External Validation of Prognostic Models in Critical Care: A Cautionary Tale From COVID-19 Pneumonitis.

OBJECTIVES BACKGROUND: To externally validate clinical prediction models that aim to predict progression to invasive ventilation or death on the ICU in patients admitted with confirmed COVID-19 pneumonitis. DESIGN: Single-center retrospective external validation study. DATA SOURCES: Routinely collected healthcare data in the ICU electronic patient record. Curated data recorded for each ICU admission for the purposes of the U.K. Intensive Care National Audit and Research Centre (ICNARC). SETTING: The ICU at Manchester Royal Infirmary, Manchester, United Kingdom. PATIENTS: Three hundred forty-nine patients admitted to ICU with confirmed COVID-19 Pneumonitis, older than 18 years, from March 1, 2020, to February 28, 2022. Three hundred two met the inclusion criteria for at least one model. Fifty-five of the 349 patients were admitted before the widespread adoption of dexamethasone for the treatment of severe COVID-19 (pre-dexamethasone patients). OUTCOMES: Ability to be externally validated, discriminate, and calibrate. METHODS: Articles meeting the inclusion criteria were identified, and those that gave sufficient details on predictors used and methods to generate predictions were tested in our cohort of patients, which matched the original publications' inclusion/exclusion criteria and endpoint. RESULTS: Thirteen clinical prediction articles were identified. There was insufficient information available to validate models in five of the articles; a further three contained predictors that were not routinely measured in our ICU cohort and were not validated; three had performance that was substantially lower than previously published (range C-statistic = 0.483-0.605 in pre-dexamethasone patients and C = 0.494-0.564 among all patients). One model retained its discriminative ability in our cohort compared with previously published results (C = 0.672 and 0.686), and one retained performance among pre-dexamethasone patients but was poor in all patients (C = 0.793 and 0.596). One model could be calibrated but with poor performance. CONCLUSIONS: Our findings, albeit from a single center, suggest that the published performance of COVID-19 prediction models may not be replicated when translated to other institutions. In light of this, we would encourage bedside intensivists to reflect on the role of clinical prediction models in their own clinical decision-making.

Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

ABSTRACT: High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL. We sequenced DNA from 371 individuals with HCMBL using a targeted sequencing panel of 59 recurrently mutated genes in CLL to identify high-impact mutations. We compared the sequencing results with that of our treatment-naïve CLL cohort (N = 855) and used Cox regression to estimate hazard ratios and 95% confidence intervals (CIs) for associations with TTFT. The frequencies of any mutated genes were lower in HCMBL (52%) than CLL (70%). At 10 years, 37% of individuals with HCMBL with any mutated gene had progressed requiring treatment compared with 10% among individuals with HCMBL with no mutations; this led to 5.4-fold shorter TTFT (95% CI, 2.6-11.0) among HCMBL with any mutated gene vs none, independent of CLL-IPI. When considering individuals with low risk of progression according to CLL-IPI, those with HCMBL with any mutations had 4.3-fold shorter TTFT (95% CI, 1.6-11.8) vs those with none. Finally, when considering both CLL-IPI and any mutated gene status, we observed individuals with HCMBL who were high risk for both prognostic factors had worse prognosis than patients with low-risk CLL (ie, 5-year progression rate of 32% vs 21%, respectively). Among HCMBL, the frequency of somatically mutated genes at diagnosis is lower than that of CLL. Accounting for both the number of mutated genes and CLL-IPI can identify individuals with HCMBL with more aggressive clinical course.

Prediction of outcomes for high-count monoclonal B lymphocytosis using an epigenetic and immunogenetic signature.

ABSTRACT: Monoclonal B-cell lymphocytosis (MBL) progresses to chronic lymphocytic leukemia (CLL) requiring therapy at 1% to 5% per year. Improved prediction of progression would greatly benefit individuals with MBL. Patients with CLL separate into 3 distinct epigenetic subtypes (epitypes) with high prognostic significance, and recently the intermediate epitype has been shown to be enriched for high-risk immunoglobulin lambda variable (IGLV) 3-21 rearrangements, impacting outcomes for these patients. Here, we employed this combined strategy to generate the epigenetic and light chain immunoglobulin (ELCLV3-21) signature to classify 219 individuals with MBL. The ELCLV3-21 high-risk signature distinguished MBL individuals with a high probability of progression (39.9% and 71.1% at 5 and 10 years, respectively). ELCLV3-21 improved the accuracy of predicting time to therapy for individuals with MBL compared with other established prognostic indicators, including the CLL international prognostic index (c-statistic, 0.767 vs 0.668, respectively). Comparing ELCLV3-21 risk groups in MBL vs a cohort of 226 patients with CLL revealed ELCLV3-21 high-risk individuals with MBL had significantly shorter time to therapy (P = .003) and reduced overall survival (P = .03) compared with ELCLV3-21 low-risk individuals with CLL. These results highlight the power of the ELCLV3-21 approach to identify individuals with a higher likelihood of adverse clinical outcome and may provide a more accurate approach to classify individuals with small B-cell clones.

Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.

Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.

Post-COVID conditions: construction of a manual for health professionals in user management / Condições pós-COVID: construção de um manual para profissionais de saúde na gestão de usuários / Condiciones post-COVID: construcción de un manual para profesionales de la salud en la gestión de usuarios

Background and Objectives: in the course of care for users affected by COVID-19, there were persistent signs and symptoms or the development of late symptoms called post-COVID conditions. Thus, it is necessary to promote Continuing Education in Health practices to meet post-COVID conditions. Thus, the study aimed to construct a manual to assist Primary Health Care (PHC) professionals in managing post-COVID conditions. Methods: the method proposed by Echer was adopted for constructing the manual, which provides six steps for structuring a manual. Moreover, this study used only five of them, and the sixth step consists of manual validity. In addition, the following guiding axes were established: objectivity, self-explanatory formulation, problematizing pedagogical approach inspired by Bordenave and Pereira and the Brazilian National Policy for Continuing Education in Health. Results: the study resulted in the construction of a manual that comprises 25 post-COVID conditions, presented in a didactic way, with content selection and language adjustment considering the target audience, with illustrations and flowcharts that facilitate the conduct of the line of clinical reasoning as well as inclusion of clinical cases aiming at bringing them closer to clinical practice. Conclusion: the manual construction allows professionals to offer the affected users a quality and resolutive assistance, minimizing the damage to their quality of life. Furthermore, it is expected that the manual will reach a wide dissemination in the most distinct health spaces, providing subsidies to health professionals.(AU)

Justificativa e Objetivos: no decorrer do atendimento aos usuários acometidos pela COVID-19, ocorreram sinais e sintomas persistentes ou desenvolvimento de sintomas tardios denominados quadros pós-COVID. Assim, é necessário promover práticas de Educação Permanente em Saúde para atender às condições pós-COVID. Assim, o estudo teve como objetivo construir um manual para auxiliar os profissionais da Atenção Primária à Saúde (APS) no manejo das condições pós-COVID. Métodos: para a construção do manual foi adotado o método proposto por Echer, que prevê seis etapas para estruturação de um manual. Além disso, este estudo utilizou apenas cinco deles, e a sexta etapa consiste na validação manual. Além disso, foram estabelecidos os seguintes eixos norteadores: objetividade, formulação autoexplicativa, abordagem pedagógica problematizadora inspirada em Bordenave e Pereira e na Política Nacional de Educação Continuada em Saúde. Resultados: o estudo resultou na construção de um manual que contempla 25 condições pós-COVID, apresentado de forma didática, com seleção de conteúdo e ajuste de linguagem considerando o público-alvo, com ilustrações e fluxogramas que facilitam a condução da linha de raciocínio clínico bem como inclusão de casos clínicos visando aproximá-los da prática clínica. Conclusão: a construção manual permite aos profissionais oferecer aos usuários acometidos uma assistência de qualidade e resolutiva, minimizando os prejuízos à sua qualidade de vida. Além disso, espera-se que o manual alcance ampla divulgação nos mais distintos espaços de saúde, proporcionando subsídios aos profissionais de saúde.(AU)

Antecedentes y Objetivos: en el transcurso de la atención a usuarios afectados por COVID-19 se presentaron signos y síntomas persistentes o el desarrollo de síntomas tardíos denominados condiciones post-COVID. Así, es necesario promover prácticas de Educación Continua en Salud para afrontar las condiciones post-COVID. Así, el estudio tuvo como objetivo construir un manual para ayudar a los profesionales de la Atención Primaria de Salud (APS) en el manejo de las condiciones post-COVID. Métodos: para la construcción del manual se adoptó el método propuesto por Echer, el cual proporciona seis pasos para estructurar un manual. Además, este estudio utilizó sólo cinco de ellos, y el sexto paso consiste en la validez manual. Además, se establecieron los siguientes ejes rectores: objetividad, formulación autoexplicativa, enfoque pedagógico problematizador inspirado en Bordenave y Pereira y la Política Nacional Brasileña de Educación Continua en Salud. Resultados: el estudio resultó en la construcción de un manual que comprende 25 condiciones post-COVID, presentado de forma didáctica, con selección de contenidos y ajuste del lenguaje considerando el público objetivo, con ilustraciones y diagramas de flujo que facilitan la conducción de la línea de razonamiento clínico. así como la inclusión de casos clínicos con el objetivo de acercarlos a la práctica clínica. Conclusión: la construcción manual permite a los profesionales ofrecer a los usuarios afectados una asistencia resolutiva y de calidad, minimizando el daño a su calidad de vida. Además, se espera que el manual alcance una amplia difusión en los más distintos espacios de salud, brindando subsidios a los profesionales de la salud.(AU)

