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Background: An increased risk of diabetes mellitus (DM) after COVID-19 has been reported in the United States, Europe, and Asia. The burden of COVID-related DM has yet to be described in Africa, where the overall risk of DM has been increasing rapidly. Our objective was to compare the prevalence of pre-DM and DM in Nigerian individuals with a history of COVID-19 to individuals without known COVID-19 infection. Methods: We undertook a retrospective cohort study with 256 individuals with a past medical history of COVID-19 with no history of pre-DM or DM and 256 individuals without a history of COVID-19 or pre-DM/DM. Participants were categorized as pre-DM (fasting capillary glucose 100–125 mg/dL) or DM (fasting capillary glucose ≥ 126 mg/dL). We employed univariate and multivariable logistic regression to identify key predictors and adjust for confounders related to hyperglycaemia risk factors. Additionally, we used multinomial logistic regression to analyze the relationship between COVID-19 history and diabetes status, distinguishing between normal, pre-diabetic, and diabetic glucose levels. All models were adjusted for age, gender, hypertension, physical activity, central adiposity, and family history of DM. Results: Compared to the control group, those with a history of COVID-19 had a similar median age (38 vs. 40 years, p = 0.84), had a higher proportion of men (63% vs. 49%), and had a lower prevalence of central adiposity (waist: hip ratio ≥ 0.90 for males and WHR ≥ 0.85 for females) (48% vs. 56.3%, p = 0.06). Of the 256 with a history of COVID-19, 44 (17%) required in-patient care. The median (interquartile range) time interval between COVID-19 diagnosis and the glycaemic assessment was 19 (IQR: 14, 24) months. Pre-DM prevalence was 27% in the post-COVID-19 group and 4% in the control group, whereas the prevalence of DM was 7% in the post-COVID-19 group and 2% in the control group. After multivariable adjustment, the odds of pre-DM were 8.12 (95% confidence interval (CI): 3.98, 16.58; p < 0.001) higher, and the odds of DM were 3.97 (95% CI: 1.16, 13.63) higher in those with a history of COVID-19 compared to controls. In the adjusted multinomial logistic regression analysis, individuals with a history of COVID-19 exhibited significantly elevated risks for pre-diabetes (RRR = 7.55, 95% CI: 3.76–15.17) and diabetes (RRR = 3.44, 95% CI: 1.01–11.71) compared to those without COVID-19. Conclusion: Previous COVID-19 was found to be a risk factor for prevalent pre-diabetes and diabetes mellitus in Nigeria. More intensive screening for DM in those with a history of COVID-19 should be considered. [ABSTRACT FROM AUTHOR]

Background Hypogonadism is common among HIV-infected men, even among men receiving antiretroviral therapy (ART). Our objective in this study was to determine the prevalence of biochemical hypogonadism among HIV-infected men compared with HIV-uninfected controls. We also examined the use of free testosterone (FT) and total testosterone (TT) measurements in the assessment of biochemical hypogonadism in HIV-infected and - uninfected men. Methods This was a cross-sectional analysis from the Multicenter AIDS Cohort Study (MACS). TT levels were measured from archived serum using liquid chromatography-tandem mass spectrometry. FT was calculated from TT and sex hormone binding globulin (SHBG) (measured by radioimmunoassay) using the Vermeulen equation. Biochemical hypogonadism was defined as having low TT, low FT, or both. Results Of 945 men in the MACS Cardiovascular Substudy, T assays were not performed in 89 because of insufficient/no stored serum (n = 18) or use of T replacement therapy (TRT) (n = 71). 530 men had morning (AM) T measurements; 364 (68.7%) were HIV-infected. The prevalence of biochemical hypogonadism was similar in HIV-infected (34/364 = 9.3%) and HIV-uninfected (12/166 = 7.2%) men. Prevalence of hypogonadism, when men on TRT (n = 71) were included in the group of hypogonadal men, was higher in HIV-infected (104/434 = 24.0%) compared with HIV-uninfected (13/167 = 7.8%) men (p < 0.0001). Of 34 HIVinfected men with biochemical hypogonadism not on TRT, 11 (32.4%) had normal TT, but low FT. Of 12 HIV-uninfected men with biochemical hypogonadism not on TRT, none were in this category (p = 0.04) - all had low TT. Conclusions The prevalence of biochemical hypogonadism in our sample of HIV-infected men was approximately 10%, with a substantial proportion of these men having a normal TT, but low FT. The measurement of AM FT, rather than TT, in the assessment of hypogonadism in HIVinfected men will likely increase diagnostic sensitivity and should be recommended. [ABSTRACT FROM AUTHOR]

Background: Resting conventional 12-lead ECG has low sensitivity for detection of coronary artery disease (CAD) and left ventricular hypertrophy (LVH) and low positive predictive value (PPV) for prediction of left ventricular systolic dysfunction (LVSD). We hypothesized that a ~5-min resting 12-lead advanced ECG test ("A-ECG") that combined results from both the advanced and conventional ECG could more accurately screen for these conditions than strictly conventional ECG. Methods: Results from nearly every conventional and advanced resting ECG parameter known from the literature to have diagnostic or predictive value were first retrospectively evaluated in 418 healthy controls and 290 patients with imaging-proven CAD, LVH and/or LVSD. Each ECG parameter was examined for potential inclusion within multiparameter A-ECG scores derived from multivariate regression models that were designed to optimally screen for disease in general or LVSD in particular. The performance of the best retrospectively-validated A-ECG scores was then compared against that of optimized pooled criteria from the strictly conventional ECG in a test set of 315 additional individuals. Results: Compared to optimized pooled criteria from the strictly conventional ECG, a 7-parameter A-ECG score validated in the training set increased the sensitivity of resting ECG for identifying disease in the test set from 78% (72-84%) to 92% (88-96%) (P < 0.0001) while also increasing specificity from 85% (77-91%) to 94% (88-98%) (P < 0.05). In diseased patients, another 5-parameter A-ECG score increased the PPV of ECG for LVSD from 53% (41-65%) to 92% (78-98%) (P < 0.0001) without compromising related negative predictive value. Conclusion: Resting 12-lead A-ECG scoring is more accurate than strictly conventional ECG in screening for CAD, LVH and LVSD. [ABSTRACT FROM AUTHOR]

Background: Fat abnormalities are common among HIV-infected persons, but few studies have compared regional body fat distribution, including visceral fat, in HIV-infected and HIV-uninfected persons and their subsequent trajectories in body composition over time. Methods: Between 1999 and 2002, 33 men with clinical evidence of lipodystrophy (LIPO+), 23 HIV-infected men without clinical evidence of lipodytrophy (LIPO-), and 33 HIV-uninfected men were recruited from the four sites of the Multicenter AIDS Cohort Study (MACS). Participants underwent dual-energy x-ray absorptiometry, quantitative computerized tomography of the abdomen and thigh, and circumference measurements of the waist, hip and thigh. Circumference measurements at each semi-annual MACS visit between recruitment and 2008 were used to compare average annual anthropometric changes in the 3 groups. Results: Body mass index (BMI) was lower in LIPO+ men than in the LIPO- men and the HIVuninfected controls (BMI: 23.6 ± 0.4 vs 26.8 ± 1.5 vs 28.7 ± 0.9 kg/m², respectively, p < 0.001). The average amount of visceral adipose tissue (VAT) was similar in all three groups (p = 0.26), but after adjustment for BMI, VAT was higher in the LIPO+ group (169 ± 10 cm²) compared to the LIPOmen (129 ± 12 cm², p = 0.03) and the HIV-uninfected group (133 ± 11 cm², p = 0.07). Subcutaneous adipose tissue (thigh, abdomen) and total extremity fat were less in the HIV-infected men (LIPO+ and LIPO-) than in the HIV-uninfected men. Over an average of 6 years of follow-up, waist circumference increased at a faster rate in LIPO+ group, compared to the LIPO- men (0.51 cm/ year vs 0.08 cm/year, p = 0.02) and HIV-uninfected control men (0.21 cm/year, p = 0.06). The annual changes in hip and thigh circumferences were similar in all three groups Conclusion: Subcutaneous lipoatrophy was observed in HIV-infected patients, even those without clinical evidence of lipodystrophy, compared to age-matched HIV-uninfected men. Despite markedly lower BMI, HIV-infected men with lipodystrophy had a similar amount of VAT as HIVuninfected men and tended to have more rapid increases in waist circumference over 6 years of follow-up. These longitudinal increases in waist circumference may contribute to the development of cardiovascular risk in HIV-infected patients with lipodystrophy. [ABSTRACT FROM AUTHOR]

Background: Minor groove binding drugs (MGBDs) interact with DNA in a sequence-specific manner and can cause changes in gene expression at the level of transcription. They serve as valuable models for protein interactions with DNA and form an important class of antitumor, antiviral, antitrypanosomal and antibacterial drugs. There is a need to extend knowledge of the sequence requirements for MGBDs from in vitro DNA binding studies to living cells. Results: Here we describe the use of microarray analysis to discover yeast genes that are affected by treatment with the MGBD berenil, thereby allowing the investigation of its sequence requirements for binding in vivo. A novel approach to sequence analysis allowed us to address hypotheses about genes that were directly or indirectly affected by drug binding. The results show that the sequence features of A/T richness and heteropolymeric character discovered by in vitro berenil binding studies are found upstream of genes hypothesized to be directly affected by berenil but not upstream of those hypothesized to be indirectly affected or those shown to be unaffected. Conclusion: The data support the conclusion that effects of berenil on gene expression in yeast cells can be explained by sequence patterns discovered by in vitro binding experiments. The results shed light on the sequence and structural rules by which berenil binds to DNA and affects the transcriptional regulation of genes and contribute generally to the development of MGBDs as tools for basic and applied research. [ABSTRACT FROM AUTHOR]

