Optimization of 1H-MRS methods for large-volume acquisition of low-concentration downfield resonances at 3 T and 7 T.

PURPOSE: This goal of this study was to optimize spectrally selective 1H-MRS methods for large-volume acquisition of low-concentration metabolites with downfield resonances at 7 T and 3 T, with particular attention paid to detection of nicotinamide adenine dinucleotide (NAD+) and tryptophan. METHODS: Spectrally selective excitation was used to avoid magnetization-transfer effects with water, and various sinc pulses were compared with a band-selective, uniform response, pure-phase (E-BURP) pulse. Localization using a single-slice selective pulse was compared with voxel-based localization that used three orthogonal refocusing pulses, and low bandwidth refocusing pulses were used to take advantage of the chemical shift displacement of water. A technique for water sideband removal was added, and a method of coil channel combination for large volumes was introduced. RESULTS: Proposed methods were compared qualitatively with previously reported techniques at 7 T. Sinc pulses resulted in reduced water signal excitation and improved spectral quality, with a symmetric, low bandwidth-time product pulse performing best. Single-slice localization allowed shorter TEs with large volumes, enhancing signal, whereas low-bandwidth slice-selective localization greatly reduced the observed water signal. Gradient cycling helped remove water sidebands, and frequency aligning and pruning individual channels narrowed spectral linewidths. High-quality brain spectra of NAD+ and tryptophan are shown in 4 subjects at 3 T. CONCLUSION: Improved spectral quality with higher downfield signal, shorter TE, lower nuisance signal, reduced artifacts, and narrower peaks was realized at 7 T. These methodological improvements allowed for previously unachievable detection of NAD+ and tryptophan in human brain at 3 T in under 5 min.

Anti-infectivity efficacy and pharmacokinetics of WHO recommended single low-dose primaquine in children with acute Plasmodium falciparum in Burkina Faso: study protocol.

BACKGROUND: Primaquine (PQ) has activity against mature P. falciparum gametocytes and proven transmission blocking efficacy (TBE) between humans and mosquitoes. WHO formerly recommended a single transmission blocking dose of 0.75 mg/kg but this was little used. Then in 2012, faced with the emergence of artemisinin-resistant P. falciparum (ARPf) in SE Asia, the WHO recommended a lower dose of 0.25 mg/kg to be added to artemisinin-based combination therapy in falciparum-infected patients in low transmission areas. This dose was considered safe in glucose-6-phosphate dehydrogenase deficiency (G6PDd) and not requiring G6PD testing. Subsequent single low-dose primaquine (SLDPQ) studies have demonstrated safety in different G6PD variants. Dosing remains challenging in children under the age of 5 because of the paucity of PQ pharmacokinetic (PK) data. We plan to assess the anti-infectivity efficacy of SLDPQ using an allometrically scaled, weight-based regimen, with a target dose of 0.25 mg/kg, in children with acute uncomplicated falciparum malaria. METHODS: This study is an open label, randomised 1:1, phase IIb study to assess TBE, tolerability, pharmacokinetics and acceptability of artesunate pyronaridine (ASPYR) administered alone or combined with SLDPQ in 56 Burkinabe children aged ≥ 6 months- < 5 years, with uncomplicated P. falciparum and a haemoglobin (Hb) concentration of ≥ 5 g/dL. We will assess TBE, using direct membrane feeding assays (DMFA), and further investigate PQ pharmacokinetics, adverse events, Hb dynamics, G6PD, sickle cells, thalassaemia and cytochrome 2D6 (CYP2D6) status, acceptability of flavoured PQ [CAST-ClinSearch Acceptability Score Test®], and the population's knowledge, attitude and practices on malaria. EXPECTED RESULTS AND DISCUSSION: We expect children to accept tablets, confirm the TBE and gametocytocidal effects of SLDPQ and then construct a PK infectivity model (including age, sex, baseline Hb, G6PD and CYP2D6 status) to define the dose response TBE relationship that may lead to fine tuning our SLDPQ regimen. Our study will complement others that have examined factors associated with Hb dynamics and PQ PK. It will provide much needed, high-quality evidence of SLDPQ in sick African children and provide reassurance that SLDPQ should be used as a strategy against emerging ARPf in Africa. TRIAL REGISTRATION: ISRCTN16297951. Registered on September 26, 2021.

Protein-truncating variant in APOL3 increases chronic kidney disease risk in epistasis with APOL1 risk alleles.

