Stability and variability of molecular subtypes: comparative analysis of primary and metastatic triple-negative breast cancer.

OBJECTIVE: Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive cancer. Although our previous study classified primary TNBC into four subtypes, comprehensive longitudinal investigations are lacking. METHODS: We assembled a large-scale, real-world cohort comprised of 880 TNBC patients [465 early-stage TNBC (eTNBC) and 415 metastatic TNBC (mTNBC) patients] who were treated at Fudan University Shanghai Cancer Center. The longitudinal dynamics of TNBC subtypes during disease progression were elucidated in this patient cohort. Comprehensive analysis was performed to compare primary and metastatic lesions within specific TNBC subtypes. RESULTS: The recurrence and metastasis rates within 3 years after initial diagnosis in the eTNBC cohort were 10.1% (47/465). The median overall survival (OS) in the mTNBC cohort was 27.2 months [95% confidence interval (CI), 24.4-30.2 months], which indicated a poor prognosis. The prognostic significance of the original molecular subtypes in both eTNBC and mTNBC patients was confirmed. Consistent molecular subtypes were maintained in 77.5% of the patients throughout disease progression with the mesenchymal-like (MES) subtype demonstrating a tendency for subtype transition and brain metastasis. Additionally, a precision treatment strategy based on the metastatic MES subtype of target lesions resulted in improved progression-free survival in the FUTURE trial. CONCLUSIONS: Our longitudinal study comprehensively revealed the clinical characteristics and survival of patients with the original TNBC subtypes and validated the consistency of most molecular subtypes throughout disease progression. However, we emphasize the major importance of repeat pathologic confirmation of the MES subtype.

Non-invasive markers of inflammation in alcohol-associated liver disease: A scoping review.

Clinical manifestations of liver inflammation in alcohol-associated liver disease (ALD) can range from asymptomatic to severe alcoholic hepatitis. While biopsy is the gold standard for identifying liver inflammation, it is an invasive procedure with risks of bleeding, visceral damage, and infection. We aim to establish the state of the current literature on non-invasive markers of inflammation in ALD. We searched Ovid MEDLINE, Embase, and the Cochrane Library for original studies on the association between one or more non-invasive biomarker(s) and histological inflammation or hepatitis in ALD patients. Exclusion criteria were lack of histological data, abstract only, non-English-language articles, and animal studies. Two independent reviewers screened abstracts, reviewed full texts, and extracted data from included papers. Our search identified 8051 unique studies. Title and abstract screening resulted in 563 studies, and full-text screening resulted in 31 studies for final inclusion. The majority were single-center observational cohorts with an average sample size of 124. Review of these studies identified 44 unique biomarkers and 8 calculated scores associated with histological inflammation and/or hepatitis, in addition to a metabolomic panel of 468 metabolites. Six studies examined diagnostic accuracy for histological inflammation and/or hepatitis. The highest area under the receiver operating characteristic curve was 0.932 using a model based on four metabolites. This review highlights the available literature on non-invasive markers of inflammation in ALD. There is a dearth of studies that evaluate the diagnostic accuracy of these biomarkers, and larger studies are needed to confirm findings identified in small cohorts.

Impact of Race and Neighborhood Socioeconomic Characteristics on Liver Cancer Diagnosis in Patients with Viral Hepatitis and Cirrhosis.

