The Neighborhood Environment and Handgrip Strength: Longitudinal Findings from the Health and Retirement Study.

BACKGROUND: Muscle strength, as measured by handgrip strength (HGS), is associated with physical function and mortality. Yet, the environmental context that influences muscle strength is poorly understood. We evaluated built and social neighborhood characteristics and their association with muscle strength over time. METHODS: Using data from the Health and Retirement Study (2006-2018), linear mixed models assessed how 11 built and social neighborhood variables were associated with baseline levels and changes in HGS over time. RESULTS: Among the 20,045 respondents (mean age = 63 years, SD = 9.7) with up to 4 HGS measures, 8,455 were men and 11,590 were women. Among men, residing in a neighborhood with a 10% increment higher score on neighborhood disadvantage was associated with ~1 kg lower HGS at baseline (B = -0.96 kg, 95% CI = -1.39, -0.53). Similarly, each 1-point increment on the physical disorder scale was associated with a -0.39 kg lower (95% CI = -0.65, -0.12) baseline HGS value. Among women, each 10% increment in neighborhood disadvantage was associated with a 0.29 kg lower HGS at baseline (B = -0.29 kg for each 10% increment, 95% CI = -0.46, -0.13). Each 1-unit increment in the number of neighborhood gyms at baseline was associated with a 0.50 kg lower HGS (B = -0.50, 95% CI = -0.76, -0.23). Each 1-point increment in physical disorder was associated with a -0.12 kg lower (95% CI = -0.24, -0.00) baseline HGS value. None of the neighborhood features were associated with HGS rate of change. CONCLUSIONS: Findings suggest that residing in neighborhoods with greater disadvantage and physical disorder may pose challenges for HGS among middle aged adults as they enter into older adulthood.

Genetic associations with neural reward responsivity to food cues in children.

Objective: To test associations of candidate obesity-related single nucleotide polymorphisms (SNPs) and obesity polygenic risk scores (PRS) with neural reward reactivity to food cues. Methods: After consuming a pre-load meal, 9-12-year-old children completed a functional magnetic resonance imaging (fMRI) paradigm with exposure to food and non-food commercials. Genetic exposures included FTO rs9939609, MC4R rs571312, and a pediatric-specific obesity PRS. A targeted region-of-interest (ROI) analysis for 7 bilateral reward regions and a whole-brain analysis were conducted. Independent associations between each genetic factor and reward responsivity to food cues in each ROI were evaluated using linear models. Results: Analyses included 151 children (M = 10.9 years). Each FTO rs9939609 obesity risk allele was related to a higher food-cue-related response in the right lateral hypothalamus after controlling for covariates including the current BMI Z-score (p < 0.01), however, the association did not remain significant after applying the multiple testing correction. MC4R rs571312 and the PRS were not related to heightened food-cue-related reward responsivity in any examined regions. The whole-brain analysis did not identify additional regions of food-cue-related response related to the examined genetic factors. Conclusion: Children genetically at risk for obesity, as indicated by the FTO genotype, may be predisposed to higher food-cue-related reward responsivity in the lateral hypothalamus in the sated state, which, in turn, could contribute to overconsumption. Clinical trial registration: https://clinicaltrials.gov/study/NCT03766191, identifier NCT03766191.

Comparing Deprivation vs Vulnerability Index Performance Using Medicare Beneficiary Surgical Outcomes.