BACKGROUND: Two coding alleles within the APOL1 gene, G1 and G2, found almost exclusively in individuals genetically similar to West African populations, contribute substantially to the pathogenesis of chronic kidney disease (CKD). The APOL gene cluster on chromosome 22 contains a total of six APOL genes that have arisen as a result of gene duplication. METHODS: Using a genome-first approach in the Penn Medicine Biobank, we identified 62 protein-altering variants in the six APOL genes with a minor allele frequency > 0.1% in a population of participants genetically similar to African reference populations and performed population-specific phenome-wide association studies. RESULTS: We identified rs1108978, a stop-gain variant in APOL3 (p.Q58*), to be significantly associated with increased CKD risk, even after conditioning on APOL1 G1/G2 carrier status. These findings were replicated in the Veterans Affairs Million Veteran Program and the All of Us Research Program. APOL3 p.Q58* was also significantly associated with a number of quantitative traits linked to CKD including decreased kidney volume. This truncating variant contributed the most risk for CKD in patients monoallelic for APOL1 G1/G2, suggesting an epistatic interaction and a potential protective effect of wild-type APOL3 against APOL1-induced kidney disease. CONCLUSION: This study demonstrates the utility of targeting population-specific variants in a genome-first approach, even in the context of well-studied gene-disease relationships. FUNDING: National Heart, Lung, and Blood Institute (F30HL172382, R01HL169378, R01HL169458), Doris Duke Foundation (grant 2023-0224), National Institute of Biomedical Imaging and Bioengineering (P41EB029460), National Center for Advancing Translational Sciences (UL1-TR-001878).

Infratubercle Anterior Closing Wedge Osteotomy Corrects Sagittal Alignment without Affecting Coronal Alignment or Patellar Height.

Background: Excessive posterior tibial slope (PTS) has been associated with a higher risk of graft failure after anterior cruciate ligament reconstruction (ACLR). Although anterior closing wedge osteotomy (ACWO) can reduce the PTS, it may also change the coronal alignment and patellar height. Purpose: To elucidate the radiological outcomes after infratubercle ACWO, specifically to evaluate its influence on perioperative changes in patellar height. Methods: Patients who underwent infratubercle ACWO with combined ACLR with a minimum follow-up of 3 months were included. Surgery was indicated when the PTS was greater than 12°. Radiological evaluation included measurements of the hip-knee-ankle angle (HKA), PTS, femoral patellar height index (FPHI), and Caton-Deschamps index (CDI) preoperatively and 3 months postoperatively. Patellar height was classified as patella baja, normal, or alta based on CDI values. Knee recurvatum was measured preoperatively and at final follow-up. Results: A total of 21 patients with a mean age of 21.6 ± 3.0 years were included. Although HKA did not significantly change, significant corrections were achieved in the PTS from 14.5° ± 1.6° to 5.7° ± 1.0° (p < 0.001). No significant change in FPHI was found (preoperative: 1.33 ± 0.11 vs postoperative: 1.30 ± 0.09). Patellar height categories showed no significant differences pre- and postoperatively, while three patients (14.3%) changed their patellar height category (all moved up one category). Knee recurvatum increased significantly from 4.9° ± 2.9° preoperatively to 7.8° ± 3.1° at the final follow-up (p < 0.001). Conclusions: Precise sagittal correction was achieved after infratubercle ACWO without altering the coronal alignment and patella height. Level of Evidence: IV, Case series.

Prevalence and associated risk factors of stunting, wasting/thinness, and underweight among primary school children in Kandahar City, Afghanistan: a cross-sectional analytical study.

BACKGROUND: Undernutrition, which includes stunting, wasting, and underweight, is a global problem, especially among children of low- and middle-income countries. To our knowledge, this study is first of its type from Afghanistan. Its main objectives were to estimate the prevalence and associated risk factors of stunting, wasting/thinness, and underweight among urban primary school children in Kandahar city of Afghanistan. METHODS: This school-based cross-sectional study was conducted among 1205 primary school children aged 6-12 years during a period of six months (October 2022-March 2023). Anthropometric measurements and other data were collected from all the participants. Data were analyzed by using descriptive statistics, Chi square test (using crude odds ratio or COR), and multivariate logistic regression (using adjusted odds ratio or AOR). RESULTS: Among the 1205 enrolled government school students, 47.4%, 19.5%, and 25.6% had stunting, wasting/thinness, and underweight, respectively. Statistically significant factors associated with stunting were age group 6-9 years (AOR 1.3, 95% CI 1.1-1.7), being girl (AOR 2.3, 95% CI 1.8-3.0), poverty (AOR 2.2, 95% CI 1.5-3.2), large family (AOR 3.0, 95% CI 2.4-3.9), illiterate mother (AOR 1.6, 95% CI 1.0-2.6), jobless head of the family (AOR 3.3, 95% CI 2.3-4.8), and skipping breakfasts (AOR 1.7, 95% CI 1.2-2.3). Main factor associated with wasting/thinness were age group 6-9 years (AOR 30.5, 95% CI 11.8-78.7), skipping breakfasts (AOR 22.9, 95% CI 13.9-37.8), and history of sickness during the past two weeks (AOR 17.0, 95% CI 6.6-43.8). Also, main factors associated with underweight were age group 6-9 years (AOR 2.6, 95% CI 1.6-4.1), skipping breakfasts (AOR 2.6, 95% CI 1.8-3.6), and poor sanitation (AOR 1.9, 95% CI 1.1-3.2). CONCLUSIONS: Stunting, wasting/thinness, and underweight are highly prevalent among primary school children (both girls and boys) in Kandahar city. It is recommended that local government (Afghanistan Ministry of Education and Ministry of Public Health) with the help of international organizations and donor agencies should implement comprehensive school-based feeding programs especially for girls. Health and nutrition education programs should be conducted with emphasis on nutrition of children aged 6-9 years as well as importance of healthy breakfast and good sanitation.

