Search

Abstract Background Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine was synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). Methods In this single arm multicohort phase I trial, we evaluated the safety and efficacy of ribociclib plus gemcitabine in patients with advanced solid tumors. Patients received gemcitabine intravenously on days 1 and 8 followed by ribociclib days 8–14, with treatment repeated every 3 weeks. Results The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800 mg daily and gemcitabine 1000 mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. Conclusions The addition of ribociclib to gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Biomarkers such as Rb status and activity of CDK2 and CDK4/6 complexes may help to select patients who may respond better to the combination of gemcitabine and ribociclib. Clinical Trial Registration NCT03237390.

Introduction: Benzodiazepines are frequently prescribed and misused therefore urine drug screening (UDS) is performed in many patient populations. Most current benzodiazepine immunoassays have poor sensitivity, particularly for detecting the metabolites of newer benzodiazepines such as lorazepam in urine. Objectives: We aimed to verify the clinical performance of the new qualitative Roche Benzodiazepines II (BNZ2) immunoassay, as well as compare its performance to the Roche Benzodiazepines Plus (BENZ) assay in two patient populations: UDS in the emergency department (ED) and compliance monitoring. Methods: An initial verification study was performed, selecting for samples containing clonazepam and lorazepam metabolites. Performance of the BNZ2 and BENZ assays was compared to liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the reference method. Sensitivity, specificity, false positive rate (FPR) and false negative rate (FNR) were determined. Results: We verified the performance claims in the initial verification and demonstrated similar precision, with coefficient of variations (CVs) of 12.8% and 7.7% for negative and positive controls, respectively. Furthermore, we observed higher clinical sensitivity and lower FNR with the BNZ2 assay in both the ED and compliance monitoring populations due to improved cross-reactivity for lorazepam and clonazepam metabolites. Despite these improvements, the BNZ2 assay was unable to detect 27% of specimens positive by LC-MS/MS, including specimens from patients using benzodiazepines without prescription. Discussion: Due to its improved performance and rapid turnaround time, the BNZ2 assay should be implemented for UDS in the ED. However, the assay should not replace LC-MS/MS testing for compliance monitoring, as unsuspected benzodiazepine use may go undetected.

Background MEDI5395 is a recombinant attenuated Newcastle disease virus engineered to express a human granulocyte-macrophage colony-stimulating factor transgene. Preclinically, MEDI5395 demonstrated broad oncolytic activity, augmented by concomitant programmed cell death-1/programmed cell death ligand-1 (PD-L1) axis blockade. Durvalumab is an anti-PD-L1 immune checkpoint inhibitor approved for the treatment of various solid tumors. We describe the results of the first-in-human study combining intravenous MEDI5395 with durvalumab in patients with advanced solid tumors.Methods This phase I, open-label, multicenter, dose-escalation, dose-expansion study recruited adult patients with advanced solid tumors, who had relapsed or were refractory or intolerant to ≥1 prior line of standard treatment. MEDI5395 was administered intravenously as six doses over 15–18 days. The dose-escalation phase assessed four-dose levels (108, 109, 1010, 1011 focus forming units (FFU)) of MEDI5395, with sequential or delayed durvalumab. Durvalumab 1500 mg was administered intravenously every 4 weeks up to 2 years. The dose-expansion phase was not initiated. The primary objectives were to evaluate safety and tolerability, dose-limiting toxicities (DLTs) and the dose and schedule of MEDI5395 plus durvalumab administration. Secondary objectives included the assessment of the efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of MEDI5395.Results 39 patients were treated with MEDI5395; 36 patients also received durvalumab. All 39 patients experienced ≥1 treatment-emergent adverse event (TEAE), most commonly fatigue (61.5%), nausea (53.8%) and chills (51.3%). Grade 3–4 TEAEs occurred in 27 (69.2%) patients; these were deemed MEDI5395-related in 12 (30.8%) patients. Two patients experienced a DLT, and the maximum tolerated dose of MEDI5395 with sequential and delayed durvalumab at study termination was 1011 and 1010 FFU, respectively. Four patients (10.3%) achieved a partial response (PR). Patients with PR or stable disease tended to have higher baseline PD-L1 and CD8+ levels in their tumor tissue. A tendency to dose-dependent pharmacokinetics of the viral genome was observed in whole blood and a tendency to dose-dependent viral shedding was observed in saliva and urine. Neutralizing antibodies were observed in all patients but did not appear to impact efficacy negatively.Conclusion This study demonstrates the feasibility, safety and preliminary efficacy of MEDI5395 with durvalumab in patients with advanced solid tumors.Trial registration number NCT03889275

Abstract Background Community based rehabilitation (CBR) aims to promote the inclusion and participation of people with disabilities, particularly in low- and middle-income countries (LMICs). Yet people with psychosocial disabilities are often excluded from CBR programmes. The restrictive inclusion criteria used by previous reviews make it difficult to identify promising examples that could otherwise help to inform the uptake of CBR for people with psychosocial disabilities. We aim to address this gap using gold standard methods for the review and synthesis of grey literature on CBR for people with psychosocial disabilities in LMICs. Methods Our search strategy was developed in consultation with an expert advisory group and covered seven grey literature databases, two customised Google Advanced searches, 34 targeted websites and four key reports. A single reviewer screened the search results and extracted relevant data using a standardised format based on the World Health Organisation’s CBR matrix. The included programmes were then checked by a second reviewer with experience in CBR to ensure they met the review’s criteria. A narrative synthesis with summative content analysis was performed to synthesise the findings. Results The 23 CBR programmes identified for inclusion spanned 19 countries and were mostly located in either rural areas or urban areas where a large proportion of the population was living in poverty. 13 were classified as livelihood programmes, eight as empowerment programmes, seven as social programmes, seven as health programmes and four as education programmes. Only two addressed all five of these components. 12 of the included programmes reported challenges to implementation, with stigma and lack of resources emerging as two of the most prominent themes. Conclusion This grey literature review identified several CBR programmes and synthesised key learning that would have otherwise been missed by a more traditional review of the published literature. However, as evaluation by implementing organisations is not always conducted to a high standard, the quality of this evidence is generally poor. A flexible monitoring and evaluation framework for CBR programmes could help to reduce heterogeneity in terms of the quality and content of reporting.

Abstract Climate change is causing persistent, widespread, and significant impacts on marine ecosystems which are predicted to interact and intensify. Overfishing and associated habitat degradation have put many fish populations and marine ecosystems at risk and is making the ocean more vulnerable to climate change and less capable of buffering against its effects. In this Perspective, we review how overfishing is disrupting the important role of marine vertebrates in the ocean carbon cycle, causing disturbance and damage to the carbon-rich seabed, and contributing to rising greenhouse gas emissions through fuel use. We discuss how implementing good fisheries management can reduce or remove many of the impacts associated with overfishing, including fish stock collapse, destruction of seabed habitats, provision of harmful subsidies and accompanying socio-economic impacts. Managing overfishing is one of the most effective strategies in protecting ocean carbon stores and can make an important contribution to climate mitigation and adaptation.

