienced. Meeting within the context of a polyamorous relationship adds a layer of complexity to our friendship that deepens the relationship. The story of our friendship showcases a specific sort of friendship, one grounded in theories of gender performance, sexuality, invisibility, and language.

Sample size re-estimation and other midcourse adjustments with sequential parallel comparison design.

Sequential parallel comparison design (SPCD) was proposed to reduce placebo response in a randomized trial with placebo comparator. Subjects are randomized between placebo and drug in stage 1 of the trial, and then, placebo non-responders are re-randomized in stage 2. Efficacy analysis includes all data from stage 1 and all placebo non-responding subjects from stage 2. This article investigates the possibility to re-estimate the sample size and adjust the design parameters, allocation proportion to placebo in stage 1 of SPCD, and weight of stage 1 data in the overall efficacy test statistic during an interim analysis.

How to Get Cost-Effectiveness Analysis Right? The Case of Vaccine Economics in Latin America.

BACKGROUND: In middle-income countries, vaccines against pneumococcal disease, rotavirus, and human papilloma virus are in general more costly, not necessarily cost saving, and less consistently cost-effective than earlier generation vaccines against measles, diphtheria, tetanus, and pertussis. Budget impact is also substantial; public spending on vaccines in countries adopting new vaccines is, on average, double the amount of countries that have not adopted. Policymakers must weigh the costs and benefits of the adoption decision carefully, given the low coverage of other kinds of cost-effective health and nonhealth interventions in these same settings and relatively flat overall public spending on health as a share of gross domestic product (GDP) over time. OBJECTIVE: This paper considers lessons learned from recent vaccine cost-effectiveness analyses and subsequent adoption decisions in Latin America a, largely under the auspices of the Pro Vac Initiative. RESULTS: The paper illustrates how small methodological choices and seemingly minor technical limitations of cost-effectiveness models can have major implications for the studies' conclusions, potentially influencing countries' subsequent vaccine adoption decisions. METHODS: We evaluate the ProVac models and technical outputs against the standards and framework set out by the International Decision Support Initiative Reference Case for economic evaluation and consider the practical effects of deviations from those standards. CONCLUSIONS: Lessons learned are discussed, including issues of appropriate comparators, GDP-based thresholds, and use of average versus incremental cost-effectiveness ratios as a convention are assessed. The article ends with recommendations for the future.

Can Radiologic Staging With Multiparametric MRI Enhance the Accuracy of the Partin Tables in Predicting Organ-Confined Prostate Cancer?

OBJECTIVE: The purpose of this study is to investigate the accuracy of multiparametric MRI with endorectal coil and Partin tables in predicting organ-confined (OC) prostate cancer in a contemporary cohort undergoing radical prostatectomy (RP) and to assess the possible added value of radiologic staging based on multiparametric MRI to the predictive accuracy of Partin tables. MATERIALS AND METHODS: One hundred fifty-eight consecutive subjects underwent 3-T multiparametric MRI with endorectal coil before RP between November 2010 and November 2013. Data were randomly split 60% and 40% into derivation (n = 95) and validation (n = 62) datasets. Multiparametric MRI was used to assess the radiologic stage, and logistic regression models were created using the derivation dataset and were fit on the independent validation dataset using multiparametric MRI staging alone and with prostate-specific antigen (PSA) level as the covariate. The probability of each patient to harbor OC disease was calculated using an updated version of Partin tables, using either clinical staging from digital rectal examination (DRE) or radiologic staging (multiparametric MRI). The AUC was calculated to evaluate accuracy of these predictive methods. RESULTS: The accuracy of multiparametric MRI to predict OC disease on pathologic analysis was greater (AUC, 0.88) than that of Partin tables (AUC, 0.70) and improved when multiparametric MRI was combined with PSA level (AUC, 0.91). The accuracy of Partin nomograms to predict OC disease decreased (AUC, 0.63) when staging was based on multiparametric MRI versus DRE. CONCLUSION: The superior predictive accuracy of multiparametric MRI compared with Partin tables to predict OC disease validates the results of smaller previously published studies. Although there is no added benefit of substituting multiparametric MRI stage for clinical stage when using Partin tables, multiparametric MRI staging information is valuable as a stand-alone test.

