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Abstract Systemic vaccination of macaques with V1-deleted (ΔV1) envelope immunogens reduce the risk of SIVmac251 acquisition by approximately 60%, with protective roles played by V2-specific ADCC and envelope-specific mucosal IL-17+NKp44+ innate lymphoid cells (ILCs). We investigated whether increased mucosal responses to V2 benefit vaccine efficacy by delivering oral nanoparticles (NPs) that release V2-scaffolded on Typhoid Toxin B (TTB) to the large intestine. Strikingly, mucosal immunization of male macaques abrogated vaccine efficacy with control TTB or empty NPs, but vaccine efficacy of up to 47.6% was preserved with V2-TTB NPs. The deleterious effects of NPs were linked to preferential recruitment of mucosal plasmacytoid dendritic cells (pDCs), reduction of protective mucosal NKp44+ ILCs, increased non-protective mucosal PMA/Ionomycin-induced IFN-γ+NKG2A-NKp44-ILCs, and increased levels of mucosal activated Ki67+CD4+ T cells, a potential target for virus infection. V2-TTB NP mucosal boosting rescued vaccine efficacy, likely via high avidity V2-specific antibodies mediating ADCC, and higher frequencies of mucosal NKp44+ ILCs and of ∆V1gp120 binding antibody-secreting B cells in the rectal mucosa. These findings emphasize the central role of systemic immunization and mucosal V2-specific antibodies in the protection afforded by ΔV1 envelope immunogens and encourage careful evaluation of vaccine delivery platforms to avoid inducing immune responses favorable to HIV transmission.

Abstract Nanofiber-based hydrogel delivery systems have recently shown great potential in biomedical applications, specifically due to their high surface-to-volume ratio of ultra-fine nanofibers and their ability to carry low solubility drugs. Herein, we introduce a visible light-triggered in situ-gelling drug vehicle (GAP Gel) composed of ascorbyl palmitate (AP) nanofibers and gelatin methacryloyl polymer. AP nanofibers form self-assembled structures through intermolecular interactions with a hydrophobic drug-loading core. We demonstrate that the hydrophilic periphery of AP nanofibers allows them to interact with other hydrophilic molecules via hydrogen bonds. The presence of AP nanofibers significantly enhances the viscoelasticity of GAP Gel in a concentration-dependent manner. Further, GAP Gel shows in vitro biocompatibility and sustained drug delivery efficacy when loaded with a hydrophobic antibiotic. Likewise, GAP Gel shows excellent in vivo biocompatibility when implanted in immunocompetent mice in various forms. Lastly, GAP Gels maintain cell viability when cultured in a 3D-environment over 7 days, establishing it as a promising and versatile hydrogel platform for the delivery of biotherapeutics.

This study explored the impact of the alternative learning activity (ALA) program offered in the Philippine Science High School-Ilocos Region Campus toward students’ leadership abilities. A mixed-methods approach was used to conduct the study through a survey of 132 student leaders affiliated with ALA clubs in the years 2022 to 2024. The results indicated that the participants exhibited strong expertise in communication, critical thinking, character development, citizenship, diversity appreciation, global understanding, and skill development in the measured indicators, suggesting that the ALA program is effective in producing well-rounded leaders. The findings also showed that almost all dimensions of leadership qualities exhibited the strong positive relationships between indicators, indicating their significant relationship and hinting that effective leadership is multidimensional. In ALA clubs, it was found that excellent leadership practices include providing diverse learning opportunities (kataguyod), offering targeted skill training (katuwang), offering mentorship and peer support (kaagapay), provision of leadership support (kalakbay), and inclusivity enhancement (kabahagi). These are beneficial practices, not only instill skills among the members but they also promote personal development. These findings show the importance of specialized leadership training in preparation for varied leadership roles.

Abstract The incidence of vector-borne disease is on the rise globally, with burdens increasing in endemic countries and outbreaks occurring in new locations. Effective mitigation and intervention strategies require models that accurately predict both spatial and temporal changes in disease dynamics, but this remains challenging due to the complex and interactive relationships between environmental variation and the vector traits that govern the transmission of vector-borne diseases. Predictions of disease risk in the literature typically assume that vector traits vary instantaneously and independently of population density, and therefore do not capture the delayed response of these same traits to past biotic and abiotic environments. We argue here that to produce accurate predictions of disease risk it is necessary to account for environmentally driven and delayed instances of phenotypic plasticity. To show this, we develop a stage and phenotypically structured model for the invasive mosquito vector, Aedes albopictus, and dengue, the second most prevalent human vector-borne disease worldwide. We find that environmental variation drives a dynamic phenotypic structure in the mosquito population, which accurately predicts global patterns of mosquito trait-abundance dynamics. In turn, this interacts with disease transmission to capture historic dengue outbreaks. By comparing the model to a suite of simpler models, we reveal that it is the delayed phenotypic structure that is critical for accurate prediction. Consequently, the incorporation of vector trait relationships into transmission models is critical to improvement of early warning systems that inform mitigation and control strategies.

Abstract The Ediacaran ocean (635-541 million years ago) is typically viewed as a stagnant, redox-stratified ocean with low phosphorus availability. However, this contradicts the high total organic carbon (up to 15 wt%) recorded in the upper Ediacaran Doushantuo Formation in South China. Here, we present a quantitative reconstruction of primary productivity and sediment total organic carbon using basin-scale simulations based on various redox-nutrient scenarios. Our results indicate that oceanic upwelling was the primary driver of enhanced primary productivity, with estimates over 2.5 times the modern ocean’s average, providing quantitative evidence for oceanic circulation in the Ediacaran Nanhua Basin. Our results also indicate the development of spatially linked but opposing redox trends, i.e., a ‘redox anticouple’, whereby the expansion of the oxic surface layer occurred concurrently with intensification of deep-water anoxia due to enhanced PP in surface and its consumption of oxidants in underlying waters. This model may explain the conflicting redox records across the Nanhua Basin. Our findings explain the unusually high rates of organic matter production and preservation in the low-pO2 Ediacaran ocean and provide a mechanism for its progressive oxygenation.

Abstract Challenges in classifying recurrent Plasmodium vivax infections constrain surveillance of antimalarial efficacy and transmission. Recurrent infections may arise from activation of dormant liver stages (relapse), blood-stage treatment failure (recrudescence) or reinfection. Molecular inference of familial relatedness (identity-by-descent or IBD) can help resolve the probable origin of recurrences. As whole genome sequencing of P. vivax remains challenging, targeted genotyping methods are needed for scalability. We describe a P. vivax marker discovery framework to identify and select panels of microhaplotypes (multi-allelic markers within small, amplifiable segments of the genome) that can accurately capture IBD. We evaluate panels of 50–250 microhaplotypes discovered in a global set of 615 P. vivax genomes. A candidate global 100-microhaplotype panel exhibits high marker diversity in the Asia-Pacific, Latin America and horn of Africa (median H E = 0.70–0.81) and identifies 89% of the polyclonal infections detected with genome-wide datasets. Data simulations reveal lower error in estimating pairwise IBD using microhaplotypes relative to traditional biallelic SNP barcodes. The candidate global panel also exhibits high accuracy in predicting geographic origin and captures local infection outbreak and bottlenecking events. Our framework is open-source enabling customised microhaplotype discovery and selection, with potential for porting to other species or data resources.

