ATRX and Its Prognostic Significance in Soft Tissue Sarcoma.

Purpose: Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan-Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. Results: High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17-0.85), P=0.02 and HR: 0.49 (0.24-0.99), P=0.05, respectively). Conclusions: High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings.

Development of a Novel Clinical Risk Score for COVID-19 Infections.

OBJECTIVE: The ongoing emergence of novel severe acute respiratory syndrome coronavirus 2 strains such as the Omicron variant amplifies the need for precision in predicting severe COVID-19 outcomes. This study presents a machine learning model, tailored to the evolving COVID-19 landscape, emphasizing novel risk factors and refining the definition of severe outcomes to predict the risk of a patient experiencing severe disease more accurately. METHODS: Utilizing electronic health records from the Healthjump database, this retrospective study examined over 1 million US COVID-19 diagnoses from March 2020 to September 2022. Our model predicts severe outcomes, including acute respiratory failure, intensive care unit admission, or ventilator use, circumventing biases associated with hospitalization, which exhibited ∼4× geographical variance of the new outcome. RESULTS: The model exceeded similar predictors with an area under the curve of 0.83 without lab data to predict patient risk. It identifies new risk factors, including acute care history, health care encounters, and distinct medication use. An increase in severe outcomes, typically 2-3× higher than subsequent months, was observed at the onset of each new strain era, followed by a plateau phase, but the risk factors remain consistent across strain eras. CONCLUSION: We offer an improved machine learning model and risk score for predicting severe outcomes during changing COVID-19 strain eras. By emphasizing a more clinically precise definition of severe outcomes, the study provides insights for resource allocation and intervention strategies, aiming to better patient outcomes and reduce health care strain. The necessity for regular model updates is highlighted to maintain relevance amidst the rapidly evolving COVID-19 epidemic.

A framework for setting enrollment goals to ensure participant diversity in sponsored clinical trials in the United States.

BACKGROUND: Diversity in clinical trials (CTs) has the potential to improve health equity and close health disparities. Underrepresentation of historically underserved groups compromises the generalizability of trial findings to the target population, hinders innovation, and contributes to low accrual. The aim of this study was to establish a transparent and reproducible process for setting trial diversity enrollment goals informed by the disease epidemiology. METHOD: An advisory board of epidemiologists with expertise in health disparities, equity, diversity, and social determinants of health was convened to evaluate and strengthen the initial goal-setting framework. Data sources used were the epidemiologic literature, US Census, and real-world data (RWD); limitations were considered and addressed where appropriate. A framework was designed to safeguard against the underrepresentation of historically medically underserved groups. A stepwise approach was created with Y/N decisions based on empirical data. RESULTS: We compared race and ethnicity distributions in the RWD of six diseases from Pfizer's portfolio chosen to represent different therapeutic areas (multiple myeloma, fungal infections, Crohn's disease, Gaucher disease, COVID-19, and Lyme disease) to the distributions in the US Census and established trial enrollment goals. Enrollment goals for potential CTs were based on RWD for multiple myeloma, Gaucher disease, and COVID-19; enrollment goals were based on the Census for fungal infections, Crohn's disease, and Lyme disease. CONCLUSIONS: We developed a transparent and reproducible framework for setting CT diversity enrollment goals. We note how limitations due to data sources can be mitigated and consider several ethical decisions in setting equitable enrollment goals.

Operative Versus Nonoperative Treatment of Acute Achilles Tendon Rupture: A Propensity Score-Matched Analysis of a Large National Dataset.

