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Abstract Background Depression is the most diagnosed mental health condition among people living with HIV. Collaborative care is an effective intervention for depression, typically delivered in primary care settings. The HIV Translating Initiatives for Depression into Effective Solutions (HITIDES) clinical intervention involves a depression care team housed off-site that supports depression care delivery by HIV care providers. In a randomized controlled trial, HITIDES significantly improved depression symptoms for veterans living with HIV and delivered cost savings. However, no HIV clinics in the Veterans Health Administration (VHA) have implemented HITIDES; as such, it is unclear what implementation strategies are necessary to launch and sustain this intervention. Methods This hybrid type-3 effectiveness-implementation trial examines the implementation and effectiveness of HITIDES in 8 VHA HIV clinics randomly assigned to one of two implementation arms. Each arm uses a different implementation strategy package. Arm 1 includes an intervention operations guide; an on-site clinical champion who, with the help of a peer community of practice, will work with local clinicians and leadership to implement HITIDES at their site; and patient engagement in implementation tools. Arm 2 includes all strategies from Arm 1 with assistance from an external facilitator. The primary implementation outcomes is reach; secondary outcomes include adoption, implementation dose, depressive symptoms, and suicidal ideation. We will conduct a budget impact analysis of the implementation strategy packages. We hypothesize that Arm 2 will be associated with greater reach and adoption and that Arm 1 will be less costly. Discussion Preliminary work identified implementation strategies acceptable to veterans living with HIV and HIV care providers; however, the effectiveness and cost of these strategies are unknown. While the depression care team can deliver services consistently with high quality, the ability of the depression care team to engage with HIV care providers at sites is unknown. Findings from this study will be used to inform selection of implementation strategies for a broad rollout to enhance depression and suicide care for people living with HIV. Trial registration ClinicalTrials.gov ID: NCT05901272, Registered 10 May 2023, https://clinicaltrials.gov/study/NCT05901272

Abstract Background The Veterans Health Administration (VHA) is the United States largest learning health system. The Diffusion of Excellence (DoE) program is a large-scale model of diffusion that identifies and diffuses evidence-informed practices across VHA. During the period of 2016-2021, 57 evidence-informed practices were implemented across 82 VHA facilities. This setting provides a unique opportunity to understand sustainment determinants and pathways. Our objective was to characterize the longitudinal pathways of practices as they transition from initial implementation to long-term sustainment at each facility. Methods A longitudinal, mixed-methods evaluation of 82 VHA facilities. Eighty-two facility representatives, chosen by leadership as points-of-contact for 57 DoE practices, were eligible for post-implementation interviews and annual sustainment surveys. Primary outcomes (implementation, sustainment), and secondary outcomes (institutionalization, effectiveness, anticipated sustainment) at four time-points were collected. We performed descriptive statistics and directed content analysis using Hailemariam et al.’s factors influencing sustainment. Results After approximately five years post-implementation (e.g., 2021 sustainment outcomes), of the 82 facilities, about one-third fully sustained their practice compared to one-third that did not fully sustain their practice because it was in a “liminal” stage (neither sustained nor discontinued) or permanently discontinued. The remaining one-third of facilities had missing 2021 sustainment outcomes. A higher percentage of facilities (70%) had inconsistent primary outcomes (changing over time) compared to facilities (30%) with consistent primary outcomes (same over time). Thirty-four percent of facilities with sustained practices reported resilience since they overcame implementation and sustainment barriers. Facilities with sustained practices reported more positive secondary outcomes compared to those that did not sustain their practice. Key factors facilitating practice sustainment included: demonstrating practice effectiveness/benefit, sufficient organizational leadership, sufficient workforce, and adaptation/alignment with local context. Key factors hindering practice sustainment included: insufficient workforce, not able to maintain practice fidelity/integrity, critical incidents related to the COVID-19 pandemic, organizational leadership did not support sustainment of practice, and no ongoing support. Conclusions We identified diverse pathways from implementation to sustainment, and our data underscore that initial implementation outcomes may not determine long-term sustainment outcomes. This longitudinal evaluation contributes to understanding impacts of the DoE program, including return on investment, achieving learning health system goals, and insights into achieving high-quality healthcare in VHA.

IntroductionDual specificity protein phosphatase 6 (DUSP6) was recently identified as a key hub gene in a causal VGF gene network that regulates late-onset Alzheimer’s disease (AD). Importantly, decreased DUSP6 levels are correlated with an increased clinical dementia rating (CDR) in human subjects, and DUSP6 levels are additionally decreased in the 5xFAD amyloidopathy mouse model.MethodsTo investigate the role of DUSP6 in AD, we stereotactically injected AAV5-DUSP6 or AAV5-GFP (control) into the dorsal hippocampus (dHc) of both female and male 5xFAD or wild type mice, to induce overexpression of DUSP6 or GFP.ResultsBarnes maze testing indicated that DUSP6 overexpression in the dHc of 5xFAD mice improved memory deficits and was associated with reduced amyloid plaque load, Aß1–40 and Aß1–42 levels, and amyloid precursor protein processing enzyme BACE1, in male but not in female mice. Microglial activation, which was increased in 5xFAD mice, was significantly reduced by dHc DUSP6 overexpression in both males and females, as was the number of “microglial clusters,” which correlated with reduced amyloid plaque size. Transcriptomic profiling of female 5xFAD hippocampus revealed upregulation of inflammatory and extracellular signal-regulated kinase pathways, while dHc DUSP6 overexpression in female 5xFAD mice downregulated a subset of genes in these pathways. Gene ontology analysis of DEGs (p < 0.05) identified a greater number of synaptic pathways that were regulated by DUSP6 overexpression in male compared to female 5xFAD.DiscussionIn summary, DUSP6 overexpression in dHc reduced amyloid deposition and memory deficits in male but not female 5xFAD mice, whereas reduced neuroinflammation and microglial activation were observed in both males and females, suggesting that DUSP6-induced reduction of microglial activation did not contribute to sex-dependent improvement in memory deficits. The sex-dependent regulation of synaptic pathways by DUSP6 overexpression, however, correlated with the improvement of spatial memory deficits in male but not female 5xFAD.

The critical current in a one-dimensional (1D) crossed-field gap is defined by the transition from a cycloidal flow to a near-Brillouin (nB) state characterized by electron flow orthogonal to both the electric and magnetic fields and uniform virtual cathode formation. Motivated by recent studies on space-charge-limited current in non-magnetic diodes, we assess the meaning of critical current in a magentically insulated two-dimensional (2D) planar crossed-field geometry. Particle-in-cell (PIC) simulations demonstrate that binary behavior between a laminar and turbulent state does not occur in 2D because the virtual cathode is nonuniform. Rather than a distinct nB state above the critical current as in 1D, there is an increase in Brillouin contribution with the presence of cycloidal components and noise even at low currents. To evaluate the electron flows in a 2D crossed-field gap in the absence of a binary transition, we developed two metrics to assess the Brillouin and cycloidal components in a 2D planar crossed-field gap for various emission widths and injection current densities by comparing the phase space plots from PIC simulations to analytical solutions for cycloidal and Brillouin flow. For a smaller emission width, less Brillouin contribution occurs for a given injection current, while maximizing the cycloidal noise requires a larger injection current. Once the virtual cathode starts to form and expand with increasing injection current, the cycloidal noise reaches its peak and then decreases while the Brillouin components become significant and increase.

Calculating pulsed electric field (PEF)-induced pore formation using the Smoluchowski equation (SME) can be computationally expensive, even when reduced to the asymptotic SME (ASME). These issues are exacerbated when incorporating additional physical phenomena, such as membrane temperature gradients or shock waves, or incorporating pore formation into multiscale models starting from an external stimulus at the organism level. This study presents a rapid method for calculating the membrane-level effects of PEFs by incorporating a semi-empirical equation for transmembrane potential (TMP)-dependent membrane conductivity into a single-shell model for calculating the TMP. The TMP calculated using this approach and the ASME agreed well for a range of electric field strengths for various PEF durations and AC frequencies below and above the threshold for pore formation. These results demonstrate the feasibility of rapidly predicting TMP, which is easily measured, during pore formation strictly from electrical properties and dynamics without needing to explicitly calculate pore dynamics, as required when using the SME and ASME.

