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Abstract Background Uptake of COVID-19 vaccines remains problematically low in the USA, especially in rural areas. COVID-19 vaccine hesitancy is associated with lower uptake, which translates to higher susceptibility to SARS-CoV-2 variants in communities where vaccination coverage is low. Because community pharmacists are among the most accessible and trusted health professionals in rural areas, this randomized clinical trial will examine implementation strategies to support rural pharmacists in delivering an adapted evidence-based intervention to reduce COVID-19 vaccine hesitancy. Methods We will use an incomplete stepped wedge trial design in which we will randomize 30 rural pharmacies (unit of analysis) to determine the effectiveness and incremental cost-effectiveness of a standard implementation approach (consisting of online training that describes the vaccine hesitancy intervention, live webinar, and resource website) compared to adding on a virtual facilitation approach (provided by a trained facilitator in support of the delivery of the vaccine hesitancy counseling intervention by pharmacists). The intervention (ASORT) has been adapted from an evidence-based vaccine communication intervention for HPV vaccines through a partnership with rural pharmacies in a practice-based research network in seven southern US states. ASORT teaches pharmacists how to identify persons eligible for COVID-19 vaccination (including a booster), solicit and address vaccine concerns in a non-confrontational way, recommend the vaccine, and repeat the steps later if needed. The primary trial outcome is fidelity to the ASORT intervention, which will be determined through ratings of recordings of pharmacists delivering the intervention. The secondary outcome is the effectiveness of the intervention, determined by rates of patients who agree to be vaccinated after receiving the intervention. Other secondary outcomes include feasibility, acceptability, adoption, reach, and cost. Cost-effectiveness and budget impact analyses will be conducted to maximize the potential for future dissemination and sustainability. Mixed methods will provide triangulation, expansion, and explanation of quantitative findings. Discussion This trial contributes to a growing evidence base on vaccine hesitancy interventions and virtual-only facilitation of evidenced-based practices in community health settings. The trial will provide the first estimate of the relative value of different implementation strategies in pharmacy settings. Trial registration NCT05926544 (clinicaltrials.gov); 07/03/2023.

Abstract Objectives The Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE) Study cluster-randomized 86 primary care practices in 10 healthcare systems to a patient-centered multifactorial fall injury prevention intervention or enhanced usual care, enrolling 5451 participants. We estimated total healthcare costs from participant-reported fall injuries receiving medical attention (FIMA) that were averted by the STRIDE intervention and tested for healthcare-system-level heterogeneity and heterogeneity of treatment effect (HTE). Methods Participants were community-dwelling adults age ≥ 70 at increased fall injury risk. We estimated practice-level total costs per person-year of follow-up (PYF), assigning unit costs to FIMA with and without an overnight hospital stay. Using independent variables for treatment arm, healthcare system, and their interaction, we fit a generalized linear model with log link, log follow-up time offset, and Tweedie error distribution. Results Unadjusted total costs per PYF were $2,034 (intervention) and $2,289 (control). The adjusted (intervention minus control) cost difference per PYF was -$167 (95% confidence interval (CI), -$491, $216). Cost heterogeneity by healthcare system was present (p = 0.035), as well as HTE (p = 0.090). Adjusted total costs per PYF in control practices varied from $1,529 to $3,684 for individual healthcare systems; one system with mean intervention minus control costs of -$2092 (95% CI, -$3,686 to -$944) per PYF accounted for HTE, but not healthcare system cost heterogeneity. Conclusions We observed substantial heterogeneity of healthcare system costs in the STRIDE study, with small reductions in healthcare costs for FIMA in the STRIDE intervention accounted for by a single healthcare system. Trial registration Clinicaltrials.gov (NCT02475850).

Abstract Background Comprehensive Behavioral Intervention for Tics (CBIT) is a first-line treatment for tic disorders that aims to improve controllability over tics that an individual finds distressing or impairing. However, it is only effective for approximately half of patients. Supplementary motor area (SMA)-directed neurocircuitry plays a strong role in motor inhibition, and activity in this region is thought to contribute to tic expression. Targeted modulation of SMA using transcranial magnetic stimulation (TMS) may increase CBIT efficacy by improving patients' ability to implement tic controllability behaviors. Methods The CBIT + TMS trial is a two-phase, milestone-driven early-stage randomized controlled trial. The trial will test whether augmenting CBIT with inhibitory, non-invasive stimulation of SMA with TMS modifies activity in SMA-mediated circuits and enhances tic controllability in youth ages 12–21 years with chronic tics. Phase 1 will directly compare two rTMS augmentation strategies (1 Hz rTMS vs. cTBS) vs. sham in N = 60 participants. Quantifiable, a priori “Go/No Go Criteria” guide the decision to proceed to phase 2 and the selection of the optimal TMS regimen. Phase 2 will compare the optimal regimen vs. sham and test the link between neural target engagement and clinical outcomes in a new sample of N = 60 participants. Discussion This clinical trial is one of few to date testing TMS augmentation of therapy in a pediatric sample. The results will provide insight into whether TMS is a potentially viable strategy for enhancing CBIT efficacy and reveal potential neural and behavioral mechanisms of change. Trial registration ClinicalTrials.gov NCT04578912 . Registered on October 8, 2020.

