Characterizing Deficit Accumulation Among Gulf War Era Veterans.

BACKGROUND: Veterans of the first Gulf War (1990-1991) are reaching middle and older adulthood in differing degrees of health and biological age. Many Gulf War veterans report myriad negative symptoms classified as Gulf War illness (GWI), a chronic multi-symptom illness. OBJECTIVES: To describe and analyze deficit accumulation, among veterans with Severe GWI (SGWI+) and those without Severe GWI (SGWI-), to assess the association between a medically unexplained illness and aging. DESIGN: This study uses a retrospective cohort design with quasi-longitudinal data. SETTING: The recruitment sample included 10,042 Gulf War era veterans across all four US Census regions. PARTICIPANTS: The analytic sample included 1,054 participants of the GWECB for whom SGWI case status could be determined and who had valid responses for at least 90% of the deficits included in the deficit accumulation index. MEASUREMENTS: Chronic health conditions were retroactively reported, including year of diagnosis, enabling us to create a longitudinal measure of deficit accumulation. This deficit accumulation index (DAI) ranged from 0-1 for each respondent in each year between 1991-2013. We compare veterans with SGWI+ to those with SGWI- using the CDC case definition. RESULTS: Most veterans in our sample could expect to spend more years with moderate or substantial deficits than without deficits. SGWI+ was associated with spending more years with substantial deficits than those with SGWI-. Veterans in middle age (age 35-65) experienced more years with substantial deficits than younger veterans. Individuals with SGWI+ had 13 times the hazard of accumulating substantial deficits than those without. CONCLUSIONS: This study demonstrated that veterans with SGWI+, even those in midlife, experienced aging as measured by accumulating deficits. Practitioners should consider patients with multi-symptom illnesses as at risk of accelerated aging, tailoring treatments to address patients' holistic needs.

The effectiveness of personalised food choice advice tailored to an individual's socio-demographic, cognitive characteristics, and sensory preferences.

Personalised dietary advice has become increasingly popular, currently however most approaches are based on an individual's genetic and phenotypic profile whilst largely ignoring other determinants such as socio economic and cognitive variables. This paper provides novel insights by testing the effectiveness of personalised healthy eating advice concurrently tailored to an individual's socio-demographic group, cognitive characteristics, and sensory preferences. We first used existing data to build a synthetic dataset based on information from 3654 households (Study 1a), and then developed a cluster model to identify individuals characterised by similar socio-demographic, cognitive, and sensory aspects (Study 1b). Finally, in Study 2 we used the characteristics of 8 clusters to build 8 separate personalised food choice advice and assess their ability to motivate the increased consumption of fruit and vegetables and decreased intakes of saturated fat and sugar. We presented 218 participants with either generic UK Government "EatWell" advice, advice that was tailored to their allocated cluster (matched personalised), or advice tailored to a different cluster (unmatched personalised). Results showed that, when compared to generic advice, participants that received matched personalised advice were significantly more likely to indicate they would change their diet. Participants were similarly motivated to increase vegetable consumption and decrease saturated fat intake when they received unmatched personalised advice, potentially highlighting the power of providing alternative food choices. Overall, this study demonstrated that the power of personalizing food choice advice, based on a combination of individual characteristics, can be more effective than current approaches in motivating dietary change. Our study also emphasizes the viability of addressing population health through automatically delivered web-based personalised advice.

Intergenerational effects of racism on amygdala and hippocampus resting state functional connectivity.