Abstract Background Treatment persistence among patients with psoriatic arthritis (PsA) is essential for achieving optimal treatment outcomes. Guselkumab, a fully human interleukin-23p19-subunit inhibitor, was approved by the United States (US) Food and Drug Administration for the treatment of active PsA in July 2020, with a dosing regimen of 100 mg at week 0, week 4, then every 8 weeks. In the Phase 3 DISCOVER-1 and DISCOVER-2 studies of patients with active PsA, 94% of guselkumab-randomized patients completed treatment through 1 year and 90% did so through 2 years (DISCOVER-2). Real-world evidence is needed to compare treatment persistence while following US prescribing guidelines (i.e., on-label persistence) for guselkumab versus subcutaneous (SC) tumor necrosis factor inhibitors (TNFis). Methods Adults with PsA receiving guselkumab or their first SC TNFi (i.e., adalimumab, certolizumab pegol, etanercept, or golimumab) between 14 July 2020 and 31 March 2022 were identified in the IQVIA PharMetrics® Plus database (first claim defined the treatment start date [index date]). Baseline characteristics and biologic use (biologic-naïve/biologic-experienced) were assessed during the 12-month period preceding the index date. Baseline characteristics were balanced between cohorts using propensity-score weighting based on the standardized mortality ratio approach. The follow-up period spanned from the index date until the earlier of the end of continuous insurance eligibility or end of data availability. On-label persistence, defined as the absence of treatment discontinuation (based on a gap of 112 days for guselkumab or 56 days for SC TNFi) or any dose escalation/reduction during follow-up, was assessed in the weighted treatment cohorts using Kaplan-Meier (KM) curves. A Cox proportional hazards model, further adjusted for baseline biologic use, was used to compare on-label persistence between the weighted cohorts. Results The guselkumab cohort included 526 patients (mean age 49.8 years; 61.2% female) and the SC TNFi cohort included 1953 patients (mean age: 48.5 years; 60.2% female). After weighting, baseline characteristics were well balanced with a mean follow-up of 12.3–12.4 months across cohorts; 51.5% of patients in the guselkumab cohort and 16.7% in the SC TNFi cohort received biologics in the 12-month baseline period. Respective rates of treatment persistence at 3, 6, 9, and 12 months were 91.2%, 84.1%, 75.9%, and 71.5% for the guselkumab cohort versus 77.3%, 61.6%, 50.0%, and 43.7% for the SC TNFi cohort (all log-rank p

Abstract Graphite in metasedimentary rocks of the Eoarchean Saglek-Hebron Gneiss Complex (Canada) is depleted in 13C and has been interpreted as one of the oldest traces of life on Earth. The variation in crystallinity of this oldest graphitic carbon could possibly confirm the effect of metamorphism on original biomass, but this is still unexplored. Here, we report specific mineral associations with graphitic carbons that also have a range of crystallinity in the Saglek-Hebron metasedimentary rocks. Petrographic, geochemical and spectroscopic analyses in the Saglek-Hebron banded iron formations suggest that poorly crystalline graphite is likely deposited from C-H-O fluids derived from thermal decomposition of syngenetic organic matter, which is preserved as crystalline graphite during prograde metamorphism. In comparison, in the Saglek-Hebron marble, disseminations of graphite co-occur with carbonate and magnetite disseminations, pointing to abiotic synthesis of graphitic carbons via decarbonation. Our results thus highlight that variably crystalline graphitic carbons in the Saglek-Hebron metasedimentary rocks are potential abiotic products on early Earth, which lay the groundwork for identifying the preservation of prebiotic organic matter through metamorphism on Earth and beyond.

**Background:** Bacillus Calmette-Guérin (BCG) can reduce recurrence and delay progression among patients with high-risk non–muscle invasive bladder cancer (NMIBC), but is associated with a substantial emotional, physical, and social burden. **Objectives:** This study evaluated the adequacy of first-line intravesical BCG treatment among high-risk NMIBC patients in the United States, including the subgroup with carcinoma in situ (CIS) of the bladder. **Methods:** Adults with high-risk NMIBC treated with BCG were selected from de-identified MarketScan® Commercial, Medicare, and Medicaid Databases (1/1/2010-2/28/2021). Adequacy of BCG induction and maintenance was evaluated from the first BCG claim until the end of the patient’s observation, using a previously published claims-based algorithm (induction: ≥5 instillations within 70 days; induction and maintenance: ≥7 instillations within 274 days of first instillation) and a definition based on the landmark Southwest Oncology Group (SWOG) trial (induction: ≥5 instillations without gaps >7 days; followed by ≥2 instillations at month 3, 6, and every 6 months thereafter). Proportions of patients with adequate BCG induction and maintenance were reported overall and compared between those with and without CIS. **Results:** Of 5803 high-risk NMIBC patients treated with first-line BCG (mean age, 67.3 years; 20.6% female), 930 (16.0%) had CIS. After first-line BCG, 56.6% received another treatment. Although 86.9% had adequate BCG induction based on the claims-based algorithm (SWOG, 73.6%), only 41.5% had adequate BCG induction and maintenance (SWOG, 1.6%). Similar trends were observed for patients with and without CIS, with higher adherence to guidelines for patients with CIS (adequate induction using claims-based algorithm: 90.3% vs 86.2%; adequate induction and maintenance: 50.8% vs 39.7%, all _P_

We present a genome assembly from an individual female Agrilus cyanescens (metallic wood-boring beetle; Arthropoda; Insecta; Coleoptera; Buprestidae). The genome sequence is 292.3 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 15.91 kilobases in length.

Background: Electronic health records (EHRs) have contributed to increased workloads for clinicians. Ambient artificial intelligence (AI) tools offer potential solutions, aiming to streamline clinical documentation and alleviate cognitive strain on healthcare providers. Objective: To assess the clinical utility of an ambient AI tool in enhancing consultation experience and the completion of clinical documentation. Methods: Outpatient consultations were simulated with actors and clinicians, comparing the AI tool against standard EHR practices. Documentation was assessed by the Sheffield Assessment Instrument for Letters (SAIL). Clinician experience was measured through questionnaires and the NASA Task Load Index. Results: AI-produced documentation achieved higher SAIL scores, with consultations 26.3% shorter on average, without impacting patient interaction time. Clinicians reported an enhanced experience and reduced task load. Conclusions: The AI tool significantly improved documentation quality and operational efficiency in simulated consultations. Clinicians recognised its potential to improve note-taking processes, indicating promise for integration into healthcare practices.

We present a genome assembly from an individual Dogs-Mercury Flea Beetle, Hermaeophaga mercurialis (Arthropoda; Insecta; Coleoptera; Chrysomelidae). The genome sequence has a length of 479.40 megabases. Most of the assembly is scaffolded into 9 chromosomal pseudomolecules. The mitochondrial genome has also been assembled and is 16.05 kilobases in length. Gene annotation of this assembly on Ensembl identified 12,633 protein-coding genes.