Background: Complementary and alternative medicine (CAM) use is prevalent among HIVinfected patients to reduce the toxicity of antiretroviral therapy. Ginseng has been used for treatment of hyperglycemia and insulin resistance, a common side effect of some HIV-1 protease inhibitors (PI). However, it is unknown whether American ginseng (AG) can reverse insulin resistance induced by the PI indinavir (IDV), and whether these two agents interact pharmacologically. We evaluated potential pharmacokinetic interactions between IDV and AG, and assessed whether AG improves IDV-induced insulin resistance. Methods: After baseline assessment of insulin sensitivity using the insulin clamp technique, healthy volunteers received IDV 800 mg q8 h for 3 days and then IDV and AG 1g q8h for 14 days. IDV pharmacokinetics and insulin sensitivity were assessed before and after AG co-administration. Results: There was no difference in the area-under the plasma-concentration-time curve after the co-administration of AG, compared to IDV alone (n = 13). Although insulin-stimulated glucose disposal per unit of insulin (M/I) decreased by an average of 14.8 ± 5.9% after 3 days of IDV (from 0.113 ± 0.012 to 0.096 ± 0.014 mg/kgFFM/min per µU/ml of insulin, p = 0.03, n = 11), M/I remained unchanged after co-administration of IDV and AG. Conclusion: IDV decreases insulin sensitivity, which is unaltered by AG co-administration. AG does not significantly affect IDV pharmacokinetics. [ABSTRACT FROM AUTHOR]

Lysosome-associated membrane protein (LAMP)-1, one of the major protein components of the lysosomal membrane, is upregulated in the human glioblastoma cell lines, U-373 MG and LN-Z308, which undergo cisplatin-induced apoptosis. These human brain tumor cell lines demonstrated apoptosis in response to cisplatin/nifedipine treatment. Both cell lines demonstrated an apoptotic response by more than one criterion. Apoptosis was demonstrated by DNA fragmentation techniques such as DNA laddering, ApopTag[sup ®] in situ labeling, and an ELISA-based method of detecting liberated oligosomes. These cells also had characteristic morphologic changes and upregulation of bax consistent with apoptosis. LAMP-1 expression at the protein and mRNA level was examined and found to increase with cisplatin/nifedipine treatment. LAMP-1 expression was examined using indirect immunofluorescent staining, Northern blot analysis and Western blot analysis. The finding of an augmentation of LAMP-1 in these cells induced to die is enigmatic. These findings raise the possibility of LAMP-1 involvement in the apoptotic process.Copyright © 2001 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Apoptosis has been implicated recently as a prominent response of the brain to a variety of insults, such as ischemia and trauma. In this study, we demonstrate that apoptosis is a prominent part of the brain’s response to a thermal insult. To examine the brain’s response to a thermal insult, a new model of thermal brain injury in the laboratory rat was developed. Water heated to 60°C was passed over an area of thinned calvarium for 1 min. This resulted in an actual brain temperature of 47–48°C. A uniform area of 2,3,5-triphenyl-tetrazolium chloride pallor was demonstrated and pyknotic neurons were seen in the area of injury by hematoxylin-eosin staining. Apoptosis was demonstrated by the characteristic DNA fragmentation seen by agarose gel electrophoresis, ApopTag in situ staining and electron microscopy. The findings of apoptosis were localized to the area of thermal injury and were time dependent, starting 6 h after the insult and peaking approximately 18 h after the insult. This represents one of the first demonstrations that apoptosis occurs in the brain in response to a thermal injury.Copyright © 2000 National Science Council, ROC and S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Previous data indicate that purified components of ginseng can inhibit HIV reverse transcriptase in vitro, suggesting that ginseng components in plasma may interfere with HIV-1 RNA detection assays. Methods: Pre- and post-dose plasma from three volunteers dosed with 3000 mg American ginseng was spiked with HIV and analyzed by the Roche COBAS Ampliprep/Taqman v2.0 HIV-1 RNA assay. Results: Presence of American ginseng had no significant effect on measured HIV-1 RNA concentration. Variation within pre- and post-dose plasma pair was insignificant and within assay performance limits. Conclusion: Plasma from subjects dosed with 3000 mg American ginseng does not interfere with the Roche COBAS Ampliprep/Taqman v2.0 HIV-1 RNA assay. This implies that in vitro inhibition of HIV reverse transcriptase by American ginseng components is unlikely to be clinically relevant. [ABSTRACT FROM AUTHOR]

Background: Humans demonstrate a number of unique adaptations that allow for the maintenance of blood pressure and brain blood flow when upright. While several physiological systems, including cerebral autoregulation, are involved in this adaptation the unique role the vestibular system plays in helping to maintain brain blood flow is just beginning to be elucidated. In this study, we tested the hypothesis that stimulation of the vestibular system, specifically the otoliths organs, would result in changes in cerebral blood flow. Results: To test our hypothesis, we stimulated the vestibular organs of 25 healthy subjects by pitch tilt (stimulates both canals and otoliths) and by translation on a centrifuge (stimulates otoliths and not the canals) at five frequencies: 0.5, 0.25, 0.125 and 0.0625 Hz for 80 sec and 0.03125 Hz for 160 sec. Changes in cerebral flow velocity (by transcranial Doppler) and blood pressure (by Finapres) were similar during both stimuli and dependent on frequency of stimulation (P < 0.01). However, changes in cerebral blood flow were in opposition to changes in blood pressure and not fully dependent on changes in end tidal CO2. Conclusion: The experimental results support our hypothesis and provide evidence that activation of the vestibular apparatus, specifically the otolith organs, directly affects cerebral blood flow regulation, independent of blood pressure and end tidal CO2 changes.

Background: There has been an exponential increase in the number of studies reporting on the toxicological effects associated with exposure to nano and microplastic particles (NMPs). The majority of these studies, however, have used monodispersed polystyrene microspheres (PSMs) as 'model' particles. Here we review the differences between the manufacture and resulting physicochemical properties of polystyrene used in commerce and the PSMs most commonly used in toxicity studies., Main Body: In general, we demonstrate that significant complexity exists as to the properties of polystyrene particles. Differences in chemical composition, size, shape, surface functionalities and other aspects raise doubt as to whether PSMs are fit-for-purpose for the study of potential adverse effects of naturally occurring NMPs. A realistic assessment of potential health implications of the exposure to environmental NMPs requires better characterisation of the particles, a robust mechanistic understanding of their interactions and effects in biological systems as well as standardised protocols to generate relevant model particles. It is proposed that multidisciplinary engagement is necessary for the development of a timely and effective strategy towards this end. We suggest a holistic framework, which must be supported by a multidisciplinary group of experts to work towards either providing access to a suite of environmentally relevant NMPs and/or developing guidance with respect to best practices that can be adopted by research groups to generate and reliably use NMPs. It is emphasized that there is a need for this group to agree to a consensus regarding what might best represent a model NMP that is consistent with environmental exposure for human health, and which can be used to support a variety of ongoing research needs, including those associated with exposure and hazard assessment, mechanistic toxicity studies, toxicokinetics and guidance regarding the prioritization of plastic and NMPs that likely represent the greatest risk to human health. It is important to acknowledge, however, that establishing a multidisciplinary group, or an expert community of practice, represents a non-trivial recommendation, and will require significant resources in terms of expertise and funding., Conclusion: There is currently an opportunity to bring together a multidisciplinary group of experts, including polymer chemists, material scientists, mechanical engineers, exposure and life-cycle assessment scientists, toxicologists, microbiologists and analytical chemists, to provide leadership and guidance regarding a consensus on defining what best represents environmentally relevant NMPs. We suggest that given the various complex issues surrounding the environmental and human health implications that exposure to NMPs represents, that a multidisciplinary group of experts are thus critical towards helping to progress the harmonization and standardization of methods., (© 2024. The Author(s).)

Background: Dyslipidemia has been associated with reduced bone mineral density and osteoporotic fractures, but the relation between lipid and bone metabolism remains poorly understood. Analysing the effects of lipoprotein subclasses on bone turnover may provide valuable insights into this association. We therefore examined whether lipoprotein subclasses, measured by proton nuclear magnetic resonance ( 1 H-NMR) spectroscopy, are associated with bone turnover markers (BTMs) and with the ultrasound-based bone stiffness index., Methods: Data from 1.349 men and 1.123 women, who participated in the population-based Study of Health in Pomerania-TREND were analysed. Serum intact amino-terminal propeptide of type I procollagen (P1NP, bone formation) and carboxy-terminal telopeptide of type I collagen (CTX, bone resorption) concentrations were measured. Associations between the lipoprotein data and the BTMs or the stiffness index were investigated using linear regression models., Results: The triglyceride or cholesterol content in very-low-density lipoprotein and intermediate-density lipoprotein particles was inversely associated with both BTMs, with effect estimates being slightly higher for CTX than for P1NP. The triglyceride content in low-density lipoprotein and high-density lipoprotein particles and the Apo-A2 content in high-density lipoprotein particles was further inversely associated with the BTMs. Associations with the ultrasound-based bone stiffness index were absent., Conclusions: Consistent inverse associations of triglycerides with bone turnover were observed, which argue for a protective effect on bone health, at least in the normal range. Yet, the presented associations did not translate into effects on the ultrasound-based bone stiffness. Further, there was no relevant gain of information by assessing the lipoprotein subclasses. Nevertheless, our study highlights the close relations between lipid and bone metabolism in the general population., (© 2024. The Author(s).)

