Time-varying associations of patient and tumor characteristics with cancer survival: an analysis of SEER data across 14 cancer sites, 2004-2017.

PURPOSE: Surveillance, Epidemiology, and End Results (SEER) cancer registries provides information about survival duration and cause of death for cancer patients. Baseline demographic and tumor characteristics such as age, sex, race, year of diagnosis, and tumor stage can inform the expected survival time of patients, but their associations with survival may not be constant over the post-diagnosis period. METHODS: Using SEER data, we examined if there were time-varying associations of patient and tumor characteristics on survival, and we assessed how these relationships differed across 14 cancer sites. Standard Cox proportional hazards models were extended to allow for time-varying associations and incorporated into a competing-risks framework, separately modeling cancer-specific and other-cause deaths. For each cancer site and for each of the five factors, we estimated the relative hazard ratio and absolute hazard over time in the presence of competing risks. RESULTS: Our comprehensive consideration of patient and tumor characteristics when estimating time-varying hazards showed that the associations of age, tumor stage at diagnosis, and race/ethnicity with risk of death (cancer-specific and other-cause) change over time for many cancers; characteristics of sex and year of diagnosis exhibit some time-varying patterns as well. Stage at diagnosis had the largest associations with survival. CONCLUSION: These findings suggest that proportional hazards assumptions are often violated when examining patient characteristics on cancer survival post-diagnosis. We discuss several interesting results where the relative hazards are time-varying and suggest possible interpretations. Based on the time-varying associations of several important covariates on survival after cancer diagnosis using a pan-cancer approach, the likelihood of the proportional hazards assumption being met or corresponding interpretation should be considered in survival analyses, as flawed inference may have implications for cancer care and policy.

Spinal cord injury-induced neurogenic bowel: A role for host-microbiome interactions in bowel pain and dysfunction.

Background and aims: Spinal cord injury (SCI) affects roughly 300,000 Americans with 17,000 new cases added annually. In addition to paralysis, 60% of people with SCI develop neurogenic bowel (NB), a syndrome characterized by slow colonic transit, constipation, and chronic abdominal pain. The knowledge gap surrounding NB mechanisms after SCI means that interventions are primarily symptom-focused and largely ineffective. The goal of the present studies was to identify mechanism(s) that initiate and maintain NB after SCI as a critical first step in the development of evidence-based, novel therapeutic treatment options. Methods: Following spinal contusion injury at T9, we observed alterations in bowel structure and function reflecting key clinical features of NB. We then leveraged tissue-specific whole transcriptome analyses (RNAseq) and fecal 16S rRNA amplicon sequencing in combination with histological, molecular, and functional (Ca2+ imaging) approaches to identify potential mechanism(s) underlying the generation of the NB phenotype. Results: In agreement with prior reports focused on SCI-induced changes in the skin, we observed a rapid and persistent increase in expression of calcitonin gene-related peptide (CGRP) expression in the colon. This is suggestive of a neurogenic inflammation-like process engaged by antidromic activity of below-level primary afferents following SCI. CGRP has been shown to disrupt colon homeostasis and negatively affect peristalsis and colon function. As predicted, contusion SCI resulted in increased colonic transit time, expansion of lymphatic nodules, colonic structural and genomic damage, and disruption of the inner, sterile intestinal mucus layer corresponding to increased CGRP expression in the colon. Gut microbiome colonization significantly shifted over 28 days leading to the increase in Anaeroplasma, a pathogenic, gram-negative microbe. Moreover, colon specific vagal afferents and enteric neurons were hyperresponsive after SCI to different agonists including fecal supernatants. Conclusions: Our data suggest that SCI results in overexpression of colonic CGRP which could alter colon structure and function. Neurogenic inflammatory-like processes and gut microbiome dysbiosis can also sensitize vagal afferents, providing a mechanism for visceral pain despite the loss of normal sensation post-SCI. These data may shed light on novel therapeutic interventions targeting this process to prevent NB development in patients.

Student Opposition to University Pouring Rights Contracts.