Background: No consensus exists regarding the superiority of operative versus nonoperative management for Achilles tendon ruptures, as multiple randomized controlled trials conducted since the advent of early mobilization protocols have found outcomes for these 2 interventions to be more similar than were previously held. Purpose: To use a large national database to (1) compare reoperation and complication rates between operative and nonoperative treatment of acute Achilles tendon ruptures and (2) evaluate trends in treatment and cost over time. Study Design: Cohort study; Level of evidence, 3. Methods: The MarketScan Commercial Claims and Encounters database was used to identify an unmatched cohort of 31,515 patients who sustained primary Achilles tendon ruptures between 2007 and 2015. Patients were stratified into operative and nonoperative treatment groups, and a propensity score-a matching algorithm-was used to establish a matched cohort of 17,996 patients (n = 8993 per treatment group). Reoperation rates, complications, and aggregate treatment costs were compared between groups with an alpha level of .05. A number needed to harm (NNH) was calculated from the absolute risk difference in complications between cohorts. Results: The operative cohort experienced a significantly larger total number of complications within 30 days of injury (1026 vs 917; P = .0088). The absolute increase in cumulative risk was 1.2% with operative treatment, which resulted in an NNH of 83. Neither 1-year (1.1% [operative] vs 1.3% [nonoperative]; P = .1201) nor 2-year reoperation rates (1.9% [operative] vs 2% [nonoperative]; P = .2810) were significantly different. Operative care was more expensive than nonoperative care at 9 months and 2 years after injury; however, there was no difference in cost between treatments at 5 years. Before matching, the rate of surgical repair for Achilles tendon rupture remained stable, from 69.7% to 71.7% between 2007 and 2015, indicating little change in practice in the United States. Conclusion: Results indicated no differences in reoperation rates between operative and nonoperative management of Achilles tendon ruptures. Operative management was associated with an increased risk of complications and higher initial costs, which dissipated over time. Between 2007 and 2015 the proportion of Achilles tendon ruptures managed operatively remained similar despite increasing evidence that nonoperative management of Achilles tendon rupture may provide equivalent outcomes.

Disparities in job characteristics by race and sex in a Southern aluminum smelting facility.

BACKGROUND: Former workers at a Southern aluminum smelting facility raised concerns that the most hazardous jobs were assigned to Black workers, but the role of workplace segregation had not been quantified or examined in the company town. Prior studies discuss race and gender disparities in working conditions, but few have documented them in the aluminum industry. METHODS: We obtained workers' company records for 1985-2007 and characterized four job metrics: prestige (sociologic rankings), worker-defined danger (worker assessments), annual wage (1985 dollars), and estimated total particulate matter (TPM) exposure (job exposure matrix). Characteristics of job at hire and trajectories were compared by race and sex using linear binomial models. RESULTS: Non-White males had the highest percentage of workers in low prestige and high danger jobs at hire and up to 20 years after. After 20 years tenure, 100% of White workers were in higher prestige and lower danger jobs. Most female workers, regardless of race, entered and remained in low-wage jobs, while 50% of all male workers maintained their initial higher-wage jobs. Non-White females had the highest prevalence of workers in low-wage jobs at hire and after 20 years-increasing from 63% (95% CI: 59-67) to 100% (95% CI: 78-100). All female workers were less likely to be in high TPM exposure jobs. Non-White males were most likely to be hired into high TPM exposure jobs, and this exposure prevalence increased as time accrued, while staying constant for other race-sex groups. CONCLUSIONS: There is evidence of job segregation by race and sex in this cohort of aluminum smelting workers. Documentation of disparities in occupational hazards is important for informing health interventions and research.

Distribution of working hour characteristics by race, age, gender, and shift schedule among U.S. manufacturing workers.

Shift work is a common occupational exposure, however, few studies have examined aspects of shift work beyond night work and long hours, such as rotational patterns or weekend work, which may contribute to poor health through disruption of the body's circadian rhythms. In this manuscript, we calculated the prevalence of working hour characteristics using algorithms for type (e.g., day), duration, intensity, rotational direction, and social aspects (e.g., weekend work) in a nationwide cohort of American manufacturing workers (N = 23,044) between 2003 and 2014. Distributions of working hour characteristics were examined by schedules (e.g., permanent day, day/night) and demographics, and were cross-classified in a matrix to examine co-occurrence. Approximately 55% of shifts may cause circadian rhythm disruption as they were non-day shifts or day shifts with a quick return or rotation, or were 13 h or longer. Older workers, female workers, and White workers worked permanent day shifts most often, while workers of color worked more day/night schedules. Night and evening shifts had more frequent shift rotations, quick returns, and longer hours than day shifts. Yet, day shifts, which are presumed to have little negative circadian impact, may cause circadian rhythm disruption as long hours, quick returns and rotations also occurred within day shifts.

