Introduction Evidence appraisal is a critical component of global health normative guidelines development by the World Health Organization (WHO). Since 2007, WHO’s handbook for guidelines development ...has outlined a structured and transparent process to ensure guidelines are informed by the latest evidence on intervention effectiveness, feasibility of implementation and considerations on other important elements such as values and preferences of users and providers, resource use, equity and human rights.1 Typically, guidelines development involves a systematic review of evidence, appraisal of the certainty of evidence in accordance with the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) framework2 and formulation of recommendations by an independent guidelines development group of experts. WHO first recommended HIVST in 2016.5 As of July 2022, 98 countries have national policies supportive of HIVST and 52 countries are routinely implementing HIVST to help achieve national and global goals.6 For HCV, despite recent advances in effective and affordable treatment, globally only 26% of the estimated 58 million people with chronic HCV infection were diagnosed as of 2021.7 New interventions and additional approaches, such as hepatitis C virus self-testing (HCVST), may help address this diagnosis gap so that more individuals can benefit from life-saving treatment. The assessments also highlighted the need for further research on potential service delivery models for HCVST, given no real-world HCVST implementation had occurred at the time of the data collection.13 Modelling on cost-effectiveness of HCVST A cost-effectiveness modelling study was conducted to identify drivers of cost of testing or HCV cure with introduction of HCVST across four countries.14 The cost-effectiveness model suggested that HCVST is likely to be costlier than standard testing but will reach more people for testing.14 Utility of using indirect evidence The systematic review identified no direct evidence on HCVST effectiveness. ...for the HCVST guidelines, no HIVST trial was identified among people who inject drugs—a key priority population for HCV. ...this population was purposefully prioritised for usability studies.
In 2017, the World Health Organization (WHO) published guidelines for the management of advanced human immunodeficiency virus (HIV) disease within a public health approach. Recent data suggest that ...more than a third of people starting antiretroviral therapy (ART) do so with advanced HIV disease, and an increasing number of patients re-present to care at an advanced stage of HIV disease following a period of disengagement from care. These guidelines recommend a standardized package of care for adults, adolescents, and children, based on the leading causes of morbidity and mortality: tuberculosis, severe bacterial infections, cryptococcal meningitis, toxoplasmosis, and Pneumocystis jirovecii pneumonia. A package of targeted interventions to reduce mortality and morbidity was recommended, based on results of 2 recent randomized trials that both showed a mortality reduction associated with delivery of a simplified intervention package. Taking these results and existing recommendations into consideration, WHO recommends that a package of care be offered to those presenting with advanced HIV disease; depending on age and CD4 cell count, the package may include opportunistic infection screening and prophylaxis, including fluconazole preemptive therapy for those who are cryptococcal antigen positive and without evidence of meningitis. Rapid ART initiation and intensified adherence interventions should also be proposed to everyone presenting with advanced HIV disease.
Background. During a World Health Organization–convened Guideline Development Group meeting, recommendations for postexposure prophylaxis (PEP) for human immunodeficiency virus were made and research ...gaps identified. Methods. We used the PEP clinical management pathway and the Grading of Evidence, Assessment, Development and Evaluation (GRADE) system as a framework to formulate future research questions, describe the most feasible study design, and identify potential biases. Results. Three key study design formats were identified to address 12 research questions: (1) survey- and interview-driven research to identify barriers to access to PEP and related clinical care; (2) establishment of a global PEP registry to generate data to inform the choice of an optimal PEP drug regimen, record drug toxicities arising from specific PEP regimens, and track follow-up and linkage to care (including transition from PEP to preexposure prophylaxis); and (3) randomized controlled trials to determine the optimal adherence promotion strategies necessary for successful outcomes following PEP. Conclusions. Positioning key clinical and programmatic research questions within the GRADE framework facilitates the formulation of an evidence-based research agenda and future revisions of guidelines.
