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Abstract Lung cancer remains the leading cause of cancer mortality, despite declining smoking rates. Previous lung cancer GWAS have identified numerous loci, but separating the genetic risks of lung cancer and smoking behavioral susceptibility remains challenging. Here, we perform multi-ancestry GWAS meta-analyses of lung cancer using the Million Veteran Program cohort (approximately 95% male cases) and a previous study of European-ancestry individuals, jointly comprising 42,102 cases and 181,270 controls, followed by replication in an independent cohort of 19,404 cases and 17,378 controls. We then carry out conditional meta-analyses on cigarettes per day and identify two novel, replicated loci, including the 19p13.11 pleiotropic cancer locus in squamous cell lung carcinoma. Overall, we report twelve novel risk loci for overall lung cancer, lung adenocarcinoma, and squamous cell lung carcinoma, nine of which are externally replicated. Finally, we perform PheWAS on polygenic risk scores for lung cancer, with and without conditioning on smoking. The unconditioned lung cancer polygenic risk score is associated with smoking status in controls, illustrating a reduced predictive utility in non-smokers. Additionally, our polygenic risk score demonstrates smoking-independent pleiotropy of lung cancer risk across neoplasms and metabolic traits.

Metatarsus adductus (MA) deformity adds to the complexity of hallux abductovalgus (HAV) correction. Scant literature exists on the outcomes of HAV correction with concomitant MA. The purpose of this study was to evaluate the literature on the outcomes, complications, and treatment strategies of HAV with concomitant MA deformity. A comprehensive systematic review was performed. Mean radiographic outcomes, patient reported outcome measure scores, and complication rates were calculated. A total of 279 articles were initially identified. 8 articles met the inclusion criteria, for a total of 237 feet. Procedures undertaken exhibited substantial heterogeneity across studies, revealing the lack of a standardized surgical approach. Studies were divided into two separate groups based on procedural selection: A) Isolated 1st ray procedures; B) Combined 1st and lesser ray procedures. The intermetatarsal, hallux valgus, and metatarsus adductus angles were all significantly improved. There was no significant difference in final radiographic angles between the two groups. Recurrence occurred in 12.2 % of patients, necessitating revision in 1.7 %. The total complication rate was 7.2 %, with nonunion as the primary complication at 1.7 %. The overall mean AOFAS score improved from 53.4 preoperatively to 88.8 postoperatively (p < 0.00001). The overall mean postoperative VAS score was 1.4. There was no significant difference in complication rates or AOFAS scores between the groups. No “gold standard” treatment exists for surgical management of HAV with MA. However, favorable functional outcomes with a low reoperation rate can be expected with a combination of arthrodesis and osteotomy procedures.

Abstract Background Early in the pandemic, the United States population experienced a sharp rise in the prevalence rates of opioid use, social isolation, and pain interference. Given the high rates of pain reported by patients on medication for opioid use disorder (MOUD), the pandemic presented a unique opportunity to disentangle the relationship between opioid use, pain, and social isolation in this high-risk population. We tested the hypothesis that pandemic-induced isolation would partially mediate change in pain interference levels experienced by patients on MOUD, even when controlling for baseline opioid use. Such work can inform the development of targeted interventions for a vulnerable, underserved population. Methods Analyses used data from a cluster randomized trial (N = 188) of patients on MOUD across eight opioid treatment programs. As part of the parent trial, participants provided pre-pandemic data on pain interference, opioid use, and socio-demographic variables. Research staff re-contacted participants between May and June 2020 and 133 participants (71% response rate) consented to complete a supplemental survey that assessed pandemic-induced isolation. Participants then completed a follow-up interview during the pandemic that again assessed pain interference and opioid use. A path model assessed whether pre-pandemic pain interference had an indirect effect on pain interference during the pandemic via pandemic-induced isolation. Results Consistent with hypotheses, we found evidence that pandemic-induced isolation partially mediated change in pain interference levels among MOUD patients during the pandemic. Higher levels of pre-pandemic pain interference and opioid use were both significantly associated with higher levels of pandemic-induced isolation. In addition, pre-pandemic pain interference was significantly related to levels of pain interference during the pandemic, and these pain levels were partially explained by the level of pandemic-induced isolation reported. Conclusions Patients on MOUD with higher use of opioids and higher rates of pain pre-pandemic were more likely to report feeling isolated during COVID-related social distancing and this, in turn, partially explained changes in levels of pain interference. These results highlight social isolation as a key risk factor for patients on MOUD and suggest that interventions promoting social connection could be associated with reduced pain interference, which in turn could improve patient quality of life. Trial registration NCT03931174 (Registered 04/30/2019).

Nucleocapsid antibody assays can be used to estimate SARS-CoV-2 infection prevalence in regions implementing spike-based COVID-19 vaccines. However, poor sensitivity of nucleocapsid antibody assays in detecting infection after vaccination has been reported. We derived a lower cutoff for identifying previous infections in a large blood donor cohort (N = 142,599) by using the Ortho VITROS Anti-SARS-CoV-2 Total-N Antibody assay, improving sensitivity while maintaining specificity >98%. We validated sensitivity in samples donated after self-reported swab-confirmed infections diagnoses. Sensitivity for first infections in unvaccinated donors was 98.1% (95% CI 98.0–98.2) and for infection after vaccination was 95.6% (95% CI 95.6–95.7) based on the standard cutoff. Regression analysis showed sensitivity was reduced in the Delta compared with Omicron period, in older donors, in asymptomatic infections,

ABSTRACT Teredinibacter turnerae is a cultivable cellulolytic Gammaproteobacterium (Cellvibrionaceae) that commonly occurs as an intracellular endosymbiont in the gills of wood‐eating bivalves of the family Teredinidae (shipworms). The genome of T. turnerae encodes a broad range of enzymes that deconstruct cellulose, hemicellulose and pectin and contribute to wood (lignocellulose) digestion in the shipworm gut. However, the mechanisms by which T. turnerae secretes lignocellulolytic enzymes are incompletely understood. Here, we show that T. turnerae cultures grown on carboxymethyl cellulose (CMC) produce membrane vesicles (MVs) that include a variety of proteins identified by liquid chromatography–mass spectrometry (LC–MS/MS) as carbohydrate‐active enzymes (CAZymes) with predicted activities against cellulose, hemicellulose and pectin. Reducing sugar assays and zymography confirm that these MVs exhibit cellulolytic activity, as evidenced by the hydrolysis of CMC. Additionally, these MVs were enriched with TonB‐dependent receptors, which are essential to carbohydrate and iron acquisition by free‐living bacteria. These observations indicate a potential role for MVs in lignocellulose utilisation by T. turnerae in the free‐living state, suggest possible mechanisms for host–symbiont interaction and may be informative for commercial applications such as enzyme production and lignocellulosic biomass conversion.

