A Community-Based Participatory Approach in Applying the Sociocultural Resilience Model in U.S-Mexico Border Communities.

BACKGROUND: Behavioral models play a key role in identifying pathways to better health and provide a foundation for health promotion interventions. However, behavioral models based in epidemiological research may be limited in relevance and utility in practice. OBJECTIVES: We describe a participatory approach within a community-based participatory research partnership for integrating epidemiological and community perspectives into the application of the sociocultural resilience model (SRM). The SRM posits that cultural processes have a symbiotic relationship with health-promoting social processes, which contribute to the health advantages among Mexicanorigin and other Latinx populations. METHODS: Community action board members engaged with academic partners to interpret and apply the SRM to a community-clinical linkages intervention implemented in the context of three U.S.-Mexico border communities. In a two-day workshop, partners engaged in a series of iterative discussions to reach common definitions and measures for SRM constructs. RESULTS: Partners described daily cultural processes as the food they eat, how they communicate, and a collectivist approach to getting things done. For intervention activities, the partners opted for intergenerational storytelling, sharing of food, and artistic forms of expression. Partners included measures of cultural nuances such as border identity and the complexities that often arise from navigating bicultural norms. CONCLUSIONS: Collaborative approaches within community-based participatory research partnerships can facilitate the adaptation and measurement of conceptual health behavior models in community practice.

Clinical associations with a polygenic predisposition to benign lower white blood cell counts.

Polygenic variation unrelated to disease contributes to interindividual variation in baseline white blood cell (WBC) counts, but its clinical significance is uncharacterized. We investigated the clinical consequences of a genetic predisposition toward lower WBC counts among 89,559 biobank participants from tertiary care centers using a polygenic score for WBC count (PGSWBC) comprising single nucleotide polymorphisms not associated with disease. A predisposition to lower WBC counts was associated with a decreased risk of identifying pathology on a bone marrow biopsy performed for a low WBC count (odds-ratio = 0.55 per standard deviation increase in PGSWBC [95%CI, 0.30-0.94], p = 0.04), an increased risk of leukopenia (a low WBC count) when treated with a chemotherapeutic (n = 1724, hazard ratio [HR] = 0.78 [0.69-0.88], p = 4.0 × 10-5) or immunosuppressant (n = 354, HR = 0.61 [0.38-0.99], p = 0.04). A predisposition to benign lower WBC counts was associated with an increased risk of discontinuing azathioprine treatment (n = 1,466, HR = 0.62 [0.44-0.87], p = 0.006). Collectively, these findings suggest that there are genetically predisposed individuals who are susceptible to escalations or alterations in clinical care that may be harmful or of little benefit.

Harnessing the power of new genetic tools to illuminate Giardia biology and pathogenesis.

Giardia is a prevalent single-celled microaerophilic intestinal parasite causing diarrheal disease and significantly impacting global health. Double diploid (essentially tetraploid) Giardia trophozoites have presented a formidable challenge to the development of molecular genetic tools to interrogate gene function. High sequence divergence and the high percentage of hypothetical proteins lacking homology to proteins in other eukaryotes have limited our understanding of Giardia protein function, slowing drug target validation and development. For more than 25 years, Giardia A and B assemblages have been readily amenable to transfection with plasmids or linear DNA templates. Here, we highlight the utility and power of genetic approaches developed to assess protein function in Giardia, with particular emphasis on the more recent clustered regularly interspaced palindromic repeats/Cas9-based methods for knockdowns and knockouts. Robust and reliable molecular genetic approaches are fundamental toward the interrogation of Giardia protein function and evaluation of druggable targets. New genetic approaches tailored for the double diploid Giardia are imperative for understanding Giardia's unique biology and pathogenesis.

Biosecurity indemnification and attitudes of United States swine producers towards the prevention of an african swine fever outbreak.

