Risankizumab versus Ustekinumab for Moderate-to-Severe Crohn's Disease.

BACKGROUND: The efficacy and safety of risankizumab as compared with ustekinumab in patients with Crohn's disease are unknown. METHODS: In this phase 3b, multicenter, open-label, randomized, controlled trial with blinded assessment of end points, patients with moderate-to-severe Crohn's disease who had had an inadequate response to anti-tumor necrosis factor (TNF) therapy or unacceptable side effects with such therapy were randomly assigned to receive risankizumab or ustekinumab at standard doses for 48 weeks. The two primary end points, which were tested sequentially, were clinical remission at week 24 (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]), which was analyzed in the first 50% of patients to complete the week 24 visit, with a noninferiority margin of 10 percentage points; and endoscopic remission at week 48 (defined as a score of ≤4, a decrease of ≥2 points from baseline, and no subscore >1 in any individual variable on the Simple Endoscopic Score for Crohn's Disease [range, 0 to 56, with higher scores indicating more severe disease]), which was analyzed for superiority in 100% of the patients. Safety was assessed in all patients who received at least one dose of risankizumab or ustekinumab. RESULTS: In the full intention-to-treat population for the efficacy analysis, 230 of 255 patients (90.2%) who received risankizumab and 193 of 265 patients (72.8%) who received ustekinumab completed all the assigned treatments. Both primary end points were met; risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 (58.6% vs. 39.5%; adjusted difference, 18.4 percentage points; 95% confidence interval [CI], 6.6 to 30.3) and superior to ustekinumab with respect to endoscopic remission at week 48 (31.8% vs. 16.2%; adjusted difference, 15.6 percentage points; 95% CI, 8.4 to 22.9; P<0.001). The incidence of adverse events appeared to be similar in the two groups. CONCLUSIONS: In this head-to-head clinical trial of risankizumab and ustekinumab involving patients with moderate-to-severe Crohn's disease who had had unacceptable side effects with anti-TNF therapy or an inadequate response to such therapy, risankizumab was noninferior to ustekinumab with respect to clinical remission at week 24 and superior with respect to endoscopic remission at week 48. (Funded by AbbVie; ClinicalTrials.gov number, NCT04524611.).

Early bolus epinephrine administration during pediatric cardiopulmonary resuscitation for bradycardia with poor perfusion: an ICU-resuscitation study.

BACKGROUND: Half of pediatric in-hospital cardiopulmonary resuscitation (CPR) events have an initial rhythm of non-pulseless bradycardia with poor perfusion. Our study objectives were to leverage granular data from the ICU-RESUScitation (ICU-RESUS) trial to: (1) determine the association of early epinephrine administration with survival outcomes in children receiving CPR for bradycardia with poor perfusion; and (2) describe the incidence and time course of the development of pulselessness. METHODS: Prespecified secondary analysis of ICU-RESUS, a multicenter cluster randomized trial of children (< 19 years) receiving CPR in 18 intensive care units in the United States. Index events (October 2016-March 2021) lasting ≥ 2 min with a documented initial rhythm of bradycardia with poor perfusion were included. Associations between early epinephrine (first 2 min of CPR) and outcomes were evaluated with Poisson multivariable regression controlling for a priori pre-arrest characteristics. Among patients with arterial lines, intra-arrest blood pressure waveforms were reviewed to determine presence of a pulse during CPR interruptions. The temporal nature of progression to pulselessness was described and outcomes were compared between patients according to subsequent pulselessness status. RESULTS: Of 452 eligible subjects, 322 (71%) received early epinephrine. The early epinephrine group had higher pre-arrest severity of illness and vasoactive-inotrope scores. Early epinephrine was not associated with survival to discharge (aRR 0.97, 95%CI 0.82, 1.14) or survival with favorable neurologic outcome (aRR 0.99, 95%CI 0.82, 1.18). Among 186 patients with invasive blood pressure waveforms, 118 (63%) had at least 1 period of pulselessness during the first 10 min of CPR; 86 (46%) by 2 min and 100 (54%) by 3 min. Sustained return of spontaneous circulation was highest after bradycardia with poor perfusion (84%) compared to bradycardia with poor perfusion progressing to pulselessness (43%) and bradycardia with poor perfusion progressing to pulselessness followed by return to bradycardia with poor perfusion (62%) (p < 0.001). CONCLUSIONS: In this cohort of pediatric CPR events with an initial rhythm of bradycardia with poor perfusion, we failed to identify an association between early bolus epinephrine and outcomes when controlling for illness severity. Most children receiving CPR for bradycardia with poor perfusion developed subsequent pulselessness, 46% within 2 min of CPR onset.

