Visual contrast sensitivity is associated with community structure integrity in cognitively unimpaired older adults: the Brain Networks and Mobility (B-NET) Study.

Older adults with impairment in contrast sensitivity (CS), the ability to visually perceive differences in light and dark, are more likely to demonstrate limitations in mobility function, but the mechanisms underlying this relationship are poorly understood. We sought to determine if functional brain networks important to visual processing and mobility may help elucidate possible neural correlates of this relationship. This cross-sectional analysis utilized functional MRI both at rest and during a motor imagery (MI) task in 192 community-dwelling, cognitively-unimpaired older adults ≥ 70 years of age from the Brain Networks and Mobility study (B-NET). Brain networks were partitioned into network communities, groups of regions that are more interconnected with each other than the rest of the brain, the spatial consistency of the communities for multiple brain subnetworks was assessed. Lower baseline binocular CS was significantly associated with degraded sensorimotor network (SMN) community structure at rest. During the MI task, lower binocular CS was significantly associated with degraded community structure in both the visual (VN) and default mode network (DMN). These findings may suggest shared neural pathways for visual and mobility dysfunction that could be targeted in future studies.

Causes, outcomes and diagnosis of acute breathlessness hospital admissions in Malawi: protocol for a multicentre prospective cohort study.

Background: Hospital admission due to breathlessness carries a significant burden to patients and healthcare systems, particularly impacting people in low-income countries. Prompt appropriate treatment is vital to improve outcomes, but this relies on accurate diagnostic tests which are of limited availability in resource-constrained settings. We will provide an accurate description of acute breathlessness presentations in a multicentre prospective cohort study in Malawi, a low resource setting in Southern Africa, and explore approaches to strengthen diagnostic capacity. Objectives: Primary objective: Delineate between causes of breathlessness among adults admitted to hospital in Malawi and report disease prevalence. Secondary objectives : Determine patient outcomes, including mortality and hospital readmission 90 days after admission; determine the diagnostic accuracy of biomarkers to differentiate between heart failure and respiratory infections (such as pneumonia) including brain natriuretic peptides, procalcitonin and C-reactive protein. Methods: This is a prospective longitudinal cohort study of adults (≥18 years) admitted to hospital with breathlessness across two hospitals: 1) Queen Elizabeth Central Hospital, Blantyre, Malawi; 2) Chiradzulu District Hospital, Chiradzulu, Malawi. Patients will be consecutively recruited within 24 hours of emergency presentation and followed-up until 90 days from hospital admission. We will conduct enhanced diagnostic tests with robust quality assurance and quality control to determine estimates of disease pathology. Diagnostic case definitions were selected following a systematic literature search. Discussion: This study will provide detailed epidemiological description of adult hospital admissions due to breathlessness in low-income settings, which is currently poorly understood. We will delineate between causes using established case definitions and conduct nested diagnostic evaluation. The results have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve both patient care and outcomes.

BACKGROUND: People admitted to hospital with symptoms of breathlessness are often severely ill and need quick, accurate assessment to facilitate timely initiation of appropriate treatments. In low resource settings, such as Malawi, limited access to diagnostic equipment impedes patient assessment. Failure to identify and treat the underlying diagnosis may lead to preventable death. AIMS: This cohort study aims to delineate between common, treatable causes of breathlessness among adult patients admitted to hospital in Malawi and measure survival. We will also evaluate the performance of blood markers to diagnose and differentiate between conditions. The results will help us develop context-appropriate diagnostic and treatment algorithms based on resources available in the health system Methods in brief: We will recruit adult patients who present to hospital with breathlessness in a central national referral hospital (Queen Elizabeth Central Hospital, Blantyre), and a district hospital (Chiradzulu District Hospital, Chiradzulu). We will conduct enhanced diagnostic tests to determine causes of breathlessness against internationally accepted diagnostic guidelines. Patients will be followed up throughout their hospital admission and after discharge, until 90 days. INTERPRETATION: This study aligns with World Health Assembly resolutions on 'Strengthening diagnostics capacity' and on 'Integrated emergency, critical and operative care for universal health coverage and protection from health emergencies'. The results of this study will have the potential to facilitate development of interventions targeted to strengthen diagnostic capacity, enable prompt and appropriate treatment, and ultimately improve care and outcomes for acutely unwell patients.

