Design of a Tool Capable of Assessing Environmental Sociocultural Physical Factors Influencing Women's Decisions on When and Where to Toilet Within Real-World Settings: Protocol for the Build and Usability Testing of a Mobile App for Use by Community-Dwelling Women.

BACKGROUND: Although surveys and apps are available for women to report urination and bladder symptoms, they do not include their decisions regarding toileting. Real-world factors can interfere with toileting decisions, which may then influence bladder health. This premise lacks data per want of a robust data collection tool. OBJECTIVE: The Prevention of Lower Urinary Tract Symptoms (PLUS) research consortium engaged a transdisciplinary team to build and test WhereIGo, a mobile data collection app for Android and iOS. The design goal was a comprehensive reporting system for capturing environmental, sociocultural, and physical factors that influence women's decisions for toileting. Aims include having (1) an innovative feature for reporting physiologic urge sensation when "thinking about my bladder" and shortly before "I just peed," (2) real-time reporting along with short look-back opportunities, and (3) ease of use anywhere. METHODS: The development team included a plain language specialist, a usability specialist, creative designers, programming experts, and PLUS scientific content experts. Both real-time and ecological momentary assessments were used to comprehensively capture influences on toileting decisions including perceived access to toileting, degree of busyness or stress or focus, beverage intake amount, urge degree, or a leakage event. The restriction on the maximal number of taps for any screen was six. PLUS consortium investigators did pilot-testing. Formal usability testing relied on the recruitment of community-dwelling women at four PLUS research sites. Women used the app for 2 consecutive days. Outcome measures were the system usability scale (SUS; 0-100 range) and the functional Mobile Application Rating Scale (1-5 range). These scales were embedded at the end of the app. The estimated a priori sample size needed, considering the SUS cut point score set at ≥74, was 40 women completing the study. RESULTS: Funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases since July 2015. The integrity of the build process was documented through multiple 5-minute videos presented to PLUS Consortium and through WhereIGo screenshots of the final product. Participants included 44 women, with 41 (93%) completing data collection. Participants ranged in age from 21 to 85 years, were predominantly non-Hispanic White (n=25, 57%), college-educated (n=25, 57%), and with incomes below US $75,000 (n=27, 62%). The SUS score was 78.0 (SE 1.7), which was higher than 75% of the 500 products tested by the SUS developers. The mean functional Mobile Application Rating Scale score was 4.4 (SE 0.08). The build and informal acceptability testing were completed in 2019, enrollment for formal usability testing completed by June 2020, and analysis was completed in 2022. CONCLUSIONS: WhereIGo is a novel app with good usability for women to report toileting decisions, urination, and fluid intake. Future research using the app could test the influence of real-time factors on bladder health. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/54046.

Synergistic effects of biological stimuli and flexion induce microcavities promote hypertrophy and inhibit chondrogenesis during in vitro culture of human mesenchymal stem cell aggregates.

Interzone/cavitation are key steps in early stage joint formation that have not been successfully developed in vitro. Further, current models of endochondral ossification, an important step in early bone formation, lack key morphology morphological structures such as microcavities found during development in vivo. This is possibly due to the lack of appropriate strategies for incorporating chemical and mechanical stimuli that are thought to be involved in joint development. We designed a bioreactor system and investigated the synergic effect of chemical stimuli (chondrogenesis-inducing [CIM] and hypertrophy-inducing medium [HIM]) and mechanical stimuli (flexion) on the growth of human mesenchymal stem cells (hMSCs) based linear aggregates under different conditions over 4 weeks of perfusion culture. Computational studies were used to evaluate tissue stress qualitatively. After harvesting, both Safranin-O and hematoxylin & eosin (H&E) staining histology demonstrated microcavity structures and void structures in the region of higher stresses for tissue aggregates cultured only in HIM under flexion. In comparison to either HIM treatment or flexion only, increased glycosaminoglycan (GAG) content in the extracellular matrix (ECM) at this region indicates the morphological change resembles the early stage of joint cavitation; while decreased type II collagen (Col II), and increased type X collagen (Col X) and vascular endothelial growth factor (VEGF) with a clear boundary in the staining section indicates it resembles the early stage of ossification. Further, cell alignment analysis indicated that cells were mostly oriented toward the direction of flexion in high-stress region only in HIM under flexion, resembling cell morphology in both joint cavitation and hypertrophic cartilage in growth plate. Collectively, our results suggest that flexion and HIM inhibit chondrogenesis and promote hypertrophy and development of microcavities that resemble the early stage of joint cavitation and endochondral ossification. We believe the tissue model described in this work can be used to develop in vitro models of joint tissue for applications such as pathophysiology and drug discovery.

Age and sex associated organ weight differences in vervets/African green monkeys (Chlorocebus aethiops sabaeus).