A dataset of over one thousand computed tomography scans of battery cells.

Battery technology is increasingly important for global electrification efforts. However, batteries are highly sensitive to small manufacturing variations that can induce reliability or safety issues. An important technology for battery quality control is computed tomography (CT) scanning, which is widely used for non-destructive 3D inspection across a variety of clinical and industrial applications. Historically, however, the utility of CT scanning for high-volume manufacturing has been limited by its low throughput as well as the difficulty of handling its large file sizes. In this work, we present a dataset of over one thousand CT scans of as-produced commercially available batteries. The dataset spans various chemistries (lithium-ion and sodium-ion) as well as various battery form factors (cylindrical, pouch, and prismatic). We evaluate seven different battery types in total. The manufacturing variability and the presence of battery defects can be observed via this dataset. This dataset may be of interest to scientists and engineers working on battery technology, computer vision, or both.

When Perfect Is the Enemy of Good: Results of a RAND Appropriateness Panel on Treat to Target in Asymptomatic IBD.

BACKGROUND: A treat-to-target strategy for inflammatory bowel disease (IBD) recommends iterative treatment adjustments to achieve clinical and endoscopic remission. In asymptomatic patients with ongoing endoscopic activity, the risk/benefit balance of this approach is unclear, particularly with prior exposure to advanced therapies. METHODS: Using the RAND/UCLA Appropriateness Method, 9 IBD specialists rated appropriateness of changing therapy in 126 scenarios of asymptomatic patients with ulcerative colitis (UC) and Crohn's disease (CD) and active endoscopic disease. Disease extent and behavior, prior treatment, prior complications, and recent disease progression were considered, as were factors that might influence decision-making, including age and pregnancy. Ratings were collected via anonymous survey, discussed at an in-person meeting, and finalized in a second anonymous survey. RESULTS: Panelists rated change in therapy as appropriate (i.e., expected benefit sufficiently outweighs potential harms from continuing therapy) in 96/126 scenarios, generally in patients with progressive, complicated, and/or extensive disease, while changing therapy was rated uncertain in 27 scenarios of mild and/or stable disease. Changing therapy was rated inappropriate in UC patients with mild and stable disease previously exposed to ≥3 therapies or with improved endoscopic activity, and in CD patients with only scattered aphthous ulcers. The validated threshold for disagreement was not crossed for any scenario. Patient age >65 years and a plan for pregnancy in the next year might influence decision-making in some settings. CONCLUSION: Appropriateness ratings can help guide clinical decision-making about changing therapy to achieve endoscopic remission in asymptomatic patients with IBD until data from ongoing randomized studies are available.

Optimizing isometric midthigh pull testing protocols: impact on peak force and rate of force development and their association with jump performance.