Background: Concerning data have revealed that viral hepatitis and hepatocellular carcinoma (HCC) disproportionally impact non-White patients and those from lower socioeconomic status. A recent study found that HCC clusters were more likely to be in high poverty areas in New York City. Aims: We aim to investigate the impacts of neighborhood characteristics on those with viral hepatitis and cirrhosis, particularly with advanced HCC diagnosis. Methods: Patients with cirrhosis and viral hepatitis admitted to a New York City health system between 2012 and 2019 were included. Those with prior liver transplants were excluded. Neighborhood characteristics were obtained from US Census. Our primary outcome was HCC and advanced HCC diagnosis. Results: This study included 348 patients; 209 without history of HCC, 20 with early HCC, 98 with advanced HCC, and 21 patients with HCC but no staging information. Patients with advanced HCC were more likely to be older, male, Asian, history of HBV, and increased mortality. They were more likely to live in areas with more foreign-born, limited English speakers, and less than high school education. After adjusting for age, sex, and payor type, Asian race and low income were independent risk factors for advanced HCC. Neighborhood factors were not associated with mortality or readmissions. Conclusion: We observed that in addition to age and sex, Asian race, lower household income, lower education, and lower English proficiency were associated with increased risk of advanced HCC. These disparities likely reflect suboptimal screening programs and linkage to care among vulnerable populations. Further efforts are crucial to validate and address these concerning disparities.

Industry relationships among authors of U.S. Clinical Practice Guidelines in cardiology from 2014 to 2020.

Clinical practice guidelines and Scientific statements are influential publications that define the standard of care for many diseases. However, little is known about industry payments and financial conflict-of-interest among authors of such publications in cardiology. We identified guidelines published between 2014 and 2020 by the American Heart Association (AHA) and the American College of Cardiology (ACC) in order to assess the payment status of CPG authors using the Open Payment Program (OPP) database.

Availability and Accessibility of Live Nonreplicating Smallpox/Mpox Vaccine.

This cross-sectional study compares the availability and accessibility of mpox vaccine sites with the number of reported cases and allocated vaccines.

Safety and Efficacy of a Novel Approach to Pulmonary Vein Isolation Using Prolonged Apneic Oxygenation.

BACKGROUND: Improved ablation catheter-tissue contact results in more effective ablation lesions. Respiratory motion causes catheter instability, which impacts durable pulmonary vein isolation (PVI). OBJECTIVES: This study sought to evaluate the safety and efficacy of a novel ablation strategy involving prolonged periods of apneic oxygenation during PVI. METHODS: We conducted a multicenter, prospective controlled study of 128 patients (mean age 63 ± 11 years; 37% women) with paroxysmal atrial fibrillation undergoing PVI. Patients underwent PVI under general anesthesia using serial 4-minute runs of apneic oxygenation (apnea group; n = 64) or using standard ventilation settings (control group; n = 64). Procedural data, arterial blood gas samples, catheter position coordinates, and ablation lesion characteristics were collected. RESULTS: Baseline characteristics between the 2 groups were similar. Catheter stability was significantly improved in the apnea group, as reflected by a decreased mean catheter displacement (1.55 ± 0.97 mm vs 2.25 ± 1.13 mm; P < 0.001) and contact force SD (4.9 ± 1.1 g vs 5.2 ± 1.5 g; P = 0.046). The percentage of lesions with a mean catheter displacement >2 mm was significantly lower in the apnea group (22% vs 44%; P < 0.001). Compared with the control group, the total ablation time to achieve PVI was reduced in the apnea group (18.8 ± 6.9 minutes vs 23.4 ± 7.8 minutes; P = 0.001). There were similar rates of first-pass PVI, acute PV reconnections and dormant PV reconnections between the two groups. CONCLUSIONS: A novel strategy of performing complete PVI during apneic oxygenation results in improved catheter stability and decreased ablation times without adverse events. (Radiofrequency Ablation of Atrial Fibrillation Under Apnea; NCT04170894).

Travel Times to Facilities Offering Oral Medication Therapy for COVID-19.

This quality improvement study evaluates access to oral COVID-19 therapeutics within communities in the 48 contiguous states and the District of Columbia.

Shoulder arthroplasty device clearance: an ancestral network analysis.