BACKGROUND: African green monkeys (AGMs, also known as vervets, Cholorocebus aethiops sabaeus) have been used in a variety of biomedical research studies. The aim of this study was to generate a reference for normal organ weights and percentage organ weights in AGMs of different age categories and sex. METHODS: The organ weights were compiled from 479 AGMs (285 females and 194 males) from 2004 to 2021. Age and sex differences of absolute and relative organ weights were analyzed using analysis of variance. RESULTS: The findings demonstrate that males had higher body and organ weights than age­matched females, but relative organ weights did not differ between males and females. At maturity, adrenal gland, brain, kidney, liver, thymus, and thyroid gland weights as a percentage of body weight declined, but relative weights of prostate gland, testes, and uterus were higher. CONCLUSION: These data should be beneficial to biomedical researchers and pathologists working with AGMs.

Adsorption of methane by modified-biochar aiming to improve the gaseous fuels storage/transport capacity: process evaluation and modeling.

The CH4 storage by adsorption on activated carbons for natural gas handling has gained interest due to the appearance of lightweight materials with large surface areas and pore volumes. Consequently, kinetic parameters estimation of the adsorptive process can play a crucial role in understanding and scaling up the system. Concerning its versatility, banana peel (BP) is a biomass with potential for obtaining different products, such as biochar, a solid residue from the biomass' thermal decomposition of difficult disposal, where through an activation process, the material porous features are taken advantage to application as adsorbent of gaseous substances. This research reported data for the CH4 adsorption kinetic modeling by biochar from BP pyrolysis. The activated biochar textural characterization showed particles with fine mesoporous structure (pore diameter ranging between 29.39 and 55.62 Å). Adsorption kinetic analysis indicated that a modified pseudo-first-order model was the most suitable to represent the experimental data, with equilibrium adsorption of 28 mg g-1 for the samples activated with 20.0% vol wt.-1 of H3PO4 and pyrolysis at 500 °C. The equilibrium constant was consistent with the Freundlich isotherm model, suggesting a physisorption mechanism, and led to a non-ideal, reversible, and not limited to monolayer CH4 adsorption.

Gene expression and chromatin conformation of microglia in virally suppressed people with HIV.

The presence of HIV in sequestered reservoirs is a central impediment to a functional cure, allowing HIV to persist despite life-long antiretroviral therapy (ART), and driving a variety of comorbid conditions. Our understanding of the latent HIV reservoir in the central nervous system is incomplete, because of difficulties in accessing human central nervous system tissues. Microglia contribute to HIV reservoirs, but the molecular phenotype of HIV-infected microglia is poorly understood. We leveraged the unique "Last Gift" rapid autopsy program, in which people with HIV are closely followed until days or even hours before death. Microglial populations were heterogeneous regarding their gene expression profiles but showed similar chromatin accessibility landscapes. Despite ART, we detected occasional microglia containing cell-associated HIV RNA and HIV DNA integrated into open regions of the host's genome (∼0.005%). Microglia with detectable HIV RNA showed an inflammatory phenotype. These results demonstrate a distinct myeloid cell reservoir in the brains of people with HIV despite suppressive ART. Strategies for curing HIV and neurocognitive impairment will need to consider the myeloid compartment to be successful.

Results of Integrated Transmission Assessment Surveys for Lymphatic Filariasis and Malaria in Haiti, 2017-2022.

Haiti is endemic for lymphatic filariasis (LF) and malaria, two mosquito-transmitted parasitic diseases targeted for elimination. The World Health Organization recommends a transmission assessment survey (TAS-1) to determine if LF prevalence is significantly beneath putative transmission thresholds (<2% antigen prevalence in Haiti, where Culex is the primary vector for Wuchereria bancrofti) to stop mass drug administration (MDA). Repeated TASs (TAS-2 and TAS-3) are recommended at 2-3-year intervals during post-treatment surveillance. From 2017 to 2022, The Carter Center assisted the Haitian Ministry of Public Health and Population in conducting 15 TASs in 11 evaluation units (EUs) encompassing 54 of the country's 146 districts. Children 6-7 years old were assessed for circulating filarial antigen (CFA) by Filariasis Test Strip: n = 5,239 in TAS-1; n = 11,866 in TAS-2; and n = 1,842 in TAS-3, of whom eight (0.15%), 20 (0.17%), and eight (0.43%) tested positive, respectively. The number of positive results in children was less than the threshold in each EU. When available, participants (n = 16,663) were also tested for malaria by rapid diagnostic test, with 31 (0.19%) children testing positive for Plasmodium falciparum. Integrated TASs provided an efficient means to collect epidemiological data for LF and malaria in Haiti. Results indicated thresholds for stopping and maintaining the halt of MDA for LF have been achieved in all EUs, with the halt of MDA for 571,358 people in four districts and the first TAS-3 surveys conducted in Haiti. Investigations are needed to assess the potential of ongoing LF transmission, especially in areas where CFA-positive samples were detected in TAS-3.

