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Aldehydes are common constituents of natural and polluted atmospheres, and their gas-phase oxidation has recently been reported to yield highly oxygenated organic molecules (HOMs) that are key players in the formation of atmospheric aerosol. However, insights into the molecular-level mechanism of this oxidation reaction have been scarce. While OH initiated oxidation of small aldehydes, with two to five carbon atoms, under high-NOx conditions generally leads to fragmentation products, longer-chain aldehydes involving an initial non-aldehydic hydrogen abstraction can be a path to molecular functionalization and growth. In this work, we conduct a joint theoretical–experimental analysis of the autoxidation chain reaction of a common aldehyde, hexanal. We computationally study the initial steps of OH oxidation at the RHF-RCCSD(T)-F12a/VDZ-F12//ωB97X-D/aug-cc-pVTZ level and show that both aldehydic (on C1) and non-aldehydic (on C4) H-abstraction channels contribute to HOMs via autoxidation. The oxidation products predominantly form through the H abstraction from C1 and C4, followed by fast unimolecular 1,6 H-shifts with rate coefficients of 1.7×10-1 and 8.6×10-1 s−1, respectively. Experimental flow reactor measurements at variable reaction times show that hexanal oxidation products including HOM monomers up to C6H11O7 and accretion products C12H22O9−10 form within 3 s reaction time. Kinetic modeling simulations including atmospherically relevant precursor concentrations agree with the experimental results and the expected timescales. Finally, we estimate the hexanal HOM yields up to seven O atoms with mechanistic details through both C1 and C4 channels.

Introduction Despite the well-recognized risk poor maternal mental health poses to early child development, it is still rarely addressed in global health programming, especially in humanitarian settings where access to health and mental health infrastructures may be limited. Recognizing the critical role of maternal psychosocial wellness in addressing the health and development of children in conflict, Action contre La Faim/Action Against Hunger (ACF) developed the Baby Friendly Spaces (BFS) program. BFS is a holistic, evidenced-based psychosocial support program that aims to enhance mothers’ wellbeing, internal resources, and child caring skills in order to create a buffer against the deleterious health and developmental impacts of conflict on children. Objectives In Bangladesh, we sought to evaluate the effectiveness of a psychosocial support program for Rohingya refugee mothers and their malnourished children under two years old living in Cox’s Bazar’s camps. Methods For this study, we used a matched pair randomization, where ten BFS program sites were allocated to either continue providing services “as usual” or to an “enhanced BFS program” after re-training and providing continuous supportive supervision of the BFS staff throughout the trial period. 600 mothers and their children were enrolled in the study and attended psychosocial stimulation activities related to child care practices and care for women. Data were collected at baseline and 8-week follow-up. Primary outcomes included maternal distress and wellbeing, functioning, and coping. For implementation purpose, a survey was administered on confidence at work for all BFS staff and a fidelity observation assessment was conducted. Results Relative to “as usual” sites, mothers in enhanced implementation sites reported greater reductions in distress (B=-.30) and improvement in wellbeing (B=.58). These differences were small, but marginally significant (p=.058; p=.038) with standard estimation; There was no significant difference between the two groups for daily functioning and coping. BFS providers in “enhanced BFS program” reported higher confidence in service delivery than their colleagues (p=.01). Fidelity varied widely across different components, with some very high and some very low adherence. There tended to be better adherence to procedures in group versus individual sessions and for some specific activities across domains, for enhanced versus standard BFS. Conclusions Findings highlight the value of innovative study approaches for real-world evidence generation. Small but feasible adjustments to implementation can both improve program delivery for maximizing impact. Consequently, low-intensity psychosocial support activities holds potential for reducing distress and improving subjective well-being of conflict affected mothers. Disclosure of Interest None Declared

Antiviral drugs have classically been developed by directly disrupting the functions of viral proteins. However, this strategy has been largely unsuccessful due to the rapid generation of viral escape mutants. It has been well established that as compared to the virus-centric approach, the strategy of developing antiviral drugs by targeting host-dependency factors (HDFs) minimizes drug resistance. However, recent reports have indicated that drug resistance against some of the host-targeting antiviral agents can in fact occur under some circumstances. Long-term selection pressure of a host-targeting antiviral agent may induce the virus to use an alternate cellular factor or alters its affinity towards the target that confers resistance. Alternatively, virus may synchronize its life cycle with the patterns of drug therapy. In addition, virus may subvert host's immune system to perpetuate under the limiting conditions of the targeted cellular factor. This review describes novel potential mechanisms that may account for the acquiring resistance against agents that target HDFs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Micro RNAs (miRNAs) have been implicated in the regulation of maturation, proliferation, differentiation, and activation of immune cells. In this study, we demonstrated that miR-29a antagonizes IFN-γ production at early times post-LSDV infection in cattle. miR-29a was predicted to target upstream IFN-γ regulators, and its inhibition resulted in enhanced IFN-γ production in sensitized peripheral blood mononuclear cells (PBMCs). Further, stimulation of PBMCs with LSDV antigen exhibited lower levels of miR-29a, concomitant with a potent cell-mediated immune response (CMI), characterized by an increase in LSDV-specific CD8+ T cell counts and enhanced levels of IFN-γ, which eventually facilitated virus clearance. In addition, a few immunocompromised cattle (developed secondary LSDV infection at ~ 6 months) that failed to mount a potent cell-mediated immune response, were shown to maintain higher miR-29a levels. Furthermore, as compared to the sensitized crossbred cattle, PBMCs from sensitized Rathi (a native Indian breed) animals exhibited lower levels of miR-29a along with an increase in CD8+ T cell counts and enhanced levels of IFN-γ. Finally, we analysed that a ≥ 60% decrease in miR-29a expression levels in the PBMCs of sensitized cattle correlated with a potent CMI response. In conclusion, miR-29a expression is involved in antagonizing the IFN-γ response in LSDV-infected cattle and may serve as a novel biomarker for the acute phase of LSDV infection, as well as predicting the functionality of T cells in sensitized cattle. In addition, Rathi cattle mount a more potent CMI response against LSDV than crossbred cattle.