Defining Essential Surgery in the US During the COVID-19 Pandemic Response.

This cohort study compares the volume of performed surgical procedures classified as essential, urgent, and nonurgent before and after elective surgeries were restricted during the COVID-19 pandemic in the US.

Risk of primary haematologic cancers following incident non-metastatic breast cancer: A Danish population-based cohort study.

BACKGROUND: Breast cancer survivors may have increased risk of subsequent haematologic cancer. We compared their risk of haematologic cancers with the general population during 38 years of follow-up. METHODS: Using population-based Danish medical registries, we assembled a nationwide cohort of women diagnosed with incident non-metastatic breast cancer during 1980-2017, with follow-up through 2018. We compared breast cancer survivors with the general population by computing standardised incidence ratios (SIR) and 95% confidence intervals (CI). RESULTS: Among 101,117 breast cancer survivors, we observed 815 incident haematologic cancers (median follow-up: 7.9 years). We observed excess risk of acute myeloid leukaemia (AML) (SIR: 1.65, 95%CI: 1.33-2.01), particularly in women who received chemotherapy (SIR: 3.33, 95%CI: 2.24-4.75) and premenopausal women (SIR: 3.23, 95%CI: 2.41-4.25). The risk of acute lymphoid leukaemia (ALL) was increased (SIR: 2.25, 95%CI: 1.29-3.66), whereas the risk of chronic lymphoid leukaemia (CLL) was decreased (SIR: 0.66, 95%CI: 0.53-0.82). An additional analysis showed elevated risk of CLL 0-6 months after breast cancer diagnosis (SIR: 3.00 95%CI: 1.75-4.80). CONCLUSION: Compared to the general population, breast cancer survivors had elevated risk of AML, particularly when treated with chemotherapy. The risk of ALL was elevated, whereas the risk of CLL was lower. The higher risk of CLL in the first six months after diagnosis likely reflects surveillance bias-due to intensified diagnostic efforts at breast cancer diagnosis and treatment-prompting earlier detection. This has likely reduced the long-term risk of CLL in breast cancer survivors.

Erratum to 'Corynebacterium Total Hip and Knee Arthroplasy Prosthetic Joint Infections' [Arthroplasty Today 6 (2020) 163-168].

[This corrects the article DOI: 10.1016/j.artd.2020.03.008.].

Race/ethnicity reporting and representation in US clinical trials: a cohort study.

Background: Systemic progress in improving trial representation is uncertain, and previous analyses of minority trial participation have been limited to small cohorts with limited exploration of driving factors. Methods: We analyzed detailed trial records from all US clinical trials registered in ClinicalTrials.gov from March 2000 to March 2020. Minority enrollment was compared to 2010 US Census demographic estimates using Wilcoxon test. We utilized logistic regression and generalized linear regression with a logit link to assess the association of possible drivers (including trials' funding source, size, phase, and design) with trials' disclosure of and amount of minority enrollment respectively. Findings: Among 20,692 US-based trials with reported results (representing ~4·76 million enrollees), only 43% (8,871/20,692) reported any race/ethnicity data. The majority of enrollees were White (median 79·7%; interquartile range [IQR] 61·9-90·0%), followed by Black (10·0%; IQR 2·5-23·5%), Hispanic/Latino (6·0%; IQR 0·43-15·4%), Asian (1·0%; IQR 0·0-4·1%), and American Indian (0·0%; IQR 0·0-0·2%). Median combined enrollment of minority race/ethnicity groups (Black, Hispanic/Latino, Asian, American Indian, Other/Multi) was below census estimates (27·6%) (p<0·001) however increased at an annual rate of 1·7%. Industry and Academic funding were negatively associated with race/ethnicity reporting (Industry adjusted odds ratio [aOR]: 0·42, 95% confidence interval [CI]: 0·38 to 0·46, p<0.0001; Academic aOR: 0·45, CI: 0·41 to 0·50, p<0.0001). Industry also had a negative association with the proportion of minority ethnicity enrollees (aOR: 0·69, CI: 0·60 to 0·79) compared to US Government-funded trials. Interpretation: Over the past two decades, the majority of US trials in ClinicalTrials.gov do not report race/ethnicity enrollment data, and minorities are underrepresented in trials with modest improvement over time. Funding: Stanford Medical Scholars Research Funding, the National Heart, Lung, and Blood Institute, NIH (1K01HL144607) and the American Heart Association/Robert Wood Johnson Medical Faculty Development Program.