Introduction: The majority of large public universities have exclusive pouring rights contracts with beverage companies that produce and market sugar-sweetened beverages. Pouring rights contracts contain provisions that conflict with recommendations from major public health organizations that institutions reduce sugar-sweetened beverage availability, marketing, and consumption. This study assessed the following among students at 3 public universities: student perception of pouring rights contracts (the extent to which they favored or opposed pouring rights contracts), the association between student socioeconomic characteristics and perception of pouring rights contracts, student estimates of pouring rights contract revenue, and the association between student pouring rights contract revenue estimates and perception of pouring rights contracts. To contextualize results, actual pouring rights contract revenue as a percentage of total revenues was estimated. Methods: A cross-sectional exploratory study was conducted among a convenience sample of 1,311 undergraduate sugar-sweetened beverages-consuming students recruited from 3 large and diverse public universities in Northern California. On an online questionnaire, undergraduate students indicated the extent to which they favored or opposed pouring rights contracts on a 10-point scale (oppose=1-5, favor=6-10) and provided a numeric estimate of the percentage of total university revenue they thought their university's pouring rights contract generated. Regression models were used to analyze differences in perception of pouring rights contracts by student socioeconomic characteristics and estimates of university revenues generated by pouring rights contracts. In addition, pouring rights contracts and financial reports were obtained from the 3 universities to estimate actual pouring rights contract revenue as a percentage of total revenues. Survey data were collected between August and November 2018 and analyzed in August 2022. Results: A large majority of students (81%) opposed pouring rights contracts, and the opposition did not significantly differ by student socioeconomic characteristics, including by levels of food security, need-based financial aid, participation in federal food assistance or healthcare programs, parental education, or parental income (all ps>0.14). The median student estimate for pouring rights contract revenue as a percentage of total university revenue was 10%. In contrast, the estimated actual annual revenue generated from the pouring rights contracts ranged from 0.01% to 0.04% at these schools. Revenue estimates were not significantly associated with participants' opposition or favoring of pouring rights contracts (p=0.65). Conclusions: A large majority of students opposed pouring rights contracts, and this opposition was similar regardless of student socioeconomic characteristics or student estimates of pouring rights contract revenues. Students markedly overestimated (by >100-1,000-fold) the percentage of university revenue that came from pouring rights contracts. University administration should consider student views on pouring rights contracts when deciding whether to exit or continue with pouring rights contracts.

Building a vertically integrated genomic learning health system: The biobank at the Colorado Center for Personalized Medicine.

Precision medicine initiatives across the globe have led to a revolution of repositories linking large-scale genomic data with electronic health records, enabling genomic analyses across the entire phenome. Many of these initiatives focus solely on research insights, leading to limited direct benefit to patients. We describe the biobank at the Colorado Center for Personalized Medicine (CCPM Biobank) that was jointly developed by the University of Colorado Anschutz Medical Campus and UCHealth to serve as a unique, dual-purpose research and clinical resource accelerating personalized medicine. This living resource currently has more than 200,000 participants with ongoing recruitment. We highlight the clinical, laboratory, regulatory, and HIPAA-compliant informatics infrastructure along with our stakeholder engagement, consent, recontact, and participant engagement strategies. We characterize aspects of genetic and geographic diversity unique to the Rocky Mountain region, the primary catchment area for CCPM Biobank participants. We leverage linked health and demographic information of the CCPM Biobank participant population to demonstrate the utility of the CCPM Biobank to replicate complex trait associations in the first 33,674 genotyped individuals across multiple disease domains. Finally, we describe our current efforts toward return of clinical genetic test results, including high-impact pathogenic variants and pharmacogenetic information, and our broader goals as the CCPM Biobank continues to grow. Bringing clinical and research interests together fosters unique clinical and translational questions that can be addressed from the large EHR-linked CCPM Biobank resource within a HIPAA- and CLIA-certified environment.

Virtual 3D Specimen Mapping in Head & Neck Oncologic Surgery.