Ressignificando o aprendizado acerca do processo de enfermagem para desenvolver raciocínio clínico

Introdução: A aplicação das etapas do processo de enfermagem na prática clínica requer aperfeiçoamento constante. Objetivo: Analisar as ressignificações do aprendizado que enfermeiros, professores e estudantes obtiveram durante oficinas de aperfeiçoamento do processo de enfermagem. Metodologia: Pesquisa Convergente Assistencial realizada por meio de cinco oficinas, na qual totalizou 12 participantes. Na análise dos dados, elaborou-se síntese, teorização e transferência para a prática das ressignificações do aprendizado. Resultados: Destacou-se que informações insuficientes no instrumento de coleta de dados gera inconsistências na identificação diagnóstica. Enfatizou-se a relevância das taxonomias na etapa do planejamento e incompreensões no manejo da Escala Likert dos indicadores. Conclusões: Discutiram-se as etapas do processo a partir da sua aplicabilidade, por se entender ser deste lugar que se devem disparar as discussões desta temática. Conclui-se a necessidade do aperfeiçoamento, por estratégias inovadoras que permitam a participação ativa dos profissionais e valorização dos serviços de saúde, assim como as oficinas produzidas no estudo que se embasaram em um modelo local, potencializando o aprendizado significativo de estudantes e professores.

Introduction: The application of the steps of the Nursing Process in clinical practice requires constant improvement. Objective: To analyze the new meanings of learning that nurses, professors, and students obtained during workshops to improve the Nursing Process. Methodology: Convergent Care Research was carried out through five workshops, in which a total of 12 participants. In the data analysis, a synthesis, theorization, and transference to the practice of the learning resignifications were elaborated. Results: It was highlighted that insufficient information in the data collection instrument generates inconsistencies in diagnostic identification. The relevance of taxonomies in the planning stage and misunderstandings in the management of the Likert Scale of indicators was emphasized. Conclusions: The stages of the process were discussed based on their applicability, as it is understood from this place that discussions on this theme should be launched. It concludes the need for improvement, through innovative strategies that allow the active participation of professionals and enhancement of health services, as well as the workshops produced in the study that were based on a local model, enhancing meaningful learning of students and teachers.

Association of Medicaid expansion with 2-year survival and time to treatment initiation in gastrointestinal cancer patients: A National Cancer Database study.

INTRODUCTION: We evaluated whether Medicaid expansion (ME) was associated with improved 2-year survival and time to treatment initiation (TTI) among patients with gastrointestinal (GI) cancer. METHODS: GI cancer patients diagnosed 40-64 years were queried from the National Cancer Database. Those diagnosed from 2010 to 2012 were considered pre-expansion; those diagnosed from 2014 to 2016 were considered post-expansion. Cox models estimated hazard ratios and 95% confidence intervals (CIs) for 2-year overall survival. Generalized estimating equations (GEE) estimated odds ratios (OR) and 95% CI of TTI within 30- and 90 days. Multivariable Difference-in-Difference models were used to compare expansion/nonexpansion cohorts pre-/post-expansion, adjusting for patient, clinical, and hospital factors. RESULTS: 377,063 patients were included. No significant difference in 2-year survival was demonstrated across ME and non-ME states overall or in site-based subgroup analysis. In stage-based subgroup analysis, 2-year survival significantly improved among stage II cancer, with an 8% decreased hazard of death at 2 years (0.92; 0.87-0.97). Those with stage IV had a 4% increased hazard of death at 2 years (1.04; 1.01-1.07). Multivariable GEE models showed increased TTI within 30 days (1.12; 1.09-1.16) and 90 days (1.22; 1.17-1.27). Site-based subgroup analyses indicated increased likelihood of TTI within 30 and 90 days among colon, liver, pancreas, rectum, and stomach cancers, by 30 days for small intestinal cancer, and by 90 days for esophageal cancer. In subgroup analyses, all stages experienced improved odds of TTI within 30 and 90 days. CONCLUSION: ME was not associated with significant improvement in 2-year survival for those with GI cancer. Although TTI increased after ME for both cohorts, the 30- and 90-day odds of TTI was higher for those from ME compared with non-ME states. Our findings add to growing evidence of associations with ME for those diagnosed with GI cancer.