Background The outcomes of planned implementation efforts have been mixed, with some applications failing to achieve the desired change or impact. While reasons for mixed findings in implementation research are multifaceted (e.g., Damschroder et al., 2009, 2022), how the implementation strategy (IS) was deployed (i.e., integrity) and its impact on the implementation outcomes of evidence-based innovations (EBIs) is under-studied and warrants further clarification. Method This article builds on the IS fidelity and mechanisms of change literature to create the Implementation Strategy Integrity Framework (ISIF). The ISIF was developed by a set of implementation science researchers in the Justice Community Opioid Innovation Network seeking to document the role of implementation strategies in influencing EBI outcomes. Results The authors identified four areas of documentation and measurement to examine the role of IS integrity on EBI outcomes. (a) Implementation Strategy Rigor (i.e., adherence, dose, and quality) requires those implementing the strategy/strategies to specify them, document adherence to the planned strategies, quality of execution, and any adaptations made. (b) Target User Responsiveness documents the extent and quality of targeted users’ participation in IS activities and how well the target users perform their roles in conducting actions intended by the implementation strategies. (c) Target Mechanism Activation notes to what degree the implementation strategies achieved the intended impact(s) on targeted factors that facilitate EBI use. Finally, (d) these three areas are combined with selected Inner and Outer Context variables to explain IS integrity’s potential moderating and mediating effects on EBI outcomes. Conclusions A framework that can define the integrity of an IS and allow for its subsequent use as an explanatory variable in EBI outcomes is necessary for better elucidating mechanisms of action. The ISIF offers a structured approach to operationalize, measure, and evaluate the application and related impacts of implementation strategies.

Tourism is an important sector, serving as an avenue to show the natural resources of a country and inhabitants' hospitality. This sector creates several opportunities for building a potential market and enhancing economic activities where tourist spots and activities flourish. Despite the numerous benefits, tourism still requires significant improvement, particularly in the Philippines, where there are abundant beautiful places. Therefore, this study aimed to develop a recommender system based on users and content collaborative filtering to provide local and foreign tourists with viable information for experience improvement. The investigation focused on improving tourist satisfaction based on three aspects such as preferences, ratings, and reviews that add options for tourist spots, activities/itineraries, destinations, and others. The machine algorithm-based journey assistant (MAJA) was designed as an interface and agent in providing help to tourists. The mean average precision (MAP) and recall were used as evaluation metrics to better understand the ability of MAJA to offer personalized experiences to unique users. The results showed that integration of the system into tourism provided a smart platform for enhancing tourist experience and destination competitiveness. Consequently, successful implementation of the system is measured by two criteria, namely the degree of tourists' pleasure during trip and the capacity of MAJA to effectively transfer tourism to less popular and less "accessible" sector.

Abstract Obesity-induced inflammation causes metabolic dysfunction, but the mechanisms remain elusive. Here we show that the innate immune transcription factor interferon regulatory factor (IRF3) adversely affects glucose homeostasis through induction of the endogenous FAHFA hydrolase androgen induced gene 1 (AIG1) in adipocytes. Adipocyte-specific knockout of IRF3 protects male mice against high-fat diet-induced insulin resistance, whereas overexpression of IRF3 or AIG1 in adipocytes promotes insulin resistance on a high-fat diet. Furthermore, pharmacological inhibition of AIG1 reversed obesity-induced insulin resistance and restored glucose homeostasis in the setting of adipocyte IRF3 overexpression. We, therefore, identify the adipocyte IRF3/AIG1 axis as a crucial link between obesity-induced inflammation and insulin resistance and suggest an approach for limiting the metabolic dysfunction accompanying obesity.

Abstract Fuchs endothelial corneal dystrophy (FECD) is a leading indication for corneal transplantation, but its molecular etiology remains poorly understood. We performed genome-wide association studies (GWAS) of FECD in the Million Veteran Program followed by multi-ancestry meta-analysis with the previous largest FECD GWAS, for a total of 3970 cases and 333,794 controls. We confirm the previous four loci, and identify eight novel loci: SSBP3, THSD7A, LAMB1, PIDD1, RORA, HS3ST3B1, LAMA5, and COL18A1. We further confirm the TCF4 locus in GWAS for admixed African and Hispanic/Latino ancestries and show an enrichment of European-ancestry haplotypes at TCF4 in FECD cases. Among the novel associations are low frequency missense variants in laminin genes LAMA5 and LAMB1 which, together with previously reported LAMC1, form laminin-511 (LM511). AlphaFold 2 protein modeling, validated through homology, suggests that mutations at LAMA5 and LAMB1 may destabilize LM511 by altering inter-domain interactions or extracellular matrix binding. Finally, phenome-wide association scans and colocalization analyses suggest that the TCF4 CTG18.1 trinucleotide repeat expansion leads to dysregulation of ion transport in the corneal endothelium and has pleiotropic effects on renal function.

Abstract Background The United States (US) continues to face decades-long increases in opioid overdose fatalities. As an opioid overdose reversal medication, naloxone can dramatically reduce opioid overdose mortality rates when distributed to people likely to experience or witness an opioid overdose and packaged with education on its use, known as overdose education and naloxone distribution (OEND). Syringe services programs (SSPs) are ideal venues for OEND with staff who are culturally competent in providing services for people who are at risk of experiencing or observing an opioid overdose. We carried out a randomized controlled trial of SSPs to understand the effectiveness of the organize and mobilize for implementation effectiveness (OMIE) approach at improving OEND implementation effectiveness within SSPs. Methods Using simple randomization, 105 SSPs were enrolled into the trial and assigned to one of two study arms — (1) dissemination of OEND best practice recommendations (Control SSPs) or the OMIE approach along with dissemination of the OEND best practice recommendations (i.e., OMIE SSPs). OMIE SSPs could participate in 60-min OMIE sessions once a month for up to 12 months. At 12-month post-baseline, 102 of 105 SSPs (97%) responded to the follow-up survey. Results The median number of sessions completed by OMIE SSPs was 10. Comparing OMIE SSPs to control SSPs, we observed significant increases in the number of participants receiving naloxone (incidence rate ratio: 2.15; 95% CI: 1.42, 3.25; p

Abstract Objective Seventy-five percent of stroke survivors, caregivers, and health care professionals (HCP) believe current therapy practices are insufficient, specifically calling out the upper extremity as an area where innovation is needed to develop highly usable prosthetics/orthotics for the stroke population. A promising method for controlling upper extremity technologies is to infer movement intention non-invasively from surface electromyography (EMG). However, existing technologies are often limited to research settings and struggle to meet user needs. Approach To address these limitations, we have developed the NeuroLife® EMG System, an investigational device which consists of a wearable forearm sleeve with 150 embedded electrodes and associated hardware and software to record and decode surface EMG. Here, we demonstrate accurate decoding of 12 functional hand, wrist, and forearm movements in chronic stroke survivors, including multiple types of grasps from participants with varying levels of impairment. We also collected usability data to assess how the system meets user needs to inform future design considerations. Main results Our decoding algorithm trained on historical- and within-session data produced an overall accuracy of 77.1 ± 5.6% across 12 movements and rest in stroke participants. For individuals with severe hand impairment, we demonstrate the ability to decode a subset of two fundamental movements and rest at 85.4 ± 6.4% accuracy. In online scenarios, two stroke survivors achieved 91.34 ± 1.53% across three movements and rest, highlighting the potential as a control mechanism for assistive technologies. Feedback from stroke survivors who tested the system indicates that the sleeve’s design meets various user needs, including being comfortable, portable, and lightweight. The sleeve is in a form factor such that it can be used at home without an expert technician and can be worn for multiple hours without discomfort. Significance The NeuroLife EMG System represents a platform technology to record and decode high-resolution EMG for the real-time control of assistive devices in a form factor designed to meet user needs. The NeuroLife EMG System is currently limited by U.S. federal law to investigational use.