Racism is an insidious problem with far-reaching effects on the lives of Black, Indigenous, and People of Color (BIPOC). The pervasive negative impact of racism on mental health is well documented. However, less is known about the potential downstream impacts of maternal experiences of racism on offspring neurodevelopment. This study sought to examine evidence for a biological pathway of intergenerational transmission of racism-related trauma. This study examined the effects of self-reported maternal experiences of racism on resting state functional connectivity (rsFC) in n = 25 neonates (13 female, 12 male) birthed by BIPOC mothers. Amygdala and hippocampus are brain regions involved in fear, memory, and anxiety, and are central nodes in brain networks associated with trauma-related change. We used average scores on the Experiences of Racism Scale as a continuous, voxel-wise regressor in seed-based, whole-brain connectivity analysis of anatomically defined amygdala and hippocampus seed regions of interest. All analyses controlled for infant sex and gestational age at the 2-week scanning session. More maternal racism-related experiences were associated with (1) stronger right amygdala rsFC with visual cortex and thalamus; and (2) stronger hippocampus rsFC with visual cortex and a temporo-parietal network, in neonates. The results of this research have implications for understanding how maternal experiences of racism may alter neurodevelopment, and for related social policy.

Transfer of micro-organisms from dry surface biofilms and the influence of long survival under conditions of poor nutrition and moisture on the virulence of Staphylococcusaureus.

BACKGROUND: Biofilms on dry hospital surfaces can enhance the persistence of micro-organisms on dry harsh clinical surfaces and can potentially act as reservoirs of infectious agents on contaminated surfaces. AIM: This study was conducted to quantify the transfer of viable Staphylococcus aureus cells from dry biofilms through touching and to investigate the impact of nutrient and moisture deprivation on virulence levels in S. aureus. METHODS: Dry biofilms of S. aureus ATCC 25923 and a defective biofilm-forming ability mutant, S. aureus 1132, were formed in 24-well plates under optimized conditions mimicking dry biofilm formation on clinical surfaces. Microbial cell transfer was induced through the touching of the dry biofilms, which were quantified on nutrient agar. To investigate the impact of nutrient and moisture deprivation on virulence levels, dry and standard biofilms as well as planktonic cells of S. aureus ATCC 25923 were inoculated into Galleria mellonella and their kill rates compared. FINDINGS: Results of this study showed that viable cells from dry biofilms of S. aureus ATCC 25923 were significantly more virulent and readily transferrable from dry biofilms through a touch test, therefore representing a greater risk of infection. The biofilm-forming capability of S. aureus strains had no significant impact on their transferability with more cells transferring when biofilm surfaces were wet. CONCLUSIONS: These findings indicate that dry biofilms on hospital surfaces may serve as a reservoir for the dissemination of pathogenic micro-organisms in hospitals, thus highlighting the importance of regular cleaning and adequate disinfection of hospital surfaces.

Seasonal mosquito (Diptera: Culicidae) dynamics and the influence of environmental variables in a land use gradient from Yucatan, Mexico.

Mosquito-borne diseases constitute a significant global impact on public and animal health. Climatic variables are recognized as major drivers in the mosquitoes' life history, principally rainfall and temperature, which directly influence mosquito abundance. Likewise, urbanization changes environmental conditions, and understanding how environmental variables and urbanization influence mosquito dynamics is crucial for the integrated management of mosquito-borne diseases, especially in the context of climate change. In this study, our aim was to observe the effect of temperature, rainfall, and the percentage of impervious surface on the abundance of mosquito species over a temporal scale of one complete year of fortnightly samplings, spanning from June 2021 to June 2022 in Yucatan, Mexico. We selected nine localities along an urbanization gradient (three natural, three rural, and three urban) from Mérida City to Reserva de la Biosfera Ría Celestún. Using BG-traps, mosquitoes were collected biweekly at each locality. Additionally, we estimated the percentage of impervious surface. Daily data of the maximum, mean and minimum temperatures, diurnal temperature range and rainfall were accumulated weekly. We calculated the accumulated quantities of temperatures and rainfall and lagged from one to four weeks before sampling for each locality. Generalized linear mixed models were then performed to study the influence of environmental variables and percentage of impervious surfaces on each of the 15 most abundant species. A total of 131,525 mosquitoes belonging to 11 genera and 49 species were sampled with BG-Sentinel traps baited with BG-lure and dry ice. The most frequently significative variable is the accumulated precipitation four weeks before the sampling. We observed a positive relationship between Cx. quinquefasciatus and Cx. thriambus with the diurnal temperature range. For Ae. aegypti, we observed a positive relationship with minimum temperature. Conversely, the percentage of impervious surface serves as a proxy of anthropogenic influence and helped us to distinguishing species exhibiting habitat preference for urban and rural environments, versus those preferring natural habitats. Our results characterize the species-specific effects of environmental variables (temperature, rainfall and impervious surface) on mosquito abundance.