Background: The impact of continuous flow resulting from contemporary left ventricular assist devices (LVAD) on renal vascular physiology is unknown. Renal resistive index (RRI) reflects arterial compliance, as well as renal vascular resistance, contributed by afferent and efferent arteriolar tone, the renal interstitium as well as renal venous pressures., Methods: Prospective, single center study with renal Doppler evaluation at baseline (pre-implant) and at 3-months support. Outcomes assessed include need for post-operative renal replacement therapy (RRT), worsening renal function (WRF) defined as persistent increase from pre-implant KDIGO chronic kidney disease stage, right ventricular (RV) failure, and survival to transplantation., Results: Pre-implant RRI did not predict cardiorenal outcomes including right heart failure, need for renal replacement therapy or worsening renal function. Post-implant RRI was significantly lower than pre-implant RRI, with a distinct Doppler waveform characteristic of continuous flow. Post-implant renal end-diastolic velocity, but not RRI, correlated strongly with LVAD flow (Spearman rho -0.99, p < 0.001), with trend toward correlation with mean arterial pressure (Spearman's rho 0.63, p = 0.129). There was a negative correlation between post-implant RRI and mean pulmonary artery pressure (Spearman's rho -0.81, p = 0.049), likely driven by elevated pulmonary capillary wedge pressure (Spearman's rho -0.83, p = 0.058)., Conclusion: The hemodynamic contributors to RRI in LVAD supported patients are complex. Higher mean pulmonary artery and pulmonary capillary wedge pressures seen in lower RRI may reflect a smaller difference in systolic and diastolic flow. Future simultaneous Doppler assessment of the LVAD outflow graft and RRI may help understand the hemodynamic interactions contributing to this index., (© 2024 International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

The purpose of this study is to gain insights into potential genetic factors contributing to the infant's vulnerability to Sudden Unexpected Infant Death (SUID). Whole Genome Sequencing (WGS) was performed on 144 infants that succumbed to SUID, and 573 healthy adults. Variants were filtered by gnomAD allele frequencies and predictions of functional consequences. Variants of interest were identified in 88 genes, in 64.6% of our cohort. Seventy-three of these have been previously associated with SIDS/SUID/SUDP. Forty-three can be characterized as cardiac genes and are related to cardiomyopathies, arrhythmias, and other conditions. Variants in 22 genes were associated with neurologic functions. Variants were also found in 13 genes reported to be pathogenic for various systemic disorders and in two genes associated with immunological function. Variants in eight genes are implicated in the response to hypoxia and the regulation of reactive oxygen species (ROS) and have not been previously described in SIDS/SUID/SUDP. Seventy-two infants met the triple risk hypothesis criteria. Our study confirms and further expands the list of genetic variants associated with SUID. The abundance of genes associated with heart disease and the discovery of variants associated with the redox metabolism have important mechanistic implications for the pathophysiology of SUID., (© 2024 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.)

Nitrate ion-based chemical ionization mass spectrometry (NO 3 - -CIMS) is widely used for detection of highly oxygenated organic molecules (HOMs). HOMs are known to participate in molecular clustering and new particle formation and growth, and hence understanding the formation pathways and amounts of these compounds in the atmosphere is essential. However, the absence of analytical standards prevents robust quantification of HOM concentrations. In addition, nitrate-based ionization is usually very selective towards the most oxygenated molecules and blind to less oxygenated compounds hindering the investigation of molecular formation pathways. Here, we explore varying concentrations of nitric acid reagent gas in the sheath flow of a chemical ionization inlet as a method for detecting a wider range of oxidation products in laboratory-simulated oxidation of benzene and naphthalene. When the concentration of reagent nitric acid is reduced, we observe an increase in signals of many oxidation products for both precursors suggesting that they are not detected at the collision limit. The sensitivity of naphthalene oxidation products is enhanced to a larger extent than that of benzene products. This enhancement in sensitivity has a negative relationship with molecular oxygen content, the oxygen-to-carbon ratio, the oxidation state of carbon, and lowered volatility. In addition, the sensitivity enhancement is lower for species that contain more exchangeable H-atoms, particularly for accretion products. While more experimental investigations are needed for providing the relationship between enhancement ratios and instrumental sensitivities, we suggest this method as a tool for routine check of collision-limited sensitivities and enhanced detection of lower-oxygenated species., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Camptothecin (CPT), an alkaloid isolated from the Camptotheca tree, has demonstrated significant anticancer properties in a range of malignancies. However, its therapeutic efficacy is limited by its hydrophobicity, poor bioavailability, and systemic toxicity. Derivatives, analogues, and nanoformulations of CPT have been synthesized to overcome these limitations. The aim of this review is to comprehensively analyze existing studies to evaluate the therapeutic efficacy, mechanistic aspects, and clinical potential of CPT and its modified forms, including derivatives, analogues, and nanoformulations, in cancer treatment. A comprehensive literature review was performed using PubMed/Medline, Scopus, and Web of Science databases; articles were selected based on specific inclusion criteria, and data were extracted on the pharmacological profile, clinical studies, and therapeutic efficacy of CPT and its different forms. Current evidence suggests that derivatives and analogues of CPT have improved water solubility, bioavailability, and reduced systemic toxicity compared to CPT. Nanoformulations further enhance targeted delivery and reduce off-target effects. Clinical trials indicate promising outcomes with enhanced survival rates and lower side effects. CPT and its modified forms hold significant promise as potent anticancer agents. Ongoing research and clinical trials are essential for establishing their long-term efficacy and safety; the evidence overwhelmingly supports further development and clinical testing of these compounds., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

mRNA vaccines were highly effective in response to the COVID-19 pandemic, making them an attractive platform to address cancers and other infectious diseases. Many new mRNA vaccines in development are multivalent, which represents a difficulty for the standard assays commonly used to characterize the critical quality attributes of monovalent formulations. Here, we present a multiplexed analytical tool with nucleic acid microarray technology using the VaxArray platform that measures the identity and quantity of mono- and multivalent mixtures of naked mRNA and mRNA encapsulated in lipid nanoparticle formulations in under 2 h without any additional preparation steps, such as extraction or RT-PCR. Using a quadrivalent mixture of encapsulated mRNA constructs that encode for four unique proteins in a vaccine formulation, the VaxArray mRNA assay was demonstrated to be highly specific for each mRNA with sensitivity < 1 µg/mL. The quantification of individual mRNAs within the lipid nanoparticle mixture resulted in a precision of ≤10% RSD and an accuracy of 100 ± 9%.

