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Introduction Determining aetiology of severe illness can be difficult, especially in settings with limited diagnostic resources, yet critical for providing life-saving care. Our objective was to describe the accuracy of antemortem clinical diagnoses in young children in high-mortality settings, compared with results of specific postmortem diagnoses obtained from Child Health and Mortality Prevention Surveillance (CHAMPS).Methods We analysed data collected during 2016–2022 from seven sites in Africa and South Asia. We compared antemortem clinical diagnoses from clinical records to a reference standard of postmortem diagnoses determined by expert panels at each site who reviewed the results of histopathological and microbiological testing of tissue, blood, and cerebrospinal fluid. We calculated test characteristics and 95% CIs of antemortem clinical diagnostic accuracy for the 10 most common causes of death. We classified diagnostic discrepancies as major and minor, per Goldman criteria later modified by Battle.Results CHAMPS enrolled 1454 deceased young children aged 1–59 months during the study period; 881 had available clinical records and were analysed. The median age at death was 11 months (IQR 4–21 months) and 47.3% (n=417) were female. We identified a clinicopathological discrepancy in 39.5% (n=348) of deaths; 82.3% of diagnostic errors were major. The sensitivity of clinician antemortem diagnosis ranged from 26% (95% CI 14.6% to 40.3%) for non-infectious respiratory diseases (eg, aspiration pneumonia, interstitial lung disease, etc) to 82.2% (95% CI 72.7% to 89.5%) for diarrhoeal diseases. Antemortem clinical diagnostic specificity ranged from 75.2% (95% CI 72.1% to 78.2%) for diarrhoeal diseases to 99.0% (95% CI 98.1% to 99.6%) for HIV.Conclusions Antemortem clinical diagnostic errors were common for young children who died in areas with high childhood mortality rates. To further reduce childhood mortality in resource-limited settings, there is an urgent need to improve antemortem diagnostic capability through advances in the availability of diagnostic testing and clinical skills.

Abstract Tislelizumab, an anti‐programmed cell death protein 1 monoclonal antibody, has demonstrated improved survival benefits over standard of care for multiple cancer indications. We present the clinical rationale and data supporting tislelizumab dose recommendation in patients with advanced tumors. The phase I, first‐in‐human, dose‐finding BGB‐A317‐001 study (data cutoff [DCO]: August 2017) examined the following tislelizumab dosing regimens: 0.5–10 mg/kg every 2 weeks (q2w), 2–5 mg/kg q2w or q3w, and 200 mg q3w. Similar objective response rates (ORRs) were reported in the 2 and 5 mg/kg q2w or q3w cohorts. Safety outcomes (grade ≥3 adverse events [AEs], AEs leading to dose modification/discontinuation, immune‐mediated AEs, and infusion‐related reactions) were generally comparable across the dosing range examined. These results, alongside the convenience of a fixed q3w dose, formed the basis of choosing 200 mg q3w as the recommended dosing regimen for further clinical use. Pooled exposure–response (E–R) analyses by logistic regression using data from study BGB‐A317‐001 (DCO: August 2020) and three additional phase I/II studies (DCOs: 2018–2020) showed no statistically significant correlation between tislelizumab pharmacokinetic exposure and ORR across multiple solid tumor types or classical Hodgkin's lymphoma, nor was exposure associated with any of the safety end points evaluated over the dose range tested. Hence, tislelizumab showed a relatively flat E–R relationship. Overall, the totality of data, including efficacy, safety, and E–R analyses, together with the relative convenience of a fixed q3w dose, provided clinical rationale for the recommended dosing regimen of tislelizumab 200 mg q3w for multiple cancer indications.