Importance: Health care researchers, professionals, payers, and policymakers are increasingly relying on publicly available composite indices of area-level socioeconomic deprivation to address health equity. Implications of index selection, however, are not well understood. Objective: To compare the performance of 2 frequently used deprivation indices using policy-relevant outcomes among Medicare beneficiaries undergoing 3 common surgical procedures. Design, Setting, and Participants: This cross-sectional study examined outcomes among Medicare beneficiaries (65 to 99 years old) undergoing 1 of 3 common surgical procedures (hip replacement, knee replacement, or coronary artery bypass grafting) between 2016 and 2019. Index discriminative performance was compared for beneficiaries residing in tracts with high- and low-deprivation levels (deciles) according to each index. Analyses were conducted between December 2022 and August 2023. Main Outcomes and Measures: Tract-level deprivation was operationalized using 2020 releases of the area deprivation index (ADI) and the social vulnerability index (SVI). Binary outcomes were unplanned surgery, 30-day readmissions, and 30-day mortality. Multivariable logistic regression models, stratified by each index, accounted for beneficiary and hospital characteristics. Results: A total of 2 433 603 Medicare beneficiaries (mean [SD] age, 73.8 [6.1] years; 1 412 968 female beneficiaries [58.1%]; 24 165 Asian [1.0%], 158 582 Black [6.5%], and 2 182 052 White [89.7%]) were included in analyses. According to both indices, beneficiaries residing in high-deprivation tracts had significantly greater adjusted odds of all outcomes for all procedures when compared with beneficiaries living in low-deprivation tracts. However, compared to ADI, SVI resulted in higher adjusted odds ratios (adjusted odds ratios, 1.17-1.31 for SVI vs 1.09-1.23 for ADI), significantly larger outcome rate differences (outcome rate difference, 0.07%-5.17% for SVI vs outcome rate difference, 0.05%-2.44% for ADI; 95% CIs excluded 0), and greater effect sizes (Cohen d, 0.076-0.546 for SVI vs 0.044-0.304 for ADI) for beneficiaries residing in high- vs low-deprivation tracts. Conclusions and Relevance: In this cross-sectional study of Medicare beneficiaries, SVI had significantly better discriminative performance-stratifying surgical outcomes over a wider range-than ADI for identifying and distinguishing between high- and low-deprivation tracts, as indexed by outcomes for common surgical procedures. Index selection requires careful consideration of index differences, index performance, and contextual factors surrounding use, especially when informing resource allocation and health care payment adjustment models to address health equity.

Participant Experiences from a Randomized Controlled Trial of Heated Yoga for Depression.

Despite decades of research on yoga and depression, subjective experiences of participants in these studies have rarely been reported, and never in individuals receiving heated yoga for depression. We examined patient-reported qualitative findings from an 8-week randomized controlled trial of heated yoga for depression. Eighty medically healthy participants with moderate-to-severe depression were randomized to 8 weeks of at least twice-weekly heated yoga classes, derived from Bikram yoga, or a waitlist control. Fifty-seven participants received a clinician-administered exit interview at intervention completion/study withdrawal. The exit interview assessed: (1) how participants felt immediately following the heated yoga sessions (acute effects), (2) what they liked or found helpful about heated yoga over the 8-week intervention (positive effects), and (3) what they disliked/did not find helpful over the 8-week intervention (negative effects). Qualitative data were analyzed using thematic analysis. Acute improvements in depressive symptoms (i.e., immediately following yoga) were the most commonly reported (n = 44, 77.2%), followed by overall positive effects on depressive symptoms (i.e., over the course of the 8-week intervention; n = 33, 57.9%), including improvements in sleep (n = 10, 17.5%), energy (n = 13, 22.8%), mood (n = 18, 31.6%), motivation (n = 2, 3.5%), and concentration/decision-making (n = 5, 8.8%). Overall negative effects (i.e., over the course of the 8-week intervention) included dislike of various aspects of the intervention (n = 19, 33.3%), such as instruction (n = 7, 12.3%), difficulty (n = 7, 12.3%), repetitiveness (n = 3, 5.3%), class length (n = 2, 3.5%), and boredom (n = 7, 12.3%). Most participants reported both overall positive and negative effects (n = 37, 64.9%). Of the rest, 19 (33.3%) reported only overall positive effects, and 1 (1.8%) reported only overall negative effects. Most participant experiences were positive. Negative effects were less common and primarily involved dislike of different aspects of the heated yoga. The findings support strong acceptability and subjective improvement in depressive symptoms in depressed individuals.

Younger and rural children are more likely to be hospitalized for SARS-CoV-2 infections.

PURPOSE: To identify characteristics of SARS-CoV-2 infection that are associated with hospitalization in children initially evaluated in a Pediatric Emergency Department (ED). METHODS: We identified cases of SARS-CoV-2 positive patients seen in the Arkansas Children's Hospital (ACH) ED or hospitalized between May 27, 2020, and April 28, 2022, using ICD-10 codes within the Pediatric Hospital Information System (PHIS) Database. We compared infection waves for differences in patient characteristics and used logistic regressions to examine which features led to a higher chance of hospitalization. FINDINGS: We included 681 pre-Delta cases, 673 Delta cases, and 970 Omicron cases. Almost 17% of patients were admitted to the hospital. Compared to Omicron-infected children, pre-Delta and Delta-infected children were twice as likely hospitalized (OR = 2.2 and 2.0, respectively; p<0.0001). Infants under one year were >3 times as likely to be hospitalized than children ages 5-14 years regardless of wave (OR = 3.42; 95%CI = 2.36-4.94). Rural children were almost three times as likely than urban children to be hospitalized across all waves (OR = 2.73; 95%CI = 1.97-3.78). Finally, those with a complex condition had nearly a 15-fold increase in odds of admission (OR = 14.6; 95%CI = 10.6-20.0). CONCLUSIONS: Children diagnosed during the pre-Delta or Delta waves were more likely to be hospitalized than those diagnosed during the Omicron wave. Younger and rural patients were more likely to be hospitalized regardless of the wave. We suspect lower vaccination rates and larger distances from medical care influenced higher hospitalization rates.