Abstract Objective Facial palsy affects patients of all backgrounds, yet no existing studies describe differences in its treatment patterns between demographic groups. Methods We used the National Surgical Quality Improvement Project database to investigate whether race and sex disparities exist in facial reanimation surgery. Patients were identified using CPT codes corresponding to facial‐nerve procedures. Results Seven hundred sixty‐one patients met criteria; 681 self‐identified as White (89.5%), 51 as Black (6.7%), 43 as Hispanic (5.6%), 23 as Asian (3.0%), and 5 patients as other (0.61%). White patients were more than twice as likely to undergo brow ptosis repair than Non‐White patients (OR 2.49, 95% CI 1.16–6.15, p = .03). After controlling for malignancy, men had longer operative times than women (480.2 vs. 413.9 min, p = .04) and higher likelihood of free tissue transfer (OR 4.1, 95% CI 1.9–9.8), fascial free tissue transfer (OR 10.7, 95% CI 2.1–195), and ectropion repair (OR 1.8, 95% CI 1.2–2.8). Conclusion Most patients undergoing facial reanimation surgery in the United States are White. Men have longer operative times and a higher likelihood of undergoing free fascial grafts and cutaneous and fascial free tissue transfer than women regardless of malignancy status. Level of Evidence 2c.

Abstract Aims We investigated titration patterns of angiotensin‐converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs) and beta‐blockers, quality of life (QoL) over 6 months, and associated 1 year outcome [all‐cause mortality/heart failure (HF) hospitalization] in a real‐world population with HF with reduced ejection fraction (HFrEF). Methods and results Participants with HFrEF (left ventricular ejection fraction 80% of patients, mineralocorticoid receptor antagonist in about half of patients, and statins in >90% of patients. At baseline, only 11% and 9% received 100% GRD for each drug class, respectively, with about half (47%) achieving ≥50% GRD for ACEis/ARBs or beta‐blockers. At 6 months, a large majority remained in the ‘stay low’ category, one third remained in ‘stay high’, whereas 10–16% up‐titrated and 4–6% down‐titrated. Patients with lower (vs. higher) N‐terminal pro‐beta‐type natriuretic peptide levels were more likely to be up‐titrated or be in ‘stay high’ for ACEis/ARBs and beta‐blockers (P = 0.002). Ischaemic aetiology, prior HF hospitalization, and enrolment in Singapore (vs. New Zealand) were independently associated with higher odds of ‘staying low’ (all P

Abstract Aims Heart failure (HF) remains a major public health problem with increasing prevalence in China. This study evaluated the clinical performance and quality measures for HF management to identify gaps in the standardization of care for patients hospitalized for HF in China. Methods and results Following the results of China‐HF stage I (2012–2015), the second stage of the China‐HF was launched in 2017. Among 113 hospitals with ≥100 cases, the China‐HF Stage II assessed the quality of care measures for HF and compared results with previous data in China and the US‐based Get with The Guidelines‐Heart Failure (GWTG‐HF) registries. In total, 34 938 patients hospitalized with HF were enrolled from January 2017 to October 2020. Echocardiographic left ventricular function and natriuretic peptide test were performed in 93.7% and 93.0% of the cases, respectively. Adherence to standardized guidelines in China‐HF stage II was higher than that in the China‐HF stage I, but generally lower than GWTG‐HF registry with 78.2% of eligible patients was prescribed oral diuretics, 78.7% renin‐angiotensin‐system inhibitors, and 82.2% beta‐blockers. Implantable cardioverter‐defibrillators and cardiac resynchronization devices were implanted in 3.9% and 14.6%, respectively. In contrast, the proportion of eligible patients discharged with spironolactone (87.8%) was higher than GWTG‐HF. The median length of hospitalization was 9 (6, 12) days, and 938 (2.8%) patients died or withdrew from treatment during hospitalization. Conclusions Despite significant improvements in the use of guideline‐recommended testing and therapy, there remain major gaps in quality of care for patients hospitalized for HF in China that are generally larger than gaps observed in the United States.

Abstract We report the safety and pharmacokinetic properties of the HIV‐1 maturation inhibitor GSK3739937 (GSK'937) in healthy participants. This was a phase I, first‐in‐human, double‐blind, randomized, placebo‐controlled, single‐ (part 1) and multiple‐ (part 2) dose escalation study with an additional open‐label relative bioavailability and food effect study (part 3). Participants received oral ascending single doses (10–800 mg) in part 1, up to 18 once‐daily 25‐ to 100‐mg or 3 once‐weekly 500‐mg doses in part 2, and single 100‐mg doses as powder‐in‐bottle or tablet (in fed and fasted states) formulations in part 3. Primary and secondary objectives were safety and pharmacokinetic assessments, respectively. Ninety‐one participants were enrolled; 38 reported 81 total adverse events (AEs). All AEs in participants receiving GSK'937 were grade 1 or 2 and resolved during the study. Most drug‐related AEs were gastrointestinal (14/17, 82%). The terminal phase half‐life of GSK'937 was ~3 days for all doses following single and repeat dosing. Geometric mean maximum concentration and total drug exposures exhibited dose‐proportional increases during part 1. Accumulation in exposure following repeat dosing was 6‐ to 7‐fold with daily dosing and ~1.7‐fold after weekly treatment, as expected due to the long half‐life. Bioavailability of GSK'937 after a meal was 1.35‐ to 1.40‐fold greater as a tablet versus powder‐in‐bottle and >2‐fold higher in fed versus fasted states when provided as a tablet. No unexpected or dose‐limiting safety events occurred. Pharmacokinetic parameters of long half‐life and accumulation of exposure following repeat dosing suggest the potential for weekly oral dosing. ClinicalTrials.gov identifier: NCT04493684.