Abstract Background Harm reduction strategies can decrease morbidity and mortality associated with substance use. Various barriers limit conversation around substance use between clinicians and patients. Graphic medicine techniques can inform and encourage patient-centered conversations about substance use. We describe the co-development of a harm reduction-focused graphic medicine comic that depicts the infectious risks associated with injection drug use and patient-centered approaches to providing education about potential risk mitigation strategies. Methods We formed a co-design group of veterans with lived experience with substance use, physicians, health services researchers, and community-based harm reduction leaders. Over the course of ten sessions, the co-design team developed a storyline and key messages, reviewed draft content and worked with a graphic designer to develop a comic incorporating the veterans’ input. During each session, co-design leads presented drafts of the comic and invited feedback from the group. The comic was edited and adapted via this iterative process. Results The comic depicts a fictionalized clinical vignette in which a patient develops an injection-related abscess and presents to their primary care provider. The dialogue highlights key healthcare principles, including patient autonomy and agency, and highlights strategies for safer use, rather than emphasizing abstinence. Feedback from co-design group participants highlights lessons learned during the development process. Discussion Graphic medicine is ideally suited for a patient-centered curriculum about harm reduction. This project is one of several interventions that will be integrated into VA facilities nationally to support incorporation of harm reduction principles into the care of persons who inject drugs.

(1) Background: Oral cavity cancer represents the most common site of origin of head and neck mucosal malignancies. A few limited studies have suggested that chronic irritation, particularly in non-healing ulcers, and fibrotic tissue from poor dentition or ill-fitting dentures had a role in developing mouth cancer. This scoping review aims to evaluate the existing evidence concerning Oral Cavicty Cancer (OCC) in non-smokers/non-drinkers and the relationship with dental trauma. (2) Methods: A scoping review of the PubMed, Embase, and Web of Science databases was completed in adherence with the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews checklist. (3) Results: Of the 33 articles that met inclusion, in 6 of them authors discussed the role of topography in dental trauma, in 11 articles authors discussed the carcinogenesis mechanism involved in chronic mucosal trauma, in 17 articles data on ill-fitting dentures was included, 4 studies dealt with the effect of broken/sharp teeth on mucosal damage, and in 7 studies the role of oral hygiene was covered. Less frequently discussed topics included gender, risk of neck nodes, and the role of potentially malignant oral disorders. (4) Conclusions: The available literature suggests a potential connection between chronic dental trauma and the development of OCC. Studies have highlighted factors such as denture use and ill-fitting dental appliances as contributors to an increased risk of oral cancer. Interestingly, we still miss data to support the hypothesis that women, particularly those without toxic habits like smoking or alcohol consumption, appear to be disproportionately affected by oral cancer related to chronic dental trauma.

Background: Recent acute anaphylaxis guideline updates have identified remaining unmet needs based on currently available therapeutic options as a critical focus. Objective: We compared the pharmacokinetic, pharmacodynamic, safety, and tolerability profiles of intranasal epinephrine with intramuscular epinephrine administered by autoinjector and manual syringe. Methods: An open-label, 3-period crossover study was conducted in 116 healthy adult volunteers to assess the bioavailability of a single 13.2 mg intranasal dose of epinephrine compared to a 0.3 mg intramuscular autoinjector and a 0.5 mg manual syringe. Patients with epinephrine concentrations of 50, 100, and 200 pg/mL at 10, 20, 30, and 60 minutes after dosing were also evaluated. Results: Pharmacokinetic parameters for the 13.2 mg intranasal dose exceeded those of the 0.3 mg autoinjector with a rapid and higher maximum observed concentration (intranasal, 429.4 pg/mL; autoinjector, 328.6 pg/mL) and greater systemic exposure (AUC0-360; intranasal, 39,060 pg∙min/mL; autoinjector, 17,440 pg∙min/mL). Similar results were observed compared to the 0.5 mg manual syringe. Pharmacokinetic parameters for opposite-nostril and same-nostril dosing were higher than both intramuscular doses, except time to reach maximum observed concentration, which was bracketed between the 2 intramuscular doses (intranasal opposite and same nostril, 20 minutes; autoinjector, 14.9 minutes; manual syringe, 45 minutes). Similar effects on blood pressure and heart rate were observed for intranasal and autoinjector administration. Intranasal epinephrine was safe and well tolerated. No serious or unexpected adverse events were reported, confirming results from earlier clinical studies. Conclusions: Bidose epinephrine spray addresses the unmet medical and patient needs for a needle-free, convenient, and effective dose-delivery system for self-administration of epinephrine that is as good as or better than the 0.3 mg autoinjector.

Abstract Objective To evaluate for correlation between intraoperative ultrasound (IOUS)‐measured tumor thickness (TT) (uTT) and histopathological TT (hTT), and to compare IOUS‐assisted resection with conventional resection in patients with oral tongue cancers. Data Sources Ovid MEDLINE (1946‐2023), Embase.com (1947‐2023), and Web of Science (All Databases 1900‐2023). Review Methods Inclusion criteria were the use of IOUS for the management of oral tongue cancer. Studies that did not report quantitative data were excluded. Additionally, studies that were not contributory to meta‐analysis, or a narrative analysis of pooled results were excluded. Selection was carried out by 2 reviewers. A total of 2417 studies were initially identified, with 12 ultimately being included in this review, and 7 included in the meta‐analysis. Data were extracted by 2 investigators and were pooled using a random‐effects model. Results Our meta‐analysis reveals a pooled correlation coefficient of 0.92 (95% confidence interval: 0.80‐0.96) for studies comparing uTT to hTT. Studies comparing IOUS‐assisted resection to conventional resection found IOUS‐assisted resection yielded wider nearest margins in all studies reporting this outcome. Conclusion IOUS reliably measures TT, similarly to that of histopathology measurement. IOUS‐assisted resection, which allows the surgeon to view the deep extent of tumor invasion, may increase closest radial margin distance compared to conventional resection. IOUS‐assisted resection may represent a more reliable approach to achieving clear margins than conventional resection.

Infection with either Rickettsia prowazekii or Orientia tsutsugamushi is common, yet diagnostic capabilities are limited due to the short window for positive identification. Until now, although targeted enrichment had been applied to increase sensitivity of sequencing-based detection for various microorganisms, it had not been applied to sequencing of R. prowazekii in clinical samples. Additionally, hybridization-based targeted enrichment strategies had only scarcely been applied to qPCR of any pathogens in clinical samples. Therefore, we tested a targeted enrichment technique as a proof of concept and found that it dramatically reduced the limits of detection of these organisms by both qPCR and high throughput sequencing. The enrichment methodology was first tested in contrived clinical samples with known spiked-in concentrations of R. prowazekii and O. tsutsugamushi DNA. This method was also evaluated using clinical samples, resulting in the simultaneous identification and characterization of O. tsutsugamushi directly from clinical specimens taken from sepsis patients. We demonstrated that the targeted enrichment technique is helpful by lowering the limit of detection, not only when applied to sequencing, but also when applied to qPCR, suggesting the technique could be applied more broadly to include other assays and/or microbes for which there are limited diagnostic or detection modalities.