Abstract The stiffness of the extracellular matrix induces differential tension within integrin-based adhesions, triggering differential mechanoresponses. However, it has been unclear if the stiffness-dependent differential tension is induced solely by myosin activity. Here, we report that in the absence of myosin contractility, 3T3 fibroblasts still transmit stiffness-dependent differential levels of traction. This myosin-independent differential traction is regulated by polymerizing actin assisted by actin nucleators Arp2/3 and formin where formin has a stronger contribution than Arp2/3 to both traction and actin flow. Intriguingly, despite only slight changes in F-actin flow speed observed in cells with the combined inhibition of Arp2/3 and myosin compared to cells with sole myosin inhibition, they show a 4-times reduction in traction than cells with myosin-only inhibition. Our analyses indicate that traditional models based on rigid F-actin are inadequate for capturing such dramatic force reduction with similar actin flow. Instead, incorporating the F-actin network’s viscoelastic properties is crucial. Our new model including the F-actin viscoelasticity reveals that Arp2/3 and formin enhance stiffness sensitivity by mechanically reinforcing the F-actin network, thereby facilitating more effective transmission of flow-induced forces. This model is validated by cell stiffness measurement with atomic force microscopy and experimental observation of model-predicted stiffness-dependent actin flow fluctuation.

Aims: Orthopaedic surgery uses many varied instruments with high-speed, high-impact, thermal energy and sometimes heavy instruments, all of which potentially result in aerosolization of contaminated blood, tissue, and bone, raising concerns for clinicians’ health. This study quantifies the aerosol exposure by measuring the number and size distribution of the particles reaching the lead surgeon during key orthopaedic operations. Methods: The aerosol yield from 17 orthopaedic open surgeries (on the knee, hip, and shoulder) was recorded at the position of the lead surgeon using an Aerodynamic Particle Sizer (APS; 0.5 to 20 μm diameter particles) sampling at 1 s time resolution. Through timestamping, detected aerosol was attributed to specific procedures. Results: Diathermy (electrocautery) and oscillating bone saw use had a high aerosol yield (> 100 particles detected per s) consistent with high exposure to aerosol in the respirable range (< 5 µm) for the lead surgeon. Pulsed lavage, reaming, osteotome use, and jig application/removal were medium aerosol yield (10 to 100 particles s-1). However, pulsed lavage aerosol was largely attributed to the saline jet, osteotome use was always brief, and jig application/removal had a large variability in the associated aerosol yield. Suctioning (with/without saline irrigation) had a low aerosol yield (< 10 particles s-1). Most surprisingly, other high-speed procedures, such as drilling and screwing, had low aerosol yields. Conclusion: This work suggests that additional precautions should be recommended for diathermy and bone sawing, such as enhanced personal protective equipment or the use of suction devices to reduce exposure. Cite this article: Bone Joint Res 2023;12(10):636–643.

IntroductionNontuberculous mycobacteria (NTM) mediated infections are important to consider in cases with neuroinflammatory presentations. We aimed to characterize cases of NTM with neurological manifestations at the National Institutes of Health (NIH) Clinical Center and review the relevant literature.Materials and methodsBetween January 1995 and December 2020, six cases were identified. Records were reviewed for demographic, clinical, and radiological characteristics. A MEDLINE search found previously reported cases. Data were extracted, followed by statistical analysis to compare two groups [cases with slow-growing mycobacteria (SGM) vs. those with rapidly growing mycobacteria (RGM)] and evaluate for predictors of survival. NIH cases were evaluated for clinical and radiological characteristics. Cases from the literature were reviewed to determine the differences between SGM and RGM cases and to identify predictors of survival.ResultsSix cases from NIH were identified (age 41 ± 13, 83% male). Five cases were caused by SGM [Mycobacterium avium complex (MAC) n = 4; Mycobacterium haemophilum n = 1] and one due to RGM (Mycobacterium abscessus). Underlying immune disorders were identified only in the SGM cases [genetic (n = 2), HIV (n = 1), sarcoidosis (n = 1), and anti-interferon-gamma antibodies (n = 1)]. All cases were diagnosed using tissue analysis. A literature review found 81 reports on 125 cases (SGM n = 85, RGM n = 38, non-identified n = 2). No immune disorder was reported in 26 cases (21%). Within SGM cases, the most common underlying disease was HIV infection (n = 55, 65%), and seizures and focal lesions were more common. In RGM cases, the most common underlying condition was neurosurgical intervention or implants (55%), and headaches and meningeal signs were common. Tissue-based diagnosis was used more for SGM than RGM (39% vs. 13%, p = 0.04). Survival rates were similar in both groups (48% SGM and 55% in RGM). Factors associated with better survival were a solitary CNS lesion (OR 5.9, p = 0.01) and a diagnosis made by CSF sampling only (OR 9.9, p = 0.04).DiscussionNTM infections cause diverse neurological manifestations, with some distinctions between SGM and RGM infections. Tissue sampling may be necessary to establish the diagnosis, and an effort should be made to identify an underlying immune disorder.

Purpose Overtriage and undertriage rates are critical metrics in trauma, influenced by both trauma team activation (TTA) criteria and compliance with these criteria. Analysis of undertriaged patients at a level I trauma center revealed suboptimal compliance with existing criteria. This study assessed triage patterns after implementing compliance-focused process interventions. Methods A physician-driven, free-text alert system was modified to a nonphysician, hospital dispatcher-guided system. The latter employed dropdown menus to maximize compliance with criteria. The preintervention period included patients who presented between May 12, 2020, and December 31, 2020. The postintervention period incorporated patients who presented from May 12, 2021, through December 31, 2021. We evaluated appropriate triage, overtriage, and undertriage using the Standardized Trauma Assessment Tool. Statistical analyses were conducted with an α level of 0.05. Results The new system was associated with improved compliance with existing TTA criteria (from 70.3% to 79.3%, P=0.023) and decreased undertriage (from 6.0% to 3.2%, P=0.002) at the expense of increasing overtriage (from 46.6% to 57.4%, P