The detection of conserved motifs by pattern recognition receptors is a crucial component of the innate detection of pathogens and danger signals via conserved pattern recognition receptors. Here the authors define a pathway that transfers partially digested material from the phagolysosomal pathway of macrophages to release at the plasma membrane which is associated with enhanced inflammatory potential, by a process they introduce as eructophagy.

Background Many patients with heart failure (HF) have severely reduced ejection fraction but do not meet threshold for consideration of advanced therapies (ie, stage D HF). The clinical profile and health care costs associated with these patients in US practice is not well described. Methods and Results We examined patients hospitalized for worsening chronic heart failure with reduced ejection fraction ≤40% from 2014 to 2019 in the GWTG‐HF (Get With The Guidelines‐Heart Failure) registry, who did not receive advanced HF therapies or have end‐stage kidney disease. Patients with severely reduced EF defined as EF ≤30% were compared with those with EF 31% to 40% in terms of clinical profile and guideline‐directed medical therapy. Among Medicare beneficiaries, postdischarge outcomes and health care expenditure were compared. Among 113 348 patients with EF ≤40%, 69% (78 589) had an EF ≤30%. Patients with severely reduced EF ≤30% tended to be younger and were more likely to be Black. Patients with EF ≤30% also tended to have fewer comorbidities and were more likely to be prescribed guideline‐directed medical therapy (“triple therapy” 28.3% versus 18.2%, P

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.

Characterizing the optimal fMRI paradigms for detecting behaviorally relevant functional connectivity (FC) patterns is a critical step to furthering our knowledge of the neural basis of behavior. Previous studies suggested that FC patterns derived from task fMRI paradigms, which we refer to as task-based FC, are better correlated with individual differences in behavior than resting-state FC, but the consistency and generalizability of this advantage across task conditions was not fully explored. Using data from resting-state fMRI and three fMRI tasks from the Adolescent Brain Cognitive Development Study ® (ABCD), we tested whether the observed improvement in behavioral prediction power of task-based FC can be attributed to changes in brain activity induced by the task design. We decomposed the task fMRI time course of each task into the task model fit (the fitted time course of the task condition regressors from the single-subject general linear model) and the task model residuals, calculated their respective FC, and compared the behavioral prediction performance of these FC estimates to resting-state FC and the original task-based FC. The FC of the task model fit was better than the FC of the task model residual and resting-state FC at predicting a measure of general cognitive ability or two measures of performance on the fMRI tasks. The superior behavioral prediction performance of the FC of the task model fit was content-specific insofar as it was only observed for fMRI tasks that probed similar cognitive constructs to the predicted behavior of interest. To our surprise, the task model parameters, the beta estimates of the task condition regressors, were equally if not more predictive of behavioral differences than all FC measures. These results showed that the observed improvement of behavioral prediction afforded by task-based FC was largely driven by the FC patterns associated with the task design. Together with previous studies, our findings highlighted the importance of task design in eliciting behaviorally meaningful brain activation and FC patterns.

BackgroundIndividuals enrolling in the Veterans Health Administration frequently report symptoms consistent with insomnia disorder. Cognitive behavioral therapy for insomnia (CBT-I) is a gold standard treatment for insomnia disorder. While the Veterans Health Administration has successfully implemented a large dissemination effort to train providers in CBT-I, the limited number of trained CBT-I providers continues to restrict the number of individuals who can receive CBT-I. Digital mental health intervention adaptations of CBT-I have been found to have similar efficacy as traditional CBT-I. To help address the unmet need for insomnia disorder treatment, the VA commissioned the creation of a freely available, internet-delivered digital mental health intervention adaptation of CBT-I known as Path to Better Sleep (PTBS). ObjectiveWe aimed to describe the use of evaluation panels composed of veterans and spouses of veterans during the development of PTBS. Specifically, we report on the methods used to conduct the panels, the feedback they provided on elements of the course relevant to user engagement, and how their feedback influenced the design and content of PTBS. MethodsA communications firm was contracted to recruit 3 veteran (n=27) and 2 spouse of veteran (n=18) panels and convene them for three 1-hour meetings. Members of the VA team identified key questions for the panels, and the communications firm prepared facilitator guides to elicit feedback on these key questions. The guides provided a script for facilitators to follow while convening the panels. The panels were telephonically conducted, with visual content displayed via remote presentation software. The communications firm prepared reports summarizing the panelists’ feedback during each panel meeting. The qualitative feedback described in these reports served as the raw material for this study. ResultsThe panel members provided markedly consistent feedback on several elements of PTBS, including recommendations to emphasize the efficacy of CBT-I techniques; clarify and simplify written content as much as possible; and ensure that content is consistent with the lived experiences of veterans. Their feedback was congruent with previous studies on the factors influencing user engagement with digital mental health interventions. Panelist feedback influenced multiple course design decisions, including reducing the effort required to use the course’s sleep diary function, making written content more concise, and selecting veteran testimonial videos that emphasized the benefits of treating chronic insomnia symptoms. ConclusionsThe veteran and spouse evaluation panels provided useful feedback during the design of PTBS. This feedback was used to make concrete revisions and design decisions consistent with existing research on improving user engagement with digital mental health interventions. We believe that many of the key feedback messages provided by these evaluation panels could prove useful to other digital mental health intervention designers.