Florida-California Cancer Research, Education and Engagement (CaRE2) Health Equity Center: Structure, Innovations, and Initial Outcomes.

INTRODUCTION: The Florida-California Cancer Research, Education, and Engagement (CaRE2) Health Equity Center is a triad partnership committed to increasing institutional capacity for cancer disparity research, the diversity of the cancer workforce, and community empowerment. This article provides an overview of the structure, process innovations, and initial outcomes from the first 4 years of the CaRE2 triad partnership. METHODS: CaRE2 serves diverse populations in Florida and California using a "molecule to the community and back" model. We prioritize research on the complex intersection of biological, environmental, and social determinants health, working together with scientific and health disparities communities, sharing expertise across institutions, bidirectional training, and community outreach. Partnership progress and outcomes were assessed using mixed methods and four Program Steering Committee meetings. RESULTS: Research capacity was increased through development of a Living Repository of 81 cancer model systems from minority patients for novel cancer drug development. CaRE2 funded 15 scientific projects resulting in 38 publications. Workforce diversity entailed supporting 94 cancer trainees (92 URM) and 34 ESIs (32 URM) who coauthored 313 CaRE2-related publications and received 48 grants. Community empowerment was promoted via outreaching to more than 3000 individuals, training 145 community cancer advocates (including 28 Community Scientist Advocates), and publishing 10 community reports. CaRE2 members and trainees together have published 639 articles, received 61 grants, and 57 awards. CONCLUSION: The CaRE2 partnership has achieved its initial aims. Infrastructure for translational cancer research was expanded at one partner institution, and cancer disparities research was expanded at the two cancer centers.

Impact of Medicaid Expansion on Stage at Diagnosis for US Adults with Pancreatic Cancer: a Population-Based Study.

INTRODUCTION: We evaluated whether Medicaid expansion is associated with earlier stage at diagnosis for pancreatic cancer taking into account key demographic, clinical, and geographic factors. METHODS: We obtained Surveillance, Epidemiology, and End-Results (SEER-18) data on individuals diagnosed with pancreatic cancer from 2007 to 2016 (< 65 years of age). We defined non-metastatic as either local or regional disease (vs. metastatic disease). To estimate the association of Medicaid expansion with pancreatic cancer stage at diagnosis, we used a difference-in-differences model, at the individual level, comparing those from early-adopting states in 2014 to non-early-adopting states. We utilized cluster-robust standard errors and explored the role of demographic factors (race, sex, insurance at diagnosis), clinical indicator (disease in the head of the pancreas), and county characteristics (Urban Influence Code, Social Deprivation Index). RESULTS: In the univariable setting, the probability of non-metastatic disease at diagnosis increased by 3.9 percentage points (ppt) for those from Medicaid expansion states post-expansion (n = 36,609). After adjustment for covariates, the ppt was attenuated to 2.7. Of particular note, we observed evidence of interactions with sex and race. The beneficial effect was less pronounced for men (increase in the probability of non-metastatic stage at diagnosis by 2.1ppt) than women (3.6ppt) and non-existent for blacks (- 3.1ppt) compared to whites (4.9ppt) and other races (4.8ppt). CONCLUSION: Medicaid expansion is associated with increased probability of non-metastatic stage at diagnosis for pancreatic cancer; however, this beneficial effect is not uniform across sex and race. This underscores the need to investigate the impact of policy and implementation strategies on pancreatic cancer survival disparities.

Desempenho do julgamento clínico de enfermeiros na aplicação do processo de enfermagem / Desempeño del juicio clínico de enfermeros en la aplicación del proceso de enfermería / Clinical judgment performance of nurses in the application of the nursing process

Objective: To verify the applicability of the Lasater Clinical Judgment Rubric (LCJR) instrument to rate nursing professionals' performance regarding the development of clinical judgment in the application of the Nursing Process (NP). Materials and methods: Descriptive survey using the LCJR instrument ­consisting of four phases and eleven dimensions­ to classify clinical judgment. Results: Thirty-four nurses from a public hospital in western Santa Catarina, Brazil, distributed in six sectors, participated in the study. Nurses were classified by performance levels in relation to the ability of clinical judgment in the application of the steps of the NP. It was observed that at the "beginner" level there is a higher prevalence of professionals related to the dimensions Search for information, Recognizing deviations from expected standards, and Technical skills, linked to the intensive care unit clinic. As for the "exemplary" level, none of the sectors scored on the analyzed dimensions. Moreover, it was found that a longer time of clinical experience and of systematic application of the steps of the NP fosters a better classification in almost all dimensions. Conclusions: Through this research, we verified the assertiveness of the use of the instrument to evaluate the clinical judgment of nurses regarding the application of the steps of the NP. Thus, the use of the LCJR is encouraged as a tool to evaluate the effectiveness of educational interventions performed to nurses and, consequently, stimulate clinical judgment.

