Estimating Asymptomatic and Symptomatic Transmission of the COVID-19 First Few Cases in Selenge Province, Mongolia.

BACKGROUND: Following the first locally transmitted case in Sukhbaatar soum, Selenge Province, we aimed to investigate the ultimate scale of the epidemic in the scenario of uninterrupted transmission. METHODS: This was a prospective case study following the locally modified WHO FFX cases generic protocol. A rapid response team collected data from November 14 to 29, 2020. We created a stochastic process to draw many transmission chains from this greater distribution to better understand and make inferences regarding the outbreak under investigation. RESULTS: The majority of the cases involved household transmissions (35, 52.2%), work transmissions (20, 29.9%), index (5, 7.5%), same apartment transmissions (2, 3.0%), school transmissions (2, 3.0%), and random contacts between individuals transmissions (1, 1.5%). The posterior means of the basic reproduction number of both the asymptomatic cases R 0 Asy $$ {R}_0^{Asy} $$ and the presymptomatic cases R 0 Pre $$ {R}_0^{Pre} $$ (1.35 [95% CrI 0.88-1.86] and 1.29 [95% CrI 0.67-2.10], respectively) were lower than that of the symptomatic cases (2.00 [95% Crl 1.38-2.76]). CONCLUSION: Our study highlights the heterogeneity of COVID-19 transmission across different symptom statuses and underscores the importance of early identification and isolation of symptomatic cases in disease control. Our approach, which combines detailed contact tracing data with advanced statistical methods, can be applied to other infectious diseases, facilitating a more nuanced understanding of disease transmission dynamics.

Model of Acute Liver Failure in an Isolated Perfused Porcine Liver-Challenges and Lessons Learned.

Acute liver failure (ALF) is a rare but devastating disease associated with substantial morbidity and a mortality rate of almost 45%. Medical treatments, apart from supportive care, are limited and liver transplantation may be the only rescue option. Large animal models, which most closely represent human disease, can be logistically and technically cumbersome, expensive and pose ethical challenges. The development of isolated organ perfusion technologies, originally intended for preservation before transplantation, offers a new platform for experimental models of liver disease, such as ALF. In this study, female domestic swine underwent hepatectomy, followed by perfusion of the isolated liver on a normothermic machine perfusion device. Five control livers were perfused for 24 h at 37 °C, while receiving supplemental oxygen and nutrition. Six livers received toxic doses of acetaminophen given over 12 h, titrated to methemoglobin levels. Perfusate was sampled every 4 h for measurement of biochemical markers of injury (e.g., aspartate aminotransferase [AST], alanine aminotransferase [ALT]). Liver biopsies were taken at the beginning, middle, and end of perfusion for histological assessment. Acetaminophen-treated livers received a median dose of 8.93 g (8.21-9.75 g) of acetaminophen, achieving a peak acetaminophen level of 3780 µmol/L (3189-3913 µmol/L). Peak values of ALT (76 vs. 105 U/L; p = 0.429) and AST (3576 vs. 4712 U/L; p = 0.429) were not significantly different between groups. However, by the end of perfusion, histology scores were significantly worse in the acetaminophen treated group (p = 0.016). All acetaminophen treated livers developed significant methemoglobinemia, with a peak methemoglobin level of 19.3%, compared to 2.0% for control livers (p = 0.004). The development of a model of ALF in the ex vivo setting was confounded by the development of toxic methemoglobinemia. Further attempts using alternative agents or dosing strategies may be warranted to explore this setting as a model of liver disease.

Systematic evidence map (SEM) template: Report format and methods used for the US EPA Integrated Risk Information System (IRIS) program, Provisional Peer Reviewed Toxicity Value (PPRTV) program, and other "fit for purpose" literature-based human health analyses.

BACKGROUND: Systematic evidence maps (SEMs) are gaining visibility in environmental health for their utility to serve as problem formulation tools and assist in decision-making, especially for priority setting. SEMs are now routinely prepared as part of the assessment development process for the US Environmental Protection Agency (EPA) Integrated Risk Information System (IRIS) and Provisional Peer Reviewed Toxicity Value (PPRTV) assessments. SEMs can also be prepared to explore the available literature for an individual chemical or groups of chemicals of emerging interest. OBJECTIVES: This document describes the typical methods used to produce SEMs for the IRIS and PPRTV Programs, as well as "fit for purpose" applications using a variety of examples drawn from existing analyses. It is intended to serve as an example base template that can be adapted as needed for the specific SEM. The presented methods include workflows intended to facilitate rapid production. The Populations, Exposures, Comparators and Outcomes (PECO) criteria are typically kept broad to identify mammalian animal bioassay and epidemiological studies that could be informative for human hazard identification. In addition, a variety of supplemental content is tracked, e.g., studies presenting information on in vitro model systems, non-mammalian model systems, exposure-level-only studies in humans, pharmacokinetic models, and absorption, distribution, metabolism, and excretion (ADME). The availability of New Approach Methods (NAMs) evidence is also tracked (e.g., high throughput, transcriptomic, in silico, etc.). Genotoxicity studies may be considered as PECO relevant or supplemental material, depending on the topic and context of the review. Standard systematic review practices (e.g., two independent reviewers per record) and specialized software applications are used to search and screen the literature and may include the use of machine learning software. Mammalian bioassay and epidemiological studies that meet the PECO criteria after full-text review are briefly summarized using structured web-based extraction forms with respect to study design and health system(s) assessed. Extracted data is available in interactive visual formats and can be downloaded in open access formats. Methods for conducting study evaluation are also presented which is conducted on a case-by-case basis, depending on the usage of the SEM.

Use of systematic evidence maps within the US environmental protection agency (EPA) integrated risk information system (IRIS) program: Advancements to date and looking ahead.