Abstract Background Contingency management (CM) is an evidence-based intervention for stimulant use and is highly effective in combination with medication for opioid use disorder. Yet, uptake of CM in opioid treatment programs that provide medication for opioid use disorder remains low. This paradox in which CM is one of the most effective interventions, yet one of the least available, represents one of the greatest research-to-practice gaps in the addiction health services field. Multi-level implementation strategies are needed to address barriers to CM implementation at both the provider- and organization-level. This type III hybrid effectiveness-implementation trial was funded by the National Institute on Drug Abuse to evaluate whether a multi-level implementation strategy, the Science of Service Laboratory (SSL), can effectively promote CM implementation in opioid treatment programs. Specific aims will test the effectiveness of the SSL on implementation outcomes (primary aim) and patient outcomes (secondary aim), as well as test putative mediators of implementation outcomes (exploratory aim). Methods Utilizing a fully powered type III hybrid effectiveness-implementation trial with a stepped wedge design, we propose to randomize a cohort of 10 opioid treatment programs to receive the SSL across four steps. Each step, an additional 2–3 opioid treatment programs will receive the SSL implementation strategy, which has three core components: didactic training, performance feedback, and external facilitation. At six intervals, each of the 10 opioid treatment programs will provide de-identified electronic medical record data from all available patient charts on CM delivery and patient outcomes. Staff from each opioid treatment program will provide feedback on contextual determinants influencing implementation at three timepoints. Discussion Between planning of this protocol and receipt of funding, the landscape for CM in the USA changed dramatically, with multiple Departments of Health launching state-wide CM initiatives. We therefore accelerated the protocol timeline and offered some cursory training resources to all sites as a preparation activity. We also began partnering with multiple Departments of Health to evaluate their rollout of CM using the measures outlined in this protocol. Trial registration This study protocol is registered via ClinicalTrials.gov Identifier: NCT05702021. Date of registration: January 27, 2023.

Abstract Background Opioid overdoses have continued to increase since the start of the COVID-19 pandemic. The pathways through which the COVID-19 pandemic has affected trajectories of opioid use and opioid-related problems are largely unknown. Using the Epidemic-Pandemic Impacts Inventory (EPII), a novel instrument that assess pandemic-related impacts across multiple life domains, we tested the hypothesis that COVID-related impacts (on e.g., interpersonal conflict, employment, infection exposure, and emotional health) experienced in the early months of the pandemic would predict changes in opioid use and opioid-related problems at follow-up. Methods This analysis was embedded within a cluster randomized type 3 implementation-effectiveness hybrid trial that had enrolled 188 patients across eight opioid treatments prior to the start of the pandemic. Participants had all been recently inducted on medication for opioid use disorder and were actively receiving treatment. Participants reported on their opioid use and opioid-related problems at baseline and 3-, 6-, and 9-month post-baseline assessments. Between May and August 2020, participants were sent an optional invitation to complete the EPII. Results One hundred thirty-three respondents completed the EPII and 129 had sufficient data to analyze the EPII and at least one subsequent follow-up. In logistic and zero-inflated negative binomial analyses adjusting for covariates, each endorsed pandemic impact in the interpersonal conflict domain was associated with 67% increased odds of endorsement of any opioid use, and each impact in the employment and infection exposure-domains was associated with 25% and 75% increases in number of endorsed opioid-related problems, respectively. Conclusions Mitigating the effect of the pandemic on patients’ interpersonal relationships and employment, and promoting greater infection control in opioid treatment programs, could be protective against negative opioid-related outcomes. Trial registration The present study describes secondary data analysis on a previously registered clinical trial: clinicaltrials.gov/ct2/show/NCT03931174.

Pediatric high-grade gliomas (pHGG) are a rare yet devastating malignancy of the central nervous system’s glial support cells, affecting children, adolescents, and young adults. Tumors of the central nervous system account for the leading cause of pediatric mortality of which high-grade gliomas present a significantly grim prognosis. While the past few decades have seen many pediatric cancers experiencing significant improvements in overall survival, the prospect of survival for patients diagnosed with pHGGs has conversely remained unchanged. This can be attributed in part to tumor heterogeneity and the existence of the blood-brain barrier. Advances in discovery research have substantiated the existence of unique subgroups of pHGGs displaying alternate responses to different therapeutics and varying degrees of overall survival. This highlights a necessity to approach discovery research and clinical management of the disease in an alternative subtype-dependent manner. This review covers traditional approaches to the therapeutic management of pHGGs, limitations of such methods and emerging alternatives. Novel mutations which predominate the pHGG landscape are highlighted and the therapeutic potential of targeting them in a subtype specific manner discussed. Collectively, this provides an insight into issues in need of transformative progress which arise during the management of pHGGs.

Glycogen storage disease type Ia (GSD Ia) is the inherited deficiency of glucose-6-phosphatase (G6Pase), associated with life-threatening hypoglycemia and long-term complications, including hepatocellular carcinoma formation. Gene replacement therapy fails to stably reverse G6Pase deficiency. We attempted genome editing using two adeno-associated virus vectors, one that expressed Staphylococcus aureus Cas9 protein and a second containing a donor transgene encoding G6Pase, in a dog model for GSD Ia. We demonstrated donor transgene integration in the liver of three adult-treated dogs accompanied by stable G6Pase expression and correction of hypoglycemia during fasting. Two puppies with GSD Ia were treated by genome editing that achieved donor transgene integration in the liver. Integration frequency ranged from 0.5% to 1% for all dogs. In adult-treated dogs, anti-SaCas9 antibodies were detected before genome editing, reflecting prior exposure to S. aureus. Nuclease activity was low, as reflected by a low percentage of indel formation at the predicted site of SaCas9 cutting that indicated double-stranded breaks followed by non-homologous end-joining. Thus, genome editing can integrate a therapeutic transgene in the liver of a large animal model, either early or later in life, and further development is warranted to provide a more stable treatment for GSD Ia.

Abstract Organic redox-active molecules are attractive as redox-flow battery (RFB) reactants because of their low anticipated costs and widely tunable properties. Unfortunately, many lab-scale flow cells experience rapid material degradation (from chemical and electrochemical decay mechanisms) and capacity fade during cycling (>0.1%/day) hindering their commercial deployment. In this work, we combine ultraviolet-visible spectrophotometry and statistical inference techniques to elucidate the Michael attack decay mechanism for 4,5-dihydroxy-1,3-benzenedisulfonic acid (BQDS), a once-promising positive electrolyte reactant for aqueous organic redox-flow batteries. We use Bayesian inference and multivariate curve resolution on the spectroscopic data to derive uncertainty-quantified reaction orders and rates for Michael attack, estimate the spectra of intermediate species and establish a quantitative connection between molecular decay and capacity fade. Our work illustrates the promise of using statistical inference to elucidate chemical and electrochemical mechanisms of capacity fade in organic redox-flow battery together with uncertainty quantification, in flow cell-based electrochemical systems.

