Clinical reasoning at the bedside has historically been grounded in pathophysiological mechanism characterized by the causal understanding of what is happening in this particular patient's body. Over the past three decades, two developments have displaced that tradition: the institutionalization of evidence-based medicine, which elevated population-level statistical evidence above individual clinical reasoning, and the rise of molecular biology, which relocated scientific prestige from organ-level integrative physiology to the receptor and the gene. Together, they have produced a clinical culture in which mechanistic reasoning at the level of the individual patient lacks both institutional support and epistemological standing. We argue that this displacement has been costly, that it was never adequately diagnosed, and that recovering mechanistic reasoning while preserving the genuine contributions of both evidence-based medicine and molecular biology is now an urgent task for clinical medicine and medical education alike. Individualized patient care, the explicit goal of contemporary medicine, cannot be achieved within a purely probabilistic framework. Our argument is not against evidence-based medicine; its contributions to clinical practice are genuine and irreversible. It is an argument for integration: population evidence and mechanistic reasoning working together, each supplying what the other cannot. Individualized care requires both.
Postural orthostatic tachycardia syndrome (POTS) as conventionally defined is a chronic condition (typically >3 months duration) incorporating reproducible symptoms of orthostatic intolerance (including dizziness/lightheadedness, and near-syncope) in the absence of orthostatic hypotension (i.e., absence of a sustained systolic blood pressure drop >20mmHg with upright posture).1-10 More recently, however, the 'POTS' landscape as applied by many clinicians has broadened; the term 'POTS' has become increasingly used to categorize a multisystem disorder the underlying etiologies of which remain unclear but may include autonomic dysfunction and/or autoimmune disorders; as such the clinical picture has evolved to encompass a wide range of non-cardiovascular symptoms such as persistent exertional intolerance, fatigue, 'brain fog', thermo-regulatory disorders, and various gastrointestinal symptoms including gastroparesis and certain food intolerance reactions. Thus, while cardiovascular disorders may be the principal manifestation of presumed 'POTS' in many patients, disturbances in a variety of body systems may dominate the clinical presentation in others. This communication, derived from a diverse group of practitioners who care for the wide range of patients often referred for 'suspected POTS', offer the view that optimizing diagnostic evaluation and subsequent care of these individuals necessitates a broad range of clinical skills; in essence involvement of a 'village' of dedicated multi-talented care providers.
Cardiovascular risk prediction models use single blood pressure measurements. Cumulative blood pressure exposure over time may better predict cardiovascular events. We used data from a large community database to examine the incremental value of 10-year cumulative blood pressure exposure over standard risk based on a single value using the Pooled Cohort Equations (PCE). The index date was set to January 1, 2018, with a 5-year prediction horizon and 10 years of prior exposure. Individuals included were 45 years of age or older, had no known cardiovascular disease and had at least 3 prior blood pressure values. The primary exposure was cumulative blood pressure over the previous 10 years, expressed as the area under the systolic blood pressure curve over 140 mmHg. We assessed the model's ability to improve prediction of "Hard cardiovascular disease" (cardiac mortality, myocardial infarction or stroke), stroke and all cause mortality beyond that achieved by the PCE. Our cohort of 614,084 individuals was divided into a derivation set of 428,826 and a validation set of 184,222 individuals. The C statistic improved by 0.8% (95% CI: 0, 0.8%), 1.3% (1.0, 1.7%), and 0% (0, 0.1%), and continuous net reclassification improvement was 0.492, 0.656 and 0.539 for the "Hard cardiovascular disease", stroke, and all-cause mortality outcomes, respectively. Cumulative blood pressure exposure over 10 years significantly improves the prediction of incident cardiovascular events and mortality above that derived from a single value. Introduction of cumulative blood pressure exposure into electronic health records might facilitate personalized risk prediction.