BACKGROUND: Isometric strength testing is widely applied in sports science. However, we hypothesized that traditional testing procedures with a dual focus on both peak force (PF) and rate of force development (RFD) may compromise the true assessment of early RFD measures and lower the associative value towards vertical jump performance. METHODS: Therefore, PF and RFD were assessed for 47 active participants (24 females, 23 males) with a traditional isometric midthigh pull (IMTP) protocol ("push as hard and fast as possible" over 4 s) and an RFD-specific protocol ("push as fast as possible" over 2 s). IMTP measures were compared to squat (SJ), countermovement (CMJ) and drop-jump (DJ) performance. RESULTS: The RFD-specific protocol provided higher RFD (P<0.05) for time domains up to 100 ms but lower PF (P<0.001). Independent of protocol, SJ and CMJ performance displayed significant, but low-to-moderate correlations with all RFD measures (r=0.30-0.52) as well as PF (r=0.44), whereas DJ did not show any correlation. CONCLUSIONS: In conclusion, an RFD-specific protocol appears relevant for the assessment of RFD in the time domain up to 100 ms. However, the observed associations between RFD/PF measures and vertical jump performance remained low-to-moderate independent of the IMTP test protocol.

Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

PURPOSE: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES. PATIENTS AND METHODS: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D). RESULTS: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11. CONCLUSION: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

Practical Guidance for Hemodynamic Assessment by Right Heart Catheterization in Management of Heart Failure.

Heart failure is a clinical syndrome characterized by the inability of the heart to meet the circulatory demands of the body without requiring an increase in intracardiac pressures at rest or with exertion. Hemodynamic parameters can be measured via right heart catheterization, which has an integral role in the full spectrum of heart failure: from ambulatory patients to those in cardiogenic shock, as well as patients being considered for left ventricular device therapy and heart transplantation. Hemodynamic data are critical for prompt recognition of clinical deterioration, assessment of prognosis, and guidance of treatment decisions. This review is a field guide for hemodynamic assessment, troubleshooting, and interpretation for clinicians treating patients with heart failure.

Enhancing Care for Older Adults and Dementia Patients with Large Language Models: Proceedings of the National Institute on Aging -Artificial Intelligence & Technology Collaboratory for Aging Research Symposium.

Large Language Models (LLMs) stand on the brink of reshaping the field of aging and dementia care, challenging the one-size-fits-all paradigm with their capacity for precision medicine and individualized treatment strategies. The "Large Pre-Trained Models with a Focus on AD/ADRD and Healthy Aging" symposium, organized by the National Institute on Aging and the Johns Hopkins AI & Technology Collaboratory for Aging Research, served as a platform for exploring this potential. The symposium brought together diverse experts to discuss the integration of LLMs in aging and dementia care. They highlighted the roles LLMs can play in clinical decision support and predictive analytics, while also addressing critical ethical concerns including bias, privacy, and the responsible use of AI. The discussions focused on the need to balance technological advancement with ethical considerations in AI deployment. In conclusion, the symposium projected a future where LLMs not only revolutionize healthcare practices but also pose significant challenges that require careful navigation.

Nurses' perspectives on the provision of self-care management education to patients with heart failure: A qualitative study at Cardiac Hospital, Dar es Salaam Tanzania.

BACKGROUND: Patients' education along with a motivation for developing self-care management skills is an essential component in the management of heart failure(HF). Self-care management education has been practiced by nurses in many hospitals. However, there is inadequate evidence for the provision of self-care management education in low-income countries including Tanzania. Lack of self-care management education to patients with HF during discharge is the most common reason for re-admission to hospitals. AIM: This study aimed to explore nurses' perspectives focusing on facilitators and barriers to the provision of self-care management education to patients with heart failure at Jakaya Kikwete Cardiac Institute, Dar es Salaam, Tanzania. MATERIALS AND METHODS: This study used a qualitative descriptive design. Purposive sampling was used to recruit 12 study participants. In-depth interviews were used to collect the data. We used thematic analysis to come up with the themes and sub-themes. RESULTS: The two major themes emerged from this study; The first theme is "Improved patient quality of life and health outcome" which describes factors that motivate nurses to continue giving self-care management education to heart failure patients. The second theme is "Reduced effective uptake of self-care management education" which describes nurses'perspectives on barriers for providing self-care management education to heart falure patients. Nurses highlight some barriers while providing self-care management education to patients with heart failure including;inadequate knowledge of self-care management among nurses, lack of privacy during the provision of self-care education, poor communication skills among nurses, and lack of learning materials. Also, nurses pointed out facilitators that influence the provision of self-care management education such as increased involvement of family members and the use of peer educators. CONCLUSIONS AND RECOMMENDATIONS: Poor self-care management for patients with heart failure results in readmission and prolonged hospital stay. Family involvement and the use of peer educators are the key steps in the improvement of self-care management for patients with HF. However, patient cognitive impairment and poverty which contribute to poor health outcomes, should be taken into consideration when planning for discharge for patients with HF. Self-care management education should be part of routine health care.