Performance of a Tic Screening Tool (MOVeIT) in Comparison to Expert Clinician Assessment in a Developmental-Behavioral Pediatrics Clinic Sample.

Youth with intellectual and developmental disabilities typically have higher rates of tics and stereotypies compared to children with otherwise typical development. Differentiating between these two pediatric movement disorders can be challenging due to overlapping clinical features, but is relevant due to distinct treatment modalities. The current study evaluated sensitivity and specificity of a tic screening measure, the Motor or Vocal Inventory of Tics (MOVeIT) in a pediatric sample enriched for stereotypy and tics. Children (n=199, age 2-15 years old) receiving care in a developmental-behavioral pediatrics clinic underwent a gold-standard diagnostic assessment by a tic expert; these evaluations were compared to the MOVeIT. The MOVeIT demonstrated good sensitivity (89.8%) and relatively lower specificity (57.1%) compared to tic expert for detecting tics in the overall sample. Specificity of the MOVeIT to identify tics improved to 75% when excluding children with co-occurring stereotypy. For children with tics and co-occurring stereotypy, sensitivity remained high (91.9%) but specificity was low (39.1%). The area under the curve (AUC) value to detect tics on the MOVeIT compared to the tic expert gold standard was significantly higher for children without stereotypy (AUC=85.7%) than those with stereotypy (AUC=64.3%, p <0.01). Overall, the ability to detect tics was better in those without co-occurring stereotypy symptoms. Further work is needed to establish the utility of the MOVeIT in populations where there is a high likelihood of co-occurring tics and stereotypy and in general population settings. Accurate distinction between tics and stereotypy will guide choices for intervention and anticipatory guidance for families.

Femoral head decentration on hip MRI: comparison between imaging planes, methods of contrast administration, and hip deformities.

OBJECTIVES: To compare the prevalence of femoral head decentration (FHD) on different MR imaging planes in patients undergoing direct/indirect hip MR arthrography (MRA) with asymptomatic controls and to evaluate its association with osseous deformities. METHODS: IRB-approved retrospective single-center study of symptomatic hips undergoing direct or indirect hip MRA at 3 T. Asymptomatic participants underwent non-contrast hip MRI at 3 T. FHD was defined as a continuous fluid layer between the acetabulum and femoral head and assessed on axial, sagittal and radial images. The association of intra-articular/intra-venous contrast agents and the prevalence of FHD was evaluated. The association of FHD with osseous deformities and joint damage was assessed using multiple logistic regression analysis. RESULTS: Three-hundred ninety-four patients (447 hips, mean age 31 ± 9 years, 247 females) were included and compared to 43 asymptomatic controls (43 hips, mean age 31 ± 6 years, 26 females). FHD was most prevalent on radial images and more frequent in symptomatic hips (30% versus 2%, p < 0.001). FHD prevalence was not associated with the presence/absence of intra-articular contrast agents (30% versus 22%, OR = 1.5 (95% CI 0.9-2.5), p = 0.125). FHD was associated with hip dysplasia (OR = 6.1 (3.3-11.1), p < 0.001), excessive femoral torsion (OR = 3.0 (1.3-6.8), p = 0.010), and severe cartilage damage (OR = 3.6 (2.0-6.7), p < 0.001). CONCLUSION: While rare in asymptomatic patients, femoral head decentration in symptomatic patients is associated with osseous deformities predisposing to hip instability, as well as with extensive cartilage damage. CRITICAL RELEVANCE STATEMENT: Decentration of the femoral head on radial MRA may be interpreted as a sign of hip instability in symptomatic hips without extensive cartilage defects. Its presence could unmask hip instability and yield promise in surgical decision-making. KEY POINTS: The best method of identifying femoral head decentration is radial MRI. The presence/absence of intra-articular contrast is not associated with femoral head decentration. Femoral head decentration is associated with hip deformities predisposing to hip instability.

