Ann Intern Med Research Articles

NIDA and FDA call for new pathways for smoking cessation

The National Institute on Drug Abuse (NIDA) and the Food and Drug Administration (FDA), in a commentary published last week in the Annals of Internal Medicine, call for innovations in research and development of smoking cessation therapies. Cigarette smoking, while decreasing, kills nearly 500,000 Americans each year. The opioid overdose epidemic kills one‐fifth of that. More than 28 million adults currently smoke in the United States. Most of them say they want to quit, but only 31% of those receive counseling and/or medications to do so. Less than 8% quit a year.

In advanced CKD, ACEis or ARBs reduce kidney failure vs. placebo or non-RAAS inhibitors at 34 mo.

Ku E, Inker LA, Tighiouart H, et al. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers for advanced chronic kidney disease: a systematic review and retrospective individual participant-level meta-analysis of clinical trials. Ann Intern Med. 2024;177:953-963. 38950402.

Impact of adrenalectomy on hypertension in patients with nonfunctional adrenal tumors: a retrospective study.

To investigate the impact of adrenalectomy on hypertension in patients with nonfunctional adrenal tumors. Between January 2020 and October 2022, patients with adrenal lesions were retrospectively screened for nonfunctional adrenal tumors at the Zhongnan Hospital of Wuhan University. All patients underwent detailed endocrinological examination and computed tomography to characterize the lesions. One year after discharge, follow-up blood pressure (BP) was assessed and compared to the blood pressure on admission. Univariate analysis and multivariate regression analysis were performed to determine factors predicting favorable hypertension outcomes after adrenalectomy. A total of 309 patients were found to be eligible, including 123 who underwent adrenalectomy. Patients who underwent adrenalectomy were stratified into two groups: (Bancos I (2022) Adrenal Incidentalomas: Insights Into Prevalence. Ann Intern Med 175:1481-1482. https://doi.org/10.7326/M22-2600 ) those with improved hypertension (n = 71), and (Fassnacht M, Tsagarakis S, Terzolo M, Tabarin A, Sahdev A, Newell-Price J et al. (2023) European Society of Endocrinology clinical practice guidelines on the management of adrenal incidentalomas, in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol 189:G1-42. https://doi.org/10.1093/ejendo/lvad066 ) those without improved hypertension (n = 52). In contrast, the blood pressure levels of conservatively treated patients remained relatively stable 1 year after discharge. Univariate analysis and multivariate regression analysis showed that body mass index (BMI) and duration of hypertension were significantly different between the hypertension improvement group and the non-improvement group (p < 0.05). Adrenalectomy has been shown to be effective in improving hypertension in certain patients with nonfunctional adrenal tumors. BMI and duration of hypertension were independent factors associated with favorable hypertension outcomes after adrenalectomy.