The Middle East, with its diverse cultures and adherence to social norms, offers a relevant case study for exploring the current research question. Using established theories of social interaction and technology acceptance, this research examines how cultural background shapes student interactions with ChatGPT. Analyzing data from 202 online surveys, our findings underscore the gender-based disparities in ChatGPT use, potentially revealing consequences for technology adoption within the Middle East. This study contributes to a deeper understanding of how cultural upbringing influences AI utilization and paves the way for developing more culturally sensitive and inclusive AI systems. By promoting a more equitable and informed approach to AI adoption in the Middle East and beyond, this research offers valuable insights for future research directions and technology applications.

PAVON has developed a malaria microscopy competency training scheme to augment competency in malaria microscopy. Here, data accrued from training activities between 2020 and 2023 in Botswana are presented. Three trainings were done for 37 central and peripheral level technicians for a two-week period. The scheme consisted of basic theory on Plasmodium parasites, malaria epidemiology and diagnosis. The practicals focused on standard slide preparation, staining, parasite detection, speciation and counting. Scores were assessed by the Wilcoxon signed rank test. Participants who excelled joined the WHO External Competency Assessment for Malaria Microscopy (ECAMM). The median competency scores for the three trainings were detection: 100 (IQR = 94–100), 100 (IQR = 94–100) and 92 (IQR = 92–100), respectively, from pre-test scores of 40 (IQR = 27–54), 44 (IQR = 32–52) and 20 (IQR = 10–40) (z = 2.937, p < 0.003, z = 3.110, p = 0.002 and (z = 2.251, p = 0.024), respectively. Speciation: 93 (IQR = 86–96), 81 (IQR = 73–96) and 88, (IQR = 88–100) from pre-test scores of 50 (IQR = 30–50), 36 (IQR = 20–45) and 17 (IQR = 17–50) (z = 2.936, p < 0.003, z = 3.152, p = 0.002 and z = 3.237, p = 0.001). The competency scores achieved in the ECAMM were 98/98 and 97/98 for sensitivity and specificity pre- and post-tests detection. The training was effective in raising the competency skills of participants and is open to NMPs (National Malaria Programs) for critical capacity building.

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Abstract Background People living with HIV are vulnerable to gender-based violence (GBV), which can negatively impact HIV treatment outcomes. National guidelines in Uganda recommend GBV screening alongside HIV treatment services. We explored barriers and facilitators to providers implementing GBV screening and referral in public antiretroviral therapy (ART) clinics in Uganda. Methods We conducted qualitative in-depth interviews. Providers were purposively sampled from 12 ART clinics to represent variation in clinical specialty and gender. We used the Theoretical Domains Framework to structure our deductive analysis. Results We conducted 30 in-depth interviews with providers implementing GBV screening and/or referral. Respondents had a median age of 36 (IQR: 30, 43) years and had been offering post-GBV care to clients for a median duration of 5 (4, 7) years. 67% of respondents identified as female and 57% were counselors. Facilitators of GBV screening and referral included providers having access to post-GBV standard operating procedures and screening tools, trainings offered by the Ministry of Health, facility-sponsored continuing medical education units and support from colleagues. Respondents indicated that referrals were uncommon, citing the following barriers: negative expectations regarding the quality and quantity of referral services; lack of financial resources to support clients, facilities, and referral partners throughout the referral process; and sociocultural factors that threatened client willingness to pursue post-GBV support services. Conclusions Findings from this evaluation support the refinement of GBV screening and referral implementation strategies that leverage facilitators and address barriers to better support individuals living with HIV and who may have heightened vulnerability to GBV.

Repair or reconstruction of the lateral collateral ligament (LCL) using autograft or allograft is a well-accepted treatment of posterolateral rotatory instability. The prevalence and causes for failure of LCL reconstruction are not well documented in the literature. Any approach to the assessment and management of failed LCL reconstruction must begin with understanding the risk factors for failure in the first place. Such understanding would likely make many failures preventable as well. In our experience, there are a number of identifiable preoperative risk factors concerning bony and/or soft tissue constraints for failure of LCL reconstruction. There are also operative factors such as tunnel and graft placement as well as excessive lateral condyle stripping that play a role in risk of failure. This report is an attempt to provide a systematic approach to identifying and managing the preoperative and operative risk factors. Further studies are warranted to determine the indications for, and success rates of surgical intervention in managing these risk factors.

Introduction: EML4-ALK is an oncogenic driver, seen in around five per cent of advanced non-small-cell lung cancer (NSCLC) patients, which can be targeted with anaplastic lymphoma kinase tyrosine kinase inhibitors with great response rates. Disease flare refers to sudden rapid disease worsening on tyrosine kinase inhibitors (TKI) discontinuation, which is associated with shorter survival and worse outcomes. Here, we review cases previously published in the literature where patients developed disease flares, and contrast this with our patients who had prolonged survival despite TKI discontinuation. Case description: We report three different patients with advanced ALK-positive NSCLC seen at our institute, who had EML4-ALK translocation variant 1 oncogenic driver on next-generation sequencing. They received treatment with several different ALK inhibitors before opting to discontinue TKI. They were able to come off TKI safely without developing disease flare and had prolonged survival. Discussion: Shorter time to progression on TKI, presence of symptoms with disease progression or central nervous system/pleural metastasis have been previously linked with development of flare, although this was not seen in our case series. Tumour response at the time of treatment discontinuation, line of therapy, overall disease burden, fusion variant and co-alteration status can affect the prognosis of these patients after ALK TKI cessation. In particular, variant 1 and wild-type TP53 status may be a suitable patient population for dose optimisation strategies. Intermittent TKI dosing strategies may help to avoid acquiring resistance mutations and prevent long-term treatment toxicities. Conclusion: It is important for clinicians to identify patients at risk for developing disease flare on TKI discontinuation to improve outcomes. Intermittent TKI dosing strategies require further investigation.

Abstract Background Molecular testing is critical to guiding treatment approaches in patients with metastatic non‐small cell lung cancer (mNSCLC), with testing delays adversely impacting the timeliness of treatment decisions. Here, we aimed to evaluate the time from initial mNSCLC diagnosis to treatment decision (TTD) following implementation of in‐house EGFR, ALK, and PD‐L1 testing at our institution. Methods We conducted a retrospective chart review of 165 patients (send‐out testing, n = 92; in‐house testing, n = 73) with newly diagnosed mNSCLC treated at our institution. Data were compared during the send‐out (March 2017–May 2019) and in‐house (July 2019–March 2021) testing periods. We performed a detailed workflow analysis to provide insight on the pre‐analytic, analytic, and post‐analytic intervals that constituted the total TTD. Results TTD was significantly shorter with in‐house testing (10 days vs. 18 days, p

Abstract Pelagic tunicates (salps, pyrosomes) and fishes generate jelly falls and/or fecal pellets that sink roughly 10 times faster than bulk oceanic detritus, but their impacts on biogeochemical cycles in the ocean interior are poorly understood. Using a coupled physical‐biogeochemical model, we find that fast‐sinking detritus decreased global net primary production and surface export, but increased deep sequestration and transfer efficiency in much of the extratropics and upwelling zones. Fast‐sinking detritus generally decreased total suboxic and hypoxic volumes, reducing a “large oxygen minimum zone (OMZ)” bias common in global biogeochemical models. Newly aerobic regions at OMZ edges exhibited reduced transfer efficiencies in contrast with global tendencies. Reductions in water column denitrification resulting from improved OMZs improved simulated nitrate deficits relative to phosphate. The carbon flux to the benthos increased by 11% with fast‐sinking detritus from fishes and pelagic tunicates, yet simulated benthic fluxes remained on the lower end of observation‐based estimates.