Objetivo: validar la aplicabilidad del instrumento Lasater Clinical Judgment Rubric (LCJR) para clasificar el desempeño de los profesionales en enfermería con relación al desarrollo del juicio clínico en la aplicación del proceso de enfermería (PE). Materiales y método: investigación descriptiva que adoptó el instrumento LCJR, compuesto de cuatro fases y once dimensiones, para clasificar el juicio clínico. Resultados: el estudio contó con la participación de 34 profesionales en enfermería de un hospital público del oeste del estado de Santa Catarina (Brasil), distribuidos en seis grupos. Los participantes fueron clasificados por niveles de desempeño en relación con la capacidad de juicio clínico en la aplicación de los pasos del PE. Se evidenció que en el nivel "principiante" existe una mayor prevalencia de profesionales relacionados con las dimensiones: Búsqueda de información, Reconocimiento de desviaciones de los estándares esperados y Habilidades técnicas, vinculadas principalmente a la práctica en unidad de cuidados intensivos. En cuanto al nivel "ejemplar", ninguno de los sectores obtuvo puntajes en las dimensiones analizadas. Además, se identificó que un tiempo mayor tanto de experiencia clínica como de aplicación sistemática de los pasos de la PE conducen a una mejor clasificación en casi todas las dimensiones. Conclusiones: a través de esta investigación fue posible validar la idoneidad del uso del LCJR para evaluar el juicio clínico de los profesionales en enfermería en cuanto a la aplicación de las etapas del PE. Por ende, se recomienda el uso de esta herramienta para evaluar la efectividad de las intervenciones educativas con estos profesionales, estimulando con ello el juicio clínico.

Objetivo: verificar a aplicabilidade do instrumento Lasater Clinical Judgment Rubric (LCJR) para classificar o desempenho dos profissionais de enfermagem quanto ao desenvolvimento do julgamento clínico na aplicação do processo de enfermagem (PE). Materiais e método: trata-se de uma pesquisa descritiva que adotou o instrumento LCJR que é fundamentado em quatro fases e onze dimensões, a fim de classificar o julgamento clínico. Resultados: participaram do estudo 34 profissionais de enfermagem de um hospital público do oeste de Santa Catarina, Brasil, distribuídos em seis setores, os quais foram classificados por níveis de desempenho com relação à habilidade de julgamento clínico na aplicação das etapas do PE. Foi evidenciado que no nível "iniciante" há uma maior prevalência de profissionais relacionados às dimensões Busca de informações, Reconhecimento de desvios dos padrões esperados e Habilidades técnicas, vinculadas principalmente à unidade de terapia intensiva clínica. Quanto ao nível "exemplar", nenhum dos setores obteve pontuação nas dimensões analisadas. Ademais, verificou-se que o maior tempo de experiência clínica e o maior tempo de aplicação sistemática das etapas do PE repercutem em uma melhor classificação nos níveis, em quase todas as dimensões. Conclusões: a partir da pesquisa, verificou-se a assertividade quanto à utilização do instrumento LCJR para avaliar o julgamento clínico de enfermeiros com relação à aplicação das etapas do PE . Dessa forma, incentiva-se o uso dessa ferramenta para avaliar a efetividade de intervenções educativas realizadas com profissionais de enfermagem e assim estimular o julgamento clínico.

Intratumoral Resolution of Driver Gene Mutation Heterogeneity in Renal Cancer Using Deep Learning.