The National Aeronautics and Space Administration (NASA)’s Operation IceBridge (OIB) was a 13-year (2009–2021) airborne mission to survey land and sea ice across the Arctic, Antarctic, and Alaska. ...Here, we review OIB’s goals, instruments, campaigns, key scientific results, and implications for future investigations of the cryosphere. OIB’s primary goal was to use airborne laser altimetry to bridge the gap in fine-resolution elevation measurements of ice from space between the conclusion of NASA’s Ice, Cloud, and land Elevation Satellite (ICESat; 2003–2009) and its follow-on, ICESat-2 (launched 2018). Additional scientific requirements were intended to contextualize observed elevation changes using a multisensor suite of radar sounders, gravimeters, magnetometers, and cameras. Using 15 different aircraft, OIB conducted 968 science flights, of which 42% were repeat surveys of land ice, 42% were surveys of previously unmapped terrain across the Greenland and Antarctic ice sheets, Arctic ice caps, and Alaskan glaciers, and 16% were surveys of sea ice. The combination of an expansive instrument suite and breadth of surveys enabled numerous fundamental advances in our understanding of the Earth’s cryosphere. For land ice, OIB dramatically improved knowledge of interannual outlet-glacier variability, ice-sheet, and outlet-glacier thicknesses, snowfall rates on ice sheets, fjord and sub-ice-shelf bathymetry, and ice-sheet hydrology. Unanticipated discoveries included a reliable method for constraining the thickness within difficult-to-sound incised troughs beneath ice sheets, the extent of the firn aquifer within the Greenland Ice Sheet, the vulnerability of many Greenland and Antarctic outlet glaciers to ocean-driven melting at their grounding zones, and the dominance of surface-melt-driven mass loss of Alaskan glaciers. For sea ice, OIB significantly advanced our understanding of spatiotemporal variability in sea ice freeboard and its snow cover, especially through combined analysis of fine-resolution altimetry, visible imagery, and snow radar measurements of the overlying snow thickness. Such analyses led to the unanticipated discovery of an interdecadal decrease in snow thickness on Arctic sea ice and numerous opportunities to validate sea ice freeboards from satellite radar altimetry. While many of its data sets have yet to be fully explored, OIB’s scientific legacy has already demonstrated the value of sustained investment in reliable airborne platforms, airborne instrument development, interagency and international collaboration, and open and rapid data access to advance our understanding of Earth’s remote polar regions and their role in the Earth system.
Abstract
Background
Clozapine is an effective antipsychotic for treatment-resistant schizophrenia for which serum levels could guide therapy decisions. It is underutilized because it requires venous ...draws and several-day determination time with high performance liquid chromatography-tandem mass spectrometry (LC/MS-MS). This project evaluates if clozapine measured with a novel immunoassay technology, which could be developed into a fingerstick test, correlate with LC/MS-MS. This project also assesses the impact of demographic and clinical variables on assay results.
Methods
117 serum samples (N=48 with schizophrenia on clozapine, N=24 with schizophrenia not on clozapine and N=45 healthy controls) were included. One aliquot was sent to a national reference laboratory (NRL) for determination by LC/MS-MS and another sent to Saladax for immunoassay (MyCare® Psychiatry Clozapine Assay Kit). The agreement was compared using Concordance Correlation Coefficient (CCC). Participants’ age, sex, race-ethnicity, smoking status, ascorbic acid, co-medications and complete metabolic panel were collected. Linear regression and mixed model were performed for both technologies correspondingly to examine the impact of these variables.
Results
Clozapine levels by the NRL had 19 false positive readings (mean 48.8 ± 14.3, range 21–138 ng/ml) in schizophrenia participants not on clozapine (N=3) and healthy controls (N=16). The immunoassay had no false positive results. A mixed effects model (with a time average of the NRL and 3 immunoassay runs), yielded a strong Pearson correlation (r=0.843, p <0.0001). The mean clozapine level was 414.98 ng/ml on the LC/MS-MS and 472 ng/ml on the immunoassay. Although immunoassay was significantly higher than the LC/MS-MS measurement (p=0.013), the agreement level was high (CCC=0.76; 95% CI 0.64, 0.84). No association was found between age, sex, smoking status, albumin, globulin, and ascorbic acid on clozapine levels; however, African-Americans (AA) had clozapine levels 113.4 ng/ml higher (standard error (SE): 55.18, p=0.045) than non-AA by LC/MS-MS and 190.8 ng/ml (SE: 80.76, p=0.022) higher by immunoassay. Additionally, total protein was related to clozapine levels (LC/MS-MS p=0.046, immunoassay p=0.046). For each unit increase in total protein an increase of 145.6 units (SE: 70.81) was predicted for LC/MS-MS and a 225.5-unit (SE: 104.60) increase for the immunoassay.
Discussion
Immunoassay results were in good agreement with LC/MS-MS results in clozapine-containing samples, indicating good assay performance. The lack of false positives in the immunoassay results may indicate higher specificity than LC/MS-MS methods. Total protein values may lead to changes in clozapine values. More work is needed to account for total protein values when decision-making with clozapine results.