Tailored delivery strategies are important for optimizing the benefit and overall reach of PrEP in sub-Saharan Africa. An integrated approach of delivering time-limited PrEP in combination with ART to serodifferent couples encourages PrEP use in the HIV-negative partner as a bridge to sustained ART use. Although PrEP has been delivered in ART clinics for many years, the processes involved in integrating PrEP into ART services are not well understood. The Partners PrEP Program was a stepped-wedge cluster randomized trial of integrated PrEP and ART delivery for HIV serodifferent couples in 12 public health facilities in central Uganda (Clinicaltrials.gov NCT03586128). Using qualitative data, we identified and characterized key implementation processes that explain how PrEP delivery was integrated into existing ART services in the Partners PrEP Program. In-depth interviews were conducted with a purposefully-selected sub-sample of 83 members of 42 participating serodifferent couples, and with 36 health care providers implementing integrated delivery. High quality training, technical supervision, and teamwork were identified as key processes supporting providers to implement PrEP delivery. Interest in the PrEP program was promoted through the numerous ways health care providers made integrated ART and PrEP meaningful for serodifferent couples, including tailored counseling messages, efforts to build confidence in integrated delivery, and strategies to create demand for PrEP. Couples in the qualitative sample responded positively to providers' efforts to promote the integrated strategy. HIV-negative partners initiated PrEP to preserve their relationships, which inspired their partners living with HIV to recommit to ART adherence. Lack of disclosure among couples and poor retention on PrEP were identified as barriers to implementation of the PrEP program. A greater emphasis on understanding the meaning of PrEP for users and its contribution to implementation promises to strengthen future research on PrEP scale up in sub-Saharan Africa.

BackgroundHIV and gender-based violence (GBV) intersect to threaten population health. The Uganda Ministry of Health recommends routine GBV screening alongside HIV care but evidence detailing its implementation in HIV care settings is limited. We evaluated screening practices in public HIV clinics to generate evidence supporting GBV screening optimization.MethodsTo evaluate GBV screening implementation in antiretroviral therapy (ART) clinics, we extracted client data from GBV registers at 12 public ART clinics in Uganda (January 2019-December 2021). We concurrently evaluated perceptions of GBV screening/referral practices by conducting in-depth qualitative interviews with providers (N = 30) and referral partners (N = 10). We contextualized quantitative findings with interview data which were analyzed using a thematic analysis approach.ResultsDuring the evaluation period, >90% of providers in participating health facilities implemented GBV screening. Among 107,767 clients served in public ART clinics, providers identified 9,290 (8.6%) clients who experienced past-year physical, sexual and/or emotional GBV of whom 86% received counseling and 19% were referred to support services-most commonly to legal services. Key factors influencing GBV screening implementation included awareness of screening guidelines; client volume; and client's level of engagement in HIV care. Providers and referral partners identified important benefits to clients (e.g., pursuit of justice and removal from violent environments) when referrals were successful. Key factors influencing referrals included financial constraints that limited referral partners' ability to provide services at no cost to clients and socio-cultural norms that inhibited client willingness to pursue support services.ConclusionsGBV screening implementation in ART clinics supports identification and referral of clients exposed to violence. The effectiveness of GBV screening may be limited by socio-cultural factors that inhibit client capacity to pursue referrals and fragmented and resource-constrained referral networks. Providers and referral partners identified allocating funds to support referrals and collaborative networking meetings as important opportunities for strengthening GBV referrals.

ImportanceThe COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood.ObjectivesTo estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case.Design, setting, and participantsIn this prospective cohort study, from March 2020-December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur.Main outcomes and measuresDaily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts.ResultsOf the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0-54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00-1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46-11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02).Conclusions and relevanceThis study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes.

AimTo examine the impact of introducing and implementing the Vayu bubble continuous positive airway pressure (bCPAP) system on neonatal survival and neonatal respiratory outcomes in a neonatal intensive care unit (NICU) in the Philippines.MethodsWe compared clinical outcomes of 1,024 neonates before to 979 neonates after introduction of Vayu bCPAP systems into a NICU. The primary outcome was survival to discharge. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were calculated. Analyses were undertaken separately for the entire NICU population and for neonates who received any form of respiratory support.ResultsThe introduction of the Vayu bCPAP system was associated with (1) significant reductions in intubation (aOR: 0.75; 95% CI: 0.58–0.96) and in the use of nasal intermittent positive-pressure ventilation (NIPPV) (aOR: 0.69; 95% CI: 0.50–0.96) among the entire NICU population and (2) a significant increase in survival to discharge (aOR: 1.53; 95% CI: 1.09–2.17) and significant reductions in intubation (aOR: 0.52; 95% CI: 0.38–0.71), surfactant administration (aOR: 0.60; 95% CI: 0.40–0.89), NIPPV use (aOR: 0.52; 95% CI: 0.36–0.76), and a composite neonatal adverse outcome (aOR: 0.60; 95% CI: 0.42–0.84) among neonates who received any form of respiratory support.ConclusionThe use of the Vayu bCPAP system in a NICU in the Philippines resulted in significant improvement in neonatal respiratory outcomes.

Background: Surgical risk in chronic thromboembolic pulmonary hypertension (CTEPH) depends on the proximity of thromboembolism on CT pulmonary angiography (CTPA). We assessed interobserver agreement for the quantification of thromboembolic lesions in CTEPH using a novel CTPA scoring index. Methods: Forty CTEPH patients (mean age, 58 ± 16 years; 19 men) with preoperative CTPA who underwent pulmonary endarterectomy (PEA) (08/2020-09/2021) were retrospectively included. Three radiologists scored each CTPA for chronic thromboembolism (occlusions, eccentric thickening, webs) using a 32-vessel model of the pulmonary vasculature, with interobserver agreement evaluated using Fleiss’ kappa. CT level of disease was determined by the most proximal chronic thromboembolism: level 1 (main pulmonary artery), 2 (lobar), 3 (segmental) and 4 (subsegmental), and compared to surgical level at PEA. Results: Interobserver agreement for CT level of disease was moderate overall (κ = 0.52). Agreement was substantial overall at the main/lobar level (κ, mean = 0.71) when excluding the left upper lobe (κ = 0.17). Though segmental and subsegmental agreement suffered (κ = 0.31), we found substantial agreement for occlusions (κ = 0.72) compared to eccentric thickening (κ = 0.45) and webs (κ = 0.14). Correlation between CT level and surgical level was strong overall (τb = 0.73) and in the right lung (τb = 0.68), but weak in the left lung (τb = 0.42) (p

Abstract Objective To identify the multilocus sequence typing (MLST) sequence types of Borrelia burgdorferi from Ixodes scapularis in Ontario, Canada. Results One hundred and eighty-five I. scapularis ticks were submitted from 134 dogs via participating clinics from April 1, 2019, to March 31, 2020. Seventeen MLST sequence types of B. burgdorferi were detected from fifty-eight cultured isolates from 21 ticks. The most common MLST sequence types were 12 and 16. Mixed infections of two MLST sequence types were detected in four ticks. Three sequence types (48, 317, 639) were new detections in Ontario.