Internet-based Surveillance Systems and Infectious Diseases Prediction: An Updated Review of the Last 10 Years and Lessons from the COVID-19 Pandemic.

The last decade has seen major advances and growth in internet-based surveillance for infectious diseases through advanced computational capacity, growing adoption of smart devices, increased availability of Artificial Intelligence (AI), alongside environmental pressures including climate and land use change contributing to increased threat and spread of pandemics and emerging infectious diseases. With the increasing burden of infectious diseases and the COVID-19 pandemic, the need for developing novel technologies and integrating internet-based data approaches to improving infectious disease surveillance is greater than ever. In this systematic review, we searched the scientific literature for research on internet-based or digital surveillance for influenza, dengue fever and COVID-19 from 2013 to 2023. We have provided an overview of recent internet-based surveillance research for emerging infectious diseases (EID), describing changes in the digital landscape, with recommendations for future research directed at public health policymakers, healthcare providers, and government health departments to enhance traditional surveillance for detecting, monitoring, reporting, and responding to influenza, dengue, and COVID-19.

Low Reducing Potentials Enabled by CaF2-Supported Graphene Electrodes in High Impedance Solutions.

We report electrochemical measurements using in situ Raman spectroscopy at graphene/D2O interfaces under extremely low applied potentials. Here, the hydrophobic and catalytically inert nature of graphene and the insulating nature of the deionized (DI) water enables potentials as low as Vapplied = -7 V vs Ag/AgCl to be applied without exceeding 200 µA/cm2 of current density. At higher currents, bubble formation (i.e., hydrogen evolution reaction) prohibits reliable spectra from being obtained from the electrode surface. Using CaF2 as the supporting substrate enables significantly lower reducing potentials to be reached compared to glass substrates, likely due to trapped charge and impurities in the glass substrate. G band Raman spectra taken under various applied electrochemical potentials exhibit a linear relationship between the G band shift (ΔωG) and the applied potential, with blueshifts as high as ΔωG = 18 cm-1. These large Raman shifts indicate a large change in the Fermi level of ΔEF = -0.43 eV for graphene electrodes in contact with water, favoring reduction half-reactions. Based on the solution resistance measurement, there is a VIR = 3.1 V voltage drop across the solution for D2O (when the applied potential was Vapplied = -7 V vs Ag/AgCl) and the effective reducing potential on the working electrode is Veffective = -3.9 V vs Ag/AgCl. We have also tested these graphene electrodes in ionic liquids [DEME][TFSI], which are limited to applied potentials above Vapplied = -2.7 V vs Ag/AgCl and a corresponding shift in the Fermi level ΔEF = -0.32 eV, indicating that pure water can provide a more robust electrolyte for reaching low reducing potentials than ionic liquids.

Tofacitinib Does Not Impair Sperm Quality in Men With Ulcerative Colitis.

We demonstrate that tofacitinib does not adversely affect semen quality or sex hormones in male patients. These first postmarketing data for tofacitinib and semen quality are reassuring. Our study raises no safety concerns, though larger studies are needed to confirm our findings.

RSV and rhinovirus increase pneumococcal carriage acquisition and density, whereas nasal inflammation is associated with bacterial shedding.