COVID-19 related messaging, beliefs, information sources, and mitigation behaviors in Virginia: a cross-sectional survey in the summer of 2020.

Background: Conflicting messages and misleading information related to the coronavirus (COVID-19) pandemic (SARS-CoV-2) have hindered mitigation efforts. It is important that trust in evidence-based public health information be maintained to effectively continue pandemic mitigation strategies. Officials, researchers, and the public can benefit from exploring how people receive information they believe and trust, and how their beliefs influence their behaviors. Methods: To gain insight and inform effective evidence-based public health messaging, we distributed an anonymous online cross-sectional survey from May to July, 2020 to Virginia residents, 18 years of age or older. Participants were surveyed about their perceptions of COVID-19, risk mitigation behaviors, messages and events they felt influenced their beliefs and behaviors, and where they obtained information that they trust. The survey also collected socio-demographic information, including gender, age, race, ethnicity, level of education, income, employment status, occupation, changes in employment due to the pandemic, political affiliation, sexual orientation, and zip code. Analyses included specific focus on the most effective behavioral measures: wearing a face mask and distancing in public. Results: Among 3,488 respondents, systematic differences were observed in information sources that people trust, events that impacted beliefs and behaviors, and how behaviors changed by socio-demographics, political identity, and geography within Virginia. Characteristics significantly associated (p < 0.025) with not wearing a mask in public included identifying as non-Hispanic white, male, Republican political identity, younger age, lower income, not trusting national science and health organizations, believing one or more non-evidence-based messages, and residing in Southwest Virginia in logistic regression. Similar, lesser in magnitude correlations, were observed for distancing in public. Conclusions: This study describes how information sources considered trustworthy vary across different populations and identities, and how these differentially correspond to beliefs and behaviors. This study can assist decision makers and the public to improve and effectively target public health messaging related to the ongoing COVID-19 pandemic and future public health challenges in Virginia and similar jurisdictions.

Metastatic Tropism in Urothelial Carcinoma With Variant Histology: A Comprehensive NCDB Analysis.

INTRODUCTION: Bladder cancer (BCa) with variant histology (VH) is notably aggressive and not as well studied as pure urothelial carcinoma (UC). The characteristics of variant BCa in the setting of metastatic disease may contribute to treatment response/resistance and subsequent disease progression. In this study, we sought to assess VH's impact on metastasis sites at presentation in metastatic BCa. METHODS: The National Cancer Database was queried from 2004 to 2019 to analyze cT1-4 cN0-3 cM1 patients with UC and VH BCa. The primary endpoint was the presence of metastasis to different organs. Binomial multivariable logistic regression was performed to determine the impact of VH on metastatic sites while controlling for multiple variables. RESULTS: Total 6005 eligible patients diagnosed with either UC or VH were included. Patients with small cell histology, the second most common VH, were more likely to have liver metastasis (OR: 4.335) while less likely to have lung metastases (OR: 0.521). Squamous cell carcinoma decreased the odds of bone metastasis (OR: 0.449). Adenocarcinoma increased the odds of lung metastases (OR: 1.690). Micropapillary VH is less likely to metastasize to the lungs (OR: 0.182) but more likely to spread to nonregional lymph nodes (OR: 2.623). Sarcomatoid subtype did not exhibit a statistically significant variation in the odds ratio for any of the metastatic sites. CONCLUSION: This study comprehensively analyzes the limited research regarding metastatic BCa and VH. Our analysis underscores each subtype exhibiting heterogeneous metastatic tropism. Importantly, these findings illustrate the role of routine somatic gene expression profiling to guide adequate staging and treatment intensification and to offer a foundation for future studies of VH BCa care.

Neonatal serious illness: operational definition.