The prognostic significance of pleural effusion in patients with acute heart failure remains insufficiently defined. Our objective was to evaluate the association between pleural effusion and long-term outcomes, stratified by loop diuretic treatment. This retrospective study included 656 elderly patients hospitalized for acute heart failure. Patients were stratified by the presence or absence of pleural effusion at admission. The primary endpoint was the composite of all-cause mortality and/or heart failure readmission. Multivariable Cox regression and interaction analyses between pleural effusion and loop diuretic use at discharge were performed. Median age was 87 (83-90) years, 65.5% were women, and 80.3% had heart failure with preserved ejection fraction. Pleural effusion was present in 40.5% of patients. After multivariable adjustment, a significant interaction was observed between pleural effusion and loop diuretic use for the combined endpoint (p for interaction = 0.043). Among patients with pleural effusion, absence of loop diuretic prescription at discharge was associated with increased risk of death and/or rehospitalization (HR 2.47, 95% CI 1.28-4.77; p = 0.007). Conversely, in patients discharged on loop diuretic, pleural effusion was not significantly associated with mortality and/or rehospitalization (HR 1.21, 95% CI 0.96-1.52; p = 0.101). In this elderly cohort of patients hospitalized for acute heart failure, the presence of pleural effusion was associated with a higher risk of death and/or readmission. The use of loop diuretic therapy at discharge appeared to attenuate this risk, supporting a potential role of individualized, congestion-guided treatment strategies in this population.
Aspirin is a standard therapy for secondary prevention in coronary artery disease, yet its antiplatelet effect varies and incomplete thromboxane-A₂ inhibition has been shown in older individuals. Because no age threshold currently guides treatment, we investigated whether aspirin efficacy differs across predefined age cut-off in patients with coronary artery disease. We analyzed data from START-ANTIPLATELET registry, a multicenter prospective registry of patients hospitalized for acute coronary syndrome and subsequently treated with at least one month of aspirin monotherapy. Patients were stratified by age ≥65 vs <65 years. The primary endpoint was major adverse cardiovascular events, evaluated using Kaplan-Meier estimates and multivariable Cox regression. A systematic review and meta-analysis were conducted to evaluate the effect of aspirin for secondary prevention in older versus younger adults. Pooled risk ratios with 95% confidence intervals were calculated using a random-effects model. 410 patients were included in the registry, of whom 53.7% had ≥65 years. Patients aged ≥65 years exhibited a substantially higher incidence of major adverse cardiovascular events than younger patients, for an absolute increase of 5 events per 1,000 patient-months. Older age was associated with increased risk of major adverse cardiovascular events (hazard ratio 4.99, 95%CI 1.11-22.58) independently of other cardiovascular risk factors (hazard ratio 3.94, 95%CI 0.84-18.65). The meta-analysis of 58,394 participants from 19 trials confirmed the increased risk of major adverse cardiovascular events among older individuals receiving aspirin compared with younger patients (RR 1.43, 95%CI 1.16-1.76). The efficacy of aspirin monotherapy for secondary coronary artery disease prevention is reduced in elderly patients from 65 years of age onward.
As the United States approaches its 250th anniversary, this perspective examines the intertwined evolution of medicine and democracy as mutually reinforcing systems grounded in shared principles of human dignity, rights, and collective responsibility. From the nation's founding, democratic ideals, including life, liberty, and the pursuit of happiness have shaped public health infrastructure, medical ethics, and access to care. Historical figures and landmark legislation illustrate how civic values have been translated into clinical practice, scientific advancement, and population health protections. Major public health achievements reflect democratic processes requiring transparency, participation, and accountability. However, persistent disparities, rising costs, fragmented systems, and erosion of trust expose fractures in the health-democracy compact. Reinvigorating this alliance demands renewed investment in equitable access, modernized public health systems, ethical governance of data and artificial intelligence, and strengthened civic health literacy. Ultimately, both medicine and democracy are active practices requiring engagement and stewardship. Their alignment remains essential to ensuring that future progress advances both individual well-being and the collective promise of a just and democratic society.
The recombinant zoster vaccine (RZV; Shingrix) was approved in 2017. In 2018, the vaccine appeared cost-effective based on available evidence and assumptions. Since then, new evidence has become available regarding long-term efficacy, completion of the 2-dose regimen, duration of immunity, and vaccine price. We adapted a previously published Markov state-transition model to compare RZV with no vaccination among immunocompetent US adults aged 50, 60, 70 and 80 years. The model simulated annual transitions between health states including healthy, acute herpes zoster, postherpetic neuralgia, other complications, and death. Key updated parameters included age-specific efficacy, duration of immunity, completion of the 2-dose regimen, and 2025 vaccine pricing. Costs and outcomes were evaluated from a societal perspective over a lifetime horizon and discounted at 3% annually. We estimated cost-effectiveness by age to identify the optimal time to vaccinate. The incremental cost-effectiveness ratio (ICER) for RZV was $161,162 per QALY at age 50, and $31,465, $16,457, and $19,230 per QALY at ages 60, 70, and 80, respectively. Vaccination was cost-effective for adults aged 60 years and older but not at age 50, using a willingness-to-pay threshold of $100,000/QALY. Results were most sensitive to vaccine price, herpes zoster incidence, and waning duration. Age-specific analysis showed that vaccination became cost-effective at approximately age 54 years. RZV is cost-effective for adults aged 54 years and older. Continued assessment of long-term protection is needed to refine these estimates and evaluate the potential need for booster doses.