Abstract Background The forms and compositions of primer gunshot residue (GSR) in shooting cases have been routinely analyzed in many crime labs by scanning electron microscope/energy-dispersive X-ray spectroscopy (SEM/EDS). Gunshot residue studies over the last 30 years have identified a contribution by residual GSR from surfaces within the firearm to GSR (the “memory effect”). In this study, we first focus on the GSR compositional differences between target, bore, and cylinder gap for a .22 caliber revolver which has received little attention in the literature. Secondly, we examine the behavior of elements involved in the residual contribution to GSR for a .22 caliber pistol. Results The compositions of target, bore, and cylinder gap GSRs from a .22 caliber revolver were determined for 11 discharge series. Breech GSR compositions from a .22 caliber pistol changed in sequential discharges revealing behavior of individual primer and bullet elements. The target GSR forms from some .22 caliber ammunitions were not spherical. Conclusions For the revolver, GSR compositions from the target, bore, and cylinder gap are divergent. Analysis of the pistol’s breech GSRs indicated mixing with the previously deposited GSRs resulting in a sequential contribution or loss of elements and redeposition of the new composition. Aluminum did not contribute to the residual GSR. The GSR composition of a discharge and its contribution to residual GSR on the internal parts of the firearm represents a complex process which likely involves a number of variables including, but not restricted to firearm design, primer composition, pressure and temperature of the discharge gas, and bullet surface composition.

Rationale & Objective: Patients with chronic kidney disease (CKD) have dysfunctional high-density lipoprotein (HDL) particles that lack cardioprotective properties; altered lipid composition may be associated with these changes. To investigate HDL lipids as potential cardiovascular risk factors in CKD, we tested the associations of HDL ceramides, sphingomyelins, and phosphatidylcholines with mortality. Study Design: We leveraged data from a longitudinal prospective cohort of participants with CKD. Setting & Participants: We included participants aged greater than 21 years with CKD, excluding those on maintenance dialysis or with prior kidney transplant. Exposure: HDL particles were isolated using density gradient ultracentrifugation. We quantified the relative abundance of HDL ceramides, sphingomyelins, and phosphatidylcholines via liquid chromatography tandem mass spectrometry (LC-MS/MS). Outcomes: Our primary outcome was all-cause mortality. Analytical Approach: We tested associations using Cox regressions adjusted for demographics, comorbid conditions, laboratory values, medication use, and highly correlated lipids with opposed effects, controlling for multiple comparisons with false discovery rates (FDR). Results: There were 168 deaths over a median follow-up of 6.12 years (interquartile range, 3.71-9.32). After adjustment, relative abundance of HDL ceramides (HR, 1.22 per standard deviation; 95% CI, 1.06-1.39), sphingomyelins with long fatty acids (HR, 1.44; 95% CI, 1.05-1.98), and saturated and monounsaturated phosphatidylcholines (HR, 1.22; 95% CI, 1.06-1.41) were significantly associated with increased risk of all-cause mortality (FDR

IntroductionAllergic reactions are mediated by human IgE antibodies that bind to and cross-link allergen molecules. The sites on allergens that are recognized by IgE antibodies have been difficult to investigate because of the paucity of IgE antibodies in a human serum. Here, we report the production of unique human IgE monoclonal antibodies to major inhaled allergens and food allergens that can be produced at scale in perpetuity.Materials and methodsThe IgE antibodies were derived from peripheral blood mononuclear cells of symptomatic allergic patients, mostly children aged 3–18 years, using hybridoma fusion technology. Total IgE and allergen-specific IgE was measured by ImmunoCAP. Their specificity was confirmed through ELISA and immunoblotting. Allergenic potency measurements were determined by ImmunoCAP inhibition. Biological activity was determined in vitro by comparing β-hexosaminidase release from a humanized rat basophilic cell line.ResultsHuman IgE monoclonal antibodies (n = 33) were derived from 17 allergic patients with symptoms of allergic rhinitis, asthma, atopic dermatitis, food allergy, eosinophilic esophagitis, or red meat allergy. The antibodies were specific for five inhaled allergens, nine food allergens, and alpha-gal and had high levels of IgE (53,450–1,702,500 kU/L) with ratios of specific IgE to total IgE ranging from

Background: Traditional gel-based (wet) electrodes for biopotential recordings have several shortcomings that limit their practicality for real-world measurements. Dry electrodes may improve usability, but they often suffer from reduced signal quality. We sought to evaluate the biopotential recording properties of a novel mixed ionic–electronic conductive (MIEC) material for improved performance. Methods: We fabricated four MIEC electrode form factors and compared their signal recording properties to two control electrodes, which are electrodes commonly used for biopotential recordings (Ag-AgCl and stainless steel). We used an agar synthetic skin to characterize the impedance of each electrode form factor. An electrical phantom setup allowed us to compare the recording quality of simulated biopotentials with ground-truth sources. Results: All MIEC electrode form factors yielded impedances in a similar range to the control electrodes (all Conclusions: The MIEC electrodes demonstrated similar and, in some cases, better signal recording characteristics than current state-of-the-art electrodes. MIEC electrodes can also be fabricated into a myriad of form factors, underscoring the great potential this novel material has across a wide range of biopotential recording applications.

The overall prognosis of thyroid cancer is excellent, but some patients have grossly invasive disease and distant metastases with limited responses to systemic therapies. Thus, relevant preclinical models are needed to investigate thyroid cancer biology and novel treatments. Different preclinical models have recently emerged with advances in thyroid cancer genetics, mouse modeling and new cell lines. Choosing the appropriate model according to the research question is crucial to studying thyroid cancer. This review will discuss the current preclinical models frequently used in thyroid cancer research, from cell lines to mouse models, and future perspectives on patient-derived and humanized preclinical models in this field.

Peripheral artery disease (PAD) is a form of atherosclerotic cardiovascular disease, affecting ∼8 million Americans, and is known to have racial and ethnic disparities. PAD has been reported to have a significantly higher prevalence in African Americans (AAs) compared to non-Hispanic European Americans (EAs). Hispanic/Latinos (HLs) have been reported to have lower or similar rates of PAD compared to EAs, despite having a paradoxically high burden of PAD risk factors; however, recent work suggests prevalence may differ between sub-groups. Here, we examined a large cohort of diverse adults in the BioMe biobank in New York City. We observed the prevalence of PAD at 1.7% in EAs vs. 8.5% and 9.4% in AAs and HLs, respectively, and among HL sub-groups, the prevalence was found at 11.4% and 11.5% in Puerto Rican and Dominican populations, respectively. Follow-up analysis that adjusted for common risk factors demonstrated that Dominicans had the highest increased risk for PAD relative to EAs [OR = 3.15 (95% CI 2.33–4.25), p < 6.44 × 10−14]. To investigate whether genetic factors may explain this increased risk, we performed admixture mapping by testing the association between local ancestry and PAD in Dominican BioMe participants (N = 1,813) separately from European, African, and Native American (NAT) continental ancestry tracts. The top association with PAD was an NAT ancestry tract at chromosome 2q35 [OR = 1.96 (SE = 0.16), p < 2.75 × 10−05) with 22.6% vs. 12.9% PAD prevalence in heterozygous NAT tract carriers versus non-carriers, respectively. Fine-mapping at this locus implicated tag SNP rs78529201 located within a long intergenic non-coding RNA (lincRNA) LINC00607, a gene expression regulator of key genes related to thrombosis and extracellular remodeling of endothelial cells, suggesting a putative link of the 2q35 locus to PAD etiology. Efforts to reproduce the signal in other Hispanic cohorts were unsuccessful. In summary, we showed how leveraging health system data helped understand nuances of PAD risk across HL sub-groups and admixture mapping approaches elucidated a putative risk locus in a Dominican population.