OBJECTIVES: (1) To operationalise our previously published definition of neonatal serious illness by applying it to a patient cohort and (2) to evaluate timing of palliative care consultation, goals of care discussions and meeting serious illness criteria. METHODS: This was a retrospective chart review. Inborn neonates delivered between January 2006 and December 2020 who died prior to neonatal intensive care unit discharge were identified through EPIC query. Kruskal-Wallis and Mann-Whitney-U tests were used to compare time intervals relating to transition to serious illness across causes of death and other factors. χ2 tests were used to examine frequency of goals of care conversations by factors. RESULTS: Eighty-eight per cent of patients met criteria for neonatal serious illness within 48 hours of life. There were no significant differences in transition to serious illness between preterm and term infants. Time to identification of serious illness varied significantly by cause of death. Palliative care was consulted for 5.7% of patients. CONCLUSION: All patients met criteria for serious illness early in life based on our definition. This definition may be useful for identifying neonates with serious illness in time to provide support. Additional work is needed to apply this definition prospectively to explore its utility for clinical care and research.

Open-Label, Single-Arm Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Clear Cell Renal Cell Carcinoma.

PURPOSE: Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS: In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS: In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION: Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

Open-Label, Single-Arm, Phase II Study of Pembrolizumab Monotherapy as First-Line Therapy in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma.

PURPOSE: Programmed death 1 (PD-1) pathway inhibitors have not been prospectively evaluated in patients with non-clear cell renal cell carcinoma (nccRCC). The phase II KEYNOTE-427 study (cohort B) was conducted to assess the efficacy and safety of single-agent pembrolizumab, a PD-1 inhibitor, in advanced nccRCC. METHODS: Patients with histologically confirmed, measurable (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) nccRCC and no prior systemic therapy received pembrolizumab 200 mg intravenously once every 3 weeks for ≤ 24 months. The primary end point was objective response rate (ORR) per RECIST v1.1. RESULTS: Among enrolled patients (N = 165), 71.5% had confirmed papillary, 12.7% had chromophobe, and 15.8% had unclassified RCC histology. Most patients (67.9%) had intermediate or poor International Metastatic RCC Database Consortium risk status and tumors with programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥ 1 (61.8%). The median time from enrollment to database cutoff was 31.5 months (range, 22.7-38.8). In all patients, the ORR was 26.7%. The median duration of response was 29.0 months; 59.7% of responses lasted ≥ 12 months. The ORR by CPS ≥ 1 and CPS < 1 status was 35.3% and 12.1%, respectively. The ORR by histology was 28.8% for papillary, 9.5% for chromophobe, and 30.8% for unclassified. Overall, the median progression-free survival was 4.2 months (95% CI, 2.9 to 5.6); the 24-month rate was 18.6%. The median overall survival was 28.9 months (95% CI, 24.3 months to not reached); the 24-month rate was 58.4%. Overall, 69.7% of patients reported treatment-related adverse events, most commonly pruritus (20.0%) and hypothyroidism (14.5%). Two deaths were treatment related (pneumonitis and cardiac arrest). CONCLUSION: First-line pembrolizumab monotherapy showed promising antitumor activity in nccRCC. The safety profile was similar to that observed in other tumor types.

Husbandry of Monodelphis domestica in the study of mammalian embryogenesis.

Monodelphis domestica, commonly called the laboratory opossum, is a useful laboratory animal for studying marsupial embryogenesis and mammalian development. Females breed year-round and the animals can be sustainably bred indoors. The authors draw on their own laboratory's experience to supplement previously published research on laboratory opossums. They describe a breeding protocol that reliably produces timed-pregnant M. domestica. Additionally, the authors discuss general laboratory opossum husbandry techniques and describe how to collect, handle and culture embryos.

Value-based tiered pricing for universal health coverage: an idea worth revisiting.

The pricing of medicines and health products ranks among the most hotly debated topics in health policy, generating controversy in richer and poorer markets alike. Creating the right pricing structure for pharmaceuticals and other healthcare products is particularly important for low- and middle-income countries, where pharmaceuticals account for a significant portion of total health expenditure; high medicine prices therefore threaten the feasibility and sustainability of nascent schemes for universal health coverage (UHC). We argue that a strategic system of value-based tiered pricing (VBTP), wherein each country would pay a price for each health product commensurate with the local value it provides, could improve access, enhance efficiency, and empower countries to negotiate with product manufacturers. This paper attempts to further understanding on the potential value of tiered pricing, barriers to its implementation, and potential strategies to overcome those.