Alcohol-associated liver disease (ALD) is a major cause of liver-related morbidity and mortality, with alcohol abstinence remaining the cornerstone of management. Pharmacologic therapies for alcohol use disorder (AUD) can support abstinence but remain underutilized in patients with ALD. The impact of Gastroenterology (GI)/hepatology involvement on the use and outcomes of medications for alcohol use disorder (MAUD) remains understudied. We conducted a retrospective chart review of patients with ALD and AUD identified by ICD-10 codes at a tertiary care liver transplant center between January 2022 and December 2023. Patients prescribed MAUD with ≥90 days of follow-up were included. Clinical characteristics, liver disease severity, and GI/hepatology involvement were assessed. Outcomes included MAUD adherence, alcohol abstinence, and negative alcohol biomarkers. Multivariable logistic regression evaluated associations with outcomes. Among 165 patients (mean age 46.3±10.8 years; 42% female; 87% White), 41% had cirrhosis, of whom 75% had Child-Pugh B/C. GI/hepatology was involved in 47% of cases. Acamprosate (52%) and naltrexone (40%) were most prescribed. At 90 days, mortality was 11%, adherence 46%, abstinence 38%, and negative biomarkers 39%. Higher MELD-Na scores were associated with adherence and abstinence. GI/hepatology-prescribed MAUD was independently associated with negative biomarkers (OR 5.37, 95% CI 1.58-18.32, p=0.007) and showed favorable associations with adherence and abstinence. MAUD are effective in patients with ALD, including cirrhosis. Outcomes were similar across prescribing providers, supporting broader GI/hepatology engagement in initiating AUD treatment.
Contemporary real-world data describing temporal trends in optimal medical therapy (OMT) in patients with chronic coronary syndrome undergoing percutaneous coronary intervention, particularly in the context of residual risk factors, are limited. We sought to evaluate temporal trends in pre-procedural OMT, and their impact on outcomes in this patient population. We included consecutive patients with stable angina and objective evidence of myocardial ischemia who underwent percutaneous coronary intervention at a single quaternary referral center between January 2012 and December 2023. Patients were stratified according to pre-procedural medical therapy intensity and uncontrolled cardiometabolic risk factors. The primary outcome was major adverse cardiovascular events (MACE) defined as composite of all-cause death, myocardial infarction, stroke, or target vessel revascularization assessed at 1-year follow-up. Among 9766 patients with chronic coronary syndrome (mean [SD] age was 67.0 [10.5] years; 27.1% female), significant trends were observed toward an increased proportion of patients presenting with more intensive medical therapy and with improved risk factor control. At 1-year, patients receiving high intensity therapy had higher rates of MACE compared with those receiving low intensity therapy (9.5% vs 6.8%; HR, 1.40; P < 0.01), but lower all-cause death (1.1% vs. 1.8%; HR, 0.59; P = 0.04). Similarly, the high risk patients experienced higher MACE compared with the low risk patients (10.8% vs. 7.9%; HR, 1.39; P < 0.01). No significant differences were observed in moderate intensity treatment and intermediate risk groups. Despite improvements in medical therapy optimization and risk factors, residual risk remained and was associated with adverse outcomes.
Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder increasingly recognized for its association with cognitive impairment and dementia. Emerging epidemiological evidence suggests that individuals with OSA have a higher risk of developing mild cognitive impairment and accelerated cognitive decline. The pathophysiological mechanisms underlying this relationship are multifactorial, involving intermittent hypoxia, sleep fragmentation, and sympathetic activation. These disturbances contribute to oxidative stress, neuroinflammation, impaired glymphatic clearance of amyloid-β and tau proteins, and cerebrovascular dysfunction, ultimately affecting brain regions critical for memory and executive function. Despite strong mechanistic and observational evidence, the impact of OSA treatment on cognitive outcomes remains uncertain. Continuous positive airway pressure (CPAP), the first-line therapy for OSA, has shown improvements in cognitive domains in observational studies; however, randomized controlled trials have yielded inconsistent results. These findings support OSA as a modifiable contributor to neurodegeneration, although definitive evidence for cognitive benefit with treatment remains lacking. Future research should focus on early intervention, longer-term randomized trials, integration of neuroimaging and biomarker endpoints to elucidate the potential for cognitive benefit with OSA treatment.