Abstract Objectives Review of the current and relevant literature to develop a list of evidence‐based recommendations that can be implemented in head and neck surgical practices. To provide rationale for the multiple aspects of comprehensive care for head and neck surgical patients. To improve postsurgical outcomes for head and neck surgical patients. Methods Extensive review of the medical literature was performed and relevant studies in both the head and neck surgery and other surgical specialties were considered for inclusion. Results A total of 18 aspects of perioperative care were included in this review. The literature search included 276 publications considered to be the most relevant and up to date evidence. Each topic is concluded with recommendation grade and quality of evidence for the recommendation. Conclusion Since it's conception, enhanced recovery after surgery (ERAS) protocols have continued to push for comprehensive and evidence based postsurgical care to improve patient outcomes. Head and neck oncology is one of the newest fields to develop a protocol. Due to the complexity of this patient population and their postsurgical needs, a multidisciplinary approach is needed to facilitate recovery while minimizing complications. Current and future advances in head and neck cancer research will serve to strengthen and add new principles to a comprehensive ERAS protocol. Level of Evidence 2a.

Summary: Background: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. Methods: We conducted a retrospective, descriptive study examining clinical data for children aged 1–59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016–June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. Findings: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted

Abstract Tislelizumab, a humanized immunoglobulin G4 monoclonal antibody, is a programmed cell death protein 1 (PD‐1) inhibitor designed to minimize Fc gamma receptor binding on macrophages to limit antibody‐dependent phagocytosis, a potential mechanism of resistance to anti–PD‐1 therapy. The pharmacokinetic (PK) profile of tislelizumab was analyzed with population PK modeling using 14,473 observed serum concentration data points from 2596 cancer patients who received intravenous (i.v.) tislelizumab at 0.5–10 mg/kg every 2 weeks or every 3 weeks (q3w), or a 200 mg i.v. flat dose q3w in 12 clinical studies. Tislelizumab exhibited linear PK across the dose range tested. Baseline body weight, albumin, tumor size, tumor type, and presence of antidrug antibodies were identified as significant covariates on central clearance, whereas baseline body weight, sex, and age significantly affected central volume of distribution. Sensitivity analysis showed that these covariates did not have clinically relevant effects on tislelizumab PK. Other covariates evaluated, including race (Asian vs. White), lactate dehydrogenase, estimated glomerular filtration rate, renal function categories, hepatic function measures and categories, Eastern Cooperative Oncology Group performance status, therapy (monotherapy vs. combination therapy), and line of therapy did not show a statistically significant impact on tislelizumab PK. These results support the use of tislelizumab 200 mg i.v. q3w without dose adjustment in a variety of patient subpopulations.

Abstract Whole‐exome sequencing of two patients with idiopathic complex neurodevelopmental disorder (NDD) identified biallelic variants of unknown significance within FIBCD1, encoding an endocytic acetyl group‐binding transmembrane receptor with no known function in the central nervous system. We found that FIBCD1 preferentially binds and endocytoses glycosaminoglycan (GAG) chondroitin sulphate‐4S (CS‐4S) and regulates GAG content of the brain extracellular matrix (ECM). In silico molecular simulation studies and GAG binding analyses of patient variants determined that such variants are loss‐of‐function by disrupting FIBCD1‐CS‐4S association. Gene knockdown in flies resulted in morphological disruption of the neuromuscular junction and motor‐related behavioural deficits. In humans and mice, FIBCD1 is expressed in discrete brain regions, including the hippocampus. Fibcd1 KO mice exhibited normal hippocampal neuronal morphology but impaired hippocampal‐dependent learning. Further, hippocampal synaptic remodelling in acute slices from Fibcd1 KO mice was deficient but restored upon enzymatically modulating the ECM. Together, we identified FIBCD1 as an endocytic receptor for GAGs in the brain ECM and a novel gene associated with an NDD, revealing a critical role in nervous system structure, function and plasticity.