Changes in Incidence of Cirrhotic and Noncirrhotic Hepatocellular Carcinoma in the United States.

INTRODUCTION: Hepatocellular carcinoma (HCC) occurs most often in a background of cirrhosis. Patients with noncirrhotic HCC represent a distinct population, which has been characterized in single-center studies, but has not been fully evaluated on a population level in the United States. MATERIALS AND METHODS: HCC cases from Surveillance, Epidemiology, and End-Results diagnosed between 2000 and 2020 were categorized as cirrhotic or noncirrhotic. Clinical and pathologic factors, age-adjusted incidence rates (AAIR), and the overall HCC-specific survival were compared between groups. RESULTS: There were 18,592 patients with cirrhosis (80.4%) and 4545 without (19.6%). AAIRs for noncirrhotic HCC remained relatively unchanged from 2010 to 2020, with a mean incidence of 0.35 per 100,000. The AAIR for cirrhotic HCC declined from 1.59 to 0.85 per 100,000 during the same period. Patients with cirrhosis were younger (median age 62 versus 65 y, P < 0.001). Patients without cirrhosis, compared to those with cirrhosis, were less likely to have elevated alpha fetoprotein (53.9% versus 62.0%, P < 0.001), had larger tumors (median tumor size 5.0 versus 3.5 cm, P < 0.001), presented more frequently with localized disease (59.9% versus 55.8%, P < 0.001), were more likely to undergo surgery (OR 2.21, 95% CI 2.07-2.36), and had better HCC-specific survival (median 40 versus 27 mo, P < 0.001). CONCLUSIONS: The relative increase in the proportion of noncirrhotic HCC in the Untied States may be due to a decline in the incidence of cirrhotic HCC. Patients with noncirrhotic HCC have larger tumors, are more likely to undergo surgical resection, and have improved cancer-specific survival.

Effect of wearable activity trackers on physical activity in children and adolescents: a systematic review and meta-analysis.

BACKGROUND: Physical inactivity in children and adolescents has become a pressing public health concern. Wearable activity trackers can allow self-monitoring of physical activity behaviour and promote autonomous motivation for exercise. However, the effects of wearable trackers on physical activity in young populations remain uncertain. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, SPORTDiscus, and Web of Science for publications from database inception up to Aug 30, 2023, without restrictions on language. Studies were eligible if they were randomised controlled trials or clustered randomised controlled trials that examined the use of wearable activity trackers to promote physical activity, reduce sedentary behaviours, or promote overall health in participants with a mean age of 19 years or younger, with no restrictions on health condition or study settings. Studies were excluded if children or adolescents were not the primary intervention cohort, or wearable activity trackers were not worn on users' bodies to objectively track users' physical activity levels. Two independent reviewers (WWA and FR) assessed eligibility of studies and contacted authors of studies if more information was needed to assess eligibility. We also searched reference lists from relevant systematic reviews and meta-analyses. Systematic review software Covidence was used for study screening and data extraction. Study characteristics including study setting, participant characteristics, intervention characteristics, comparator, and outcome measurements were extracted from eligible studies. The two primary outcomes were objectively measured daily steps and moderate-to-vigorous physical activity. We used a random-effects model with Hartung-Knapp adjustments to calculate standardised mean differences. Between-study heterogeneity was examined using Higgins I2 and Cochran Q statistic. Publication bias was assessed using Egger's regression test. This systematic review was registered with PROSPERO, CRD42023397248. FINDINGS: We identified 9619 studies from our database research and 174 studies from searching relevant systematic reviews and meta-analyses, of which 105 were subjected to full text screening. We included 21 eligible studies, involving 3676 children and adolescents (1618 [44%] were female and 2058 [56%] were male, mean age was 13·7 years [SD 2·7]) in our systematic review and meta-analysis. Ten studies were included in the estimation of the effect of wearable activity trackers on objectively measured daily steps and 11 were included for objectively measured moderate-to-vigorous physical activity. Compared with controls, we found a significant increase in objectively measured daily steps (standardised mean difference 0·37 [95% CI 0·09 to 0·65; p=0·013]; Q 47·60 [p<0·0001]; I2 72·7% [95% CI 53·4 to 84·0]), but not for moderate-to-vigorous physical activity (-0·08 [-0·18 to 0·02; p=0·11]; Q 10·26 [p=0·74]; I2 0·0% [0·0 to 53·6]). INTERPRETATION: Wearable activity trackers might increase daily steps in young cohorts of various health statuses, but not moderate-to-vigorous physical activity, highlighting the potential of wearable trackers for motivating physical activity in children and adolescents. More rigorously designed trials that minimise missing data are warranted to validate our positive findings on steps and to explore possible long-term effects. FUNDING: The Hong Kong University Grants Committee and Seed Fund for Basic Research of the University of Hong Kong.

