Severe alcohol-associated hepatitis (sAH) is a leading indication for liver transplant (LT). However, access to LT begins with referral, a step that may not have been previously characterized using prospective multicenter data with detailed measures of social determinants of health. To examine the association of clinical severity and neighborhood disadvantage with referral, wait-listing, transplant, and short-term mortality in patients hospitalized with sAH. This prospective multicenter cohort study was a secondary analysis of the Alcohol-Associated Hepatitis Network observational cohort. It included patients hospitalized with sAH (Model for End-Stage Liver Disease [MELD] >20) across 5 US transplant centers from May 6, 2019, to November 8, 2023. Clinical, demographic, and social determinants of health data, including the Area Deprivation Index (ADI), were collected prospectively. Clinical severity (MELD score) and neighborhood-level disadvantage (ADI). The primary outcomes were referral for LT evaluation, wait-listing, and receipt of LT, and the secondary outcome was 180-day mortality. Logistic regression and generalized additive models were used to evaluate independent and interactive associations of MELD and ADI with outcomes. The cohort included 325 patients (mean [SD] age, 44.8 [10.2] years; 197 males [60.6%]). The mean (SD) MELD score was 29.2 (7.6), and the mean (SD) ADI was 56.2 (24.4). Only 120 patients (36.9%) were referred for LT. In multivariable analysis, higher MELD scores were associated with lower referral odds (odds ratio, 1.13 [95% CI, 1.07-1.18]; P < .001). ADI was not associated with referral odds (odds ratio, 0.99 [95% CI, 0.97-1.00]; P = .06). Generalized additive model analyses demonstrated significant MELD × ADI interactions for referral (P for interaction = .01), wait-listing (P for interaction = .004), and mortality (P for interaction = .01). At a MELD score 20 to 30, referral probability was 40% to 60% among patients with an ADI less than 30 vs 20% among those with an ADI 30 or more. Among patients with a MELD score 20 to 30, mortality exceeded 20% in those with an ADI 60 or more compared with 10% to 20% in those with an ADI less than 20. In this multicenter cohort study of severe alcohol-associated hepatitis, neighborhood disadvantage was associated with referral at intermediate MELD scores. These findings suggest that referral is a critical leverage point for interventions and that outreach and navigation strategies informed by social context may improve access to LT.

Transradial access (TRA) has emerged as a promising alternative to standard transfemoral access (TFA) for interventional cardiac procedures, but its application for examination of the cerebral circulation has not been tested in a clinical trial. To compare the efficacy and safety of TRA with TFA for diagnostic cerebral angiography. This investigator-initiated, multicenter, open-label, noninferiority randomized clinical trial with a blinded outcome assessment was conducted at 13 sites in China. Patients eligible for cerebral angiography were randomized between September 15, 2023, and November 4, 2024, with final follow-up performed on November 27, 2024. The primary analysis was performed in the intention-to-treat population; secondary analyses were performed in the per-protocol population. Patients were randomly allocated to TRA (n = 431) or TFA (n = 430) for diagnostic cerebral angiography. The primary outcome was the success of diagnostic cerebral angiography. Secondary outcomes were success in achieving an accurate diagnosis, duration of angiography and fluoroscopy, time in bed, and patient-reported satisfaction on an 11-point visual analog scale for pain (ranging from 0 [none] to 10 [worst possible]) within 24 hours after the procedure. The noninferiority margin was an absolute difference of 5% in success of angiographic diagnosis and success of accurate diagnosis. A total of 858 patients (median age, 58.4 [IQR, 52.0-67.0] years; 479 [55.8%] male) completed the trial. Success of diagnostic cerebral angiography in the TRA group was lower than that in the TFA group (392 of 431 [91.0%] vs 409 of 427 [95.8%]; difference, -4.8 percentage points [pp] [95% CI, -8.1 to -1.5 pp]; relative risk [RR], 0.95 [95% CI, 0.92-0.98]; P = .46 for noninferiority test). The success rate of accurate diagnosis was 78.9% in the TRA group vs 91.1% in the TFA group (difference, -12.2 pp [95% CI, -16.9 to -7.5 pp]; RR, 0.87 [95% CI, 0.82-0.92]; P = .99 for noninferiority test). Compared with the TFA group, the TRA group had longer median times for angiography (33.7 [IQR, 23.0-40.0] vs 38.7 [IQR, 26.0-47.0] minutes; P < .001) and fluoroscopy (10.6 [IQR, 5.6-12.9] vs 11.8 [IQR, 6.2-15.0] minutes; P = .02); the TRA group had significantly shorter median time in bed (188.4 [IQR, 3.0-180.0] vs 1079.0 [IQR, 842.0-1366.0] minutes; P < .001) and lower median pain scores (0.5 [IQR, 0.0-1.0] vs 0.7 [IQR, 0.0-1.0]; P < .001). Overall angiography complications were comparable between the groups (19 of 445 [4.3%] vs 25 of 413 [6.1%]; P = .28), but TRA had more radial artery puncture failures than TFA. In this randomized clinical trial of patients undergoing diagnostic cerebral angiography, TRA was not shown to be noninferior to TFA with regard to the success rate of diagnostic cerebral angiography. Additional research, including superiority trials, is needed to clearly define the comparative benefits of TRA and TFA. ClinicalTrials.gov Identifier: NCT05401669.

