The performance status gap in immunotherapy for frail patients with advanced non-small cell lung cancer.

PURPOSE: In advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitor (ICI) monotherapy is often preferred over intensive ICI treatment for frail patients and those with poor performance status (PS). Among those with poor PS, the additional effect of frailty on treatment selection and mortality is unknown. METHODS: Patients in the veterans affairs national precision oncology program from 1/2019-12/2021 who received first-line ICI for advanced NSCLC were followed until death or study end 6/2022. Association of an electronic frailty index with treatment selection was examined using logistic regression stratified by PS. We also examined overall survival (OS) on intensive treatment using Cox regression stratified by PS. Intensive treatment was defined as concurrent use of platinum-doublet chemotherapy and/or dual checkpoint blockade and non-intensive as ICI monotherapy. RESULTS: Of 1547 patients receiving any ICI, 66.2% were frail, 33.8% had poor PS (≥ 2), and 25.8% were both. Frail patients received less intensive treatment than non-frail patients in both PS subgroups (Good PS: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.51 - 0.88; Poor PS: OR 0.69, 95% CI 0.44 - 1.10). Among 731 patients receiving intensive treatment, frailty was associated with lower OS for those with good PS (hazard ratio [HR] 1.53, 95% CI 1.2 - 1.96), but no association was observed with poor PS (HR 1.03, 95% CI 0.67 - 1.58). CONCLUSION: Frail patients with both good and poor PS received less intensive treatment. However, frailty has a limited effect on survival among those with poor PS. These findings suggest that PS, not frailty, drives survival on intensive treatment.

Risk of severe coronavirus disease 2019 despite vaccination in patients requiring treatment with immune-suppressive drugs: A nationwide cohort study of US Veterans.

BACKGROUND: Patients taking immune-suppressive drugs are at increased risk of severe coronavirus disease 2019 (COVID-19), not fully ameliorated by vaccination. We assessed the contributions of clinical and demographic factors to the risk of severe disease despite vaccination in patients taking immune-suppressive medications for solid organ transplantation (SOT), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis. METHODS: Veterans Health Administration electronic health records were used to identify patients diagnosed with RA, IBD, psoriasis, or SOT who had been vaccinated against severe acute respiratory syndrome coronavirus 2, were subsequently infected, and had received immune-suppressive drugs within 3 months before infection. The association of severe (defined as hypoxemia, mechanical ventilation, dexamethasone use, or death) versus non-severe COVID-19 with the use of immune-suppressive and antiviral drugs and clinical covariates was assessed by multivariable logistic regression. RESULTS: Severe COVID-19 was more common in patients with SOT (230/1011, 22.7%) than RA (173/1355, 12.8%), IBD (51/742, 6.9%), or psoriasis (82/1125, 7.3%). Age was strongly associated with severe COVID-19, adjusted odds ratio (aOR) of 1.04 (CI 1.03-1.05) per year. Comorbidities indicating chronic brain, heart, lung, or kidney damage were also associated with severity, aOR 1.35-2.38. The use of glucocorticoids was associated with increased risk (aOR 1.66, CI 1.39-2.18). Treatment with antivirals was associated with reduced severity, for example, aOR 0.28 (CI 0.13-0.62) for nirmatrelvir/ritonavir. CONCLUSION: The risk of severe COVID-19 despite vaccination is substantial in patients taking immune-suppressive drugs, more so in patients with SOT than in patients with inflammatory diseases. Age and severe comorbidities contribute to risk, as in the general population. Oral antivirals were very beneficial but not widely used.

Antidepressant exposure and long-term dementia risk in a nationwide retrospective study on US veterans with midlife major depressive disorder.