Obesity paradox in patients with reduced ejection fraction eligible for device implantation - an observational study.

AIMS: Patients with obesity have an overall higher cardiovascular risk, at the same time obesity could be associated with a better outcome in a certain subgroup of patients, a phenomenon known as the obesity paradox. Data are scarce in candidates for cardiac resynchronization therapy (CRT). We aimed to investigate the association between body mass index (BMI) and all-cause mortality in patients eligible for CRT. METHODS: Altogether 1,585 patients underwent cardiac resynchronization therapy between 2000-2020 and were categorized based on their BMI, 459 (29%) patients with normal weight (BMI < 25 kg/m2), 641 (40%) patients with overweight (BMI 25- < 30 kg/m2) and 485 (31%) with obesity (BMI ≥ 30 kg/m2). The primary endpoint was all-cause mortality, heart transplantation, and left ventricular assist device implantation. We assessed periprocedural complications and 6-month echocardiographic response. RESULTS: Normal-weight patients were older compared to patients with overweight or obesity (70 years vs. 69 years vs. 68 years; P 2 26% vs. BMI 25- < 30 kg/m2 37% vs. BMI ≥ 30 kg/m2 48%; P 2 71% vs. BMI 25- < 30 kg/m2 74% vs. BMI ≥ 30 kg/m2 82%; P 2 group, 61% in the BMI 25- < 30 kg/m2 group and 58% in the BMI ≥ 30 kg/m2 group (log-rank P2 25% vs. BMI 25- < 30 kg/m2 28% vs. BMI ≥ 30 kg/m2 26%; P = 0.48). Left ventricular ejection fraction improved significantly in all patient groups (BMI < 25 kg/m2 median ∆ $$ \Delta $$ -LVEF 7% vs. BMI 25- < 30 kg/m2 median ∆ $$ \Delta $$ -LVEF 7.5% vs. BMI ≥ 30 kg/m2 median ∆ $$ \Delta $$ -LVEF 6%; P < 0.0001) with a similar proportion of developing reverse remodeling (BMI < 25 kg/m2 58% vs. BMI 25- < 30 kg/m2 61% vs. BMI ≥ 30 kg/m2 57%; P = 0.48); P = 0.75). CONCLUSIONS: The obesity paradox was present in our HF cohort at long-term, patients underwent CRT implantation with obesity and free of comorbidities showed mortality benefit compared to normal weight patients. Patients with obesity showed similar echocardiographic response and safety outcomes compared to normal weight patients.

NRG Oncology White Paper on the Relative Biological Effectiveness in Proton Therapy.

This position paper, led by the NRG Oncology Particle Therapy Work Group, focuses on the concept of relative biologic effect (RBE) in clinical proton therapy (PT), with the goal of providing recommendations for the next-generation clinical trials with PT on the best practice of investigating and using RBE, which could deviate from the current standard proton RBE value of 1.1 relative to photons. In part 1, current clinical utilization and practice are reviewed, giving the context and history of RBE. Evidence for variation in RBE is presented along with the concept of linear energy transfer (LET). The intertwined nature of tumor radiobiology, normal tissue constraints, and treatment planning with LET and RBE considerations is then reviewed. Part 2 summarizes current and past clinical data and then suggests the next steps to explore and employ tools for improved dynamic models for RBE. In part 3, approaches and methods for the next generation of prospective clinical trials are explored, with the goal of optimizing RBE to be both more reflective of clinical reality and also deployable in trials to allow clinical validation and interpatient comparisons. These concepts provide the foundation for personalized biologic treatments reviewed in part 4. Finally, we conclude with a summary including short- and long-term scientific focus points for clinical PT. The practicalities and capacity to use RBE in treatment planning are reviewed and considered with more biological data in hand. The intermediate step of LET optimization is summarized and proposed as a potential bridge to the ultimate goal of case-specific RBE planning that can be achieved as a hypothesis-generating tool in near-term proton trials.