Opportunities exist to leverage mobile phones to replace or supplement in-person supervision of lay counselors. However, contextual variables, such as network connectivity and provider preferences, must be considered. Using an iterative and mixed methods approach, we co-developed implementation guidelines to support the implementation of mobile phone supervision with lay counselors and supervisors delivering a culturally adapted trauma-focused cognitive behavioral therapy in Western Kenya. Guidelines were shared and discussed with lay counselors in educational outreach visits led by supervisors. We evaluated the impact of guidelines and outreach on the acceptability, feasibility, and usability of mobile phone supervision. Guidelines were associated with significant improvements in acceptability and usability of mobile phone supervision. There was no evidence of a significant difference in feasibility. Qualitative interviews with lay counselors and supervisors contextualized how guidelines impacted acceptability and feasibility – by setting expectations for mobile phone supervision, emphasizing importance, increasing comfort, and sharing strategies to improve mobile phone supervision. Introducing and discussing co-developed implementation guidelines significantly improved the acceptability and usability of mobile phone supervision. This approach may provide a flexible and scalable model to address challenges with implementing evidence-based practices and implementation strategies in lower-resourced areas.

Early neuropathology mechanisms in neurodevelopmental disorders are partially understood because routine anatomical magnetic resonance imaging (MRI) cannot detect subtle brain microstructural changes in vivo during postnatal development. Therefore, we investigated the potential value of magnetic resonance elastography (MRE) and diffusion tensor imaging (DTI) in a rat model of neurodevelopmental disorder induced by maternal immune activation. We studied 12 offspring of mothers injected with polyriboinosinic-polyribocytidylic acid (poly (I:C), 4 mg/kg) on gestational day 15, plus 8 controls. T2-weighted anatomical MR images, MRE (800 Hz) and DTI (30 gradient directions, b = 765.8 s/mm2, 5 images, b = 0 s/mm2) were collected when the rats were 4 and 10 weeks old, and results were compared with histological analysis performed at week 10. Ventricles were ~1.4 fold larger from week 4 in poly (I:C) rats than in controls. No other morphological abnormalities were detected in poly(I:C) rats. At week 4, larger ventricles were correlated with lower external capsule fractional anisotropy and internal capsule radial diffusion (Pearson, r = -0.53, 95% confidence intervals (CI) [-0.79 to -0.12], and r = -0.45, 95% CI [-0.74 to -0.01], respectively). The mean and radial diffusion of the corpus callosum, the mean and axial diffusion of the internal capsule and the radial diffusion properties in the external capsule increased with age for poly (I:C) rats only (Sidak's comparison, P

Zanubrutinib is a potent, second‐generation Bruton’s tyrosine kinase inhibitor that is currently being investigated in patients with B‐cell malignancies and recently received accelerated approval in the United States for treatment of relapsed/refractory mantle cell lymphoma. The objective of this analysis was to develop a population pharmacokinetic (PK) model to characterize the PKs of zanubrutinib and identify the potential impact of intrinsic and extrinsic covariates on zanubrutinib PK. Data across nine clinical studies of patients with B‐cell malignancies and data of healthy volunteers (HVs) were included in this analysis, at total daily doses ranging from 20 to 320 mg. In total, 4,925 zanubrutinib plasma samples from 632 subjects were analyzed using nonlinear mixed‐effects modeling. Zanubrutinib PKs were adequately described by a two‐compartment model with sequential zero‐order then first‐order absorption, and first‐order elimination. A time‐dependent residual error model was implemented in order to better capture the observed maximum concentration variability in subjects. Baseline alanine aminotransferase and health status (HVs or patients with B‐cell malignancies) were identified as statistically significant covariates on the PKs of zanubrutinib. These factors are unlikely to be clinically meaningful based on a sensitivity analysis. No statistically significant differences in the PKs of zanubrutinib were observed based on age, sex, race (Asian, white, and other), body weight, mild or moderate renal impairment (creatinine clearance ≥ 30 mL/minute as estimated by Cockcroft‐Gault), baseline aspartate aminotransferase, bilirubin, tumor type, or use of acid‐reducing agents (including proton pump inhibitors). These results support that no dose adjustment is considered necessary based on the aforementioned factors.