Exploring a Role for Gut Microbiota to Modulate Aldosterone

Hypertension is associated with an increased risk of mortality for numerous conditions including heart disease, diabetes, and renal disease (D. Aune, Biomed Res Int, 2021). Hypertension is often viewed as idiopathic and treatment is seldom aimed at addressing an underlying mechanism; however, a recent study indicates that primary aldosteronism is an underappreciated cause of idiopathic hypertension (J. Brown, Ann Intern Med, 2020). Here, we investigate for the first time the influence of gut microbiota on aldosterone regulation. To pursue this, we used C57Bl/6 mice (n=20; males) housed in the Johns Hopkins Animal Care Facility and fed a specific pathogen-free diet. Whole blood from submandibular cheek bleeds were collected into K2EDTA-treated tubes at baseline and mice were allowed to recover. Mice were then treated with antibiotics (ABX; 1g/L ampicillin, 1g/L neomycin, and 0.5g/L vancomycin) in their drinking water ad libitum for a total of 7 days to dramatically suppress gut microbes. Whole blood via submandibular cheek bleeds were collected after 24hrs, and at day 7 on ABXs. Mice were sacrificed on day 7 of ABX. Plasma samples from baseline, 24hrs on ABX and 7 days on ABX were used to determine aldosterone concentration and plasma renin activity (PRA) via ELISA. In addition, 24hr urine samples were collected at baseline and at day 7 on ABXs. Statistics were calculated using paired, one-way ANOVA; data below are mean ± SD. Our results demonstrate that plasma aldosterone and PRA, as well as urine aldosterone, were significantly increased from baseline to 7 days on ABX treatment (plasma aldo (pg/mL): 295.1 ± 164.8 vs 634.9 ± 290.4, p= 0.0197; plasma PRA (ng Ang-1/mL/hr): 191.8 ± 137.6 vs 325.9 ± 141.5, p= 0.0108; urine aldo (pg/mL): 2019 ± 322.1 vs 2668 ± 292.0, p = 0.0047). However, there was no significant difference in plasma aldosterone from baseline to 24hrs on ABX treatment (295.1 ± 164.8 vs 434.5 ± 245.3, p= 0.1047). In contrast, we observed a significant increase in angiotensin I from baseline to 24hrs on ABX treatment (191.8 ± 137.6 vs 355.8 ± 139.6, p=0.0041), and this increase was sustained until day 7 (325.9 ± 141.5 vs baseline, p=0.0108). Preliminary data suggest aldosterone is also increased in the plasma of germ-free mice (without gut microbes) compared to conventionalized controls (750.4 ± 265.0, n= 6, vs 314.4 ± 260.3, n=4, p=0.0667), implying that gut microbiota normally act to suppress plasma aldosterone. Taken together, we demonstrate that in the absence of gut microbiota, plasma aldosterone, urine aldosterone, and PRA are significantly increased. Understanding how gut microbes influence aldosterone levels could provide valuable insights into the development and treatment of hypertension. This knowledge may open new avenues for therapeutic interventions, such as probiotics or dietary modifications, to help regulate blood pressure. William Townsend Porter Predoctoral Fellowship from the American Physiological Society (BNM), Johns Hopkins Post-baccalaureate Research Education Program (PREP; R25GM109441 to ADM), the NIDDK Diabetic Complications Consortium (RRID:SCR_001415m www.diacomp.org, grants DK076169 and DK 115255 (subaward to JLP)) and American Heart Association Established Investigator Award (to JLP). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Promoting speaking-up behaviours among nurses working in the care for older people: A scoping review.

To explore interventions employed to foster speaking-up behaviours of registered nurses (RNs) working in the care of older people. Scoping review. The updated Joann Briggs Institute scoping review methodological guidelines were followed. CINAHL, PubMed, PsycINFO, and Scopus were searched. A total of 1691 titles and abstracts were screened, resulting in 11 articles that met the inclusion criteria. Analysis focused upon intervention types, methodologies, speaking up strategies, barriers and effectiveness. Education was the most used intervention. There is a lack of published research on successful interventions to promote speaking-up behaviours in the care of older people, particularly relating to poor care practices. Evidence of speaking-up interventions in the residential aged care setting is absent. This highlights the need to develop strategies to support the RN to lead and enable others to raise care concerns. Developing strategies that enable staff, care recipients and their families to speak up about care concerns is a vital future area for nursing practice development. Nursing leadership of such strategies is central to improving the quality of care for older people, particularly those living in residential aged care. Older people receiving care should feel respected and be treated humanely. Evidence suggests this is often not the case. This review found a paucity of interventions to promote speaking-up about poor care practices among RNs working in the care of older people. Future research needs to address this, to empower RNs and improve the care afforded to older people. The PRISMA-ScR (Tricco etal., Annals of Internal Medicine, 169, 467-473, 2018) were adhered to throughout this scoping review. No patient or public contribution in this review.

Palliative care needs of people and/or their families with serious and/or chronic health conditions in low- or middle-income country (LMIC) humanitarian settings—a systematic scoping review protocol

BackgroundPalliative care in low- or middle-income country (LMIC) humanitarian settings is a new area, experiencing a degree of increased momentum over recent years. The review contributes to this growing body of knowledge, in addition to identifying gaps for future research. The overall aim is to systematically explore the evidence on palliative care needs of patients and/or their families in LMIC humanitarian settings.MethodsArksey and O’Malley’s (Int J Soc Res Methodol. 8:19-32, 2005) scoping review framework forms the basis of the study design, following further guidance from Levac et al. (Implement Sci 5:1-9, 2010), the Joanna Briggs Institute (JBI) Peters et al. (JBI Reviewer’s Manual JBI: 406-452, 2020), and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) from Tricco et al. (Ann Intern Med 169:467-73, 2018). This incorporates a five-step approach and the population, concept, and context (PCC) framework. Using already identified key words/terms, searches for both published research and gray literature from January 2012 to October 2022 will be undertaken using databases (likely to include Cumulative Index of Nursing and Allied Health (CINAHL), MEDLINE, Embase, Global Health, Scopus, Applied Social Science Index and s (ASSIA), Web of Science, Policy Commons, JSTOR, Library Network International Monetary Fund and World Bank, Google Advanced Search, and Google Scholar) in addition to selected pre-print sites and websites. Data selection will be undertaken based on the inclusion and exclusion criteria and will be reviewed at each stage by two reviewers, with a third to resolve any differences. Extracted data will be charted in a table. Ethical approval is not required for this review.DiscussionFindings will be presented in tables and diagrams/charts, followed by a narrative description. The review will run from late October 2022 to early 2023. This is the first systematic scoping review specifically exploring the palliative care needs of patients and/or their family, in LMIC humanitarian settings. The paper from the review findings will be submitted for publication in 2023.