Epidemiological studies report the impact of co-infection with pneumococcus and respiratory viruses upon disease rates and outcomes, but their effect on pneumococcal carriage acquisition and bacterial load is scarcely described. Here, we assess this by combining natural viral infection with controlled human pneumococcal infection in 581 healthy adults screened for upper respiratory tract viral infection before intranasal pneumococcal challenge. Across all adults, respiratory syncytial virus (RSV) and rhinovirus asymptomatic infection confer a substantial increase in secondary infection with pneumococcus. RSV also has a major impact on pneumococcal density up to 9 days post challenge. We also study rates and kinetics of bacterial shedding through the nose and oral route in a subset. High levels of pneumococcal colonization density and nasal inflammation are strongly correlated with increased odds of nasal shedding as opposed to cough shedding. Protection against respiratory viral infections and control of pneumococcal density may contribute to preventing pneumococcal disease and reducing bacterial spread.

Ultralow Power In-Sensor Neuronal Computing with Oscillatory Retinal Neurons for Frequency-Multiplexed, Parallel Machine Vision.

In-sensor and near-sensor computing architectures enable multiply accumulate operations to be carried out directly at the point of sensing. In-sensor architectures offer dramatic power and speed improvements over traditional von Neumann architectures by eliminating multiple analog-to-digital conversions, data storage, and data movement operations. Current in-sensor processing approaches rely on tunable sensors or additional weighting elements to perform linear functions such as multiply accumulate operations as the sensor acquires data. This work implements in-sensor computing with an oscillatory retinal neuron device that converts incident optical signals into voltage oscillations. A computing scheme is introduced based on the frequency shift of coupled oscillators that enables parallel, frequency multiplexed, nonlinear operations on the inputs. An experimentally implemented 3 × 3 focal plane array of coupled neurons shows that functions approximating edge detection, thresholding, and segmentation occur in parallel. An example of inference on handwritten digits from the MNIST database is also experimentally demonstrated with a 3 × 3 array of coupled neurons feeding into a single hidden layer neural network, approximating a liquid-state machine. Finally, the equivalent energy consumption to carry out image processing operations, including peripherals such as the Fourier transform circuits, is projected to be <20 fJ/OP, possibly reaching as low as 15 aJ/OP.

Comparison of Effectiveness and Safety of Microwave Ablation of Colorectal Liver Metastases Adjacent to the Diaphragm versus Non-adjacent.

PURPOSE: To assess compare the efficacy effectiveness and safety of percutaneous microwave ablation (MWA) for subdiaphragmatic versus non-subdiaphragmatic colorectal liver metastasis (CLM). MATERIALS AND METHODS: This is a retrospective analysis of a prospectively created microwave ablation (MWA) database, from two prospective clinical trials for CLM patients treated in a single-tertiary center from 2012-2023. Subdiaphragmatic CLM was defined as a tumor located <1 cm from the diaphragm. Minimal Ablation Margin (MM) was calculated with 3D software using the post-ablation contrast enhanced CT. Adverse events were assessed with SIR classification for 6 months. RESULTS: 209 CLMs underwent 191 MWA sessions in 143 patients. Mean tumor diameter was 1.52±0.53 cm. 83/209(39.7%) CLMs were subdiaphragmatic. There was no difference in local tumor progression-free survival (LTPFS) between subdiaphragmatic and non-subdiaphragmatic CLMs (HR:0.65,95%CI:0.37-1.16, p=0.15). MM of 5-10 mm, and >10 mm was documented in 49.3% vs 46.8%, (p=0.83) and in 21.6% vs12.6% (p=0.16) for subdiaphragmatic and non-subdiaphragmatic CLMs.12-month LTPFS was similar between groups (HR:0.65,95%CI:0.37-1.16, p=0.15) without LTP for MM >10mm. There were 3 grade IV adverse events: one diaphragmatic perforation, one liver abscess and one biloma. Pneumothorax was associated with subdiaphragmatic location (p<0.001) and transpulmonary approach (p<0.001). Median hospital stay was 2 days (IQR: 1-3) for patients necessitating thoracostomy (n=20, 9.6%) compared to 1 day for those that did not (IQR: 1-8) without long-term sequelae. CONCLUSION: MWA of subdiaphragmatic CLM is effective and safe, without difference in success and 12-month LTPFS. Pneumothorax was associated with subdiaphragmatic location and thoracostomy that resulted in longer hospitalization without long-term sequelae.