The development of right heart failure (RHF) in patients with advanced heart failure following left ventricular assist device (LVAD) implantation remains difficult to predict. We proposed a novel composite hemodynamic index-the right ventricular-arterial compliance index (RVACi), derived from pulmonary artery pulse pressure (PAPP), ejection time (ET), heart rate (HR), and cardiac output (CO), with and expressed as mm Hg·s/L. We then conducted a retrospective, single-center analysis comparing the predictive value of RVACi for the development of RHF or unplanned right ventricular (RV) mechanical circulatory support following LVAD implantation against existing hemodynamic indices. One hundred patients were enrolled after screening 232 patients over a 10 year period, with 74 patients having complete hemodynamic data for RVACi calculation. There was good correlation between pulmonary arterial capacitance (R² = 0.48) and pulmonary vascular resistance (R² = 0.63) with RVACi, but not RV stroke work index or pulmonary artery pulsatility index. Reduced baseline RVACi (52 ± 23 vs. 92 ± 55 mm Hg·s/L; p = 0.02) was the strongest hemodynamic predictor of unplanned RV mechanical circulatory support requirement in patients following LVAD insertion. Composite pulsatile hemodynamic indices including RVACi may provide additional insight over existing hemodynamic indices for the prediction of RHF and need for RV mechanical circulatory support., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Background: Continuous glucose monitoring (CGM) systems allow detailed assessment of postprandial glucose responses (PPGR), offering new insights into food choices' impact on dysglycemia. However, current approaches to analyze PPGR using a CGM require manual meal logging, limiting the scalability of CGM-driven applications like personalized nutrition and at-home diabetes risk assessment., Objective: We propose a machine learning (ML) framework to automatically identify and characterize breakfast-related PPGRs from CGM profiles in adults at risk of or living with noninsulin-treated type 2 diabetes (T2D)., Methods: Our PPGR estimation framework uses a random forest ML algorithm trained on 15 adults without diabetes who wore a CGM for up to four weeks. The algorithm performance was evaluated on a held-out subset of the participants' CGM data as well as on an external validation data set of 36 individuals at risk for or with noninsulin-treated T2D., Results: Our algorithm's estimations of breakfast PPGRs displayed no statistically significant differences to annotated PPGRs, in terms of incremental area under the curve and glucose rise ( P > .05 for both data sets), while a small difference in prebreakfast glucose was found in the nondiabetes data set ( P = .005) but not in the validation T2D data set ( P = .18)., Conclusions: We designed an ML framework to automatically estimate the timing of meal events from CGM data in individuals without diabetes and in individuals at risk or with T2D. This could provide a more scalable approach for analyzing postprandial glycemia, increasing the feasibility of CGM-based precision nutrition and diabetes risk assessment applications., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The dataset consists of survey data on pedestrian crosswalk usage behavior in high-density urban areas of a developing country, specifically collected from Dhaka, the capital city of Bangladesh. Data were gathered through a questionnaire survey conducted at twelve key locations, covering eight attributes related to crosswalk behavior and the demographic details of respondents. The survey yielded 682 valid responses, focusing on factors such as the suitability of crosswalk locations, guard rails, and lighting. The dataset is structured to support analyses using supervised machine learning techniques, facilitating reproducibility, secondary analysis, and policy development for pedestrian safety improvements. Furthermore, the dataset can be reused for cross-validation of future studies, comparison with pedestrian behavior in similar urban settings, and the development of predictive models to enhance pedestrian infrastructure in other developing regions., (© 2024 The Author(s).)

Avian nephritis virus (ANV), which belongs to the family Astroviridae , is associated with different clinical manifestations (enteric and kidney disorders) in poultry. Despite being a significant pathogen of the avian industry worldwide, information regarding genetic features of these viruses in India is scarce. In this study, 386 intestinal samples collected from 37 slaughterhouses in two north Indian states (Rajasthan and Haryana) were screened for ANV with reverse transcription PCR (RT-PCR) targeting the conserved ORF1b gene, followed by nucleotide sequencing of the amplified product. RT-PCR and sequencing confirmed the presence of ANV in 32 clinical samples (8.29%), with concurrent infections of infectious bronchitis virus, chicken astrovirus, and fowl adenoviruses observed in some clinical samples ( n = 4). Virus isolations were successful from four out of 12 ANV-positive clinical samples passaged via the yolk-sac route in specific-pathogen-free embryonated chicken eggs. Additionally, the near-complete genomes of two viruses were determined through sequencing. Phylogenetic analysis based on full-length capsid protein sequences classified the viruses into ANV genotype 4 (ANV4), and to the best of our knowledge this is the first report of ANV4 from India. This study revealed the presence and circulation of new strains of ANV in Indian poultry. Genetic profiling and isolation of the viruses in this study will not only aid in the development of diagnostic tools and vaccines for ANV but also offer valuable insights into its epidemiology.