A Randomized Clinical Trial Comparing the Effects of Mindfulness-Based and Cognitive Behavioral Therapy-Based Stress Reduction in Medical Students

IntroductionMedical students face an enormous amount of stress (Dyrbye LN et al. Ann Intern Med 2008; 149: 334-41). They suffer from higher rates of depression, anxiety, and suicide compared to the general population. Despite experiencing more mental health problems, there is a lack of research exploring ways to improve their mental health. Although there are a few small sample studies investigating the effectiveness of Mindfulness-Based Stress Reduction (MBSR) on medical students, there is no study comparing its effectiveness against an active intervention group in the literature (van Dijk I et al. Acad Med 2017; 92: 1012-1021)ObjectivesWe aimed to compare the effects of the Mindfulness-Based Stress Reduction (MBSR) and the Cognitive Behavioural Based Stress Reduction (CBSR) group interventions on depressive and anxious symptoms and perceived stress of medical students.Methods323 medical students applied to participate in one of the group interventions and were assessed with the Mini International Neuropsychiatric Interview. Of these, 253 (77% female, mean age=21.9 ± 2.9 years) were allocated into online MBSR (n=127) and online CBSR (n=126) groups after randomization. Their anxiety and depressive symptoms and perceived stress levels were assessed at baseline and after 8 weeks of interventions. 33,2% of participants (MBSR: n=39; CBSR: n=45) completed the protocol by attending five or more sessions. Both intention-to-treat (ITT) analysis and per-protocol (PP) analysis were used to assess outcomes. In the ITT analysis, we used multiple imputation to address missing values. All assessments and group interventions were done online.ResultsIn the ITT analysis, both MBSR and CBSR were found to be slight to moderately effective in reducing symptoms of depression (MBSR: d=.50; CBSR: d=.40), anxiety (MBSR:d=.73; CBSR: d=.52), and perceived stress (MBSR: d=.48; CBSR: d=.42), but they were no superior to each other. In the PP analysis, both interventions moderately to strongly improved the symptoms of depression (MBSR: d=1.03; CBSR: d=.74), anxiety (MBSR: r=-.74; CBSR: r=-.72), and perceived stress (MBSR: r=-.80; CBSR: r=-.68). While there was no statistically significant difference between them in reducing depressive symptoms and perceived stress, MBSR was found to be significantly more effective than CBSR in reducing anxiety symptoms (u=469, z=-2.756, p=0.006).ConclusionsBoth MBSR and CBSR improve symptoms of depression and anxiety in medical students after 8 weeks of interventions. Completing the protocol or attending more sessions may increase the effectiveness of the interventions. While the interventions did not show superiority to each other in terms of effectiveness in reducing depressive symptoms and perceived stress, MBSR appears to be more effective in reducing anxiety symptoms compared to CBSR in the group that completed the protocol.Disclosure of InterestNone Declared

Cognitively enhanced tai chi improved cognition vs. tai chi or stretching at 24 wk in older adults with MCI or memory concerns.

Li F, Harmer P, Eckstrom E, et al. Clinical effectiveness of cognitively enhanced tai ji quan training on global cognition and dual-task performance during walking in older adults with mild cognitive impairment or self-reported memory concerns: a randomized controlled trial. Ann Intern Med. 2023;176:1498-1507. 37903365.

Cardiac Arrest During Delivery Hospitalization: A Cohort Study

(Ann Intern Med. 2023;176:472–479) Cardiac arrest is a rare but serious complication in the parturient and is associated with very poor outcomes. The objective of this study was to assess the incidence of cardiac arrest from 2017 to 2019 in the United States by patient demographics, co-morbidity, and type and size of hospital. This analysis can aid in identifying strategies to reduce pregnancy-related maternal morbidity and mortality.