Background The ratio of 24,25‐dihydroxyvitamin D3/25‐hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25‐hydroxyvitamin D (25[OH]D), and 1,25‐dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross‐sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25‐dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography–tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression‐calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross‐sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non‐Hispanic White race and ethnicity, 42% non‐Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow‐up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95–1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0–1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Ulcerative colitis (UC) is a type of inflammatory bowel disease characterized by inflammation, ulcers and irritation of the mucosal lining. Oral drug delivery in UC encounters challenges because of multifaceted barriers. Dexamethasone-loaded galactosylated-PLGA/Eudragit S100/pullulan nanocargoes (Dexa-GP/ES/Pu NCs) have been developed with a dual stimuli-sensitive coating responsive to both colonic pH and microbiota, and an underneath galactosylated-PLGA core (GP). The galactose ligand of the GP preferentially binds to the macrophage galactose type-lectin-C (MGL-2) surface receptor. Therefore, both stimuli and ligand-mediated targeting facilitate nanocargoes to deliver Dexa specifically to the colon with enhanced macrophage uptake. Modified emulsion method coupled with a solvent evaporation coating technique was employed to prepare Dexa-GP/ES/Pu NCs. The nanocargoes were tested using in vitro, ex vivo techniques and dextran sodium sulfate (DSS) induced UC model. Prepared nanocargoes had desired physicochemical properties, drug release, cell uptake and cellular viability. Investigations using a DSS-colitis model showed high localization and mitigation of colitis with downregulation of NF-ĸB and COX-2, and restoration of clinical, histopathological, biochemical indices, antioxidant balance, microbial alterations, FTIR spectra, and epithelial junctions’ integrity. Thus, Dexa-GP/ES/Pu NCs found to be biocompatible nanocargoes capable of delivering drugs to the inflamed colon with unique targeting properties for prolonged duration.

AbstractThe Northern Sunfish (Lepomis peltastes Cope, 1870) is threatened in New York state, USA, but this was not the case before 1940 when the NY Biological Survey documented the species at scattered, specialized habitats in six watersheds in the central and western parts of the state. After 1940 the historic populations could not be detected, but a new population was discovered in 1974 in lower Tonawanda Creek and the nearby Erie Canal. Northern Sunfish, and a few of their hybrids with other Lepomis species, were caught at these locations during irregular sampling through 2009, but no Northern Sunfish were caught after 2009. The objectives of our study were to: (1) Determine the extent of Northern Sunfish hybridization with other Lepomis species, and (2) Evaluate how well identifications of Lepomis species and their hybrids agreed among field keys, morphometric measurements and meristic counts, and genetic methods. In 2013, we collected Northern Sunfish (descended from fish captured in lower Tonawanda Creek from 2006-2009) from NY State Department of Environmental Conservation rearing ponds, plus wild Green Sunfish (L. cyanellus Rafinesque, 1819), Pumpkinseed (L. gibbosus Linnaeus, 1758), Bluegill (L. macrochirus Rafinesque, 1819), and suspected Lepomis hybrids from lower Tonawanda Creek. Ultimately, 91 fish were identified using field keys, morphometric-meristic analysis, and mtDNA and nuclear DNA analysis. Assuming genetic analysis provided accurate identification, we found 7 Bluegill × Northern Sunfish, 8 Bluegill × Pumpkinseed, 13 Bluegill × Green Sunfish, and 3 Green Sunfish × Pumpkinseed hybrids in our sample (female parent listed second in these crosses). Keyed and morphometric-meristic identifications did not differ in accuracy and averaged 81% of genetic identification accuracy. After Northern Sunfish stocking (not in our study area) and sampling from 2008 to 2018 in several watersheds with appropriate habitat and no recaptures after 2014, we conclude that the Northern Sunfish is extirpated in western New York state.

Abstract Remdesivir is the first US Food and Drug Administration (FDA)‐approved drug for the treatment of coronavirus disease 2019 (COVID‐19). We conducted a retrospective pharmacogenetic study to examine remdesivir‐associated liver enzyme elevation among Million Veteran Program participants hospitalized with COVID‐19 between March 15, 2020, and June 30, 2021. Pharmacogene phenotypes were assigned using Stargazer. Linear regression was performed on peak log‐transformed enzyme values, stratified by population, adjusted for age, sex, baseline liver enzymes, comorbidities, and 10 population‐specific principal components. Patients on remdesivir had higher peak alanine aminotransferase (ALT) values following treatment initiation compared with patients not receiving remdesivir. Remdesivir administration was associated with a 33% and 24% higher peak ALT in non‐Hispanic White (NHW) and non‐Hispanic Black (NHB) participants (p

Rapid diagnosis and implementation of treatments is crucial in many genetic conditions. Here the authors describe Genome-to-Treatment, a virtual disease management system that can achieve a rapid diagnosis by expedited whole genome sequencing in 13.5 hours and provide guidance to clinicians for possible therapies.

Abstract Patients supported by mechanical ventilation require frequent invasive blood gas samples to monitor and adjust the level of support. We developed a transparent and novel blood gas estimation model to provide continuous monitoring of blood pH and arterial CO2 in between gaps of blood draws, using only readily available noninvasive data sources in ventilated patients. The model was trained on a derivation dataset (1,883 patients, 12,344 samples) from a tertiary pediatric intensive care center, and tested on a validation dataset (286 patients, 4030 samples) from the same center obtained at a later time. The model uses pairwise non-linear interactions between predictors and provides point-estimates of blood gas pH and arterial CO2 along with a range of prediction uncertainty. The model predicted within Clinical Laboratory Improvement Amendments of 1988 (CLIA) acceptable blood gas machine equivalent in 74% of pH samples and 80% of PCO2 samples. Prediction uncertainty from the model improved estimation accuracy by 15% by identifying and abstaining on a minority of high-uncertainty samples. The proposed model estimates blood gas pH and CO2 accurately in a large percentage of samples. The model’s abstention recommendation coupled with ranked display of top predictors for each estimation lends itself to real-time monitoring of gaps between blood draws, and the model may help users determine when a new blood draw is required and delay blood draws when not needed.

Orton and Symons et al. compare respiratory particle sizes and emission rates by sampling exhalates from participants at rest, and while speaking or exercising. They find that vocalisation produces larger particles and that while emission rates are similar between speaking and vigorous exercise, very vigorous exercise leads to higher rates.