Fermented plant-based products are rapidly gaining popularity. Jerusalem artichoke is a medicinal plant that can be used to make fermented beverages. Samples were subjected to pretreatment (ultrasound at 35 kHz for 2, 4, and 6 min, freezing at -80 °C and -17 °C) while an untreated sample was used as control. It was shown that all types of pretreatments did not lead to an increase in protein, solids, polyphenols, and carbohydrates compared to the control sample. The greatest decrease in the values of these indicators occurs when pre-freezing tubers are used for Jerusalem artichoke dispersion production. It was also found that samples frozen at -80 °C had a significantly higher concentration of Ca, Si, Mg, and P whereas untreated samples frozen at -17 °C had more Al, K, Cu, Sr, and Cr. The processing method can affect the sensory descriptors of Jerusalem artichoke tuber dispersions to different extents, but the preference was for the control sample without pre-treatment. The fermentation of Jerusalem artichoke tuber dispersions demonstrated that S. thermophilus induced the most rapid fermentation (pH 4.75 in 5 h). The highest antioxidant activity after fermentation (55.39% FRSA) was shown for L. acidophilus H9, while the highest % FRSA value during the storage period was for L. bulgaricus (67.5%) on day 5 after fermentation. The highest viability among all selected microorganisms was detected for L. bulgaricus, L. acidophilus AT-41, and B. coagulans MTCC 5856 with the increase in biomass content by 2.3, 2.27, and 2.12 log 10 CFU/ml after fermentation. According to the results of sensory evaluation using hybrid hedonic scale the best results were shown for samples fermented with L. bulgaricus., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mutations in the cohesin complex components (STAG2, RAD21, SMC1A, SMC3, and PDS5B) are recurrent genetic drivers in myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Whether the different cohesin subunit mutations share clinical characteristics and prognostic significance is not known. We analyzed 790 cohesin-mutant patients from the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), 390 of which had available outcome data, and identified subunit-specific clinical, prognostic, and genetic characteristics suggestive of distinct ontogenies. We found that STAG2 mutations are acquired at MDS stage and are associated with secondary AML, adverse prognosis, and co-occurrence of secondary AML-type mutations. In contrast, mutations in RAD21, SMC1A and SMC3 share features with de novo AML with better prognosis, and co-occurrence with de novo AML-type lesions. The findings show the heterogeneous nature of cohesin complex mutations, and inform clinical and prognostic classification, as well as distinct biology of the cohesin complex., (© 2024. The Author(s).)

Objective: This nationwide study aimed to investigate risk factors associated with FIP and determine optimal sample submission strategies for its diagnosis., Methods: A total of 14,035 clinical samples from cats across the US were analyzed by means of reverse transcriptase quantitative PCR to detect replicating feline coronavirus (FCoV). χ2 and logistic regression analyses were conducted to assess the association between FCoV detection rates and risk factors such as age, gender, breed, and types of submitted samples., Results: Higher FCoV detection rates were observed in younger cats, particularly those aged 0 to 1 year, and in male cats. Purebred cats, notably British Shorthairs [OR: 2.81; P < .001], showed a higher incidence of FCoV infection than other cats. Peritoneal fluid (OR, 7.51; P < .001) exhibited higher FCoV detection rates than other samples, while lower rates were seen in blood samples (OR, 0.08; P < .001) than in other samples. High FCoV detection rates were found in urine, kidney, and lymph node samples., Conclusions: The study identified significant risk factors associated with FIP. Optimal sample submission strategies, particularly emphasizing the use of peritoneal fluid, kidney, and lymph node, were identified to improve FIP detection rates. Urine yielded a relatively high frequency of infection and viral loads compared with most other samples., Clinical Relevance: Understanding the risk factors and optimizing sample selection for FIP diagnosis can aid in the early detection and management of the disease, ultimately improving outcomes for affected cats. These findings contribute valuable insights to FIP epidemiology and underscore the importance of continued research to enhance diagnostic strategies and disease management approaches.

Bovine leukemia virus (BLV) is the etiological agent of enzootic bovine leukosis and causes a persistent infection that can leave cattle with no symptoms. Many countries have been able to successfully eradicate BLV through improved detection and management methods. However, with the increasing novel molecular detection methods there have been few efforts to standardize these results at global scale. This study aimed to determine the interlaboratory accuracy and agreement of 11 molecular tests in detecting BLV. Each qPCR/ddPCR method varied by target gene, primer design, DNA input and chemistries. DNA samples were extracted from blood of BLV-seropositive cattle and lyophilized to grant a better preservation during shipping to all participants around the globe. Twenty nine out of 44 samples were correctly identified by the 11 labs and all methods exhibited a diagnostic sensitivity between 74 and 100%. Agreement amongst different assays was linked to BLV copy numbers present in samples and the characteristics of each assay (i.e., BLV target sequence). Finally, the mean correlation value for all assays was within the range of strong correlation. This study highlights the importance of continuous need for standardization and harmonization amongst assays and the different participants. The results underscore the need of an international calibrator to estimate the efficiency (standard curve) of the different assays and improve quantitation accuracy. Additionally, this will inform future participants about the variability associated with emerging chemistries, methods, and technologies used to study BLV. Altogether, by improving tests performance worldwide it will positively aid in the eradication efforts., (© 2024. The Author(s).)

Dengue is a serious epidemic for Bangladesh affecting thousands of lives. This study aimed to identify and determine the prevalence of the circulating variants of dengue virus (DENV) and their association with demographics and clinical manifestations among the dengue-infected patients. A total of 711 participants with NS1 antigen positivity were enrolled, followed by viral RNA extraction from the collected blood samples and a multiplex real-time reverse transcription-polymerase chain reaction (RT-PCR) assay to determine the dengue virus serotypes. Of 711 dengue-infected patients, 503 (70.7%) were male. Among different age groups, most of the patients were 21-30 years old (n = 255, 35.9%). The DENV2 (n = 483, 67.9%) serotype was more prevalent than the DENV3 (n = 144, 20.3%) and DENV1 (n = 84, 11.8%). The duration of fever was highest in the DENV-1 patients (4.79 ± 1.84 days) in contrast to DENV-3 (4.48 ± 1.68 days) and DENV-2 (4.33 ± 1.45 days) (P = 0.039). Importantly, five highly populated areas were identified as dengue hotspots in Chittagong metropolitan city. Our results provide crucial insights into the patterns of dengue virus transmission and severity among southern Bangladeshi population, thereby aiding in the development of targeted public health interventions and management strategies to combat future outbreaks.