OBJECTIVES: Virtual 3D specimen mapping of oncologic surgical specimens provides a visual record of the specimen and margin sampling sites which can be utilized in a variety of cancer care settings. Our objective was to perform a retrospective review of head and neck surgical oncology cases where the specimen was mapped post-operatively and to evaluate the utility of these 3D specimen maps amongst the multidisciplinary cancer care team. METHODS: A retrospective review of our 3D specimen model biorepository was performed. Surgical specimens were 3D scanned and then graphically annotated (or "mapped") during routine pathologic processing. The resulting 3D specimen maps were distributed to the multidisciplinary oncologic care team. Final margin status and any use of the 3D specimen maps were recorded. RESULTS: A total of 28 cases were included. Virtual 3D specimen maps were utilized by the cancer care team in 8 cases (29%), including 2 positive margin cases, 2 close margin cases, and 4 indeterminate margin cases. 3D specimen maps were used to visualize positive margin sites for pathologist-surgeon communication as a visual reference during tumor board discussions and to inform radiation treatment planning. CONCLUSION: Post-operative virtual 3D specimen mapping of oncologic specimens creates a permanent visual record of the specimen and the margins sampled and may serve as a beneficial tool for communication amongst the multidisciplinary cancer care team. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:191-197, 2024.

Surrogacy validation for time-to-event outcomes with illness-death frailty models.

A common practice in clinical trials is to evaluate a treatment effect on an intermediate outcome when the true outcome of interest would be difficult or costly to measure. We consider how to validate intermediate outcomes in a causally-valid way when the trial outcomes are time-to-event. Using counterfactual outcomes, those that would be observed if the counterfactual treatment had been given, the causal association paradigm assesses the relationship of the treatment effect on the surrogate outcome with the treatment effect on the true, primary outcome. In particular, we propose illness-death models to accommodate the censored and semicompeting risk structure of survival data. The proposed causal version of these models involves estimable and counterfactual frailty terms. Via these multistate models, we characterize what a valid surrogate would look like using a causal effect predictiveness plot. We evaluate the estimation properties of a Bayesian method using Markov chain Monte Carlo and assess the sensitivity of our model assumptions. Our motivating data source is a localized prostate cancer clinical trial where the two survival outcomes are time to distant metastasis and time to death.

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding.

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception. However, an inhibitor against this kinase with exquisite selectivity has not reached the market because of the structural similarity between CDKs. In this paper, we describe the development and mechanism of action of type III inhibitors that bind CDK2 with nanomolar affinity. Notably, these anthranilic acid inhibitors exhibit a strong negative cooperative relationship with cyclin binding, which remains an underexplored mechanism for CDK2 inhibition. Furthermore, the binding profile of these compounds in both biophysical and cellular assays demonstrate the promise of this series for further development into a therapeutic selective for CDK2 over highly similar kinases like CDK1. The potential of these inhibitors as contraceptive agents is seen by incubation with spermatocyte chromosome spreads from mouse testicular explants, where they recapitulate Cdk2-/- and Spdya-/- phenotypes.

A Conversation About the Ethics of Past and Future Memory Care Models: Perspectives from the First Two European Dementia Villages.

Dementia care organizations face a range of daunting environmental changes and challenges. Internationally, there is a long history of efforts to improve quality of care and life for individuals with dementia. In a time of particular attention to the images of older adults confined to a single or shared room in a care facility due to COVID-19, autonomy becomes the overarching problem, not only because in general institutions limit the freedom of frail elders, but because the existential conditions that create the need for long term care such as chronic disease, cognitive decline, and the need for general support with activities of daily living (ADLs) rail against the autonomy of independent self-sufficiency. Additionally, these environments are institutional in design and size, with little access to outdoor spaces and other amenities. This perspective manuscript addresses the ethics of past and future memory care models, looking specifically at the European Dementia Village (DV) model. This model allows for autonomy and continuation of patterns of daily living through housing integrated with exterior walks, gardens, restaurants, and amenities within familiar and normal surroundings. This pioneering health care experiment negotiates rivaling discourses of intimacy, professionalization, and medicalization. In order to get a deeper understanding of the culture and ethics of this integrated care model, the first two dementia village sites were visited which included meetings with care staff and administrators. Those conversations and observations led to a series of aligned themes relating to the ethics of the DV model which include: the strength of the social approach, clinical support, resident/staff collaborations, and advocating for ethical dementia care. Rethinking the ethics of dementia care entails individual perspectives and group discussions on what can keep individuals social connected within their care community, including focusing on strengths of the individual and normalized daily routines.

Solutions for surrogacy validation with longitudinal outcomes for a gene therapy.