Evaluation of expanded 2-aminobenzothiazole library as inhibitors of a model histidine kinase and virulence suppressors in Pseudomonas aeruginosa.

Bacterial resistance to antibiotics is a rapidly increasing threat to human health. New strategies to combat resistant organisms are desperately needed. One potential avenue is targeting two-component systems, which are the main bacterial signal transduction pathways used to regulate development, metabolism, virulence, and antibiotic resistance. These systems consist of a homodimeric membrane-bound sensor histidine kinase, and a cognate effector, the response regulator. Histidine kinases play an essential role in the regulation of multiple virulence mechanisms including toxin production, immune evasion, and antibiotic resistance. Targeting virulence, as opposed to development of bactericidal compounds, could reduce evolutionary pressure for acquired resistance. Additionally, compounds targeting the highly conserved catalytic and adenosine triphosphate-binding (CA) domain have the potential to impair multiple two-component systems that regulate virulence in one or more pathogens. We conducted in vitro structure-activity relationship studies of 2-aminobenzothiazole-based inhibitors designed to target the CA domain. We found that these compounds, which inhibit the model histidine kinase, HK853 from Thermotoga maritima, have anti-virulence activities inPseudomonas aeruginosa, reducing motility phenotypes and toxin production associated with the pathogenic functions of this bacterium.

Controlling nano- and microfilament morphology by strategically placing chiral centers in the side chains of bent-core molecules.

Self-assembled lamellar nano- and microfilaments formed by select types of bent-core molecules are prime examples of the interplay between molecular conformation and morphological chirality. Here, we demonstrate how the strategic placement of chiral centers at C-1 and/or C-3 in the terminal alkyloxy side chains, largely based on a priori calculations of molecular conformation, leads to the predictable formation of increasingly complex nano- and microfilament morphologies. Adding to the previously described diversity of twisted and writhed filament types, we here demonstrate and explain the formation and coexistence of flat nanoribbons, nanocylinders, or nano- as well as microfilaments where the morphology spontaneously changes along the filament long axis. For some these more exotic types of filament morphology, helical multilayer filaments suddenly unwind to form flat nanoribbons that also twist again under preservation (not perversion) of the helical twist sense. Moreover, the morphologies formed by this series of molecules now allows us to demonstrate the complete transformation from flat multilayer ribbons over microfilaments and helical-wrapped nanocylinders to helical nanofilaments depending on the number and position of chiral centers in the aliphatic side chains.

Real-world six-month outcomes in patients switched to faricimab following partial response to anti-VEGF therapy for neovascular age-related macular degeneration and diabetic macular oedema.

BACKGROUND: Landmark studies reported on faricimab efficacy and safety predominantly in treatment naïve patients, but outcomes following switch from other anti-VEGF therapies are lacking. We evaluated patients switched to faricimab who had previously shown a partial response to other anti-VEGF injections for neovascular age-related macular degeneration (nAMD) and diabetic macular oedema (DMO). METHODS: Retrospective study at the Oxford Eye Hospital. Patients switched to faricimab from January to April 2023 with six months follow-up were identified via electronic medical records. RESULTS: A total of 116 patients (151 eyes) were included. In 88 patients with nAMD (107 eyes), mean visual acuity remained stable: 62±17 ETDRS letters at baseline; 62±18 at six months (p > 0.05). Central subfield thickness (CST) reduced from 294 ± 73 µm to 270 ± 53 µm (p < 0.05) at six months. Subretinal or intraretinal fluid was present in 102 eyes (95%) at baseline and 75 eyes (70%) at follow-up (p < 0.05). Pigment epithelial detachment height decreased from 233 ± 134 µm to 188 ± 147 µm (p < 0.05). Mean treatment interval increased by 1.7 weeks (p < 0.05) and was extended in 61 eyes (57%) at six months. In 28 patients with DMO (44 eyes), visual acuity remained stable: 69 ± 15 letters at baseline; 70±15 at six months (p > 0.05). CST reduced from 355 ± 87 µm to 317 ± 82 µm (p < 0.05). Mean treatment interval increased by 1.4 weeks (p < 0.05) and was extended in 21 eyes (46%) by six months. CONCLUSIONS: Switching to faricimab in treatment resistant eyes led to improved anatomical response and extended treatment interval in a significant proportion of patients. Ongoing review of real-world data will inform longer-term outcomes of safety and effectiveness.