Background Standard first-line therapies for metastatic colorectal cancer (mCRC) include fluoropyrimidine-containing regimens with oxaliplatin and/or irinotecan and a biologic agent. Immunotherapy may enhance antitumor activity in combination with standard therapies in patients with mCRC. Here, we present phase 2 results of nivolumab plus standard-of-care therapy (SOC; 5-fluorouracil/leucovorin/oxaliplatin/bevacizumab) versus SOC in the first-line treatment of patients with mCRC (CheckMate 9X8).Methods CheckMate 9X8 was a multicenter, open-label, randomized, phase 2/3 trial. Eligible patients were at least 18 years of age with unresectable mCRC and no prior chemotherapy for metastatic disease. Patients were randomized 2:1 to receive nivolumab 240 mg plus SOC or SOC alone every 2 weeks. The primary endpoint was progression-free survival (PFS) by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors V.1.1. Secondary endpoints included PFS by investigator assessment; objective response rate (ORR), disease control rate, duration of response, and time to response, all by BICR and investigator assessments; overall survival; and safety. Preplanned exploratory biomarker analyses were also performed.Results From February 2018 through April 2019, 310 patients were enrolled, of which 195 patients were randomized to nivolumab plus SOC (n=127) or SOC (n=68). At 21.5-month minimum follow-up, PFS with nivolumab plus SOC versus SOC did not meet the prespecified threshold for statistical significance; median PFS by BICR was 11.9 months in both arms (HR, 0.81 (95% CI, 0.53 to 1.23); p=0.30). Higher PFS rates after 12 months (18 months: 28% vs 9%), higher ORR (60% vs 46%), and durable responses (median 12.9 vs 9.3 months) were observed with nivolumab plus SOC versus SOC. Grade 3–4 treatment-related adverse events were reported in 75% versus 48% of patients; no new safety signals were identified.Conclusions The CheckMate 9X8 trial investigating first-line nivolumab plus SOC versus SOC in patients with mCRC did not meet its primary endpoint of PFS by BICR. Nivolumab plus SOC showed numerically higher PFS rates after 12 months, a higher response rate, and more durable responses compared with SOC alone, with acceptable safety. Further investigation to identify subgroups of patients with mCRC that may benefit from nivolumab plus SOC versus SOC in the first-line setting is warranted.Trial registration number NCT03414983.

Abstract Insect pests cause tremendous impact to agriculture worldwide. Species identification is crucial for implementing appropriate measures of pest control but can be challenging in closely related species. True fruit flies of the genus Anastrepha Schiner (Diptera: Tephritidae) include some of the most serious agricultural pests in the Americas, with the Anastrepha fraterculus (Wiedemann) complex being one of the most important due to its extreme polyphagy and wide distribution across most of the New World tropics and subtropics. The eight morphotypes described for this complex as well as other closely related species are classified in the fraterculus species group, whose evolutionary relationships are unresolved due to incomplete lineage sorting and introgression. We performed multifaceted phylogenomic approaches using thousands of genes to unravel the evolutionary relationships within the A. fraterculus complex to provide a baseline for molecular diagnosis of these pests. We used a methodology that accommodates variable sources of data (transcriptome, genome, and whole‐genome shotgun sequencing) and developed a tool to align and filter orthologs, generating reliable datasets for phylogenetic studies. We inferred 3031 gene trees that displayed high levels of discordance. Nevertheless, the topologies of the inferred coalescent species trees were consistent across methods and datasets, except for one lineage in the A. fraterculus complex. Furthermore, network analysis indicated introgression across lineages in the fraterculus group. We present a robust phylogeny of the group that provides insights into the intricate patterns of evolution of the A. fraterculus complex supporting the hypothesis that this complex is an assemblage of closely related cryptic lineages that have evolved under interspecific gene flow. Despite this complex evolutionary scenario, our subsampling analysis revealed that a set of as few as 80 loci has a similar phylogenetic resolution as the genome‐scale dataset, offering a foundation to develop more efficient diagnostic tools in this species group.

Abstract Multiple electron emission mechanisms often contribute in electron devices, motivating theoretical studies characterizing the transitions between them. Previous studies unified thermionic and field emission, defined by the Richardson-Laue-Dushman (RLD) and Fowler–Nordheim (FN) equations, respectively, with the Child-Langmuir (CL) law for vacuum space-charge limited current (SCLC); another study unified FN and CL with the Mott-Gurney (MG) law for collisional SCLC. However, thermionic emission, which introduces a nonzero injection velocity, may also occur in gas, motivating this analysis to unify RLD, FN, CL, and MG. We exactly calculate the current density as a function of applied voltage over a range of injection velocity (i.e., temperature), mobility, and gap distance. This exact solution approaches RLD, FN, and generalized CL (GCL) and MG (GMG) for nonzero injection velocity under appropriate limits. For nonzero initial velocity, GMG approaches zero for sufficiently small applied voltage and mobility, making these gaps always space-charge limited by either GMG at low voltage or GCL at high voltage. The third-order nexus between FN, GMG, and GCL changes negligibly from the zero initial velocity calculation over ten orders of magnitude of applied voltage. These results provide a closed form solution for GMG and guidance on thermionic emission in a collisional gap.

Rickettsioses, often underreported, pose public health challenges. Rickettsia asembonensis is a potential emerging pathogen that was previously detected in humans, animals, and a variety of arthropods. While its pathogenicity in humans remains unclear, it poses a potential public health threat. Here, we present an extended epidemiological, diagnostic, and genetic analysis of the information provided in a preliminary report on the investigation of rickettsiae in Peru. In particular, we report the detection of R. asembonensis in blood specimens collected from four human patients with an acute undifferentiated fever of a seven- to nine-day duration, all of whom tested negative for other vector-borne pathogens. Additionally, we describe the replicative capacity of the R. asembonensis isolates in cell cultures.

IntroductionThe Veterans Health Administration (VHA) Diffusion of Excellence (DoE) program provides a system to identify, replicate, and spread promising practices across the largest integrated healthcare system in the United States. DoE identifies innovations that have been successfully implemented in the VHA through a Shark Tank style competition. VHA facility and regional directors bid resources needed to replicate promising practices. Winning facilities/regions receive external facilitation to aid in replication/implementation over the course of a year. DoE staff then support diffusion of successful practices across the nationwide VHA.MethodsOrganized around the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) Framework, we summarize results of an ongoing long-term mixed-methods implementation evaluation of DoE. Data sources include: Shark Tank application and bid details, tracking practice adoptions through a Diffusion Marketplace, characteristics of VHA facilities, focus groups with Shark Tank bidders, structured observations of DoE events, surveys of DoE program participants, and semi-structured interviews of national VHA program office leaders, VHA healthcare system/facility executives, practice developers, implementation teams and facilitators.ResultsIn the first eight Shark Tanks (2016–2022), 3,280 Shark Tank applications were submitted; 88 were designated DoE Promising Practices (i.e., practices receive facilitated replication). DoE has effectively spread practices across the VHA, with 1,440 documented instances of adoption/replication of practices across the VHA. This includes 180 adoptions/replications in facilities located in rural areas. Leadership decisions to adopt innovations are often based on big picture considerations such as constituency support and linkage to organizational goals. DoE Promising Practices that have the greatest national spread have been successfully replicated at new sites during the facilitated replication process, have close partnerships with VHA national program offices, and tend to be less expensive to implement. Two indicators of sustainment indicate that 56 of the 88 Promising Practices are still being diffused across the VHA; 56% of facilities originally replicating the practices have sustained them, even up to 6 years after the first Shark Tank.ConclusionDoE has developed a sustainable process for the identification, replication, and spread of promising practices as part of a learning health system committed to providing equitable access to high quality care.

Why are some species sexually dimorphic while other closely related species are not? While all females in genus Strauzia share a multiply-banded wing pattern typical of many other true fruit flies, males of four species have noticeably elongated wings with banding patterns “coalesced” into a continuous dark streak across much of the wing. We take an integrative phylogenetic approach to explore the evolution of this dimorphism and develop general hypotheses underlying the evolution of wing dimorphism in flies. We find that the origin of coalesced and other darkened male wing patterns correlate with the inferred origin of host plant sharing in Strauzia. While wing shape among non-host-sharing species tended to be conserved across the phylogeny, shapes of male wings for Strauzia species sharing the same host plant were more different from one another than expected under Brownian models of evolution and overall rates of wing shape change differed between non-host-sharing species and host-sharing species. A survey of North American Tephritidae finds just three other genera with specialist species that share host plants. Host-sharing species in these genera also have wing patterns unusual for each genus. Only genus Eutreta is like Strauzia in having the unusual wing patterns only in males, and of genera that have multiple species sharing hosts, only in Eutreta and Strauzia do males hold territories while females search for mates. We hypothesize that in species that share host plants, those where females actively search for males in the presence of congeners may be more likely to evolve sexually dimorphic wing patterns.