Since 2019, Lumpy skin disease (LSD) has suddenly spread in many Asian countries, including India. LSD primarily occurs in cattle. However, recent LSD outbreaks in India have also revealed significant morbidity and production losses in buffaloes. This has raised concerns about the role of buffaloes in the epidemiology and transmission of LSD and necessitates the inclusion of buffaloes in the mass vaccination program for the prevention and control of the disease in the country. However, there is no significant data on the immune response in buffaloes following vaccination with the LSD vaccine. In this study, we evaluated antibody- and cell-mediated immune responses following vaccination with a newly developed live-attenuated LSD vaccine (Lumpi-ProVac Ind ). The detectable amount of anti-LSDV antibodies was observed at 1-2 months following vaccination, with a peak antibody titer at 3 months. Upon stimulation of the peripheral blood mononuclear cells (PBMCs) with the UV-inactivated LSDV antigen, there was a significant increase in CD8 + T cell counts in vaccinated animals as compared to the unvaccinated animals. Besides, vaccinated animals also showed a significant increase in IFN-γ levels upon antigenic stimulation of their PBMCs with LSDV antigen. In conclusion, the buffaloes also mount a potent antibody- and cell-mediated immune response following vaccination with Lumpi-ProVac Ind ., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Ship-breaking yards are recognized for releasing hazardous polycyclic aromatic hydrocarbons (PAHs), leading to severe environmental pollution in the sediment of ship-breaking areas. This study assessed the concentrations of 16 priority PAHs in surface sediments collected from the intertidal zone adjacent to the Sitakund ship-breaking yards. The samples underwent Soxhlet extraction and detection using PerkinElmer GC-Clarus 690 and MS-Clarus SQ8C with an Elite-5MS capillary column (30 m × 0.25 mm ID × 0.25 µm). The study utilized PAH concentrations to reveal spatial distribution patterns, identify point sources, and assess potential toxicity. The total PAH concentration ranged from 1899.2 to 156,800.08 ng g -1 dw, while the concentration of 7 carcinogenic PAHs ranged from 822.03 to 1899.15 ng g -1 dw. High molecular weight PAHs dominated among the 16 PAHs, whereas low molecular weight PAHs, such as 2-ring PAHs, were negligible. Source characterization based on different molecular ratios suggested that PAHs in the area originated from pyrolytic processes related to ship dismantling, fishing activities, and water transportation for people. The observed PAH concentrations exceeded both national and international standards for sedimentary PAH levels, indicating significant ecological risks. The total TEQcarc values of sediment samples varied from 564.41 to 10,695.12 ng g -1 , with a mean value of 3091.25 ng g -1 . The study's findings underscore the immediate biological damage that PAH contamination in the Sitakund ship-breaking area could cause, emphasizing the need for effective control measures to ensure ecological and human safety., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Type 1 cardiorenal syndrome is associated with significant excess morbidity and mortality in patients with severe acute decompensated heart failure. Previous trials of vasoactive drugs and ultrafiltration have not shown superiority over placebo or intravenous diuretics. Pilot data suggest short-term mechanical support devices may support diuresis in the cardiorenal syndrome. We evaluated the intra-aortic balloon pump (IABP) and a novel intra-aortic entrainment pump (IAEP) in a mock circulation loop (MCL) biventricular systolic heart failure model, to assess impact on renal flow and cardiac hemodynamics. Both devices produced similar and only modest increase in renal flow (IABP 3.3% vs. IAEP 4.3%) and cardiac output, with associated reduction in afterload elastance in the MCL. There were minor changes in coronary flow, increase with IABP and minor decrease with IAEP. Differences in device preload and afterload did not impact percentage change in renal flow with IABP therapy, however, there was a trend toward higher percentage flow change with IAEP in response to high baseline renal flow. The IAEP performed best in a smaller aorta and with more superior positioning within the descending aorta. Demonstrated changes in MCL flow during IAEP were of lower magnitude than previous animal studies, possibly due to lack of autoregulation and hormonal responses., Competing Interests: Disclosure: The authors have no conflicts of interest to report., (Copyright © ASAIO 2024.)

Background: The Diabetes Telemedicine Mediterranean Diet (DiaTeleMed) Study is a fully remote randomized clinical trial evaluating personalized dietary management in individuals with type 2 diabetes (T2D). The study aims to test the efficacy of a personalized behavioral approach for dietary management of moderately controlled T2D, versus a standardized behavioral intervention that uses one-size-fits-all dietary recommendations, versus a usual care control (UCC). The primary outcome will compare the impact of each intervention on the mean amplitude of glycemic excursions (MAGE)., Methods: Eligible participants are between 21 and 80 years of age diagnosed with moderately controlled T2D (HbA1c: 6.0 to 8.0%) and managed on lifestyle alone or lifestyle plus metformin. Participants must be willing and able to attend virtual counseling sessions and log meals into a dietary tracking smartphone application (DayTwo), and wear a continuous glucose monitor (CGM) for up to 12 days. Participants are randomized with equal allocation (n = 255, n = 85 per arm) to one of three arms: (1) Personalized, (2) Standardized, or (3) UCC. Measurements occur at 0 (baseline), 3, and 6 months. All participants receive isocaloric energy and macronutrient targets to meet Mediterranean diet guidelines, in addition to 14 intervention contacts over 6 months (4 weekly then 10 biweekly) to cover diabetes self-management education. The first 4 UCC intervention contacts are delivered via synchronous videoconferences followed by educational video links. Participants in Standardized receive the same educational content as those in the UCC arm, following the same schedule. However, all intervention contacts are conducted via synchronous videoconferences, paired with Social Cognitive Theory (SCT)-based behavioral counseling, plus dietary self-monitoring of planned meals using a mobile app that provides real-time feedback on calories and macronutrients. Participants in the Personalized arm receive all elements of the Standardized intervention, in addition to real-time feedback on predicted post-prandial glycemic response (PPGR) to meals and snacks logged into the mobile app., Discussion: The DiaTeleMed Study aims to address an important gap in the current landscape of precision nutrition by determining the contributions of behavioral counseling and personalized nutrition recommendations on glycemic control in individuals with T2D. The fully remote methodology of the study allows for scalability and innovative delivery of personalized dietary recommendations at a population level., Trial Registration: ClinicalTrials.gov NCT05046886. Registered on September 16, 2021., (© 2024. The Author(s).)