Background: Multi-Arm, Multi-Stage (MAMS) clinical trial designs allow for multiple therapies to be compared across a spectrum of clinical trial phases. MAMS designs fall under several overarching design groups, including adaptive designs (AD) and multi-arm (MA) designs. Factorial clinical trials designs represent a combination of factorial and MAMS trial designs and can provide increased efficiency relative to fixed, traditional designs. We explore design choices associated with Factorial Adaptive Multi-Arm Multi-Stage (FAST) designs, which represent the combination of factorial and MAMS designs., Methods: Simulation studies were conducted to assess the impact of the type of analyses, the timing of analyses, and the effect size observed across multiple outcomes on trial operating characteristics for a FAST design. Given multiple outcomes types assessed within the hypothetical trial, the primary analysis approach for each assessment varied depending on data type., Results: The simulation studies demonstrate that the proposed class of FAST trial designs can offer a framework to potentially provide improvements relative to other trial designs, such as a MAMS or factorial trial. Further, we note that the design implementation decisions, such as the timing and type of analyses conducted throughout trial, can have a great impact on trial operating characteristics., Conclusions: Motivated by a trial currently under design, our work shows that the FAST category of trial can potentially offer benefits similar to both MAMS and factorial designs; however, the chosen design aspects which can be included in a FAST trial need to be thoroughly explored during the planning phase., (© 2024. The Author(s).)

Background: Environmental bacteria in animal healthcare facilities may constitute a risk for healthcare-associated infections (HAI). Knowledge of the bacterial microflora composition and factors influencing the environmental bacterial load can support tailored interventions to lower the risk for HAI. The aims of this study were to: (1) quantify and identify environmental bacteria in one operating room (OR) and one ultrasound room (UR) in a small animal hospital, (2) compare the bacterial load to threshold values suggested for use in human healthcare facilities, (3) characterise the genetic relationship between selected bacterial species to assess clonal dissemination, and (4) investigate factors associated with bacterial load during surgery. Settle plates were used for passive air sampling and dip slides for surface sampling. Bacteria were identified by Matrix Assisted Laser Desorption-Time Of Flight. Antimicrobial susceptibility was determined by broth microdilution. Single nucleotide polymorphism-analysis was performed to identify genetically related isolates. Linear regression was performed to analyse associations between observed explanatory factors and bacterial load., Results: The bacterial load on settle plates and dip slides were low both in the OR and the UR, most of the samples were below threshold values suggested for use in human healthcare facilities. All settle plates sampled during surgery were below the threshold values suggested for use in human clean surgical procedures. Staphylococcus spp. and Micrococcus spp. were the dominating species. There was no indication of clonal relationship among the sequenced isolates. Bacteria carrying genes conveying resistance to disinfectants were revealed. Air change and compliance with hygiene routines were sufficient in the OR. No other factors possibly associated with the bacterial load were identified., Conclusions: This study presents a generally low bacterial load in the studied OR and UR, indicating a low risk of transmission of infectious agents from the clinical environment. The results show that it is possible to achieve bacterial loads below threshold values suggested for use in human healthcare facilities in ORs in small animal hospitals and thus posing a reduced risk of HAI. Bacteria carrying genes conveying resistance to disinfectants indicates that resistant bacteria can persist in the clinical environment, with increased risk for HAI., (© 2024. The Author(s).)

Background: Major depressive disorder (MDD) poses a significant global health burden with available treatments limited by inconsistent efficacy and notable side effects. Classic psychedelics, including lysergic acid diethylamide (LSD), have garnered attention for their potential in treating psychiatric disorders. Microdosing, the repeated consumption of sub-hallucinogenic doses of psychedelics, has emerged as a self-treatment approach for depression within lay communities. Building upon preliminary evidence and the successful completion of an open-label pilot trial of microdosing LSD for depression (LSDDEP1), this protocol outlines a phase 2b randomised controlled trial (LSDDEP2). The main objective of LSDDEP2 is to assess the modification of depressive symptoms, measured by the Montgomery-Åsberg Depression Rating Scale (MADRS), following a regimen of LSD microdoses versus placebo., Methods: This is a randomised, double-dummy, triple-blind, active placebo-controlled, parallel groups trial of LSD microdosing in patients meeting DSM-5 criteria for major depressive disorder. Participants will undergo an 8-week LSD microdosing regimen using the titratable MB-22001 formulation taking two doses a week. All doses will be self-administered at home and will be titratable from 4 to 20 μg based on subjective perception and tolerability. In addition to depression symptoms, outcome will include psychiatric and personality inventories, sleep and activity tracking, electroencephalography (EEG), blood biomarkers, semi-structured interviews, and safety (e.g. adverse event, laboratory exam) measures., Discussion: This study will be the first randomised controlled trial to administer controlled microdoses of LSD for treatment of MDD in participants' naturalistic environment. The measures included are designed to assess the drug's safety, mechanism, and treatment efficacy over placebo in this population. The results of this study will be important for assessing the viability of psychedelic microdosing as an additional treatment option and for informing the direction of future clinical trials., Trial Registration: ANZCTR, ACTRN12624000128594. Prospectively Registered on 13 February 2024., (© 2024. The Author(s).)

Background: Individualized treatment for commercial tobacco smoking cessation, such as through the utilization of the nicotine metabolite ratio (NMR), offers potential clinical benefit. NMR is a metabolism-informed biomarker that can be used to guide medication selection. NMR testing is particularly promising for tobacco cessation efforts in populations with high rates of smoking, such as some Alaska Native and American Indian (AN/AI) communities. To date, no prior study has evaluated the implementation of NMR-guided tobacco cessation with AN/AI populations., Methods: The present "QUIT" protocol is a two-phase study that will occur at Southcentral Foundation (SCF), an Alaska Native-owned health system, serving 70,000 AN/AI people, based in Anchorage, Alaska. In Phase one, qualitative interviews with customer-owners (patients), providers and administrators (n = 36) and a 10-participant beta-test will be used to refine a strategy to implement NMR testing in the health system. Phase two will involve a single-arm pilot trial (n = 50) and qualitative interviews throughout data collection (n = 48) to evaluate the implementation strategy and explore the real-world acceptability and feasibility of NMR testing to guide tobacco cessation with AN/AI populations., Discussion: This study utilizes a community-based participatory approach to refine and implement a nicotine metabolism-informed smoking cessation program in a Tribal healthcare setting. The process and findings from this study will reflect the importance of customer-owner choice and honor the lived experience involved in quitting commercial tobacco. Pilot study data will inform the effect and sample sizes required for a future pragmatic trial of NMR-guided smoking cessation., Trial Registration: This study will be registered with clinicaltrials.gov after the beta test is complete and the final IRB protocol is approved., (© 2024. The Author(s).)

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children's Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP., (© 2024. The Author(s).)

Background: Infections caused by multi-drug resistant Gram-negative pathogens are associated with worse clinical outcomes in critically ill patients. We evaluated hospital outcomes based on adequacy of overall and newer antibacterial therapy for Enterobacterales (ENT) and Pseudomonas aeruginosa (PsA) in US patients., Methods: Hospitalized adults ≥ 18 years old with facility-reported antibiotic susceptibility from 2018-2022 across 161 facilities in the BD Insights Research Database were identified as ENT- or PsA-positive. Generalized linear mixed models were used to evaluate the impact of inadequate empiric therapy (IET) and time to initiate newer antibacterials (ceftazidime-avibactam; ceftolozane-tazobactam; cefiderocol; meropenem-vaborbactam; eravacycline; and imipenem-cilcastatin-relebactam) on hospital mortality and post-culture length of stay (LOS)., Results: Among 229,320 ENT and 36,027 PsA susceptibility results, 1.7% and 16.8% were carbapenem non-susceptible (carb-NS), respectively. Median time to first susceptibility result was longer for carb-NS vs. carb susceptible in ENT (64 h vs. 48 h) and PsA (67 h vs. 60 h). For ENT, IET was associated with significantly higher mortality (odds ratio [OR],1.29 [95% CI, 1.16-1.43, P < 0.0001]) and longer hospital LOS (14.8 vs. 13.3, P < 0.0001). Delayed start to newer antibacterial therapy was associated with significantly greater hospital mortality for ENT (P = 0.0182) and PsA (P = 0.0249) and significantly longer post-culture LOS for ENT (P < 0.0001) and PsA (P < 0.0001)., Conclusions: Overall, IET and delayed use of newer antibacterials are associated with significantly worse hospital outcomes. More rapid identification of high-risk patients can facilitate adequate therapy and timely use of newer antibacterials developed for resistant Gram-negative pathogens., (© 2024. The Author(s).)

Background: Renal cell carcinoma (RCC), one of the most fatal urologic tumors, accounts for approximately 3% of all adult cancers and exhibits a high metastatic index at diagnosis and a high rate of relapse. Radical or partial nephrectomy is a curative option for nonmetastatic RCCs. Targeted therapy has been shown to improve the survival of patients with metastatic RCCs. However, the underlying cellular and molecular events associated with RCC pathogenesis are not well known., Methods: To investigate the clinical role of the transcription factor activator protein (AP)-2α in RCC, methylated CpG island recovery assays and microarray analysis were employed. COBRA and RT‒qPCR assays were performed to assess AP-2α expression in RCC., Results: A negative correlation was noted between AP-2α mRNA expression levels and methylation status. Multivariate analyses showed that AP-2α mRNA was a major risk factor not only for overall and disease-free survival in RCC but also for disease-free survival in clear cell RCC., Conclusions: Our results indicated that AP-2α expression was deregulated in RCC and associated with overall patient survival and disease-free survival. Such findings suggest that AP-2α might play an important role in the pathogenesis of RCC., (© 2024. The Author(s).)