Background Lenvatinib plus pembrolizumab demonstrated clinically meaningful benefit in patients with previously treated advanced endometrial carcinoma in Study 111/KEYNOTE-146 (NCT02501096). In these exploratory analyses from this study, we evaluated the associations between clinical outcomes and gene expression signature scores and descriptively summarized response in biomarker subpopulations defined by tumor mutational burden (TMB) and DNA variants for individual genes of interest.Methods Patients with histologically confirmed metastatic endometrial carcinoma received oral lenvatinib 20 mg once daily plus intravenous pembrolizumab 200 mg every 3 weeks for 35 cycles. Archived formalin-fixed paraffin-embedded tissue was obtained from all patients. T-cell–inflamed gene expression profile (TcellinfGEP) and 11 other gene signatures were evaluated by RNA sequencing. TMB, hotspot mutations in PIK3CA (oncogene), and deleterious mutations in PTEN and TP53 (tumor suppressor genes) were evaluated by whole-exome sequencing (WES).Results 93 and 79 patients were included in the RNA-sequencing-evaluable and WES-evaluable populations, respectively. No statistically significant associations were observed between any of the RNA-sequencing signature scores and objective response rate or progression-free survival. Area under the receiver operating characteristic curve values for response ranged from 0.39 to 0.54; all 95% CIs included 0.50. Responses were seen regardless of TMB (≥175 or

Abstract Background South Africa bears a large HIV burden with 7.8 million people with HIV (PWH). However, due to suboptimal antiretroviral therapy (ART) adherence and retention in care, only 66% of PWH in South Africa are virally suppressed. Standard care only allows for suboptimal adherence detection when routine testing indicates unsuppressed virus. Several adherence interventions are known to improve HIV outcomes, yet few are implemented in routinely due to the resources required. Therefore, determining scalable evidence-based adherence support interventions for resource-limited settings (RLS) is a priority. The multiphase optimization strategy (MOST) framework allows for simultaneous evaluation of multiple intervention components and their interactions. We propose to use MOST to identify the intervention combination with the highest levels of efficacy and cost-effectiveness that is feasible and acceptable in primary care clinics in Cape Town. Methods We will employ a fractional factorial design to identify the most promising intervention components for inclusion in a multi-component intervention package to be tested in a future randomized controlled trial. We will recruit 512 participants initiating ART between March 2022 and February 2024 in three Cape Town clinics and evaluate acceptability, feasibility, and cost-effectiveness of intervention combinations. Participants will be randomized to one of 16 conditions with different combinations of three adherence monitoring components: rapid outreach following (1) unsuppressed virus, (2) missed pharmacy refill collection, and/or (3) missed doses as detected by an electronic adherence monitoring device; and two adherence support components: (1) weekly check-in texts and (2) enhanced peer support. We will assess viral suppression (

Empirical models aim to predict spatial variability in concentrations of outdoor air pollution. For year-2010 concentrations of PM~2.5~ in the US, we intercompared six national-scale empirical models, each generated by a different research group. Despite differences in methods and independent variables for the models, we find a relatively high degree of agreement among model predictions (e.g., correlations of 0.84 to 0.92, RMSD (root-mean-square-difference; units: μg/m^3^) of 0.8 to 1.4, or on average \~12% of the average concentration; many best-fit lines are near the 1:1 line).

BackgroundTeledermatology has been utilized in the United States Department of Veterans Affairs (VA) for decades but continues to have incomplete penetration. VA has funded an initiative to enhance access to dermatology services since 2017 to support asynchronous teledermatology for Veterans living in rural areas. As part of an ongoing evaluation of this program, we assessed the teledermatology activity between the fiscal years 2020 and 2022. We focused on the second cohort of the initiative, comprising six VA facilities and their 54 referral clinics.MethodsWe studied teledermatology programs at cohort facilities using the reach, effectiveness, adoption, implementation, and maintenance framework. We used a mixed-methods design including annual online reports completed by participating facilities and VA administrative data. When possible, we compared the data from the 3 years of teledermatology funding with the baseline year prior to the start of funding.FindingsReach: Compared with the baseline year, there was a 100% increase in encounters and a 62% increase in patients seen at the funded facilities. Over 500 clinicians and support staff members were trained. Effectiveness: In FY 2022, primary or specialty care clinics affiliated with the funded facilities had more dermatology programs than primary or specialty care clinics across the VA (83% vs. 71% of sites). Adoption: By the end of the funding period, teledermatology constituted 16% of dermatology encounters at the funded facilities compared with 12% nationally. This reflected an increase from 9.2% at the funded facilities and 10.3% nationally prior to the funding period. Implementation: The continued funding for staff and equipment facilitated the expansion to rural areas. Maintenance: By the end of the funding period, all facilities indicated that they had fully implemented their program for patients of targeted primary care providers. The Program Sustainability Index scores generally increased during the funding period.ConclusionsTargeted funding to support asynchronous teledermatology implementation for rural Veterans increased its reach, adoption, and implementation, ultimately improving access. Providing program guidance with staffing and training resources can increase the impact of these programs. Ongoing efforts to maintain and increase communication between primary care and dermatology will be needed to sustain success.

Abstract Background There are challenges associated with measuring sustainment of evidence-informed practices (EIPs). First, the terms sustainability and sustainment are often falsely conflated: sustainability assesses the likelihood of an EIP being in use in the future while sustainment assesses the extent to which an EIP is (or is not) in use. Second, grant funding often ends before sustainment can be assessed. The Veterans Health Administration (VHA) Diffusion of Excellence (DoE) program is one of few large-scale models of diffusion; it seeks to identify and disseminate practices across the VHA system. The DoE sponsors “Shark Tank” competitions, in which leaders bid on the opportunity to implement a practice with approximately 6 months of implementation support. As part of an ongoing evaluation of the DoE, we sought to develop and pilot a pragmatic survey tool to assess sustainment of DoE practices. Methods In June 2020, surveys were sent to 64 facilities that were part of the DoE evaluation. We began analysis by comparing alignment of quantitative and qualitative responses; some facility representatives reported in the open-text box of the survey that their practice was on a temporary hold due to COVID-19 but answered the primary outcome question differently. As a result, the team reclassified the primary outcome of these facilities to Sustained: Temporary COVID-Hold. Following this reclassification, the number and percent of facilities in each category was calculated. We used directed content analysis, guided by the Consolidated Framework for Implementation Research (CFIR), to analyze open-text box responses. Results A representative from forty-one facilities (64%) completed the survey. Among responding facilities, 29/41 sustained their practice, 1/41 partially sustained their practice, 8/41 had not sustained their practice, and 3/41 had never implemented their practice. Sustainment rates increased between Cohorts 1–4. Conclusions The initial development and piloting of our pragmatic survey allowed us to assess sustainment of DoE practices. Planned updates to the survey will enable flexibility in assessing sustainment and its determinants at any phase after adoption. This assessment approach can flex with the longitudinal and dynamic nature of sustainment, including capturing nuances in outcomes when practices are on a temporary hold. If additional piloting illustrates the survey is useful, we plan to assess the reliability and validity of this measure for broader use in the field.

Anastrepha is the most diverse and economically important genus of Tephritidae in the American tropics and subtropics. The striking morphology of the third instars of Anastrepha caballeroi Norrbom, Anastrepha crebra Stone, Anastrepha haplacantha Norrbom & Korytkowski, Anastrepha korytkowskii Norrbom, Anastrepha nolazcoae Norrbom & Korytkowski, and three newly discovered and as yet formally unnamed species (Anastrepha sp. Peru-82, Anastrepha sp. nr. protuberans, and Anastrepha sp. Sur-16), and the more typical morphology of Anastrepha aphelocentema Stone, are described using light and scanning electron microscopy. To contribute to a better understanding of the interspecific and intraspecific variation among species in the mucronota species group and facilitate phylogenetic studies, we integrate molecular and morphological techniques to confirm the identity and describe third instars. Larva-adult associations and the identification of described larvae were confirmed using DNA barcodes. We provide diagnostic characters to distinguish larvae among these nine species of the mucronota group and separate them from those of the 29 other Anastrepha species previously described. We introduce the vertical comb-like processes on the oral margin as a novel character, and the unusual character states, including position and shape of the preoral lobe, and dentate or fringed posterior margins of the oral ridges and accessory plates. Our comparative morphology concurs with most previously inferred phylogenetic relationships within the mucronota group.