Risk for Congenital Anomalies in Children Conceived With Medically Assisted Fertility Treatment

(Abstracted from Ann Intern Med 2023;176:1308–1320) In the United States, more than 2% of all infants are conceived by assisted reproductive technology (ART). Children born from ART have been shown to have up to 50% increased risk for congenital anomalies (CAs) compared with naturally conceived children.

Clinical trials of pharmacological interventions for SARS-CoV-2 published in leading medical journals report adherence but not how it was assessed.

Adherence to pharmacological interventions in clinical trials is crucial for accurate identification of beneficial and adverse outcomes. The ways in which adherence to interventions should be reported in trial publications are described in the Template for Intervention Description and Replication (TIDieR), a 12-item extension of the Consolidated Standards of Reporting Trials reporting guidelines. The objective of this study was to assess compliance with TIDieR Items 11 and 12 of randomized controlled trials (RCTs) of interventions in SARS-CoV-2 infection published in 5 selected journals during 2021. We assessed pharmacological interventions for SARS-CoV-2 infection reported in RCTs published in 2021 in the Annals of Internal Medicine, The BMJ, JAMA, The Lancet and The New England Journal for Medicine for compliance with TIDieR items addressing intervention adherence (Items 11 and 12). We calculated proportional adherence for pharmacological and comparator interventions where available. We found 75 eligible RCTs. Twenty-eight (37%) reported results of SARS-CoV-2 vaccinations. Compliance with Items 11 and 12 could be assessed in 71 of these 75. Of the 71 RCTs, 37 (52%) reported how adherence was assessed (Item 11), and 70 reported adherence rates (Item 12). Only 1 of the 71 RCTs (1.4%, 0-7.6%) fully complied with TIDieR Items 11 and 12. Half of RCTs of SARS-CoV-2 pharmacological interventions published in leading medical journals in 2021 complied with reporting of how adherence assessments were made and almost none complied with both TIDieR Items 11 and 12. The implications for interpretation, application and replication of findings based on these publications warrant consideration.

Frequency of limitations statements in original research articles of United States leading medical journals: A meta-research protocol.

Limitation declarations are commonly deemed essential to uphold intellectual humility for scientific research, but little has been reported about the limitation statements in published original research articles. This meta-research study aims to investigate the trends of limitation statements among three leading general medical journals in the US. This cross-sectional study will compile a data set of full-length original research articles published in the New England Journal of Medicine, Journal of the American Medical Association, and Annals of Internal Medicine between 2002 and 2022. Limitation statement will be recognized by two investigators, and a predefined set of sensitive keywords is used for sensitivity analysis. Frequency of limitation statements within the main text of research articles and trends for different study designs, including their association with the corresponding reporting guidelines, are the main measurements. We employ the Cochran-Armitage test for trend analysis. The findings of this study will provide an overview of the limitation statements in leading general medical journals in the US. The results may contribute to future research to identify factors that are associated with the presence of limitation statements.

In older adults, postoperative oral haloperidol vs. antipsychotics was linked to similar risk for in-hospital adverse events.

Kim DH, Lee SB, Park CM, et al. Comparative safety analysis of oral antipsychotics for in-hospital adverse clinical events in older adults after major surgery: a nationwide cohort study. Ann Intern Med. 2023;176:1153-1162. 37665998.

Allogeneic Hematopoietic Cell Transplantation in the 7 th Decade of Life and Beyond