Ventilation does not affect close-range transmission of influenza virus in a ferret playpen setup.

Sustained community spread of influenza viruses relies on efficient person-to-person transmission. Current experimental transmission systems do not mimic environmental conditions (e.g., air exchange rates, flow patterns), host behaviors, or exposure durations relevant to real-world settings. Therefore, results from these traditional systems may not be representative of influenza virus transmission in humans. To address this pitfall, we developed a close-range transmission setup that implements a play-based scenario and used it to investigate the impact of ventilation rates on transmission. In this setup, four immunologically naive recipient ferrets were exposed to a donor ferret infected with a genetically barcoded 2009 H1N1 virus (H1N1pdm09) for 4 h. The ferrets interacted in a shared space that included toys, similar to a childcare setting. Transmission efficiency was assessed under low and high ventilation, with air exchange rates of ~1.3 h-1 and 23 h-1, respectively. Transmission efficiencies observed in three independent replicate studies were similar between ventilation conditions. The presence of infectious virus or viral RNA on surfaces and in air throughout the exposure area was also not impacted by the ventilation rate. While high viral genetic diversity in donor ferret nasal washes was maintained during infection, recipient ferret nasal washes displayed low diversity, revealing a narrow transmission bottleneck regardless of ventilation rate. Examining the frequency and duration of ferret physical touches revealed no link between these interactions and a successful transmission event. Our findings indicate that exposures characterized by frequent, close-range interactions and the presence of fomites can overcome the benefits of increased ventilation.

Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.

BACKGROUND: CFAP410 (Cilia and Flagella Associated Protein 410) encodes a protein that has an important role in the development and function of cilia. In ophthalmology, pathogenic variants in CFAP410 have been described in association with cone rod dystrophy, retinitis pigmentosa, with or without macular staphyloma, or with systemic abnormalities such as skeletal dysplasia and amyotrophic lateral sclerosis. Herein, we report a consanguineous family with a novel homozygous CFAP410 c.335_346del variant with cone only degeneration and no systemic features. METHODS: A retrospective analysis of ophthalmic history, examination, retinal imaging, electrophysiology and microperimetry was performed as well as genetic testing with in silico pathogenicity predictions and a literature review. RESULTS: A systemically well 28-year-old female of Pakistani ethnicity with parental consanguinity and no relevant family history, presented with childhood-onset poor central vision and photophobia. Best-corrected visual acuity and colour vision were reduced (0.5 LogMAR, 6/17 Ishihara plates (right) and 0.6 LogMAR, 3/17 Ishihara plates (left). Fundus examination showed no pigmentary retinopathy, no macular staphyloma and autofluorescence was unremarkable. Optical coherence tomography showed subtle signs of intermittent disruption of the ellipsoid zone. Microperimetry demonstrated a reduction in central retinal sensitivity. Electrodiagnostic testing confirmed a reduction in cone-driven responses. Whole-genome sequencing identified an in-frame homozygous deletion of 12 base pairs at c.335_346del in CFAP410. CONCLUSIONS: The non-syndromic cone dystrophy phenotype reported herein expands the genotypic and phenotypic spectra of CFAP410-associated ciliopathies and highlights the need for light of potential future genetic therapies.

Payer Coverage Considerations for Alzheimer Disease Blood-Based Biomarker Tests.

This Viewpoint discusses proactively preparing to make informed payer coverage decisions to help address current disparities in Alzheimer disease diagnosis and treatment.

Changes in the lipidome are associated with immune activation and subclinical vascular disease in youth with HIV in Uganda.

This study examined the changes in the lipidome and associations with immune activation and cardiovascular disease markers in youth living with perinatally acquired HIV (YPHIV). The serum lipidome was measured in ART-treated YPHIV (n=100) and HIV- Ugandan children (n=98) Plasma markers of systemic inflammation, monocyte activation, gut integrity, T cell activation, as well as and common carotid artery intima-media thickness (IMT) and pulse wave velocity (PWV) were evaluated at baseline and 96 weeks. Overall, median age was 12 years,52% were females. Total cholesterol, LDL, and HDL were similar between the groups, however, the concentrations of ceramides, diacylglycerols, free fatty acids, lysophysophatidylcholines and phosphatidylcholines, were higher in YPHIV (P≤0.03). Increases in phosphatidylethanolamine (16:0 and 18:0) correlated with increases in sCD163, OxLDL, CRP, IFAB and PWV in PHIV (r≥0.3). YPHIV, successfully suppressed on ART, have elevated lipid species that are associated with CVD, specificallypalmitic acid (C16:0) and stearic acid (C18:0).