Acute nicotinamide riboside supplementation increases human cerebral NAD+ levels in vivo.

PURPOSE: The purpose of this study was to determine the effect of acute nicotinamide riboside (NR) supplementation on cerebral nicotinamide adenine dinucleotide (NAD+) levels in the human brain in vivo by means of downfield proton MRS (DF 1H MRS). METHODS: DF 1H MRS was performed on 10 healthy volunteers in a 7.0 T MRI scanner with spectrally selective excitation and spatially selective localization to determine cerebral NAD+ levels on two back-to-back days: once after an overnight fast (baseline) and once 4 h after oral ingestion of nicotinamide riboside (900 mg). Additionally, two more baseline scans were performed following the same paradigm to assess test-retest reliability of the NAD+ levels in the absence of NR. RESULTS: NR supplementation increased mean NAD+ concentration compared to the baseline (0.458 ± 0.053 vs. 0.392 ± 0.058 mM; p < 0.001). The additional two baseline scans demonstrated no differences in mean NAD+ concentrations (0.425 ± 0.118 vs. 0.405 ± 0.082 mM; p = 0.45), and no difference from the first baseline scan (F(2, 16) = 0.907; p = 0.424). CONCLUSION: These preliminary results confirm that acute NR supplementation increases cerebral NAD+ levels in healthy human volunteers and shows the promise of DF 1H MRS utility for robust detection of NAD+ in humans in vivo.

Bioequivalence of a new coated 15 mg primaquine formulation for malaria elimination.

BACKGROUND: With only one 15 mg primaquine tablet registered by a stringent regulatory authority and marketed, more quality-assured primaquine is needed to meet the demands of malaria elimination. METHODS: A classic, two sequence, crossover study, with a 10-day wash out period, of 15 mg of IPCA-produced test primaquine tablets and 15 mg of Sanofi reference primaquine tablets was conducted. Healthy volunteers, aged 18-45 years, without glucose-6-phosphate dehydrogenase deficiency, a baseline haemoglobin ≥ 11 g/dL, creatinine clearance ≥ 70 mL/min/1.73 ms, and body mass index of 18.5-30 kg/m2 were randomized to either test or reference primaquine, administered on an empty stomach with 240 mL of water. Plasma primaquine and carboxyprimaquine concentrations were measured at baseline, then 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2.0, 2.333, 2.667, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 8.0, 10.0, 12.0, 16.0, 24.0, 36.0, 48.0 and 72.0 h by liquid chromatography coupled to tandem mass spectrometry. Primaquine pharmacokinetic profiles were evaluated by non-compartmental analysis and bioequivalence concluded if the 90% confidence intervals (CI) of geometric mean (GM) ratios of test vs. reference formulation for the peak concentrations (Cmax) and area under the drug concentration-time (AUC0-t) were within 80.00 to 125.00%. RESULTS: 47 of 50 volunteers, median age 33 years, completed both dosing rounds and were included in the bioequivalence analysis. For primaquine, GM Cmax values for test and reference formulations were 62.12 vs. 59.63 ng/mL, resulting in a GM ratio (90% CI) of 104.17% (96.92-111.96%); the corresponding GM AUC0-t values were 596.56 vs. 564.09 ngxh/mL, for a GM ratio of 105.76% (99.76-112.08%). Intra-subject coefficient of variation was 20.99% for Cmax and 16.83% for AUC0-t. Median clearances and volumes of distribution were similar between the test and reference products: 24.6 vs. 25.2 L/h, 189.4 vs. 191.0 L, whilst the median half-lives were the same, 5.2 h. CONCLUSION: IPCA primaquine was bioequivalent to the Sanofi primaquine. This opens the door to prequalification, registration in malaria endemic countries, and programmatic use for malaria elimination. Trial registration The trial registration reference is ISRCTN 54640699.

Variability Between Full-Length Lateral Radiographs and Standard Short Knee Radiographs When Evaluating Posterior Tibial Slope in Revision ACL Patients.