Abstract Aims Recent trials have evaluated sodium–glucose co‐transporter 2 inhibitors in patients with heart failure (HF). We sought to assess the robustness of findings from these trials using the fragility index (FI). Methods and results Fragility index is defined as the minimum number of patients that must be moved from the ‘non‐event’ to the ‘event’ group to turn a statistically significant result to non‐significant. In addition to FI, fragility quotient [(FQ); FI divided by the sample size] was calculated to assess the proportion of events that must be moved to change the significance. For statistically non‐significant outcomes, reverse fragility index (RFI) and reverse fragility quotient (RFQ) were calculated. Robustness of findings after pooling data from all three trials was also assessed. A robust reduction in first HF hospitalization or cardiovascular mortality was seen with dapagliflozin (FI = 62 and FQ = 0.013), empagliflozin (FI = 50 and FQ = 0.013), and sotagliflozin (FI = 60 and FQ = 0.049). Dapagliflozin nominally improved all‐cause and cardiovascular mortality, with modest FI (n = 8 and 5) and FQ (0.002 and 0.001). Empagliflozin and sotagliflozin did not demonstrate statistically significant reductions in all‐cause mortality, with modest RFI (empagliflozin: RFI = 26 and RFQ = 0.007; sotagliflozin: RFI = 6 and RFQ = 0.005). A similar trend was seen with cardiovascular mortality (empagliflozin: RFI = 24 and RFQ = 0.006; sotagliflozin: RFI = 7 and RFQ = 0.006). Upon meta‐analysis, the result for first HF hospitalization or cardiovascular mortality was robust (FI = 95 and FQ = 0.010). The reductions in all‐cause (FI = 12 and FQ = 0.001) and cardiovascular mortality (FI = 9 and FQ = 0.001), while statistically significant, were fragile. Conclusion Improvement in the composite outcome of first HF hospitalization or cardiovascular death was highly concordant and robust across sodium–glucose co‐transporter 2 inhibitor trials. In contrast, secondary endpoints of all‐cause and cardiovascular mortality were statistically fragile, underscoring the need to power trials for mortality to fully understand the benefit of therapies on fatal events.

Abstract Aims Hospitalization for heart failure (HF) constitutes a major healthcare and economic burden. Trends and characteristics of hospitalizations for HF for the recent years are not clear. We sought to determine the trends and characteristics of hospitalization for HF in the United States. Method and results A retrospective analysis of the National Inpatient Sample weighted data between 1 January 2004 and 31 December 2018, which included hospitalized adults ≥ 18 years with primary discharge diagnosis of HF using International Classification of Diseases‐9/10 administrative codes. Main outcomes were trends in hospitalizations for HF (per 1000 person) and inpatient mortality (%) between 2004 and 2018. Conclusions Hospitalizations for HF have been increasing across both sexes and age groups since 2013, whereas inpatient mortality has been decreasing over the study period. Blacks have the highest risk of hospitalization for HF, and Whites have the highest in‐hospital mortality. There are significant racial and geographic disparities related to hospitalizations for HF.

Abstract Background There is uncertainty and limited data regarding initiation of sodium-glucose cotransporter 2 (SGLT2) inhibitors among patients hospitalized with acute heart failure (AHF). This systematic review and meta-analysis aim to establish the efficacy and safety of SGLT2 inhibitors initiated in patients hospitalized for AHF. Methods PubMed/Medline, Embase, and Cochrane library were searched using the following terms: (“sglt2" and "acute heart failure") and (“sglt2" and "worsening heart failure") from inception till November 15th, 2021 for randomized controlled trials (RCTs) comparing the efficacy and safety of initiating an SGLT2 inhibitor compared with placebo in patients with AHF. Major cardiovascular and diabetes scientific meetings in 2021 were also searched for relevant studies. Prespecified efficacy outcomes were all-cause mortality, rehospitalization for heart failure, and improvement in Kansas City Cardiomyopathy Questionnaire (KCCQ) scale score. Prespecified safety outcomes were acute kidney injury (AKI), hypotension, and hypoglycemia. Random effects odds ratio (OR) and mean difference with 95% confidence intervals (CIs) were calculated. Results Three RCTs with a total of 1831 patients were included. Initiation of SGLT2 inhibitors in patients with AHF reduced the risk of rehospitalization for heart failure (OR 0.52; 95% CI [0.42, 0.65]) and improved Kansas City Cardiomyopathy Questionnaire scores (mean difference 4.12; 95% CI [0.1.89, 6.53]). There was no statistically significant effect for initiation of SGLT2 inhibitors in patients with AHF on all-cause mortality (OR 0.70; 95% CI [0.46, 1.08]). Initiation of SGLT2 inhibitors in patients with AHF did not increase the acute kidney injury (OR 0.76; 95% CI [0.50, 1.16]), hypotension (OR 1.17; 95% CI [0.80, 1.71]), or hypoglycemia (OR 1.51; 95% CI [0.86, 2.65]). Conclusion Initiation of SGLT2 inhibitors in patients hospitalized for AHF during hospitalization or early post-discharge (within 3 days) reduces the risk of rehospitalization for heart failure and improves patient-reported outcomes with no excess risk of adverse effects.