Summary: While insulin resistance (IR) is associated with inflammation in white adipose tissue, we report a non-inflammatory adipose mechanism of high fat-induced IR mediated by loss of Pref-1. Pref-1, released from adipose Pref-1+ cells with characteristics of M2 macrophages, endothelial cells or progenitors, inhibits MIF release from both Pref-1+ cells and adipocytes by binding with integrin β1 and inhibiting the mobilization of p115. High palmitic acid induces PAR2 expression in Pref-1+ cells, downregulating Pref-1 expression and release in an AMPK-dependent manner. The loss of Pref-1 increases adipose MIF secretion contributing to non-inflammatory IR in obesity. Treatment with Pref-1 blunts the increase in circulating plasma MIF levels and subsequent IR induced by a high palmitic acid diet. Thus, high levels of fatty acids suppress Pref-1 expression and secretion, through increased activation of PAR2, resulting in an increase in MIF secretion and a non-inflammatory adipose mechanism of IR.

Introduction: In stage IV NSCLC with solitary or oligometastatic brain metastasis, surgical resection of the primary and definitive management of the brain metastasis is an accepted standard. However, the effect of systemic chemotherapy after surgical resection on overall survival is not well-established. Methods: We used the National Cancer Database to retrospectively identify individuals with NSCLC as the primary tumor along with synchronous brain metastases who underwent thoracic resection with or without adjuvant chemotherapy. Chi-square and Wilcoxon rank sum tests were performed to compare categorical and continuous variables, respectively, across the treatment groups. Kaplan-Meier and Cox proportional modeling were done to determine the survival benefit. Results: A total of 310 (71.9%) of the cohort received perioperative chemotherapy, most of whom (79.4%) received it in the adjuvant setting. Patients receiving chemotherapy were likely to be younger (p = 0.002), privately insured (p = 0.01), and receive radiation (p < 0.001). Perioperative chemotherapy was significantly associated with survival on both univariate (hazard ratio = 0.71[0.52 – 0.99]) and multivariable (hazard ratio = 0.66 [0.47 – 0.92]) in addition to age (p = 0.03), Charlson-Deyo score (p = 0.02), pathologic N stage (p = 0.02), and adenocarcinoma histology (p = 0.02). Kaplan-Meier analysis confirmed this result with a significantly better survival with perioperative chemotherapy (p = 0.02). Further subgroup analysis using pathologic N stage revealed similar effect in pN1 (p = 0.001), but not pN0 (p = 0.2) patients. Conclusions: Perioperative chemotherapy for pN0-1 NSCLC with synchronous brain metastasis is associated with improved OS in this analysis.

Objectives To (1) understand what behaviours, beliefs, demographics and structural factors predict US adults’ intention to get a COVID-19 vaccination, (2) identify segments of the population (‘personas’) who share similar factors predicting vaccination intention, (3) create a ‘typing tool’ to predict which persona people belong to and (4) track changes in the distribution of personas over time and across the USA.Design Three surveys: two on a probability-based household panel (NORC’s AmeriSpeak) and one on Facebook.Setting The first two surveys were conducted in January 2021 and March 2021 when the COVID-19 vaccine had just been made available in the USA. The Facebook survey ran from May 2021 to February 2022.Participants All participants were aged 18+ and living in the USA.Outcome measures In our predictive model, the outcome variable was self-reported vaccination intention (0–10 scale). In our typing tool model, the outcome variable was the five personas identified by our clustering algorithm.Results Only 1% of variation in vaccination intention was explained by demographics, with about 70% explained by psychobehavioural factors. We identified five personas with distinct psychobehavioural profiles: COVID Sceptics (believe at least two COVID-19 conspiracy theories), System Distrusters (believe people of their race/ethnicity do not receive fair healthcare treatment), Cost Anxious (concerns about time and finances), Watchful (prefer to wait and see) and Enthusiasts (want to get vaccinated as soon as possible). The distribution of personas varies at the state level. Over time, we saw an increase in the proportion of personas who are less willing to get vaccinated.Conclusions Psychobehavioural segmentation allows us to identify why people are unvaccinated, not just who is unvaccinated. It can help practitioners tailor the right intervention to the right person at the right time to optimally influence behaviour.

IntroductionNecrotizing enterocolitis (NEC) is a potentially fatal intestinal disease primarily affecting preterm infants. Early diagnosis of neonates with NEC is crucial to improving outcomes; however, traditional diagnostic tools remain inadequate. Biomarkers represent an opportunity to improve the speed and accuracy of diagnosis, but they are not routinely used in clinical practice.MethodsIn this study, we utilized an aptamer-based proteomic discovery assay to identify new serum biomarkers of NEC. We compared levels of serum proteins in neonates with and without NEC and identified ten differentially expressed serum proteins between these groups.ResultsWe detected two proteins, C-C motif chemokine ligand 16 (CCL16) and immunoglobulin heavy constant alpha 1 and 2 heterodimer (IGHA1 IGHA2), that were significantly increased during NEC and eight that were significantly decreased. Generation of receiver operating characteristic (ROC) curves revealed that alpha-fetoprotein (AUC = 0.926), glucagon (AUC = 0.860), and IGHA1 IGHA2 (AUC = 0.826) were the proteins that best differentiated patients with and without NEC.DiscussionThese findings indicate that further investigation into these serum proteins as a biomarker for NEC is warranted. In the future, laboratory tests incorporating these differentially expressed proteins may improve the ability of clinicians to diagnose infants with NEC rapidly and accurately.

Abstract Undernutrition is a public health challenge in sub-Saharan countries, including Uganda. In a previous randomized controlled trial (RCT) with a nutrition, hygiene and stimulation education intervention among mothers of 6 months’ old children, we found less caries in the intervention group when the children were 36 months of age. We now examined the effects of (i) the intervention on the microbiota, (ii) microbiota on caries, and (iii) the intervention and microbiota on caries. The original RCT comprised 511 mother/child pairs whereas in the current study we had access to data from 344/511 (67%) children aged 36 months. The saliva microbiota was determined using 16S rRNA gene sequencing. Carious lesions (a proxy for dental health) were identified using close-up intra-oral photographs of the upper front teeth. Statistical models were used to determine host-microbiota associations. The intervention had a significant effect on the microbiota, e.g. an increase in Streptococcus abundance and decreases in Alloprevotella and Tannerella. Significant associations between the microbiota and dental caries were identified: Positive associations of Capnocytophaga and Tannerella suggest that these taxa may be deleterious to dental health while negative associations of Granulicatella, Fusobacterium, and Abiotrophia suggest taxa potentially beneficial or benign contributors to dental health. Based on taxonomic profiles, the effects of the intervention and microbiota on dental health may be independent of one another. Educational interventions with emphasis on nutrition and oral hygiene may provide a feasible strategy to decrease progression of childhood caries in low-resource settings.