Exploring women's bladder self-care practices: A qualitative secondary analysis.

AIMS: To describe women's experiences with a range of bladder self-care practices. DESIGN: We conducted a secondary, directed content analysis of qualitative data from the Study of Habits, Attitudes, Realities and Experiences, a multisite focus group study designed to explore adolescent and adult women's experiences, perceptions, beliefs, knowledge and behaviours related to bladder health. This study was conducted by the National Institute of Diabetes and Digestive and Kidney Diseases' Prevention of Lower Urinary Tract Symptoms Research Consortium. Study methods were informed by the Consortium's conceptual framework, based on a social ecological model adapted from Glass and McAtee's Society-Behavior-Biology Nexus. METHODS: Participants were recruited at seven geographically diverse United States research centres between July 2017 and April 2018. Data for the current analysis were collected using a semi-structured discussion group with 36 focus groups involving 316 community-dwelling adult women aged 18-93 years. Coded text was re-examined according to eight self-care behavioural domains identified through literature review and expert opinion as potentially influencing bladder health. RESULTS: Participants described many self-care practices they had adopted to prevent bladder problems or manage existing symptoms and conditions. Eight themes were identified: 'Choosing fluids, foods and medications'; 'Dressing for bladder health'; 'Promoting bodily cleanliness'; 'Managing toileting environments'; 'Timing when to void'; 'Exercising pelvic floor muscles for bladder control'; 'Limiting physical activities that challenge the bladder' and 'Staying home and navigating when away'. Thirteen subthemes were derived from five of the eight themes. CONCLUSION: Women use a broad array of self-care practices related to their bladder health. Research is needed to examine the efficacy of self-care behaviours for preventing or managing bladder symptoms and conditions, and to discern potential risks. Results have important implications for development of bladder health promotion interventions and public health messaging around women's bladder health. IMPLICATIONS FOR THE PROFESSION AND/OR PATIENT CARE: This study provides a comprehensive framework for understanding women's bladder self-care practices, which can be used by clinicians and public health professionals in designing interventions to promote bladder health and function. IMPACT: Women with and without lower urinary tract symptoms use a broad range of self-care practices that may affect their bladder health, including some that may be harmful. Because of the high prevalence of bladder symptoms in women, this study may help patient assessment and counselling regarding self-care practices. REPORTING METHOD: This study was reported according to the Standards for Reporting Qualitative Research (SRQR). PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution.

Analysis of Cerebrospinal Fluid, Plasma ß-Amyloid Biomarkers, and Cognition from a 2-Year Phase 2 Trial Evaluating Oral ALZ-801/Valiltramiprosate in APOE4 Carriers with Early Alzheimer's Disease Using Quantitative Systems Pharmacology Model.

INTRODUCTION: ALZ-801/valiltramiprosate is an oral, small-molecule inhibitor of beta-amyloid (Aß) aggregation and oligomer formation in late-stage development as a disease-modifying therapy for early Alzheimer's disease (AD). The present investigation provides a quantitative systems pharmacology (QSP) analysis of amyloid fluid biomarkers and cognitive results from a 2-year ALZ-801 Phase 2 trial in APOE4 carriers with early AD. METHODS: The single-arm, open-label phase 2 study evaluated effects of ALZ-801 265 mg two times daily (BID) on cerebrospinal fluid (CSF) and plasma amyloid fluid biomarkers over 104 weeks in APOE4 carriers with early AD [Mini-Mental State Examination (MMSE) ≥ 22]. Subjects with positive CSF biomarkers for amyloid (Aß42/Aß40) and tau pathology (p-tau181) were enrolled, with serial CSF and plasma levels of Aß42 and Aß40 measured over 104 weeks. Longitudinal changes of CSF Aß42, plasma Aß42/Aß40 ratio, and cognitive Rey Auditory Verbal Learning Test (RAVLT) were compared with the established natural disease trajectories in AD using a QSP approach. The natural disease trajectory data for amyloid biomarkers and RAVLT were extracted from a QSP model and an Alzheimer's disease neuroimaging initiative population model, respectively. Analyses were stratified by disease severity and sex. RESULTS: A total of 84 subjects were enrolled. Excluding one subject who withdrew at the early stage of the trial, data from 83 subjects were used for this analysis. The ALZ-801 treatment arrested the progressive decline in CSF Aß42 level and plasma Aß42/Aß40 ratio, and stabilized RAVLT over 104 weeks. Both sexes showed comparable responses to ALZ-801, whereas mild cognitive impairment (MCI) subjects (MMSE ≥ 27) exhibited a larger biomarker response compared with more advanced mild AD subjects (MMSE 22-26). CONCLUSIONS: In this genetically defined and biomarker-enriched early AD population, the QSP analysis demonstrated a positive therapeutic effect of oral ALZ-801 265 mg BID by arresting the natural decline of monomeric CSF and plasma amyloid biomarkers, consistent with the target engagement to prevent their aggregation into soluble neurotoxic oligomers and subsequently into insoluble fibrils and plaques over 104 weeks. Accompanying the amyloid biomarker changes, ALZ-801 also stabilized the natural trajectory decline of the RAVLT memory test, suggesting that the clinical benefits are consistent with its mechanism of action. This sequential effect arresting the disease progression on biomarkers and cognitive decline was more pronounced in the earlier symptomatic stages of AD. The QSP analysis provides fluid biomarker and clinical evidence for ALZ-801 as a first-in-class, oral small-molecule anti-Aß oligomer agent with disease modification potential in AD. TRIAL REGISTRY: https://clinicaltrials.gov/study/NCT04693520.