APPROACH e-PROM system: a user-centered development and evaluation of an electronic patient-reported outcomes measurement system for management of coronary artery disease.

BACKGROUND: Coronary artery disease (CAD) confers increased risks of premature mortality, non-fatal morbidity, and significant impairment in functional status and health-related quality of life. Routine administration of electronic patient-reported outcome measures (PROMs) and its real time delivery to care providers is known to have the potential to inform routine cardiac care and to improve quality of care and patient outcomes. This study describes a user-centered development and evaluation of the Alberta Provincial Project for Outcomes Assessment (APPROACH) electronic Patient Reported Outcomes Measurement (e-PROM) system. This e-PROM system is an electronic system for the administration of PROMs to patients with CAD and the delivery of the summarized information to their care providers to facilitate patient-physician communication and shared decision-making. This electronic platform was designed to be accessible via web-based and hand-held devices. Heuristic and user acceptance evaluation were conducted with patients and attending care providers. RESULTS: The APPROACH e-PROM system was co-developed with patients and care providers, research investigators, informaticians and information technology experts. Five PROMs were selected for inclusion in the online platform after consultations with patient partners, care providers, and PROMs experts: the Seattle Angina Questionnaire, Patient Health Questionnaire, EuroQOL, and Medical Outcomes Study Social Support Survey, and Self-Care of Coronary Heart Disease Inventory. The heuristic evaluation was completed by four design experts who examined the usability of the prototype interfaces. User acceptance testing was completed with 13 patients and 10 cardiologists who evaluated prototype user interfaces of the e-PROM system. CONCLUSION: Both patients and physicians found the APPROACH e-PROM system to be easy to use, understandable, and acceptable. The APPROACH e-PROM system provides a user-informed electronic platform designed to incorporate PROMs into the delivery of individualized cardiac care for persons with CAD.

Clinical, Imaging, and Technical Factors Associated with Successful Genomic Profiling of Bone Biopsy Tissue in Prostate Cancer.

BACKGROUND AND OBJECTIVE: The source of tissue for genomic profiling of metastatic castration-resistant prostate cancer (mCRPC) is often limited to osseous metastases. To guide patient management, metastatic site selection and the technique for targeted bone biopsies are critical for identifying deleterious gene mutations. Our objective was to identify key parameters associated with successful large-panel DNA sequencing. METHODS: We analyzed parameters for 243 men with progressing mCRPC who underwent 269 bone biopsies for genomic profiling between 2014 and 2018. Univariate and multivariate analyses were performed for clinical, imaging (bone scan; fluorodeoxyglucose [FDG] positron emission tomography [PET]; computed tomography [CT]; magnetic resonance imaging), and technical (biopsy site, number of samples, needle gauge) features associated with successful genomic profiling. KEY FINDINGS AND LIMITATIONS: Overall, 159 of 269 biopsies (59%) generated sufficient tumor material for a genomic profile. Seventy (26%) of the failures were histopathologically negative for mCRPC and 40 (15%) had insufficient tumor for genomic profiling. Of 199 mCRPC samples submitted for molecular testing, 159 (80%) yielded a genomic profile. On univariate analysis, PSA, serum acid phosphatase, number of biopsy samples, FDG PET positivity, CT attenuation, and CT morphology were significantly associated with genomic profiling success. On multivariate analysis, higher FDG maximum standardized uptake value (odds ratio [OR] 7.51, 95% confidence interval [CI] 3.01-18.78; p < 0.001), higher number of biopsy samples (OR 4.73, 95% CI 1.49-15.02; p = 0.008), and lower mean CT attenuation (OR 0.4, 95% CI 0.18-0.89; p = 0.025) were significantly associated with sequencing success. CONCLUSIONS AND CLINICAL IMPLICATIONS: In patients with mCRPC, bone biopsies from sites with metabolic activity and lower CT attenuation are associated with higher success rates for genomic profiling via a large-panel DNA sequencing platform. PATIENT SUMMARY: We identified factors associated with successful genetic testing of bone tissue for patients with metastatic prostate cancer. Our findings may help in guiding the right scan technique and biopsy site for personalized treatment planning.