Introduction COVID-19 has placed substantial strain on the US nursing workforce. We measured the correlation between the number of state-specific COVID-19 hospitalizations per nurse and COVID-19 deaths, and assessed factors associated with nurses reporting an intention to leave their current job from stressors like those associated with COVID-19, including stress and burnout. Methods This study was of a cross-sectional design. Data came from the 2018 National Sample Survey of Registered Nurses (i.e. baseline) and the CDC COVID Data Tracker. Descriptive and multivariable analyses were performed at p

BackgroundDepression commonly occurs in heart failure patients, and negatively influences quality of life and disease prognosis. This study explored heart failure and depression-related research from a bibliometric perspective.MethodsRelevant publications were searched on June 24, 2022. The Bibliometrix package in R was used to conduct quantitative analyses including the trends in publications, and related countries, articles, authors and keywords. VOSviewer software was used to conduct the visualization map on co-word, co-author, and institution co-authorship analyses. CiteSpace software was used to illustrate the top keywords with citation burst.ResultsA total of 8,221 publications in the heart failure and depression-related research field were published between 1983 and 2022. In this field, the United States had the most publications (N = 3,013; 36.65%) and highest total citation (N = 149, 376), followed by China, Germany, Italy and Japan. Author Moser and Duke University were the most productive author and institution, respectively. Circulation is the most influential journal. Apart from “heart failure” and “depression,” “quality of life,” “mortality” and “myocardial infarction” were the most frequently used keywords in this research area; whereas more recently, “self care” and “anxiety” have been used more frequently.ConclusionThis bibliometric analysis showed a rapid growth of research related to heart failure and depression from 1989 to 2021, which was mostly led by North America and Europe. Future directions in this research area include issues concerning self-care and anxiety about heart failure. As most of the existing literature were published in English, publications in other languages should be examined in the future.

Background: Anxiety disorders are highly prevalent and chronic disorders with treatment resistance to current pharmacotherapies occurring in approximately one in three patients. It has been postulated that flumazenil (FMZ) is efficacious in the management of anxiety disorders via the removal of α 4 β2δ gamma-aminobutyric acid A receptors. Objective: To assess the safety and feasibility of continuous low-dose FMZ infusions for the management of generalised anxiety disorder (GAD) and collect preliminary efficacy data. Design: Uncontrolled, open-label pilot study. Method: Participants had a primary diagnosis of generalised anxiety disorder (GAD) and received two consecutive subcutaneous continuous low-dose FMZ infusions. Each infusion contained 16 mg of FMZ and was delivered over 96 ± 19.2 h. The total dose of FMZ delivered was 32 mg over approximately 8 days. Sodium valproate was given to participants at risk of seizure. The primary outcome was the change in stress and anxiety subscale scores on the Depression Anxiety Stress Scale–21 between baseline, day 8, and day 28. Results: Nine participants with a primary diagnosis of GAD were treated with subcutaneous continuous low-dose FMZ infusions; seven participants met the criteria for treatment resistance. There was a significant decrease in anxiety and stress between baseline and day 8 and baseline and day 28. There was also a significant improvement in subjective sleep quality from baseline to day 28 measured by the Jenkins Sleep Scale. No serious adverse events occurred. Conclusion: This study presents preliminary results for subcutaneous continuous low-dose FMZ’s effectiveness and safety in GAD. The findings suggest that it is a safe, well-tolerated, and feasible treatment option in this group of patients. Future randomised control trials are needed in this field to determine the efficacy of this treatment.

# Background Significant effort has gone into the identification and quantification of the underlying mechanisms of primary ACL injury. Secondary ACL injury is observed in approximately 1/4 to 1/3 of athletes who return to sport following ACL reconstruction. However, little has been done to evaluate the mechanisms and playing circumstances surrounding these repeat injuries. # Hypothesis/Purpose The purpose of this study was to characterize the mechanisms of non-contact secondary ACL injuries using video analysis. It was hypothesized that in video recordings of secondary ACL injury, athletes would exhibit greater frontal plane hip and knee angles, but not greater hip and knee flexion, at 66 ms following initial contact (IC) as compared to at IC and 33ms following IC. # Study Design Cross-Sectional Study # Methods Twenty-six video recordings of competitive athletes experiencing secondary ACL ruptures via noncontact mechanisms were analyzed for lower extremity joint kinematics, playing situation, and player attention. Kinematics were assessed at IC as well as 33 ms (1 broadcast frame) and 66 ms (2 broadcast frames) following IC. # Results Knee flexion and knee frontal plane angles were greater at 66 ms than IC (p ≤ 0.03). Hip, trunk, and ankle frontal plane angles were not greater at 66 ms than IC (p ≥ 0.22). Injuries were distributed between attacking play (n=14) and defending (n=8). Player attention was most commonly focused on the ball (n=12) or an opponent (n=7). A single-leg landing accounted for just over half of the injuries (54%), while a cutting motion accounted for the remainder of the injuries (46%). # Conclusion Secondary ACL injury was most likely to occur during landing or a sidestep cut with player attention external to their own body. Knee valgus collapse combined with limited hip motion was identified in the majority of secondary injuries. # Level of Evidence Level IIIb

Abstract Patients with aortic valve stenosis (AVS) have sexually dimorphic phenotypes in their valve tissue, where male valvular tissue adopts a calcified phenotype and female tissue becomes more fibrotic. The molecular mechanisms that regulate sex‐specific calcification in valvular tissue remain poorly understood. Here, we explored the role of osteopontin (OPN), a pro‐fibrotic but anti‐calcific bone sialoprotein, in regulating the calcification of female aortic valve tissue. Recognizing that OPN mediates calcification processes, we hypothesized that aortic valvular interstitial cells (VICs) in female tissue have reduced expression of osteogenic markers in the presence of elevated OPN relative to male VICs. Human female valve leaflets displayed reduced and smaller microcalcifications, but increased OPN expression relative to male leaflets. To understand how OPN expression contributes to observed sex dimorphisms in valve tissue, we employed enzymatically degradable hydrogels as a 3D cell culture platform to recapitulate male or female VIC interactions with the extracellular matrix. Using this system, we recapitulated sex differences observed in human tissue, specifically demonstrating that female VICs exposed to calcifying medium have smaller mineral deposits within the hydrogel relative to male VICs. We identified a change in OPN dynamics in female VICs in the presence of calcification stimuli, where OPN deposition localized from the extracellular matrix to perinuclear regions. Additionally, exogenously delivered endothelin‐1 to encapsulated VICs increased OPN gene expression in male cells, which resulted in reduced calcification. Collectively, our results suggest that increased OPN in female valve tissue may play a sex‐specific role in mitigating mineralization during AVS progression.