Background: Increased posterior tibial slope (PTS) has been identified as a risk factor for failure after anterior cruciate ligament (ACL) reconstruction. Correction of PTS may improve outcomes after revision ACL reconstruction. There are conflicting reports demonstrating the measurement of the PTS on standard short knee (SSK) radiographs versus full-length lateral (FLL) radiographs including the entire tibia. Purpose/Hypothesis: To compare PTS measurements between SSK and FLL radiographs in patients who failed primary ACL reconstruction. It was hypothesized that there would be high variability between the SSK and FLL radiographic measurements. Study Design: Cohort study (diagnosis); Level of evidence, 2. Methods: The medial and lateral PTS were measured on the SSK and FLL radiographs of 33 patients with failed primary ACL reconstructions. All measurements were performed by 2 trained independent observers (A.A.M., J.S.), and inter- and intraobserver reliability were calculated using the intraclass correlation coefficient (ICC). Measurements recorded by the observer with the higher intraobserver ICC were used for comparison of the PTS on SSK versus FLL radiographs. Results: Both the inter- and the intraobserver reliability values of the PTS measurements were excellent. There was a significant difference in mean PTS on the medial plateau as measured on the SSK and FLL radiographs (11.2°± 5.3° vs 12.5°± 4.6°; P = .03), with the FLL radiographs demonstrating higher PTS. There was also a significant difference in the mean PTS on the lateral plateau as measured on SSK versus FLL radiographs (10.7°± 4.3° vs 12.2°± 4°, respectively; P = .01), with the FLL radiographs demonstrating higher PTS. Notably, 66.67% of the absolute measurements for PTS on the medial plateau differed by ≥2°, with variability as high as 8.5°. Conclusion: Results indicated that FLL and SSK radiographs are not interchangeable measurements for PTS associated with failed ACL reconstruction. Because FLL radiographs demonstrate less variability than SSK radiographs, we recommend obtaining them to evaluate these complex patients.

Diversity and molecular characterization of insect-specific flaviviruses in mosquitoes (Diptera: Culicidae) collected in central and northern Argentina.

The genus Flavivirus comprises approximately 80 different viruses. Phylogenetic relationships among its members indicate a clear ecological separation between those viruses transmitted by mosquitoes, ticks, with no known vector, and insect-specific Flaviviruses. The diversity and phylogenetic relationships among insect-specific flaviviruses circulating in the central and northern regions of Argentina were studied by performing molecular detection and characterization of the NS5 protein gene in mosquitoes collected in Córdoba, Chaco and Tucumán provinces. Overall, 68 out of 1776 pools were positive. CxFV, KRV and CFAV circulate in the 3 studied provinces. Several mosquito species (Aedes aegypti, Culex bidens, Cx. dolosus, Cx. interfor, Cx. quinquefasciatus, Cx. saltanensis, Haemagogus spegazzini) were found infected. A wide circulation of CxFV was observed in the central-northern region of Argentina. CxFV strains detected in our study clustered with strains circulating in Santa Fe and Buenos Aires provinces (Argentina), and other countries such as Indonesia, Mexico, Uganda and Taiwan. The presence of these viruses in mosquitoes could play an important role from the public health perspective, because it has been shown that previous CxFV infection can increase or block the infection of the mosquito by other pathogenic flaviviruses.

The Benefits of Technology for Engaging Aging Adults: Findings From the PRISM 2.0 Trial.

Background and Objectives: Technology has potential for providing support for aging adults. This study evaluated the Personal Reminder Information and Social Management 2.0 (PRISM 2.0) software, in terms of enhancing social engagement and quality of life, and decreasing loneliness among older adults. Research Design and Methods: The randomized field trial conducted in diverse living contexts (rural locations, senior housing, and assisted living communities [ALC]). Two hundred and forty-five adults, aged 64 to 99 years, were randomly assigned to the PRISM 2.0 (integrated software system designed for aging through an iterative design process) or a Standard Tablet (without PRISM) Control condition, where participants received the same amount of contact and training as those in the PRISM 2.0 condition. Primary outcomes included measures of loneliness, social support, social connectedness, and quality of life. Secondary outcomes included measures of social isolation, mobile device proficiency, and technology readiness. Data were collected at baseline and 6 and 9 months postrandomization. This article focuses on the 6-month outcomes due to coronavirus disease 2019-related data challenges at 9 months. Results: Contrary to our hypothesis, participants in rural locations and senior housing in both conditions reported less loneliness and social isolation, and greater social support and quality of life at 6 months, and an increase in mobile device proficiency. Participants in the ALCs in both conditions also evidenced an increase in mobile device proficiency. Improvements in quality of life and health-related quality of life were associated with decreases in loneliness. Discussion and Implications: This study provides compelling evidence about the benefits of technology for older adults in terms of enhancing social outcomes and quality of life. However, the findings also underscore that for technology applications to be successful, they need to be adapted to the abilities and needs of the user group and instructional support needs to be provided. Clinical Trials Registration #: NCT03116399.

Melanoma Deaths by Thickness: Most Melanoma Deaths Are Not Attributable to Thin Melanomas.