Intratumoral heterogeneity arising from tumor evolution poses significant challenges biologically and clinically. Dissecting this complexity may benefit from deep learning (DL) algorithms, which can infer molecular features from ubiquitous hematoxylin and eosin (H&E)-stained tissue sections. Although DL algorithms have been developed to predict some driver mutations from H&E images, the ability of these DL algorithms to resolve intratumoral mutation heterogeneity at subclonal spatial resolution is unexplored. Here, we apply DL to a paradigm of intratumoral heterogeneity, clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer. Matched IHC and H&E images were leveraged to develop DL models for predicting intratumoral genetic heterogeneity of the three most frequently mutated ccRCC genes, BAP1, PBRM1, and SETD2. DL models were generated on a large cohort (N = 1,282) and tested on several independent cohorts, including a TCGA cohort (N = 363 patients) and two tissue microarray (TMA) cohorts (N = 118 and 365 patients). These models were also expanded to a patient-derived xenograft (PDX) TMA, affording analysis of homotopic and heterotopic interactions of tumor and stroma. The status of all three genes could be inferred by DL, with BAP1 showing the highest sensitivity and performance within and across tissue samples (AUC = 0.87-0.89 on holdout). BAP1 results were validated on independent human (AUC = 0.77-0.84) and PDX (AUC = 0.80) cohorts. Finally, BAP1 predictions correlated with clinical outputs such as disease-specific survival. Overall, these data show that DL models can resolve intratumoral heterogeneity in cancer with potential diagnostic, prognostic, and biological implications. SIGNIFICANCE: This work demonstrates the potential for deep learning analysis of histopathologic images to serve as a fast, low-cost method to assess genetic intratumoral heterogeneity. See related commentary by Song et al., p. 2672.

Design and rationale of GUARDD-US: A pragmatic, randomized trial of genetic testing for APOL1 and pharmacogenomic predictors of antihypertensive efficacy in patients with hypertension.

RATIONALE AND OBJECTIVE: APOL1 risk alleles are associated with increased cardiovascular and chronic kidney disease (CKD) risk. It is unknown whether knowledge of APOL1 risk status motivates patients and providers to attain recommended blood pressure (BP) targets to reduce cardiovascular disease. STUDY DESIGN: Multicenter, pragmatic, randomized controlled clinical trial. SETTING AND PARTICIPANTS: 6650 individuals with African ancestry and hypertension from 13 health systems. INTERVENTION: APOL1 genotyping with clinical decision support (CDS) results are returned to participants and providers immediately (intervention) or at 6 months (control). A subset of participants are re-randomized to pharmacogenomic testing for relevant antihypertensive medications (pharmacogenomic sub-study). CDS alerts encourage appropriate CKD screening and antihypertensive agent use. OUTCOMES: Blood pressure and surveys are assessed at baseline, 3 and 6 months. The primary outcome is change in systolic BP from enrollment to 3 months in individuals with two APOL1 risk alleles. Secondary outcomes include new diagnoses of CKD, systolic blood pressure at 6 months, diastolic BP, and survey results. The pharmacogenomic sub-study will evaluate the relationship of pharmacogenomic genotype and change in systolic BP between baseline and 3 months. RESULTS: To date, the trial has enrolled 3423 participants. CONCLUSIONS: The effect of patient and provider knowledge of APOL1 genotype on systolic blood pressure has not been well-studied. GUARDD-US addresses whether blood pressure improves when patients and providers have this information. GUARDD-US provides a CDS framework for primary care and specialty clinics to incorporate APOL1 genetic risk and pharmacogenomic prescribing in the electronic health record. TRIAL REGISTRATION: ClinicalTrials.govNCT04191824.

Frailty and risk of mortality in older cancer survivors and adults without a cancer history: Evidence from the National Health and Nutrition Examination Survey, 1999-2014.

BACKGROUND: Epidemiologic evidence reporting the role of frailty in survival among older adults with a prior cancer diagnosis is limited. METHODS: A total of 2050 older adults (≥60 years old) surviving for at least 1 year after a cancer diagnosis and 9474 older adults without a cancer history from the National Health and Nutrition Examination Survey (1999-2014) were included for analysis. The exposure variable, a 45-item frailty index (FI), was categorized on the basis of validated cutoffs (FI ≤ 0.10 [fit], 0.10 < FI ≤ 0.21 [prefrail], and FI > 0.21 [frail]). All-cause mortality was ascertained via the National Death Index. Multivariable Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) and 95% confidence interval (CIs) for the FI, and this was followed by restricted cubic splines depicting dose-response curves. RESULTS: For older cancer survivors, the mean age at the baseline was 72.6 years (SD, 7.1 years); 5.9% were fit, 38.2% were prefrail, and 55.9% were frail. Older adults without a cancer history were slightly younger (mean age, 70.0 years) and less frail (47.9% were frail). At each level of the FI, cancer survivors (1.9 per 100 person-years for FI ≤ 0.10, 3.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 7.5 per 100 person-years for FI > 0.21) had higher mortality than their cancer-free counterparts (1.4 per 100 person-years for FI ≤ 0.10, 2.4 per 100 person-years for 0.10 < FI ≤ 0.21, and 5.4 per 100 person-years for FI > 0.21). The multivariable model suggested a positive association between the FI and all-cause mortality for survivors (aHR for FI > 0.21 vs FI ≤ 0.10, 2.80; 95% CI, 1.73-4.53) and participants without a cancer history (aHR for FI > 0.21 vs FI ≤ 0.10, 2.75; 95% CI, 2.29-3.32). Restricted cubic splines indicated that all-cause mortality risk increased with the FI in a monotonic pattern. CONCLUSIONS: Frailty is associated with a higher risk of death in older cancer survivors and the elderly without a cancer history.