Background Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in patients with CKD.Methods We conducted a randomized, placebo-controlled, double-blind, crossover trial comparing CoQ10, NR, and placebo in 25 patients with an estimated glomerular filtration rate (eGFR) of less than 60mL/min/1.73 m2. Participants received NR (1,000 mg/day), CoQ10 (1,200 mg/day), or placebo for 6 weeks each. The primary outcomes were aerobic capacity measured by peak rate of oxygen consumption (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semitargeted plasma metabolomics and lipidomics.Results Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9 ± 9.2 mL/min/1.73 m2. Compared with placebo, we found no differences in VO2 peak (P = 0.30, 0.17), total work (P = 0.47, 0.77), and total work efficiency (P = 0.46, 0.55) after NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30 W (P = 0.03) and VO2 at 60 W (P = 0.07) compared with placebo. No changes in eGFR were observed after NR or CoQ10 treatment (P = 0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium- and long-chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that were involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.Conclusions Six weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.Trial registration ClinicalTrials.gov NCT03579693.Funding National Institutes of Diabetes and Digestive and Kidney Diseases (grants R01 DK101509, R03 DK114502, R01 DK125794, and R01 DK101509).

BackgroundHuman Immunoglobulin E monoclonal antibodies (hIgE mAb) are unique tools for investigating IgE responses. Here, the biological activity of hIgE mAb, derived from immortalized B cells harvested from the blood of allergic donors, targeting three allergens (Der p 2, Fel d 1 and Ara h 2) was investigated.MethodsThree Der p 2-, three Fel d 1- and five Ara h 2-specific hIgE mAb produced by human B cell hybridomas, were combined in pairs and used to passively sensitize humanized rat basophilic leukemia cells and compared with sensitization using serum pools. Sensitized cells were stimulated with corresponding allergens (recombinant or purified), allergen extracts or structural homologs, having 40-88% sequence similarity, and compared for mediator (β-hexosaminidase) release.ResultsOne, two and eight pairs of Der p 2-, Fel d 1- and Ara h 2-specific hIgE mAb, respectively, produced significant mediator release (>50%). A minimum hIgE mAb concentration of 15-30 kU/L and a minimum antigen concentration between 0.01-0.1 µg/mL were sufficient to induce a pronounced mediator release. Individual sensitization with one Ara h 2-specific hIgE mAb was able to induce crosslinking independently of a second specific hIgE mAb. Der p 2- and Ara h 2-specific mAb showed a high allergen specificity when compared to homologs. Mediator release from cells sensitized with hIgE mAb was comparable to serum sensitization.ConclusionThe biological activity of hIgE mAb reported here provides the foundation for novel methods of standardization and quality control of allergen products and for mechanistic studies of IgE-mediated allergic diseases, using hIgE mAb.

The relationship between structure and performance in alkaline Zn batteries is undeniable, where anode utilization, dendrite formation, shape change, and passivation issues are all addressable through anode morphology. While tailoring 3D hosts can improve the electrode performance, these practices are inherently limited by scaffolds that increase the mass or volume. Herein, a direct write strategy for producing template‐free metallic 3D Zn electrode architectures is discussed. Concentrated inks are customized to build designs with low electrical resistivity (5 × 10−4 Ω cm), submillimeter sizes (200 μm filaments), and high mechanical stability (Young's modulus of 0.1–0.5 GPa at relative densities of 0.28–0.46). A printed Zn lattice anode versus NiOOH cathode with an alkaline polymer gel electrolyte is then demonstrated. This Zn||NiOOH cell operates for over 650 cycles at high rates of 25 mA cm−2 with an average areal capacity of 11.89 mAh cm−2, a cumulative capacity of 7.8 Ah cm−2, and a volumetric capacity of 23.78 mAh cm−3. A thicker Zn anode achieves an ultrahigh areal capacity of 85.45 mAh cm−2 and a volumetric capacity of 81.45 mAh cm−3 without significant microstructural changes after 50 cycles.

Abstract Background Genetic variants have been found to influence red blood cell (RBC) susceptibility to hemolytic stress and affect transfusion outcomes and the severity of blood diseases. Males have a higher susceptibility to hemolysis than females, but little is known about the genetic mechanism contributing to the difference. Results To investigate the sex differences in RBC susceptibility to hemolysis, we conducted a sex-stratified genome-wide association study and a genome-wide gene-by-sex interaction scan in a multi-ethnic dataset with 12,231 blood donors who have in vitro osmotic hemolysis measurements during routine blood storage. The estimated SNP-based heritability for osmotic hemolysis was found to be significantly higher in males than in females (0.46 vs. 0.41). We identified SNPs associated with sex-specific susceptibility to osmotic hemolysis in five loci (SPTA1, KCNA6, SLC4A1, SUMO1P1, and PAX8) that impact RBC function and hemolysis. Conclusion Our study established a best practice to identify sex-specific genetic modifiers for sexually dimorphic traits in datasets with mixed ancestries, providing evidence of different genetic regulations of RBC susceptibility to hemolysis between sexes. These and other variants may help explain observed sex differences in the severity of hemolytic diseases, such as sickle cell and malaria, as well as the viability of red cell storage and recovery.

Summary: Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.

Most current anti-viral vaccines elicit a humoral and cellular immune response via the pathway of phagocytic cell mediated viral antigen presentation to B and T cell surface receptors. However, this pathway results in reduced ability to neutralize S-protein Receptor Binding Domains (RBDs) from several Variants of Concern (VOC) and the rapid waning of memory B cell response requiring vaccine reformulation to cover dominant VOC S-proteins and multiple boosters. Here we show for the first time in mice and humans, that a bacterially derived, non-living, nanocell (EDV; EnGeneIC Dream Vector) packaged with plasmid expressed SARS-CoV-2 S-protein and α-galactosyl ceramide adjuvant (EDV-COVID-αGC), stimulates an alternate pathway due to dendritic cells (DC) displaying both S-polypeptides and αGC thereby recruiting and activating iNKT cells with release of IFNγ. This triggers DC activation/maturation, activation of follicular helper T cells (TFH), cognate help to B cells with secretion of a cytokine milieu promoting B cell maturation, somatic hypermutation in germinal centers to result in high affinity antibodies. Surrogate virus neutralization tests show 90-100% neutralization of ancestral and early VOC in mice and human trial volunteers. EDV-COVID-αGC as a third dose booster neutralized Omicron BA. 4/5. Serum and PBMC analyses reveal long lasting S-specific memory B and T cells. In contrast, control EDVs lacking αGC, did not engage the iNKT/DC pathway resulting in antibody responses unable to neutralize all VOCs and had a reduced B cell memory. The vaccine is lyophilized, stored and transported at room temperature with a shelf-life of over a year.