This study investigates the complex interaction between ozone and the autoxidation of 1-hexene over a wide temperature range (300-800 K), overlapping atmospheric and combustion regimes. It is found that atmospheric molecular mechanisms initiate the oxidation of 1-hexene from room temperature up to combustion temperatures, leading to the formation of highly oxygenated organic molecules. As temperature rises, the highly oxygenated organic molecules contribute to radical-branching decomposition pathways inducing a high reactivity in the low-temperature combustion region, i.e., from 550 K. Above 650 K, the thermal decomposition of ozone into oxygen atoms becomes the dominant process, and a remarkable enhancement of the conversion is observed due to their diradical nature, counteracting the significant negative temperature coefficient behavior usually observed for 1-hexene. In order to better characterize the formation of heavy oxygenated organic molecules at the lowest temperatures, two analytical performance methods have been combined for the first time: synchrotron-based mass-selected photoelectron spectroscopy and orbitrap chemical ionization mass spectrometry. At the lowest studied temperatures (below 400 K), this analytical work has demonstrated the formation of the ketohydroperoxides usually found during the LTC oxidation of 1-hexene, as well as of molecules containing up to nine O atoms.

New particle formation (NPF) is a major source of atmospheric aerosol particles, including cloud condensation nuclei (CCN), by number globally. Previous research has highlighted that NPF is less frequent but more intense at roadsides compared to urban background. Here, we closely examine NPF at both background and roadside sites in urban Central Europe. We show that the concentration of oxygenated organic molecules (OOMs) is greater at the roadside, and the condensation of OOMs along with sulfuric acid onto new particles is sufficient to explain the growth at both sites. We identify a hitherto unreported traffic-related OOM source contributing 29% and 16% to total OOMs at the roadside and background, respectively. Critically, this hitherto undiscovered OOM source is an essential component of urban NPF. Without their contribution to growth rates and the subsequent enhancements to particle survival, the number of >50 nm particles produced by NPF would be reduced by a factor of 21 at the roadside site. Reductions to hydrocarbon emissions from road traffic may thereby reduce particle numbers and CCN counts.

Sulfur trioxide (SO 3 ) is an important oxide of sulfur and a key intermediate in the formation of sulfuric acid (H 2 SO 4 , SA) in the Earth's atmosphere. This conversion to SA occurs rapidly due to the reaction of SO 3 with a water dimer. However, gas-phase SO 3 has been measured directly at concentrations that are comparable to that of SA under polluted mega-city conditions, indicating gaps in our current understanding of the sources and fates of SO 3 . Its reaction with atmospheric acids could be one such fate that can have significant implications for atmospheric chemistry. In the present investigation, laboratory experiments were conducted in a flow reactor to generate a range of previously uncharacterized condensable sulfur-containing reaction products by reacting SO 3 with a set of atmospherically relevant inorganic and organic acids at room temperature and atmospheric pressure. Specifically, key inorganic acids known to be responsible for most ambient new particle formation events, iodic acid (HIO 3 , IA) and SA, are observed to react promptly with SO 3 to form iodic sulfuric anhydride (IO 3 SO 3 H, ISA) and disulfuric acid (H 2 S 2 O 7 , DSA). Carboxylic sulfuric anhydrides (CSAs) were observed to form by the reaction of SO 3 with C 2 and C 3 monocarboxylic (acetic and propanoic acid) and dicarboxylic (oxalic and malonic acid)-carboxylic acids. The formed products were detected by a nitrate-ion-based chemical ionization atmospheric pressure interface time-of-flight mass spectrometer (NO 3 - -CI-APi-TOF; NO 3 - -CIMS). Quantum chemical methods were used to compute the relevant SO 3 reaction rate coefficients, probe the reaction mechanisms, and model the ionization chemistry inherent in the detection of the products by NO 3 - -CIMS. Additionally, we use NO 3 - -CIMS ambient data to report that significant concentrations of SO 3 and its acid anhydride reaction products are present under polluted, marine and polar, and volcanic plume conditions. Considering that these regions are rich in the acid precursors studied here, the reported reactions need to be accounted for in the modeling of atmospheric new particle formation.

The inhibition of p38 mitogen-activated protein kinase (p38-MAPK) by small molecule chemical inhibitors was previously shown to impair severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication, however, mechanisms underlying antiviral activity remains unexplored. In this study, reduced growth of SARS-CoV-2 in p38- α knockout Vero cells, together with enhanced viral yield in cells transfected with construct expressing p38 α , suggested that p38-MAPK is essential for the propagation of SARS-CoV-2. The SARS-CoV-2 was also shown to induce phosphorylation (activation) of p38, at time when transcription/translational activities are considered to be at the peak levels. Further, we demonstrated that p38 supports viral RNA/protein synthesis without affecting viral attachment, entry, and budding in the target cells. In conclusion, we provide mechanistic insights on the regulation of SARS-CoV-2 replication by p38 MAPK., Competing Interests: Conflict of interestThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© The Author(s), under exclusive licence to Indian Virological Society 2024.)

Background: This study evaluated the effectiveness of Baby Friendly Spaces (BFS), a psychosocial support program for Rohingya refugee mothers of malnourished young children in Bangladesh. Because BFS was already being implemented, we examined the benefit of enhancing implementation supports., Methods: In matched pairs, 10 sites were randomized to provide BFS treatment as usual (BFS-TAU) or to receive enhanced implementation support (BFS-IE). 600 mothers were enrolled and reported on maternal distress, functional impairment, subjective well-being and coping at baseline and 8-week follow-up. Data were analyzed using multilevel linear regression models to account for clustering; sensitivity analyses adjusted for the small number of clusters., Results: Significant within-group improvements in BFSIE were observed for distres (-.48, p = .014), functional impairment (-.30, p = .002) and subjective well-being (.92, p = .011); improvements in BFS-TAU were smaller and not statistically significant. Between-group comparisons favored BFS-IE for distress (β = -.30, p = .058) and well-being (β = .58, p = .038). Sensitivity adjustments produced p-values above .05 for all between-group comparisons., Discussion: Feasible adjustments to implementation can improve program delivery to increase impact on maternal distress and well-being. Although results should be interpreted with caution, study design limitations are common in pragmatic, field-based research., Competing Interests: The authors declare none., (© The Author(s) 2024.)