Meeting report: Considerations for trial design and endpoints in licensing therapeutic HPV16/18 vaccines to prevent cervical cancer.

Cervical cancer is a major cause of morbidity and mortality globally with a disproportionate impact on women in low- and middle-income countries. In 2021, the World Health Organization (WHO) called for increased vaccination, screening, and treatment to eliminate cervical cancer. However, even with widespread rollout of human papillomavirus (HPV) prophylactic vaccines, millions of women who previously acquired HPV infections will remain at risk for progression to cancer for decades to come. The development and licensing of an affordable, accessible therapeutic HPV vaccine, designed to clear or control carcinogenic HPV and/or to induce regression precancer could significantly contribute to the elimination efforts, particularly benefiting those who missed out on the prophylactic vaccine. One barrier to development of such vaccines is clarity around the regulatory pathway for licensure. In Washington, D.C. on September 12-13, 2023, a meeting was convened to provide input and guidance on trial design with associated ethical and regulatory considerations. This report summarizes the discussion and conclusions from the meeting. Expert presentation topics included the current state of research, potential regulatory challenges, WHO preferred product characteristics, modeling results of impact of vaccine implementation, epidemiology and natural history of HPV infection, immune responses related to viral clearance and/or precancer regression including potential biomarkers, and ethical considerations. Panel discussions were held to explore specific trial design recommendations to support the licensure process for two vaccine indications: (1) treatment of prevalent HPV infection or (2) treatment of cervical precancers. Discussion covered inclusion/exclusion criteria, study endpoints, sample size and power, safety, study length, and additional data needed, which are reported here. Further research of HPV natural history is needed to address identified gaps in regulatory guidance, especially for therapeutic vaccines intended to treat existing HPV infections.

Sex ratio at birth across 100 years in Sweden and risk of cardiovascular disease and all-cause mortality - a national register study.

The human sex ratio at birth (SRB) undergoes temporary changes around a mean proportion of 0.51 male births. SRB has been well studied for historical, geographical, and secular trends, but until now not linked to health outcomes in the total population, e.g. for cardiovascular disease (CVD) or mortality during follow-up of birth cohorts. We used linkage analysis based on national registers in Sweden that cover all births from 1900 to 2016. SRB at birth was calculated by every 10-year birth cohort in all survivors living in 1997 for a follow-up analysis of risk of CVD and mortality with data from national registers. When the highest quartile of SRB was used as reference, a slightly increased risk of fatal CVD (HR 1.03 (95% confidence intervals, CI): 1.02-1.04), non-fatal CVD (HR 1.01; 95%CI: 1.01-1.02) and mortality (HR 1.02; 95%CI, 1.01-1.03) was found after full adjustments in men belonging to the lowest SRB quartile. A similar pattern was also found for fatal CHD in women. in the lowest SBR quartile compared to the highest, HR 1.03 (95%CI: 1.02-1.05). In conclusion, in birth cohorts with a relatively lower than expected number of males born, long-term adverse health effects were observed with slightly increased cardiovascular risk and total mortality at the population level. This could indicate that men belonging to so-called "culled cohorts" in a developed country during the 20th century are characterized by a slightly increased risk that could reflect negative early life influences and environmental exposures in pregnant women resulting in selective loss of male embryos or fetuses. In a public health perspective SRB could be of some importance to monitor as an aspect of birth statistics linked to relatively minor population health effects.