Inadequate nutrition and insufficient stimulation in early childhood can lead to long-term deficits in cognitive and social development. Evidence for policy and decision-making regarding the cost of delivering nutrition education is lacking in low and middle-income countries (LMIC). In rural Uganda, we conducted a cluster-randomized controlled trial (RCT) examining the effect of a maternal nutrition education intervention on developmental outcomes among children aged 6-8 months. This intervention led to significantly improved cognitive scores when the children reached the age of 20-24 months. When considering the potential for this intervention's future implementation, the desired effects should be weighed against the increased costs. This study therefore aimed to assess the cost-effectiveness of this education intervention compared with current practice. Health outcome data were based on the RCT. Cost data were initially identified by reviewing publications from the RCT, while more detailed information was obtained by interviewing researchers involved in processing the intervention. This study considered a healthcare provider perspective for an 18-months' time horizon. The control group was considered as the current practice for the future large-scale implementation of this intervention. A cost-effectiveness analysis was performed, including calculations of incremental cost-effectiveness ratios (ICERs). In addition, uncertainty in the results was characterized using one-way and probabilistic sensitivity analyses. The ICER for the education intervention compared with current practice was USD ($) 16.50 per cognitive composite score gained, with an incremental cost of $265.79 and an incremental cognitive composite score of 16.11. The sensitivity analyses indicated the robustness of these results. The ICER was sensitive to changes in cognitive composite score and the cost of personnel. The education intervention can be considered cost-effective compared with the current practice. The outcome of this study, including the cost analysis, health outcome, cost-effectiveness, and sensitivity analysis, can be useful to inform policymakers and stakeholders about effective resource allocation processes in Uganda and possibly other LMIC.

Most animals establish long-term symbiotic associations with bacteria that are critical for normal host physiology. The symbiosis that forms between the Hawaiian squid Euprymna scolopes and the bioluminescent bacterium Vibrio fischeri serves as an important model system for investigating the molecular mechanisms that promote animal-bacterial symbioses. E. scolopes hatch from their eggs uncolonized, which has led to the development of squid-colonization assays that are based on introducing culture-grown V. fischeri cells to freshly hatched juvenile squid. Recent studies have revealed that strains often exhibit large differences in how they establish symbiosis. Therefore, we sought to develop a simplified and reproducible protocol that permits researchers to determine appropriate inoculum levels and provides a platform to standardize the assay across different laboratories. In our protocol, we adapt a method commonly used for evaluating the infectivity of pathogens to quantify the symbiotic capacity of V. fischeri strains. The resulting metric, the symbiotic dose-50 (SD50), estimates the inoculum level that is necessary for a specific V. fischeri strain to establish a light-emitting symbiosis. Relative to other protocols, our method requires 2-5-fold fewer animals. Furthermore, the power analysis presented here suggests that the protocol can detect up to a 3-fold change in the SD50 between different strains.

Monkeypox (MPX) is a viral zoonotic disease that was endemic to Central and West Africa. However, during the first half of 2022, MPX spread to almost 60 countries all over the world. Smallpox vaccines are about 85% effective in preventing MPX infections. Our objective is to determine whether the vaccines should be mandated or whether voluntary use of the vaccine could be enough to stop the MPX outbreak. We incorporate a standard SVEIR compartmental model of MPX transmission into a game-theoretical framework. We study a vaccination game in which individuals decide whether or not to vaccinate by assessing their benefits and costs. We solve the game for Nash equilibria, i.e., the vaccination rates the individuals would likely adopt without any outside intervention. We show that, without vaccination, MPX can become endemic in previously non-endemic regions, including the United States. We also show that to "not vaccinate" is often an optimal solution from the individual's perspective. Moreover, we demonstrate that, for some parameter values, there are multiple equilibria of the vaccination game, and they exhibit a backward bifurcation. Thus, without centrally mandated minimal vaccination rates, the population could easily revert to no vaccination scenario.

People with kidney disease are disproportionately affected by atherosclerosis for unclear reasons. Soluble urokinase plasminogen activator receptor (suPAR) is an immune-derived mediator of kidney disease, levels of which are strongly associated with cardiovascular outcomes. We assessed suPAR’s pathogenic involvement in atherosclerosis using epidemiologic, genetic, and experimental approaches. We found serum suPAR levels to be predictive of coronary artery calcification and cardiovascular events in 5,406 participants without known coronary disease. In a genome-wide association meta-analysis including over 25,000 individuals, we identified a missense variant in the plasminogen activator, urokinase receptor (PLAUR) gene (rs4760), confirmed experimentally to lead to higher suPAR levels. Mendelian randomization analysis in the UK Biobank using rs4760 indicated a causal association between genetically predicted suPAR levels and atherosclerotic phenotypes. In an experimental model of atherosclerosis, proprotein convertase subtilisin/kexin–9 (Pcsk9) transfection in mice overexpressing suPAR (suPARTg) led to substantially increased atherosclerotic plaques with necrotic cores and macrophage infiltration compared with those in WT mice, despite similar cholesterol levels. Prior to induction of atherosclerosis, aortas of suPARTg mice excreted higher levels of CCL2 and had higher monocyte counts compared with WT aortas. Aortic and circulating suPARTg monocytes exhibited a proinflammatory profile and enhanced chemotaxis. These findings characterize suPAR as a pathogenic factor for atherosclerosis acting at least partially through modulation of monocyte function.

Variability is inevitable in human movement and posture, including piano performance, although little research has been conducted in this area. The purpose of this study was to determine if, when comparing individuals to themselves, pianists demonstrate consistent postural angles within a task across multiple measurements and to ascertain if, between various tasks, there are discernible task-related postural patterns. Fifteen pianists participated in this study. Each pianist returned for a total of three measurement sessions. The tasks they were required to perform at each session were quiet sitting, raising their hands on and off the keyboard, playing an ascending and descending scale, sight reading, and playing a piece in three expressive conditions (i.e., deadpan, projected, exaggerated). The following postural angles were calculated based on motion capture data collected during the performance of these tasks: craniovertebral angle, head tilt, head-neck-trunk angle, trunk angle, thoracic angle, thoracolumbar angle, and lumbar angle. The within-person variability ratio across the three measurements was calculated for each angle and across all tasks. Task-related patterns in angles were examined by comparing the same postural angle across different tasks. Results showed that there is a considerable amount of within-person variability, but not enough to be inconsistent over time. Task-related patterns indicate that reading a musical score or playing at the extreme ends of the keyboard tend to involve leaning closer to the instrument. Implications for future studies, intervention studies in particular, include taking more than a single baseline measurement to provide a more accurate picture of an individual pianist's typical posture.

Conventional antibodies and their derived fragments are difficult to deploy against intracellular targets in live cells, due to their bulk and structural complexity. Nanobodies provide an alternative modality, with well-documented examples of intracellular expression. Despite their promise as intracellular reagents, there has not been a systematic study of nanobody intracellular expression. Here, we examined intracellular expression of 75 nanobodies from the Protein Data Bank. Surprisingly, a majority of these nanobodies were unstable in cells, illustrated by aggregation and clearance. Using comparative analysis and framework mutagenesis, we developed a general approach that stabilized a great majority of nanobodies that were originally unstable intracellularly, without significantly compromising target binding. This approach led to the identification of distinct sequence features that impacted the intracellular stability of tested nanobodies. Mutationally stabilized nanobody expression was found to extend to in vivo contexts, in the murine retina and in E. coli. These data provide for improvements in nanobody engineering for intracellular applications, potentiating a growing field of intracellular interrogation and intervention.