Animal disease outbreaks, such as the recent outbreak of African Swine Fever in 2018, are a major concern for stakeholders across the food supply chain due to their potential to disrupt global food security, cause economic losses, and threaten animal welfare. As a result of their transboundary nature, discussions have shifted to preventive measures aimed at protecting livestock while ensuring food security and safety. Emergency assistance has been a critical response option during pandemics. However, this may not be sustainable in the long run because the expectation of government bailout may encourage risk taking behaviours. Our hypothesis is that an indemnity policy that is conditioned on showing biosecurity practices would increase compliance and reduce government expenditure during disease outbreaks. We developed and launched a survey from March to July 2022 targeted at swine producers across the US. From the survey, we examined livestock farmers' attitudes and intentions regarding biosecurity investment and assessed their attitudes towards the purchase of livestock insurance and reporting suspected infected livestock on their farm. We used a partial proportion odds model analysis to examine the model. Our analysis revealed that intention to call a veterinarian, trust in government agencies and risk perception of farmers were instrumental in the willingness to self-invest in biosecurity, purchase livestock insurance, and promptly report infected livestock on their farms. This provides evidence that biosecurity compliance would increase if indemnification was tied to a demonstration of effort to adopt biosecurity practices. We also show that individuals who have been in the industry for a longer period may become complacent and less likely to report outbreaks. Farmers with a higher share of income from their production operations bear a greater risk from their operational income and are more willing to report any suspected infections on their farms. The data suggest that motivating the willingness of farmers to invest in biosecurity while overcoming cost concerns is achievable.

Structures and interactions forming stable shellac-casein nanocomplexes with a pH-cycle.

Casein forms diverse structures with functionalities tunable by complexation with surfactants, and shellac is an emerging surfactant. In the present work, molecular and mesoscopic structures of shellac and micellar casein and the underlying interactions after treatment with a pH-cycle were investigated. Dispersions with 0.5 % w/v shellac and various shellac:casein mass ratios were prepared at pH 12.0 to dissolve shellac and dissociate casein micelles, followed by neutralization to pH 7.0 to form complexes. Both covalent and non-covalent (hydrogen bonding, electrostatic, and hydrophobic) interactions contributed to the complex formation. The formed complexes had an average diameter of ~80 nm. The complexation of shellac and casein prevented the precipitation of protonated shellac during neutralization, and dispersions with casein:shellac mass ratios of 2:1 and above were absent of precipitates at pH 7.0. The formed nanocomplexes may have applications for preparing novel colloidal systems and loading lipophilic bioactive compounds.

Prostate Radiotherapy in Low-volume Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis.

BACKGROUND AND OBJECTIVE: The utility of prostate radiotherapy (RT) is unclear in men with metastatic hormone-sensitive prostate cancer (mHSPC) receiving intensified systemic therapy with androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). We performed a network meta-analysis of randomized controlled trials (RCTs) to investigate the role of prostate RT in low-volume mHSPC. METHODS: Bibliographic databases and conference proceedings were searched through July 2023 for RCTs evaluating the addition of ARPIs or prostate RT to standard of care (SOC) systemic therapy, defined as ADT or ADT plus docetaxel, for the initial treatment of mHSPC. We focused exclusively on aggregate data from the low-volume mHSPC subpopulation in these trials. We pooled the treatment arms into four groups: SOC, SOC plus ARPI, SOC plus RT, and SOC plus ARPI plus RT. The primary outcome was overall survival (OS). To compare treatment strategies, a fixed-effects Bayesian network meta-analysis was undertaken, while a Bayesian network meta-regression was performed to account for across-trial differences in docetaxel use as part of SOC and in proportions of patients with de novo presentation. KEY FINDINGS AND LIMITATIONS: Ten RCTs comprising 4423 patients were eligible. The Surface Under the Cumulative Ranking Curve scores were 0.0006, 0.45, 0.62, and 0.94 for SOC, SOC plus RT, SOC plus ARPI, and SOC plus ARPI plus RT, respectively. On a meta-regression, in a population with de novo mHSPC and no docetaxel use, we did not find sufficient evidence of a difference in OS between SOC plus ARPI plus RT versus SOC plus ARPI (hazard ratio [HR]: 0.76; 95% credible interval: 0.51-1.16) and SOC plus RT versus SOC plus ARPI (HR: 1.10; 95% credible interval: 0.92-1.42). CONCLUSIONS AND CLINICAL IMPLICATIONS: There was some evidence that SOC plus ARPI plus RT reduced mortality compared with the next best strategy of SOC plus ARPI in patients with low-volume de novo mHSPC. A meta-analysis with individual patient data or an RCT is needed to confirm these findings.