Background: Low health literacy is costly and observed among justice-impacted adults (JIA), a group that often faces numerous barriers in accessing healthcare and a disproportionate burden of illness. Health literacy interventions for JIA are critically needed to improve healthcare access and related outcomes., Methods: This manuscript describes the protocol for a longitudinal mixed-methods randomized clinical trial that assesses the effectiveness of a coach-guided health literacy intervention on JIA's healthcare access. The intervention was previously piloted with justice impacted adults. We will recruit 300 JIA ages 18 + in San Diego, California. Participants will be randomized 1:1 to the Treatment Group (i.e., coach-guided intervention providing 12 sessions of individualized health coaching and service navigation over 6 months) or the Control Group (i.e., self-study of the health coaching program, and brief service navigation support). We will quantitatively assess JIA's healthcare access defined as: use of healthcare, health insurance status, and regular source of care at 6-months as the primary outcomes. Participants will also be surveyed at 12-months. Statistical analyses will incorporate the intent-to-treat (ITT) principle and we will estimate mixed-effects logistic regression for the primary outcomes. We will also conduct qualitative interviews at 6 and 12-months with 40 purposively sampled participants, stratified by study arm, who reported healthcare access barriers at baseline. Interviews will explore participants' satisfaction with the intervention, healthcare attitudes, self-efficacy for and barriers to healthcare access over time, perceived contribution of the intervention to health and well-being, and diffusion of intervention-related information within participants' social networks. We will conduct deductive thematic analyses of qualitative data., Discussion: Low health literacy among JIA is a foundational challenge requiring tailored intervention strategies. Findings from this trial may inform policies and the structure of service delivery models to build health literacy among JIA in institutional and community settings throughout the United States and elsewhere., Trial Registration: This study is registered with the United States' ClinicalTrials.gov registry under protocol # 161,903., (© 2024. The Author(s).)

Background: Substance misuse poses a significant public health challenge, characterized by premature morbidity and mortality, and heightened healthcare utilization. While studies have demonstrated that previous hospitalizations and emergency department visits are associated with increased mortality in patients with substance misuse, it is unknown whether prior utilization of emergency medical service (EMS) is similarly associated with poor outcomes among this population. The objective of this study is to determine the association between EMS utilization in the 30 days before a hospitalization or emergency department visit and in-hospital outcomes among patients with substance misuse., Methods: We conducted a retrospective analysis of adult emergency department visits and hospitalizations (referred to as a hospital encounter) between 2017 and 2021 within the Substance Misuse Data Commons, which maintains electronic health records from substance misuse patients seen at two University of Wisconsin hospitals, linked with state agency, claims, and socioeconomic datasets. Using regression models, we examined the association between EMS use and the outcomes of in-hospital death, hospital length of stay, intensive care unit (ICU) admission, and critical illness events, defined by invasive mechanical ventilation or vasoactive drug administration. Models were adjusted for age, comorbidities, initial severity of illness, substance misuse type, and socioeconomic status., Results: Among 19,402 encounters, individuals with substance misuse who had at least one EMS incident within 30 days of a hospital encounter experienced a higher likelihood of in-hospital mortality (OR 1.52, 95% CI [1.05 - 2.14]) compared to those without prior EMS use, after adjusting for confounders. Using EMS in the 30 days prior to an encounter was associated with a small increase in hospital length of stay but was not associated with ICU admission or critical illness events., Conclusions: Individuals with substance misuse who have used EMS in the month preceding a hospital encounter are at an increased risk of in-hospital mortality. Enhanced monitoring of EMS users in this population could improve overall patient outcomes., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The current report investigates fusion rates and patient-reported outcomes following lumbar spinal surgery using cellular bone allograft (CBA) in patients with risk factors for non-union., Methods: A prospective, open label study was conducted in subjects undergoing lumbar spinal fusion with CBA (NCT02969616) to assess fusion success rates and patient-reported outcomes in subjects with risk factors for non-union. Subjects were categorized into low-risk (≤ 1 risk factors) and high-risk (> 1 risk factors) groups. Radiographic fusion status was evaluated by an independent review of dynamic radiographs and CT scans. Patient-reported outcome measures included quality of life (EQ-5D), Oswestry Disability Index (ODI) and Visual Analog Scales (VAS) for back and leg pain. Adverse event reporting was conducted throughout 24-months of follow-up., Results: A total of 274 subjects were enrolled: 140 subjects (51.1%) were categorized into the high-risk group (> 1 risk factor) and 134 subjects (48.9%) into the low-risk group (≤ 1 risk factors). The overall mean age at screening was 58.8 years (SD 12.5) with a higher distribution of females (63.1%) than males (36.9%). No statistical difference in fusion rates were observed between the low-risk (90.0%) and high-risk (93.9%) groups (p > 0.05). A statistically significant improvement in patient-reported outcomes (EQ-5D, ODI and VAS) was observed at all time points (p < 0.05) in both low and high-risk groups. The low-risk group showed enhanced improvement at multiple timepoints in EQ-5D, ODI, VAS-Back pain and VAS-Leg pain scores compared to the high-risk group (p < 0.05). The number of AEs were similar among risk groups., Conclusions: This study demonstrates high fusion rates following lumbar spinal surgery using CBA, regardless of associated risk factors. Patient reported outcomes and fusion rates were not adversely affected by risk factor profiles., Trial Registration: NCT02969616 (21/11/2016)., (© 2024. The Author(s).)

Background: Gut dysbiosis has been linked with both HIV infection and diabetes, but its interplay with metabolic and inflammatory responses in diabetes, particularly in the context of HIV infection, remains unclear., Methods: We first conducted a cross-sectional association analysis to characterize the gut microbial, circulating metabolite, and immune/inflammatory protein features associated with diabetes in up to 493 women (~ 146 with prevalent diabetes with 69.9% HIV +) of the Women's Interagency HIV Study. Prospective analyses were then conducted to determine associations of identified metabolites with incident diabetes over 12 years of follow-up in 694 participants (391 women from WIHS and 303 men from the Multicenter AIDS Cohort Study; 166 incident cases were recorded) with and without HIV infection. Mediation analyses were conducted to explore whether gut bacteria-diabetes associations are explained by altered metabolites and proteins., Results: Seven gut bacterial genera were identified to be associated with diabetes (FDR-q <  0.1), with positive associations for Shigella, Escherichia, Megasphaera, and Lactobacillus, and inverse associations for Adlercreutzia, Ruminococcus, and Intestinibacter. Importantly, the associations of most species, especially Adlercreutzia and Ruminococcus, were largely independent of antidiabetic medications use. Meanwhile, 18 proteins and 76 metabolites, including 3 microbially derived metabolites (trimethylamine N-oxide, phenylacetylglutamine (PAGln), imidazolepropionic acid (IMP)), 50 lipids (e.g., diradylglycerols (DGs) and triradylglycerols (TGs)) and 23 non-lipid metabolites, were associated with diabetes (FDR-q <  0.1), with the majority showing positive associations and more than half of them (59/76) associated with incident diabetes. In mediation analyses, several proteins, especially interleukin-18 receptor 1 and osteoprotegerin, IMP and PAGln partially mediate the observed bacterial genera-diabetes associations, particularly for those of Adlercreutzia and Escherichia. Many diabetes-associated metabolites and proteins were altered in HIV, but no effect modification on their associations with diabetes was observed by HIV., Conclusion: Among individuals with and without HIV, multiple gut bacterial genera, blood metabolites, and proinflammatory proteins were associated with diabetes. The observed mediated effects by metabolites and proteins in genera-diabetes associations highlighted the potential involvement of inflammatory and metabolic perturbations in the link between gut dysbiosis and diabetes in the context of HIV infection., (© 2024. The Author(s).)

Background: Researchers have highlighted the importance of early access to concussion care within one week of injury in reducing recovery times. However, a persisting question for concussion researchers is "just how early is important?" The purpose of this study was to examine differences in recovery time as predicted by the number of days elapsed since injury (DSI) to initial evaluation among patients who had access to a specialty concussion clinic within seven days. We hypothesized that DSI group membership, even within seven days, would significantly predict risk of protracted recovery (i.e., beyond 21 days)., Methods: In this archival study, retrospective data were gathered from electronic medical records between September 2020 to March 2022. Records of participants between ages 12-18, those diagnosed with a sports-related concussion based on initial clinic visit diagnosis by a medical provider and those who established care within seven days of injury at a large pediatric specialty concussion clinic were examined. Participants were divided into three DSI groups (patients seen in < 48 h: "acute", patients seen between 49 h < and < 96 h: "sub-acute", and patients seen between 97 < and < 168 h: "post-acute"). A general linear model was constructed to examine relationships between relevant concussion factors (e.g., Post Concussion Scale Score, neurodevelopmental history, psychiatric history, concussion history, migraine history, overall VOMS change score, cognitive testing, sex, age, race, and ethnicity) that were either significant in the preliminary analysis or in clinical judgement and recovery time. Adjusted odds ratios (OR) were derived from a binary logistic regression model, in which recovery time was normal (≤ 21 recovery days) or protracted (> 21 recovery days)., Results: A total of 856 participants were eligible. Adolescents in the acute group (M = 15.12, SD = 8.04) had shorter recovery times in days compared to those in the sub-acute (M = 17.98, SD = 10.18) and post-acute (M = 21.12, SD = 10.12; F = 26.00, p < .001) groups. Further, participants in the acute (OR = 4.16) and sub-acute (OR = 1.37) groups who accessed specialty concussion clinics within 48 h were 4 times more likely to have a normal recovery and recovered approximately 6 days faster than the post-acute care group., Conclusions: Earlier concussion care access predicted recovery times and was associated with lower risk for protracted recovery., (© 2024. The Author(s).)