IntroductionEncouraging the activation of brain repair mechanisms and fostering spontaneous functional recovery in stroke patients hold great promise for alleviating the global burden of this condition and allowing an extended therapeutic time window. Cell-based regenerative therapy (with mesenchymal stem/stromal cells, such as adipose-derived stem cells [ADSCs]) is particularly attractive considering its excellent safety profile, low immunogenicity after allogeneic application, and well-established functional benefits on stroke recovery in animal models. This study aims to assess the efficacy and safety effects of intravenous (IV) infusion of freshly cultured allogeneic ADSCs on recovery after ischemic stroke.Population and methodsRESSTORE is a multicentric, randomized 1:1 controlled double-blind clinical trial. Eighty patients will be enrolled in nine French stroke centers. The main inclusion criteria are ≥18 years of age, acute hemispheric ischemic stroke, and a National Institutes of Health Stroke Scale (NIHSS) score of ≥7, including a motor subscore of ≥3. According to the previous dose-escalation safety trial data, the maximum tolerated dose of 3 million ADSCs/kg was selected. IV infusion was performed within 10 days following stroke onset, with a follow-up over 2 years.OutcomesThe primary endpoint is the motor NIHSS subscore, computed as the sum of the upper limb, lower limb, and hand scores, measured 6 months after stroke onset to assess motor recovery. The secondary outcomes are the occurrence of death/serious adverse events, clinical scores (the detailed NIHSS scores, Montreal Cognitive Assessment scores, modified Rankin Scale scores, Aphasia Handicap Scores, Depression Intensity Scale Circles scores, Fatigue Scale scores, etc.), immune monitoring (for the first 30 patients), and multimodal biomarkers derived from diffusion and functional magnetic resonance imaging.DiscussionThis study may provide some evidence for the effects of freshly cultured allogenic ADSCs IV infusion in subacute stroke that may help design a larger international randomized controlled trial.

Hydrogen plays a crucial role in improving sustainability and offering a clean and efficient energy carrier that significantly reduces greenhouse gas emissions. However, the primary method of industrial hydrogen production, steam methane reforming (SMR), relies on the combustion of hydrocarbons as the heating source for the reforming reactions, resulting in significant carbon emissions. To address this issue, an experimental setup of an electrically-heated steam methane reformer (e-SMR) has been constructed at UCLA, and a lumped first-principle dynamic process model was built based on parameters estimated from the experimental data in a previous study. Subsequently, the first-principle dynamic process model was implemented into the computational model predictive control (MPC) scheme, successfully driving the hydrogen production rate to the desired setpoint. While these works are important and pave the way for developing MPC for large-scale e-SMR processes, the first-principle process model may not accurately reflect the actual process behavior, particularly as the process behavior changes with time. Therefore, the development and establishment of an adaptive data-driven approach for implementing model predictive control in the e-SMR process is necessary. To address this need, the present work investigates the construction of recurrent neural network (RNN) models for an e-SMR process in-depth, utilizing data from an experimentally-validated first-principle model. Specifically, a long short-term memory (LSTM) layer was utilized in the RNN model to effectively capture the complex correlations present in long-term sequential data. Subsequently, this LSTM-based RNN process model was employed to design an MPC, and its performance was evaluated through comparison with proportional–integral (PI) control. To address potential disturbances and variability in a typical e-SMR process, three distinct approaches were developed: MPC with an integrator, MPC with real-time online retraining (transfer learning), and offset-free MPC. These approaches effectively eliminated the offset caused by disturbances. Overall, this study underscores the effectiveness of utilizing RNN models to capture process dynamics in an experimental e-SMR process. It also outlines strategies for employing RNN-based control and multiple approaches to address disturbances in general processes with partially infrequent and delayed measurement feedback. This approach is particularly valuable in scenarios where developing first-principle models for a new process may be challenging.

Abstract Background This study aimed to understand treatment patterns, acute healthcare use, and cost patterns among adults with treatment-resistant depression (TRD) who completed induction treatment with esketamine nasal spray in the United States (US). Per label, induction is defined as administration twice a week for 4 weeks, after which maintenance is started on a weekly basis for 4 weeks, and thereafter, patients are treated weekly or bimonthly. Methods Adults with one or more esketamine claim (index date) on or after March 5, 2019 were selected from Optum’s de-identified Clinformatics® Data Mart Database (January 2016–June 2022). Before the index date, patients had evidence of TRD and ≥ 12 months of continuous insurance eligibility (baseline period). Patients with eight or more esketamine treatment sessions were included in the main cohort. A subgroup included patients with one or more baseline mental health (MH)-related inpatient (IP) admission or emergency department (ED) visit (i.e., prior acute healthcare users). Treatment patterns were described during the follow-up period (index date until earliest of end of insurance eligibility or data); acute healthcare (i.e., IP and ED) resource use and costs (2021 US dollars) were reported during the baseline and follow-up periods. Results Of the 322 patients in the main cohort, 111 comprised the subgroup of prior acute healthcare users. During the follow-up period, mean time from index date to eighth esketamine session was 73.2 days in the main cohort and 78.8 days in the subgroup (per label, 28 days). Further, 75.2% of the main cohort and 73.9% of the subgroup completed four or more esketamine maintenance sessions following induction. In the main cohort, mean all-cause acute healthcare costs per patient per month (PPPM) decreased from baseline ($837) to follow-up ($770). Similar reductions were observed for mean MH-related acute healthcare costs PPPM (baseline $648, follow-up $577). In the subgroup, mean all-cause acute healthcare costs PPPM also decreased (baseline $2323, follow-up $1423), driven by mean MH-related acute healthcare costs PPPM (baseline $1880, follow-up $1139). Mean all-cause acute healthcare use per ten patients per month remained largely stable from baseline to follow-up in the main cohort (IP days: baseline 2.24, follow-up 2.13; ED visits: baseline 1.33, follow-up 1.45) and decreased in the subgroup (IP days: baseline 6.38, follow-up 4.56; ED visits: baseline 2.58, follow-up 2.41). Trends in mean MH-related acute healthcare use were similar. Conclusion Patients generally required more time than label recommendation to complete esketamine induction treatment, and most went on to have 12 or more esketamine sessions. Completion of induction treatment correlated with reductions in mean all-cause and MH-related acute healthcare costs. Larger reductions were seen in the subgroup of prior acute healthcare users.

Abstract Introduction Reusable nebulizer–compressor combinations deliver inhaled medications for patients with chronic lung diseases. On hospital discharge, the patient may take home the disposable nebulizer that was packaged and combine it with their home compressor. Though this practice may reduce waste, it can increase variability in medication delivery. Our study compared several reusable and disposable nebulizers packaged with compressor kits used in the US. We included a common disposable hospital nebulizer that may not be supplied with popular home kits but may be brought home after a hospitalization or emergency department visit. We focused on fine droplet mass

Abstract We present a transmon qubit fabrication technique that yields systematic improvements in T 1 relaxation times. We encapsulate the surface of niobium and prevent the formation of its lossy surface oxide. By maintaining the same superconducting metal and only varying the surface, this comparative investigation examining different capping materials, such as tantalum, aluminum, titanium nitride, and gold, as well as substrates across different qubit foundries demonstrates the detrimental impact that niobium oxides have on coherence times of superconducting qubits, compared to native oxides of tantalum, aluminum or titanium nitride. Our surface-encapsulated niobium qubit devices exhibit T 1 relaxation times 2–5 times longer than baseline qubit devices with native niobium oxides. When capping niobium with tantalum, we obtain median qubit lifetimes above 300 μs, with maximum values up to 600 μs. Our comparative structural and chemical analysis provides insight into why amorphous niobium oxides may induce higher losses compared to other amorphous oxides.