INTRODUCTION: The use of antidepressants in major depressive disorder (MDD) has been reported to influence long-term risk of Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), but studies are conflicting. METHODS: We used inverse probability weighted (IPW) Cox models with time-varying covariates in a retrospective cohort study among midlife veterans with MDD within the US Veterans Affairs healthcare system from January 1, 2000 to June 1, 2022. RESULTS: A total of 35,200 patients with MDD were identified. No associations were seen regarding the effect of being exposed to any antidepressant versus no exposure on AD/ADRD risk (events = 1,056, hazard ratio = 0.94, 95% confidence interval: 0.81 to 1.09) or the exposure to specific antidepressant classes versus no exposure. A risk reduction was observed for female patients in a stratified analysis; however, the number of cases was small. DISCUSSION: Our study suggests that antidepressant exposure has no effect on AD/ADRD risk. The association in female patients should be interpreted with caution and requires further attention. HIGHLIGHTS: We studied whether antidepressant use was associated with future dementia risk. We specifically focused on patients after their first-ever diagnosis of depression. We used IPW Cox models with time-varying covariates and a large observation window. Our study did not identify an effect of antidepressant use on dementia risk. A risk reduction was observed in female patients, but the number of cases was small.

Venous thromboembolism risk in cancer patients receiving first-line immune checkpoint inhibitor versus chemotherapy.

It remains unclear if immune checkpoint inhibitor (ICI) therapy is associated with higher rate of venous thromboembolism (VTE) compared with cytotoxic chemotherapy (chemo) in patients with comparable cancer type, staging, and comorbidities. Using the national Veterans Affairs healthcare system database from 2016 to 2021, we performed a propensity score (PS)-weighted retrospective cohort study to compare the incidence of VTE in patients with selected stage III/IV cancer receiving first-line ICI versus chemo. The PS model utilized overlap weights to balance age, sex, race, treatment year, VTE history, paralysis/immobilization, prolonged hospitalization, cancer type, staging, time between diagnosis and treatment, and National Cancer Institute comorbidity index. Weighted Cox regressions with robust standard error were used to assess the hazard ratio (HR) and 95% confidence interval (CI). We found that among comparable advanced cancers, first-line ICI (n = 1823) and first-line chemo (n = 6345) had similar rates of VTE (8.49% for ICI and 8.36% for chemo at 6 months). The weighted HR was 1.06 (95% CI 0.88-1.26) for ICI versus chemo. In a subgroup analysis restricted to lung cancers, first-line ICI/chemo (n = 828), ICI monotherapy (n = 428), and chemo monotherapy (n = 4371) had similar rates of VTE (9.60% for ICI/chemo, 10.04% for ICI, and 8.91% for chemo at 6 months). The weighted HR was 1.05 (95% CI 0.77-1.42) for ICI versus chemo, and 1.08 (95% CI 0.83-1.42) for ICI/chemo versus chemo. In conclusion, ICI as a systemic therapy has a similarly elevated risk as cytotoxic chemo for VTE occurrence in cancer patients. This finding can inform future prospective studies exploring thromboprophylaxis strategies.

Validation of algorithms to select patients with multiple myeloma and patients initiating myeloma treatment in the national Veterans Affairs Healthcare System.

BACKGROUND: We aimed to evaluate and compare the performance of multiple myeloma (MM) selection algorithms for use in Veterans Affairs (VA) research. METHODS: Using the VA Corporate Data Warehouse (CDW), the VA Cancer Registry (VACR), and VA pharmacy data, we randomly selected 500 patients from 01/01/1999 to 06/01/2021 who had (1) either one MM diagnostic code OR were listed in the VACR as having MM AND (2) at least one MM treatment code. A team reviewed oncology notes for each veteran to annotate details regarding MM diagnosis and initial treatment within VA. We evaluated inter-annotator agreement and compared the performance of four published algorithms (two developed and validated external to VA data and two used in VA data). RESULTS: A total of 859 patients were reviewed to obtain 500 patients who were annotated as having MM and initiating MM treatment in VA. Agreement was high among annotators for all variables: MM diagnosis (98.3% agreement, Kappa = 0.93); initial treatment in VA (91.8% agreement; Kappa = 0.77); and initial treatment classification (87.6% agreement; Kappa = 0.86). VA Algorithms were more specific and had higher PPVs than non-VA algorithms for both MM diagnosis and initial treatment in VA. We developed the "VA Recommended Algorithm," which had the highest PPV among all algorithms in identifying patients diagnosed with MM (PPV = 0.98, 95% CI = 0.95-0.99) and in identifying patients who initiated their MM treatment in VA (PPV = 0.93, 95% CI = 0.90-0.96). CONCLUSION: Our VA Recommended Algorithm optimizes sensitivity and PPV for cohort selection and treatment classification.