Abstract Statistical models built using different data sources and methods can exhibit conflicting patterns. We used the northern stock of black sea bass (Centropristis striata) as a case study to assess the impacts of using different fisheries data sources and laboratory‐derived physiological metrics in the development of thermal habitat models for marine fishes. We constructed thermal habitat models using generalized additive models (GAMs) based on various fisheries datasets as input, including the NOAA Northeast Fisheries Science Center (NEFSC) bottom trawl surveys, various inshore fisheries‐independent trawl surveys (state waters), NEFSC fisheries‐dependent observer data, and laboratory‐based physiological metrics. We compared each model's GAM response curve and coupled them to historical ocean conditions in the U.S. Northeast Shelf using bias‐corrected ocean temperature output from a regional ocean model. Thermal habitat models based on shelf‐wide data (NEFSC fisheries‐dependent observer data and fisheries‐independent spring and fall surveys) explained the most variation in black sea bass presence/absence data at ~15% deviance explained. Models based on a narrower range of sampled thermal habitat from inshore survey data in the Northeast Area Monitoring and Assessment Program (NEAMAP) and the geographically isolated Long Island Sound data performed poorly. All models had similar lower thermal limits around 8.5℃, but thermal optima, when present, ranged from 16.7 to 24.8℃. The GAMs could reliably predict habitat from years excluded from model training, but due to strong seasonal temperature fluctuations in the region, could not be used to predict habitat in seasons excluded from training. We conclude that survey data source can greatly impact development and interpretation of thermal habitat models for marine fishes. We suggest that model development be based on data sources that sample the widest range of ocean temperature and physical habitat throughout multiple seasons when possible, and encourage thorough consideration of how data gaps may influence model uncertainty.

BackgroundCIMAvax-EGF is an epidermal growth factor (EGF)-depleting immunotherapy which has shown survival benefit as a switch maintenance treatment after platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC). The primary objective of this trial is to establish the safety and recommended phase II dose (RP2D) of CIMAvax-EGF in combination with nivolumab as second-line therapy for NSCLC.MethodsPatients with immune checkpoint inhibitor-naive metastatic NSCLC were enrolled using a “3+3” dose-escalation design. Toxicities were graded according to CTCAE V4.03. Thirteen patients (one unevaluable), the majority with PD-L1 0%, were enrolled into two dose levels of CIMAvax-EGF.FindingsThe combination was determined to be safe and tolerable. The recommended phase 2 dose of CIMAvax-EGF was 2.4 mg. Humoral response to CIMAvax-EGF was achieved earlier and in a greater number of patients with the combination compared to historical control. Four out of 12 evaluable patients had an objective response.

Abstract Both termites and large mammalian herbivores (LMH) are savanna ecosystem engineers that have profound impacts on ecosystem structure and function. Both of these savanna engineers modulate many common and shared dietary resources such as woody and herbaceous plant biomass, yet few studies have addressed how they impact one another. In particular, it is unclear how herbivores may influence the abundance of long‐lived termite mounds via changes in termite dietary resources such as woody and herbaceous biomass. While it has long been assumed that abundance and areal cover of termite mounds in the landscape remain relatively stable, most data are observational, and few experiments have tested how termite mound patterns may respond to biotic factors such as changes in large herbivore communities. Here, we use a broad tree density gradient and two landscape‐scale experimental manipulations—the first a multi‐guild large herbivore exclosure experiment (20 years after establishment) and the second a tree removal experiment (8 years after establishment)—to demonstrate that patterns in Odontotermes termite mound abundance and cover are unexpectedly dynamic. Termite mound abundance, but areal cover not significantly, is positively associated with experimentally controlled presence of cattle, but not wild mesoherbivores (15–1,000 kg) or megaherbivores (elephants and giraffes). Herbaceous productivity and tree density, termite dietary resources that are significantly affected by different LMH treatments, are both positive predictors of termite mound abundance. Experimental reductions of tree densities are associated with lower abundances of termite mounds. These results reveal a richly interacting web of relationships among multiple savanna ecosystem engineers and suggest that termite mound abundance and areal cover are intimately tied to herbivore‐driven resource availability.

Abstract Background Published by the World Health Organization (WHO) and United Nations High Commissioner for Refugees (UNHCR) in 2015, the mental health Gap Action Programme Humanitarian Intervention Guide (mhGAP-HIG) recommends brief versions of structured psychological interventions for people experiencing symptoms of common mental disorders (CMDs). mhGAP-HIG acknowledges a growing body of evidence suggesting these interventions can be delivered by lay workers to people affected by humanitarian crises in low- and middle-income countries (LMICs). However, there has not yet been a systematic review and synthesis of this evidence. This paper reports the results of a systematic review of qualitative, quantitative, and mixed-methods studies assessing the implementation and/or effectiveness of talk therapies for CMDs when provided by lay workers in LMICs to adults who have survived or are currently living in humanitarian situations. Methods Seven electronic databases were searched: MEDLINE, Embase, PsycINFO, PsycEXTRA, Global Health, Cochrane Library, and ClinicalTrials.gov . We also hand-searched the contents pages of three academic journals, reference lists of 30 systematic reviews, and online resource directories of two mental health networks. A preliminary list of included studies was circulated to topical experts for review, and all included studies were backward and forward searched. All titles, abstracts, and full-texts were independently double-screened. Quality appraisal and data extraction were carried out by a single reviewer and checked by a second reviewer, using standardised tools. Any disagreements were discussed and referred to a third reviewer as needed. Results We identified 23 unique studies and carried out a narrative synthesis of patient and implementation outcome data. Every evaluation of the effectiveness of lay-delivered talk therapies for adults affected by humanitarian crises in LMICs showed some treatment effect for at least one CMD, and often multiple CMDs. Implementation research generally found these interventions to be acceptable, appropriate and feasible to implement, with good fidelity to manualised therapies. Conclusion Although results are promising, particularly for individually-delivered talk therapies based on cognitive behavioural therapy techniques, there is a high degree of heterogeneity in this literature. We make several recommendations on how to improve the quality and generalisability of research on this topic, to facilitate further evidence synthesis. Trial registration PROSPERO registration number: CRD42017058287 .

There is an urgent need to discover blood-based biomarkers to predict response to immune checkpoint inhibitors (ICI). Here the authors show that effective ICI therapy correlates with increased frequency of circulating CX3CR1+CD8+ T cells in preclinical tumor models and in a cohort of patients with non-small cell lung cancer treated with anti-PD-1.

Small cell lung cancer (SCLC) is a leading cause of cancer death worldwide, with few treatment options. Rovalpituzumab tesirine (Rova‐T) is an antibody‐drug conjugate that targets delta‐like 3 on SCLC cells to deliver a cytotoxic payload directly to tumor cells. In this study, the cardiac safety profile of Rova‐T was assessed by evaluating changes in QT interval, electrocardiogram (ECG) waveform, heart rate, and proarrhythmic adverse events (AEs) after treatment with Rova‐T in patients with previously treated extensive‐stage SCLC. Patients underwent ECG monitoring for 2 weeks after each of 2 i.v. infusions of 0.3 mg/kg Rova‐T over 30 minutes, administered 6 weeks apart. Forty‐six patients received at least one dose of Rova‐T. At the geometric mean Rova‐T maximum serum concentration of 7,940 ng/mL, ECG monitoring showed no significant changes in the Fridericia‐corrected QT (QTcF) interval; the upper limit of the 2‐sided 90% confidence interval did not exceed 10 msec for any time point. There were no clinically significant changes in QRS or PR intervals, ECG waveforms, or heart rate after Rova‐T administration. All patients experienced a treatment‐emergent AE (TEAE); 78% had a grade ≥ 3 TEAE, 59% had a serious TEAE, and 41% had a cardiac‐related TEAE. The TEAEs that might signal proarrhythmia tendencies were uncommon. Confirmed partial responses were observed in 24% of patients. Based on the evaluation of ECG data collected in this study from patients treated with Rova‐T at 0.3 mg/kg i.v. administered every 6 weeks, a QTcF effect of clinical concern can be excluded.