Valid surrogate endpoints S can be used as a substitute for a true outcome of interest T to measure treatment efficacy in a clinical trial. We propose a causal inference approach to validate a surrogate by incorporating longitudinal measurements of the true outcomes using a mixed modeling approach, and we define models and quantities for validation that may vary across the study period using principal surrogacy criteria. We consider a surrogate-dependent treatment efficacy curve that allows us to validate the surrogate at different time points. We extend these methods to accommodate a delayed-start treatment design where all patients eventually receive the treatment. Not all parameters are identified in the general setting. We apply a Bayesian approach for estimation and inference, utilizing more informative prior distributions for selected parameters. We consider the sensitivity of these prior assumptions as well as assumptions of independence among certain counterfactual quantities conditional on pretreatment covariates to improve identifiability. We examine the frequentist properties (bias of point and variance estimates, credible interval coverage) of a Bayesian imputation method. Our work is motivated by a clinical trial of a gene therapy where the functional outcomes are measured repeatedly throughout the trial.

Persistent organic pollutant exposure contributes to Black/White differences in leukocyte telomere length in the National Health and Nutrition Examination Survey.

Despite racial disparities in diseases of aging and premature mortality, non-Hispanic Black Americans tend to have longer leukocyte telomere length (LTL), a biomarker of cellular aging, than non-Hispanic White Americans. Previous findings suggest that exposure to certain persistent organic pollutants (POPs) is both racially-patterned and associated with longer LTL. We examine whether Black/White differences in LTL are explained by differences in exposure to 15 POPs by estimating the indirect effect (IE) of self-reported race on LTL that is mediated through nine polychlorinated biphenyls (PCBs), three furans, and three dioxins, as well as their mixtures. Our study population includes 1,251 adults from the 1999-2000 and 2001-2002 cycles of the cross-sectional National Health and Nutrition Examination Survey. We characterized single-pollutant mediation effects by constructing survey-weighted linear regression models. We also implemented various approaches to quantify a global mediation effect of all POPs, including unpenalized linear regression, ridge regression, and examination of three summary exposure scores. We found support for the hypothesis that exposure to PCBs partially mediates Black/White differences in LTL. In single-pollutant models, there were significant IEs of race on LTL through six individual PCBs (118, 138, 153, 170, 180, and 187). Ridge regression (0.013, CI 0.001, 0.023; 26.0% mediated) and models examining summative exposure scores with linear combinations derived from principal components analysis (0.019, CI 0.009, 0.029; 34.8% mediated) and Toxic Equivalency Quotient (TEQ) scores (0.016, CI 0.005, 0.026; 28.8% mediated) showed significant IEs when incorporating survey weights. Exposures to individual POPs and their mixtures, which may arise from residential and occupational segregation, may help explain why Black Americans have longer LTL than their White counterparts, providing an environmental explanation for counterintuitive race differences in cellular aging.

Combined comparative genomics and clinical modeling reveals plasmid-encoded genes are independently associated with Klebsiella infection.

Members of the Klebsiella pneumoniae species complex frequently colonize the gut and colonization is associated with subsequent infection. To identify genes associated with progression from colonization to infection, we undertook a case-control comparative genomics study. Concordant cases (N = 85), where colonizing and invasive isolates were identical strain types, were matched to asymptomatically colonizing controls (N = 160). Thirty-seven genes are associated with infection, 27 of which remain significant following adjustment for patient variables and bacterial phylogeny. Infection-associated genes are not previously characterized virulence factors, but instead a diverse group of stress resistance, regulatory and antibiotic resistance genes, despite careful adjustment for antibiotic exposure. Many genes are plasmid borne, and for some, the relationship with infection is mediated by gut dominance. Five genes were validated in a geographically-independent cohort of colonized patients. This study identifies several genes reproducibly associated with progression to infection in patients colonized by diverse Klebsiella.

The case for investing in the prevention and control of non-communicable diseases in the six countries of the Gulf Cooperation Council: an economic evaluation.