Changes in urinary glutathione sulfonamide (GSA) levels between admission and discharge of patients with cystic fibrosis.

There is an urgent need to develop sensitive, non-invasive biomarkers that can track airway inflammatory activity for patients with cystic fibrosis (CF). Urinary glutathione sulfonamide (GSA) levels correlate well with GSA levels in BAL samples and other markers of neutrophilic inflammation, suggesting that this biomarker may be suitable for tracking disease activity in this population. We recruited 102 children (median 11.5 years-old) and 64 adults (median 32.5 years-old) who were admitted to hospital for management of an acute pulmonary exacerbation and/or eradication of infectious agents such as Pseudomonas aeruginosa or Staphylococcus aureus. Our aim was to explore how urinary GSA levels changed across admission timepoints. Urine samples were collected at admission and discharge, and GSA measured by liquid chromatography with mass spectrometry. Paired admission-discharge results were compared using Wilcoxon signed-rank test. Paired admission-discharge samples were available for 53 children and 60 adults. A statistically significant difference was observed between admission-discharge for children and adults. Spearman's correlation analysis identified a correlation between urinary GSA levels and sex and S. aureus infection for children only. Our preliminary findings suggest that urinary GSA is responsive to the resolution of an acute pulmonary exacerbation and therefore warrants further studies in this population.

Biomechanical Comparison of Anterior Cervical Plate Fixation Versus Integrated Fixation Cage for Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: Cadaveric, biomechanic study. OBJECTIVE: To compare the range of motion profiles of the cervical spine following one-level anterior cervical discectomy and fusion (ACDF) constructs instrumented with either an interbody cage and anterior plate or integrated fixation cage in a cadaveric model. SUMMARY OF BACKGROUND DATA: While anterior plates with interbody cages are the most common construct of fixation in ACDF, newer integrated cage-plate devices seek to provide similar stability with a decreased implant profile. However, differences in postoperative cervical range of motion between the 2 constructs remain unclear. METHODS: Six cadaveric spines were segmented into 2 functional spine units (FSUs): C2-C5 and C6-T2. Each FSU was nondestructively bent in flexion-extension (FE), right-left lateral bending (LB), and right-left axial rotation (AR) at a rate of 0.5°/s under a constant axial load until a limit of 2-Nm was reached to evaluate baseline range of motion (ROM). Matched pairs were then randomly assigned to undergo instrumentation with either the standard anterior cage and plate (CP) or the integrated fixation cage (IF). Following instrumentation, ROM was then remeasured as previously described. RESULTS: For CP fixation, ROM increased by 61.2±31.7% for FE, 36.3±20.4% for LB, and 31.7±19.1% for AR. For IF fixation, ROM increased by 64.2±15.5% for FE, 56.7±39.8% for LB, and 94.5±65.1% for AR. There was no significant difference in motion between each group across FE, LB, and AR. CONCLUSION: This biomechanical study demonstrated increased motion in both the CP and IF groups relative to the intact, un-instrumented state. However, our model showed no differences in ROM between CP and IF constructs in any direction of motion. These results suggest that either method of instrumentation is a suitable option for ACDF with respect to constructing stiffness at time zero.

Catharanthine Modulates Mesolimbic Dopamine Transmission and Nicotine Psychomotor Effects via Inhibition of α6-Nicotinic Receptors and Dopamine Transporters.