Effects of Oral ALZ-801/Valiltramiprosate on Plasma Biomarkers, Brain Hippocampal Volume, and Cognition: Results of 2-Year Single-Arm, Open-Label, Phase 2 Trial in APOE4 Carriers with Early Alzheimer's Disease.

INTRODUCTION: ALZ-801/valiltramiprosate is a small-molecule oral inhibitor of beta amyloid (Aß) aggregation and oligomer formation being studied in a phase 2 trial in APOE4 carriers with early Alzheimer's disease (AD) to evaluate treatment effects on fluid and imaging biomarkers and cognitive assessments. METHODS: The single-arm, open-label phase 2 trial was designed to evaluate the effects of the ALZ-801 265 mg tablet taken twice daily (after 2 weeks once daily) on plasma fluid AD biomarkers, hippocampal volume (HV), and cognition over 104 weeks in APOE4 carriers. The study enrolled subjects aged 50-80 years, with early AD [Mini-Mental State Examination (MMSE) ≥ 22, Clinical Dementia Rating-Global (CDR-G) 0.5 or 1], apolipoprotein E4 (APOE4) genotypes including APOE4/4 and APOE3/4 genotypes, and positive cerebrospinal fluid (CSF) AD biomarkers or prior amyloid scans. The primary outcome was plasma p-tau181, HV evaluated by magnetic resonance imaging (MRI) was the key secondary outcome, and plasma Aß42 and Aß40 were the secondary biomarker outcomes. The cognitive outcomes were the Rey Auditory Verbal Learning Test and the Digit Symbol Substitution Test. Safety and tolerability evaluations included treatment-emergent adverse events and amyloid-related imaging abnormalities (ARIA). The study was designed and powered to detect 15% reduction from baseline in plasma p-tau181 at the 104-week endpoint. A sample size of 80 subjects provided adequate power to detect this difference at a significance level of 0.05 using a two-sided paired t-test. RESULTS: The enrolled population of 84 subjects (31 homozygotes and 53 heterozygotes) was 52% females, mean age 69 years, MMSE 25.7 [70% mild cognitive impairment (MCI), 30% mild AD] with 55% on cholinesterase inhibitors. Plasma p-tau181 reduction from baseline was significant (31%, p = 0.045) at 104 weeks and all prior visits; HV atrophy was significantly reduced (p = 0.0014) compared with matched external controls from an observational Early AD study. Memory scores showed minimal decline from baseline over 104 weeks and correlated significantly with decreased HV atrophy (Spearman's 0.44, p = 0.002). Common adverse events were COVID infection and mild nausea, and no drug-related serious adverse events were reported. Of 14 early terminations, 6 were due to nonserious treatment-emergent adverse events and 1 death due to COVID. There was no vasogenic brain edema observed on MRI over 104 weeks. CONCLUSIONS: The effect of ALZ-801 on reducing plasma p-tau181 over 2 years demonstrates target engagement and supports its anti-Aß oligomer action that leads to a robust decrease in amyloid-induced brain neurodegeneration. The significant correlation between reduced HV atrophy and cognitive stability over 2 years suggests a disease-modifying effect of ALZ-801 treatment in patients with early AD. Together with the favorable safety profile with no events of vasogenic brain edema, these results support further evaluation of ALZ-801 in a broader population of APOE4 carriers, who represent two-thirds of patients with AD. TRIAL REGISTRATION: https://clinicaltrials.gov/study/NCT04693520 .

Amino Acid Uptake Limitations during Human Mesenchymal Stem Cell-Based Chondrogenesis.