Global Health Needs Modernized Containment Strategies to Prepare for the Next Pandemic.

COVID-19 continues to be a public health crisis, while severely impacting global financial markets causing significant economic and social hardship. As with any emerging disease, pharmaceutical interventions required time, emphasizing the initial and continuing need for non-pharmaceutical interventions. We highlight the role of anthropological and historical perspectives to inform approaches to non-pharmaceutical interventions for future preparedness. The National Academy of Medicine, a not-for-profit, non-governmental US-based medical watchdog organization, published a key document early in the COVID-19 pandemic which points to inadequate quarantine and containment infrastructure as a significant obstacle to an effective pandemic response. In considering how to implement effective quarantine policies and infrastructure, we argue that it is essential to take a longitudinal approach to assess interventions that have been effective in past pandemics while simultaneously addressing and eliminating the negative socio-historical legacies of ineffective quarantine practices. Our overview reinforces the need for social equity and compassion when implementing containment.

Disease-Specific Health Disparities: A Targeted Review Focusing on Race and Ethnicity.

BACKGROUND: Wide disparities in health status exist in the United States across race and ethnicity, broadly driven by social determinants of health-most notably race and ethnic group differences in income, education, and occupational status. However, disparities in disease frequency or severity remain underappreciated for many individual diseases whose distribution in the population varies. Such information is not readily accessible, nor emphasized in treatment guidelines or reviews used by practitioners. Specifically, a summary on disease-specific evidence of disparities from population-based studies is lacking. Our goal was to summarize the published evidence for specific disease disparities in the United States so that this knowledge becomes more widely available "at the bedside". We hope this summary stimulates health equity research at the disease level so that these disparities can be addressed effectively. METHODS: A targeted literature review of disorders in Pfizer's current pipeline was conducted. The 38 diseases included metabolic disorders, cancers, inflammatory conditions, dermatologic disorders, rare diseases, and infectious targets of vaccines under development. Online searches in Ovid and Google were performed to identify sources focused on differences in disease rates and severity between non-Hispanic Whites and Black/African Americans, and between non-Hispanic Whites and Hispanics. As a model for how this might be accomplished for all disorders, disparities in disease rates and disease severity were scored to make the results of our review most readily accessible. After primary review of each condition by one author, another undertook an independent review. Differences between reviewers were resolved through discussion. RESULTS: For Black/African Americans, 29 of the 38 disorders revealed a robust excess in incidence, prevalence, or severity. After sickle cell anemia, the largest excesses in frequency were identified for multiple myeloma and hidradenitis suppurativa. For Hispanics, there was evidence of disparity in 19 diseases. Most notable were metabolic disorders, including non-alcoholic steatohepatitis (NASH). CONCLUSIONS: This review summarized recent disease-specific evidence of disparities based on race and ethnicity across multiple diseases, to inform clinicians and health equity research. Our findings may be well known to researchers and specialists in their respective fields but may not be common knowledge to health care providers or public health and policy institutions. Our hope is that this effort spurs research into the causes of the many disease disparities that exist in the United States.

Long COVID and Medicine's Two Cultures.

Medicine has separated the two cultures of biological science and social science in research, even though they are intimately connected in the lives of our patients. To understand the cause, progression, and treatment of long COVID , biology and biography, the patient's lived experience, must be studied together.

Population health science as a unifying foundation for translational clinical and public health research.