Background: Long-term benzodiazepine dependence carries significant health risks which might be reduced with low-cost patient self-management interventions. A booklet version of one such intervention (Eliminating Medications Through Patient Ownership of End Results; EMPOWER) proved effective in a Canadian clinical trial with older adults. Digitizing such an intervention for electronic delivery and tailoring it to different populations could expand its reach. Accordingly, this article describes the protocol for a randomized controlled trial to test the effectiveness of an electronically-delivered, direct-to-patient benzodiazepine cessation intervention tailored to U.S. military veterans. Methods: Design: Two-arm individually randomized controlled trial. Setting: US Veterans Health Administration primary care clinics. Participants: Primary care patients taking benzodiazepines for three or more months and having access to a smartphone, tablet or desktop computer. Intervention and comparator: Participants will be randomized to receive either the electronically-delivered EMPOWER (EMPOWER-ED) protocol or asked to continue to follow provider recommendations regarding their benzodiazepine use (treatment-as-usual). Measurements: The primary outcomes are complete benzodiazepine cessation and 25% dose reduction, assessed using administrative and self-report data, between baseline and six-month follow-up. Secondary outcomes are self-reported anxiety symptoms, sleep quality, and overall health and quality of life, measured at baseline and 6-month follow-up, and benzodiazepine cessation at 12-month follow-up. Comments: This randomized controlled trial will evaluate whether the accessibility and effectiveness of a promising intervention for benzodiazepine cessation can be improved through digitization and population tailoring.

Interferon (IFN) is an important component of antiviral immunity, but can also be exploited by bacteria for immune evasion. Here the authors show that Listeria monocytogenes (Lm) induces type I IFN to suppress the degradation of Lm virulence proteins, ActA and LLO, and promote Lm infection in an IFITM3-dependent manner, thereby hinting at a potential target for antimicrobial therapy.

Iron is a potent catalyst of oxidative stress and cellular proliferation implicated in renal cell carcinoma (RCC) tumorigenesis, yet it also drives ferroptosis that suppresses cancer progression and represents a novel therapeutic target for advanced RCC. The von Hippel Lindau (VHL)/hypoxia-inducible factor-α (HIF-α) axis is a major regulator of cellular iron, and its inactivation underlying most clear cell (cc) RCC tumors introduces both iron dependency and ferroptosis susceptibility. Despite the central role for iron in VHL/HIF-α signaling and ferroptosis, RCC iron levels and their dynamics during RCC initiation/progression are poorly defined. Here, we conducted a large-scale investigation into the incidence and prognostic significance of total tissue iron in ccRCC and non-ccRCC patient primary tumor cancer cells, tumor microenvironment (TME), metastases and non-neoplastic kidneys. Prussian Blue staining was performed to detect non-heme iron accumulation in over 1600 needle-core sections across multiple tissue microarrays. We found that RCC had significantly higher iron staining scores compared with other solid cancers and, on average, >40 times higher than adjacent renal epithelium. RCC cell iron levels correlated positively with TME iron levels and inversely with RCC levels of the main iron uptake protein, transferrin receptor 1 (TfR1/TFRC/CD71). Intriguingly, RCC iron levels, including in the TME, decreased significantly with pathologic (size/stage/grade) progression, sarcomatoid dedifferentiation, and metastasis, particularly among patients with ccRCC, despite increasing TfR1 levels, consistent with an increasingly iron-deficient tumor state. Opposite to tumor iron changes, adjacent renal epithelial iron increased significantly with RCC/ccRCC progression, sarcomatoid dedifferentiation, and metastasis. Lower tumor iron and higher renal epithelial iron each predicted significantly shorter ccRCC patient metastasis-free survival. In conclusion, iron accumulation typifies RCC tumors but declines toward a relative iron-deficient tumor state during progression to metastasis, despite precisely opposite dynamics in adjacent renal epithelium. These findings raise questions regarding the historically presumed selective advantage for high iron during all phases of cancer evolution, suggesting instead distinct tissue-specific roles during RCC carcinogenesis and early tumorigenesis versus later progression. Future study is warranted to determine how the relative iron deficiency of advanced RCC contributes to ferroptosis resistance and/or introduces a heightened susceptibility to iron deprivation that might be therapeutically exploitable.

Tourette syndrome (TS) is characterized by multiple motor and vocal tics, and high-comorbidity rates with other neuropsychiatric disorders. Obsessive compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), major depressive disorder (MDD), and anxiety disorders (AXDs) are among the most prevalent TS comorbidities. To date, studies on TS brain structure and function have been limited in size with efforts mostly fragmented. This leads to low-statistical power, discordant results due to differences in approaches, and hinders the ability to stratify patients according to clinical parameters and investigate comorbidity patterns. Here, we present the scientific premise, perspectives, and key goals that have motivated the establishment of the Enhancing Neuroimaging Genetics through Meta-Analysis for TS (ENIGMA-TS) working group. The ENIGMA-TS working group is an international collaborative effort bringing together a large network of investigators who aim to understand brain structure and function in TS and dissect the underlying neurobiology that leads to observed comorbidity patterns and clinical heterogeneity. Previously collected TS neuroimaging data will be analyzed jointly and integrated with TS genomic data, as well as equivalently large and already existing studies of highly comorbid OCD, ADHD, ASD, MDD, and AXD. Our work highlights the power of collaborative efforts and transdiagnostic approaches, and points to the existence of different TS subtypes. ENIGMA-TS will offer large-scale, high-powered studies that will lead to important insights toward understanding brain structure and function and genetic effects in TS and related disorders, and the identification of biomarkers that could help inform improved clinical practice.