A mino acids are the essential building blocks for collagen and proteoglycan, which are the main constituents for cartilage extracellular matrix (ECM). Synthesis of ECM proteins requires the uptake of various essential/nonessential amino acids. Analyzing amino acid metabolism during chondrogenesis can help to relate tissue quality to amino acid metabolism under different conditions. In our study, we studied amino acid uptake/secretion using human mesenchymal stem cell (hMSC)-based aggregate chondrogenesis in a serum-free induction medium with a defined chemical formulation. The initial glucose level and medium-change frequency were varied. Our results showed that essential amino acid uptake increased with time during hMSCs chondrogenesis for all initial glucose levels and medium-change frequencies. Essential amino acid uptake rates were initial glucose-level independent. The DNA-normalized glycosaminoglycans and hydroxyproline content of chondrogenic aggregates correlated with cumulative uptake of leucine, valine, and tryptophan regardless of initial glucose levels and medium-change frequencies. Collectively, our results show that amino acid uptake rates during in vitro chondrogenesis were insufficient to produce a tissue with an ECM content similar to that of human neonatal cartilage or adult cartilage. Furthermore, this deficiency was likely related to the downregulation of some key amino acid transporters in the cells. Such deficiency could be partially improved by increasing the amino acid availability in the chondrogenic medium by changing culture conditions.

Genetic variant detection in a South African haemophilia B population.

BACKGROUND: Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. METHODS: Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. RESULTS AND DISCUSSION: A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. CONCLUSION: The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Effect of Intrapersonal and Interpersonal Behavior Change Strategies on Physical Activity Among Older Adults: A Randomized Clinical Trial.

Importance: Despite guidelines that recommend physical activity (PA), little is known about which types of behavior change strategies (BCSs) effectively promote sustained increases in PA in older adults who are insufficiently active. Objective: To determine whether intrapersonal BCSs (eg, goal setting) or interpersonal BCSs (eg, peer-to-peer sharing or learning) combined with the Otago Exercise Program (17 strength and balance exercises and a walking program that are learned and individually tailored, with instruction to perform 3 times per week at home or location of choice) and a wearable PA monitor help older adults sustain increases in their PA. Design, Setting, and Participants: This 2 × 2 factorial randomized clinical trial (Community-Based Intervention Effects on Older Adults' Physical Activity) of community-dwelling older adults 70 years or older with PA levels below minimum national PA guidelines was conducted in urban community centers. Dates of enrollment were from November 17, 2017, to June 15, 2021, with final follow-up assessments completed on September 2, 2022. Interventions: Participants were randomized to intrapersonal (eg, goal setting) BCSs, interpersonal (eg, problem-solving with peer-to-peer sharing and learning) BCSs, intrapersonal and interpersonal BCSs, or an attention control group. All interventions included a PA monitor and 8 weekly small-group meetings with discussion, practice, and instructions to implement the exercise program and relevant BCSs independently between meetings and after the intervention. Main Outcomes and Measures: The primary outcome was daily minutes of objectively measured total PA (light, moderate, or vigorous intensities) averaged over 7 to 10 days, measured at baseline and after the intervention at 1 week, 6 months, and 12 months. Results: Among 309 participants (mean [SD] age, 77.4 [5.0] years; 240 women [77.7%]), 305 (98.7%) completed the intervention, and 302 (97.7%) had complete data. Participants receiving PA interventions with interpersonal BCS components exhibited greater increases in total PA than did those who did not at 1 week (204 vs 177 PA minutes per day; adjusted difference, 27.1 [95% CI, 17.2-37.0]; P < .001), 6 months (195 vs 175 PA minutes per day; adjusted difference, 20.8 [95% CI, 10.0-31.6]; P < .001), and 12 months (195 vs 168 PA minutes per day; adjusted difference, 27.5 [95% CI, 16.2-38.8]; P < .001) after the intervention. Compared with participants who did not receive interventions with intrapersonal BCS components, participants who received intrapersonal BCSs exhibited no significant changes in total PA at 1 week (192 vs 190 PA minutes per day; adjusted difference, 1.8 [95% CI, -8.6 to 12.2]; P = .73), 6 months (183 vs 187 PA minutes per day; adjusted difference, -3.9 [95% CI, -15.0 to 7.1]; P = .49), or 12 months (177 vs 186 PA minutes per day; adjusted difference, -8.8 [95% CI, -20.5 to 2.9]; P = .14) after the intervention. Interactions between intrapersonal and interpersonal BCSs were not significant. Conclusions and Relevance: In this randomized clinical trial, older adults with low levels of PA who received interpersonal BCSs, the exercise program, and a PA monitor exhibited significant increases in their PA for up to 12 months after the intervention. Intrapersonal BCSs elicited no significant PA changes and did not interact with interpersonal BCSs. Our findings suggest that because effects of a PA intervention on sustained increases in older adults' PA were augmented with interpersonal but not intrapersonal BCSs, approaches to disseminating and implementing the intervention should be considered. Trial Registration: ClinicalTrials.gov Identifier: NCT03326141.

Estimation of the transmission delays in the basal ganglia of the macaque monkey and subsequent predictions about oscillatory activity under dopamine depletion.