INTRODUCTION: Previous population-based studies have reported that the majority of melanoma mortality is related to patients with thin (≤1 mm Breslow thickness) melanomas. The aim of the present study was to evaluate the relative proportion of melanoma-specific deaths across all stages of melanoma at diagnosis over the past 20 y in the United States. METHODS: A review of all cutaneous melanoma cases in the US Surveillance, Epidemiology, and End Results registry from 2004 to 2020 was performed. Breslow thickness was categorized as thin (≤1.0 mm), intermediate (>1-4 mm), or thick (>4 mm). All-cause deaths and melanoma-specific deaths were compared across tumor thickness and stage groups at diagnosis. Survival analysis was performed with nonmelanoma deaths considered as a competing risk to estimate the cumulative incidence of melanoma-specific death. RESULTS: Most melanoma deaths occurred in patients who initially presented with local disease (53%) compared to regional (36%) or distant (11%) disease (P < 0.001). However, most (66%) of the melanoma-specific deaths in patients who presented with localized disease were in those with intermediate or thick (i.e., Breslow thickness >1.0 mm) primary tumors compared to those with thin melanomas (34%). The cumulative incidence of melanoma-specific death at 10 y in patients with localized thin melanomas at the time of diagnosis was 2.6% (95% confidence intervals 2.5%-2.7%). CONCLUSIONS: The public health burden in terms of melanoma-specific mortality is related to patients with tumors >1 mm Breslow thickness, many of whom have regional and distant metastatic disease at the time of diagnosis, not patients with thin melanomas.

CT imaging-derived phenotypes for abdominal muscle and their association with age and sex in a medical biobank.

The study of muscle mass as an imaging-derived phenotype (IDP) may yield new insights into determining the normal and pathologic variations in muscle mass in the population. This can be done by determining 3D abdominal muscle mass from 12 distinct abdominal muscle regions and groups using computed tomography (CT) in a racially diverse medical biobank. To develop a fully automatic technique for assessment of CT abdominal muscle IDPs and preliminarily determine abdominal muscle IDP variations with age and sex in a clinically and racially diverse medical biobank. This retrospective study was conducted using the Penn Medicine BioBank (PMBB), a research protocol that recruits adult participants during outpatient visits at hospitals in the Penn Medicine network. We developed a deep residual U-Net (ResUNet) to segment 12 abdominal muscle groups including the left and right psoas, quadratus lumborum, erector spinae, gluteus medius, rectus abdominis, and lateral abdominals. 110 CT studies were randomly selected for training, validation, and testing. 44 of the 110 CT studies were selected to enrich the dataset with representative cases of intra-abdominal and abdominal wall pathology. The studies were divided into non-overlapping training, validation and testing sets. Model performance was evaluated using the Sørensen-Dice coefficient. Volumes of individual muscle groups were plotted to distribution curves. To investigate associations between muscle IDPs, age, and sex, deep learning model segmentations were performed on a larger abdominal CT dataset from PMBB consisting of 295 studies. Multivariable models were used to determine relationships between muscle mass, age and sex. The model's performance (Dice scores) on the test data was the following: psoas: 0.85 ± 0.12, quadratus lumborum: 0.72 ± 0.14, erector spinae: 0.92 ± 0.07, gluteus medius: 0.90 ± 0.08, rectus abdominis: 0.85 ± 0.08, lateral abdominals: 0.85 ± 0.09. The average Dice score across all muscle groups was 0.86 ± 0.11. Average total muscle mass for females was 2041 ± 560.7 g with a high of 2256 ± 560.1 g (41-50 year old cohort) and a change of - 0.96 g/year, declining to an average mass of 1579 ± 408.8 g (81-100 year old cohort). Average total muscle mass for males was 3086 ± 769.1 g with a high of 3385 ± 819.3 g (51-60 year old cohort) and a change of - 1.73 g/year, declining to an average mass of 2629 ± 536.7 g (81-100 year old cohort). Quadratus lumborum was most highly correlated with age for both sexes (correlation coefficient of - 0.5). Gluteus medius mass in females was positively correlated with age with a coefficient of 0.22. These preliminary findings show that our CNN can automate detailed abdominal muscle volume measurement. Unlike prior efforts, this technique provides 3D muscle segmentations of individual muscles. This technique will dramatically impact sarcopenia diagnosis and research, elucidating its clinical and public health implications. Our results suggest a peak age range for muscle mass and an expected rate of decline, both of which vary between genders. Future goals are to investigate genetic variants for sarcopenia and malnutrition, while describing genotype-phenotype associations of muscle mass in healthy humans using imaging-derived phenotypes. It is feasible to obtain 3D abdominal muscle IDPs with high accuracy from patients in a medical biobank using fully automated machine learning methods. Abdominal muscle IDPs showed significant variations in lean mass by age and sex. In the future, this tool can be leveraged to perform a genome-wide association study across the medical biobank and determine genetic variants associated with early or accelerated muscle wasting.

Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study.

AIMS: Despite clear guideline recommendations for initiating four drug classes in all patients with heart failure (HF) with reduced ejection fraction (HFrEF) and the availability of rapid titration schemes, information on real-world implementation lags behind. Closely following the 2021 ESC HF guidelines and 2023 focused update, the TITRATE-HF study started to prospectively investigate the use, sequencing, and titration of guideline-directed medical therapy (GDMT) in HF patients, including the identification of implementation barriers. METHODS AND RESULTS: TITRATE-HF is an ongoing long-term HF registry conducted in the Netherlands. Overall, 4288 patients from 48 hospitals were included. Among these patients, 1732 presented with de novo, 2240 with chronic, and 316 with worsening HF. The median age was 71 years (interquartile range [IQR] 63-78), 29% were female, and median ejection fraction was 35% (IQR 25-40). In total, 44% of chronic and worsening HFrEF patients were prescribed quadruple therapy. However, only 1% of HFrEF patients achieved target dose for all drug classes. In addition, quadruple therapy was more often prescribed to patients treated in a dedicated HF outpatient clinic as compared to a general cardiology outpatient clinic. In each GDMT drug class, 19% to 36% of non-use in HFrEF patients was related to side-effects, intolerances, or contraindications. In the de novo HF cohort, 49% of patients already used one or more GDMT drug classes for other indications than HF. CONCLUSION: This first analysis of the TITRATE-HF study reports relatively high use of GDMT in a contemporary HF cohort, while still showing room for improvement regarding quadruple therapy. Importantly, the use and dose of GDMT were suboptimal, with the reasons often remaining unclear. This underscores the urgency for further optimization of GDMT and implementation strategies within HF management.

Three-dimensional aortic geometry: clinical correlates, prognostic value and genetic architecture.

Aortic structure and function impact cardiovascular health through multiple mechanisms. Aortic structural degeneration increases left ventricular afterload, pulse pressure and promotes target organ damage. Despite the impact of aortic structure on cardiovascular health, aortic 3D-geometry has yet to be comprehensively assessed. Using a convolutional neural network (U-Net) combined with morphological operations, we quantified aortic 3D-geometric phenotypes (AGPs) from 53,612 participants in the UK Biobank and 8,066 participants in the Penn Medicine Biobank. AGPs reflective of structural aortic degeneration, characterized by arch unfolding, descending aortic lengthening and luminal dilation exhibited cross-sectional associations with hypertension and cardiac diseases, and were predictive for new-onset hypertension, heart failure, cardiomyopathy, and atrial fibrillation. We identified 237 novel genetic loci associated with 3D-AGPs. Fibrillin-2 gene polymorphisms were identified as key determinants of aortic arch-3D structure. Mendelian randomization identified putative causal effects of aortic geometry on the risk of chronic kidney disease and stroke.

Optimization of 1H MR spectroscopy methods for large volume acquisition of low concentration downfield resonances at 3T and 7T.

Purpose: This goal of this study was to optimize spectrally selective 1H MRS methods for large volume acquisition of low concentration metabolites with downfield resonances at 7T and 3T, with particular attention paid to detection of nicotinamide adenine dinucleotide (NAD+) and tryptophan. Methods: Spectrally selective excitation was used to avoid magnetization transfer effects with water, and various sinc pulses were compared to a pure-phase E-BURP pulse. Localization using a single slice selective pulse was compared to voxel-based localization that used three orthogonal refocusing pulses, and low bandwidth refocusing pulses were used to take advantage of the chemical shift displacement of water. A technique for water sideband removal was added, and a method of coil channel combination for large volumes was introduced. Results: Proposed methods were compared qualitatively to previously-reported techniques at 7T. Sinc pulses resulted in reduced water signal excitation and improved spectral quality, with a symmetric, low bandwidth-time product pulse performing best. Single slice localization allowed shorter TEs with large volumes, enhancing signal, while low bandwidth slice selective localization greatly reduced the observed water signal. Gradient cycling helped remove water sidebands, and frequency aligning and pruning individual channels narrowed spectral linewidths. High quality brain spectra of NAD+ and tryptophan are shown in four subjects at 3T. Conclusion: Improved spectral quality with higher downfield signal, shorter TE, lower nuisance signal, reduced artifacts, and narrower peaks was realized at 7T. These methodological improvements allowed for previously unachievable detection of NAD+ and tryptophan in human brain at 3T in under five minutes.