Background The upper age limit for patients undergoing allogeneic hematopoietic cell transplantation (HCT) has increased over the past several years due to continued improvements in supportive care and increased expertise in management of older recipients of allogeneic HCT. This change is particularly important for hematologic malignancies such as acute myeloid leukemia (AML) where the median age at diagnosis is in the late 60s and HCT provides, in many instances, the only potential chance of cure. While some previous analyses have suggested favorable post-HCT outcomes for older AML patients in general, information is limited about allogeneic HCT for patients aged 70 years or older. Here, we set out to retrospectively analyze post-HCT outcomes for those aged 70+ and compare these outcomes to those aged 60-69 in a large single-center observational study. Methods Eligible patients were identified using our Fred Hutchinson Cancer Center database of transplant outcomes. All patients signed consents at time of HCT. Severity of disease was categorized as previously described (McDonald GB et al Ann Intern Med 2020). Kaplan-Meier estimates were used to evaluate overall survival (OS) and relapse-free survival (RFS); cumulative incidence estimates were used to summarize relapse and non-relapse mortality (NRM). Multivariable Cox regression models were fit to compare outcomes across age groups after adjusting for potential imbalances in various factors between groups. In addition, we used a multivariable model for overall mortality (OM) to identify risk factors for death in this population. Results We identified 1237 patients given allogeneic HCT between 2000-2022 aged at least 60 years old, 229 (18.5%) of whom were of age 70+. Baseline characteristics included severity of disease, donor type, patient CMV serostatus, conditioning intensity (Table 1). The median OS among patients 60-69 was 2.8 years (95% confidence interval, 2.4-3.6 years) and among those 70+, 1.8 years (1.3-2.9 years). Point estimates of OS at 3, 5, and 7 years were 49% (46-52%), 46% (43-49%), and 37% (34-40%), respectively for patients aged 60-69, and 43% (36-49%), 38% (31-45%), and 28% (21-36%), respectively, for patients age 70+. In the subgroup of patients age 75+ (n=29), the 3- and 5-year point estimates of OS were each 41% (22-59%). The unadjusted hazard ratio (HR, 70+ vs. 60-69) for death was 1.24 (1.04-1.49, p=0.02). However, after adjusting for various factors (Table 2), the adjusted HR for death was 1.02 (0.76-1.36, p=0.90), suggesting the apparent reduction in OS for the 70+ group relative to the 60-69 group was largely due to a higher proportion of adverse risk factors in the 70+ group. Median RFS for the two groups were 1.9 years (1.4-2.3 years) and 1.3 years (0.9-1.8 years), respectively. Similar to the HR for death, the unadjusted HR for RFS failure was significant at 1.23 (1.03-1.46, p=0.02), but the adjusted HR for was no longer significant at 0.96 (0.72-1.26, p=0.74). The unadjusted and adjusted HRs for relapse were 1.10 (0.84-1.44, p=0.51) and 0.77 (0.50-1.17, p=0.22), respectively, and for NRM 1.33 (1.06-1.67, p=.02) and 1.12 (0.77-1.61, p=0.56), respectively. Factors that were demonstrably associated with increased mortality included severity of disease, patient/donor CMV serostatus, conditioning intensity, and type of donor (Table 2). Conclusions We report here on one of the largest groups of patients aged 70+ receiving allogeneic HCT in a single center. Our results suggest that allogeneic HCT is feasible and potentially safe in this age group as compared to the group aged 60-69. These results should be encouraging for consideration of patients 70+ for allogeneic HCT. We are in process of complementing our analyses with information on comorbidities. On the other hand, 7-year OS for all older pts (60-80.9 years old) ranged from 28-37%, highlighting the need for dedicated HCT trials targeting this group of older patients to further improve outcomes.

Extended Thromboprophylaxis in Patients Hospitalized with COVID-19 at Time of Discharge from the Hospital Is Not Associated with an Improvement in Quality of Life: Results from the Activ 4c Clinical Trial