Iboga alkaloids, also known as coronaridine congeners, have shown promise in the treatment of alcohol and opioid use disorders. The objective of this study was to evaluate the effects of catharanthine and 18-methoxycoronaridine (18-MC) on dopamine (DA) transmission and cholinergic interneurons in the mesolimbic DA system, nicotine-induced locomotor activity, and nicotine-taking behavior. Utilizing ex vivo fast-scan cyclic voltammetry (FSCV) in the nucleus accumbens core of male mice, we found that catharanthine or 18-MC differentially inhibited evoked DA release. Catharanthine inhibition of evoked DA release was significantly reduced by both α4 and α6 nicotinic acetylcholine receptors (nAChRs) antagonists. Additionally, catharanthine substantially increased DA release more than vehicle during high-frequency stimulation, although less potently than an α4 nAChR antagonist, which confirms previous work with nAChR antagonists. Interestingly, while catharanthine slowed DA reuptake measured via FSCV ex vivo, it also increased extracellular DA in striatal dialysate from anesthetized mice in vivo in a dose-dependent manner. Superfusion of catharanthine or 18-MC inhibited the firing rate of striatal cholinergic interneurons in a concentration dependent manner, which are known to potently modulate presynaptic DA release. Catharanthine or 18-MC suppressed acetylcholine currents in oocytes expressing recombinant rat α6/α3ß2ß3 or α6/α3ß4 nAChRs. In behavioral experiments using male Sprague-Dawley rats, systemic administration of catharanthine or 18-MC blocked nicotine enhancement of locomotor activity. Importantly, catharanthine attenuated nicotine self-administration in a dose-dependent manner while having no effect on food reinforcement. Lastly, administration of catharanthine and nicotine together greatly increased head twitch responses, indicating a potential synergistic hallucinogenic effect. These findings demonstrate that catharanthine and 18-MC have similar, but not identical effects on striatal DA dynamics, striatal cholinergic interneuron activity and nicotine psychomotor effects.

Late fall synthetic acaricide application is effective at reducing host-seeking adult and nymphal Ixodes scapularis (Ixodida: Ixodidae) abundances the following spring.

Based on increases in reported cases of tick-borne illnesses, expanding ranges of native ticks, and repeated documentation of arrivals of nonnative tick species, there is a clear need for their effective management in the United States. Synthetic acaricides have proven efficacious in tick management, but real/perceived negative impacts to the environment and nontarget, beneficial insects must be addressed. We sought to determine whether late fall synthetic acaricide application, when most susceptible beneficial insects are presumably dormant or have migrated, could effectively manage host-seeking spring Ixodes scapularis Say abundances as compared to traditional spring application. We compared results of delivery of Demand CS (lambda-cyhalothrin) via truck-mounted high-pressure spray and powered backpack blower as well as delivery of granular Demand G to experimental control (water) in peridomestic habitats in fall 2021, spring 2022, and combined fall 2021/spring 2022. High-pressure fall delivery of Demand CS and backpack delivery of Demand G significantly reduced host-seeking adult I. scapularis abundances within-season and the following spring combined by 100% and 94%, respectively. No host-seeking nymphal I. scapularis were documented in spring after fall only, spring only, or fall and spring combined delivery of Demand CS via high-pressure or powered backpack blower. No adult I. scapularis were documented at any time posttreatment on locations that received high-pressure delivery of Demand CS. We conclude that high-pressure delivery of Demand CS in late fall successfully eliminated multiple stages of host-seeking I. scapularis through the following spring while likely limiting exposure of beneficial insects to synthetic pyrethroids.

Human Saposin B Ligand Binding and Presentation to α-Galactosidase A.

Sphingolipid activator protein B (saposin B; SapB) is an essential activator of globotriaosylceramide (Gb3) catabolism by α-galactosidase A. However, the manner by which SapB stimulates α-galactosidase A activity remains unknown. To uncover the molecular mechanism of SapB presenting Gb3 to α-galactosidase A, we subjected the fluorescent substrate globotriaosylceramide-nitrobenzoxidazole (Gb3-NBD) to a series of biochemical and structural assays involving SapB. First, we showed that SapB stably binds Gb3-NBD using a fluorescence equilibrium binding assay, isolates Gb3-NBD from micelles, and facilitates α-galactosidase A cleavage of Gb3-NBD in vitro. Second, we crystallized SapB in the presence of Gb3-NBD and validated the ligand-bound assembly. Third, we captured transient interactions between SapB and α-galactosidase A by chemical cross-linking. Finally, we determined the crystal structure of SapB bound to α-galactosidase A. These findings establish general principles for molecular recognition in saposin:hydrolase complexes and highlight the utility of NBD reporter lipids in saposin biochemistry and structural biology.

Common questions and misconceptions about protein supplementation: what does the scientific evidence really show?