Risk prediction has been a cornerstone of efforts to prevent clinical deterioration in hospitalized patients.However, despite guideline recommendations for use of early warning scores (EWSs) as part of a rapid response system, substantial questions remain about which scores to use and how best to implement them to reduce in-hospital cardiac arrest and mortality. 1The study by Covino and colleagues 2 adds to those questions by demonstrating that patient age impacts not only the discrimination and calibration of different models but also the weighting of physiologic inputs to the model.In their study comparing EWSs in emergency department patients aged 80 years and older, the authors demonstrated that while the area under the receiver operating characteristic curve for predicting intensive care unit admission or death decreased slightly with increasing age for most scores, the Rapid Emergency Medicine Score (REMS), 1 of only 2 of the tested models that included age, discriminated better in patients older than 94 years and was also the best calibrated of the scores.In addition, they included a variable importance analysis demonstrating several interactions between age and other model inputs, with supplemental oxygen and systolic blood pressure, for example, having more of an impact on risk in patients older than 86 years.This study 2 serves as an important reminder that age is both a key covariate and a potential confounder in clinical deterioration prediction, raising the question of why its inclusion is not more ubiquitous in EWSs.Age is a well-known predictor of mortality, which the developers of the National Early Warning Score (NEWS) were keenly aware of and had previously published on, 3 suggesting that the decision to omit age from NEWS was a methodologic one rather than evidence based.Furthermore, these findings echo broader work comparing machine learning-based EWSs with traditional scores, where models that implicitly account for interactions often achieve higher discrimination. 4aditional EWSs, such as the Modified Early Warning Score and NEWS, were intentionally simple, relying on fixed thresholds, additive points, and transparent interpretation, features that were essential in the era of paper charting and manual calculation.In contrast, modern artificial intelligence and machine learning models add complexity in calculation and interpretability but can be trained to account for interactions between predictors, reflecting the clinical reality that physiology rarely behaves linearly or independently.More importantly, prior work suggests that the success or failure of early warning systems may depend less on model performance than on how predictions are operationalized.Studies of rapid response systems have demonstrated that even well-validated scores may fail to reduce adverse outcomes when alerts are poorly timed, poorly targeted, or lack clear response pathways. 5terpreted literally, the findings from Covino et al 2 could be used to argue that hospitals should use NEWS in younger emergency department patients and REMS in older ones.That approach would retain model simplicity while accounting for age-specific interactions.However, it would also introduce substantial complexity for frontline clinicians, who would need to be familiar with multiple scores and workflows.In this context, adding multiple age-stratified scores may paradoxically worsen performance by increasing cognitive burden and reducing adherence, even if each individual model is statistically optimized for its subgroup.