Diffusion imaging aims to non-invasively characterize the anatomy and integrity of the brain's white matter fibers. We evaluated the accuracy and reliability of commonly used diffusion imaging methods as a function of data quantity and analysis method, using both simulations and highly sampled individual-specific data (927–1442 diffusion weighted images [DWIs] per individual). Diffusion imaging methods that allow for crossing fibers (FSL's BedpostX [BPX], DSI Studio's Constant Solid Angle Q-Ball Imaging [CSA-QBI], MRtrix3’s Constrained Spherical Deconvolution [CSD]) estimated excess fibers when insufficient data were present and/or when the data did not match the model priors. To reduce such overfitting, we developed a novel Bayesian Multi-tensor Model-selection (BaMM) method and applied it to the popular ball-and-stick model used in BedpostX within the FSL software package. BaMM was robust to overfitting and showed high reliability and the relatively best crossing-fiber accuracy with increasing amounts of diffusion data. Thus, sufficient data and an overfitting resistant analysis method enhance precision diffusion imaging. For potential clinical applications of diffusion imaging, such as neurosurgical planning and deep brain stimulation (DBS), the quantities of data required to achieve diffusion imaging reliability are lower than those needed for functional MRI.

Imaging the infant brain with MRI has improved our understanding of early neurodevelopment. However, head motion during MRI acquisition is detrimental to both functional and structural MRI scan quality. Though infants are typically scanned while asleep, they commonly exhibit motion during scanning causing data loss. Our group has shown that providing MRI technicians with real-time motion estimates via Framewise Integrated Real-Time MRI Monitoring (FIRMM) software helps obtain high-quality, low motion fMRI data. By estimating head motion in real time and displaying motion metrics to the MR technician during an fMRI scan, FIRMM can improve scanning efficiency. Here, we compared average framewise displacement (FD), a proxy for head motion, and the amount of usable fMRI data (FD ≤ 0.2 mm) in infants scanned with (n = 407) and without FIRMM (n = 295). Using a mixed-effects model, we found that the addition of FIRMM to current state-of-the-art infant scanning protocols significantly increased the amount of usable fMRI data acquired per infant, demonstrating its value for research and clinical infant neuroimaging.

Abstract Aims Discontinuation or non‐publication of trials may hinder scientific progress and violates the commitment made to research participants. We sought to identify the prevalence of discontinuation and non‐publication of heart failure (HF) clinical trials. Methods and results We conducted a cross‐sectional search of ClinicalTrials.gov to identify all completed and discontinued HF clinical trials. We limited our search to only include trials that were completed by 31 December 2017. Trials were investigated to identify reasons for discontinuation. Informative termination was defined as trial termination due to safety or efficacy concerns. Data pertaining to the trial phase, funding, intervention, enrolment, and trial completion date were extracted for each trial. A total of 572 trials were included. Of these, 21% (n = 118) were discontinued before completion. Patient accrual was the most frequently cited reason (n = 42; 36%) for trial discontinuation, followed by informative termination (n = 16; 14%) and funding (n = 14; 12%). Overall, 24 780 patients were enrolled in trials that were terminated. Of trials that were completed and not terminated, nearly one‐third (n = 131/454; 29%) were not published. Seventy‐nine (24%) trials were published within 12 months, 192 (59%) within 24 months, and 252 (78%) trials within 36 months. Conclusions Discontinuation and non‐publication of HF trials is common. This raises ethical concerns towards participants who volunteer for research and are exposed to potential risks, inconvenience, and discomfort without furthering scientific progress.

Abstract Aims This study aimed to investigate the reporting of subgroup analyses in heart failure (HF) randomized controlled trials (RCTs) and to determine the strength and credibility of subgroup claims. Methods and results All primary HF RCTs published in nine high‐impact journals from 1 January 2008 to 31 December 2017 were included. Multivariable regression analysis was used to identify factors that may favour the reporting of results in specific subgroups. Strength of the subgroup effect claimed was classified into (i) strong, (ii) likely, or (iii) suggestive. Credibility of subgroup claim was scored using a pre‐specified 10 pointer criteria. Of the 261 HF RCTs studied, 107 (41%) reported subgroup analyses. Twenty‐five (23%) RCTs claimed a subgroup effect for the primary outcome of which six (24%) made a strong claim, eight (32%) claimed a likely effect, and 11 (44%) suggested a possible subgroup effect. Seven of the 25 RCTs did not employ interaction testing for subgroup claims of the primary outcome. Three out of 10 pre‐specified credibility criteria were satisfied by half of the trials. Fourteen trials justified the choice of subgroups, and 10 explicitly stated they were underpowered to detect differences within subgroups. Source of funding did not influence the frequency of reporting subgroup analyses (OR 0.53, 95% CI 0.78–3.62, P = 0.52). Conclusions Appropriate credibility criteria were rarely met even by HF RCTs that held strong subgroup claims. Subgroup analyses should be pre‐specified, be adequately powered, present interaction terms, and be replicated in independent data before being integrated into clinical decision making.