Risk factors of SARS-CoV-2 infection and complications from COVID-19 in lung cancer patients.

BACKGROUND: Identifying lung cancer patients at an increased risk of getting SARS-CoV-2-related complications will facilitate tailored therapy to maximize the benefit of anti-cancer therapy, while decreasing the likelihood of COVID-19 complications. This analysis aimed to identify the characteristics of lung cancer patients that predict for increased risk of death or serious SARS-CoV-2 infection. PATIENTS AND METHODS: This was a retrospective cohort study of patients with lung cancer diagnosed October 1, 2015, and December 1, 2020, and a diagnosis of COVID-19 between February 2, 2020, and December 1, 2020, within the Veterans Health Administration. Serious SARS-CoV-2 infection was defined as hospitalization, ICU admission, or mechanical ventilation or intubation within 2 weeks of COVID-19 diagnosis. For categorical variables, differences were assessed using Χ2 tests, while Kruskal-Wallis rank-sum test was used for continuous variables. Multivariable logistic regression models were fit relative to onset of serious SARS-CoV-2 infection and death from SARS-CoV-2 infection. RESULTS: COVID-19 infection was diagnosed in 352 lung cancer patients. Of these, 61 patients (17.3%) died within four weeks of diagnosis with COVID-19, and 42 others (11.9%) experienced a severe infection. Patients who had fatal or severe infection were older and had lower hemoglobin levels than those with mild or moderate infection. Factors associated with death from SARS-CoV-2 infection included increasing age, immune checkpoint inhibitor therapy and low hemoglobin level. CONCLUSIONS:  The mortality of lung cancer patients from COVID-19 disease in the present cohort was less than previously reported in the literature. The identification of risk factors associated with severe or fatal outcomes informs management of patients with lung cancer who develop COVID-19 disease.

Structural barriers for retention of HIV/AIDS patients after initiating antiretroviral therapy in outpatient clinics of Vietnam.

Little evidence is available about structural factors associated with the retention in care for people living with HIV/AIDS (PLWH) in Vietnam. This retrospective longitudinal study was conducted among PLWH initiating antiretroviral therapy (ART) in 62 ART clinics from 15 provinces, to estimate retention rates and identify specific related structural factors. Facility-related factors such as location, duration of HIV service implantation, level of healthcare facility, frequency of drugs dispensed, integration of HIV care were examined. Cox proportional hazard model was employed to estimate the retention rate and association between facility-level factors and loss-to-follow up (LTFU). Among 20,119 patients, the retention rates after 6, 12, 24, 36 and 48 months were 96.5% (95% CI = 96.2%-96.7%), 93.6% (95% CI = 93.2%-93.9%), 90.2% (95% CI = 89.8%-90.6%), 87.9% (95% CI = 87.4%-88.4%) and 86.0% (95% CI = 85.4%-86.5%), respectively. Facility-level factors associated with increased risk of LTFU included duration of HIV service implementation, frequency of drug dispensed per month, integration of HIV care and of treatment procedures into general care, clinics at central or provincial level and in the Middle region of Vietnam. Such association should be addressed in future care planning and HIV/AIDS management to ensure greater coverage of therapy in Vietnam.

Increased relative proportions of advanced melanoma among veterans: A comparative analysis with the Surveillance, Epidemiology, and End Results registry.

