The myth of the medical breakthrough: Smallpox, vaccination, and Jenner reconsidered

AbstractA discussion of the particulars leading to the eradication of smallpox is pertinent to both investigators and the public as the clamor for more “breakthroughs” intensifies. The rational allocation of biomedical research funds is increasingly threatened by disease-advocacy groups and congressional earmarking. An overly simplistic view of how advances truly occur promises only to stunt the growth of researchers and research areas not capable of immediate great breakthroughs. The authors review the contributions of Jenner and his countless predecessors to give a more accurate account of how “overnight medical breakthroughs” truly occur—through years of work conducted by many people, often across several continents.In the public eye, few achievements are regarded with such excitement and awe as the medical breakthrough. Developments such as the discovery of penicillin and the eradication of polio and smallpox have each become a great story built around a singular hero. Edward Jenner, for example, is credited with discovering a means of safely conferring immunity to smallpox. The success of vaccination and subsequent eradication of this disease elevated Jenner to a status in medical history that is rivaled by few.However, the story of the eradication of smallpox does not start or end with the work of Jenner. Men such as Benjamin Jesty and Reverend Cotton Mather as well as unnamed physicians from tenth century China to eighteenth century Turkey also made critical contributions to the crowning achievement. Inoculation to prevent smallpox was commonplace in Europe for generations prior to Jenner's work. Jenner himself was inoculated as a child. In fact, vaccination with cowpox matter was documented in England over 20 years prior to Jenner's work.The authors' review of primary and secondary sources indicates that although Jenner's contribution was significant, it was only one of many. It is extremely rare that a single individual or experiment generates a quantum leap in understanding; this “lone genius” paradigm is potentially injurious to the research process. Wildly unrealistic expectations can only yield unsuccessful scientific investigation, but small steps by investigators supported by an informed public can build toward a giant leap, as the story of smallpox eradication clearly demonstrates

Relative risks of COVID-19 fatality between the first and second waves of the pandemic in Ontario, Canada

OBJECTIVES: To examine whether the case fatality rate (CFR) of COVID-19 decreased over time and whether the COVID-19 testing rate is a driving factor for the changes if the CFR decreased. METHODS: Analyzing COVID-19 cases, deaths and tests in Ontario, Canada, we compared the CFR between the first wave and the second wave across 26 public health units in Ontario. We also explored whether a high testing rate was associated with a large CFR decrease. RESULTS: The first wave CFR ranged from 0.004 to 0.146, whereas the second wave CFR ranged from 0.003 to 0.034. The pooled RR estimate of second wave COVID-19 case fatality, compared with first wave, was 0.24 (95% CI: 0.19-0.32). Additionally, COVID-19 testing percentages were not associated with the estimated relative risk (P=0.246). CONCLUSIONS: The COVID-19 CFR decreased significantly in Ontario during the second wave, and COVID-19 testing was not a driving factor for this decrease

Predictors of Venous Thromboembolism in Patients with Advanced Common Solid Cancers

There is uncertainty about risk heterogeneity for venous thromboembolism (VTE) in older patients with advanced cancer and whether patients can be stratified according to VTE risk. We performed a retrospective cohort study of the linked Medicare-Surveillance, Epidemiology, and End Results cancer registry in older patients with advanced cancer of lung, breast, colon, prostate, or pancreas diagnosed between 1995–1999. We used survival analysis with demographics, comorbidities, and tumor characteristics/treatment as independent variables. Outcome was VTE diagnosed at least one month after cancer diagnosis. VTE rate was highest in the first year (3.4%). Compared to prostate cancer (1.4 VTEs/100 person-years), there was marked variability in VTE risk (hazard ratio (HR) for male-colon cancer 3.73 (95% CI 2.1–6.62), female-colon cancer HR 6.6 (3.83–11.38), up to female-pancreas cancer HR 21.57 (12.21–38.09). Stage IV cancer and chemotherapy resulted in higher risk (HRs 1.75 (1.44–2.12) and 1.31 (1.0–1.57), resp.). Stratifying the cohort by cancer type and stage using recursive partitioning analysis yielded five groups of VTE rates (nonlocalized prostate cancer 1.4 VTEs/100 person-years, to nonlocalized pancreatic cancer 17.4 VTEs/100 patient-years). In a high-risk population with advanced cancer, substantial variability in VTE risk exists, with notable differences according to cancer type and stage

Incidence of Heart Failure or Cardiomyopathy After Adjuvant Trastuzumab Therapy for Breast Cancer