Introduction. Post-acute sequelae of SARS-CoV2 infection, or PASC, is defined as the presence of persistent symptoms for at least two months after an acute infection with COVID-19. A potential pathophysiologic mechanism for PASC is microvascular thrombosis. Using EQ-5D-5L index scores, we previously reported that extended thromboprophylaxis for 30 days with apixaban did not impact quality of life (QoL) at 30 or 90 days after discharge (Wang et al, Ann Intern Med 2023; 176:515-523). The purpose of this investigation was to determine whether anticoagulation had a variable impact on the individual domains measured by EQ-5D-5L. Methods. ACTIV 4c was a prospective, randomized, placebo-controlled, double-blind clinical trial comparing post-discharge thromboprophylaxis with apixaban 2.5 mg twice daily to placebo for 30 days in patients hospitalized with COVID-19. Participants were enrolled at 107 hospitals in the US between February 2021 and June 2022. We ascertained symptoms and QoL by EQ-5D-5L at 2 days, 30 days, and 90 days after hospital discharge by electronic or telephone follow-up. The five domains of EQ-5D-5L are: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each domain has 5 levels of response, ranging from “no problems/none” to “unable to perform/extreme”, which are used to determine individual scores. We analyzed the impact of treatment (placebo vs. apixaban), antiplatelet therapy (yes vs. no), and highest WHO severity score during hospitalization (score &amp;lt;5 vs. score ≥5) on degree of impairment at 2, 30, and 90 days post-discharge using a chi-square test for those participants who completed the survey at each timepoint. We also used a proportional odds model to test for at least moderate impairment in each EQ-5D-5L domain, also at 30 and 90 days, using odds ratios adjusted for age (restricted cubic spline with 3 knots), sex, D-dimer (normal or abnormal), BMI (restricted cubic spline with 3 knots), antiplatelet usage (yes/no - at enrollment), WHO severity score (&amp;lt;=5 vs. &amp;gt; 5), and the randomized treatment. Results. We randomized 1217 participants hospitalized with acute COVID-19 onto ACTIV 4c, with 610 participants assigned to apixaban and 607 participants to placebo. A total of 208 participants taking apixaban (43.5%) and 219 participants taking placebo (45.0%) reported moderate or greater impairment in one or more of the EQ-5D-5L domains by 2 days after hospital discharge. The individual domain most frequently reported as impaired was usual activities (33.0% of all study participants). By 30 days after discharge, 151 participants taking apixaban (30.8%) and 165 taking placebo (33.4%) reported moderate or greater impairment in one or more domains. The individual domain with the largest improvement was usual activities, affecting 17.4% of all study participants. By 90 days, 152 participants taking apixaban (31.5%) and 142 participants taking placebo (28.5%) reported moderate or greater impairment in one or more domains. Extended thromboprophylaxis with apixaban was not associated with improved scores for any of the individual EQ-5D-5L domains at 30 days or 90 days (Table 1). Stratification by WHO severity score during hospitalization revealed a significant improvement in the domain for usual activities for participants with score &amp;lt;5 compared to those with a score ≥5 (p=0.015) by 30 days, but this difference was not present by 90 days. Stratification by anti-platelet use did not identify any domains with improvement associated with antiplatelet therapy at 30 or 90 days. Using adjusted odds ratios, we did not find a benefit for apixaban at 30 days (Figure 1) or at 90 days (data not shown). Conclusion. Almost half of patients hospitalized with COVID-19 have decreased QoL at time of discharge, with the greatest impact on performance of usual activities. Impaired QoL persists for up to 90 days after hospital discharge in one-third of patients. Extended thromboprophylaxis with apixaban for 30 days at the time of hospital discharge in participants with acute COVID-19 was not associated with improvements in QoL as assessed by EQ-5D-5L.

Development and Validation of the Early-Stage Hodgkin Lymphoma (HL) International Prognostication Index (E-HIPI): A Report from the Hodgkin Lymphoma International Study for Individual Care (HoLISTIC) Consortium