BACKGROUND: While the non-communicable disease (NCD) burden in the countries of the Gulf Cooperation Council (GCC) (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates) has surged over the past decades, the costs and return on investment (ROI) of implementing cost-effective, WHO-recommended NCD interventions have not been established. METHODS: We performed an economic analysis to estimate the ROI from scaling up four sets of NCD interventions over 15 years. We estimated the direct costs of the four main NCDs (cancer, diabetes, cardiovascular diseases and chronic respiratory diseases) using a prevalence-based, bottom-up cost-of-illness approach. We estimated indirect costs based on productivity loss due to absenteeism, presenteeism and premature deaths. We costed the scaling up of interventions using the WHO Costing Tool and assessed the health impact of interventions using the OneHealth Tool. We calculated ROI by comparing productivity and social benefits with the total costs of implementing the interventions. RESULTS: The four main NCDs cost the GCC economy nearly US$50 billion in 2019, equal to 3.3% of its gross domestic product. The indirect costs are estimated at US$20 billion or 40% of the total burden. Implementing the four modelled intervention packages in the six GCC countries over 15 years will cost US$14 billion, with an ROI of US$4.9 for every US$1 invested and significant health and social benefits, including 290 000 averted premature deaths. CONCLUSION: Based on the results of these six investment cases, we recommend actions to scale up current WHO-recommended cost-effective interventions, strengthen whole-of-government action, drive the NCD legislative agenda, build out the evidence base, generate additional advocacy material, and increase regional collaboration and data-sharing to establish best practices and monitor impact.

A multi-phase intervention study of sports bra prescription for elite UK female athletes preparing for the Tokyo Olympics and Paralympics.

Athletes report poor breast/bra knowledge, breast pain, sports bras causing lacerations and chafing, negatively affecting sports performance. No bra interventions to address these issues are reported. Working with 142 UK female athletes preparing for Tokyo Olympics/Paralympics (27 sports), this multi-phase intervention assessed breast/bra knowledge, preferences, issues via surveys and breast/bra assessments. Data were used to develop two sports bras. A total of 112 athletes were prescribed one of the new bras through individual assessments. After four weeks, wear athletes completed evaluations. Pre-intervention breast/bra knowledge was low (83% ≤average), multiple breast/bra issues were reported and most athletes wore ill-fitting, loose bras, offering limited support. Post-intervention, 63% reported improved knowledge and 97% reported their prescribed bra as better than their original bra. Eighty-seven per cent reported benefitting from this intervention, with 17% reporting improved performance. This intervention effectively assessed sports bra needs, developed and implemented solutions, which improved knowledge and potentially performance for some UK athletes.

TAK-676: A Novel Stimulator of Interferon Genes (STING) Agonist Promoting Durable IFN-dependent Antitumor Immunity in Preclinical Studies.

Oncology therapies targeting the immune system have improved patient outcomes across a wide range of tumor types, but resistance due to an inadequate T-cell response in a suppressive tumor microenvironment (TME) remains a significant problem. New therapies that activate an innate immune response and relieve this suppression may be beneficial to overcome this hurdle. TAK-676 is a synthetic novel stimulator of interferon genes (STING) agonist designed for intravenous administration. Here we demonstrate that TAK-676 dose-dependently triggers activation of the STING signaling pathway and activation of type I interferons. Furthermore, we show that TAK-676 is a highly potent modulator of both the innate and adaptive immune system and that it promotes the activation of dendritic cells, natural killer cells, and T cells in preclinical models. In syngeneic murine tumor models in vivo, TAK-676 induces dose-dependent cytokine responses and increases the activation and proliferation of immune cells within the TME and tumor-associated lymphoid tissue. We also demonstrate that TAK-676 dosing results in significant STING-dependent antitumor activity, including complete regressions and durable memory T-cell immunity. We show that TAK-676 is well tolerated, exhibits dose-proportional pharmacokinetics in plasma, and exhibits higher exposure in tumor. The intravenous administration of TAK-676 provides potential treatment benefit in a broad range of tumor types. Further study of TAK-676 in first-in-human phase I trials is ongoing. Significance: TAK-676 is a novel systemic STING agonist demonstrating robust activation of innate and adaptive immune activity resulting in durable antitumor responses within multiple syngeneic tumor models. Clinical investigation of TAK-676 is ongoing.

Estimating COVID-19 Vaccination and Booster Effectiveness Using Electronic Health Records From an Academic Medical Center in Michigan.