An interim exploratory proteomics biomarker analysis of a phase 2 clinical trial to assess the impact of CT1812 in Alzheimer's disease.

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aß) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Inclusivity and decolonisation of the post-graduate public health curriculum: Reflections from a student-led approach.

The future of successful public health practice requires public health students to be educated within a decolonised curriculum that challenges the historical biases and inequalities that are deeply embedded within global public health and society. In this commentary, we reflect on what it can mean and why it's important to decolonise and diversify a public health curriculum. We describe how we used a student-led approach to begin this process, and share recommendations that are applicable to national and international curricula.

Measurements of nematic susceptibility with phase sensitive nuclear magnetic resonance in pulsed strain fields.

We present nuclear magnetic resonance data in BaFe2As2 in the presence of pulsed strain fields that are interleaved in time with the radio frequency excitation pulses. In this approach, the preceding nuclear magnetization acquires a phase shift that is proportional to the strain and pulse time. The sensitivity of this approach is limited by the homogeneous decoherence time, T2, rather than the inhomogeneous linewidth. We measure the nematic susceptibility as a function of temperature and demonstrate a three orders of magnitude improvement in sensitivity. This approach will enable studies of the strain response in a broad range of materials that previously were inaccessible due to inhomogeneous broadening.

Slicing through silos: Development and evaluation of a hospital-based telehealth hepatitis C virus treatment program.

BACKGROUND: There exist many barriers to hepatitis C virus (HCV) treatment for those with substance use disorder (SUD) or who lack access to routine medical care. A hospital-based telehealth program was developed to provide treatment opportunities for hospitalized patients living with HCV. METHODS: This single site prospective cohort study conducted from July 2022 to March 2023 aimed to measure linkage to care with an HCV clinician and initiation of HCV treatment in hospitalized patients. Patients were assessed in-person by a social worker then seen via telehealth by a clinician who prescribed either glecaprevir/pibrentasvir or sofosbuvir/velpatasvir. Treatment was initiated with pharmacist assistance. The team conducted in-person and/or telephonic outreach during and after hospitalization. Cure was confirmed by sustained virologic response at 12 weeks (SVR12) post-treatment. RESULTS: A total of 25 patients were enrolled and completed telehealth visits. All patients had a history of SUD and 18 (72 %) were unstably housed. Nineteen patients (76 %) initiated treatment, and 14 (56 %) successfully completed treatment. Twelve patients (48 %) completed post-treatment labs, including two who prematurely discontinued treatment. Eleven patients (44 %) achieved confirmed cure with SVR12. CONCLUSION: A hospital-based, multidisciplinary telehealth program can be an innovative care model to successfully treat HCV in a difficult-to-treat patient populations.

Evaluating the effects of hypoxic storage on platelet function and health using a novel storage system.

BACKGROUND: Thousands of units of whole blood (WB) and blood components are transfused daily to treat trauma patients. Improved methods for blood storage are critical to support trauma-related care. The Hemanext ONE® system offers a unique method for hypoxic storage of WB, with successfully demonstrated storage of clinically viable RBCs. This work evaluated the system for the storage of WB, focusing on platelet health and function. STUDY DESIGN AND METHODS: WB was collected from healthy donors and processed through the Hemanext ONE® system. Hemoglobin oxygen saturation (HbSO2) levels of WB were depleted to 10%, 20%, or 30% of total HbSO2 and then stored in PVC bags sealed in oxygen-impermeable bags (except for normoxic control) with samples collected on days 1, 7, and 14 post-processing. Flow cytometry assessed the activation and apoptosis of platelets. Clot dynamics were assessed based on aggregometry and thromboelastography assays, as well as thrombin generation using a calibrated-automated thrombogram method. RESULTS: Hypoxic storage conditions were maintained throughout the storage period. Hypoxia triggered increased lactate production, but pH changes were negligible compared to normoxic control. Storage at 10% HbSO2 had a significant impact on platelet function, resulting in increased activation and reduced clot formation and aggregation. These effects were less significant at 20% and 30% HbSO2. DISCUSSION: This study indicates that platelets are sensitive to hypoxic storage and suffer significant metabolic and functional deterioration when stored at or below 10% HbSO2.