Microstructures of sleep electroencephalography (EEG) are closely related to cognition and undergo age-dependent changes. However, their multidimensional nature makes them challenging to interpret using conventional approaches. The machine learning-based EEG brain age index (BAI) measures the deviation between sleep EEG-based brain age and chronological age. To determine the association between sleep BAI and incident dementia in community-dwelling populations. For this individual participant data (IPD) meta-analysis, sleep study data from 5 community-based longitudinal cohorts were pooled. These cohorts included the Multi-Ethnic Study of Atherosclerosis (MESA; 2010-2013), the Atherosclerosis Risk in Communities (ARIC) study (1987-1989), the Framingham Heart Study-Offspring Study (FHS-OS; 1995-1998), the Osteoporotic Fractures in Men Study (MrOS; 2003-2005), and the Study of Osteoporotic Fractures (SOF; 2002-2004). Adults (aged ≥18 years) without dementia at the time of polysomnography were included. The BAI was computed using interpretable machine learning, incorporating sleep EEG features extracted from central channels in overnight, home-based polysomnography. Fine-Gray models were used to assess the association between BAI and incident dementia within each cohort, accounting for death as a competing risk. Cohort-specific estimates were then pooled using random-effects meta-analysis. Analyses were performed between March 2024 and September 2025. Incident dementia or probable dementia was determined in each cohort, with death as a competing risk. This meta-analysis included 7105 participants from the MESA (n = 1802; mean [SD] age, 69.3 [9.0] years; 956 females [53.1%]), ARIC (n = 1796; 62.5 [5.7] years; 918 females [51.1%]), FHS-OS (n = 617; 59.5 [8.9] years; 318 females [51.5%]), MrOS (n = 2639 males [100%]; 76.0 [5.3] years), and SOF (n = 251 females [100%]; 82.7 [2.9] years) cohorts. The median (IQR) time to dementia was 4.8 (4.2-5.6) years in the MESA cohort (n = 119 [6.6%]), 16.9 (14.9-19.8) years in the ARIC cohort (n = 354 [19.7%]), 13.1 (8.5-16.2) years in the FHS-OS cohort (n = 59 [9.6%]), 3.6 (1.3-7.1) years in the MrOS cohort (n = 470 [17.8%]), and 4.6 (4.2-5.2) years in the SOF cohort (n = 86 [34.3%]). Across the cohorts, each 10-year increase in BAI was associated with a 39% higher risk of incident dementia (hazard ratio [HR], 1.39 [95% CI, 1.21-1.59]; P < .001) after adjustment for covariates. These associations remained after additional adjustment for comorbidities and apnea-hypopnea index scores (HR, 1.31 [95% CI, 1.14-1.50]; P < .001) and apolipoprotein E ε4 (HR, 1.22 [95% CI, 1.02-1.45]; P = .03), and they were consistent across sex and age groups. In this IPD meta-analysis, a higher sleep EEG-based BAI was associated with a higher risk of incident dementia. These findings highlight the need to evaluate the predictive value of the BAI as a noninvasive digital marker for early detection of dementia in community settings.

This qualitative study uses a large free-text dataset to describe reasons for comfort and discomfort with documentation of health-related social needs in the electronic health record among caregivers of pediatric patients.

Annual tobacco-related death estimates are 480 000 in the US and 8 million worldwide, surpassing mortality for other abused substances. Most smoking cessation interventions result in modest long-term success. To compare prolonged smoking abstinence rates in smokers receiving psilocybin plus cognitive behavioral therapy (CBT) with those receiving the nicotine patch plus CBT. In this pilot randomized clinical trial, participants and investigators were unblinded to treatment condition, including an optional crossover after completion of the primary end point. Data were collected from psychiatrically healthy adult smokers from January 20, 2015, to May 8, 2023, at the Johns Hopkins Bayview Medical Center, an academic medical center and teaching hospital in Baltimore, Maryland. The trial randomized cigarette smokers to receive either 1 high dose (30 mg/70 kg) of psilocybin or initiate 8 to 10 weeks of US Food and Drug Administration-approved nicotine patch treatment on the target quit date. Both groups received a 13-week manualized CBT program for smoking cessation. Biochemically verified prolonged smoking abstinence (primary) and 7-day point prevalence abstinence (secondary) at 6 months after the target quit date were compared between groups using intention-to-treat analysis. A total of 82 psychiatrically healthy adult smokers (mean [SD] age, 47.6 [12.0] years; 49 [59.8%] male) participated in the study, with 68 (82.9%) completing the 6-month follow-up. At 6-month follow-up, 17 participants receiving psilocybin (40.5%) exhibited biochemically verified prolonged abstinence compared with 4 participants using the nicotine patch (10.0%) (odds ratio, 6.12; 95% CI, 1.99-23.26; P = .003), and 22 participants receiving psilocybin (52.4%) exhibited biochemically verified 7-day point prevalence abstinence compared with 10 participants using the nicotine patch (25.0%) (odds ratio, 3.30; 95% CI, 1.32-8.70; P = .01). No serious adverse events were attributed to psilocybin or nicotine patch. In this pilot randomized clinical trial, 1 dose of psilocybin with manualized CBT significantly increased long-term abstinence compared with nicotine patch treatment with CBT. Psilocybin abstinence rates were higher than typical treatments, suggesting promise for tobacco smoking cessation. ClinicalTrials.gov Identifier: NCT01943994.