Background: The hallux plays a crucial role in maintaining standing balance and facilitating forward and backward movements during gait., Case Presentation: A 21-year-old Japanese patient, suffering from a traumatic hallux deficit with only a portion of the basal phalanx intact, underwent rehabilitation treatment. The thenar area exhibited instability, leading to impaired balance and walking difficulties. Biomechanical assessment revealed the need for a rehabilitation strategy for the foot, as well as the knee, hip, and trunk. A rehabilitation protocol was designed to enhance medial foot loading during walking and standing, including balance and trunk strength training. After a 12-week rehabilitation period, the patient's gait showed significant improvement. Specifically, the load response and single-support phases of the gait cycle on the affected side increased from 46.9% to 49.3%, while the pre-swing phase decreased from 14.6% to 11.6%. The vertical component of the ground reaction force rose from 599.8 to 647.5 N. The enhanced stability from balance training and increased muscle strength contributed to the patient's improved walking and balance., Conclusion: A patient with a traumatic hallux deficit underwent conservative treatment through strategic rehabilitation according to biomechanical assessment. This case report underscores the value of biomechanical gait analysis in the conservative management of similar conditions., (© 2024. The Author(s).)

Background: Naloxone is an effective and safe opioid reversal medication now approved by the U.S. Food and Drug Administration (FDA) for use with or without a prescription. Despite this, naloxone dissemination lags at a time when U.S. opioid-related mortality expands. The authors proposed distributing naloxone to all U.S. medical students using established statewide standing prescription orders for naloxone, eliminating the financial burden of over-the-counter costs on students and streamlining workflow for the pharmacy. By focusing naloxone distribution on medical students, we are able to capitalize on a group that is already primed on healthcare intervention, while also working to combat stigma in the emerging physician workforce., Methods: Beginning August 2022, the authors established a partnership between Harvard Medical School (HMS) and the outpatient pharmacy at Brigham and Women's Hospital (BWH) to facilitate access to naloxone for HMS medical students. BWH developed a HIPAA-secure electronic form to collect individual prescription information. BWH pharmacists processed submissions daily, integrating the naloxone prescription requests into their workflow for in-person pick-up or mail-order delivery. The electronic form was disseminated to medical students through a required longitudinal addiction medicine curriculum, listserv messaging, and an extracurricular harm reduction workshop., Results: Over the 2022-2023 academic year, 63 medical students obtained naloxone kits (two doses per kit) through this collaboration., Conclusions: We propose that medical schools advocate for a hospital pharmacy-initiated workflow focused on convenience and accessibility to expand naloxone access to medical students as a strategy to strengthen the U.S. emergency response and prevention efforts aimed at reducing opioid-related morbidity and mortality. Expansion of our program to BWH internal medicine residents increased our distribution to over 110 healthcare workers, and efforts to expand the program to other BWH training programs and clinical sites such as the emergency department and outpatient infectious disease clinics are underway. With more than 90,000 medical students in the U.S., we believe that widespread implementation of targeted naloxone training and distribution to this population is an accessible approach to combating the public health crisis of opioid-related overdoses., (© 2024. The Author(s).)

Purpose: Percentage of positive cores involved on a systemic prostate biopsy has been established as a risk factor for adverse oncologic outcomes and is a National Comprehensive Cancer Network (NCCN) independent parameter for unfavorable intermediate-risk disease. Most data from a radiation standpoint was published in an era of conventional fractionation. We explore whether the higher biological dose delivered with SBRT can mitigate this risk factor., Methods: A large single institutional database was interrogated to identify all patients diagnosed with localized prostate cancer (PCa) treated with 5-fraction SBRT without ADT. Pathology results were reviewed to determine detailed core involvement as well as Gleason score (GS). High-volume biopsy core involvement was defined as ≥ 50%. Weighted Gleason core involvement was reviewed, giving higher weight to higher-grade cancer. The PSA kinetics and oncologic outcomes were analyzed for association with core involvement., Results: From 2009 to 2018, 1590 patients were identified who underwent SBRT for localized PCa. High-volume core involvement was a relatively rare event observed in 19% of our cohort, which was observed more in patients with small prostates (p < 0.0001) and/or intermediate-risk disease (p = 0.005). Higher PSA nadir was observed in those patients with low-volume core involvement within the intermediate-risk cohort (p = 0.004), which was confirmed when core involvement was analyzed as a continuous variable weighted by Gleason score (p = 0.049). High-volume core involvement was not associated with biochemical progression (p = 0.234)., Conclusions: With a median follow-up of over 4 years, biochemical progression was not associated with pretreatment high-volume core involvement for patients treated with 5-fraction SBRT alone. In the era of prostate SBRT and MRI-directed prostate biopsies, the use of high-volume core involvement as an independent predictor of unfavorable intermediate risk disease should be revisited., (© 2024. The Author(s).)

Background: Although whole-genome sequencing (WGS) is the preferred genotyping method for most genomic analyses, limitations are often experienced when studying genomes characterized by a high percentage of repetitive elements, high linkage, and recombination deserts. The Asian tiger mosquito (Aedes albopictus), for example, has a genome comprising up to 72% repetitive elements, and therefore we set out to develop a single-nucleotide polymorphism (SNP) chip to be more cost-effective. Aedes albopictus is an invasive species originating from Southeast Asia that has recently spread around the world and is a vector for many human diseases. Developing an accessible genotyping platform is essential in advancing biological control methods and understanding the population dynamics of this pest species, with significant implications for public health., Methods: We designed a SNP chip for Ae. albopictus (Aealbo chip) based on approximately 2.7 million SNPs identified using WGS data from 819 worldwide samples. We validated the chip using laboratory single-pair crosses, comparing technical replicates, and comparing genotypes of samples genotyped by WGS and the SNP chip. We then used the chip for a population genomic analysis of 237 samples from 28 sites in the native range to evaluate its usefulness in describing patterns of genomic variation and tracing the origins of invasions., Results: Probes on the Aealbo chip targeted 175,396 SNPs in coding and non-coding regions across all three chromosomes, with a density of 102 SNPs per 1 Mb window, and at least one SNP in each of the 17,461 protein-coding genes. Overall, 70% of the probes captured the genetic variation. Segregation analysis found that 98% of the SNPs followed expectations of single-copy Mendelian genes. Comparisons with WGS indicated that sites with genotype disagreements were mostly heterozygotes at loci with WGS read depth < 20, while there was near complete agreement with WGS read depths > 20, indicating that the chip more accurately detects heterozygotes than low-coverage WGS. Sample sizes did not affect the accuracy of the SNP chip genotype calls. Ancestry analyses identified four to five genetic clusters in the native range with various levels of admixture., Conclusions: The Aealbo chip is highly accurate, is concordant with genotypes from WGS with high sequence coverage, and may be more accurate than low-coverage WGS., (© 2024. The Author(s).)

Background: Affect can influence people's perceptions, decisions, and the way they make sense of an experience. Some studies show that having one's cell phone removed will lead to negative emotional reactions, while others have found no significant impact on how we feel. In this paper we investigate the impact of cell phone possession and removal on participant's affective state., Methods: We use a randomized double-blind procedure to examine whether cell phone removal enhances negativity, promotes positivity, or is emotionally inconsequential. We measure affect using a PANAS self-report scale as well as a less transparent temporal-estimation procedure., Results: Our findings suggest that cell phone possession or removal has no influence on a person's affective state., Conclusions: Measured through both the PANAS self-report scale and temporal estimation task, affect remained consistent regardless of cell phone possession. These results suggest that cell phones may not carry the emotional weight often attributed to them. This finding challenges a common theme revolving around the negative emotional impact of cell phones and technology. Consequently, these findings may have important implications for the generally perceived notion that cell phones are having a negative effect on people's emotions., (© 2024. The Author(s).)