ObjectivesThe purpose of this study was to estimate heart failure (HF) and cardiomyopathy (CM) rates after adjuvant trastuzumab therapy and chemotherapy in a population of older women with early-stage breast cancer.BackgroundNewer biologic therapies for breast cancer such as trastuzumab have been reported to increase HF and CM in clinical trials, especially in combination with anthracycline chemotherapy. Elderly patients, however, typically have a higher prevalence of cardiovascular risk factors and have been underrepresented in trastuzumab clinical trials.MethodsUsing Surveillance, Epidemiology, and End Results-Medicare data from 2000 through 2007, we identified women 67 to 94 years of age with early-stage breast cancer. We calculated 3-year incidence rates of HF or CM for the following mutually exclusive treatment groups: trastuzumab (with or without nonanthracycline chemotherapy), anthracycline plus trastuzumab, anthracycline (without trastuzumab and with or without nonanthracycline chemotherapy), other nonanthracycline chemotherapy, or no adjuvant chemotherapy or trastuzumab therapy. HF or CM events were ascertained from administrative Medicare claims. Poisson regression was used to quantify risk of HF or CM, adjusting for sociodemographic factors, cancer characteristics, and cardiovascular conditions.ResultsWe identified 45,537 older women (mean age: 76.2 years, standard deviation: 6.2 years) with early-stage breast cancer. Adjusted 3-year HF or CM incidence rates were higher for patients receiving trastuzumab (32.1 per 100 patients) and anthracycline plus trastuzumab (41.9 per 100 patients) compared with no adjuvant therapy (18.1 per 100 patients, p < 0.001). Adding trastuzumab to anthracycline therapy added 12.1, 17.9, and 21.7 HF or CM events per 100 patients over 1, 2, and 3 years of follow-up, respectively.ConclusionsHF or CM are common complications after trastuzumab therapy for older women, with higher rates than those reported from clinical trials

Thoroughness of Mediastinal Staging in Stage IIIA Non-small Cell Lung Cancer

IntroductionGuidelines recommend that patients with clinical stage IIIA non-small cell lung cancer (NSCLC) undergo histologic confirmation of pathologic lymph nodes. Studies have suggested that invasive mediastinal staging is underutilized, although practice patterns have not been rigorously evaluated.MethodsWe used the Surveillance, Epidemiology, and End Results-Medicare database to identify patients with stage IIIA NSCLC diagnosed from 1998 through 2005. Invasive staging and use of positron emission tomography (PET) scanning were assessed using Medicare claims. Multivariable logistic regression was used to identify patient characteristics associated with use of invasive staging.ResultsOf 7583 stage IIIA NSCLC patients, 1678 (22%) underwent invasive staging. Patients who received curative intent cancer treatment were more likely to undergo invasive staging than patients who did not receive cancer-specific therapy (30% versus 9.8%, adjusted odds ratio, 3.31; 95% confidence interval, 2.78–3.95). The oldest patients (age, 85–94 years) were less likely to receive invasive staging than the youngest (age, 67–69 years; 27.6% versus 11.9%; odds ratio, 0.46; 95% confidence interval, 0.34–0.61). Sex, marital status, income, and race were not associated with the use of the invasive staging. The use of invasive staging was stable throughout the study period, despite an increase in the use of PET scanning from less than 10% of patients before 2000 to almost 70% in 2005.ConclusionNearly 80% of Medicare beneficiaries with stage IIIA NSCLC do not receive guideline adherent mediastinal staging; this failure cannot be entirely explained by patient factors or a reliance on PET imaging. Incentives to encourage use of invasive staging may improve care

Anti-Hypertensive Medications and Cardiovascular Events in Older Adults with Multiple Chronic Conditions

Importance Randomized trials of anti-hypertensive treatment demonstrating reduced risk of cardiovascular events in older adults included participants with less comorbidity than clinical populations. Whether these results generalize to all older adults, most of whom have multiple chronic conditions, is uncertain. Objective: To determine the association between anti-hypertensive medications and CV events and mortality in a nationally representative population of older adults. Design: Competing risk analysis with propensity score adjustment and matching in the Medicare Current Beneficiary Survey cohort over three-year follow-up through 2010. Participants and Setting 4,961 community-living participants with hypertension. Exposure Anti-hypertensive medication intensity, based on standardized daily dose for each anti-hypertensive medication class participants used. Main Outcomes and Measures Cardiovascular events (myocardial infarction, unstable angina, cardiac revascularization, stroke, and hospitalizations for heart failure) and mortality. Results: Of 4,961 participants, 14.1% received no anti-hypertensives; 54.6% received moderate, and 31.3% received high, anti-hypertensive intensity. During follow-up, 1,247 participants (25.1%) experienced cardiovascular events; 837 participants (16.9%) died. Of deaths, 430 (51.4%) occurred in participants who experienced cardiovascular events during follow-up. In the propensity score adjusted cohort, after adjusting for propensity score and other covariates, neither moderate (adjusted hazard ratio, 1.08 [95% CI, 0.89–1.32]) nor high (1.16 [0.94–1.43]) anti-hypertensive intensity was associated with experiencing cardiovascular events. The hazard ratio for death among all participants was 0.79 [0.65–0.97] in the moderate, and 0.72 [0.58–0.91] in the high intensity groups compared with those receiving no anti-hypertensives. Among participants who experienced cardiovascular events, the hazard ratio for death was 0.65 [0.48–0.87] and 0.58 [0.42–0.80] in the moderate and high intensity groups, respectively. Results were similar in the propensity score-matched subcohort. Conclusions and Relevance In this nationally representative cohort of older adults, anti-hypertensive treatment was associated with reduced mortality but not cardiovascular events. Whether RCT results generalize to older adults with multiple chronic conditions remains uncertain