Chlamydia trachomatis ( Ct ) infections are the most common sexually transmitted infection (STI). Despite effective antibiotics for Ct , undetected infections or delayed treatment can lead to infertility, ectopic pregnancies, and chronic pelvic pain. Besides humans, chlamydia poses similar health challenges in animals such as C. suis ( Cs ) in pigs. Based on the similarities between humans and pigs, as well as their chlamydia species, we use pigs as a large biomedical animal model for chlamydia research. In this study, we used the pig model to develop a vaccine candidate against Ct . The vaccine candidate consists of TriAdj-adjuvanted chlamydial-protease-like activity factor (CPAF) protein. We tested two weekly administration options-twice intranasal (IN) followed by twice intramuscular (IM) and twice IM followed by twice IN. We assessed the humoral immune response in both serum using CPAF-specific IgG (including antibody avidity determination) and also in cervical and rectal swabs using CPAF-specific IgG and IgA ELISAs. The systemic T-cell response was analyzed following in vitro CPAF restimulation via IFN-γ and IL-17 ELISpots, as well as intracellular cytokine staining flow cytometry. Our data demonstrate that while the IN/IM vaccination mainly led to non-significant systemic immune responses, the vaccine candidate is highly immunogenic if administered IM/IN. This vaccination strategy induced high serum anti-CPAF IgG levels with strong avidity, as well as high IgA and IgG levels in vaginal and rectal swabs and in uterine horn flushes. In addition, this vaccination strategy prompted a pronounced cellular immune response. Besides inducing IL-17 production, the vaccine candidate induced a strong IFN-γ response with CD4 T cells. In IM/IN-vaccinated pigs, these cells also significantly downregulated their CCR7 expression, a sign of differentiation into peripheral-tissue-homing effector/memory cells. Conclusively, this study demonstrates the strong immunogenicity of the IM/IN-administered TriAdj-adjuvanted Ct CPAF vaccine candidate. Future studies will test the vaccine efficacy of this promising Ct vaccine candidate. In addition, this project demonstrates the suitability of the Cs pre-exposed outbred pig model for Ct vaccine development. Thereby, we aim to open the bottleneck of large animal models to facilitate the progression of Ct vaccine candidates into clinical trials.

In this study, we demonstrated the antiviral efficacy of hesperetin against multiple poxviruses, including buffalopox virus (BPXV), vaccinia virus (VACV), and lumpy skin disease virus (LSDV). The time-of-addition and virus step-specific assays indicated that hesperetin reduces the levels of viral DNA, mRNA, and proteins in the target cells. Further, by immunoprecipitation (IP) of the viral RNA from BPXV-infected Vero cells and a cell-free RNA-IP assay, we demonstrated that hesperetin-induced reduction in BPXV protein synthesis is also consistent with diminished interaction between eukaryotic translation initiation factor eIF4E and the 5' cap of viral mRNA. Molecular docking and MD simulation studies were also consistent with the binding of hesperetin to the cap-binding pocket of eIF4E, adopting a conformation similar to m7GTP binding. Furthermore, in a BPXV egg infection model, hesperetin was shown to suppress the development of pock lesions on the chorioallantoic membrane and associated mortality in the chicken embryos. Most importantly, long-term culture of BPXV in the presence of hesperetin did not induce the generation of drug-resistant viral mutants. In conclusion, we, for the first time, demonstrated the antiviral activity of hesperetin against multiple poxviruses, besides providing some insights into its potential mechanisms of action., (© 2024 Wiley Periodicals LLC.)

Background: Accurately identifying eating patterns, specifically the timing, frequency, and distribution of eating occasions (EOs), is important for assessing eating behaviors, especially for preventing and managing obesity and type 2 diabetes (T2D). However, existing methods to study EOs rely on self-report, which may be prone to misreporting and bias and has a high user burden. Therefore, objective methods are needed., Methods: We aim to compare EO timing using objective and subjective methods. Participants self-reported EO with a smartphone app (self-report [SR]), wore the ActiGraph GT9X on their dominant wrist, and wore a continuous glucose monitor (CGM, Abbott Libre Pro) for 10 days. EOs were detected from wrist motion (WM) using a motion-based classifier and from CGM using a simulation-based system. We described EO timing and explored how timing identified with WM and CGM compares with SR., Results: Participants ( n = 39) were 59 ± 11 years old, mostly female (62%) and White (51%) with a body mass index (BMI) of 34.2 ± 4.7 kg/m 2 . All had prediabetes or moderately controlled T2D. The median time-of-day first EO (and interquartile range) for SR, WM, and CGM were 08:24 (07:00-09:59), 9:42 (07:46-12:26), and 06:55 (04:23-10:03), respectively. The median last EO for SR, WM, and CGM were 20:20 (16:50-21:42), 20:12 (18:30-21:41), and 21:43 (20:35-22:16), respectively. The overlap between SR and CGM was 55% to 80% of EO detected with tolerance periods of ±30, 60, and 120 minutes. The overlap between SR and WM was 52% to 65% EO detected with tolerance periods of ±30, 60, and 120 minutes., Conclusion: The continuous glucose monitor and WM detected overlapping but not identical meals and may provide complementary information to self-reported EO., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.J.P. is the CEO of TAIN Nutrition, LLC. No other authors have conflicts of interest to disclose.

Authors are often faced with the decision of whether to maximize traditional impact metrics or minimize costs when choosing where to publish the results of their research. Many subscription-based journals now offer the option of paying an article processing charge (APC) to make their work open. Though such "hybrid" journals make research more accessible to readers, their APCs often come with high price tags and can exclude authors who lack the capacity to pay to make their research accessible. Here, we tested if paying to publish open access in a subscription-based journal benefited authors by conferring more citations relative to closed access articles. We identified 146,415 articles published in 152 hybrid journals in the field of biology from 2013-2018 to compare the number of citations between various types of open access and closed access articles. In a simple generalized linear model analysis of our full dataset, we found that publishing open access in hybrid journals that offer the option confers an average citation advantage to authors of 17.8 citations compared to closed access articles in similar journals. After taking into account the number of authors, Journal Citation Reports 2020 Quartile, year of publication, and Web of Science category, we still found that open access generated significantly more citations than closed access ( p  < 0.0001). However, results were complex, with exact differences in citation rates among access types impacted by these other variables. This citation advantage based on access type was even similar when comparing open and closed access articles published in the same issue of a journal ( p  < 0.0001). However, by examining articles where the authors paid an article processing charge, we found that cost itself was not predictive of citation rates ( p  = 0.14). Based on our findings of access type and other model parameters, we suggest that, in the case of the 152 journals we analyzed, paying for open access does confer a citation advantage. For authors with limited budgets, we recommend pursuing open access alternatives that do not require paying a fee as they still yielded more citations than closed access. For authors who are considering where to submit their next article, we offer additional suggestions on how to balance exposure via citations with publishing costs., Competing Interests: The authors declare there are no competing interests., (©2024 Clark et al.)