Inhaled corticosteroid (ICS)-long-acting β-agonist (LABA) inhalers are generally considered therapeutically equivalent when treating chronic obstructive pulmonary disease (COPD). However, metered-dose inhalers in the class are associated with substantially higher greenhouse gas emissions than dry powder formulations, and studies have raised questions about potential intraclass differences in clinical outcomes among patients receiving ICS-LABAs. To analyze COPD exacerbations and pneumonia hospitalizations associated with once-daily fluticasone furoate-vilanterol dry powder inhalers, twice-daily fluticasone propionate-salmeterol dry powder inhalers, and twice-daily budesonide-formoterol metered-dose inhalers in adults with COPD. This cohort study was conducted using longitudinal commercial claims data of US adults aged 40 years or older with COPD. Patients were 1:1 pairwise propensity score matched into 3 cohorts: (1) new users receiving fluticasone furoate-vilanterol vs budesonide-formoterol between January 1, 2014, and February 29, 2024; (2) new users receiving fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol between January 1, 2014, and February 29, 2024; and (3) new users receiving fluticasone propionate-salmeterol vs budesonide-formoterol between January 1, 2007, and February 29, 2024. Receipt of a once-daily fluticasone furoate-vilanterol dry powder inhaler (Breo Ellipta; GSK), twice-daily fluticasone propionate-salmeterol dry powder inhaler (Advair Diskus; GSK), or twice-daily budesonide-formoterol metered-dose inhaler (Symbicort; AstraZeneca). The primary outcomes were first moderate or severe COPD exacerbation and first pneumonia hospitalization. Hazard ratios and 95% CIs were estimated using Cox proportional hazards regression models. The cohorts included 38 070 matched pairs of patients receiving fluticasone furoate-vilanterol vs budesonide-formoterol (58.8% women; mean [SD] age, 71.0 [9.0] years), 20 471 matched pairs of patients receiving fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol (58.3% women; mean [SD] age, 69.9 [9.2] years), and 55 627 matched pairs of patients receiving fluticasone propionate-salmeterol vs budesonide-formoterol (56.2% women; mean [SD] age, 68.3 [9.0] years). Patients receiving fluticasone furoate-vilanterol had a 9% lower risk of moderate or severe COPD exacerbations compared with those receiving budesonide-formoterol (hazard ratio [HR], 0.91 [95% CI, 0.88-0.94]; number needed to treat [NNT] = 40) and a 6% lower risk compared with those receiving fluticasone propionate-salmeterol (HR, 0.94 [95% CI, 0.89-0.98]; NNT = 40). The risk of moderate or severe COPD exacerbation was similar for patients receiving fluticasone propionate-salmeterol and budesonide-formoterol (HR, 0.98 [95% CI, 0.95-1.01]). No differences were observed in the risk of pneumonia hospitalization across the 3 cohorts (fluticasone furoate-vilanterol vs budesonide-formoterol: HR, 1.03 [95% CI, 0.96-1.11]; fluticasone furoate-vilanterol vs fluticasone propionate-salmeterol: HR, 0.93 [95% CI, 0.85-1.03]; and fluticasone propionate-salmeterol vs budesonide-formoterol: HR, 1.04 [95% CI, 0.98-1.10]). In this cohort study of new ICS-LABA users with COPD, once-daily dry powder fluticasone furoate-vilanterol inhalers were associated with slightly improved clinical outcomes compared with twice-daily metered-dose budesonide-formoterol inhalers and twice-daily dry powder fluticasone propionate-salmeterol inhalers. Further studies are needed to explore potential intraclass differences among inhalers used to treat COPD.