The timescales of the dynamics of a system depend on the combination of the timescales of its components and of its transmission delays between components. Here, we combine experimental stimulation data from 10 studies in macaque monkeys that reveal the timing of excitatory and inhibitory events in the basal ganglia circuit, to estimate its set of transmission delays. In doing so, we reveal possible inconsistencies in the existing data, calling for replications, and we propose two possible sets of transmission delays. We then integrate these delays in a model of the primate basal ganglia that does not rely on direct and indirect pathways' segregation and show that extrastriatal dopaminergic depletion in the external part of the globus pallidus and in the subthalamic nucleus is sufficient to generate ß-band oscillations (in the high part, 20-35 Hz, of the band). More specifically, we show that D2 and D5 dopamine receptors in these nuclei play opposing roles in the emergence of these oscillations, thereby explaining how completely deactivating D5 receptors in the subthalamic nucleus can, paradoxically, cancel oscillations.

Circadian Disruption across Lifespan Impairs Glucose Homeostasis and Insulin Sensitivity in Adult Mice.

Circadian rhythm disruption is associated with impaired glucose homeostasis and type 2 diabetes. For example, night shift work is associated with an increased risk of gestational diabetes. However, the effects of chronic circadian disruption since early life on adult metabolic health trajectory remain unknown. Here, using the "Short Day" (SD) mouse model, in which an 8 h/8 h light/dark (LD) cycle was used to disrupt mouse circadian rhythms across the lifespan, we investigated glucose homeostasis in adult mice. Adult SD mice were fully entrained into the 8 h/8 h LD cycle, and control mice were entrained into the 12 h/12 h LD cycle. Under a normal chow diet, female and male SD mice displayed a normal body weight trajectory. However, female but not male SD mice under a normal chow diet displayed glucose intolerance and insulin resistance, which are associated with impaired insulin signaling/AKT in the skeletal muscle and liver. Under high-fat diet (HFD) challenges, male but not female SD mice demonstrated increased body weight gain compared to controls. Both male and female SD mice developed glucose intolerance under HFD. Taken together, these results demonstrate that environmental disruption of circadian rhythms contributes to obesity in a sexually dimorphic manner but increases the risk of glucose intolerance and insulin resistance in both males and females.

A genus in the bacterial phylum Aquificota appears to be endemic to Aotearoa-New Zealand.

Allopatric speciation has been difficult to examine among microorganisms, with prior reports of endemism restricted to sub-genus level taxa. Previous microbial community analysis via 16S rRNA gene sequencing of 925 geothermal springs from the Taupo Volcanic Zone (TVZ), Aotearoa-New Zealand, revealed widespread distribution and abundance of a single bacterial genus across 686 of these ecosystems (pH 1.2-9.6 and 17.4-99.8 °C). Here, we present evidence to suggest that this genus, Venenivibrio (phylum Aquificota), is endemic to Aotearoa-New Zealand. A specific environmental niche that increases habitat isolation was identified, with maximal read abundance of Venenivibrio occurring at pH 4-6, 50-70 °C, and low oxidation-reduction potentials. This was further highlighted by genomic and culture-based analyses of the only characterised species for the genus, Venenivibrio stagnispumantis CP.B2T, which confirmed a chemolithoautotrophic metabolism dependent on hydrogen oxidation. While similarity between Venenivibrio populations illustrated that dispersal is not limited across the TVZ, extensive amplicon, metagenomic, and phylogenomic analyses of global microbial communities from DNA sequence databases indicates Venenivibrio is geographically restricted to the Aotearoa-New Zealand archipelago. We conclude that geographic isolation, complemented by physicochemical constraints, has resulted in the establishment of an endemic bacterial genus.

Geospatial analysis of Plasmodium falciparum serological indicators: school versus community sampling in a low-transmission malaria setting.

BACKGROUND: Due to low numbers of active infections and persons presenting to health facilities for malaria treatment, case-based surveillance is inefficient for understanding the remaining disease burden in low malaria transmission settings. Serological data through the detection of IgG antibodies from previous malaria parasite exposure can fill this gap by providing a nuanced picture of where sustained transmission remains. Study enrollment at sites of gathering provides a potential approach to spatially estimate malaria exposure and could preclude the need for more intensive community-based sampling. METHODS: This study compared spatial estimates of malaria exposure from cross-sectional school- and community-based sampling in Haiti. A total of 52,405 blood samples were collected from 2012 to 2017. Multiplex bead assays (MBAs) tested IgG against P. falciparum liver stage antigen-1 (LSA-1), apical membrane antigen 1 (AMA1), and merozoite surface protein 1 (MSP1). Predictive geospatial models of seropositivity adjusted for environmental covariates, and results were compared using correlations by coordinate points and communes across Haiti. RESULTS: Consistent directional associations were observed between seroprevalence and environmental covariates for elevation (negative), air temperature (negative), and travel time to urban centers (positive). Spearman's rank correlation for predicted seroprevalence at coordinate points was lowest for LSA-1 (ρ = 0.10, 95% CI: 0.09-0.11), but improved for AMA1 (ρ = 0.36, 95% CI: 0.35-0.37) and MSP1 (ρ = 0.48, 95% CI: 0.47-0.49). CONCLUSIONS: In settings approaching P. falciparum elimination, case-based prevalence data does not provide a resolution of ongoing malaria transmission in the population. Immunogenic antigen targets (e.g., AMA1, MSP1) that give higher population rates of seropositivity provide moderate correlation to gold standard community sampling designs and are a feasible approach to discern foci of residual P. falciparum transmission in an area.