Background: There are a lack of clinical prediction tools in early-stage Hodgkin lymphoma (E-HL). We developed and validated a modern-day model, known as E-HIPI, to predict progression-free survival (PFS) within the first 5 years (y) incorporating detailed individual patient (pt) data from international clinical trials and prospective registry data that were standardized, normalized &amp; harmonized as part of the HoLISTIC Consortium (www.hodgkinconsortium.org). Methods: Model development utilized Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines (Moons, Ann Intern Med 2015) on a cohort of 3,080 newly-diagnosed E-HL pts treated on 4 seminal phase 3 clinical trials (NCIC: Meyer, NEJM 2012; RAPID: Radford, NEJM 2015; EORTC-GELA H9U: Ferme, E ur J Cancer 2017; EORTC/LYSA/FIL H10: Andre, JCO 2017). External validation was done in an independent cohort of 462 E-HL pts from a large registry (Princess Margaret, Toronto). Pts with classic HL, stage I or II disease, and ages 18-65 y were included. The primary outcome was PFS. Cox models were utilized with follow-up truncated at 5 years. Baseline predictors were: sex, stage, B symptoms, histology, number &amp; location of nodal sites, and continuous data values of age, maximum tumor diameter (MTD), white blood cell count (WBC), lymphocyte count, hemoglobin, albumin &amp; erythrocyte sedimentation rate (ESR). Multiple imputation was used for missing data. To consider possible non-linear relationships for continuous variables we examined plots &amp; cubic splines. We used backward elimination ( P&amp;lt;0.1) to develop the models &amp; internal validation with 200 bootstrap samples was conducted to estimate optimism &amp; correct for overfitting. The final prediction equations applied optimism corrections to beta coefficients &amp; hazard ratios (HR). Sensitivity analyses included model results stratified by PET staging (vs CT) and each HL trial. The models were evaluated in the external validation cohort &amp; compared using c-statistics. Model scores were also grouped by tertiles for visualization in Kaplan-Meier (KM) curves. Results: Median age in the development cohort was 35y; 51% were female; 81% had nodular sclerosis &amp; 77% stage II disease; 26% had B symptoms; 32% had mediastinal bulk (≥10cm or &amp;gt;1/3 diameter) and the mean MTD was 6.4 cm (interquartile range (IQR), 3.9-8.2). Median follow-up was 60 months (IQR 45-75). KM estimates at 5y was 90.7% (264 events) for PFS, and 97.1% (78 events) for overall survival (OS). After backward elimination, significant variables retained were age, sex, nodal location (cervical region), MTD &amp; albumin. Stage, ESR, or the number of nodal sites were not significant. Age was modeled with piecewise linear splines due to its non-linear relationship. See the Table for the final prediction model and optimism-corrected HRs. Optimism-corrected c-statistics in the development model was 0.63. Sensitivity analyses of stratification by type of imaging at staging or by each clinical trial demonstrated no change in model parameters or c-statistics. Most baseline characteristics and outcomes of the external validation cohort were similar besides median follow-up time (74 months, IQR 37-129). C-statistics for the E-HIPI model in external validation was 0.63. In addition, observed 5y outcomes stratified by tertile of predicted risk in the external cohort separated pts into a low &amp; higher-risk group, which comprised 1/3 &amp; 2/3 of pts, respectively ( Figure). Finally, model diagnostics revealed the potential for time dependency in the retained covariates. Further assessment of differential prediction between early (&amp;lt;2y) vs. later (2-5y) PFS events is ongoing. Conclusion: Following TRIPOD methodology, we rigorously developed and externally validated the E-HIPI among &amp;gt;3,500 E-HL pts.Discrete risk groups were delineated, and we identified several novel factors, including nodal location, sex &amp; key continuous variables that predict 5y PFS. Additional model refinement is underway, including formal calibration &amp; external validation via other HL registries (Stanford, Mayo/Iowa SPORE). A web-based calculator to simplify application of the E-HIPI will also be presented at ASH. Future planned modeling includes integration of differing treatments &amp; response-adapted imaging via multistate modeling to enrich individualized survival estimates and simulation modeling to predict late consequences.

Exploring communication apprehension in nursing and healthcare education: A scoping review

AbstractCommunication among healthcare professionals is critical to optimizing patient outcomes, and communication education is incorporated into the educational programs of healthcare professions students. Communication can be a source of stress for new healthcare professionals, however, there is a lack of research on communication apprehension (CA) in healthcare students, especially in nursing education. This scoping review sought to explore CA and factors associated with CA among healthcare professions students. This scoping review report was guided by the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses extension for Scoping Reviews (Tricco et al., Annals of Internal Medicine, 2018, 169, 467–473). Twenty studies of healthcare professions students were included for analysis. The percentage of health professions students with high CA ranged from 0.7% to 27%. Five out of seven intervention studies demonstrated a significant decrease in CA after the intervention. This review identified inconsistent associations between CA and various individual and educational factors. More research is needed utilizing rigorous research designs, designs employing qualitative methodology, and studies to investigate the impact of language on CA in health professions students who speak English as a second language.

Double-Negative Results Matter: A Reevaluation of Sensitivities for Detecting SARS-CoV-2 Infection Using Saliva Versus Nasopharyngeal Swabs.

In a recent systematic review, Bastos et al. (Ann Intern Med. 2021;174(4):501-510) compared the sensitivities of saliva sampling and nasopharyngeal swabs in the detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by assuming a composite reference standard defined as positive if either test is positive and negative if both tests are negative (double negative). Even under a perfect specificity assumption, this approach ignores the double-negative results and risks overestimating the sensitivities due to residual misclassification. In this article, we first illustrate the impact of double-negative results in the estimation of the sensitivities in a single study, and then propose a 2-step latent class meta-analysis method for reevaluating both sensitivities using the same published data set as that used in Bastos et al. by properly including the observed double-negative results. We also conduct extensive simulation studies to compare the performance of the proposed method with Bastos et al.'s method for varied levels of prevalence and between-study heterogeneity. The results demonstrate that the sensitivities are overestimated noticeably using Bastos et al.'s method, and the proposed method provides a more accurate evaluation with nearly no bias and close-to-nominal coverage probability. In conclusion, double-negative results can significantly impact the estimated sensitivities when a gold standard is absent, and thus they should be properly incorporated.