This article presents a new design of a compact fractal antenna that operates across various wireless communication applications with wideband functionality. With a peak gain of 6.8 dB and a radiation efficiency ranging from 91% to 94%, the designed antenna operates in the frequency range of 3.2-7.5 GHz. The antenna consists of a rectangular radiator with integrated rectangular slots on one side of an FR4 substrate, while a partial ground plane is etched on the other side. The fabricated prototype was tested and measured. The results present a good agreement with the simulated results. The results presented by this antenna demonstrate high competitiveness for wireless communication applications such as Wi-Fi and WLAN and presents a promising solution to meet the increasing demand for compact and high-performance wireless communication devices. Additionally, the antenna has a small size of only 34 × 30 × 1.6 mm 3 , making it suitable for applications where space is limited. Overall, this paper provides an innovative and efficient design that offers excellent performance and is suitable for various wireless communication applications., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The cycling of next-generation, high-capacity silicon (Si) anodes capable of 3579 mAh·g -1 is greatly hindered by the instability of the solid-electrolyte interphase (SEI). The large volume changes of Si during (de)lithiation cause continuous cracking of the SEI and its reconstruction, leading to loss of lithium inventory and extensive consumption of electrolyte. The SEI formed in situ during cell cycling is mostly composed of molecular fragments and oligomers, the structure of which is difficult to tailor. In contrast, ex situ formation of a synthetic SEI provides greater flexibility to deposit long-chain, polymeric, and elastomeric components potentially capable of maintaining integrity against the large ∼350% volume expansion of Si while also enabling electronic passivation of the surface for longer cycling and calendar life. Furthermore, polymers are amenable to structural modifications, and the desired elasticity can be targeted by selection of the SEI polymer feedstock. Herein, electrophoretic deposition (EPD) is used to apply chitosan as a synthetic SEI on model Si thin film electrodes. Comparison of synthetic SEIs obtained without (Si/Chit) and with CH 3 COOLi (Si/Chit+CH 3 COOLi) added during EPD is performed to demonstrate a facile route to tuning of the polymer SEI chemistry. Atomic force and scanning electron microscopy reveal that addition of CH 3 COOLi at EPD assists in conformal deposition of the synthetic SEI. During electrochemical cycling, the Chit+CH 3 COOLi coating nearly doubles the capacity retention versus the reference bare Si thin film. X-ray photoelectron and Fourier transform infrared spectroscopy reveal that CH 3 COOLi caps the -NH 2 groups of chitosan through amidation during EPD, which suppresses the catalytic reduction of the electrolyte. The presented approach demonstrates and validates EPD as a low-capital route to achieving and chemistry-tuning synthetic SEIs on Si electrodes. More broadly, the method is a promising avenue toward controlled and tailored polymeric SEIs on various conversion-type electrodes with high particle volumetric expansion.

In type 2 diabetes (T2D), the dawn phenomenon is an overnight glucose rise recognized to contribute to overall glycemia and is a potential target for therapeutic intervention. Existing CGM-based approaches do not account for sensor error, which can mask the true extent of the dawn phenomenon. To address this challenge, we developed a probabilistic framework that incorporates sensor error to assign a probability to the occurrence of dawn phenomenon. In contrast, the current approaches label glucose fluctuations as dawn phenomena as a binary yes/no. We compared the proposed probabilistic model with a standard binary model on CGM data from 173 participants (71% female, 87% Hispanic/Latino, 54 ± 12 years, with either a diagnosis of T2D for six months or with an elevated risk of T2D) stratified by HbA 1c levels into normal but at risk for T2D, with pre-T2D, or with non-insulin-treated T2D. The probabilistic model revealed a higher dawn phenomenon frequency in T2D [49% (95% CI 37-63%)] compared to pre-T2D [36% (95% CI 31-48%), p = 0.01] and at-risk participants [34% (95% CI 27-39%), p < 0.0001]. While these trends were also found using the binary approach, the probabilistic model identified significantly greater dawn phenomenon frequency than the traditional binary model across all three HbA 1c sub-groups (p < 0.0001), indicating its potential to detect the dawn phenomenon earlier across diabetes risk categories., (© 2024. The Author(s).)

Competing Interests: P.S.M. has received “in kind” support from Transmedics and XVIVO through provision of research modules for preclinical research on donor heart preservation. The other authors declare no conflicts of interest.

Digital phenotyping refers to characterizing human bio-behavior through wearables, personal devices, and digital health technologies. Digital phenotyping in populations facing a disproportionate burden of type 2 diabetes (T2D) and health disparities continues to lag compared to other populations. Here, we report our study demonstrating the application of multimodal digital phenotyping, i.e., the simultaneous use of CGM, physical activity monitors, and meal tracking in Hispanic/Latino individuals with or at risk of T2D. For 14 days, 36 Hispanic/Latino adults (28 female, 14 with non-insulin treated T2D) wore a continuous glucose monitor (CGM) and a physical activity monitor (Actigraph) while simultaneously logging meals using the MyFitnessPal app. We model meal events and daily digital biomarkers representing diet, physical activity choices, and corresponding glycemic response. We develop a digital biomarker for meal events that differentiates meal events into normal and elevated categories. We examine the contribution of daily digital biomarkers of elevated meal event count and step count on daily time-in-range 54-140 mg/dL (TIR 54-140 ) and average glucose. After adjusting for step count, a change in elevated meal event count from zero to two decreases TIR 54-140 by 4.0% (p = 0.003). An increase in 1000 steps in post-meal step count also reduces the meal event glucose response by 641 min mg/dL (p = 0.0006) and reduces the odds of an elevated meal event by 55% (p < 0.0001). The proposed meal event digital biomarkers may provide an opportunity for non-pharmacologic interventions for Hispanic/Latino adults facing a disproportionate burden of T2D., (© 2024. The Author(s).)