Abstract Objectives To develop a novel laryngoscope device capable of dynamically measuring force and torque measurements in real‐time during intubation and to explore the efficacy of such a device through a face validation simulation. Methods The torque sensor laryngoscope is designed for use during intubation and is modeled after a standard, single‐use plastic laryngoscope. After device calibration, a face validation study was performed with intubation experts in the field. Quantitative data (intubation force metrics) and qualitative data (expert feedback on the device) were collected from three intubations using a Mac blade and three intubations with the Miller blade. Results Three experts (two anesthesiologists and one otolaryngologist) participated in the study. The mean maximum force exerted with the Mac blade was 24.5 N (95% confidence interval [CI], 22.3–26.8). The average force exerted was 13.6 N (95% CI, 11.7–15.5). The average total suspension time was 13.1 s (95% CI, 10.4–15.8). The average total impulse was 164.6 N·s (95% CI, 147.9–181.4). The mean maximum force exerted with the Miller blade was 31.6 N (95% CI, 26.4–36.8). The average force exerted was 15.8 N (95% CI, 13.8–17.9). The average total suspension time was 11.3 s (95% CI, 9.9–12.6). The average total impulse was 216.2 N·s (95% CI, 186.5–245.9). The mean maximum force (p = .0265) and total impulse (p = .009) were significantly higher in the Miller blade trials than in the Mac blade trials. Survey results found that this device, while bulky, intubated similarly to standard‐use models and has potential as an intubation teaching tool. Conclusion The torque sensor laryngoscope can measure and display real‐time intubation force metrics for multiple laryngoscope blades. Initial validation studies showed a significantly lower maximum force and total impulse when intubating with the Mac blade than with the Miller blade. Face validation survey results were positive and suggested the potential for this device as a teaching tool. Level of Evidence Level 5.

Determining the time evolution of reactions at the quantum mechanical level improves our understanding of molecular dynamics. Here, authors separate the breakup of water, one bond at a time, from other processes leading to the same final products and experimentally identify, separate, and follow step by step two breakup paths of the transient OD+ fragment.

DUSP4 is a member of the DUSP (dual-specificity phosphatase) subfamily that is selective to the mitogen-activated protein kinases (MAPK) and has been implicated in a range of biological processes and functions in Alzheimer’s disease (AD). In this study, we utilized the stereotactic delivery of adeno-associated virus (AAV)-DUSP4 to overexpress DUSP4 in the dorsal hippocampus of 5xFAD and wildtype (WT) mice, then used mass spectrometry (MS)-based proteomics along with the label-free quantification to profile the proteome and phosphoproteome in the hippocampus. We identified protein expression and phosphorylation patterns modulated in 5xFAD mice and examined the sex-specific impact of DUSP4 overexpression on the 5xFAD proteome/phosphoproteome. In 5xFAD mice, a substantial number of proteins were up- or down-regulated in both male and female mice in comparison to age and sex-matched WT mice, many of which are involved in AD-related biological processes, such as activated immune response or suppressed synaptic activities. Many proteins in pathways, such as immune response were found to be suppressed in response to DUSP4 overexpression in male 5xFAD mice. In contrast, such a shift was absent in female mice. For the phosphoproteome, we detected an array of phosphorylation sites regulated in 5xFAD compared to WT and modulated via DUSP4 overexpression in each sex. Interestingly, 5xFAD- and DUSP4-associated phosphorylation changes occurred in opposite directions. Strikingly, both the 5xFAD- and DUSP4-associated phosphorylation changes were found to be mostly in neurons and play key roles in neuronal processes and synaptic functions. Site-centric pathway analysis revealed that both the 5xFAD- and DUSP4-associated phosphorylation sites were enriched for a number of kinase sets in females but only a limited number of sets of kinases in male mice. Taken together, our results suggest that male and female 5xFAD mice responded to DUSP4 overexpression via shared and sex-specific molecular mechanisms, which might underly similar reductions in amyloid pathology in both sexes while learning deficits were reduced in only females with DUSP4 overexpression. Finally, we validated our findings with the sex-specific AD-associated proteomes in human cohorts and further developed DUSP4-centric proteomic network models and signaling maps for each sex.

Racial-ethnic minority populations in the US are disproportionately exposed to airborne fine particulate matter (PM _2.5 ), but few national studies have focused individually on the sources that contribute to these disparities. We address this gap by conducting a comprehensive analysis of PM _2.5 exposure disparities by race-ethnicity in the US, focusing on three source-categories: mobile-sources, cooking, and all other sources combined. Our approach is based on high-resolution, national land-use regression estimates of source-resolved PM _2.5 components, derived from high-resolution aerosol mass spectrometer measurements. We find that each of these sources contributes approximately one-third of the overall PM _2.5 exposure disparities by race-ethnicity. While the importance of mobile-source tailpipe emissions is well recognized, our study underscores the significance of cooking emissions in creating PM _2.5 exposure disparities. This finding represents a potentially significant opportunity to reduce these disparities, as cooking emissions are currently largely unregulated. It has important implications for policymakers and public health advocates aiming to address the persistent issue of racial-ethnic disparities in air pollution.

Abstract Distributed Acoustic Sensing (DAS) is a promising technique to improve the rapid detection and characterization of earthquakes. Previous DAS studies mainly focus on the phase information but less on the amplitude information. In this study, we compile earthquake data from two DAS arrays in California, USA, and one submarine array in Sanriku, Japan. We develop a data‐driven method to obtain the first scaling relation between DAS amplitude and earthquake magnitude. Our results reveal that the earthquake amplitudes recorded by DAS in different regions follow a similar scaling relation. The scaling relation can provide a rapid earthquake magnitude estimation and effectively avoid uncertainties caused by the conversion to ground motions. Our results show that the scaling relation appears transferable to new regions with calibrations. The scaling relation highlights the great potential of DAS in earthquake source characterization and early warning.

[This corrects the article DOI: 10.1371/journal.pntd.0010611.].

Summary: Background: Anti-programmed cell death protein 1 antibodies plus multikinase inhibitors have shown encouraging activity in several tumour types, including colorectal cancer. This study assessed regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Methods: This single-arm, open-label, multicentre phase 2 study enrolled adults from 13 sites in the USA with previously treated advanced microsatellite stable/mismatch repair-proficient metastatic colorectal cancer. Eligible patients had known extended RAS and BRAF status, progression or intolerance to no more than two (for extended RAS mutant) or three (for extended RAS wild type) lines of systemic chemotherapy and an Eastern Cooperative Oncology Group performance status of 0 or 1. Regorafenib 80 mg/day was administered orally for 3 weeks on/1 week off (increased to 120 mg/day if 80 mg/day was well tolerated) with intravenous nivolumab 480 mg every 4 weeks. Primary endpoint was objective response rate. Secondary endpoints included safety, overall survival, and progression-free survival. Exploratory endpoints included biomarkers associated with antitumour activity. Patients who received at least one dose of study intervention were included in the efficacy and safety analyses. Tumour assessments were carried out every 8 weeks for the first year, and every 12 weeks thereafter until progressive disease/end of the study, and objective response rate was analysed after all patients had met the criteria for primary completion of five post-baseline scans and either 10-months’ follow-up or drop out. This trial is registered with ClinicalTrials.gov, number NCT04126733. Findings: Between 14 October 2019 and 14 January 2020, 94 patients were enrolled, 70 received treatment. Five patients had a partial response, yielding an objective response rate of 7% (95% CI 2.4–15.9; p = 0.27). All responders had no liver metastases at baseline. Median overall survival (data immature) and progression-free survival were 11.9 months (95% CI 7.0–not evaluable) and 1.8 months (95% CI 1.8–2.4), respectively. Most patients (97%, 68/70) experienced a treatment-related adverse event; 51% were grade 1 or 2, 40% were grade 3, 3% were grade 4, and 3% were grade 5. The most common (≥20%) events were fatigue (26/70), palmar-plantar erythrodysesthesia syndrome (19/70), maculopapular rash (17/70), increased blood bilirubin (14/70), and decreased appetite (14/70). Higher baseline expression of tumour biomarkers of immune sensitivity correlated with antitumour activity. Interpretation: Further studies are warranted to identify subgroups of patients with clinical characteristics or biomarkers that would benefit most from treatment with regorafenib plus nivolumab. Funding: Bayer/Bristol Myers Squibb.