Metabolic stress is an important cause of pathological atrial remodeling and atrial fibrillation. AMPK is a ubiquitous master metabolic regulator, yet its biological function in the atria is poorly understood in both health and disease. We investigated the impact of atrium-selective cardiac AMPK deletion on electrophysiological and structural remodeling in mice. Loss of atrial AMPK expression caused atrial changes in electrophysiological properties and atrial ectopic activity prior to the onset of spontaneous atrial fibrillation. Concomitant transcriptional downregulation of connexins and atrial ion channel subunits manifested with delayed left atrial activation and repolarization. The early molecular and electrophysiological abnormalities preceded left atrial structural remodeling and interstitial fibrosis. AMPK inactivation induced downregulation of transcription factors (Mef2c and Pitx2c) linked to connexin and ion channel transcriptional reprogramming. Thus, AMPK plays an essential homeostatic role in atria, protecting against adverse remodeling potentially by regulating key transcription factors that control the expression of atrial ion channels and gap junction proteins.

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Abstract Background Lack of sustainable access to clean drinking water continues to be an issue of paramount global importance, leading to millions of preventable deaths annually. Best practices for providing sustainable access to clean drinking water, however, remain unclear. Widespread installation of low-cost, in-home, point of use water filtration systems is a promising strategy. Methods We conducted a prospective, randomized, controlled trial whereby 16 villages were selected and randomly assigned to one of four treatment arms based on the installation location of Sawyer® PointONE™ filters (filter in both home and school; filter in home only; filter in school only; control group). Water samples and self-reported information on diarrhea were collected at multiple times throughout the study. Results Self-reported household prevalence of diarrhea decreased from 25.6 to 9.76% from installation to follow-up (at least 7 days, and up to 200 days post-filter installation). These declines were also observed in diarrhea with economic or educational consequences (diarrhea which led to medical treatment and/or missing school or work) with baseline prevalence of 9.64% declining to 1.57%. Decreases in diarrhea prevalence were observed across age groups. There was no evidence of a loss of efficacy of filters up to 200 days post-filter installation. Installation of filters in schools was not associated with decreases in diarrhea prevalence in school-aged children or family members. Unfiltered water samples both at schools and homes contained potential waterborne bacterial pathogens, dissolved heavy metals and metals associated with particulates. All dissolved metals were detected at levels below World Health Organization action guidelines. Conclusions This controlled trial provides strong evidence of the effectiveness of point-of-use, hollow fiber membrane filters at reducing diarrhea from bacterial sources up to 200 days post-installation when installed in homes. No statistically significant reduction in diarrhea was found when filters were installed in schools. Further research is needed in order to explore filter efficacy and utilization after 200 days post-installation. Trial registration ClinicalTrials.gov, NCT03972618 . Registered 3 June 2019—retrospectively registered.

Abstract Background The blacklegged tick (BLT) is a vector for the bacterium Borrelia burgdorferi (Bb), which causes Lyme disease. Range expansion of the BLT in Canada is related to an increased risk of Lyme disease in many regions. Current literature, such as the 2018 American College of Veterinary Internal Medicine consensus statement, suggests that there may be differences in the approaches of veterinarians who encounter dogs exposed to Bb and dogs with Lyme disease. Objectives To determine current knowledge, attitudes, and practices of Canadian veterinarians regarding Lyme disease in dogs. Animals None. Methods An online survey was distributed to Canadian veterinarians through veterinary associations and industries. Survey responses were analyzed using descriptive statistics, spatial analysis, Fisher's exact tests, and univariable logistic regression. Results At the completion of the survey, 192 responses were received from veterinarians practicing in all 10 Canadian provinces. Answers to short scenario and treatment questions reflected a wide variety of clinical approaches taken by veterinarians. Regional differences were seen in reported tick distribution and clinical approaches. Conclusions and Clinical Importance Regional differences and generalized differences were found in approaches used by responding Canadian veterinarians with regard to managing Bb exposure and Lyme disease in dogs. We identified areas for future research and knowledge mobilization for veterinarians.

Abstract Background A recent editorial urged those working in global mental health to “change the conversation” on coronavirus disease (Covid-19) by putting more focus on the needs of people with severe mental health conditions. UPSIDES (Using Peer Support In Developing Empowering mental health Services) is a six-country consortium carrying out implementation research on peer support for people with severe mental health conditions in high- (Germany, Israel), lower middle- (India) and low-income (Tanzania, Uganda) settings. This commentary briefly outlines some of the key challenges faced by UPSIDES sites in low- and middle-income countries as a result of Covid-19, sharing early lessons that may also apply to other services seeking to address the needs of people with severe mental health conditions in similar contexts. Challenges and lessons learned The key take-away from experiences in India, Tanzania and Uganda is that inequalities in terms of access to mobile technologies, as well as to secure employment and benefits, put peer support workers in particularly vulnerable situations precisely when they and their peers are also at their most isolated. Establishing more resilient peer support services requires attention to the already precarious situation of people with severe mental health conditions in low-resource settings, even before a crisis like Covid-19 occurs. While it is essential to maintain contact with peer support workers and peers to whatever extent is possible remotely, alternatives to face-to-face delivery of psychosocial interventions are not always straightforward to implement and can make it more difficult to observe individuals’ reactions, talk about emotional issues and offer appropriate support. Conclusions In environments where mental health care was already heavily medicalized and mostly limited to medications issued by psychiatric institutions, Covid-19 threatens burgeoning efforts to pursue a more holistic and person-centered model of care for people with severe mental health conditions. As countries emerge from lockdown, those working in global mental health will need to redouble their efforts not only to make up for lost time and help individuals cope with the added stressors of Covid-19 in their communities, but also to regain lost ground in mental health care reform and in broader conversations about mental health in low-resource settings.

Abstract Due to severe shortages of specialist mental health personnel in low- and middle-income countries (LMICs), psychological therapies are increasingly being delivered by non-specialist health workers (NSHWs). Previous reviews have investigated the effectiveness of NSHW-delivered psychological therapies, including cognitive behavioural therapy (CBT), in LMIC settings. This systematic review aims to synthesise findings on the implementation outcomes of NSHW-delivered CBT interventions addressing common mental disorders and substance-use disorders in LMICs. Four databases were searched, yielding 3211 records, 18 of which met all inclusion criteria. We extracted and synthesised qualitative and quantitative data across eight implementation outcomes: acceptability, adoption, appropriateness, feasibility, fidelity, implementation cost, penetration and sustainability. Findings suggest that delivery of CBT-based interventions by NSHWs can be acceptable, appropriate and feasible in LMIC settings. However, more research is needed to better evaluate these and other under-reported implementation outcomes.