Introduction: Observational studies of COVID-19 vaccines' effectiveness can provide crucial information regarding the strength and durability of protection against SARS-CoV-2 infection and whether the protective response varies across different patient subpopulations and in the context of different SARS-CoV-2 variants. Methods: We used a test-negative study design to assess vaccine effectiveness against SARS-CoV-2 infection and severe COVID-19 resulting in hospitalization, intensive care unit admission, or death using electronic health records data of 170,741 adults who had been tested for COVID-19 at the University of Michigan Medical Center between January 1 and December 31, 2021. We estimated vaccine effectiveness by comparing the odds of vaccination between cases and controls during each 2021 calendar quarter and stratified all outcomes by vaccine type, patient demographic and clinical characteristics, and booster status. Results: Unvaccinated individuals had more than double the rate of infections (12.1% vs 4.7%) and >3 times the rate of severe COVID-19 outcomes (1.4% vs 0.4%) than vaccinated individuals. COVID-19 vaccines were 62.1% (95% CI=60.3, 63.8) effective against a new infection, with protection waning in the last 2 quarters of 2021. The vaccine effectiveness against severe disease overall was 73.7% (95% CI=69.6, 77.3) and remained high throughout 2021. Data from the last quarter of 2021 indicated that adding a booster dose augmented effectiveness against infection up to 87.3% (95% CI=85.0, 89.2) and against severe outcomes up to 94.0% (95% CI=89.5, 96.6). Pfizer-BioNTech and Moderna vaccines showed comparable performance when controlling for vaccination timing. Vaccine effectiveness was greater in more socioeconomically affluent areas and among healthcare workers; otherwise, we did not detect any significant modification of vaccine effectiveness by covariates, including gender, race, and SES. Conclusions: COVID-19 vaccines were highly protective against infection and severe COVID-19 resulting in hospitalization, intensive care unit admission, or death. Administration of a booster dose significantly increased vaccine effectiveness against both outcomes. Ongoing surveillance is required to assess the durability of these findings.

Compartmental and COMSOL Multiphysics 3D Modeling of Drug Diffusion to the Vitreous Following the Administration of a Sustained-Release Drug Delivery System.

The purpose of this study was to examine antibiotic drug transport from a hydrogel drug delivery system (DDS) using a computational model and a 3D model of the eye. Hydrogel DDSs loaded with vancomycin (VAN) were synthesized and release behavior was characterized in vitro. Four different compartmental and four COMSOL models of the eye were developed to describe transport into the vitreous originating from a DDS placed topically, in the subconjunctiva, subretinally, and intravitreally. The concentration of the simulated DDS was assumed to be the initial concentration of the hydrogel DDS. The simulation was executed over 1500 and 100 h for the compartmental and COMSOL models, respectively. Based on the MATLAB model, topical, subconjunctival, subretinal and vitreous administration took most (~500 h to least (0 h) amount of time to reach peak concentrations in the vitreous, respectively. All routes successfully achieved therapeutic levels of drug (0.007 mg/mL) in the vitreous. These models predict the relative build-up of drug in the vitreous following DDS administration in four different points of origin in the eye. Our model may eventually be used to explore the minimum loading dose of drug required in our DDS leading to reduced drug use and waste.

Community Visioning for Innovation in Integrated Dementia Care: Stakeholder Focus Group Outcomes.

It is estimated that 5.4 million Americans have some form of dementia and these numbers are expected to rise in the coming decades, leading to an unprecedented demand for memory care housing and services. In searching for innovative options to create more autonomy and better quality of life in dementia care settings, repurposing existing structures, in particular vacant urban malls, may be 1 option for the large sites needed for the European model of dementia villages. These settings may become sustainable Dementia Friendly City Centers (DFCC), because in the case of enclosed mall construction, the internal infrastructure is in place for lighting, HVAC, with varied spatial configuration of public spaces. This paper describes the community engagement research being conducted by a research team at a Midwestern university, laying groundwork for the DFCC model for centralized dementia programs, services, and attached housing. Using graphics and plans for the DFCC model using an 800 000 ft2 closed mall site, focus groups were conducted with family caregivers of individuals with dementia and long-term care residents to gather their input and response to the model. The participants identified both opportunities and barriers in using an adaptive reuse of a large site for an innovative integrated dementia care model and through the cross-case analysis of the focus group findings, 5 themes were identified which include: community education and acceptance; amenities and activities; maintaining family connections; resident adaptation and staffing.