BACKGROUND: The US Food and Drug Administration (FDA) oversees medical device regulation and oversight in the United States, and the majority of shoulder arthroplasty devices are cleared via the 510(k) pathway, in which a device demonstrates "substantial equivalence" to a previously cleared predicate. The purpose of this study was to determine an interconnected ancestral network of shoulder arthroplasty devices and determine equivalency ties to devices subsequently recalled by the FDA for design-related issues. METHODS: The FDA 510(k) database was used to identify all legally marketed shoulder arthroplasty devices from May 28, 1976, to July 1, 2021. Direct predicate information obtained via clearance summary documents associated with each device was used to generate an ancestral genealogy network for all shoulder arthroplasty devices cleared between July 1, 2020, and July 1, 2021. FDA design recalls were analyzed, and the number of descendant devices was calculated for each recalled device. RESULTS: An evaluation of all 476 510(k) premarket notification pathway-cleared shoulder devices since 1976 identified 0-313 descendant devices for each. Eighty of these devices (16.8%) have since been recalled, of which 10 recalls were directly related to implant design issues. Furthermore, among 29 of the most recently cleared devices (July 1, 2020-July 1, 2021), 16 (55.2%) claim predicates devices that have subsequently been withdrawn from the market because of design-related failures. CONCLUSIONS: Shoulder arthroplasty devices are linked together via an interconnected FDA 510(k) equivalency approval network dating back to 1976 despite substantive changes in material specifications and device design, many of which have since been recalled. Many of the cleared modern devices claim predicates based on subsequently recalled prostheses.

Impact of a Medical Clinic Relocation on Travel Time: A Tale of 2 Modes of Transportation.

The aim of this study was to quantify access disparities by examining the impact of a medical clinic relocation on travel time differences for patients using private cars versus public transit. Longitude and latitude of patient home addresses were extracted from electronic medical records for the 4 years before the clinic move. Using offline, open-source, and HIPAA-compliant routing software, roundtrip travel times were computed from each home address to the old and new clinic locations via car and bus. Mean roundtrip travel time by a car changed from 41.3 (IQR 16.1-80.7) to 45.4 (IQR 25.9-78.1) minutes, a 9.9% increase. Mean roundtrip travel time by public transit changed from 67.5 (IQR 51.5-100.2) to 120.8 (100.3-156.1) minutes, a 78.9% increase. Even clinic relocations that minimally impact car travel times can nevertheless yield substantial changes to those traveling by public transit. Clinics and health systems that wish to reduce barriers to accessing health care, especially among those already facing structural inequities, would benefit from utilizing the analytic approach described here.

The Complex Process of Using the Interconnected Knee Arthroplasty Device Clearance Pathway.

Background: The clearance of medical devices by the US Food and Drug Administration (FDA) has remained largely unchanged since 1976, when the Medical Device Amendments Act established a system classifying devices into 3 categories based on safety risk to the consumer. The system allows for the clearance of many orthopedics devices through the 510(k) premarket pathway, which is based on "predicate ancestors," previously cleared devices that are "substantially equivalent." Purpose: We sought to trace the predicate ancestors of modern total knee arthroplasty (TKA) devices, specifically those recently cleared for marketing by the 510(k) pathway that claim substantial equivalence to prior devices, despite potential differences in material science and design. In addition, we aimed to document which TKA devices cleared by the 510(k) pathway have substantial equivalence to devices that have since been recalled by the FDA. Methods: To create a comprehensive list of TKA devices, we used FDA Classification Process Codes corresponding to knee arthroplasty to search the FDA's databases from May 28, 1976, the start of the 510(k) process, to May 1, 2021. Of 1309 resulting devices, 89 were excluded as not related to arthroplasty. For each of the remaining devices, we analyzed the descendant devices that claimed substantial equivalence, either directly or indirectly. We used data of recalled designs to determine both the absolute number of recalled devices and the number of currently cleared devices that presented substantial equivalence claims upon predicates that have since been recalled. Results: Of 1220 knee devices cleared or approved, 6 (0.5%) were approved through the premarket approval application (PMA) process, and 1214 (99.5%) were cleared through the 510(k) pathway. Of the 1214 cleared devices, 217 (17.9%) have been recalled and 204 (16.8%) have ties to at least 1 recalled predicate device linked through generational claims of substantial equivalence. We found 90 devices (7.4%) linked directly to a recalled predicate device. Conclusions: Most knee arthroplasty devices are cleared for marketing through reliance on a complex web of equivalency to previously cleared predicates. We found that many TKA devices thus connected were cleared decades apart, with multiple iterations of design and material modifications. Many currently marketed TKA devices have claimed equivalency to predicates that have been recalled. Our findings suggest the need for novel regulatory strategies that might further patient safety while balancing the unwanted effects of regulatory burden.