Abstract Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS‐HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter‐quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P

Abstract Background Many point-of-care ultrasound devices are now “pocket-sized” or handheld, allowing easy transport during travel and facilitating use in crowded spaces or in austere low-resource settings. Concerns remain about their durability, image quality, and clinical utility in those environments. Method Five emergency physicians with training in point-of-care ultrasound employed the Butterfly iQ, a novel handheld ultrasound device, in routine clinical care in a busy, high-acuity African emergency department over a period of 10 weeks. We retrospectively evaluated the performance of the Butterfly iQ from the perspectives of both the clinicians using the device and expert ultrasound faculty reviewing the images. Results We found advantages of the Butterfly iQ in a high-acuity African emergency department include its use of a single probe for multiple functions, small size, ease of transport, relatively low cost, and good image quality in most functions. Disadvantages include large probe footprint, lower, though still adequate, cardiac imaging quality, frequent overheating, and reliance on internet-based cloud storage, but these were surmountable. We also report a wide variety of patient presentations, pathology, and procedures to which the device was used. Conclusion We conclude the Butterfly iQ is an effective, though imperfect, point-of-care ultrasound device in a low-resource emergency setting. We will continue to employ the device in clinical emergency care and teaching in this setting.

Abstract Aims We sought to conduct a meta‐analysis regarding the safety and efficacy of sodium‐glucose co‐transporter 2 (SGLT2) inhibitors in patients with heart failure (HF). Methods and results MEDLINE, Scopus, Cochrane CENTRAL, and ClinicalTrials.gov were searched from their inception to November 2020 for placebo‐controlled randomized controlled trials of SGLT2 inhibitors. Randomized controlled trials were selected if they reported at least one of the prespecified outcomes in patients with HF. Hazard ratios (HRs) or risk ratios and their corresponding 95% confidence intervals were pooled using a random‐effects model. A total of seven trials including 16 820 HF patients (N = 8884 in the SGLT2 inhibitor arms; N = 7936 in the placebo arms) were included. In the overall HF cohort, SGLT2 inhibitors compared with placebo significantly reduced the risk of the composite endpoint of first HF hospitalization or cardiovascular death [HR: 0.77 (0.72–0.83); P

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models’ performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts’ clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta‐analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point‐of‐care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta‐analyzed c‐statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta‐analyzed c‐statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Abstract The COVID‐19 outbreak has disrupted global health care networks and caused thousands of deaths and an international economic downturn. Multiple drugs are being used on patients with COVID‐19 based on theoretical and in vitro therapeutic targets. Several of these therapies have been studied, but many have limited evidence behind their use, and clinical trials to evaluate their efficacy are either ongoing or have not yet begun. This review summarizes the existing evidence for medications currently under investigation for treatment of COVID‐19, including remdesivir, chloroquine/hydroxychlorquine, convalescent plasma, lopinavir/ritonavir, IL‐6 inhibitors, corticosteroids, and angiotensin‐converting enzyme inhibitors.

Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts.

Engagement is a multifaceted construct and a likely mechanism by which digital interventions achieve clinical improvements. To date, clinical research on digital mental health interventions (DMHIs) has overwhelmingly defined engagement and assessed its association with clinical outcomes through the objective/behavioral metrics of use of or interactions with a DMHI, such as number of log-ins or time spent using the technology. However, engagement also entails users' subjective experience. Research is largely lacking that tests the relationship between subjective metrics of engagement and clinical outcomes. The purpose of this study is to present a proof-of-concept exploratory evaluation of the association between subjective engagement measures of a mobile DMHI with changes in depression and anxiety. Adult primary care patients (N = 146) who screened positive for depression or anxiety were randomized to receive a DMHI, IntelliCare, immediately or following an 8-week waitlist. Subjective engagement was measured via the Usefulness, Satisfaction, and Ease of Use (USE) Questionnaire. Across both conditions, results showed that individuals who perceived a mobile intervention as more useful, easy to use and learn, and satisfying had greater improvements in depression and anxiety over eight weeks. Findings support our proposed experimental therapeutics framework that hypothesizes objective/behavioral and subjective engagement metrics as mechanisms that lead to changes in clinical outcomes, as well as support directing intervention design efforts for DMHIs to target the user experience.

Background Sacubitril/Valsartan has been highly efficacious in randomized trials of heart failure with reduced ejection fraction (HFrEF). However, the effectiveness of sacubitril/valsartan in older patients hospitalized for HFrEF in real‐world US practice is unclear. Methods and Results This study included Medicare beneficiaries age ≥65 years who were hospitalized for HFrEF ≤40% in the Get With The Guidelines–Heart Failure registry between October 2015 and December 2018, and eligible for sacubitril/valsartan. Associations between discharge prescription of sacubitril/valsartan and clinical outcomes were assessed after inverse probability of treatment weighting and adjustment for other HFrEF medications. Overall, 1551 (10.9%) patients were discharged on sacubitril/valsartan. Of those not prescribed sacubitril/valsartan, 7857 (62.0%) were prescribed an angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker. Over 12‐month follow‐up, compared with a discharge prescription of angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker, sacubitril/valsartan was independently associated with lower all‐cause mortality (adjusted hazard ratio [HR], 0.82; 95% CI, 0.72–0.94; P=0.004) but not all‐cause hospitalization (adjusted HR, 0.97; 95% CI, 0.89–1.07; P=0.55) or heart failure hospitalization (adjusted HR, 1.04; 95% CI, 0.91–1.18; P=0.59). Patients prescribed sacubitril/valsartan versus those without a prescription had lower risk of all‐cause mortality (adjusted HR, 0.69; 95% CI, 0.60–0.79; P