Despite continuous improvements in neonatal resuscitation and stabilization in the last decades, thermal management immediately after birth remains an unresolved issue in preterm infants. To compare 2 strategies of thermal management (plastic wrapping with or without drying) for preventing heat loss at birth in very preterm infants. This multicenter, unblinded, randomized clinical trial was conducted among very preterm infants (birth weight <1500 g and/or gestational age ≤30 weeks 6 days) at 21 tertiary care hospitals in Italy from February 21, 2023, to July 18, 2024. Eligible neonates were randomly allocated to either drying before plastic wrapping in the delivery room (intervention arm) or plastic wrapping without drying (control arm). The primary outcome was the proportion of participants with normothermia (36.5-37.5 °C) at admission to the neonatal intensive care unit (NICU). The secondary outcomes included hypothermia (<36.5 °C), moderate to severe hypothermia (<36.0 °C), and hyperthermia (>37.5 °C) at NICU admission, temperature at 1 hour after NICU admission, intraventricular hemorrhage, respiratory distress syndrome, late-onset sepsis, bronchopulmonary dysplasia, and mortality before hospital discharge. Overall, 354 very preterm infants were randomized (180 [50.8%] female; mean [SD] gestational age, 28.6 [2.5] weeks); all received the allocated intervention and were included in the analysis. Normothermia at NICU admission was achieved in 81 of 177 dried infants (45.8%) and 82 of 177 undried infants (46.3%; risk ratio, 0.99; 95% CI, 0.79-1.24). The mean (SD) neonatal temperature at NICU admission was 36.4 °C (0.8 °C) in dried neonates and 36.5 °C (0.7 °C) in undried neonates (mean difference, -0.1 °C; 95% CI, -0.2 °C to 0.1 °C). In-hospital mortality included 26 of 177 dried neonates (14.7%) and 10 of 177 undried neonates (5.6%) (unadjusted risk ratio, 2.60; 95% CI, 1.29-5.23). The other secondary outcome measures were not different between the 2 arms. In this multicenter randomized clinical trial, drying before plastic wrapping provided no benefit to very preterm infants in maintaining normothermia at NICU admission. Most deaths could be expected due to the compromised profile of the neonates, with no pathophysiological explanation related to the trial interventions. Approximately half of the infants were outside the normal thermal range at NICU admission; hence, thermal management remains a challenge requiring further investigations. ClinicalTrials.gov Identifier: NCT05740072.

Racial disparities in cancer care are well-documented.Although a variety of interventions have been implemented to address these disparities, the extent to which they have narrowed gaps in treatment remains an area of active research.In this context, Lynch et al 1 examined whether previously observed racial disparities in treatment of early-stage lung cancer persist in more contemporary practice.They used the Surveillance, Epidemiology, and End Results Program-Medicare database from 2005 to 2019. 1 Their primary outcome was receipt of curative therapy, defined as either surgical resection or radiotherapy, with a secondary outcome of receiving preferred treatment, defined as either lobectomy or stereotactic body radiation therapy (SBRT).Using multivariable analysis, the authors adjusted for race, year of diagnosis, a race-year interaction term, variables reflecting access to primary care, and additional clinical and sociodemographic characteristics.They found that non-Hispanic Black patients with early-stage lung cancer were less likely than their non-Hispanic White counterparts to undergo curative therapy, largely owing to lower rates of surgical resection. 1Black patients were also less likely to undergo SBRT during its early adoption (2011-2013); this disparity narrowed and was no longer statistically significant in the 2017 to 2019 study period.Overall, rates of radiotherapy were not consistently different by race.These associations persisted after adjustment for clinical and sociodemographic factors, highlighting the need for additional progress before achieving racial equity in cancer care.Taken together, this study 1 suggests that the largest and most persistent inequity is not in the type of radiation or surgery delivered once a modality is chosen, but in whether Black patients access surgical treatment at all, and whether they shared equitably in SBRT adoption in earlier years.These findings of racial disparities in the rate of surgical resection, with no consistent racial differences in radiotherapy receipt, invite comparison between the 2 modalities.Upstream factors are multifaceted, with patient factors such as comorbidities and frailty and system factors such as referral patterns and support for navigating treatment, all likely contributing.Regarding patient factors, the authors found that, on average, Black patients had higher rates of medical comorbidities and were less likely to have a primary care physician. 1ack patients who are less connected to primary care may be referred later, less frequently, or not at all for surgical evaluation.However, access to a primary care physician alone may not fully mitigate these difficulties.Recent work showed differential specialty referral patterns based on race. 2 These disparate referral patterns may negatively affect a patient's surgical candidacy, with downstream consequences for the likelihood of receiving curative oncologic treatment.Relatedly, social determinants of health such as financial toxicity or health literacy may play a role in influencing adherence to curative treatment for lung cancer, highlighting the need for financial navigation and assistance with transportation and other nonmedical costs to reduce financial toxicity and address cost-related barriers that undermine adherence to curative treatment. 3nch et al 1 also utilized a claims-based frailty measure that was validated with patient-reported outcomes.This approach may partially mitigate, but not fully eliminate, the influence of clinical bias in preoperative decision-making.Recent work demonstrating that racially and ethnically minoritized patients are rated as more frail on subjective than objective measures would suggest that subjective assessments could disproportionately disqualify Black patients from surgery, even when claimsbased frailty appears similar.Therefore, broader use of objective frailty measures in both practice and research is an important step toward equitable cancer care.