Synthetic data, artificially generated by computer programs, has become more widely used in the financial domain to mitigate privacy concerns. Variational Autoencoder (VAE) is one of the most popular deep-learning models for generating synthetic data. However, VAE is often considered a “black box” due to its opaqueness. Although some studies have been conducted to provide explanatory insights into VAE, research focusing on explaining how the input data could influence VAE to create synthetic data, especially for tabular data, is still lacking. However, in the financial industry, most data are stored in a tabular format. This paper proposes a sensitivity-based method to assess the impact of inputted tabular data on how VAE synthesizes data. This sensitivity-based method can provide both global and local interpretations efficiently and intuitively. To test this method, a simulated dataset and three Kaggle banking tabular datasets were employed. The results confirmed the applicability of this proposed method.

Novel furoxan/coumarin hybrids were synthesized, and pharmacologic studies showed that the compounds displayed potent antiproliferation activities via downregulating both the phosphatidylinositide 3-kinase (PI3K) pathway and the mitogen-activated protein kinase (MAPK) pathway. To investigate the preclinical pharmacokinetic (PK) properties of three candidate compounds (CY-14S-4A83, CY-16S-4A43, and CY-16S-4A93), liquid chromatography, in tandem with the mass spectrometry LC-MS/MS method, was developed and validated for the simultaneous determination of these compounds. The absorption, distribution, metabolism, and excretion (ADME) properties were investigated in in vitro studies and in rats. Meanwhile, physiologically based pharmacokinetic (PBPK) models were constructed using only in vitro data to obtain detailed PK information. Good linearity was observed over the concentration range of 0.01–1.0 μg/mL. The free drug fraction (fu) values of the compounds were less than 3%, and the clearance (CL) values were 414.5 ± 145.7 mL/h/kg, 2624.6 ± 648.4 mL/h/kg, and 500.6 ± 195.2 mL/h/kg, respectively. The predicted peak plasma concentration (Cmax) and the area under the concentration-time curve (AUC) were overestimated for the CY-16S-4A43 PBPK model compared with the experimental ones (fold error > 2), suggesting that tissue accumulation and additional elimination pathways may exist. In conclusion, the LC-MS/MS method was successively applied in the preclinical PK studies, and the detailed information from PBPK modeling may improve decision-making in subsequent new drug development.

The Western Regional Storage Trust (WEST), is a distributed shared print journal repository program serving research libraries, college and university libraries, and library consortia in the Western Region of the United States. WEST solicits serial bibliographic records and related holdings biennially, which are evaluated and identified as candidates for shared print archiving using a complex collection analysis process. California Digital Library’s Discovery & Delivery WEST operations team (WEST-Ops) supports the functionality behind this collection analysis process used by WEST program staff (WEST-Staff) and members. For WEST, proposals for shared print archiving have been historically predicated on what is known as an Ulrich’s journal family, which pulls together related serial titles, for example, succeeding and preceding serial titles, their supplements, and foreign language parallel titles. Ulrich’s, while it has been invaluable, proves problematic in several ways, resulting in the approximate omission of half of the journal titles submitted for collection analysis. Part of WEST’s effectiveness in archiving hinges upon its ability to analyze local serials data across its membership as holistically as possible. The process that enables this analysis, and subsequent archiving proposals, is dependent on Ulrich’s journal family, for which ISSN has been traditionally used to match and cluster all related titles within a particular family. As such, the process is limited in that many journals have never been assigned ISSNs, especially older publications, or member bibliographic records may lack an ISSN(s), though the ISSN may exist in an OCLC primary record. Building a mechanism for matching on ISSNs that goes beyond the base set of primary, former, and succeeding titles, expands the number of eligible ISSNs that facilitate Ulrich’s journal family matching. Furthermore, when no matches in Ulrich’s can be made based on ISSN, other types of control numbers within a bibliographic record may be used to match with records that have been previously matched with an Ulrich’s journal family via ISSN, resulting in a significant increase in the number of titles eligible for collection analysis. This paper will discuss problems in Ulrich’s journal family matching, improved functional methodologies developed to address those problems, and potential strategies to improve in serial title clustering in the future.