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer

BACKGROUND: First-line treatment with nivolumab plus ipilimumab (N+I) or nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), yet researchers have not concomitantly compared the cost-effectiveness of N+I and N+I+chemotherapy with chemotherapy alone. MATERIALS AND METHODS: Using outcomes data from the CheckMate 227 and CheckMate 9LA phase 3 randomized trials, we developed a Markov model with lifetime horizon to compare the costs and effectiveness of N+I and N+I+chemotherapy versus chemotherapy from the U.S. health care sector perspective. Subgroup analysis by programmed death-ligand 1 (PD-L1) expression levels (≥1% and <1%) and probabilistic analysis were performed. RESULTS: The incremental cost-effectiveness ratio (ICER) of N+I versus chemotherapy was $239,072 per QALY, and$838,198 per QALY for N+I+chemotherapy versus N+I. The ICER of N+I versus chemotherapy was $246,584 per QALY for patients with PD-L1 ≥ 1$185,620 per QALY for those with PD-L1 < 1%. In probabilistic analysis, N+I had a 2.6% probability of being cost-effective at a willingness-to-pay threshold of $150,000 per QALY. The probability was 0.4% for patients with PD-L1 ≥ 1% and 10.6% for patients with PD-L1 < 1%. CONCLUSION: First-line N+I or N+I+chemotherapy for metastatic NSCLC was not cost-effective regardless of PD-L1 expression levels from the U.S. health care sector perspective

Racial and ethnic differences in internal medicine residency assessments

IMPORTANCE: Previous studies have demonstrated racial and ethnic inequities in medical student assessments, awards, and faculty promotions at academic medical centers. Few data exist about similar racial and ethnic disparities at the level of graduate medical education. OBJECTIVE: To examine the association between race and ethnicity and performance assessments among a national cohort of internal medicine residents. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study evaluated assessments of performance for 9026 internal medicine residents from the graduating classes of 2016 and 2017 at Accreditation Council of Graduate Medical Education (ACGME)-accredited internal medicine residency programs in the US. Analyses were conducted between July 1, 2020, and June 31, 2022. MAIN OUTCOMES AND MEASURES: The primary outcome was midyear and year-end total ACGME Milestone scores for underrepresented in medicine (URiM [Hispanic only; non-Hispanic American Indian, Alaska Native, or Native Hawaiian/Pacific Islander only; or non-Hispanic Black/African American]) and Asian residents compared with White residents as determined by their Clinical Competency Committees and residency program directors. Differences in scores between Asian and URiM residents compared with White residents were also compared for each of the 6 competency domains as supportive outcomes. RESULTS: The study cohort included 9026 residents from 305 internal medicine residency programs. Of these residents, 3994 (44.2%) were female, 3258 (36.1%) were Asian, 1216 (13.5%) were URiM, and 4552 (50.4%) were White. In the fully adjusted model, no difference was found in the initial midyear total Milestone scores between URiM and White residents, but there was a difference between Asian and White residents, which favored White residents (mean [SD] difference in scores for Asian residents: -1.27 [0.38]; P \u3c .001). In the second year of training, White residents received increasingly higher scores relative to URiM and Asian residents. These racial disparities peaked in postgraduate year (PGY) 2 (mean [SD] difference in scores for URiM residents, -2.54 [0.38]; P \u3c .001; mean [SD] difference in scores for Asian residents, -1.9 [0.27]; P \u3c .001). By the final year 3 assessment, the gap between White and Asian and URiM residents\u27 scores narrowed, and no racial or ethnic differences were found. Trends in racial and ethnic differences among the 6 competency domains mirrored total Milestone scores, with differences peaking in PGY2 and then decreasing in PGY3 such that parity in assessment was reached in all competency domains by the end of training. CONCLUSIONS AND RELEVANCE: In this cohort study, URiM and Asian internal medicine residents received lower ratings on performance assessments than their White peers during the first and second years of training, which may reflect racial bias in assessment. This disparity in assessment may limit opportunities for physicians from minoritized racial and ethnic groups and hinder physician workforce diversity