Separated both in academics and practice since the Rockefeller Foundation effort to "liberate" public health from perceived subservience to clinical medicine a century ago, research in public health and clinical medicine have evolved separately. Today, translational research in population health science offers a means of fostering their convergence, with potentially great benefit to both domains. Although evidence that the two fields need not and should not be entirely distinct in their methods and goals has been accumulating for over a decade, the prodigious efforts of biomedical and social sciences over the past year to address the COVID-19 pandemic has placed this unifying approach to translational research in both fields in a new light. Specifically, the coalescence of clinical and population-level strategies to control disease and novel uses of population-level data and tools in research relating to the pandemic have illuminated a promising future for translational research. We exploit this unique window to re-examine how translational research is conducted and where it may be going. We first discuss the transformation that has transpired in the research firmament over the past two decades and the opportunities these changes afford. Next, we present some of the challenges-technical, cultural, legal, and ethical- that need attention if these opportunities are to be successfully exploited. Finally, we present some recommendations for addressing these challenges.

Investigating readmission rates for patients undergoing oncologic resection and endoprosthetic reconstruction for primary sarcomas and tumors involving bone.

BACKGROUND: Little is known about the drivers of readmission in patients undergoing Orthopaedic oncologic resection. The goal of this study was to identify factors independently associated with 90-day readmission for patients undergoing oncologic resection and subsequent prosthetic reconstruction for primary tumors involving bone. METHODS: This was a retrospective comparative cohort study of patients treated from 2008 to 2019 who underwent endoprosthetic reconstruction for a primary bone tumor or soft tissue tumor involving bone, as well as those who underwent a revision endoprosthetic reconstruction if the primary endoprosthetic reconstruction was performed for an oncologic resection. The primary outcome measure was unplanned 90-day readmission. RESULTS: A total of 149 patients were identified who underwent 191 surgeries were for a primary bone or soft tissue tumor. The 90-day readmission rate was 28.3%. Female gender, depression, higher tumor grade, vascular reconstruction, longer procedure duration, longer length of stay (LOS), multiple surgeries during an admission and disposition to a Skilled Nursing Facility were associated with readmission (p < 0.05). In a multivariate analysis, female sex, higher tumor grade and longer procedure duration were independently associated with risk of readmission (p < 0.05). CONCLUSIONS: Readmission rates are high following endoprosthetic reconstruction for Orthopaedic oncologic resections. Further work is necessary to help minimize unplanned readmissions.

Cardiovascular outcomes associated with prescription of sodium-glucose co-transporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in patients with diabetes and chronic kidney disease.

AIM: To determine the association with cardiovascular (CV) outcomes of sodium-glucose co-transporter-2 (SGLT-2) inhibitors compared with dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). MATERIALS AND METHODS: We conducted a population-based cohort study of new users of SGLT-2 inhibitors and DPP-4 inhibitors with T2D and CKD using data from Optum Clinformatics DataMart. We assembled three cohorts: T2D/no CKD, T2D/CKD 1-2, and T2D/CKD 3a. The study outcomes were (a) time to first heart failure (HF) hospitalization and (b) time to a composite CV endpoint comprised of non-fatal myocardial infarction (MI) or stroke. After inverse probability of treatment weighting, we used proportional hazards regression to estimate hazard ratios (HR) and 95% confidence intervals (CI). RESULTS: New users of SGLT-2 inhibitors versus DPP-4 inhibitors had lower risks of HF hospitalization in the T2D/no CKD (HR, 0.76; 95% CI, 0.70, 0.82) and T2D/CKD 1-2 (HR, 0.63; 95% CI, 0.48, 0.84) cohorts, but no significant association was present in the T2D/CKD 3a cohort. Compared with prescription of DPP-4 inhibitors, SGLT-2 inhibitors were associated with lower risks of non-fatal MI or stroke of 23% (HR, 0.77; 95% CI, 0.70, 0.85) in the T2D/no CKD cohort, but no significant associations were present in the T2D/CKD 1-2 and T2D/CKD 3a cohorts. CONCLUSIONS: Incident prescription of SGLT-2 inhibitors was associated with lower risks of HF hospitalization but not with non-fatal MI or stroke despite suggesting benefit, relative to prescription of DPP-4 inhibitor across different stages of CKD.