Abstract Background The U.S. Food and Drug Administration encourages the incorporation of the patient voice throughout the medical device total product lifecycle. This study examined the incorporation of patient-reported outcome (PRO) instruments in the evaluation of medical devices over a six-year period. PRO instruments used to inform study endpoints were extracted from the summary documents and clinical trial data of premarket authorizations posted on publicly available FDA databases between October 1, 2014—September 30, 2020. Results PROs were included in 53% of authorizations, with 34% using PROs as primary and secondary endpoints. This study found that PRO instruments were used in each type of marketing authorization and in all medical specialties examined in this study. Conclusions Expanding the current collaborative efforts to develop and modify PRO instruments may help to improve use of PROs in medical device evaluations.

Objective Intradural spinal tumors are uncommon and while associations between clinical characteristics and surgical outcomes have been explored, there remains a paucity of literature unifying diverse predictors into an integrated risk model. To predict postresection outcomes for patients with spinal tumors. Methods IBM MarketScan Claims Database was queried for adult patients receiving surgery for intradural tumors between 2007 and 2016. Primary outcomes-of-interest were nonhome discharge and 90-day postdischarge readmissions. Secondary outcomes included hospitalization duration and postoperative complications. Risk modeling was developed using a regularized logistic regression framework (LASSO, least absolute shrinkage and selection operator) and validated in a withheld subset. Results A total of 5,060 adult patients were included. Most surgeries utilized a posterior approach (n=5,023, 99.3%) and tumors were most commonly found in the thoracic region (n=1,941, 38.4%), followed by the lumbar (n=1,781, 35.2%) and cervical (n=1,294, 25.6%) regions. Compared to models using only tumor-specific or patient-specific features, our integrated models demonstrated better discrimination (area under the curve [AUC] [nonhome discharge] = 0.786; AUC [90-day readmissions] = 0.693) and accuracy (Brier score [nonhome discharge] = 0.155; Brier score [90-day readmissions] = 0.093). Compared to those predicted to be lowest risk, patients predicted to be highest-risk for nonhome discharge required continued care 16.3 times more frequently (64.5% vs. 3.9%). Similarly, patients predicted to be at highest risk for postdischarge readmissions were readmitted 7.3 times as often as those predicted to be at lowest risk (32.6% vs. 4.4%). Conclusion Using a diverse set of clinical characteristics spanning tumor-, patient-, and hospitalization-derived data, we developed and validated risk models integrating diverse clinical data for predicting nonhome discharge and postdischarge readmissions.

Adding an orthogonal magnetic field to a diode is crucial for multiple applications, including high power generation. These crossed-field diodes (CFDs) have curved electron trajectories that store current in the gap. Above a critical magnetic field referred to as the Hull cutoff, electrons emitted from the cathode fail to cross the anode-cathode gap, leading to magnetic insulation and the storage or transport of all the current. Normally, the Hull cutoff may be easily calculated from diode geometry and boundary conditions; however, dissipative effects in the circuit or the addition of a protective shunt resistor may introduce an external resistance in series that causes a mismatch between the applied voltage and the voltage drop across the gap. For non-magnetically-insulated CFDs, non-zero net current flows in the circuit due to space-charge limited current (SCLC) in the gap. In this paper, we examine several models for crossed-field SCLC below the Hull cutoff to determine the impedance of the CFD. We find that the resistor reduces the voltage drop across the gap, reducing the magnetic field necessary for magnetic insulation below the typical Hull cutoff, which in turn lowers the SCLC. One-dimensional particle-in-cell simulations show that adding the series resistor causes electron trajectories to oscillate between insulated and non-insulated states for CFDs operating within 30% of the conventional Hull cutoff; these findings are validated by further examination of the theory. Extensions to other perturbations, such as AC modulation and magnetic field tilts, are discussed.

Tumor suppressor BRCA2 is known to stabilize and restart stalled DNA replication forks. Here the authors show that BRCA2 is recruited to the replication fork through its interaction with MCM10 and inhibits Primase-Polymerase-mediated repriming, lesion bypass and single strand DNA gap formation after DNA damage.

The objective of this study was to estimate all-cause, cardiopulmonary, and cancer mortality associations for long-term exposure to ultrafine particles (UFP) and primary PM2.5 components. We utilized high-resolution, national-scale exposure estimates for UFP (measured as particle number concentration; PNC) and three primary PM2.5 components, namely black carbon (BC), traffic-emitted organic PM2.5 (hereafter, hydrocarbon-like organic aerosols; HOA), and cooking-emitted organic PM2.5 (cooking organic aerosols; COA). Two analytic cohorts were constructed from a nationally representative U.S. health survey. The larger cohort consisted of 617,997 adults with information on a broad set of individual-level risk factors; the smaller cohort was further restricted to those with information on physical activity (n = 396,470). In single-pollutant models, PNC was significantly associated with all-cause (larger cohort HR = 1.03, 95% CI [1.02, 1.04]; smaller cohort HR = 1.02, 95% CI [1.00, 1.04]) and cancer mortality (larger cohort HR = 1.05, 95% CI [1.02, 1.08]; smaller cohort HR = 1.06, 95% CI [1.02, 1.10]). In two-pollutant models, mortality associations varied based on co-pollutant adjustment; PNC mortality associations were generally robust to controlling for PM10-2.5 and SO2, but not PM2.5. In contrast, we found some evidence that the HOA and COA mortality associations are independent of total PM2.5 mass exposure. Nevertheless, PM2.5 mass was the most robust predictor of air pollution related mortality, providing some support for current regulatory policies.

Background Scrub typhus is a vector-borne febrile illness caused by Orientia tsutsugamushi transmitted by the bite of Trombiculid mites. O. tsutsugamushi has a high genetic diversity and is increasingly recognized to have a wider global distribution than previously assumed. Methodology/principle findings We evaluated the clinical outcomes and host immune responses of the two most relevant human pathogenic strains of O. tsutsugamushi; Karp (n = 4) and Gilliam (n = 4) in a time-course study over 80 days post infection (dpi) in a standardized scrub typhus non-human primate rhesus macaque model. We observed distinct features in clinical progression and immune response between the two strains; Gilliam-infected macaques developed more pronounced systemic infection characterized by an earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. C-reactive protein (CRP) plasma levels, interferon gamma (IFN-γ, interleukin-1 receptor antagonist (IL-1ra), IL-15 serum concentrations, CRP/IL10- and IFN-γ/IL-10 ratios correlated positively with bacterial load in blood, implying activation of the innate immune response and preferential development of a T helper-type 1 immune response. The O. tsutsugamushi-specific immune memory responses in cells isolated from skin and lymph nodes at 80 dpi were more markedly elevated in the Gilliam-infected macaques than in the Karp-infected group. The comparative cytokine response dynamics of both strains revealed significant up-regulation of IFN-γ, tumor necrosis factor (TNF), IL-15, IL-6, IL-18, regulatory IL-1ra, IL-10, IL-8 and granulocyte-colony-stimulating factor (G-CSF). These data suggest that the clinical outcomes and host immune responses to scrub typhus could be associated with counter balancing effects of pro- and anti-inflammatory cytokine-mediated responses. Currently, no data on characterized time-course comparisons of O. tsutsugamushi strains regarding measures of disease severity and immune response is available. Our study provides evidence for the strain-specificity of host responses in scrub typhus, which supports our understanding of processes at the initial inoculation site (eschar), systemic disease progression, protective and/or pathogenic host immune mechanisms and cellular immune memory function. Conclusions/significance This study characterised an improved intradermal rhesus macaque challenge model for scrub typhus, whereby the Gilliam strain infection associated with higher disease severity in the rhesus macaque model than the previous Karp strain infection. Difficulties associated with inoculum quantitation for obligate-intracellular bacteria were overcome by using functional inoculum titrations in outbred mice. The Gilliam-based rhesus macaque model provides improved endpoint measurements and contributes towards the identification of correlates of protection for future vaccine development. Author summary Scrub typhus is a mite-borne rickettsial illness, which is potentially severe if untreated or diagnosis is delayed or missed. This easily treatable disease is endemic in southeastern and eastern parts of Asia, but is increasingly recognised to have a global distribution. In endemic areas, where infected vectors transmit different strains of Orientia tsutsugamushi—the causative pathogen of scrub typhus—the diversity of these bacterial strains poses a serious obstacle for developing effective diagnostics and a universal scrub typhus vaccine. Comparison studies on the host immune responses against various strains are rare and there is limited evidence on strain-specific immune responses over the disease course. In this study, we characterized the clinical disease progression from the start of infection to full convalescence in a well-characterised non-human primate rhesus macaque model, infected with the two most prevalent O. tsutsugamushi strains; Karp and Gillam, and compared the time course dynamics of bacteremia with correlations of various immune response mechanisms. We found that Gilliam strain infection associated with higher disease severity, earlier onset of bacteremia, lymph node enlargement, eschar lesions and higher inflammatory markers during the acute phase of infection, when compared to the Karp strain. The findings suggest that a Gilliam strain infection in rhesus macaques provides improved endpoint measurements when compared to Karp strain infections, which is useful for future vaccine development.