Protein supplementation often refers to increasing the intake of this particular macronutrient through dietary supplements in the form of powders, ready-to-drink shakes, and bars. The primary purpose of protein supplementation is to augment dietary protein intake, aiding individuals in meeting their protein requirements, especially when it may be challenging to do so through regular food (i.e. chicken, beef, fish, pork, etc.) sources alone. A large body of evidence shows that protein has an important role in exercising and sedentary individuals. A PubMed search of "protein and exercise performance" reveals thousands of publications. Despite the considerable volume of evidence, it is somewhat surprising that several persistent questions and misconceptions about protein exist. The following are addressed: 1) Is protein harmful to your kidneys? 2) Does consuming "excess" protein increase fat mass? 3) Can dietary protein have a harmful effect on bone health? 4) Can vegans and vegetarians consume enough protein to support training adaptations? 5) Is cheese or peanut butter a good protein source? 6) Does consuming meat (i.e., animal protein) cause unfavorable health outcomes? 7) Do you need protein if you are not physically active? 8) Do you need to consume protein ≤ 1 hour following resistance training sessions to create an anabolic environment in skeletal muscle? 9) Do endurance athletes need additional protein? 10) Does one need protein supplements to meet the daily requirements of exercise-trained individuals? 11) Is there a limit to how much protein one can consume in a single meal? To address these questions, we have conducted a thorough scientific assessment of the literature concerning protein supplementation.

A domain-swapped CaMKII conformation facilitates linker-mediated allosteric regulation.

Ca2+ signaling plays a key role in physiological processes such as memory formation and cardiac function. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is the primary kinase that responds to Ca2+ inputs in these cells. There are four CaMKII paralogs in mammals which are alternatively spliced in the variable linker region to create upwards of 70 different variants. In this study, we systematically studied different linker regions and determined that the position of charged residues within the linker region modulates the Ca2+/CaM sensitivity of the holoenzyme. We present an X-ray crystal structure of full-length CaMKIIδ that shows a domain-swapped conformation of the subunits within the dodecameric holoenzyme. In this structure, the kinase domain of one subunit is docked onto the hub domain of a different subunit, providing an additional interface within the holoenzyme. Mutations at the equatorial and lateral interfaces revealed that the kinase-hub interaction dissociates as the hub-hub interfaces are disturbed, which led alterations in the stoichiometry of CaMKII holoenzyme and Ca2+/CaM sensitivity. Molecular dynamics simulations of linker-containing domain-swapped and non-domain-swapped CaMKIIs reveal that the domain-swapped configuration facilitates an interaction between the calmodulin binding domain and the variable linker region, such that dynamic electrostatic forces between charges on these segments can modulate the equilibrium between the compact and extended conformational states of the holoenzyme. Small angle X-ray scattering data confirms that a negatively charged linker CaMKII holoenzyme adopts a more compact conformation compared to a positively charged linker. These data support a model where patches of charged linker residues interact with the calmodulin binding domain to allosterically regulate sensitivity to Ca2+/CaM. Our findings provide a new framework for understanding CaMKII structure and allosteric regulation by the variable linker region in Ca2+-sensitive cells.

Enhancing Eastern Equine Encephalitis Virus Surveillance in New Jersey: Optimized Collection of Culiseta Melanura.

Eastern equine encephalitis virus (EEEV) causes the most clinically severe neuroinvasive arboviral disease in the United States. The virus is endemic in eastern and Gulf Coast states and the Great Lakes region, causing cases annually. To detect EEEV circulation in its enzootic cycle before the virus infects humans and other mammals, mosquito control agencies in New Jersey have conducted mosquito surveillance using a series of permanent wooden resting box sites since 1975. We conducted 2 field studies, 1 evaluating resting traps and 1 evaluating efficacy of CO2 lures, to optimize collection of Culiseta melanura, the primary enzootic vector of EEEV. Resulting mosquito samples were subjected to molecular analysis to determine EEEV infection rates. Corrugated plastic boxes trapped more bloodfed Cs. melanura than other resting trap types (resting boxes, Centers for Disease Control and Prevention [CDC] resting traps, or fiber pots) and were similar to resting boxes in total number of female Cs. melanura caught. Further, non-baited CDC light traps were more successful in trapping host-seeking Cs. melanura than those baited with dry ice, a CO2 lure. The EEEV RNA was identified in Cs. melanura, Aedes vexans, Anopheles quadrimaculatus, and Uranotaenia sapphirina. Our findings indicate that corrugated plastic boxes and non-CO2 baited traps could improve detection of Cs. melanura. Mosquito control agencies are encouraged to periodically assess their surveillance strategy for EEEV.