Impact of Medicaid Expansion on Pancreatic Cancer: An Examination of Sociodemographic Disparity in 1-Year Survival.

BACKGROUND: This study examined the effect of Medicaid expansion on 1-year survival of pancreatic cancer for nonelderly adults. We further evaluated whether sociodemographic and county characteristics alter the association of Medicaid expansion and 1-year survival. STUDY DESIGN: We obtained data from the Surveillance Epidemiology and End-Results dataset on individuals diagnosed with pancreatic cancer from 2007 to 2015. A Difference-in-Differences model compared those from early-adopting states to non-early-adopting states, before and after adoption (2014), while taking into consideration sociodemographic and county characteristics to estimate the effect of Medicaid expansion on 1-year survival. RESULTS: In the univariable Difference-in-Differences model, the probability of 1-year survival for pancreatic cancer increased by 4.8 percentage points (ppt) for those from Medicaid expansion states postexpansion (n = 35,347). After adjustment for covariates, the probability of 1-year survival was reduced to 0.8 ppt. Interestingly, after multivariable adjustment the effect of living in an expansion state on 1-year survival was similar for men and women (0.6 ppt for men vs 1.2 ppt for women), was also similar for Whites (2.6 ppt), and was higher in those of other races (5.9 ppt) but decreased for Blacks (-2.0 ppt). Those who were insured (-0.1 ppt) or uninsured (-2.2 ppt) experienced a decrease in the probability of 1-year survival; however, those who were covered by Medicaid at diagnosis experienced an increase in the probability of 1-year survival (7.4 ppt). CONCLUSIONS: Medicaid expansion during or after 2014 is associated with an increase in the probability of 1-year survival for pancreatic cancer; however, this effect is attenuated after adjustment for sociodemographic characteristics. Of note, the positive association was more pronounced in certain categories of key covariates suggesting further inquiry focused on these subgroups.

Novel plasma glycoprotein biomarkers predict progression-free survival in surgically resected clear cell renal cell carcinoma.

INTRODUCTION: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS). METHODS: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrell's C-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves. RESULTS: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate P ≤ 0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio (HR) of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR = 6.47, P = 9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR = 10.69, P = 0.001), clusterin A2G2 motif (HR = 7.38, P = 0.002), complement component C8A A2G2S2 motif (HR = 11.59, P = 0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR = 6.30, P = 0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9 to 10.7, all with P-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (P < 0.0001). CONCLUSION: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.

A Tale of Two Waves: Changes in the Use of Noninvasive Ventilation and Prone Positioning in Critical Care Management of Coronavirus Disease 2019.