Resiliency among older adults receiving lung cancer treatment (ROAR-LCT): A novel supportive care intervention for older adults with advanced lung cancer.

INTRODUCTION: Novel supportive care interventions designed for an aging population with lung cancer are urgently needed. We aimed to determine the feasibility of a novel supportive care physical therapy (PT) plus progressive muscle relaxation (PMR) intervention delivered to older adults with advanced lung cancer in the United States (US). MATERIALS AND METHODS: This clinical trial, Resiliency Among Older Adults Receiving Lung Cancer Treatment (ROAR-LCT: NCT04229381), recruited adults aged ≥60 years with unresectable stage III/IV non-small cell (NSCLC) or small cell lung cancer (SCLC) receiving cancer treatment at The James Thoracic Oncology Center (planned enrollment, N = 20). There were no exclusion criteria pertaining to performance status, laboratory values, prior cancer diagnoses, comorbidities, or brain metastases. Participants were evaluated by PT and psychology and given an exercise pedaler, resistance bands, a relaxation voice recording, and instructions at study initiation. Participants were evaluated in-person by PTs and psychologists at the start and end of the 12-session intervention, with the intervening sessions conducted via virtual health. Participants completed self-reported measures of functional status, symptoms, and mood longitudinally with the following instruments: EQ-5D-5L, Patient Health Questionnaire-9, and General Anxiety Disorder-7. PT assessments included the Short Physical Performance Battery (SPPB) and the two-minute walk test. Feasibility was defined as at least 60% of participants completing at least 70% of all intervention sessions. Optional gut microbiome samples and activity monitoring data (ActiGraph®) were also collected. RESULTS: The ROAR-LCT study concluded after consenting 22 patients. Among the 22 consented, 18 (81.8%) started the intervention; 11 participants (61.1%) completed at least 70% of all study sessions. All participants with SCLC completed the intervention. Reasons for withdrawal included progression of disease or hospitalization. The majority (88.9%) of patients who started were able to complete at least one virtual health session. Participants' functional status, SPPB, depression, and anxiety scores were stable from pre- to post-intervention. Participants who withdrew had worse baseline scores across domains. Seven microbiome and six ActiGraph® samples were collected. DISCUSSION: This is one of the first PT + PMR supportive care interventions using virtual health among older adults with advanced lung cancer to achieve feasibility in the US.

Ataxia telangiectasia-mutated rs56009889 and risk of common cancers.

A polymorphic variant in the ataxia telangiectasia-mutated (ATM) gene, rs56009889, was recently associated with an increased risk of lung cancer. We studied the role of this variant in the etiology of other cancers. Data from three population-based case-control studies of colon, breast, and lung cancer were used. Participants in these studies (4517 cases, 3383 controls) underwent a genome-wide association study using 500K Illumina OncoArray. The frequency of the AG/AA genotypes differed between Ashkenazi (4.6%) and Sephardi (0.2%) Jews (P < 0.001). AG/AA frequency was significantly higher in Ashkenazi lung cancer (11.9%) than in controls (2.8%) [adjusted odds ratio (OR) = 5.4]. Females had a higher risk than males (OR = 12.8 versus 3.5). The adjusted OR for colorectal cancer was 1.40 [95% confidence interval (CI) = 1.01-2.0, P = 0.045] and for breast cancer was 1.43 (95% CI = 1.01-2.04, P = 0.046). Never-smokers variant carriers were at higher risk of lung and colon, but not breast, cancer. Cases with the AG/AA genotype had lower mean age at diagnosis, but this difference was significant only for breast cancer (-3.2 years, P = 0.007). No associations were observed with overall survival. Among the breast cancer subjects, the OR for having triple-negative tumors was 0.45 for AG/AA versus GG genotype (95% CI = 0.2-0.9, P = 0.02). We confirm the strong association between ATM rs56009889 and lung cancer risk in Ashkenazi Jews and report a mild association with the risk of breast cancer and colorectal cancer.