Position statement The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the use of a ketogenic diet in healthy exercising adults, with a focus on exercise performance and body composition. However, this review does not address the use of exogenous ketone supplements. The following points summarize the position of the ISSN:1. A ketogenic diet induces a state of nutritional ketosis, which is generally defined as serum ketone levels above 0.5 mM. While many factors can impact what amount of daily carbohydrate intake will result in these levels, a broad guideline is a daily dietary carbohydrate intake of less than 50 grams per day.2. Nutritional ketosis achieved through carbohydrate restriction and a high dietary fat intake is not intrinsically harmful and should not be confused with ketoacidosis, a life-threatening condition most commonly seen in clinical populations and metabolic dysregulation.3. A ketogenic diet has largely neutral or detrimental effects on athletic performance compared to a diet higher in carbohydrates and lower in fat, despite achieving significantly elevated levels of fat oxidation during exercise (~1.5 g/min).4. The endurance effects of a ketogenic diet may be influenced by both training status and duration of the dietary intervention, but further research is necessary to elucidate these possibilities. All studies involving elite athletes showed a performance decrement from a ketogenic diet, all lasting six weeks or less. Of the two studies lasting more than six weeks, only one reported a statistically significant benefit of a ketogenic diet.5. A ketogenic diet tends to have similar effects on maximal strength or strength gains from a resistance training program compared to a diet higher in carbohydrates. However, a minority of studies show superior effects of non-ketogenic comparators.6. When compared to a diet higher in carbohydrates and lower in fat, a ketogenic diet may cause greater losses in body weight, fat mass, and fat-free mass, but may also heighten losses of lean tissue. However, this is likely due to differences in calorie and protein intake, as well as shifts in fluid balance.7. There is insufficient evidence to determine if a ketogenic diet affects males and females differently. However, there is a strong mechanistic basis for sex differences to exist in response to a ketogenic diet.

AbstractPurpose: Real-world data comparing long-term performance of interleukin (IL)-23 and IL-17 inhibitors in psoriasis are limited. This study compared treatment persistence and remission among patients initiating guselkumab versus IL-17 inhibitors.Methods: Adults with psoriasis initiating guselkumab, secukinumab, or ixekizumab treatment (index date) were identified from Merative™ MarketScan® Research Databases (01/01/2016–10/31/2021). Persistence was defined as no index biologic supply gaps of twice the labeled maintenance dosing interval. Remission was defined using an exploratory approach as index biologic discontinuation for ≥6 months without psoriasis-related inpatient admissions and treatments.Results: There were 3516 and 6066 patients in the guselkumab versus secukinumab comparison, and 3805 and 4674 patients in guselkumab versus ixekizumab comparison. At 18 months, the guselkumab cohort demonstrated about twice the persistence rate as secukinumab (hazard ratio [HR] = 2.15; p < 0.001) and ixekizumab cohorts (HR = 1.77; p < 0.001). At 6 months after index biologic discontinuation, the guselkumab cohort was 31% and 40% more likely to achieve remission than secukinumab (rate ratio [RR] = 1.31; p < 0.001) and ixekizumab cohorts (RR = 1.40; p < 0.001).Conclusions: Guselkumab was associated with greater persistence and likelihood of remission than IL-17 inhibitors, indicating greater disease control and modification potential.

**Background:** The use of androgen receptor signaling inhibitors, including apalutamide, in combination with androgen deprivation therapy is recommended for the treatment of metastatic castration-sensitive prostate cancer (mCSPC) and non-metastatic castration-resistant prostate cancer (nmCRPC). **Objective:** To describe real-world treatment patterns and clinical outcomes among patients with mCSPC or nmCRPC who initiated apalutamide in the United States. **Methods:** A retrospective cohort study of patients with mCSPC or nmCRPC who initiated apalutamide was conducted using electronic medical record data from US community-based urology practices (Feb. 1, 2017–April 1, 2022). Persistence with apalutamide was reported at 6-, 12-, and 18-months post treatment initiation. Clinical outcomes described up to 24 months after apalutamide initiation using Kaplan-Meier analyses included progression to castration resistance, castration resistance-free survival (CRFS), and metastasis-free survival (MFS). Outcomes were reported separately based on mCSPC or nmCRPC status and race (ie, Black or non-Black). **Results:** This study included 589 patients with mCSPC (mean age, 75.9 years) and 406 patients with nmCRPC (mean age, 78.8 years). Using a treatment gap of >90 days, persistence with apalutamide at 12 months remained high for both the mCSPC (94.9%) and nmCRPC (92.7%) cohorts, and results were descriptively similar among Black and non-Black patients, and when a treatment gap of >60 days was considered. In patients with mCSPC, overall progression to castration resistance rates at 12 and 24 months were 20.9% and 33.5%, and overall CRFS rates were 76.2% and 62.0%, respectively. In patients with nmCRPC, overall MFS rates at 12 and 24 months were 89.7% and 75.4%, respectively. Rates of these clinical outcomes were descriptively similar between Black and non-Black patients. **Discussion:** While clinical trials have demonstrated the efficacy and safety of apalutamide, there is limited real-world data describing treatment persistence and clinical outcomes among patients with mCSPC and nmCRPC who initiated apalutamide. **Conclusions:** In this real-world study of patients with mCSPC or nmCRPC initiated on apalutamide, treatment persistence was high and apalutamide demonstrated robust real-world effectiveness with respect to progression to castration resistance, CRFS, and MFS, overall and among Black and non-Black patients.

Introduction Relapses in ANCA-associated vasculitis (AAV) increase the incidence of end-organ damage and their prevention requires prolonged immunosuppressive therapy. Rituximab, a type I anti-CD20 B cell depleting monoclonal antibody, is the current standard of care for induction of disease remission. Rituximab is not always effective and is associated with a high subsequent relapse risk. Obinutuzumab is a type II anti-CD20 humanised monoclonal antibody with the potential to obtain greater tissue B cell depletion than rituximab and reduce relapse risk in AAV.Methods and analysis ObiVas is a randomised, phase II, double-blind controlled trial that will compare the mechanistic effects of rituximab and obinutuzumab in the induction treatment of patients with AAV positive for proteinase 3 ANCA (PR3-ANCA). 26 patients, either newly diagnosed or relapsing, will be recruited from a single centre and randomised in a 1:1 ratio to receive 1000 mg rituximab or obinutuzumab as induction therapy on days 1 and 15, alongside a tapering glucocorticoid regimen. The primary end point is CD19+ B cell depletion in nasal-associated lymphoid tissue (NALT), assessed as change from baseline to week 26. Secondary outcomes will compare the safety and clinical efficacy of rituximab and obinutuzumab and their impact on immune biomarkers, including tissue and peripheral blood lymphocyte subsets and PR3-ANCA binding levels. Patients are followed through to week 78. The trial opened for recruitment in January 2023 and is forecasted to complete recruitment by the end of 2024.Ethics and dissemination For all patients, informed written consent will be obtained in keeping with Good Clinical Practice. Trial results will be disseminated to the relevant scientific, clinical and patient communities on trial closure. NALT data analysis will start before trial completion. Other analyses will be reported after trial completion. This trial was given ethical approval by Edgbaston (West Midlands) Research Ethics Committee (approval reference 22/WM/0174).Trial registration number ISRCTN13069630.