New treatments and increased experience are changing the management of hospitalized coronavirus disease 2019 patients but the impact on ICU management is unclear. OBJECTIVES: To examine characteristics, ventilatory management, and outcomes of critically ill patients in two distinct waves of the pandemic. DESIGN SETTING AND PARTICIPANTS: Observational cohort study in an ICU in a single-center university-affiliated U.K. hospital. Two-hundred ten adults with coronavirus disease 2019 admitted to ICU between March 17, 2020, to May 31, 2020, and September 1, 2020, to December 10, 2020, with hourly data and 100% follow-up to ICU discharge. MAIN OUTCOMES AND MEASURES: Data were extracted from the electronic medical record for patient characteristics and clinical data. Patients were classified into distinct waves of the pandemic and assessed for differences between the two waves. RESULTS: The duration of noninvasive ventilation/nasal high flow increased in wave 2 versus wave 1, both in self-ventilating patients (107 vs 72 hr; p = 0.02), and in those ultimately requiring invasive mechanical ventilation (34 vs 10 hr; p = 0.02). The proportion of survivors treated without invasive mechanical ventilation increased in wave 2 (59% vs 39%; p = 0.01). In both waves, longer duration of noninvasive ventilation/nasal high flow prior to intubation was associated with higher ICU mortality (survivors 10 hr [4-21 hr] vs nonsurvivors 50 hr [23-124 hr]; p < 0.01). Proned invasive mechanical ventilation was common (54.7%) and prolonged. In wave 2, invasive mechanical ventilation patients were generally more hypoxic with proning initiated at lower Pao2/Fio2 ratios (81 vs 116 mm Hg; p = 0.02) and yielding smaller improvements in Fio2 requirements. Continued proning episodes despite poor responses were commonplace and typically futile. Length of stay for patients requiring tracheostomy increased markedly in wave 2 (51.3 vs 33.7 d; p = 0.03). Overall survival remained similar in wave 2 (68.0% vs 60.9%; p = 0.31). CONCLUSIONS AND RELEVANCE: Our data suggest that management of critically ill coronavirus disease 2019 patients is changing with more survivors avoiding invasive mechanical ventilation. Duration of noninvasive ventilation/nasal high flow use is increasing, which may be associated with worsening outcomes for individuals who require invasive mechanical ventilation. Among invasively ventilated patients, changes in the use of and response to prone positioning and increased length of stay following tracheostomy may imply that the care of these patients is becoming more challenging.

Antibiotic Duration After Urethroplasty: An Attempt at Improving Antibiotic Stewardship.

OBJECTIVE: To evaluate if decreasing postop abx prophylaxis affects UTI and wound infection rates in patients following urethroplasty. METHODS: A retrospective review of patients who underwent urethroplasty from 9/2017 - 3/2020 by a single surgeon was performed. All patients received urine culture specific perioperative IV abx prior to urethroplasty and kept a urethral catheter for 3 weeks postop. Patients undergoing a urethroplasty from 9/2017 to 12/2018 received extended postop abx prophylaxis for 3 weeks until catheter removal (Group 1). Patients from 12/2018 to 3/2020 received abx for 3 days around catheter removal (Group 2). UTIs, abx complications, and wound infections between groups were evaluated. UTIs were defined as a positive urine culture or reported lower urinary tract symptoms/fevers treated with empiric abx. RESULTS: 120 patients underwent urethroplasty. Group 1 consisted of 60 patients with mean age of 51.9 years and mean stricture length of 3.6 cm. Group 2 had 60 patients with mean age of 53.1 years and mean stricture length of 3.8 cm. 10 patients had UTIs after urethroplasty. There was no significant difference in UTI (6.7% vs 11.7%; P = 0.529) or wound infection rates (3.3% vs 1.7%;' P = 1.000) between the two groups. CONCLUSION: Extended postoperative antibiotic prophylaxis does not appear to significantly affect UTI or wound infection rates following urethroplasty. The retrospective nature of the study has limitations, however, this is the first comparison of two different antibiotic administration protocols to our knowledge.

Lower disease control rates and survival outcomes among Blacks with pharyngeal squamous cell carcinomas compared with Whites: a retrospective analysis at the University of Florida.

Disparate clinical outcomes for pharyngeal squamous cell carcinoma (PSCC) of the oropharynx (OPSCC) and hypopharynx (HPSCC) have been observed in Black compared with White patients. Higher tobacco and alcohol use has been associated with decreased survival in Black patients with PSCC. Higher human papilloma virus (HPV) infection rates, associated with specific subsites of the oropharynx, are linked to improved overall survival (OS). Using an institutional cohort of Black and White patients with PSCC, we performed a retrospective analysis using multiple disease endpoints including local control (LC), local-regional control (LRC), freedom from distant metastases (DMFS), OS, cause-specific survival (CSS), and recorded tobacco and alcohol use. 1419 patients [Black (n = 111) and White (n = 1,308)] treated for PSCC from 1973 to 2013 were evaluated. PSCC 5- and 10-year LC, LRC, and DMFS and CSS rates were lower for Blacks. Notably, Black patients with OPSCC had higher stage cancers, higher percentage of soft palate tumors, and lower percentage of base of tongue cancers, were more likely to receive radiotherapy, and had higher tobacco and alcohol use. OS was significantly lower in Black patients at both anatomic sites, with the greatest difference observed for OPSCC. Multivariate analysis showed race and tobacco independently predicted DMFS, OS, and CSS; however, tobacco use had a greater impact on DMFS (HR 2.5, p = 0.021) than race (HR 1.9, p = 0.027). Overall, we propose that the higher burden of tobacco use along with a lower rate of tumors arising from traditional HPV-related subsites were important contributors to disparate disease outcomes seen in our Black patients.