Background: Alcohol use disorder (AUD) affects nearly 5% of the world’s adult population. Despite treatment, AUD often manifests with relapse to binge drinking, which has been associated with corticostriatal hypersynchrony involving the nucleus accumbens (NAc). Methods: A modified “Drinking in the Dark” protocol was used to provoke binge-like alcohol drinking. We implemented Coordinated Reset Stimulation (CRS), a computationally designed, spatio-temporal stimulation algorithm, to desynchronize abnormal neuronal activity via a deep brain stimulation (DBS) electrode in the NAc of mice exhibiting binge-like alcohol drinking. Integral CRS charge injected would be 2.5% of that of conventional high-frequency DBS. Results: NAc CRS delivery during only the initial phase of exposure to alcohol and prior to the exposure (but not during) significantly reduced binge-like drinking without interfering with social behavior or locomotor activity. Conclusions: NAc CRS ameliorates binge-like alcohol drinking and preliminarily exhibits sustained aftereffects that are suggestive of an unlearning of hypersynchrony.

Crapemyrtle bark scale (CMBS; Acanthococcus lagerstroemiae Kuwana) is an invasive insect that was first discovered in the United States in 2004. The polyphagous feeding habit of CMBS has allowed it to infest a wide range of plant species beyond its primary host, Lagerstroemia. Using molecular approaches, we studied the genetic relationships between CMBS specimens and their hosts from different geographic locations. Naturally occurring CMBS infestations were confirmed on American beautyberry (Callicarpa americana L.), a native plant species in the United States, and spirea (Spiraea L.). The new infestation of CMBS found on Spiraea raises the alarm that other economically important crops in the Amygdaloideae subfamily (subfamily under Rosaceae) might be susceptible to CMBS attacks.

In vitro platelet activation is established in various clinical settings for wound healing and tissue regeneration. After separating platelet rich plasma (PRP) from whole blood, a biochemical activator, typically bovine thrombin (BT), is applied to activate PRP, which clots the PRP and releases growth factors beneficial for wound healing. BT's drawbacks, particularly cost, availability, workflow challenges, and potential immune responses, motivated the development of ex vivo electrical activation of PRP using pulsed electric fields (PEFs) with durations on the order of hundreds of nanoseconds and electric field strengths from ~10-100 kV/cm. PEFs permeabilize platelets to facilitate Ca2+ transport into the cells to induce platelet activation; however, membrane permeabilization does not require PEFs of such short duration and high intensity. This study demonstrates that 5-100 μs duration PEFs effectively activate platelets. Treating PRP with ten different single pulse waveforms with durations between 5 and 100 μs induces similar or higher levels of platelet derived, vascular endothelial, and epidermal growth factor release compared to BT. These results indicate the potential clinical relevance of microsecond PEFs for platelet stimulation, which may reduce the expense and device footprint for PEF mediated platelet stimulation compared to nanosecond pulse generators, facilitating technology transition for clinical and trauma applications.

Nsp15 is a uridine specific endoribonuclease present in all coronaviruses. Here, the authors determine the cryo-EM structures of SARS-CoV-2 Nsp15 in the apo and UTP-bound states, which together with biochemical experiments, mass spectrometry and molecular dynamics simulations provide insights into the catalytic mechanism of Nsp15 and its conformational dynamics.

Epidemic typhus, caused by Rickettsia prowazekii bacteria and transmitted through body lice (Pediculus humanus corporis), was a major public health threat in Eastern Europe as a consequence of World War II. In 2022, war and the resulting population displacement in Ukraine risks the return of this serious disease.

Scrub typhus is a potentially severe rickettsiosis, caused by Orientia tsutsugamushi in the Asia-Pacific region. Recently, however, two distinct pathogens, “Candidatus Orientia chuto” and “Candidatus Orientia chiloensis”, have been discovered in the Middle East and South America, respectively. Since the novel pathogens differ significantly from O. tsutsugamushi, many established diagnostic methods are unreliable. This work describes the development and validation of a new quantitative real-time PCR (qPCR) assay (Orien16S) for the detection of all known Orientia species. Based on a 94 bp sequence of the 16S rRNA gene (rrs), Orien16S recognized DNA samples from O. tsutsugamushi (n = 41), Ca. O. chiloensis (n = 5), and Ca. O. chuto (n = 1), but was negative for DNA preparations from closely related rickettsiae and other members of the order Rickettsiales (n = 22) as well as unrelated bacterial species (n = 11). After its implementation in Chile, the assay was verified, correctly identifying all tested eschar and buffy coat samples (n = 28) of clinical suspected cases. Furthermore, Orien16S detected Orientia DNA in trombiculid mites collected in endemic regions in southern Chile. The presented novel qPCR assay provides a useful tool for detecting Orientia and diagnosing scrub typhus from all geographical regions.

Scrub typhus is a potentially fatal rickettsiosis caused by Orientia species intracellular bacteria of the genus Orientia. Although considered to be restricted to the Asia Pacific region, scrub typhus has recently been discovered in southern Chile. We analyzed Orientia gene sequences of 16S rRNA (rrs) and 47-kDa (htrA) from 18 scrub typhus patients from Chile. Sequences were ≥99.7% identical among the samples for both amplified genes. Their diversity was 3.1%–3.5% for rrs and 11.2%–11.8% for htrA compared with O. tsusugamushi and 3.0% for rrs and 14.8% for htrA compared with Candidatus Orientia chuto. Phylogenetic analyses of both genes grouped the specimens from Chile in a different clade from other Orientia species. Our results indicate that Orientia isolates from Chile constitute a novel species, which, until they are cultivated and fully characterized, we propose to designate as Candidatus Orientia chiloensis, after the Chiloé Archipelago where the pathogen was identified.