Blinded Intraoperative Quantitative Indocyanine Green Metrics Associate With Intestinal Margin Acceptance in Colorectal Surgery.

BACKGROUND: Indocyanine green is a useful tool in colorectal surgery. Quantitative values may enhance and standardize its application. OBJECTIVE: To determine whether quantitative indocyanine green metrics correlate with standard subjective indocyanine green perfusion assessment in acceptance or rejection of anastomotic margins. DESIGN: Prospective single-arm, single-institution cohort study. Surgeons viewed subjective indocyanine green images but were blinded to quantitative indocyanine green metrics. SETTING: Tertiary academic center. PATIENTS: Adults undergoing planned intestinal resection. MAIN OUTCOME MEASURES: Accepted perfusion and rejected perfusion of the intestinal margin were defined by the absence or presence of ischemia by subjective indocyanine green and gross inspection. The primary outcomes included quantitative indocyanine green values, maximum fluorescence, and time-to-maximum fluorescence in accepted compared to rejected perfusion. Secondary outcomes included maximum fluorescence and time-to-maximum fluorescence values in anastomotic leak. RESULTS: There were 89 perfusion assessments comprising 156 intestinal segments. Nine segments were subjectively assessed to have poor perfusion by visual inspection and subjective indocyanine green. Maximum fluorescence (% intensity) exhibited higher intensity in accepted perfusion (accepted perfusion 161% [82%-351%] vs rejected perfusion 63% [10%-76%]; p = 0.03). Similarly, time-to-maximum fluorescence (seconds) was earlier in accepted perfusion compared to rejected perfusion (10 seconds [1-40] vs 120 seconds [90-120]; p < 0.01). Increased BMI was associated with higher maximum fluorescence. Anastomotic leak did not correlate with maximum fluorescence or time-to-maximum fluorescence. LIMITATIONS: Small cohort study, not powered to measure the association between quantitative indocyanine green metrics and anastomotic leak. CONCLUSIONS: We demonstrated that blinded quantitative values reliably correlate with subjective indocyanine green perfusion assessment. Time-to-maximum intensity is an important metric in perfusion evaluation. Quantitative indocyanine green metrics may enhance intraoperative intestinal perfusion assessment. Future studies may attempt to correlate quantitative indocyanine green values with anastomotic leak. See Video Abstract . LAS MTRICAS CUANTITATIVAS INTRAOPERATORIAS CIEGAS DEL VERDE DE INDOCIANINA SE ASOCIAN CON LA ACEPTACIN DEL MARGEN INTESTINAL EN LA CIRUGA COLORRECTAL: ANTECEDENTES:El verde de indocianina es una herramienta útil en la cirugía colorrectal. Los valores cuantitativos pueden mejorar y estandarizar su aplicación.OBJETIVO:Determinar si las métricas cuantitativas de verde de indocianina se correlacionan con la evaluación subjetiva estándar de perfusión de verde de indocianina en la aceptación o rechazo de los márgenes anastomóticos.DISEÑO:Estudio de cohorte prospectivo de un solo brazo y de una sola institución. Los cirujanos vieron imágenes subjetivas de verde de indocianina, pero no conocían las métricas cuantitativas de verde de indocianina.AJUSTE:Centro académico terciario.PACIENTES:Adultos sometidos a resección intestinal planificada.PRINCIPALES MEDIDAS DE RESULTADO:La perfusión aceptada y la perfusión rechazada del margen intestinal se definieron por la ausencia o presencia de isquemia mediante verde de indocianina subjetiva y la inspección macroscópica. Los resultados primarios fueron los valores cuantitativos de verde de indocianina, la fluorescencia máxima y el tiempo hasta la fluorescencia máxima en la perfusión aceptada en comparación con la rechazada. Los resultados secundarios incluyeron la fluorescencia máxima y el tiempo hasta alcanzar los valores máximos de fluorescencia en la fuga anastomótica.RESULTADOS:Se realizaron 89 evaluaciones de perfusión, comprendiendo 156 segmentos intestinales. Se evaluó subjetivamente que 9 segmentos tenían mala perfusión mediante inspección visual y verde de indocianina subjetiva. La fluorescencia máxima (% de intensidad) mostró una mayor intensidad en la perfusión aceptada [Perfusión aceptada 161% (82-351) vs Perfusión rechazada 63% (10-76); p = 0,03]. De manera similar, el tiempo hasta la fluorescencia máxima (segundos) fue más temprano en la perfusión aceptada en comparación con la rechazada [10 s (1-40) frente a 120 s (90-120); p < 0,01]. Aumento del índice de masa corporal asociado con una fluorescencia máxima más alta. La fuga anastomótica no se correlacionó con la fluorescencia máxima ni con el tiempo hasta la fluorescencia máxima.LIMITACIONES:Estudio de cohorte pequeño, sin poder para medir la asociación entre las mediciones cuantitativas del verde de indocianina y la fuga anastomótica.CONCLUSIÓN:Demostramos que los valores cuantitativos ciegos se correlacionan de manera confiable con la evaluación subjetiva de la perfusión de verde de indocianina. El tiempo hasta la intensidad máxima es una métrica importante en la evaluación de la perfusión. Las métricas cuantitativas de verde de indocianina pueden mejorar la evaluación de la perfusión intestinal intraoperatoria. Los estudios futuros pueden intentar correlacionar los valores cuantitativos de verde de indocianina con la fuga anastomótica. (Traducción-Dr. Yolanda Colorado).