Characterization of covalent inhibitors that disrupt the interaction between the tandem SH2 domains of SYK and FCER1G phospho-ITAM.

RNA sequencing and genetic data support spleen tyrosine kinase (SYK) and high affinity immunoglobulin epsilon receptor subunit gamma (FCER1G) as putative targets to be modulated for Alzheimer's disease (AD) therapy. FCER1G is a component of Fc receptor complexes that contain an immunoreceptor tyrosine-based activation motif (ITAM). SYK interacts with the Fc receptor by binding to doubly phosphorylated ITAM (p-ITAM) via its two tandem SH2 domains (SYK-tSH2). Interaction of the FCER1G p-ITAM with SYK-tSH2 enables SYK activation via phosphorylation. Since SYK activation is reported to exacerbate AD pathology, we hypothesized that disruption of this interaction would be beneficial for AD patients. Herein, we developed biochemical and biophysical assays to enable the discovery of small molecules that perturb the interaction between the FCER1G p-ITAM and SYK-tSH2. We identified two distinct chemotypes using a high-throughput screen (HTS) and orthogonally assessed their binding. Both chemotypes covalently modify SYK-tSH2 and inhibit its interaction with FCER1G p-ITAM, however, these compounds lack selectivity and this limits their utility as chemical tools.

In ovo administration of the Marek's disease vaccine in conjunction with 25-hydroxyvitamin D3 and its subsequent effects on the performance and immunity-related characteristics of Ross 708 broiler hatchlings1,2,3.

The combined effects of the in ovo injection of commercial Marek's disease vaccine (MDV) and various levels of 25-hydroxyvitamin D3 (25OHD3) on the hatch variables, immunological measurements, and gene expression of Ross 708 hatchling broilers were investigated. A total of 5 in ovo injection treatments that were applied at 18 d of incubation (doi) included: 1) noninjected (control); or a 50 µL solution volume of 2) MDV alone; or MDV combined with 3) 0.6 µg of 25OHD3; 4) 1.2 µg of 25OHD3; or 5) 2.4 µg of 25OHD3. At hatch, hatchability of set and live embryonated eggs, hatchling body weight, hatch residue analysis, serum IgY and alpha-1 acid glycoprotein (AGP) concentrations, and the expression of genes related to immunity (INFα, INFß, INFγ, TLR-3, and TLR-21) and vitamin D3 activity (1 α-hydroxylase, 24 hydroxylase, and vitamin D receptor) were determined. No significant treatment differences were observed for hatchability of set and live embryonated eggs, or for serum IgY and AGP concentrations. However, hatchling body weight was higher when MDV was combined with either 1.2 or 2.4 µg of 25OHD3 than when MDV was provided alone or in combination with 0.6 µg of 25OHD3. Also, in comparison to the noninjected treatment group, the expression of the genes for 1 α-hydroxylase and 24 hydroxylase was improved when MDV was combined with either 1.2 or 2.4 µg of 25OHD3. Lastly, expression of the genes linked to viral detection (TLR-3) and antibody production (INF-ß) was increased in those treatments that contained any level of 25OHD3. These results indicate that in comparison to controls, the effects of MDV were observed to be greater on hatchling BW and splenic gene expression when it was administered in combination with the 1.2 or 2.4 µg doses of 25OHD3. Further research is needed to determine the posthatch effects of the administration of various levels of 25OHD3 in combination with MDV.