Information on the burden of postacute sequelae of SARS-CoV-2 infection (or long COVID) in patients with cancer during endemicity is limited. To evaluate the risk of postacute diagnoses and/or symptoms compatible with long COVID in a population-based cohort of patients with cancer and high rates of vaccination and/or boosting who were infected during Omicron predominance compared with those with negative test results (hereinafter, noninfected patients). Results were additionally stratified by COVID-19 severity and receipt of therapeutics. This retrospective, population-based cohort study used health care claims databases to construct cohorts of adult patients with cancer in Singapore who were infected with SARS-CoV-2 during Omicron predominance (January 1 through December 31, 2022), and contemporaneous noninfected patients. Patients were followed up to 300 days from the index date and data were analyzed from February 1, 2022, through October 27, 2023. SARS-CoV-2 infection. Competing risks regression (death as a competing risk), with overlap weights applied, was used to estimate risks of new-incident diagnoses and/or symptoms compatible with long COVID following SARS-CoV-2 infection in patients with cancer compared with noninfected patients. Risks of postacute sequelae following COVID-19 hospitalization in patients with cancer were further contrasted against influenza hospitalizations (January 1, 2017, to December 31, 2022). A total of 76 807 patients with cancer were included in the analysis (48 279 [62.9%] female); 39 256 had SARS-CoV-2 infection and 37 551 were noninfected patients. The mean (SD) age was 63.9 (13.7) years. The mean (SD) follow-up time was 263.1 (36.2) days for patients infected with SARS-CoV-2 and 264.8 (32.5) days for noninfected patients. Most patients had solid-organ cancer (72 497 of 76 807 [94.4%]) and were boosted (71 550 of 76 807 [93.2%]); only a minority with SARS-CoV-2 infection (3571 of 39 256 [9.1%]) required acute hospitalization. No significant difference in risk of postacute diagnoses compatible with long COVID was observed in patients with SARS-CoV-2 infection (hazard ratio [HR], 0.98; 95% CI, 0.92-1.04) compared with noninfected patients. While risk of postacute symptoms following COVID-19 was modestly increased (HR, 1.09; 95% CI, 1.01-1.19; P = .048), statistical significance was not attained after adjustment for multiple comparisons. However, significantly increased risk of postacute sequelae was observed among patients hospitalized for COVID-19 compared with noninfected patients (HR for any diagnosis, 1.36 [95% CI, 1.18-1.56]; HR for any symptom, 1.48 [95% CI, 1.22-1.76]; P < .001 for both); risks remained elevated even among hospitalized cases receiving COVID-19 therapeutics. Risks of postacute sequelae following COVID-19 hospitalization in patients with cancer did not significantly differ from those associated with seasonal influenza hospitalizations. The findings of this cohort study suggest that among highly boosted patients with cancer, the overall risk of postacute sequelae following Omicron SARS-CoV-2 infection was not significantly elevated compared with noninfected patients; however, patients who were hospitalized for COVID-19 remained at increased risk of postacute sequelae despite administration of COVID-19 therapeutics. These findings further suggest that COVID-19 vaccination and boosting remain important in mitigating the risk of long COVID among immunocompromised patients during endemicity.