Organic-rich shales from the uppermost Doushantuo Fm. (South China) record one of the most negative carbonate carbon isotopic excursions in Earth’s history, known as the Shuram excursion, and contain meter to micro-size spheroids. In this study, we use Raman and energy dispersive spectroscopy to identify and describe the most common diagenetic spheroids to refine our understanding of the profound perturbations of the carbon cycle and the evolution of pore fluid chemistry imprinted in the sedimentary Precambrian record, especially in the late Ediacaran. The presence of 13C-depleted carbonate concretions or organic matter (OM) enclosed by lenticular dolomitic structures within the host shale unit suggests OM remineralisation and anaerobic oxidation, resulting in authigenic carbonate precipitation during the earliest stages of sediment diagenesis. Other mineralogical features, however, point to high levels of primary production, such as apatite bands that host spheroidal microfossils with highly fluorescent quartz and OM within abiotic concretions. These observations highlight the importance of considering co-occurring biotic and abiotic processes in explaining the formation of diagenetic spheroids in ancient sedimentary environments. From an astrobiology perspective, the interplay of biotic and abiotic processes reflects the complexity of early life systems and the environments that may exist on other terrestrial planets. Understanding the signatures of biotic and abiotic interactions in the Doushantuo Fm. is crucial for identifying potential biosignatures in extraterrestrial materials, thereby enhancing our understanding of life’s universality and adaptability in diverse and extreme environments.

Summary: A heterologous Ad26/MVA vaccine was given prior to an analytic treatment interruption (ATI) in people living with HIV-1 (mainly CRF01_AE) who initiated antiretroviral treatment (ART) during acute HIV-1. We investigate the impact of Ad26/MVA vaccination on antibody (Ab)-mediated immune responses and their effect on time to viral rebound. The vaccine mainly triggers vaccine-matched binding Abs while, upon viral rebound post ATI, infection-specific CRF01_AE binding Abs increase in all participants. Binding Abs are not associated with time to viral rebound. The Ad26/MVA mosaic vaccine profile consists of correlated non-CRF01_AE binding Ab and Fc effector features, with strong Ab-dependent cellular phagocytosis (ADCP) responses. CRF01_AE-specific ADCP responses (measured either prior to or post ATI) are significantly higher in individuals with delayed viral rebound. Our results suggest that vaccines eliciting cross-reactive responses with circulating viruses in a target population could be beneficial and that ADCP responses may play a role in viral control post treatment interruption.

The surge in demand for hydrogen (H2) across diverse sectors, including clean energy transportation and chemical synthesis, underscores the need for a thorough investigation into H2 production dynamics and the development of effective controllers for industrial applications. This paper focuses on an electrically heated steam methane reforming (SMR) process for H2 production, offering advantages such as enhanced environmental sustainability, compactness, efficiency, and controllability compared to conventional reforming methods. Electric heating of the entire system allows for adjustments in current to control reactor temperature, thereby impacting hydrogen production rates. However, accurately modeling hydrogen production dynamics presents a formidable challenge, as complex models with high precision are computationally unsuitable for real-time control integration. Considering these factors, an accurate and efficient first-principles-based lumped-parameter model is developed to provide a dependable estimation of hydrogen production in an electrically-heated steam methane reformer. This model is validated experimentally and then utilized in a model predictive controller (MPC). To obtain the necessary state estimate information for the MPC, an extended Luenberger observer (ELO) method is employed to estimate state variables from limited, infrequent and delayed measurements of gas-phase reactor outlet stream and frequent measurements of the reactor temperature. Simulation comparisons with a proportional-integral (PI) controller reveal a much faster response in achieving the desired H2 production rate under the estimation-based MPC. Additionally, the simulations demonstrate the robustness of the controller to process variability such as a decrease in catalyst activation energy, commonly encountered in the SMR process, highlighting its effectiveness in maintaining stable operation under varying process conditions.

Abstract Sub-Saharan Africa is under-represented in global biodiversity datasets, particularly regarding the impact of land use on species’ population abundances. Drawing on recent advances in expert elicitation to ensure data consistency, 200 experts were convened using a modified-Delphi process to estimate ‘intactness scores’: the remaining proportion of an ‘intact’ reference population of a species group in a particular land use, on a scale from 0 (no remaining individuals) to 1 (same abundance as the reference) and, in rare cases, to 2 (populations that thrive in human-modified landscapes). The resulting bii4africa dataset contains intactness scores representing terrestrial vertebrates (tetrapods: ±5,400 amphibians, reptiles, birds, mammals) and vascular plants (±45,000 forbs, graminoids, trees, shrubs) in sub-Saharan Africa across the region’s major land uses (urban, cropland, rangeland, plantation, protected, etc.) and intensities (e.g., large-scale vs smallholder cropland). This dataset was co-produced as part of the Biodiversity Intactness Index for Africa Project. Additional uses include assessing ecosystem condition; rectifying geographic/taxonomic biases in global biodiversity indicators and maps; and informing the Red List of Ecosystems.

Abstract The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.

Summary: Little is known of the scale of avoidable injuries presenting to medical services on a national level in the UK. This study aimed to assess the type and incidence of preventable wrist and hand injuries (as defined by the core research team) at a national level in the UK. 28 UK hospitals undertook a service evaluation of all hand trauma cases presenting to their units over a 2 week period in early 2021 identifying demographical and aetiological information about injuries sustained. 1909 patients were included (184 children) with a median age of 40 (IQR 25-59) years. The commonest five types of injury were fractures of the wrist; single phalangeal or metacarpal fractures; fingertip injuries; and infection, with the most common mechanisms being mechanical falls and manual labour. This is the first extensive survey of preventable hand injuries in the UK, identifying a need for further work into prevention to reduce healthcare burden and cost. 50% of injuries presenting to hand surgeons are preventable, with the most common injuries being single fractures of the wrist, phalanx and metacarpal. Few preventable injuries were related to alcohol or narcotic intoxication. Further research is needed to identify how to initiate injury prevention measures for hand injuries, particularly focussed towards hand fracture prevention.

We present a genome assembly from an individual male Euspilapteryx auroguttella (the Yellow-dotted Stilt; Arthropoda; Insecta; Lepidoptera; Gracillariidae). The genome sequence is 331.9 megabases in span. Most of the assembly is scaffolded into 30 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 16.94 kilobases in length.

We present a genome assembly from an individual male Dorcus parallelipipedus (the lesser stag beetle; Arthropoda; Insecta; Coleoptera; Lucanidae). The genome sequence is 470.9 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules, including the X and Y sex chromosomes. The mitochondrial genome has also been assembled and is 18.19 kilobases in length.