This was funded in part by NIMH R56 (MH105571-02) and NIMH R01 (MH102215). Saladax provided funding for the immunoassay (MyCare® Psychiatry Clozapine Assay Kit*) results.*CE/RUO in US
End-to-end (E2E) spoken language understanding (SLU) systems can infer the semantics of a spoken utterance directly from an audio signal. However, training an E2E system remains a challenge, largely ...due to the scarcity of paired audio-semantics data. In this paper, we consider an E2E system as a multi-modal model, with audio and text functioning as its two modalities, and use a cross-modal latent space (CMLS) architecture, where a shared latent space is learned between the 'acoustic' and 'text' embeddings. We propose using different multi-modal losses to explicitly align the acoustic embedding to the text embeddings (obtained via a semantically powerful pre-trained BERT model) in the latent space. We train the CMLS model on two publicly available E2E datasets and one internal dataset, across different cross-modal losses. Our proposed triplet loss function achieves the best performance. It achieves a relative improvement of 22.1% over an E2E model without a cross-modal space and a relative improvement of 2.8% over a previously published CMLS model using L 2 loss on our internal dataset.
Tiny Signal-to-Interpretation (TinyS2I) has been recently introduced as an ultra low-footprint end-to-end spoken language understanding (SLU) model. This architecture is capable of running in ultra ...resource constrained environments like voice assistant devices, while at the same time reducing latency. In this work, we propose an extension to TinyS2I and train a multilingual system supporting several languages. Multilingual TinyS2I models show little to no degradation compared to their monolingual counterparts. Increasing the network size in width and depth improves the classification accuracy for mono- and multilingual setups, with the multilingual one improving beyond the monolingual accuracy. This enables users to interact with the device in the language of their choice and dynamically switch between languages without an explicit language setting or accuracy degradation.
AbstractAs steel structures become larger, taller, and longer, the demand for high-strength steel increases. High-strength steels exhibit different mechanical characteristics and hysteretic behavior ...for dynamic deformation than for quasi-static deformation. This is attributable to the strain rate and temperature dependence of steel materials when nonuniformly deformed in the plastic region. Therefore, to analyze and design structures using high-strength steels under dynamic cyclic loading, such as earthquake loading, it is necessary to consider the special dynamic hysteresis model of high-strength steels. In particular, when using finite-element (FE) analysis programs one should use the proper material characteristics for those steels. In this paper, dynamic hysteresis models for standard high-strength steels, with tensile strengths of 600 and 800 MPa, are formulated based on results of tensile tests and low-cycle fatigue tests over a range of strain rates from 10−4−10 s−1. A three-dimensional elastic-plastic finite-element analysis program using a newly formulated dynamic hysteresis model is developed by the writers. Accuracy and validity of the developed finite-element analysis program is verified by correlation of the analytical and experimental results.
The hepatocyte growth factor (HGF)/c-Met pathway is often dysregulated in non–small-cell lung cancer (NSCLC). HGF activation of c-Met induces cyclooxygenase-2 (COX-2), resulting in downstream ...stimulation by prostaglandin E2 of additional pathways. Targeting both c-Met and COX-2 might lead to enhanced antitumor effects by blocking signaling upstream and downstream of c-Met.
Effects of crizotinib or celecoxib alone or in combination were tested in NSCLC cells in vitro and in mice transgenic for airway expression of human HGF.
Proliferation and invasion of NSCLC cells treated with a combination of crizotinib and celecoxib were significantly lower compared with single treatments. Transgenic mice showed enhanced COX-2 expression localized to preneoplastic areas following exposure to the tobacco carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, which was not present without carcinogen exposure. This shows that COX-2 activity is present during lung tumor development in a high HGF environment. After 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone treatment, a significant decrease in the number of lung tumors per animal was observed after 13-week treatments of crizotinib, celecoxib, or the combination compared with placebo (p < 0.001). With combination treatment, the number of tumors was also significantly lower than single agent treatment (p < 0.001). In the resulting lung tumors, P-c-Met, COX-2, prostaglandin E2, and P-MAPK were significantly downmodulated by combination treatment compared with single treatment. Expression of the epithelial-mesenchymal transition markers E-cadherin and snail was also modulated by combination treatment.
In the presence of high HGF, dual inhibition of c-Met and COX-2 may enhance antitumor effects. This combination may have clinical potential in NSCLCs with high HGF/c-Met expression or epithelial-mesenchymal transition phenotype.
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