Alesha Wale,1 Mark Ireland,2 Rowan Yemm,1 Sarah Hiom,3 Alison Jones,3 John Paul Spark,3 Mark Francis,4 Karen May,5 Louise Allen,5 Steve Ridd,6 Efi Mantzourani1,7 1School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Cardiff, Wales, UK; 2Community Pharmacy Wales, Cardiff, Wales, UK; 3St. Mary’s Pharmaceutical Unit, Cardiff, Wales, UK; 4Swansea Bay University Health Board, Swansea, Wales, UK; 5Cardiff and Vale University Health Board, Swansea, Wales, UK; 6Mayberry Pharmacy, Cardiff, Wales, UK; 7NHS Wales Informatics Service, Cardiff, Wales, UKCorrespondence: Efi Mantzourani Email MantzouraniE1@cardiff.ac.ukObjective: Community pharmacy staff are responsible for obtaining and supplying unlicensed “special” medicines to patients in primary care. Less well-defined parameters for safe and effective use of unlicensed compared to licensed medicines, along with issues around maintaining consistency between care settings or among manufacturers, have been associated with increased risks. This study aimed to explore the views and experiences of community pharmacy staff on accessing and supplying unlicensed “special” medicines to patients in Wales and the perceived impact of challenges faced on patient care.Methods: A qualitative, phenomenological approach was employed, involving semi-structured interviews with pharmacists and pharmacy technicians working at one small chain of community pharmacies in Wales. The interview schedule focused on the personal experiences and perceptions of the participants on the processes involved in accessing and supplying unlicensed “special” medicines from a community pharmacy. Interviews were audio-recorded and transcribed verbatim.Results: A total of six participants completed the interview. Three main themes were constructed from inductive thematic analysis of the transcribed interviews: requirement for additional patient responsibilities; influences on the confidence felt by pharmacy staff when accessing and supplying unlicensed “special” medicines; and continuity of supply.Conclusion: This study gives a preliminary insight into the views and experiences of community pharmacy staff in Wales when accessing and supplying unlicensed “special” medicines. Further research is required to see if these views and experiences are representative of community pharmacy staff across the country.Keywords: unlicensed medicines, “special” medicines, specials, community pharmacy, transfer of care, medicines supply, transmural care, off-label, compounding

Abstract Background One goal of health systems seeking to evolve into learning health systems is to accelerate the implementation and sustainment of evidence-based practices (EBPs). As part of this evolution, the Veterans Health Administration (VHA) developed the Innovation Ecosystem, which includes the Diffusion of Excellence (DoE), a program that identifies and diffuses Gold Status Practices (GSPs) across facilities. The DoE hosts an annual “Shark Tank” competition in which leaders bid on the opportunity to implement a GSP with 6 months of implementation support. Over 750 diverse practices were submitted in cohorts 2 and 3 of Shark Tank; 23 were designated GSPs and were implemented in 31 VA networks or facilities. As part of a national evaluation of the DoE, we identified factors contributing to GSP implementation and sustainment. Methods Our sequential mixed methods evaluation of cohorts 2 and 3 of Shark Tank included semi-structured interviews with at least one representative from 30/31 implementing teams (N = 78/105 people invited) and survey responses from 29/31 teams (N = 39/47 invited). Interviews focused on factors influencing implementation and future sustainment. Surveys focused on sustainment 1.5–2 years after implementation. The Consolidated Framework for Implementation Research (CFIR) informed data collection and directed content analysis. Ordinal scales were developed inductively to rank implementation and sustainment outcomes. Results Over 50% of teams (17/30) successfully implemented their GSP within the 6-month implementation period. Despite extensive implementation support, significant barriers related to centralized decision-making, staffing, and resources led to partial (n = 6) or no (n = 7) implementation for the remaining teams. While 12/17 initially successful implementation teams reported sustained use of their GSP, over half of the initially unsuccessful teams (n = 7/13) also reported sustained GSP use 1.5 years after the initial implementation period. When asked at 6 months, 18/27 teams with complete data accurately anticipated their future sustainability based on reported sustainment an average of 1.5 years later. Conclusions Most teams implemented within 6 months and/or sustained their GSP 1.5 years later. High levels of implementation and sustainment across diverse practices and teams suggest that VHA’s DoE is a successful large-scale model of diffusion. Team predictions about sustainability after the first 6 months of implementation provide a promising early assessment and point of intervention to increase sustainability.

The first records of six Anastrepha species are reported for the state of Paraná, Brazil, namely A. amita Zucchi, 1979; A. barnesi Aldrich, 1925; A. consobrina (Loew, 1873); A. manihoti Lima, 1934; A. morvasi Uramoto & Zucchi, 1999; and A. punctata Hendel, 1914. Citharexylum solanaceum Cham. (Verbenaceae) is recorded as a new host plant for A. amita, and Inga vera Willd. (Fabaceae) as new host plant for A. distincta. With these new records the number of species of Anastrepha recorded from Paraná is increased from 15 to 21.

Nonlinear transmission lines (NLTLs) have been increasingly studied to produce high power microwaves (HPM) at higher repetition rates than conventional HPM devices without requiring the same auxiliary systems. The ability to array NLTLs to produce higher power and achieve beam steering provides an additional capability. This review summarizes the various NLTL topologies designed to achieve these design objectives. Specifically, we summarize modeling and experimental studies for three primary topologies: the lumped element NLTL, the split ring resonator, and the traditional transmission line geometry using nonlinear materials. The lumped element NLTL and the traditional transmission line constructed with nonlinear materials lend themselves to higher power applications, while the split ring resonator is better suited for applications involving antennas. We provide a detailed summary of past studies for these topologies and conclude by exploring ongoing work and future opportunities for technological development.

Here, using cryo-EM and smFRET, Henderson et al. show how tryptophan 571 in the HIV-1 Env acts as a conformational switch during receptor-mediated viral entry and design HIV-1 Env proteins that cannot undergo conformational changes. This has important implications for HIV-1 vaccine design.

Background Surging volumes of patients with COVID-19 and the high infectiousness of SARS-CoV-2 challenged hospital infection control/safety, staffing, care delivery and operations as few crises have. Imperatives to ensure security of patient information, defend against cybersecurity threats and accurately identify/authenticate patients and staff were undiminished, which fostered creative use cases where hospitals leveraged identity access and management (IAM) technologies to improve infection control and minimise disruption of clinical and administrative workflows.Methods Working with a leading IAM solution provider, implementation personnel in the USA and UK identified all hospitals/health systems where an innovative use of IAM technology improved facility infection control and pandemic response management. Interviews/communications with hospital clinical informatics leaders collected information describing the use case deployed.Results Eight innovative/valuable hospital use cases are described: symptom-free attestation by clinicians at shift start; detection of clinician exposure/contact tracing; reporting of clinician temperature checks; inpatient telehealth consults in isolation units; virtual visits between isolated patients and families; touchless single sign-on authentication; secure access enabled for rapid expansion of personnel working remotely; and monitoring of temporary worker attendance.Discussion No systematic, comprehensive survey of all implemented IAM client sites was conducted, and other use cases may be undetected. A standardised reporting/information sharing vehicle is needed whereby IAM use cases aiding facility pandemic response and infection control can be disseminated.Conclusions Clinical care, infection control and facility operations were improved using IAM solutions during COVID-19. Facility end-user innovation in how IAM solutions are deployed can improve infection control/patient safety, care delivery and clinical workflows during surges of epidemic infectious diseases.

Objective Laryngeal fractures are rare injuries; recent data describing these injuries and associated examination findings are limited. This study aims to describe injury etiology and outcomes associated with laryngeal fractures. Study Design Retrospective case series. Setting Academic tertiary center. Methods Patients with laryngeal fractures from 2005 to 2020 were identified in a retrospective chart review. Patient demographics, injury mechanisms, management, and voice outcomes were examined. Fracture type, radiologic, and endolaryngeal examination findings were analyzed for associations between fracture etiology and examination characteristics. Results Laryngeal fractures most commonly occurred at the thyroid cartilage. Fractures were most commonly due to sport-related injuries. Mechanism of injury was not associated with specific radiologic or endolaryngeal findings. Mechanism of injury was additionally not significantly associated with the need for intubation, surgical intervention, or tracheotomy. Fracture location was significantly associated with intubation requirement ( P = .015), with 40% of patients with concomitant thyroid and cricoid fractures requiring intubation. Mechanism of injury significantly correlated with dysphonia at follow-up ( P = .033). Mechanism of injury, fracture location, and surgical management were not associated with increased vocal fold injury or dysphonia. Conclusion There are no significant correlations between injury mechanism and fracture location, characteristics, radiologic findings, or endolaryngeal findings. These features emphasize the importance of a thorough and comprehensive laryngeal examination.