BACKGROUND: The Surveillance, Epidemiology, and End Results (SEER) program reflects a third of the population of the United States. However, SEER may not be generalizable to the veteran population. Because veterans comprise a high-risk population, this discrepancy may limit our understanding of the epidemiology of melanoma in such high-risk populations. OBJECTIVES: To assess differences in demographics, tumor characteristics, and melanoma-specific survival (MSS) in veterans compared to the general population. METHODS: Data were collected from the Veterans Affairs Cancer Registry (VACR) and SEER (18 registries) from 2009 to 2017. RESULTS: We identified 15,334 veterans and 166,265 SEER patients with melanoma. Veterans were more likely to present with regional or distant disease (17.5% vs 13.0% in SEER). In VACR relative to SEER, the 5-year MSS was lower across all ages, except those diagnosed at ≥80 years. From 2009 to 2017, MSS by stage was lower across all stages in VACR. However, for stage IV melanomas diagnosed in 2015 to 2017 compared to 2011-2014, 2-year MSS increased from 37.8% to 51.5% in VACR versus 36.4% to 44.8% in SEER. LIMITATIONS: Unique veteran demographics and missing data inherent to VACR. CONCLUSION: Compared to SEER, veterans with melanoma were diagnosed at later stages; however, both exhibited recent improvement in stage IV MSS.

Factors associated with the speed and scope of diffusion of COVID-19 therapeutics in a nationwide healthcare setting: a mixed-methods investigation.

BACKGROUND: The global COVID-19 pandemic is an opportunity to evaluate factors associated with high levels of adoption of different therapeutics in a real-world setting. The aim of this nationwide, retrospective cohort study was to evaluate the diffusion and adoption of novel therapeutics with an emerging evidence basis and to identify factors that influenced physicians' treatment decisions. METHODS: Cohort creation: A cohort of Veteran patients with a microbiologically confirmed diagnosis of SARS-CoV2 were identified, and cases were classified by disease severity (outpatient, inpatient with mild and severe disease, intensive care unit ICU]). After classification of disease severity, the proportion of cases (outpatients) and admissions (inpatients) in each category receiving each type of medication were plotted as a function of time. Identification of milestones and guidance changes: Key medications used for the management of COVID-19 milestones in the release of primary research results in various forms (e.g. via press release, preprint or publication in a traditional medical journal), policy events and dates of key guidelines were identified and plotted as a timeline. After a timeline was created, time points were compared to changes in medication use, and factors potentially impacting the magnitude (i.e. proportion of patients who received the treatment) and the speed (i.e. the slope of the change in use) of practice changes were evaluated. RESULTS: Dexamethasone and remdesivir, the first two medications with clinical trial data to support their use, underwent the most rapid, complete and sustained diffusion and adoption; the majority of practice changes occurred after press releases and preprints were available and prior to guideline changes, although some additional uptake occurred following guideline updates. Medications that were not "first in class", that were identified later in the pandemic, and that had higher perceived risk had slower and less complete uptake regardless of the strength and quality of the evidence supporting the intervention. CONCLUSIONS: Our findings suggest that traditional and social media platforms and preprint releases were major catalysts of practice change, particularly prior to the identification of effective treatments. The "first available treatment in class" impact appeared to be the single most important factor determining the speed and scope of diffusion.

Potential long-term effect of tumor necrosis factor inhibitors on dementia risk: A propensity score matched retrospective cohort study in US veterans.