Molecular Epidemiology of Mayaro Virus among Febrile Patients, Roraima State, Brazil, 2018-2021.

We detected Mayaro virus (MAYV) in 3.4% (28/822) of febrile patients tested during 2018-2021 from Roraima State, Brazil. We also isolated MAYV strains and confirmed that these cases were caused by genotype D. Improved surveillance is needed to better determine the burden of MAYV in the Amazon Region.

Defining remission in childhood-onset lupus: PReS-endorsed consensus definitions by an international task force.

OBJECTIVE: To derive childhood-onset SLE (cSLE) specific remission definitions for future treat-to-target (T2T) trials, observational studies, and clinical practice. METHODS: The cSLE International T2T Task Force conducted Delphi surveys exploring paediatric perspectives on adult-onset SLE remission targets. A modified nominal group technique was used to discuss, refine, and agree on the cSLE remission target criteria. RESULTS: The Task Force proposed two definitions of remission: 'cSLE clinical remission on steroids (cCR)' and 'cSLE clinical remission off steroids (cCR-0)'. The common criteria are: (1) Clinical-SLEDAI-2 K = 0; (2) PGA score < 0.5 (0-3 scale); (4) stable antimalarials, immunosuppressive, and biologic therapy (changes due to side-effects, adherence, weight, or when building up to target dose allowed). Criterion (3) in cCR is the prednisolone dose ≤0.1 mg/kg/day (maximum 5 mg/day), whereas in cCR-0 it is zero. CONCLUSIONS: cSLE definitions of remission have been proposed, maintaining sufficient alignment with the adult-SLE definition to facilitate life-course research.

Fat malabsorption in short bowel syndrome: A review of pathophysiology and management.

Fat malabsorption is central to the pathophysiology of short bowel syndrome (SBS). It occurs in patients with insufficient intestinal surface area and/or function to maintain metabolic and growth demands. Rapid intestinal transit and impaired bile acid recycling further contribute to fat malabsorption. A significant portion of patients require parenteral nutrition (PN) for their survival but may develop sepsis and liver dysfunction as a result. Despite advancements in the treatment of SBS, fat malabsorption remains a chronic issue for this vulnerable patient population. Peer-reviewed literature was assessed on the topic of fat malabsorption in SBS. Current management of patients with SBS involves dietary considerations, PN management, antidiarrheals, glucagon-like peptide 2 agonists, and multidisciplinary teams. Clinical trials have focused on improving intestinal fat absorption by facilitating fat digestion with pancreatic enzymes. Targeting fat malabsorption in SBS is a potential pathway to improving lifestyle and reducing morbidity and mortality in this rare disease.

Yellow Fever Emergence: Role of Heterologous Flavivirus Immunity in Preventing Urban Transmission.

During major, recent yellow fever (YF) epidemics in Brazil, human cases were attributed only to spillover infections from sylvatic transmission with no evidence of human amplification. Furthermore, the historic absence of YF in Asia, despite abundant peridomestic Aedes aegypti and naive human populations, represents a longstanding enigma. We tested the hypothesis that immunity from dengue (DENV) and Zika (ZIKV) flaviviruses limits YF virus (YFV) viremia and transmission by Ae. aegypti . Prior DENV and ZIKV immunity consistently suppressed YFV viremia in experimentally infected macaques, leading to reductions in Ae. aegypti infection when mosquitoes were fed on infected animals. These results indicate that, in DENV- and ZIKV-endemic regions such as South America and Asia, flavivirus immunity suppresses YFV human amplification potential, reducing the risk of urban outbreaks. One-Sentence Summary: Immunity from dengue and Zika viruses suppresses yellow fever viremia, preventing infection of mosquitoes and reducing the risk of epidemics.