Gene Therapy for Achromatopsia.

Achromatopsia is the most common cone dysfunction syndrome, affecting 1 in 30,000 people. It is an autosomal recessive disorder with a heterogeneous genetic background with variants reported in CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, and ATF6. Up to 90% of achromatopsia patients harbour mutations in CNGA3 or CNB3, which encode for the alpha and beta subunits of the cone cyclic nucleotide-gated (CNG) channel in cone-specific phototransduction. The condition presents at birth or early infancy with poor visual acuity, nystagmus, photophobia, and colour vision loss in all axes. Multimodal retinal imaging has provided insightful information to characterise achromatopsia patients based on their genotype. There is no FDA-approved treatment for achromatopsia; however, studies have reported several preclinical gene therapies with anatomical and functional improvements reported in vivo. There are currently five gene therapy clinical trials registered for human patients at the phase I/II stage and for CNGA3 or CNGB3 causing achromatopsia. This review aims to discuss the genetics of achromatopsia, genotypic and phenotypic correlations in multimodal retinal imaging, and the developments and challenges in gene therapy clinical trials.

Proteinuria and albuminuria among a global primary CVD prevention cohort of PWH: prevalence and associated factors.

OBJECTIVES: To determine baseline prevalence of proteinuria and albuminuria among REPRIEVE participants and evaluate associated risk factors. DESIGN: Cross sectional analysis of a baseline sample of participants from the REPRIEVE Trial. METHODS: REPRIEVE is an international primary cardiovascular prevention RCT of pitavastatin calcium vs. placebo among PWH on antiretroviral therapy. A representative subset (2791 participants) had urine collected at study entry. Urine protein to creatinine ratios (uPCR) and albumin to creatinine ratios (uACR) were classified as normal, moderately increased and severely increased. These were dichotomized to Normal or Abnormal for log-binomial regression analysis. Demographic, cardiometabolic, and HIV-specific data were compared among those with normal versus abnormal results. RESULTS: Overall, median age 49 years, 41% female sex, 47% black or African American race, 36% had eGFR <90 mL/min/1.73 mm2. For uPCR, 27% had moderately or severely increased values. For uACR, 9% had moderately or severely increased values. In the fully adjusted model for proteinuria, female sex, older age, residence in sub-Saharan Africa or East Asia, lower BMI, lower CD4 cell count, and use of TDF were associated with abnormal values. In the fully adjusted model for albuminuria, a diagnosis of HTN was associated with abnormal values. CONCLUSIONS: Abnormal proteinuria and albuminuria remain common (27% and 9%) despite controlled HIV. Lower current CD4 count and TDF use were strongly associated with proteinuria. Certain modifiable comorbidities, including HTN and smoking, were associated with abnormal values. In PWH with preserved eGFR, urine measures identify subclinical kidney disease and afford the opportunity for intervention.

Springing into action: Comparing escape responses between bipedal and quadrupedal rodents.

Predation is a fundamental selective pressure on animal morphology, as morphology is directly linked with physical performance and evasion. Bipedal heteromyid rodents, which are characterized by unique morphological traits such as enlarged hindlimbs, appear to be more successful than sympatric quadrupedal rodents at escaping predators such as snakes and owls, but no studies have directly compared the escape performance of bipedal and quadrupedal rodents. We used simulated predator attacks to compare the evasive jumping ability of bipedal kangaroo rats (Dipodomys) to that of three quadrupedal rodent groups-pocket mice (Chaetodipus), woodrats (Neotoma), and ground squirrels (Otospermophilus). Jumping performance of pocket mice was remarkably similar to that of kangaroo rats, which may be driven by their shared anatomical features (such as enlarged hindlimb muscles) and facilitated by their relatively small body size. Woodrats and ground squirrels, in contrast, almost never jumped as a startle response, and they took longer to perform evasive escape maneuvers than the heteromyid species (kangaroo rats and pocket mice). Among the heteromyids, take-off velocity was the only jump performance metric that differed significantly between species. These results support the idea that bipedal body plans facilitate vertical leaping in larger-bodied rodents as a means of predator escape and that vertical leaping likely translates to better evasion success.