Pharmacy deserts: More than where pharmacies are.

BACKGROUND: In the United States, geographic access is a major driver of health care disparities. Studies have shown that pharmacy deserts are prevalent in the United States, even in major metropolitan areas. However, one limitation often cited by these studies is the use of distance rather than travel time to define pharmacy deserts. OBJECTIVE: The aim of this study was to assess pharmacy deserts using travel time and to provide a more holistic approach by incorporating analysis of private vehicles and public transportation. METHODS: Pharmacy details were collected from the National Provider Identifier database and neighborhood characteristics from collected census data for the four largest U.S. cities. Pharmacy access was evaluated using open-source routing engines. We determined neighborhoods in pharmacy deserts using both distance and travel time analyses. Sensitivity analysis was performed to determine changes to pharmacy deserts based on small changes in travel time. RESULTS: Of 4654 neighborhoods identified in the four cities of interest, 670 (14.4%) neighborhoods were in pharmacy deserts based on distance. Despite accounting for 28.9% of all neighborhoods, predominantly white neighborhoods only accounted for 4.3% of pharmacy deserts. When evaluating pharmacy deserts by car and public transportation, predominantly white neighborhoods accounted for 2.3% and 1.7% of total pharmacy deserts, respectively. Finally, by reducing travel time from 15 minutes to 10 minutes, pharmacy deserts by car and public transportation increased by 105% and 199%, respectively. All but 3 of the new pharmacy deserts found in the sensitivity analysis were found in nonpredominantly white neighborhoods. CONCLUSION: Using travel time and incorporating modes of transportation, we found that disparities in pharmacy access are more than just where pharmacies are located geographically. There are additional layers of disparities, such as access to public transportation, that need to be addressed to reduce the number of pharmacy deserts.

Safety and Efficacy of Microwave Ablation for Hepatocellular Carcinoma in the Setting of Transjugular Intrahepatic Portosystemic Shunt.

This retrospective analysis reviews five patients with transjugular intrahepatic portosystemic shunt (TIPS) who underwent percutaneous microwave ablation of hepatocellular carcinoma between January 2017 and September 2020. Mean tumor diameter was 2.0 cm (range 1.3-2.9 cm), and mean tumor distance from TIPS was 2.3 cm (range 1.5-3.3 cm). There were no major adverse events, and the TIPS patency was 100% post-ablation. The technical success rate was 100%, and the complete response rate was 100%. In this small study, percutaneous microwave ablation appears safe and effective for the treatment of hepatocellular carcinoma in patients with TIPS in the short-term follow-up period.

Laboratory parameters and outcomes in hospitalized adults with COVID-19: a scoping review.

BACKGROUND: Laboratory parameters and the associated clinical outcomes have been an area of focus in COVID-19 research globally. PURPOSE: We performed a scoping review to synthesize laboratory values described in the literature and their associations with mortality and disease severity. METHODS: We identified all primary studies involving laboratory values with clinical outcomes as a primary endpoint by performing data searches in various systematic review databases until 10th August, 2020. Two reviewers independently reviewed all abstracts (13,568 articles) and full text (1126 articles) data. A total of 529 studies involving 165,020 patients from 28 different countries were included. Investigation of the number of studies and patients from a geographical perspective showed that the majority of published literature from January-March 2020 to April-June 2020 was from Asia, though there was a temporal shift in published studies to Europe and the Americas. For each laboratory value, the proportion of studies that noted a statistically significant (p < 0.05) correlation with adverse clinical outcomes (e.g., mortality, disease severity) was tabulated. RESULTS AND CONCLUSION: Among frequently reported laboratory values, blood urea nitrogen was the most often reported predictor of mortality (91%); neutrophil-to-lymphocyte ratio was the most frequent statistically significant laboratory parameter in predicting disease severity (96%). This review highlights the temporal progression of laboratory value frequencies, as well as potentially distinct utilities of different markers for clinical outcomes of COVID-19. Future research pathways include using this collected data for focused quantitative meta-analyses of particular laboratory values correlated with clinical outcomes of mortality and disease severity.