The rapid increase of publicly available chemical structures and associated experimental data presents a valuable opportunity to build robust QSAR models for applications in different fields. However, the common concern is the quality of both the chemical structure information and associated experimental data. This is especially true when those data are collected from multiple sources as chemical substance mappings can contain many duplicate structures and molecular inconsistencies. Such issues can impact the resulting molecular descriptors and their mappings to experimental data and, subsequently, the quality of the derived models in terms of accuracy, repeatability, and reliability. Herein we describe the development of an automated workflow to standardize chemical structures according to a set of standard rules and generate two and/or three-dimensional "QSAR-ready" forms prior to the calculation of molecular descriptors. The workflow was designed in the KNIME workflow environment and consists of three high-level steps. First, a structure encoding is read, and then the resulting in-memory representation is cross-referenced with any existing identifiers for consistency. Finally, the structure is standardized using a series of operations including desalting, stripping of stereochemistry (for two-dimensional structures), standardization of tautomers and nitro groups, valence correction, neutralization when possible, and then removal of duplicates. This workflow was initially developed to support collaborative modeling QSAR projects to ensure consistency of the results from the different participants. It was then updated and generalized for other modeling applications. This included modification of the "QSAR-ready" workflow to generate "MS-ready structures" to support the generation of substance mappings and searches for software applications related to non-targeted analysis mass spectrometry. Both QSAR and MS-ready workflows are freely available in KNIME, via standalone versions on GitHub, and as docker container resources for the scientific community. Scientific contribution: This work pioneers an automated workflow in KNIME, systematically standardizing chemical structures to ensure their readiness for QSAR modeling and broader scientific applications. By addressing data quality concerns through desalting, stereochemistry stripping, and normalization, it optimizes molecular descriptors' accuracy and reliability. The freely available resources in KNIME, GitHub, and docker containers democratize access, benefiting collaborative research and advancing diverse modeling endeavors in chemistry and mass spectrometry., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: The purpose of this paper is to evaluate the impact of modifying the published scoring system to address identified potential weaknesses in the published scoring system for the Evaluation of Activity Surveys in Youth (EASY). A secondary purpose was to evaluate the EASY on children in Grades 1-5. The EASY is a self-report physical activity instrument for youth., Methods: Original EASY survey results were collected at one time point from an online panel from participants across the United States as part of a larger cross-sectional University of Minnesota project looking at children's specific activity and sports participation between June and August 2019. Data was evaluated using three common scoring methods: simple summation, mean, and transformed summation. Data was compared by Grades 1-5 and 6-8., Results: The summary statistics of the scores show that there is no statistically significant difference across the scoring methods by population. A paired t-test evaluation of the different scoring methods shows that while the scores are very similar within methodology (simple summation, mean, transformed sum) they are all statistically significantly different from one another, which demonstrates that for any given individual the specific scoring methodology used can result in meaningful differences. The transformed sum provided the strongest methodologic result. Analysis also concluded that administering the scale by proxy to children from grades 1-5 resulted in similar responses to those in Grades 6-8 broadening the appropriate populations able to use this scale., Conclusion: The transformed sum is the preferred scoring method., Trial Registration: Not applicable., (© 2024. The Author(s).)

Background: Public health programs are charged with implementing evidence-based interventions to support public health improvement; however, to achieve long-term population-based benefits, these interventions must be sustained. Empirical evidence suggests that program sustainability can be improved through training and technical assistance, but few resources are available to support public health programs in building capacity for sustainability., Methods: This study sought to build capacity for sustainability among state tobacco control programs through a multiyear, group-randomized trial that developed, tested, and evaluated a novel Program Sustainability Action Planning Model and Training Curricula. Using Kolb's experiential learning theory, we developed this action-oriented training model to address the program-related domains proven to impact capacity for sustainability as outlined in the Program Sustainability Framework. We evaluated the intervention using a longitudinal mixed-effects model using Program Sustainability Assessment (PSAT) scores from three time points. The main predictors in our model included group (control vs intervention) and type of dosage (active and passive). Covariates included state-level American Lung Association Score (proxy for tobacco control policy environment) and percent of CDC-recommended funding (proxy for program resources)., Results: Twenty-three of the 24 state tobacco control programs were included in the analyses: 11 received the training intervention and 12 were control. Results of the longitudinal mixed-effects linear regression model, where the annual PSAT score was the outcome, showed that states in the intervention condition reported significantly higher PSAT scores. The effects of CDC-recommended funding and American Lung Association smoke-free scores (proxy for policy environment) were small but statistically significant., Conclusion: This study found that the Program Sustainability Action Planning Model and Training Curricula was effective in building capacity for sustainability. The training was most beneficial for programs that had made less policy progress than others, implying that tailored training may be most appropriate for programs possibly struggling to make progress. Finally, while funding had a small, statistically significant effect on our model, it virtually made no difference for the average program in our study. This suggests that other factors may be more or equally important as the level of funding a program receives., Clinicaltrials: gov, NCT03598114. Registered on July 26, 2018., (© 2024. The Author(s).)

Background: Youth swimming performance is determined by several physiological, biomechanical and anthropometric characteristics. This review aimed to identify physical performance determinants of youth swimming performance, assessing strength, power, anaerobic, aerobic and body composition measures. ̇ METHODS: Searches were conducted in electronic databases (PubMed and Web of Science) using keywords relating to swimming and physiological measures, supplemented by citation searching of similar reviews. A total of 843 studies were identified in the initial search. The following inclusion criteria were used: participants were competitive/trained swimmers; swimming time-trial or event was conducted; data was provided on one or more physiological parameters; study was published in English and peer-reviewed. A total of 43 studies met the inclusion criteria. Risk of bias was assessed using Joanna Briggs Institute (JBI) checklist., Results: Cross-sectional studies scored between 4-8 and randomised-controlled trials scored 8-9 on their respective JBI checklists. Youth swimming performance was determined by muscle strength, muscle power, lean body mass, anaerobic and aerobic metabolism measures in most studies, where improved performance values of these variables were conducive to swimming performance. Body fat percentage did not have a clear relationship in youth swimming performance., Conclusions: Findings of this review suggest that greater levels of muscle strength, muscle power and lean body mass are favourable in swimming performance, with muscle strength and muscle power particularly beneficial for start and turn performance. Anaerobic and aerobic metabolism measures were good determinants of swimming performance, with middle- and long-distance events more influenced by the latter. Body fat percentage has a nuanced relationship with swimming performance, where further investigation is required. Findings were inconsistent across studies, potentially due to unidentified confounding factors., Key Points: • Greater muscular strength and power qualities, anaerobic and aerobic capacities, and lean body mass are conducive to swimming performance. • Body fat percentage has a nuanced relationship with swimming performance. • Practitioners should consider general strength and power training as a useful tool to enhance performance in their youth competitors., (© 2024. The Author(s).)

Background: Dermatomyositis is an idiopathic inflammatory myopathy characterised by rashes and progressive muscle weakness. The recent ProDERM (Progress in DERMatomyositis) study is the first large randomised, placebo-controlled trial to establish the efficacy and safety of intravenous immunoglobulin (IVIg) in adult patients with dermatomyositis. Objectives of this analysis were to closely examine the safety and tolerability of IVIg in patients from the ProDERM study., Methods: ProDERM was a double-blind, randomised, placebo-controlled, multicentre, phase 3 study. In the first period (weeks 0-16), adults with active dermatomyositis received 2.0 g/kg IVIg (Octagam 10%; Octapharma AG) or placebo every 4 weeks. In the open-label extension period (weeks 16-40), all patients received IVIg for 6 additional cycles; dose reduction (1.0 g/kg) was permitted if patients were stable. Treatment-emergent adverse events (TEAEs) were documented., Results: The 95 patients enrolled were randomised to receive IVIg (N = 47) or placebo (N = 48) in the first period, with 5 switching from placebo to IVIg. Overall, 664 IVIg infusion cycles were administered. During the first period, 113 TEAEs were possibly/probably related to treatment in 30/52 patients (57.7%) receiving IVIg and 38 in 11 patients (22.9%) on placebo. Eight patients discontinued therapy due to IVIg-related TEAEs. Eight thromboembolic events (TEEs) occurred in six patients on IVIg; six in five patients were deemed possibly/probably related to IVIg. Patients with TEEs exhibited more baseline TEE risk factors than those without TEEs (2.4-15.2-fold higher). Lowering infusion rate reduced the rate of TEEs, and none occurred at the lower IVIg dose. No haemolytic transfusion reactions or deaths occurred., Conclusions: Results from this study demonstrate that IVIg has a favourable safety profile for treatment of adult dermatomyositis patients and provides evidence that will help to inform treatment choice for these patients. Dermatomyositis patients receiving high-dose IVIg should be monitored for TEEs, and a low rate of infusion should be used to minimise TEE risk, particularly in those with pre-existing risk factors., Trial Registration: ProDERM study (NCT02728752)., (© 2024. The Author(s).)

Background: Patients diagnosed with low-risk prostate cancer (PCa) are confronted with a difficult decision regarding whether to undergo definitive treatment or to pursue an active surveillance protocol. This is potentially further complicated by the possibility that patients and physicians may place different value on factors that influence this decision. We conducted a qualitative investigation to better understand patient and physician perceptions of factors influencing treatment decisions for low-risk PCa., Methods: Semi-structured interviews were conducted among 43 racially and ethnically diverse patients diagnosed with low-risk PCa, who were identified through a population-based cancer registry, and 15 physicians who were selected to represent a variety of practice settings in the Greater San Francisco Bay Area., Results: Patients and physicians both described several key individual (e.g., clinical) and interpersonal (e.g., healthcare communications) factors as important for treatment decision-making. Overall, physicians' perceptions largely mirrored patients' perceptions. First, we observed differences in treatment preferences by age and stage of life. At older ages, there was a preference for less invasive options. However, at younger ages, we found varying opinions among both patients and physicians. Second, patients and physicians both described concerns about side effects including physical functioning and non-physical considerations. Third, we observed differences in expectations and the level of difficulty for clinical conversations based on information needs and resources between patients and physicians. Finally, we discovered that patients and physicians perceived patients' prior knowledge and the support of family/friends as facilitators of clinical conversations., Conclusions: Our study suggests that the gap between patient and physician perceptions on the influence of clinical and communication factors on treatment decision-making is not large. The consensus we observed points to the importance of developing relevant clinical communication roadmaps as well as high quality and accessible patient education materials., (© 2023. The Author(s).)