Kirigami, the art of introducing cuts in thin sheets to enable articulation and deployment, has become an inspiration for a novel class of mechanical metamaterials with unusual properties. Here we complement the use of periodic tiling patterns for kirigami designs by showing that quasicrystals can also serve as the basis for designing deployable kirigami structures, and analyze the geometrical, topological, and mechanical properties of these aperiodic kirigami structures.

[This corrects the article DOI: 10.1371/journal.pone.0194809.].

Abstract. Introduction:. Prescription opioid use and misuse has accelerated rapidly in the United States over the past 2 decades. Orthopaedic surgeons are the third highest prescribers of opioids, and thus are contributing to this problem at a significant rate. Despite a surge in the number of publications on this issue, there has been little emphasis in the literature on disentangling the various factors contributing to opioid use and misuse among fracture patients. The goal of this study was to describe areas of focus and identify knowledge gaps present in the current literature on this important issue. Methods:. We employed a scoping review technique due to its ability to successfully address a broad research question. In order to better understand the type of information deemed relevant by opioid researchers, we further analyzed our search results by sorting the publications into the following categories: consumer-focused, provider-focused, focus on substitutes, industry-focused, and focus on regulations (at the institution, profession, and government level). Results:. The search strategies generated 8760 citations; of these, 1166 publications satisfied our inclusion criteria. Around 607 of these final abstracts were marked as “extremely relevant” (52%) and the other 559 (48%) were marked “relevant.” About 36.4% of the total included articles applied to the providers and 19.6% provided information on the consumer. A total of 25.2% of the included papers concerned substitutes for opioids, 15.7% focused on regulatory power in the opioid industry, and 14% considered opioids as an industry, including power of both current stakeholders and potential new entrants. Discussion:. The present study provides a thorough summary of existing literature on opioid use and misuse relevant to musculoskeletal trauma patients. Furthermore, the categorical division of the literature provides a unique perspective into the drivers contributing to the opioid epidemic, and may assist in development of effective interventions to reduce excessive opioid use following traumatic injuries. Our review allowed us to identify important aspects of the opioid industry and various drivers of abuse that were absent from the literature including involvement of the pharmaceutical industry on the opioid epidemic, the involvement of insurance companies in opioid distribution, and the use of nonopioid alternative medications such as nonsteroidal anti-inflammatory drugs (NSAIDs).

BACKGROUND:The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors. METHODS:PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis®) inhibited Hh signaling. RESULTS:Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model. CONCLUSION:Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent.

Melanoma is generally refractory to current chemotherapy, thus new treatment strategies are needed. In this study, we synthesized a series of spirooxindole derivatives (SOID-1 to SOID-12) and evaluated their antitumor effects on melanoma. Among the 12 spirooxindole derivatives, SOID-8 showed the strongest antitumor activity by viability screening. SOID-8 inhibited viability of A2058, A375, SK-MEL-5 and SK-MEL-28 human melanoma cells in a dose- and time-dependent manner. SOID-8 also induced apoptosis of these tumor cells, which was confirmed by positive Annexin V staining and an increase of poly(ADP-ribose) polymerase cleavage. The antiapoptotic protein Mcl-1, a member of the Bcl-2 family, was downregulated and correlated with SOID-8 induced apoptosis. In addition, SOID-8 reduced tyrosine phosphorylation of Signal Tansducer and Activator of Transcription 3 (STAT3) in both dose- and time-dependent manners. This inhibition was associated with decreased levels of phosphorylation of Janus-activated kinase-2 (JAK2), an upstream kinase that mediates STAT3 phosphorylation at Tyr705. Accordingly, SOID-8 inhibited IL-6-induced activation of STAT3 and JAK2 in melanoma cells. Finally, SOID-8 suppressed melanoma tumor growth in a mouse xenograft model, accompanied with a decrease of phosphorylation of JAK2 and STAT3. Our results indicate that the antitumor activity of SOID-8 is at least partially due to inhibition of JAK2/STAT3 signaling in melanoma cells. These findings suggest that the spirooxindole derivative SOID-8 is a promising lead compound for further development of new preventive and therapeutic agents for melanoma.