Abstract Background This paper describes a protocol for determining the incidence of serious fall injuries for Strategies to Reduce Injuries and Develop Confidence in Elders (STRIDE), a large, multicenter pragmatic clinical trial with limited resources for event adjudication. We describe how administrative data (from participating health systems and Medicare claims) can be used to confirm participant-reported events, with more time- and resource-intensive full-text medical record data used only on an “as-needed” basis. Methods STRIDE is a pragmatic cluster-randomized controlled trial involving 5451 participants age ≥ 70 and at increased risk for falls, served by 86 primary care practices in 10 US health systems. The STRIDE intervention involves a nurse falls care manager who assesses a participant’s underlying risks for falls, suggests interventions using motivational interviewing, and then creates, implements and longitudinally follows up on an individualized care plan with the participant (and caregiver when appropriate), in partnership with the participant’s primary care provider. STRIDE’s primary outcome is serious fall injuries, defined as a fall resulting in: (1) medical attention billable according to Medicare guidelines with a) fracture (excluding isolated thoracic vertebral and/or lumbar vertebral fracture), b) joint dislocation, or c) cut requiring closure; OR (2) overnight hospitalization with a) head injury, b) sprain or strain, c) bruising or swelling, or d) other injury determined to be “serious” (i.e., burn, rhabdomyolysis, or internal injury). Two sources of data are required to confirm a serious fall injury. The primary data source is the participant’s self-report of a fall leading to medical attention, identified during telephone interview every 4 months, with the confirmatory source being (1) administrative data capturing encounters at the participating health systems or Medicare claims and/or (2) the full text of medical records requested only as needed. Discussion Adjudication is ongoing, with over 1000 potentially qualifying events adjudicated to date. Administrative data can be successfully used for adjudication, as part of a hybrid approach that retrieves full-text medical records only when needed. With the continued refinement and availability of administrative data sources, future studies may be able to use administrative data completely in lieu of medical record review to maximize the quality of adjudication with finite resources. Trial registration ClinicalTrials.gov (NCT02475850).

Despite advances in diabetic wound care, many amputations are still needed each year due to their diabetic wounds, so a more effective therapy is warranted. Herein, we show that the dental pulp-derived stem cell (DPSC) products are effective in wound healing in diabetic NOD/SCID mice. Our results showed that the topical application of DPSC secretory products accelerated wound closure by inducing faster re-epithelialization, angiogenesis, and recellularization. In addition, the number of neutrophils producing myeloperoxidase, which mediates persisting inflammation, was also reduced. NFκB and its downstream effector molecules like IL-6 cause sustained pro-inflammatory activity and were reduced after the application of DPSC products in the experimental wounds. Moreover, the DPSC products also inhibited the activation of NFκB, and its translocation to the nucleus, by which it initiates the inflammation. Furthermore, the levels of TGF-β, and IL-10, potent anti-inflammatory molecules, were also increased after the addition of DPSC products. Mechanistically, we showed that this wound-healing process was mediated by the upregulation and activation of Smad 1 and 2 molecules. In sum, we have defined the cellular and molecular mechanisms by which DPSC products accelerated diabetic wound closure, which can be used to treat diabetic wounds in the near future.

Abstract Objectives With a rapidly growing list of candidate immune‐based cancer therapeutics, there is a critical need to generate highly reliable animal models to preclinically evaluate the efficacy of emerging immune‐based therapies, facilitating successful clinical translation. Our aim was to design and validate a novel in vivo model (called Xenomimetic or ‘X’ mouse) that allows monitoring of the ability of human tumor‐specific T cells to suppress tumor growth following their entry into the tumor. Methods Tumor xenografts are established rapidly in the greater omentum of globally immunodeficient NOD‐scid IL2Rγnull (NSG) mice following an intraperitoneal injection of melanoma target cells expressing tumor neoantigen peptides, as well as green fluorescent protein and/or luciferase. Changes in tumor burden, as well as in the number and phenotype of adoptively transferred patient‐derived tumor neoantigen‐specific T cells in response to immunotherapy, are measured by imaging to detect fluorescence/luminescence and flow cytometry, respectively. Results The tumors progress rapidly and disseminate in the mice unless patient‐derived tumor‐specific T cells are introduced. An initial T cell‐mediated tumor arrest is later followed by a tumor escape, which correlates with the upregulation of the checkpoint molecules programmed cell death‐1 (PD‐1) and lymphocyte‐activation gene 3 (LAG3) on T cells. Treatment with immune‐based therapies that target these checkpoints, such as anti‐PD‐1 antibody (nivolumab) or interleukin‐12 (IL‐12), prevented or delayed the tumor escape. Furthermore, IL‐12 treatment suppressed PD‐1 and LAG3 upregulation on T cells. Conclusion Together, these results validate the X‐mouse model and establish its potential to preclinically evaluate the therapeutic efficacy of immune‐based therapies.