Background: Autologous bone grafts are the gold standard for spinal fusion; however, harvesting autologous bone can result in donor site infection, hematomas, increased operative time, and prolonged pain. Cellular bone allografts (CBAs) are a viable alternative that avoids the need for bone harvesting and may increase fusion success alone or when used as an adjunct material. The present study examined the efficacy and safety of CBA when used as an adjunct graft material to lumbar arthrodesis., Methods: A prospective, single-arm, multicenter clinical trial (NCT02969616) was conducted in adult subjects (> 18 years of age) undergoing lumbar spinal fusion with CBA graft (CBA used as primary (≥ 50% by volume), with augmentation up to 50%). Radiographic fusion status was assessed by an independent review of dynamic radiographs and CT scans. Clinical outcomes were assessed with the Oswestry Disability Index (ODI), and Visual Analog Scales (VAS) score for back and leg pain. Adverse events were assessed through the 24-month follow-up period. The presented data represents an analysis of available subjects (n = 86) who completed 24 months of postoperative follow-up at the time the data was locked for analysis., Results: Postoperative 24-month fusion success was achieved in 95.3% of subjects (n = 82/86) undergoing lumbar spinal surgery. Clinical outcomes showed statistically significant improvements in ODI (46.3% improvement), VAS-Back pain (75.5% improvement), and VAS-Leg pain (85.5% improvement) (p < 0.01) scores at Month 24. No subject characteristics or surgical factors were associated with pseudoarthrosis. A favorable safety profile with a limited number of adverse events was observed., Conclusions: The use of CBA as an adjunct graft material showed high rates of successful lumbar arthrodesis and significant improvements in pain and disability scores. CBA provides an alternative to autograft with comparable fusion success rates and clinical benefits., Trial Registration: NCT02969616., (© 2023. The Author(s).)

Background: Little is known about how physical activity influences the relationship between neuroticism and cognitive function and cognitive decline., Methods: Data from the Chicago Health and Aging Project (CHAP) was utilized to conduct this study. CHAP is a population-based cohort study of chronic conditions in older adults. Participants completed in-home interviews cycles of three years from 1993-2012. Mixed effects regression models were conducted to test the associations between physical activity, neuroticism, and the interaction between neuroticism and physical activity on outcomes: global cognitive function, global cognitive decline, episodic memory, decline in episodic memory, perceptual speed, and decline in perceptual speed. Stratified mixed effects regression models by physical activity level were conducted to test the associations between neuroticism and global cognitive function and global cognitive decline., Results: A total of 7,685 participants were eligible for this study. Participants were 62% female and 64% African American. We found statistically significant associations for the interaction of high physical activity and neuroticism on baseline global cognitive function (β = 0.017 (SE = 0.007), p = .010) and on the interaction of neuroticism and high physical activity on baseline episodic memory (β = 0.020 (SE = .009), p = .021) and on decline in episodic memory over time (β = -0.003 (SE = .001), p = .039)., Conclusion: Higher physical activity lessened the association between higher neuroticism and poor cognitive outcomes., (© 2023. The Author(s).)

Background: Limited information exists regarding how medical students' specialty interests evolve throughout medical school, particularly interest in surgical versus non-surgical specialties. Our objective was to identify medical students' specialty interests before and after medical school and the most important curricular and non-curricular factors that shaped their specialty choice., Methods: An online 22-question voluntary, anonymized survey was designed to assess specialty interests and factors impacting specialty choice at a single medical school in the United States. The study was pilot-tested with focus groups. The final questionnaire was distributed to final-year medical students from the Classes of 2020 and 2021. Responses were measured on a 5-point Likert scale (1 = strong negative impact to 5 = strong positive impact)., Results: 102 of 184 students (55%) from Class of 2020 and 85 of 174 students (49%) from Class of 2021 participated. Of 187 respondents, the majority (60%) decided on their specialty during third year. 74 of 147 students (50%) pursued a specialty among their initial specialty interests. Students with initial surgical interests were significantly (p < 0.001) less likely to choose surgical specialties (42%) compared to students with initial non-surgical interests choosing non-surgical specialties (79%). Pre-clinical years (3.67 ± 0.96) were perceived to have a significantly (p < 0.001) less positive impact on specialty interests and choice compared to clinical years. Among pre-clinical factors, physician shadowing (3.80 ± 0.83) was perceived to have the significantly (p < 0.001) greatest positive impact. During clinicals, 34% of respondents indicated that order of clerkships impacted specialty choice. 112 of 171 respondents (65%) indicated that mentorship impacted specialty choice. Physicians in the chosen specialty were perceived to have the strongest impact (4.67 ± 0.49). 65 of 171 respondents (38%) indicated that peers impacted specialty choice with classmates (3.98 ± 0.87) and near-peers (3.83 ± 0.74) perceived to have a positive impact., Conclusions: Specialty interests changed during medical school for a significant portion of students (50%). Those with initial surgical interests were more likely to change their specialty interests. Pre-clinicals were reported to have less impact on specialty choice compared to clinicals. Implementing factors such as shadowing and physician/peer mentorship, which may positively impact specialty choice, into pre-clinical curricula warrants further investigation., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Globally, an estimated 260 million people suffer from depression [1], and there is a clear need for the development of new, alternative antidepressant therapies. In light of problems with the tolerability and efficacy of available treatments [2], a global trend is emerging for patients to self-treat depression with microdoses of psychedelic drugs such as lysergic acid diethylamide (LSD) and psilocybin [3]. Beyond anecdotal reports from those who self-medicate in this way, few clinical trials have evaluated this practice. In our recently published phase 1 study in healthy volunteers [4], we determined that LSD microdosing was relatively safe and well tolerated in that cohort. Furthermore, the data demonstrated that conducting such microdosing trials is broadly feasible, with excellent adherence and compliance to the regimen observed. In this open-label pilot trial of patients with major depressive disorder (LSDDEP1), we will test the tolerability and feasibility of an 8-week regimen of LSD microdosing in this patient group prior to a larger subsequent randomised controlled trial (LSDDEP2)., Methods: Twenty patients meeting the DSM-5 criteria for major depressive disorder will receive an 8-week LSD microdosing treatment regimen. The treatment protocol will use a sublingual formulation of LSD (MB-22001) delivered twice per week under a titration schedule using a dose of 5-15 µg. Tolerability will be assessed by quantifying the percentage of participants who withdraw from the trial due to adverse events attributable to the treatment regimen, while feasibility will be assessed by quantifying the percentage of attended clinic visits once enrolled. To determine whether there is any antidepressant response to the LSD microdosing regimen, MADRS scores will be assessed at baseline and 2, 4, 6, and 8 weeks after the commencement of the regimen., Discussion: The results of LSDDEP1 will provide valuable information regarding the tolerability and feasibility of a proposed LSD microdosing regimen in patients with MDD. Such information is critically important to optimise trial design prior to commencing a subsequent and more resource-intensive randomised controlled trial., Trial Registration: ANZCTR, ACTRN12623000486628. Registered on 12 May 2023., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Polymorphic ventricular tachycardia (PMVT) is a rare genetic disease associated with structurally normal hearts which in 8% of cases can lead to sudden cardiac death, typically exercise-induced. We previously showed a link between the RyR2-H29D mutation and a clinical phenotype of short-coupled PMVT at rest using patient-specific hiPSC-derived cardiomyocytes (hiPSC-CMs). In the present study, we evaluated the effects of clinical and experimental anti-arrhythmic drugs on the intracellular Ca 2+ handling, contractile and molecular properties in PMVT hiPSC-CMs in order to model a personalized medicine approach in vitro., Methods: Previously, a blood sample from a patient carrying the RyR2-H29D mutation was collected and reprogrammed into several clones of RyR2-H29D hiPSCs, and in addition we generated an isogenic control by reverting the RyR2-H29D mutation using CRIPSR/Cas9 technology. Here, we tested 4 drugs with anti-arrhythmic properties: propranolol, verapamil, flecainide, and the Rycal S107. We performed fluorescence confocal microscopy, video-image-based analyses and biochemical analyses to investigate the impact of these drugs on the functional and molecular features of the PMVT RyR2-H29D hiPSC-CMs., Results: The voltage-dependent Ca 2+ channel inhibitor verapamil did not prevent the aberrant release of sarcoplasmic reticulum (SR) Ca 2+ in the RyR2-H29D hiPSC-CMs, whereas it was prevented by S107, flecainide or propranolol. Cardiac tissue comprised of RyR2-H29D hiPSC-CMs exhibited aberrant contractile properties that were largely prevented by S107, flecainide and propranolol. These 3 drugs also recovered synchronous contraction in RyR2-H29D cardiac tissue, while verapamil did not. At the biochemical level, S107 was the only drug able to restore calstabin2 binding to RyR2 as observed in the isogenic control., Conclusions: By testing 4 drugs on patient-specific PMVT hiPSC-CMs, we concluded that S107 and flecainide are the most potent molecules in terms of preventing the abnormal SR Ca 2+ release and contractile properties in RyR2-H29D hiPSC-CMs, whereas the effect of propranolol is partial, and verapamil appears ineffective. In contrast with the 3 other drugs, S107 was able to prevent a major post-translational modification of RyR2-H29D mutant channels, the loss of calstabin2 binding to RyR2. Using patient-specific hiPSC and CRISPR/Cas9 technologies, we showed that S107 is the most efficient in vitro candidate for treating the short-coupled PMVT at rest., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Inclusions of TAR DNA-binding protein 43 kDa (TDP-43) has been designated limbic-predominant, age-related TDP-43 encephalopathy (LATE), with or without co-occurrence of Alzheimer's disease (AD). Approximately, 30-70% AD cases present TDP-43 proteinopathy (AD-TDP), and a greater disease severity compared to AD patients without TDP-43 pathology. However, it remains unclear to what extent TDP-43 dysfunction is involved in AD pathogenesis., Methods: To investigate whether TDP-43 dysfunction is a prominent feature in AD-TDP cases, we evaluated whether non-conserved cryptic exons, which serve as a marker of TDP-43 dysfunction in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD-TDP), accumulate in AD-TDP brains. We assessed a cohort of 192 post-mortem brains from three different brain regions: amygdala, hippocampus, and frontal cortex. Following RNA and protein extraction, qRT-PCR and immunoassays were performed to quantify the accumulation of cryptic RNA targets and phosphorylated TDP-43 pathology, respectively., Results: We detected the accumulation of misspliced cryptic or skiptic RNAs of STMN2, KCNQ2, UNC13A, CAMK2B, and SYT7 in the amygdala and hippocampus of AD-TDP cases. The topographic distribution of cryptic RNA accumulation mimicked that of phosphorylated TDP-43, regardless of TDP-43 subtype classification. Further, cryptic RNAs efficiently discriminated AD-TDP cases from controls., Conclusions: Overall, our results indicate that cryptic RNAs may represent an intriguing new therapeutic and diagnostic target in AD, and that methods aimed at detecting and measuring these species in patient biofluids could be used as a reliable tool to assess TDP-43 pathology in AD. Our work also raises the possibility that TDP-43 dysfunction and related changes in cryptic splicing could represent a common molecular mechanism shared between AD-TDP and FTLD-TDP., (© 2023. Editorial Group and BioMed Central Ltd., part of Springer Nature.)