We present a genome assembly from an individual female Anaspis maculata (false flower beetle; Arthropoda; Insecta; Coleoptera; Scraptiidae). The genome sequence is 757.8 megabases in span. Most of the assembly is scaffolded into 8 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 16.31 kilobases in length. Gene annotation of this assembly on Ensembl identified 21,965 protein coding genes.

The cognitive load theory suggests that completing a task relies on the interplay between sensory input, working memory, and long-term memory. Cognitive overload occurs when the working memory’s limited capacity is exceeded due to excessive information processing. In health care, clinicians face increasing cognitive load as the complexity of patient care has risen, leading to potential burnout. Electronic health records (EHRs) have become a common feature in modern health care, offering improved access to data and the ability to provide better patient care. They have been added to the electronic ecosystem alongside emails and other resources, such as guidelines and literature searches. Concerns have arisen in recent years that despite many benefits, the use of EHRs may lead to cognitive overload, which can impact the performance and well-being of clinicians. We aimed to review the impact of EHR use on cognitive load and how it correlates with physician burnout. Additionally, we wanted to identify potential strategies recommended in the literature that could be implemented to decrease the cognitive burden associated with the use of EHRs, with the goal of reducing clinician burnout. Using a comprehensive literature review on the topic, we have explored the link between EHR use, cognitive load, and burnout among health care professionals. We have also noted key factors that can help reduce EHR-related cognitive load, which may help reduce clinician burnout. The research findings suggest that inadequate efforts to present large amounts of clinical data to users in a manner that allows the user to control the cognitive burden in the EHR and the complexity of the user interfaces, thus adding more “work” to tasks, can lead to cognitive overload and burnout; this calls for strategies to mitigate these effects. Several factors, such as the presentation of information in the EHR, the specialty, the health care setting, and the time spent completing documentation and navigating systems, can contribute to this excess cognitive load and result in burnout. Potential strategies to mitigate this might include improving user interfaces, streamlining information, and reducing documentation burden requirements for clinicians. New technologies may facilitate these strategies. The review highlights the importance of addressing cognitive overload as one of the unintended consequences of EHR adoption and potential strategies for mitigation, identifying gaps in the current literature that require further exploration.

We present a genome assembly from an individual male Perizoma affinitatum (the Rivulet moth; Arthropoda; Insecta; Lepidoptera; Geometridae). The genome sequence is 357.7 megabases in span. Most of the assembly is scaffolded into 25 chromosomal pseudomolecules, including the Z sex chromosome. The mitochondrial genome has also been assembled and is 15.9 kilobases in length.

Steam methane reforming (SMR) is one of the most widely used hydrogen (H2) production processes. In addition to its extensive utilization in industrial sectors, hydrogen is expanding it share as a clean energy carrier, and more sustainable and efficient H2 production methods are continuously being explored and developed. One method replaces conventional fossil fuel-based heating with electrical heating through the flow of electrons across the reformer. At UCLA, an experimental setup was built of an electrically heated steam methane reforming process. This paper describes the system components, explains the digitalization of the experimental setup and introduces methods for building a first-principles-based dynamic process model using parameters estimated via data-driven methods from process experimental data. The modeling approach uses a lumped parameter approximation and employs algebraic equations to solve for gas-phase variables. The reaction parameters are calculated from steady-state experimental data, and the temperature change is modeled with respect to change in electric current using a first-order dynamic model. The overall dynamic process model is then used in a computational model predictive control (MPC) scheme to drive the process to a new H2 production set-point under unperturbed and steam flowrate disturbance cases. The performance and robustness of the proposed MPC scheme are compared to the ones of a classical proportional–integral (PI) controller and are demonstrated to be superior in terms of closed-loop response, robustness, and constraint handling.

Abstract Ethiopia has the greatest burden of Plasmodium vivax in Africa, but little is known about the epidemiological landscape of parasites across the country. We analysed the genomic diversity of 137 P. vivax isolates collected nine Ethiopian districts from 2012 to 2016. Signatures of selection were detected by cross-country comparisons with isolates from Thailand (n = 104) and Indonesia (n = 111), representing regions with low and high chloroquine resistance respectively. 26% (35/137) of Ethiopian infections were polyclonal, and 48.5% (17/35) of these comprised highly related clones (within-host identity-by-descent > 25%), indicating frequent co-transmission and superinfection. Parasite gene flow between districts could not be explained entirely by geographic distance, with economic and cultural factors hypothesised to have an impact on connectivity. Amplification of the duffy binding protein gene (pvdbp1) was prevalent across all districts (16–75%). Cross-population haplotype homozygosity revealed positive selection in a region proximal to the putative chloroquine resistance transporter gene (pvcrt-o). An S25P variant in amino acid transporter 1 (pvaat1), whose homologue has recently been implicated in P. falciparum chloroquine resistance evolution, was prevalent in Ethiopia (96%) but not Thailand or Indonesia (35–53%). The genomic architecture in Ethiopia highlights circulating variants of potential public health concern in an endemic setting with evidence of stable transmission.

Abstract Increasing oxygenation of the early Ediacaran Ocean is thought to have been responsible for the emergence of early animals. Although geochemical studies have suggested periods of oceanic oxygenation in the Ediacaran, direct evidence for seafloor oxygenation has been lacking. Here, we report frequent occurrences of distinctive, sub-millimetric, and early diagenetic pyrite-marcasite rosettes in phosphorites from the lower Ediacaran Doushantuo Formation (Weng’an, South China). They typically consist of a nucleus of framboidal pyrite, a cortex of radiating marcasite blades intergrown with quartz, and a rim of second-generation pyrite, recording partial oxidative dissolution of pyrite and co-precipitation of marcasite and quartz. This inference is further supported by near-zero carbon isotope values of the host dolostone, similarly low sulfur isotope values for pyrite and marcasite, and evident Fe-isotope fractionation between marcasite and pyrite. Collectively, our findings reveal intermittent bottom-water and porewater oxygenation events, providing direct evidence of high-frequency oxygenation of Ediacaran continental shelves.

Abstract Colombia aims to eliminate malaria by 2030 but remains one of the highest burden countries in the Americas. Plasmodium vivax contributes half of all malaria cases, with its control challenged by relapsing parasitaemia, drug resistance and cross-border spread. Using 64 Colombian P. vivax genomes collected between 2013 and 2017, we explored diversity and selection in two major foci of transmission: Chocó and Córdoba. Open-access data from other countries were used for comparative assessment of drug resistance candidates and to assess cross-border spread. Across Colombia, polyclonal infections were infrequent (12%), and infection connectivity was relatively high (median IBD = 5%), consistent with low endemicity. Chocó exhibited a higher frequency of polyclonal infections (23%) than Córdoba (7%), although the difference was not significant (P = 0.300). Most Colombian infections carried double pvdhfr (95%) and single pvdhps (71%) mutants, but other drug resistance mutations were less prevalent (

Abstract The anti-apoptotic function of Bcl-xL in the heart during ischemia/reperfusion is diminished by K-Ras-Mst1-mediated phosphorylation of Ser14, which allows dissociation of Bcl-xL from Bax and promotes cardiomyocyte death. Here we show that Ser14 phosphorylation of Bcl-xL is also promoted by hemodynamic stress in the heart, through the H-Ras-ERK pathway. Bcl-xL Ser14 phosphorylation-resistant knock-in male mice develop less cardiac hypertrophy and exhibit contractile dysfunction and increased mortality during acute pressure overload. Bcl-xL Ser14 phosphorylation enhances the Ca2+ transient by blocking the inhibitory interaction between Bcl-xL and IP3Rs, thereby promoting Ca2+ release and activation of the calcineurin-NFAT pathway, a Ca2+-dependent mechanism that promotes cardiac hypertrophy. These results suggest that phosphorylation of Bcl-xL at Ser14 in response to acute pressure overload plays an essential role in mediating compensatory hypertrophy by inducing the release of Bcl-xL from IP3Rs, alleviating the negative constraint of Bcl-xL upon the IP3R-NFAT pathway.