INTRODUCTION: Tumor necrosis factor (TNF) inhibitors are widely used to treat rheumatoid arthritis (RA) and their potential to retard Alzheimer's disease (AD) progression has been reported. However, their long-term effects on the dementia/AD risk remain unknown. METHODS: A propensity scored matched retrospective cohort study was conducted among 40,207 patients with RA within the US Veterans Affairs health-care system from 2000 to 2020. RESULTS: A total of 2510 patients with RA prescribed TNF inhibitors were 1:2 matched to control patients. TNF inhibitor use was associated with reduced dementia risk (hazard ratio [HR]: 0.64, 95% confidence interval [CI]: 0.52-0.80), which was consistent as the study period increased from 5 to 20 years after RA diagnosis. TNF inhibitor use also showed a long-term effect in reducing the risk of AD (HR: 0.57, 95% CI: 0.39-0.83) during the 20 years of follow-up. CONCLUSION: TNF inhibitor use is associated with lower long-term risk of dementia/AD among US veterans with RA.

Survival Outcomes of Vietnamese People with HIV after Initiating Antiretroviral Treatment: Role of Clinic-Related Factors.

Given the rapid development of HIV clinics in Vietnam, this study evaluates the infrastructure surrounding this expansion, identifying clinic-related factors that impact survival outcomes. A retrospective longitudinal study was conducted among people living with HIV (PLWH) who initiated antiretroviral therapy (ART) between 2011 and 2015 among 62 ART clinics in 15 provinces. The mortality rate during the 717674.1 person-years of observation (PYO) was 0.29/100 PYO. Location in rural areas (versus urban) and in Central Vietnam (versus Northern Vietnam) were associated with higher risk of mortality. The risk was lower among clinics that had peer-educators. As Vietnam's HIV/AIDS program continues to expand, this data supports increasing resource allocation for rural clinics, incorporation of ART with the community's existing healthcare infrastructure in its efforts to decentralize, and integration of services to reflect patients' anticipated needs.

Dried blood spots perform well to identify patients with active HCV infection in Vietnam.

Recently, treatment advances in direct-acting antivirals have radically changed the management of HCV patients. However, in resource-limited countries, identification of patients with active HCV infection is still challenging in remote settings due to the limited access to laboratories able to measure HCV viral load. This study evaluated whether dried blood spots (DBS) transferred to a central laboratory could overcome this challenge. A total of 315 HCV-infected patients, naïve to anti-HCV treatment, provided each three type of samples: plasma, DBS with calibrated quantities of venous blood and DBS with uncalibrated quantities of capillary blood. Qualitative comparison was conducted in terms of detection of HCV viral load on DBS as opposed to plasma to estimate sensitivity and specificity. Quantitative comparisons were conducted by means of correlation estimation. Of the 250 patients with detected plasma HCV viral load, 245 also had detectable DBS HCV viral load (capillary or venous) leading to a sensitivity of 98.0% (95% confidence interval (CI): 95.4%-99.3%); importantly, all measurements with a plasma HCV viral load >118 IU/mL were also detected in DBS. When HCV was not detected in plasma, it was also not detected in DBS resulting in 100% specificity (95% CI: 94.5%-100%). Quantitative HCV viral load results were very similar when utilizing plasma or DBS sample types as illustrated by correlations >0.99. In conclusion, DBS sample types, with either uncalibrated capillary blood or calibrated venous blood, performed well to distinguish patients with active HCV infection, and who therefore need treatment, from other patients.

Functionalization of activated methylene C-H bonds with nitroarenes and sulfur for the synthesis of thioamides.

We report a method to obtain arylthioamides by the functionalization of sp3 C-H bonds in phenylacetic acids and benzyl alcohols. Reactions proceeded without the use of any solvents and were compatible with many functionalities and heterocycles. These conditions allow for a rapid synthesis of thioamides from simple, commercial substrates.

Projecting the epidemiological effect, cost-effectiveness and transmission of HIV drug resistance in Vietnam associated with viral load monitoring strategies.