The Interconnected Ancestral Network of Hip Arthroplasty Device Approval.

BACKGROUND: In the United States, the most overwhelming medical devices, including hip arthroplasty devices, are cleared for human use by demonstration of "substantial equivalence" to a predicate, previously approved marketed device. This study examined the predicate approval lineages of modern hip arthroplasty devices. METHODS: The FDA 510(k) and premarket approval databases were searched to identify all approved hip arthroplasty devices since the database's inception in May 28, 1976. Ancestral predicate lineages were created using approval documentation, and FDA recall data were used to identify recalled devices. RESULTS: Evaluating 2,118 hip arthroplasty devices approved from 1976 to 2020, we found that the number of descendant devices for each approved device varied from 0 to 242. Many descendant devices served as predicates for other devices, leading to frequent indirect connections of equivalency across a wide range of implants. Two hundred forty-six (11.6%) devices were recalled for various reasons, with 34 (1.6%) related to implant design. Evaluating the predicate lineage of 51 hip arthroplasty devices approved between May 1, 2019, and May 1, 2020, 32 of 51 (62.7%) devices were linked, directly or indirectly, to predicates which were recalled for design issues. CONCLUSIONS: The lineage of hip arthroplasty device predicates reflects a complex ancestral web of equivalency across a wide range of implants, although their material and design properties may be different. Several currently approved devices were approved on substantial equivalence claims to products that were subsequently recalled from the market for implant design issues. These findings present several policy considerations for regulators, physicians, and the medical device industry.

Troponin and Other Biomarker Levels and Outcomes Among Patients Hospitalized With COVID-19: Derivation and Validation of the HA2T2 COVID-19 Mortality Risk Score.

Background The independent prognostic value of troponin and other biomarker elevation among patients with coronavirus disease 2019 (COVID-19) are unclear. We sought to characterize biomarker levels in patients hospitalized with COVID-19 and develop and validate a mortality risk score. Methods and Results An observational cohort study of 1053 patients with COVID-19 was conducted. Patients with all of the following biomarkers measured-troponin-I, B-type natriuretic peptide, C-reactive protein, ferritin, and d-dimer (n=446) -were identified. Maximum levels for each biomarker were recorded. The primary end point was 30-day in-hospital mortality. Multivariable logistic regression was used to construct a mortality risk score. Validation of the risk score was performed using an independent patient cohort (n=440). Mean age of patients was 65.0±15.2 years and 65.3% were men. Overall, 444 (99.6%) had elevation of any biomarker. Among tested biomarkers, troponin-I ≥0.34 ng/mL was the only independent predictor of 30-day mortality (adjusted odds ratio, 4.38; P<0.001). Patients with a mortality score using hypoxia on presentation, age, and troponin-I elevation, age (HA2T2) ≥3 had a 30-day mortality of 43.7% while those with a score <3 had mortality of 5.9%. Area under the receiver operating characteristic curve of the HA2T2 score was 0.834 for the derivation cohort and 0.784 for the validation cohort. Conclusions Elevated troponin and other biomarker levels are commonly seen in patients hospitalized with COVID-19. High troponin levels are a potent predictor of 30-day in-hospital mortality. A simple risk score can stratify patients at risk for COVID-19-associated mortality.