Ketone bodies are considered alternative fuels for the brain when glucose availability is limited. To determine the neuroregenerative potential of D,L-sodium-beta-hydroxybutyrate (D/L-BHB), Sprague Dawley rat primary cortical neurons were exposed to simulated central nervous system injury using a scratch assay. The neuronal cell migration, cell density and degree of regeneration in the damaged areas (gaps) in the absence (control) and presence of BHB (2 mM) were documented with automated live-cell imaging by the CytoSMART system over 24 h, which was followed by immunocytochemistry, labeling synapsin-I and β3-tubulin. The cell density was significantly higher in the gaps with BHB treatment after 24 h compared to the control. In the control, only 1.5% of the measured gap areas became narrower over 24 h, while in the BHB-treated samples 49.23% of the measured gap areas became narrower over 24 h. In the control, the gap expanded by 63.81% post-injury, while the gap size decreased by 10.83% in response to BHB treatment, compared to the baseline. The cell density increased by 97.27% and the gap size was reduced by 74.64% in response to BHB, compared to the control. The distance travelled and velocity of migrating cells were significantly higher with BHB treatment, while more synapsin-I and β3-tubulin were found in the BHB-treated samples after 24 h, compared to the control. The results demonstrate that D/L-BHB enhanced neuronal migration and molecular processes associated with neural regeneration and axonogenesis. These results may have clinical therapeutic applications in the future for nervous system injuries, such as for stroke, concussion and TBI patients.

(1) Background: The rise in electronic cigarette (E-cigarette) popularity, especially among adolescents, has prompted research to investigate potential effects on health. Although much research has been carried out on the effect on lung health, the first site exposed to vaping—the oral cavity—has received relatively little attention. The aims of this study were twofold: to examine the effects of E-liquids on the viability and hydrophobicity of oral commensal streptococci, and the effects of E-cigarette-generated aerosols on the biomass and viability of oral commensal streptococci. (2) Methods: Quantitative and confocal biofilm analysis, live–dead staining, and hydrophobicity assays were used to determine the effect on oral commensal streptococci after exposure to E-liquids and/or E-cigarette-generated aerosols. (3) Results: E-liquids and flavors have a bactericidal effect on multispecies oral commensal biofilms and increase the hydrophobicity of oral commensal streptococci. Flavorless and some flavored E-liquid aerosols have a bactericidal effect on oral commensal biofilms while having no effect on overall biomass. (4) Conclusions: These results indicate that E-liquids/E-cigarette-generated aerosols alter the chemical interactions and viability of oral commensal streptococci. Consequently, the use of E-cigarettes has the potential to alter the status of disease and health in the oral cavity and, by extension, affect systemic health.

Abstract Resistance to insecticides in Anopheles mosquitoes threatens the effectiveness of malaria control, but the genetics of resistance are only partially understood. We performed a large scale multi-country genome-wide association study of resistance to two widely used insecticides: deltamethrin and pirimiphos-methyl, using sequencing data from An. gambiae and An. coluzzii from ten locations in West Africa. Resistance was highly multi-genic, multi-allelic and variable between populations. While the strongest and most consistent association with deltamethrin resistance came from Cyp6aa1, this was based on several independent copy number variants (CNVs) in An. coluzzii, and on a non-CNV haplotype in An. gambiae. For pirimiphos-methyl, signals included Ace1, cytochrome P450s, glutathione S-transferases and the nAChR target site of neonicotinoid insecticides. The regions around Cyp9k1 and the Tep family of immune genes showed evidence of cross-resistance to both insecticides. These locally-varying, multi-allelic patterns highlight the challenges involved in genomic monitoring of resistance, and may form the basis for improved surveillance methods.

Abstract Plastic pollution is distributed patchily around the world’s oceans. Likewise, marine organisms that are vulnerable to plastic ingestion or entanglement have uneven distributions. Understanding where wildlife encounters plastic is crucial for targeting research and mitigation. Oceanic seabirds, particularly petrels, frequently ingest plastic, are highly threatened, and cover vast distances during foraging and migration. However, the spatial overlap between petrels and plastics is poorly understood. Here we combine marine plastic density estimates with individual movement data for 7137 birds of 77 petrel species to estimate relative exposure risk. We identify high exposure risk areas in the Mediterranean and Black seas, and the northeast Pacific, northwest Pacific, South Atlantic and southwest Indian oceans. Plastic exposure risk varies greatly among species and populations, and between breeding and non-breeding seasons. Exposure risk is disproportionately high for Threatened species. Outside the Mediterranean and Black seas, exposure risk is highest in the high seas and Exclusive Economic Zones (EEZs) of the USA, Japan, and the UK. Birds generally had higher plastic exposure risk outside the EEZ of the country where they breed. We identify conservation and research priorities, and highlight that international collaboration is key to addressing the impacts of marine plastic on wide-ranging species.

Abstract Background Patient affordability is an important nonclinical consideration for treatment access among patients with schizophrenia. Objective This study evaluated and measured out-of-pocket (OOP) costs for antipsychotics (APs) among Medicaid beneficiaries with schizophrenia. Methods Adults with a schizophrenia diagnosis, ≥ 1 AP claim, and continuous Medicaid eligibility were identified in the MarketScan® Medicaid Database (1 January 2018–31 December 2018). OOP AP pharmacy costs ($US 2019) were normalized for a 30-day supply. Results were descriptively reported by route of administration [ROA; orals (OAPs), long-acting injectables (LAIs)], generic/branded status within ROAs, and dosing schedule within LAIs. The proportion of total (pharmacy and medical) OOP costs AP-attributable was described. Results In 2018, 48,656 Medicaid beneficiaries with schizophrenia were identified (mean age 46.7 years, 41.1% female, 43.4% Black). Mean annual total OOP costs were $59.97, $6.65 of which was AP attributable. Overall, 39.2%, 38.3%, and 42.3% of beneficiaries with a corresponding claim had OOP costs > $0 for any AP, OAP, and LAI, respectively. Mean OOP costs per patient per 30-day claim (PPPC) were $0.64 for OAPs and $0.86 for LAIs. By LAI dosing schedule, mean OOP costs PPPC were $0.95, $0.90, $0.57, and $0.39 for twice-monthly, monthly, once-every-2-months, and once-every-3-months LAIs, respectively. Across ROAs and generic/branded status, projected OOP AP costs per-patient-per-year for beneficiaries assumed fully adherent ranged from $4.52 to $13.70, representing < 25% of total OOP costs. Conclusion OOP AP costs for Medicaid beneficiaries represented a small fraction of total OOP costs. LAIs with longer dosing schedules had numerically lower mean OOP costs, which were lowest for once-every-3-months LAIs among all APs.