Inherited Germline Variants in Urinary Tract Cancer: A Multicenter Whole-Exome Sequencing Analysis and Correlation With Clinical Features and Tumor Genomics.

PURPOSE: This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). METHODS: Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. RESULTS: Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease (P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without (P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. CONCLUSION: Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Description and Cross-Sectional Analyses of 25,880 Adults and Children in the UK National Registry of Rare Kidney Diseases Cohort.

Introduction: The National Registry of Rare Kidney Diseases (RaDaR) collects data from people living with rare kidney diseases across the UK, and is the world's largest, rare kidney disease registry. We present the clinical demographics and renal function of 25,880 prevalent patients and sought evidence of bias in recruitment to RaDaR. Methods: RaDaR is linked with the UK Renal Registry (UKRR, with which all UK patients receiving kidney replacement therapy [KRT] are registered). We assessed ethnicity and socioeconomic status in the following: (i) prevalent RaDaR patients receiving KRT compared with patients with eligible rare disease diagnoses receiving KRT in the UKRR, (ii) patients recruited to RaDaR compared with all eligible unrecruited patients at 2 renal centers, and (iii) the age-stratified ethnicity distribution of RaDaR patients with autosomal dominant polycystic kidney disease (ADPKD) was compared to that of the English census. Results: We found evidence of disparities in ethnicity and social deprivation in recruitment to RaDaR; however, these were not consistent across comparisons. Compared with either adults recruited to RaDaR or the English population, children recruited to RaDaR were more likely to be of Asian ethnicity (17.3% vs. 7.5%, P-value < 0.0001) and live in more socially deprived areas (30.3% vs. 17.3% in the most deprived Index of Multiple Deprivation (IMD) quintile, P-value < 0.0001). Conclusion: We observed no evidence of systematic biases in recruitment of patients into RaDaR; however, the data provide empirical evidence of negative economic and social consequences (across all ethnicities) experienced by families with children affected by rare kidney diseases.

Dosing and Safety Profile of Aficamten in Symptomatic Obstructive Hypertrophic Cardiomyopathy: Results From SEQUOIA-HCM.

BACKGROUND: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). METHODS AND RESULTS: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5-20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site-interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8-24), and washout (weeks 24-28), and included major adverse cardiac events, new-onset atrial fibrillation, implantable cardioverter-defibrillator discharges, LVEF <50%, and treatment-emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5-, 10-, 15-, and 20-mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by -0.9% (95% CI, -1.3 to -0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per-protocol dose reduction for site-interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment-emergent adverse events were similar between treatment groups, including atrial fibrillation. CONCLUSIONS: A site-based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA-HCM. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05186818.

Safety and efficacy of thermal ablation of adrenal metastases secondary to lung cancer.