OBJECTIVES: The objective of this study was to investigate the potential epidemiological impact of viral load (VL) monitoring and its cost-effectiveness in Vietnam, where transmitted HIV drug resistance (TDR) prevalence has increased from <5% to 5%-15% in the past decade. METHODS: Using a population-based mathematical model driven by data from Vietnam, we simulated scenarios of various combinations of VL testing coverage, VL thresholds for second-line ART initiation and availability of HIV drug-resistance tests. We assessed the cost per disability-adjusted life year (DALY) averted for each scenario. RESULTS: Projecting expected ART scale-up levels, to approximately double the number of people on ART by 2030, will lead to an estimated 18 510 cases (95% CI: 9120-34 600 cases) of TDR and 55 180 cases (95% CI: 40 540-65 900 cases) of acquired drug resistance (ADR) in the absence of VL monitoring. This projection corresponds to a TDR prevalence of 16% (95% CI: 11%-24%) and ADR of 18% (95% CI: 15%-20%). Annual or biennial VL monitoring with 30% coverage is expected to relieve 12%-31% of TDR (2260-5860 cases), 25%-59% of ADR (9620-22 650 cases), 2%-6% of HIV-related deaths (360-880 cases) and 19 270-51 400 DALYs during 2015-30. The 30% coverage of VL monitoring is estimated to cost US$4848-5154 per DALY averted. The projected additional cost for implementing this strategy is US$105-268 million over 2015-30. CONCLUSIONS: Our study suggests that a programmatically achievable 30% coverage of VL monitoring can have considerable benefits for individuals and leads to population health benefits by reducing the overall national burden of HIV drug resistance. It is marginally cost-effective according to common willingness-to-pay thresholds.

Pretreatment HIV-1 drug resistance to first-line drugs: results from a baseline assessment of a large cohort initiating ART in Vietnam, 2009-10.

OBJECTIVES: The objective of this study was to determine the prevalence and correlates of pretreatment drug resistance (PDR) to first-line antiretroviral drugs among people initiating therapy for HIV in Vietnam. METHODS: Blood was collected during November 2009 to October 2010 from people consecutively initiating ART in four purposively selected public outpatient clinics in three Vietnamese cities. At each study site, recruitment lasted for 6-10 months until the target sample size (range 120-130 individuals) had been reached. The viral load was measured in 501 samples; 490 samples (viral load ≥1000 copies/mL) were genotyped using a nucleotide population-based sequencing assay. Self-reported demographic and clinical data were elicited through interviews. We classified drug-resistance-associated mutations (DRMs) according to the 2009 WHO surveillance list. RESULTS: DRMs were identified in 17/490 participants (3.5%; 95% CI 2.2%-5.5%). The prevalence of DRMs was 1.6% (8/490) against NRTIs, 1.6% (8/490) against NNRTIs and 0.8% (4/490) against PIs; three (0.6%) participants were resistant to both NRTIs and NNRTIs. The overall prevalence of PDR to first-line drugs was low [2.7% (13/490); 95% CI 1.6%-4.4%]. The prevalence of PDR to first-line drugs was greater among 198 HIV-infected participants who injected drugs than among 286 participants who reported risks for sexually acquired HIV (4.0% versus 1.4%, P = 0.079). Multivariable logistic regression analysis suggested that PDR to first-line drugs was significantly higher among people who injected drugs (OR = 3.94; 95% CI 1.13-13.68). CONCLUSIONS: With low PDR, first-line ART may be effective in Vietnam and pretreatment genotyping may be unnecessary. Continuing strategies for the prevention and surveillance of antiretroviral resistance are important for maintaining a low prevalence of antiretroviral resistance in Vietnam. The association between resistance and injection drug use warrants further research.

Automating Clinical Trial Matches Via Natural Language Processing of Synthetic Electronic Health Records and Clinical Trial Eligibility Criteria.

Clinical trials are critical to many medical advances; however, recruiting patients remains a persistent obstacle. Automated clinical trial matching could expedite recruitment across all trial phases. We detail our initial efforts towards automating the matching process by linking realistic synthetic electronic health records to clinical trial eligibility criteria using natural language processing methods. We also demonstrate how the Sørensen-Dice Index can be adapted to quantify match quality between a patient and a clinical trial.