Abstract Objectives To develop a novel remote head impulse test (rHIT), and to provide preliminary data validating the rHIT vestibular‐ocular reflex (VOR) gains against the in‐clinic vHIT. Methods A convenience sample of 10 patients referred for vestibular assessment at our institution was recruited. In‐clinic vHIT was used to quantify lateral VOR gains. Patients subsequently underwent an rHIT protocol, whereby patients performed active, lateral head rotations while their eyes and heads were recorded using a laptop camera and video‐conferencing software. The vHIT and rHIT VOR gains were compared using paired t‐tests, and a Pearson correlation coefficient between the gains was calculated. Absolute accuracy, sensitivity, and specificity of the rHIT were additionally calculated. Results Of the 10 patients recruited, 4 were male, and the average ± standard deviation (SD) age was 61.4 ± 15.3 years. As determined by the vHIT, 2 patients had normal bilateral VOR gains, 6 with unilateral vestibular hypofunction, and 2 with bilateral vestibular hypofunction. The correlation between the rHIT and vHIT gains was 0.73 (p

We present a genome assembly from an individual female Agrilus cyanescens (metallic wood-boring beetle; Arthropoda; Insecta; Coleoptera; Buprestidae). The genome sequence is 292.3 megabases in span. Most of the assembly is scaffolded into 10 chromosomal pseudomolecules, including the X sex chromosome. The mitochondrial genome has also been assembled and is 15.91 kilobases in length.

The RV144 Thai phase III clinical trial’s canarypox–protein HIV vaccine regimen showed modest efficacy in reducing infection. We therefore sought to determine the effects of vaccine administration on innate cell activation and subsequent associations with vaccine-induced immune responses. RV306 was a randomized, double-blind clinical trial in HIV-uninfected Thai adults that tested delayed boosting following the RV144 regimen. PBMC collected from RV306 participants prior to and 3 days after the last boost were used to investigate innate immune cell activation. Our analysis showed an increase in CD38+ mucosal associated invariant T (MAIT) cells, CD38+ invariant natural killer T (iNKT) cells, CD38+ γδ T cells, CD38+, CD69+ and HLA-DR+ NK cells 3 days after vaccine administration. An increase in CD14-CD16+ non-classical monocytes and CD14+CD16+ intermediate monocytes accompanied by a decrease in CD14+CD16- classical monocytes was also associated with vaccine administration. Inclusion of ALVAC-HIV in the boost did not further increase MAIT, iNKT, γδ T, and NK cell activation or increase the proportion of non-classical monocytes. Additionally, NK cell activation 3 days after vaccination was positively associated with antibody titers of HIV Env-specific total IgG and IgG1. Vδ1 T cell activation 3 days after vaccine administration was associated with HIV Env-specific IgG3 titers. Finally, we observed trending associations between MAIT cell activation and Env-specific IgG3 titers and between NK cell activation and TH023 pseudovirus neutralization titers. Our study identifies a potential role for innate cells, specifically NK, MAIT, and γδ T cells, in promoting antibody responses following HIV-1 vaccine administration.

Introduction Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with severe aplastic anaemia (sAA) not eligible or suitable for allogeneic stem cell transplant. While patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve haematological responses in sAA. Avatrombopag is a second-generation TPO-A with potential advantages over eltrombopag. However, to date avatrombopag has not been studied in sAA.Methods and analysis Investigator-initiated, single-arm registry-based Bayesian Optimal Phase II trial of avatrombopag conducted in two cohorts, patients with untreated sAA (FIRST cohort) and in patients with sAA that has relapsed or is refractory to IST (NEXT cohort). In the FIRST cohort, participants receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily, with dose adjusted according to platelet count. Participants in the NEXT cohort receive avatrombopag at 60 mg oral daily from day 1 until day 180, with or without additional IST at the discretion of the treating clinician.For each cohort, two primary endpoints (haematological response and acquired clonal evolution) are jointly monitored and the trial reviewed at each interim analysis where a ‘go/no-go’ decision is made by evaluating the posterior probability of the events of interests.Ethics and dissemination The trial has received ethics approval (Monash Health RES-18-0000707A). The trial conduct will comply with ICH-GCP and all applicable regulatory requirements. The results of the trial will be submitted to a peer-review journal for publication.Trial registration number ACTRN12619001042134, ACTRN12619001043123.

This paper summarizes the structure and findings from the first Workshop on Troubles and Failures in Conversations between Humans and Robots. The workshop was organized to bring together a small, interdisciplinary group of researchers working on miscommunication from two complementary perspectives. One group of technology-oriented researchers was made up of roboticists, Human-Robot Interaction (HRI) researchers and dialogue system experts. The second group involved experts from conversation analysis, cognitive science, and linguistics. Uniting both groups of researchers is the belief that communication failures between humans and machines need to be taken seriously and that a systematic analysis of such failures may open fruitful avenues in research beyond current practices to improve such systems, including both speech-centric and multimodal interfaces. This workshop represents a starting point for this endeavour. The aim of the workshop was threefold: Firstly, to establish an interdisciplinary network of researchers that share a common interest in investigating communicative failures with a particular view towards robotic speech interfaces; secondly, to gain a partial overview of the “failure landscape” as experienced by roboticists and HRI researchers; and thirdly, to determine the potential for creating a robotic benchmark scenario for testing future speech interfaces with respect to the identified failures. The present article summarizes both the “failure landscape” surveyed during the workshop as well as the outcomes of the attempt to define a benchmark scenario.

Abstract Rucksack marches (‘rucks’) are strenuous, military‐relevant exercises that may benefit from pre‐event fuelling. The purpose of this investigation was to explore whether acute ingestion of carbohydrate‐ or lipid‐based nutritional bars before rucking can elicit unique advantages that augment exercise performance. Recreationally active and healthy males (n = 29) were randomized and counterbalanced to consume 1000 kcal derived from a novel, energy‐dense (percentage energy from carbohydrate/fat/protein: 5/83/12) ketogenic bar (KB), or isocaloric high‐carbohydrate bars (CB; 61/23/16) 3 h before a time‐to‐exhaustion (TTE) ruck. Conditions were separated by a 1‐week washout. The rucksack weight was standardized to 30% of bodyweight. Steady‐state treadmill pace was set at 3.2 km/h (0.89 m/s) and 14% grade. TTE was the primary outcome; respiratory exchange ratio (RER), capillary ketones (R‐β‐hydroxybutyrate), glucose and lactate, plus subjective thirst/hunger were the secondary outcomes. Mean TTE was similar between conditions (KB: 55 ± 25 vs. CB: 54 ± 22 min; P = 0.687). The RER and substrate oxidation rates revealed greater fat and carbohydrate oxidation after the KB and CB, respectively (all P