Oxylipin Dynamics Following A Single Bout of Yoga Exercise: A Pilot Randomized Controlled Trial Secondary Analysis.

Background: Yoga may promote health via a complex modulation of inflammation. Little is known about oxylipins, a class of circulating mediators involved in inflammation resolution. Objective: To explore the acute effects of yoga exercise on systemic levels of oxylipins. Methods: This is a secondary analysis of a three-arm (high-intensity-yoga: HY, n = 10); moderate-intensity-yoga: MY, n = 10; and no-intervention-control: CON, n = 10) pilot randomized controlled trial employing a single bout of yoga exercise. Blood samples (baseline and 4-timepoint post-intervention) were used for an unbiased metabolipidomic profiling analysis. Net Areas Under the Curve per oxylipin were evaluated for each group. Results: Lipoxin(LX)B4, prostaglandin(PG)D2, and resolvin(Rv)D3 exhibited a greater magnitude of change in HY compared with MY and CON. Conclusion: Findings inform the design of future trials exploring the acute effects of yoga exercise on oxylipins' systemic levels.

Monoclonal Antibody Generation Using Single B Cell Screening for Treating Infectious Diseases.

The screening of antigen-specific B cells has been pivotal for biotherapeutic development for over four decades. Conventional antibody discovery strategies, including hybridoma technology and single B cell screening, remain widely used based on their simplicity, accessibility, and proven track record. Technological advances and the urgent demand for infectious disease applications have shifted paradigms in single B cell screening, resulting in increased throughput and decreased time and labor, ultimately enabling the rapid identification of monoclonal antibodies with desired biological and biophysical properties. Herein, we provide an overview of conventional and emergent single B cell screening approaches and highlight their potential strengths and weaknesses. We also detail the impact of innovative technologies-including miniaturization, microfluidics, multiplexing, and deep sequencing-on the recent identification of broadly neutralizing antibodies for infectious disease applications. Overall, the coronavirus disease 2019 (COVID-19) pandemic has reinvigorated efforts to improve the efficiency of monoclonal antibody discovery, resulting in the broad application of innovative antibody discovery methodologies for treating a myriad of infectious diseases and pathological conditions.

Using near misses, artificial intelligence, and machine learning to predict maritime incidents: A U.S. Coast Guard case study.

Two recent trends made this project possible: (1) The recognition that near misses can be predictors of future negative events and (2) enhanced artificial intelligence (AI) and machine learning (ML) tools that make data analytics accessible for many organizations. Increasingly, organizations are learning from prior incidents to improve safety and reduce accidents. The U.S. Coast Guard (USCG) uses a reporting system called the Marine Information for Safety and Law Enforcement (MISLE) database. Because many of the incidents that appear in this database are minor ones, this project initially focused on determining if near misses in MISLE could be predictors of future accidents. The analysis showed that recent near-miss counts are useful for predicting future serious casualties at the waterway level. Using this finding, a predictive AI/ML model was built for each waterway type by vessel combination. Random forest decision tree AI/ML models were used to identify waterways at significant accident risk. An R-based predictive model was designed to be run monthly, using data from prior months to make future predictions. The prediction models were trained on data from 2007 to 2022 and tested on 10 months of data from 2022, where prior months were added to test the next month. The overall accuracy of the predictions was 92%-99.9%, depending on model characteristics. The predictions of the models were considered accurate enough to be potentially useful in future prevention efforts for the USCG and may be generalizable to other industries that have near-miss data and a desire to identify and manage risks.

Performance and Fatigue Patterns in Elite Cyclists During 6 h of Simulated Road Racing.