In Phase 2 and Phase 3 Trials, Broadening the Definition of Acute Vaso-Occlusive Pain to Include at Least One Episode of Pain Requiring Nsaids, Opioids, or Both Treatments at Home within 30 Days of a Physician Visit

Introduction:Despite the high incidence of acute painful events in children and adults with SCD, there is a lack of consensus on the acute pain definition in controlled clinical trials. To address this limitation, we elected to have three definitions of acute vaso-occlusive pain based on the setting for the pain location: inpatient, outpatient, ED, or at home. Based on the results of the SPRING Trial, the primary stroke prevention trial in children with SCD conducted in Nigeria (The Lancet Haematol. 2022 Jan 1;9(1):e26-37), and the PISCES study (Annals of internal medicine. 2008 Jan 15;148(2):94-101), most acute pain events in low-middle and high-income countries occur at home. We tested the hypothesis that the majority of negative phase 2 and phase 3-controlled trials for SCD failed to consider acute pain events in all four settings. Methods: To identify the relevant Phase II and III trials with acute pain as an outcome, we conducted a literature review using the website clinicaltrials.gov with the following key terms: “Sickle Cell Disease,” and “Vaso-occlusive.”. Studies that were not Phase II or Phase III were excluded from our search. We identified Phase 2 or 3 SCD pain trials published between 2015 and 2023. Inclusion criteria: definitions in the clinicaltrials.gov trial page, protocol, or method section. An inclusive, consensus definition for vaso-occlusive pain was chosen from the SPRING Trial. This definition was compared to the acute vaso-occlusive pain definitions of both SCD Phase 2 and 3 trials, with vaso-occlusive pain as a primary or secondary outcome. Based on the SPRING Trial and the results of the PISCES study, we elected to have three definitions of acute vaso-occlusive pain: 1. inpatient uncomplicated pain that excludes a concomitant diagnosis of acute chest syndrome; 2. Pain that required either an inpatient or outpatient visit and opioid treatment; and 3. An acute pain event at home requiring NSAIDs, opioids, or both. Only uncomplicated pain events were included to avoid double counting participants who developed acute chest syndrome or strokes that may have preceded the vaso-occlusive pain event. Results: We identified 35 articles based on our criteria. Our study sample included 3 clinical trials that led to the FDA approval for therapy to prevent acute vaso-occlusive pain events (FDA-approved therapy trials). Among these 35 trials, 32 clinical trials did not provide any evidence of the therapeutic benefits of the experimental agent (negative controlled trials). The three randomized controlled trials that led to FDA approval for therapy to prevent acute pain were: Hydroxyurea, L-Glutamine, and Crizanlizumab. Hospitalization for pain was included in all three FDA-approved therapy trials and 34.4% (11/32) of negative controlled trials. The ED visits in the pain definition were included in all 3 FDA-approved therapy trials and 28.1% (9/32) of negative controlled trials. Outpatient visits in the pain definition were included in all 3 FDA-approved therapy trials and 21.9% (7/32) of negative controlled trials. Home pain episodes were included in none of the FDA-approved therapy trials and 9.4% (3/32) of negative controlled trials. Finally, 43.8% (14/32) negative controlled trials were excluded as they failed to define vaso-occlusive pain in their methods or definition section and 15.6% (5/32) negative controlled trials did not have a publication. Conclusion: Most controlled trials designed to evaluate the efficacy of new treatment did not include the setting where pain occurs most frequently, at home. For future therapeutic trials designed to address whether a new therapy decreases the incidence rate of acute pain, we recommend an assessment of pain in all 4 four settings (Hospitalization, ED, Outpatient, and Home).

In healthy older adults, low-dose aspirin increased incident anemia at a median 4.7 y.

McQuilten ZK, Thao LT, Pasricha SR, et al. Effect of low-dose aspirin versus placebo on incidence of anemia in the elderly: a secondary analysis of the Aspirin in Reducing Events in the Elderly trial. Ann Intern Med. 2023;176:913-921. 37335992.