Background: Despite substantial illness burden and healthcare utilization conferred by pain from vaso-occlusive episodes (VOE) in children with sickle cell disease (SCD), disease-modifying therapies to effectively treat SCD-VOE are lacking. The aim of the Sickle Cell Disease Treatment with Arginine Therapy (STArT) Trial is to provide definitive evidence regarding the efficacy of intravenous arginine as a treatment for acute SCD-VOE among children, adolescents, and young adults., Methods: STArT is a double-blind, placebo-controlled, randomized, phase 3, multicenter trial of intravenous arginine therapy in 360 children, adolescents, and young adults who present with SCD-VOE. The STArT Trial is being conducted at 10 sites in the USA through the Pediatric Emergency Care Applied Research Network (PECARN). Enrollment began in 2021 and will continue for 5 years. Within 12 h of receiving their first dose of intravenous opioids, enrolled participants are randomized 1:1 to receive either (1) a one-time loading dose of L-arginine (200 mg/kg with a maximum of 20 g) administered intravenously followed by a standard dose of 100 mg/kg (maximum 10 g) three times a day or (2) a one-time placebo loading dose of normal saline followed by normal saline three times per day at equivalent volumes and duration as the study drug. Participants, research staff, and investigators are blinded to the participant's randomization. All clinical care is provided in accordance with the institution-specific standard of care for SCD-VOE based on the 2014 National Heart, Lung, and Blood Institute guidelines. The primary outcome is time to SCD-VOE pain crisis resolution, defined as the time (in hours) from study drug delivery to the last dose of parenteral opioid delivery. Secondary outcomes include total parental opioid use and patient-reported outcomes. In addition, the trial will characterize alterations in the arginine metabolome and mitochondrial function in children with SCD-VOE., Discussion: Building on the foundation of established relationships between emergency medicine providers and hematologists in a multicenter research network to ensure adequate participant accrual, the STArT Trial will provide definitive information about the efficacy of intravenous arginine for the treatment of SCD-VOE for children., Trial Registration: The STArT Trial was registered in ClinicalTrials.gov on April 9, 2021, and enrollment began on June 21, 2021 (NCT04839354)., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Palliative care is an effective model of care focused on maximizing quality of life and relieving the suffering of people with serious illnesses, including dementia. Evidence shows that many people receiving care in nursing homes are eligible for and would benefit from palliative care services. Yet, palliative care is not consistently available in nursing home settings. There is a need to test pragmatic strategies to implement palliative care programs in nursing homes., Methods/design: The UPLIFT-AD (Utilizing Palliative Leaders in Facilities to Transform care for people with Alzheimer's Disease) study is a pragmatic stepped wedge trial in 16 nursing homes in Maryland and Indiana, testing the effectiveness of the intervention while assessing its implementation. The proposed intervention is a palliative care program, including 1) training at least two facility staff as Palliative Care Leads, 2) training for all staff in general principles of palliative care, 3) structured screening for palliative care needs, and 4) on-site specialty palliative care consultations for a one-year intervention period. All residents with at least moderate cognitive impairment, present in the facility for at least 30 days, and not on hospice at baseline are considered eligible. Opt-out consent is obtained from legal decision-makers. Outcome assessments measuring symptoms and quality of care are obtained from staff and family proxy respondents at four time points: pre-implementation (baseline), six months after implementation, at 12 months (conclusion of implementation), and six months after the end of implementation. Palliative care attitudes and practices are assessed through surveys of frontline nursing home staff both pre- and post-implementation. Qualitative and quantitative implementation data, including fidelity assessments and interviews with Palliative Care Leads, are also collected. The study will follow the Declaration of Helsinki., Discussion: This trial assesses the implementation and effectiveness of a robust palliative care intervention for residents with moderate-to-advanced cognitive impairment in 16 diverse nursing homes. The intervention represents an innovative, pragmatic approach that includes both internal capacity-building of frontline nursing home staff, and support from external palliative care specialty consultants., Trial Registration: The project is registered on ClinicalTrials.gov: NCT04520698., (© 2023. The Author(s).)

Background: Trust is essential for healthy, reciprocal relationships; creating safe environments; engaging in transparent interactions; successfully negotiating power differentials; supporting equity and putting trauma informed approaches into practice. Less is known, however, about the ways that trust-building may be at the forefront of consideration during community capacity building efforts, what trust-building elements are perceived as essential for optimally engaging communities, and what practices might support these efforts., Methods: The present study examines an evolving understanding of trust-building over the course of 3 years, from qualitative data derived during interviews with nine agency leads from a large and diverse urban community, who are spearheading community-based partnerships to create more trauma-informed communities and foster resiliency., Results: Data reflected fourteen trust-building elements, captured by three themes: 1) Building relationships and engagement (e.g., behavioral practices such as meeting people "where they are at" and creating safe spaces), 2) Embodying core values of trustworthiness (e.g., traits such as being transparent and embodying benevolence), and 3) Sharing decision-making, championing autonomy, and addressing barriers to trust (e.g., collaborative practices such as creating a shared vision and goals and addressing systemic inequities). These trust-building elements are presented in the Community Circle of Trust-Building, which provides an accessible, visual format that can facilitate capacity building efforts within organizations and with the broader community; guide the selection of training opportunities that support healthy interpersonal relationships; and aid in the identification of relevant, supporting frameworks (e.g., health equity, trauma-informed practices, inclusive leadership models)., Conclusions: Community engagement and trust are essential for overall health and well-being, increasing equitable access to resources, and supporting an effective and connected citizenry. These data shed light on opportunities for trust-building and thoughtful engagement among agencies working directly with community members in large urban areas., (© 2023. The Author(s).)

Background: The prevalence of type 1 diabetes (T1D) is increasing in low-income countries including Malawi. In this setting, care is frequently impacted by challenges in diagnosis and management. Access to high-quality T1D care remains limited in Malawi, with fairly low availability and high cost of insulin and other supplies and diagnostics, lack of T1D knowledge, and absence of readily accessible guidelines. In the Neno district, Partners In Health established advanced care clinics at district hospitals to provide comprehensive, free care for T1D and other noncommunicable diseases. Prior to this study, experiences in care for people living with T1D (PLWT1D) at these clinics remained unexplored. Here we examine the impact of living with T1D, knowledge and self-management of, and facilitators and barriers to T1D care in Neno District, Malawi., Methods: We conducted a qualitative study utilizing behavior change theory that consisted of twenty-three semi-structured interviews conducted in Neno, Malawi in January 2021 with PLWT1D, their families, providers, and civil society members to explore the psychosocial and economic impact of living with T1D, T1D knowledge and self-management, and facilitators and barriers to accessing care. Interviews were analyzed thematically using a deductive approach., Results: We found that PLWT1D had good knowledge and practice of self-management activities for T1D. Key facilitators to care identified by informants included extensive patient education and availability and provision of free insulin and supplies. Significant barriers included distance from health facilities, food insecurity, and low literacy/numeracy. Informants described T1D as having a notable psychosocial and economic impact on PWLT1D and their families, notably worrying about having a lifelong condition, high transportation costs, and reduced working ability. While home visits and transport refunds helped facilitate access to the clinic, informants reported the refunds as inadequate given high transport costs faced by patients., Conclusions: T1D was found to have a significant impact on PLWT1D and their families. Our findings represent important areas of consideration in design and implementation of effective programs for treating PLWT1D in resource-limited settings. Facilitators to care identified by informants may be applicable and beneficial in similar settings, while persisting barriers represent areas for continued improvement in Neno., (© 2023. The Author(s).)