Fatigue resistance is vital for success in elite road cycling, as repeated, intense efforts challenge the athletes' ability to sustain peak performance throughout prolonged races. The present study combined recurrent performance testing and physiological measures during 6 h simulated racing with laboratory testing to investigate factors influencing fatigue resistance. Twelve male national elite cyclists (25 ± 3 years; 76 ± 6 kg and VO2max of 5.2 ± 0.5 L/min) completed incremental power and maximal fat oxidation tests. Subsequently, they underwent field testing with physiological measures and fatigue responses evaluated through peak sprint power and 5 km time trial (TT) testing after 0, 2, 4, and 6 h of exercise. Peak power declined from 1362 ± 176 W in first sprint to 1271 ± 152 W after 2 h (p < 0.01) and then stabilized. In contrast, TT mean power gradually declined from 412 ± 38 W in the first TT to 384 ± 41 W in the final trial, with individual losses ranging from 2% to 14% and moderately correlated (r2 = 0.45) to accumulated exercise time above lactate threshold. High carbohydrate intake (~90 g/h) maintained blood glucose levels, but post-TT [lactate] decreased from 15.1 ± 2 mM to 7.1 ± 2.3 mM, while fat oxidation increased from 0.7 ± 0.3 g/min at 0 h to 1.1 ± 0.1 g/min after 6 h. The study identifies fatigue patterns in national elite cyclists. Peak sprint power stabilized after an initial impairment from 0 to 2 h, while TT power gradually declined over the 6 h simulated race, with increased differentiation in fatigue responses among athletes.

Validation of the Interpersonal Relationships in Eating Disorders (IR-ED) Scale in an Eating Disorder Sample.

OBJECTIVE: Interpersonal problems have been identified as a plausible mechanism underlying the onset and maintenance of eating disorders. The Interpersonal Relationships in Eating Disorders (IR-ED) scale is the first eating disorders-specific measure of interpersonal problems, which was developed in a nonclinical sample. The aims of the current study were to (a) confirm the factor structure of the IR-ED within a large clinical sample, (b) investigate measurement invariance of the IR-ED across nonclinical and clinical samples, (c) examine the convergent validity of the IR-ED using a generic measure of interpersonal problems, and (d) investigate the incremental clinical utility of the IR-ED in uniquely predicting eating disorder symptomatology. METHOD: Treatment-seeking individuals (N = 437) completed the IR-ED at their initial assessment appointment at a specialist eating disorder outpatient service. RESULTS: A multiple-group confirmatory factor analysis supported an invariant bifactor structure comprising a general interpersonal problems factor and two group factors-Avoidance of Body Evaluation and Food-Related Interpersonal Tension. Convergent validity was demonstrated by a large, statistically significant correlation with a generic measure of interpersonal problems (r = 0.62, p < 0.001). A series of structural equation models further revealed unique incremental predictive utility of the IR-ED for eating disorder symptomatology. DISCUSSION: The IR-ED has strong psychometric properties and may prove beneficial in the assessment, formulation, and treatment of eating-specific interpersonal problems among patients with eating disorders.

Relational One Health: A more-than-biomedical framework for more-than-human health, and lessons learned from Brazil, Ethiopia, and Israel.

The One Health conceptual framework envisions human, animal, and environmental health as interconnected. This framework has achieved remarkable progress in the control of zoonotic diseases, but it commonly neglects the environmental domain, implicitly prioritizes human life over the life of other beings, and fails to consider the political, cultural, social, historical, and economic contexts that shape the health of multispecies collectives. We have developed a novel theoretical framework, Relational One Health, which expands the boundaries of One Health, clearly defines the environmental domain, and provides an avenue for engagement with critical theory. We present a systematic literature review of One Health frameworks to demonstrate the novelty of Relational One Health, and to orient it with respect to other critically-engaged frameworks for One Health. Our results indicate that while Relational One Health complements several earlier frameworks, these other frameworks are either not intended for research, or for narrow sets of research questions. We then demonstrate the utility of Relational One Health for One Health research through case studies in Brazil, Israel, and Ethiopia. Empirical research which is grounded in theory can speak collectively, increasing the impact of individual studies and the field as a whole. One Health is uniquely poised to address several wicked challenges facing the 21st century-climate change, pandemics, neglected zoonoses, and biodiversity collapse-and a unifying theoretical tradition is key to generating the evidence needed to meet these challenges.