Transferring inpatients between wards drives large nosocomial COVID-19 outbreaks, Wales, 2020-22: a matched case-control study using routine and enhanced surveillance data.

BACKGROUND: The role of the hospital environment in the spread of COVID-19 is unclear. AIM: To measure associations between ward characteristics and outbreak size to inform mitigations. METHODS: Wards with large (case wards) and small (control wards) outbreaks in three acute hospitals were compared. Cases were healthcare-associated COVID-19 inpatients (positive polymerase chain reaction test ≥8 days post admission). Case wards were adult medical/surgical wards with ≥10 cases within rolling 14-day periods, between April 1st, 2020 and April 30th, 2022. Control wards were equivalents with 2-9 cases. Demographic and laboratory data were extracted from routine surveillance systems. Continuous data were aggregated fortnightly and analysed as binary variables according to median values. Each case ward was compared with two control wards matched on outbreak start date (±14 days) to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) using univariable and conditional multivariable logistic regression. FINDINGS: From 170 outbreaks (median: 5 cases; interquartile range: 2-9), 35 case wards were identified. Community admissions were lower in case wards vs control wards (5 vs 10 median admissions; P<0.01, respectively), whereas transfers between wards within the same hospital were higher (58 vs 29 median transfers; P<0.01, respectively). Wards with more transfers in the preceding fortnight were significantly more likely to experience a large outbreak (≥35 vs <35 transfers; adjusted OR: 9.08; 95% CI: 2.5-33). CONCLUSION: We recommend safely minimizing patient movements, such as by asking clinicians to record the rationale for transfer, to reduce the likelihood of disease transmission.

Can We Miniaturize CT Technology for a Successful Mobile Stroke Unit Roll-Out?

Mortality from stroke remains high in Australia, especially for patients located outside the metropolitan cities. This is because they have limited access to specialized stroke facilities for optimal stroke treatment. Mobile stroke units have the capability to take CT scanners out to the patient however current CT commercial scanner designs are large and heavy. As such, this paper aims to design and develop a lightweight CT scanner for use in a mobile stroke unit (either road-based or air-based ambulance) to bring healthcare solution to patients in the rural and remote areas. We used the engineering design optimization approach to redesign and reduce the weight of the existing CT scanner with without compromised it structural performance. We managed to reduce the weight the CT scanner by three-fold while reducing design costs by allowing numerous simulations to be performed using computer software to achieve our design goals. The results are not only useful to optimize CT scanner structure to retrofit on a mobile stroke unit, but also bring the medical device solution to the market and support scalable solution to the larger community. Such an advance will allow for improved equity in healthcare whereby patients can be treated irrespective of location.

Pharmacologic enhancement of retromer rescues endosomal pathology induced by defects in the Alzheimer's gene SORL1.

The SORL1 gene (SORLA) is strongly associated with risk of developing Alzheimer's disease (AD). SORLA is a regulator of endosomal trafficking in neurons and interacts with retromer, a complex that is a "master conductor" of endosomal trafficking. Small molecules can increase retromer expression in vitro, enhancing its function. We treated hiPSC-derived cortical neurons that are either fully deficient, haploinsufficient, or that harbor one copy of SORL1 variants linked to AD with TPT-260, a retromer-enhancing molecule. We show significant increases in retromer subunit VPS26B expression. We tested whether endosomal, amyloid, and TAU pathologies were corrected. We observed that the degree of rescue by TPT-260 treatment depended on the number of copies of functional SORL1 and which SORL1 variant was expressed. Using a disease-relevant preclinical model, our work illuminates how the SORL1-retromer pathway can be therapeutically harnessed.

Increased homozygosity due to endogamy results in fitness consequences in a human population.

Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of "inbreeding," calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we do not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effect of FROH on completed fertility in a cohort of postreproductive women (n = 69). We find that higher FROH is significantly associated with lower fertility. Our data suggest a multilocus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.