Vertical sleeve gastrectomy improves glucose-insulin homeostasis by enhancing ß-cell function and survival via FGF15/19.

Vertical sleeve gastrectomy (VSG) restores glucose homeostasis in obese mice and humans. In addition, the increased fibroblast growth factor (FGF)15/19 circulating level postsurgery has been implicated in this effect. However, the impact of FGF15/19 on pancreatic islets remains unclear. Using a diet-induced obese mice model, we demonstrate that VSG attenuates insulin hypersecretion in isolated pancreatic islets, likely due to morphological alterations in the endocrine pancreas such as reduction in islet, ß-cell, and α-cell mass. In addition, VSG relieves gene expression of endoplasmic reticulum (ER) stress and inflammation markers in islets from obese mice. Incubation of INS-1E ß-cells with serum from obese mice induced dysfunction and cell death, whereas these conditions were not induced with serum from obese mice submitted to VSG, implicating the involvement of a humoral factor. Indeed, VSG increased FGF15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E cells treated with the serum from these mice. Moreover, exposing INS-1E cells to an FGFR inhibitor abolished the effects of VSG serum on insulin secretion and cell death. Also, recombinant FGF19 prevents INS-1E cells from dysfunction and death induced by serum from obese mice. These findings indicate that the amelioration of glucose-insulin homeostasis promoted by VSG is mediated, at least in part, by FGF15/19. Therefore, approaches promoting FGF15/19 release or action may restore pancreatic islet function in obesity.NEW & NOTEWORTHY Vertical sleeve gastrectomy (VSG) decreases insulin secretion, endoplasmic reticulum (ER) stress, and inflammation in pancreatic islets from obese mice. In addition, VSG increased fibroblast growth factor (FGF)15 circulating levels in obese mice, as well as the expression of FGF receptor 1 (Fgfr1) and its coreceptor ß-klotho (Klb), both in pancreatic islets from VSG mice and in INS-1E ß-cells treated with the serum from these mice. Serum from operated mice protects INS-1E cells from dysfunction and apoptosis, which was mediated by FGF15/19.

Associations Between Psychosocial Needs, Carbohydrate-Counting Behavior, and App Satisfaction: A Randomized Crossover App Trial on 92 Adults With Diabetes.

To examine whether psychosocial needs in diabetes care are associated with carbohydrate counting and if carbohydrate counting is associated with satisfaction with diabetes applications' usability, a randomized crossover trial of 92 adults with type 1 or 2 diabetes requiring insulin therapy tested two top-rated diabetes applications, mySugr and OnTrack Diabetes. Survey responses on demographics, psychosocial needs (perceived competence, autonomy, and connectivity), carbohydrate-counting frequency, and application satisfaction were modeled using mixed-effect linear regressions to test associations. Participants ranged between 19 and 74 years old (mean, 54 years) and predominantly had type 2 diabetes (70%). Among the three tested domains of psychosocial needs, only competence-not autonomy or connectivity-was found to be associated with carbohydrate-counting frequency. No association between carbohydrate-counting behavior and application satisfaction was found. In conclusion, perceived competence in diabetes care is an important factor in carbohydrate counting; clinicians may improve adherence to carbohydrate counting with strategies designed to improve perceived competence. Carbohydrate-counting behavior is complex; its impact on patient satisfaction of diabetes application usability is multifactorial and warrants consideration of patient demographics such as sex as well as application features for automated carbohydrate counting.