Incorporating baseline covariates to validate surrogate endpoints with a constant biomarker under control arm.

A surrogate endpoint S in a clinical trial is an outcome that may be measured earlier or more easily than the true outcome of interest T. In this work, we extend causal inference approaches to validate such a surrogate using potential outcomes. The causal association paradigm assesses the relationship of the treatment effect on the surrogate with the treatment effect on the true endpoint. Using the principal surrogacy criteria, we utilize the joint conditional distribution of the potential outcomes T, given the potential outcomes S. In particular, our setting of interest allows us to assume the surrogate under the placebo, S(0) , is zero-valued, and we incorporate baseline covariates in the setting of normally distributed endpoints. We develop Bayesian methods to incorporate conditional independence and other modeling assumptions and explore their impact on the assessment of surrogacy. We demonstrate our approach via simulation and data that mimics an ongoing study of a muscular dystrophy gene therapy.

Measurement of Klebsiella Intestinal Colonization Density To Assess Infection Risk.

Klebsiella pneumoniae and the closely related species K. variicola and K. quasipneumoniae are common causes of health care-associated infections, and patients frequently become infected with their intestinal colonizing strain. To assess the association between Klebsiella colonization density and subsequent infections, a case-control study was performed. A multiplex quantitative PCR (qPCR) assay was developed and validated to quantify Klebsiella (K. pneumoniae, K. variicola, and K. quasipneumoniae combined) relative to total bacterial DNA copies in rectal swabs. Cases of Klebsiella infection were identified based on clinical definitions and having a clinical culture isolate and a preceding or coincident colonization isolate with the same wzi capsular sequence type. Controls were colonized patients without subsequent infection and were matched 2:1 to cases based on age, sex, and rectal swab collection date. qPCR from rectal swab samples was used to measure the association between the relative abundance of Klebsiella and subsequent infections. The Klebsiella relative abundance by qPCR was highly correlated with 16S sequencing (ρ = 0.79; P < 0.001). The median Klebsiella relative abundance was higher in cases (15.7% [interquartile range {IQR}, 0.93 to 52.6%]) (n = 83) than in controls (1.01% [IQR, 0.02 to 12.8%]) (n = 155) (P < 0.0001). Adjusting for multiple clinical covariates using inverse probability of treatment weighting, a Klebsiella relative abundance of >22% was associated with infection overall (odds ratio [OR], 2.87 [95% confidence interval {CI}, 1.64 to 5.03]) (P = 0.0003) and with bacteremia in a secondary analysis (OR, 4.137 [95% CI, 1.448 to 11.818]) (P = 0.0084). Measurement of colonization density by qPCR could represent a novel approach to identify hospitalized patients at risk for Klebsiella infection. IMPORTANCE Colonization by bacterial pathogens often precedes infection and offers a window of opportunity to prevent these infections in the first place. Klebsiella colonization is significantly and reproducibly associated with subsequent infection; however, factors that enhance or mitigate this risk in individual patients are unclear. This study developed an assay to measure the density of Klebsiella colonization, relative to total fecal bacteria, in rectal swabs from hospitalized patients. Applying this assay to 238 colonized patients, a high Klebsiella density, defined as >22% of total bacteria, was significantly associated with subsequent infection. Based on widely available PCR technology, this type of assay could be deployed in clinical laboratories to identify patients at an increased risk of Klebsiella infections. As novel therapeutics are developed to eliminate pathogens from the gut microbiome, a rapid Klebsiella colonization density assay could identify patients who would benefit from this type of infection prevention intervention.

Current Key Challenges in Managing Maternal Sepsis.

Sepsis resulting from maternal infection is the second leading cause of pregnancy-related death. Although screening and initial care of a septic nonpregnant patient is standardized in nonpregnant adults, many challenges exist for early recognition and management of sepsis and septic shock in the obstetric population. Because most sepsis research excludes pregnant patients, there are many challenges that contribute to a lack of standardized approach to maternal sepsis. These challenges include inconsistent early warning sign criteria, lack of validated screening tools, adaptation of bundle components for maternal physiology, delivery considerations, and knowing when to transfer the patient to a higher level of care. To overcome these challenges, reduce variation in care, and improve patient outcomes, it is important for clinicians to plan, practice, and implement a maternal sepsis bundle.