Anti-Hypertensive Medications and Cardiovascular Events in Older Adults with Multiple Chronic Conditions

Importance Randomized trials of anti-hypertensive treatment demonstrating reduced risk of cardiovascular events in older adults included participants with less comorbidity than clinical populations. Whether these results generalize to all older adults, most of whom have multiple chronic conditions, is uncertain. Objective To determine the association between anti-hypertensive medications and CV events and mortality in a nationally representative population of older adults. Design Competing risk analysis with propensity score adjustment and matching in the Medicare Current Beneficiary Survey cohort over three-year follow-up through 2010. Participants and Setting 4,961 community-living participants with hypertension. Exposure Anti-hypertensive medication intensity, based on standardized daily dose for each anti-hypertensive medication class participants used. Main Outcomes and Measures Cardiovascular events (myocardial infarction, unstable angina, cardiac revascularization, stroke, and hospitalizations for heart failure) and mortality. Results Of 4,961 participants, 14.1% received no anti-hypertensives; 54.6% received moderate, and 31.3% received high, anti-hypertensive intensity. During follow-up, 1,247 participants (25.1%) experienced cardiovascular events; 837 participants (16.9%) died. Of deaths, 430 (51.4%) occurred in participants who experienced cardiovascular events during follow-up. In the propensity score adjusted cohort, after adjusting for propensity score and other covariates, neither moderate (adjusted hazard ratio, 1.08 [95% CI, 0.89–1.32]) nor high (1.16 [0.94–1.43]) anti-hypertensive intensity was associated with experiencing cardiovascular events. The hazard ratio for death among all participants was 0.79 [0.65–0.97] in the moderate, and 0.72 [0.58–0.91] in the high intensity groups compared with those receiving no anti-hypertensives. Among participants who experienced cardiovascular events, the hazard ratio for death was 0.65 [0.48–0.87] and 0.58 [0.42–0.80] in the moderate and high intensity groups, respectively. Results were similar in the propensity score-matched subcohort. Conclusions and Relevance In this nationally representative cohort of older adults, anti-hypertensive treatment was associated with reduced mortality but not cardiovascular events. Whether RCT results generalize to older adults with multiple chronic conditions remains uncertain

Are Racial and Ethnic Minorities Less Willing to Participate in Health Research?

BACKGROUND: It is widely claimed that racial and ethnic minorities, especially in the US, are less willing than non-minority individuals to participate in health research. Yet, there is a paucity of empirical data to substantiate this claim. METHODS AND FINDINGS: We performed a comprehensive literature search to identify all published health research studies that report consent rates by race or ethnicity. We found 20 health research studies that reported consent rates by race or ethnicity. These 20 studies reported the enrollment decisions of over 70,000 individuals for a broad range of research, from interviews to drug treatment to surgical trials. Eighteen of the twenty studies were single-site studies conducted exclusively in the US or multi-site studies where the majority of sites (i.e., at least 2/3) were in the US. Of the remaining two studies, the Concorde study was conducted at 74 sites in the United Kingdom, Ireland, and France, while the Delta study was conducted at 152 sites in Europe and 23 sites in Australia and New Zealand. For the three interview or non-intervention studies, African-Americans had a nonsignificantly lower overall consent rate than non-Hispanic whites (82.2% versus 83.5%; odds ratio [OR] = 0.92; 95% confidence interval [CI] 0.84–1.02). For these same three studies, Hispanics had a nonsignificantly higher overall consent rate than non-Hispanic whites (86.1% versus 83.5%; OR = 1.37; 95% CI 0.94–1.98). For the ten clinical intervention studies, African-Americans' overall consent rate was nonsignificantly higher than that of non-Hispanic whites (45.3% versus 41.8%; OR = 1.06; 95% CI 0.78–1.45). For these same ten studies, Hispanics had a statistically significant higher overall consent rate than non-Hispanic whites (55.9% versus 41.8%; OR = 1.33; 95% CI 1.08–1.65). For the seven surgery trials, which report all minority groups together, minorities as a group had a nonsignificantly higher overall consent rate than non-Hispanic whites (65.8% versus 47.8%; OR = 1.26; 95% CI 0.89–1.77). Given the preponderance of US sites, the vast majority of these individuals from minority groups were African-Americans or Hispanics from the US. CONCLUSIONS: We found very small differences in the willingness of minorities, most of whom were African-Americans and Hispanics in the US, to participate in health research compared to non-Hispanic whites. These findings, based on the research enrollment decisions of over 70,000 individuals, the vast majority from the US, suggest that racial and ethnic minorities in the US are as willing as non-Hispanic whites to participate in health research. Hence, efforts to increase minority participation in health research should focus on ensuring access to health research for all groups, rather than changing minority attitudes