OBJECTIVES: Assess safety and efficacy of thermal ablation for adrenal metastases (AM) secondary to non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: This retrospective study included patients with NSCLC AM treated with thermal ablation between 2/2010-11/2021. Local tumor progression free survival (LTPFS) and overall survival (OS) were calculated using Kaplan-Meier method. Adverse events were graded using Common Terminology Criteria for Adverse Events v5. RESULTS: Seven patients (mean age ± SD, 63.9 ± 12.5 years; 6 males) with seven AM were treated in eight sessions. Retreatment was performed in one patient with residual disease. Five sessions were with microwave ablation and 3 with radiofrequency ablation. Mean tumor size was 20.1 ± 7.0 mm. Median number of ablation probes used was 1 (range, 1-5), with a median of 3 activations (range, 1-3), and average ablation time of 14.4 ± 15.0 minutes. Response based on RECIST v 1.1 or PERCIST criteria revealed stable disease in 1 tumor, progression of disease in 3 tumors (one was re-ablated), and partial response in 3 tumors. Median LTPFS was not reached (NR) [95 % CI: 1- NR]. Median OS was 47.97 months (95 % CI: 18.63- NR). Intraprocedural hypertension (blood pressure ≥180 mmHg) occurred during 5/8 (62.5 %) sessions and intraoperative tachycardia occurred during 2/8 (25 %) sessions. Complications within one month of ablation occurred in 3/8 (37.5 %) sessions: grade 2 pneumothorax, grade 1 hematuria, and grade 2 adrenal insufficiency. CONCLUSIONS: In this small series, thermal ablation for NSCLC AM resulted in prolonged local control and OS with no major complications.

Risk factors for severe outcomes of coronavirus disease 2019 through the waves of the pandemic: Comparing patients with and without solid organ transplantation.

BACKGROUND: While coronavirus disease 2019 (COVID-19) is no longer a public health emergency, certain patients remain at risk of severe outcomes. To better understand changing risk profiles, we studied the risk factors for patients with and without solid organ transplantation (SOT) through the various waves of the pandemic. METHODS: Using the National COVID Cohort Collaborative we studied a cohort of adult patients testing positive for COVID-19 between January 1, 2020, and May 2, 2022. We separated the data into waves of COVID-19 as defined by the Centers for Disease Control. In our primary outcome, we used multivariable survival analysis to look at various risk factors for hospitalization in those with and without SOT. RESULTS: A total of 3,570,032 patients were captured. We found an overall risk attenuation of adverse COVID-19-associated outcomes over time. In both non-SOT and SOT populations, diabetes, chronic kidney disease, and congestive heart failure were risk factors for hospitalization. For SOT specifically, longer time periods between transplant and COVID-19 were protective and age was a risk factor. Notably, asthma was not a risk factor for major adverse renal cardiovascular events, hospitalization, or mortality in either group. CONCLUSIONS: Our study provides a longitudinal view of the risks associated with adverse COVID-related outcomes amongst SOT and non-SOT patients, and how these risk factors evolved over time. Our work will help inform providers and policymakers to better target high-risk patients.

Knowing what to know: Implications of the choice of prior distribution on the behavior of adaptive design optimization.

Adaptive design optimization (ADO) is a state-of-the-art technique for experimental design (Cavagnaro et al., 2010). ADO dynamically identifies stimuli that, in expectation, yield the most information about a hypothetical construct of interest (e.g., parameters of a cognitive model). To calculate this expectation, ADO leverages the modeler's existing knowledge, specified in the form of a prior distribution. Informative priors align with the distribution of the focal construct in the participant population. This alignment is assumed by ADO's internal assessment of expected information gain. If the prior is instead misinformative, i.e., does not align with the participant population, ADO's estimates of expected information gain could be inaccurate. In many cases, the true distribution that characterizes the participant population is unknown, and experimenters rely on heuristics in their choice of prior and without an understanding of how this choice affects ADO's behavior. Our work introduces a mathematical framework that facilitates investigation of the consequences of the choice of prior distribution on the efficiency of experiments designed using ADO. Through theoretical and empirical results, we show that, in the context of prior misinformation, measures of expected information gain are distinct from the correctness of the corresponding inference. Through a series of simulation experiments, we show that, in the case of parameter estimation, ADO nevertheless outperforms other design methods. Conversely, in the case of model selection, misinformative priors can lead inference to favor the wrong model, and rather than mitigating this pitfall, ADO exacerbates it.