Over the past few years, the industry has experienced significant growth, leading to what is now known as Industry 4.0. This advancement has been characterized by the automation of robots. Industries have embraced mobile robots to enhance efficiency in specific manufacturing tasks, aiming for optimal results and reducing human errors. Moreover, robots can perform tasks in areas inaccessible to humans, such as hard-to-reach zones or hazardous environments. However, the challenge lies in the lack of knowledge about the operation and proper use of the robot. This work presents the development of a teleoperation system using HTC Vive Pro 2 virtual reality goggles. This allows individuals to immerse themselves in a fully virtual environment to become familiar with the operation and control of the KUKA youBot robot. The virtual reality experience is created in Unity, and through this, robot movements are executed, followed by a connection to ROS (Robot Operating System). To prevent potential damage to the real robot, a simulation is conducted in Gazebo, facilitating the understanding of the robot’s operation.

Abstract Background The Grasha-Riechmann teaching styles, which includes three didactic and two prescriptive styles, have been shown to help enhance learning within educational settings. Although an adaption of the Grasha-Riechmann style classification has enabled coaching styles to be identified for use as part of quality improvement (QI) initiatives, research has not examined the styles actually utilized by coaches within a QI initiative or how the styles change overtime when the coach is guiding an organization through change implementation. Interactions between coaches and HIV service organization (HSO) staff participating in a large implementation research experiment called the Substance Abuse Treatment to HIV care (SAT2HIV) Project were evaluated to begin building an evidence base to address this gap in implementation research. Methods Implementation & Sustainment Facilitation (ISF) Strategy meetings (n = 137) between coaches and HSO staff were recorded and professionally transcribed. Thematic coding classifications were developed from the Grasha-Riechmann framework and applied to a purposively selected sample of transcripts (n = 66). Four coders independently coded transcripts using NVivo to facilitate text identification, organization, and retrieval for analysis. Coaching style use and changes across the three ISF phases were explored. Results Facilitator and formal authority were the two coaching styles predominately used. Facilitator sub-themes shifted from asking questions and providing support to supporting independent action over time. Coaches’ use of formal authority sub-styles shifted notably across time from setting expectations or ensuring preparation to offering affirmation or feedback about changes that the HSO’s were implementing. The use of the delegator or personal model coaching styles occurred infrequently. Conclusions The current research extends implementation research’s understanding of coaching. More specifically, findings indicate it is feasible to use the Grasha-Riechmann framework to qualitatively identify coaching styles utilized in a facilitation-based implementation strategy. More importantly, results provide insights into how different coaching styles were utilized to implement an evidence-based practice. Further research is needed to examine how coaching styles differ by organization, impact implementation fidelity, and influence both implementation outcomes and client outcomes. Trial registration ClinicalTrials.gov NCT02495402 . Registered on July 6, 2015.

Abstract We discuss how colour flows can be used to simplify the computation of matrix elements, and in the context of parton shower Monte Carlos with accuracy beyond leading-colour. We show that, by systematically employing them, the results for tree-level matrix elements and their soft limits can be given in a closed form that does not require any colour algebra. The colour flows that we define are a natural generalization of those exploited by existing Monte Carlos; we construct their representations in terms of different but conceptually equivalent quantities, namely colour loops and dipole graphs, and examine how these objects may help to extend the accuracy of Monte Carlos through the inclusion of subleading-colour effects. We show how the results that we obtain can be used, with trivial modifications, in the context of QCD+QED simulations, since we are able to put the gluon and photon soft-radiation patterns on the same footing. We also comment on some peculiar properties of gluon-only colour flows, and their relationships with established results in the mathematics of permutations.

The decarboxylation of 9-cis-octadecenoic (oleic) acid to aromatic and aliphatic hydrocarbons suitable as blend components for aviation fuel applications utilising ruthenium dodecacarbonyl [Ru3(CO)12] with a variety of other catalysts is presented. Due to the different relative rates of decarboxylation and hydrogenation/dehydrogenation, different product distributions are possible when the catalyst is varied. Chloro-1,5-cyclooctadiene iridium (I) dimer [(C8H12IrCl)2] gave a similar conversion to the ruthenium system but provided an altered product distribution. Aromatic contents of up to 35% were achieved in the iridium system, thereby providing a wider range of blending options for fuel producers. Additionally, both catalytic systems were found to decarboxylate high-oleic soybean oil fatty acids, giving a product of similar energy content to that obtained using high grade oleic acid.

Abstract Background Opioid-related overdoses and harms have been declared a public health emergency in the United States, highlighting an urgent need to implement evidence-based treatments. Contingency management (CM) is one of the most effective behavioral interventions when delivered in combination with medication for opioid use disorder, but its implementation in opioid treatment programs is woefully limited. Project MIMIC (Maximizing Implementation of Motivational Incentives in Clinics) was funded by the National Institute on Drug Abuse to identify effective strategies for helping opioid treatment programs improve CM implementation as an adjunct to medication. Specific aims will test the impact of two different strategies on implementation outcomes (primary aim) and patient outcomes (secondary aims), as well as test putative mediators of implementation effectiveness (exploratory aim). Methods A 3-cohort, cluster-randomized, type 3 hybrid design is used with the opioid treatment programs as the unit of randomization. Thirty programs are randomized to one of two conditions. The control condition is the Addiction Technology Transfer Center (ATTC) Network implementation strategy, which consists of three core approaches: didactic training, performance feedback, and on-going consultation. The experimental condition is an enhanced ATTC strategy, with the same core ATTC elements plus two additional theory-driven elements. The two additional elements are Pay-for-Performance, which aims to increase implementing staff’s extrinsic motivations, and Implementation & Sustainment Facilitation, which targets staff’s intrinsic motivations. Data will be collected using a novel, CM Tracker tool to document CM session delivery, session audio recordings, provider surveys, and patient surveys. Implementation outcomes include CM Exposure (number of CM sessions delivered per patient), CM Skill (ratings of CM fidelity), and CM Sustainment (number of patients receiving CM after removal of support). Patient outcomes include self-reported opioid abstinence and opioid-related problems (both assessed at 3- and 6-months post-baseline). Discussion There is urgent public health need to improve the implementation of CM as an adjunct to medication for opioid use disorder. Consistent with its hybrid type 3 design, Project MIMIC is advancing implementation science by comparing impacts of these two multifaceted strategies on both implementation and patient outcomes, and by examining the extent to which the impacts of those strategies can be explained by putative mediators. Trial registration: This clinical trial has been registered with clinicaltrials.gov (NCT03931174). Registered April 30, 2019. https://clinicaltrials.gov/ct2/show/NCT03931174?term=project+mimic&draw=2&rank=1

From late spring of 2020 to the present, the U.S. educational conversation about learning in K-12 public schools during the pandemic has been about the fact that students did not learn as much, widening the achievement gap due to digital learning. Some K-12 public schools and school districts have reported no learning loss. This exploratory study examined elements shared by teachers, administrators, and parents that accounted for potential reasons why these individual K-12 public school districts did not experience the learning loss during digital learning that has been at the center stage of the narrative about educational experiences during the pandemic. Analysis of the results showed four elements that were central to these school districts' experiences: having an instructional framework; determining a clear pedagogical function; connecting technology to the pedagogical function; capitalizing on formative assessments. Data also revealed that the participants tended to believe that a focus on pedagogy before technology integration was crucial.