Night-shift work has been associated with adverse cardiovascular outcomes. It remains unclear whether the cardiovascular association of night-shift exposure differs according to underlying baseline cardiovascular susceptibility and whether short-term intensity and longer-term duration show similar patterns. We analyzed 85,322 UK Biobank participants with occupational night-shift information. Baseline cardiovascular disease risk profile was classified as low, intermediate, or high using a composite score based on cardiovascular disease polygenic risk score tertiles, current smoking, obesity, low moderate-to-vigorous physical activity, and insomnia. Night-shift exposure was evaluated in two ways: monthly intensity and yearly duration, each categorized as none, low, or high. Incident cardiovascular disease was identified from inpatient records. Cox proportional hazards models were evaluated for the associations. Of 85,322 participants, 24,696 were classified as low cardiovascular disease risk, 49,332 as intermediate risk, and 11,294 as high risk. Across all strata, workers without night-shift exposure generally had the lowest incidence of cardiovascular disease . In the low-risk group, high monthly intensity and high yearly duration were each associated with similar increased risk and having more pronounced in high-risk group. For monthly intensity, the aHR were 1.35 (95% CI 1.19-1.52) and 1.22 (95% CI 1.08-1.37) for low- and high-intensity groups, respectively, whereas for yearly duration the corresponding aHR were 1.21 (95% CI 1.06-1.37) and 1.34 (95% CI 1.19-1.51). Among workers with occupational night-shift information, the association between night-shift exposure and incident cardiovascular disease was strongest in those with greater baseline cardiovascular susceptibility. Compared with monthly intensity, yearly duration showed a more consistent exposure-response pattern.
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Obesity is a major global health burden with profound cardiovascular implications, contributing to morbidity, mortality, and healthcare costs. Excess adiposity promotes atherosclerosis, hypertension, atrial fibrillation, heart failure, stroke, and venous thromboembolism through entangled mechanisms, including adipose tissue dysfunction, chronic low-grade inflammation, immune dysregulation, endothelial impairment, insulin resistance, and neurohormonal activation. Dysfunctional adipose tissue, including perivascular and epicardial fat, actively contributes to vascular inflammation, cardiac remodeling, and arrhythmogenesis. Although the "obesity paradox" has been described, obesity remains strongly associated with earlier and more severe cardiovascular events. Recent therapeutic advances, particularly incretin therapies, have improved the management of obesity and its consequences by realizing notable weight loss and metabolic benefits. However, important gaps in obesity phenotyping, cardiovascular risk stratification, and individualized therapy persist, supporting integrated precision-medicine and public-health strategies to reduce obesity-related cardiovascular burden.
Chronic respiratory diseases, including chronic obstructive pulmonary disease (COPD), asthma, and asthma-COPD overlap (ACO), contribute to significant health burdens. Understanding patient characteristics, sleep patterns, and mortality factors is critical for improving management. Data from the UK Biobank were used to compare the baseline characteristics, sleep patterns, and mortality rates of 14,326 COPD, asthma, and ACO patients. Multivariable logistic and linear regression analyses were conducted to identify factors affecting mortality and sleep. COPD patients were older, with higher smoking rates and mortality compared to ACO and asthma patients (P < 0.001). Asthma patients had the highest BMI (29.76), while ACO patients showed the highest diabetes prevalence (14.2%) and asthma patients had the highest hypertension prevalence (46.9%) (P < 0.001). Asthma patients exhibited the poorest sleep quality, with higher rates of short sleep duration, insomnia, and daytime dozing compared to COPD and ACO patients (P < 0.001). Multivariable analysis revealed that COPD patients had higher mortality risks compared to ACO patients (P < 0.001), and poor sleep scores and diabetes were significantly associated with increased mortality (P < 0.001). Asthma patients had significantly lower sleep scores than ACO patients (P < 0.001). ACO patients showed intermediate outcomes, with worse sleep than asthma patients but better than COPD patients. Poor sleep quality, along with diabetes and smoking, was linked to higher mortality. Addressing sleep disturbances may reduce mortality in ACO and COPD patients, warranting further research on targeted interventions.
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