Systematic evidence maps (SEMs) are increasingly used to inform decision-making and risk management priority-setting and to serve as problem formulation tools to refine the focus of questions that get addressed in full systematic reviews. Within the U.S. Environmental Protection Agency (EPA) Office of Research and Development (ORD) Integrated Risk Information System (IRIS), SEMs have been used to inform data gaps, determine the need for updated assessments, inform assessment priorities, and inform development of study evaluation considerations, among other uses. Increased utilization of SEMs across the environmental health field has the potential to increase transparency and efficiency for data gathering, problem formulation, read-across, and evidence surveillance. Use of the SEM templates published in the companion text (Thayer et al.) can promote harmonization in the environmental health community and create more opportunities for sharing extracted content.

Assessing author willingness to enter study information into structured data templates as part of the manuscript submission process: A pilot study.

Background: Environmental health and other researchers can benefit from automated or semi-automated summaries of data within published studies as summarizing study methods and results is time and resource intensive. Automated summaries can be designed to identify and extract details of interest pertaining to the study design, population, testing agent/intervention, or outcome (etc.). Much of the data reported across existing publications lack unified structure, standardization and machine-readable formats or may be presented in complex tables which serve as barriers that impede the development of automated data extraction methodologies.As full automation of data extraction seems unlikely soon, encouraging investigators to submit structured summaries of methods and results in standardized formats with meta-data tagging of content may be of value during the publication process. This would produce machine-readable content to facilitate automated data extraction, establish sharable data repositories, help make research data FAIR, and could improve reporting quality. Objectives: A pilot study was conducted to assess the feasibility of asking participants to summarize study methods and results using a structured, web-based data extraction model as a potential workflow that could be implemented during the manuscript submission process. Methods: Eight participants entered study details and data into the Health Assessment Workplace Collaborative (HAWC). Participants were surveyed after the extraction exercise to ascertain 1) whether this extraction exercise will impact their conducting and reporting of future research, 2) the ease of data extraction, including which fields were easiest and relatively more problematic to extract and 3) the amount of time taken to perform data extractions and other related tasks. Investigators then presented participants the potential benefits of providing structured data in the format they were extracting. After this, participants were surveyed about 1) their willingness to provide structured data during the publication process and 2) whether they felt the potential application of structured data entry approaches and their implementation during the journal submission process should continue to be further explored. Conclusions: Routine provision of structured data that summarizes key information from research studies could reduce the amount of effort required for reusing that data in the future, such as in systematic reviews or agency scientific assessments. Our pilot study suggests that directly asking authors to provide that data, via structured templates, may be a viable approach to achieving this: participants were willing to do so, and the overall process was not prohibitively arduous. We also found some support for the hypothesis that use of study templates may have halo benefits in improving the conduct and completeness of reporting of future research. While limitations in the generalizability of our findings mean that the conditions of success of templates cannot be assumed, further research into how such templates might be designed and implemented does seem to have enough chance of success that it ought to be undertaken.

Systematic Evidence Map for Over One Hundred and Fifty Per- and Polyfluoroalkyl Substances (PFAS).

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) are a large class of synthetic (man-made) chemicals widely used in consumer products and industrial processes. Thousands of distinct PFAS exist in commerce. The 2019 U.S. Environmental Protection Agency (U.S. EPA) Per- and Polyfluoroalkyl Substances (PFAS) Action Plan outlines a multiprogram national research plan to address the challenge of PFAS. One component of this strategy involves the use of systematic evidence map (SEM) approaches to characterize the evidence base for hundreds of PFAS. OBJECTIVE: SEM methods were used to summarize available epidemiological and animal bioassay evidence for a set of ∼150 PFAS that were prioritized in 2019 by the U.S. EPA's Center for Computational Toxicology and Exposure (CCTE) for in vitro toxicity and toxicokinetic assay testing. METHODS: Systematic review methods were used to identify and screen literature using manual review and machine-learning software. The Populations, Exposures, Comparators, and Outcomes (PECO) criteria were kept broad to identify mammalian animal bioassay and epidemiological studies that could inform human hazard identification. A variety of supplemental content was also tracked, including information on in vitro model systems; exposure measurement-only studies in humans; and absorption, distribution, metabolism, and excretion (ADME). Animal bioassay and epidemiology studies meeting PECO criteria were summarized with respect to study design, and health system(s) were assessed. Because animal bioassay studies with ≥21-d exposure duration (or reproductive/developmental study design) were most useful to CCTE analyses, these studies underwent study evaluation and detailed data extraction. All data extraction is publicly available online as interactive visuals with downloadable metadata. RESULTS: More than 40,000 studies were identified from scientific databases. Screening processes identified 44 animal and 148 epidemiology studies from the peer-reviewed literature and 95 animal and 50 epidemiology studies from gray literature that met PECO criteria. Epidemiological evidence (available for 15 PFAS) mostly assessed the reproductive, endocrine, developmental, metabolic, cardiovascular, and immune systems. Animal evidence (available for 40 PFAS) commonly assessed effects in the reproductive, developmental, urinary, immunological, and hepatic systems. Overall, 45 PFAS had evidence across animal and epidemiology data streams. DISCUSSION: Many of the ∼150 PFAS were data poor. Epidemiological and animal evidence were lacking for most of the PFAS included in our search. By disseminating this information, we hope to facilitate additional assessment work by providing the initial scoping literature survey and identifying key research needs. Future research on data-poor PFAS will help support a more complete understanding of the potential health effects from PFAS exposures. https://doi.org/10.1289/EHP10343.

Cost-utility analysis of normothermic machine perfusion compared to static cold storage in liver transplantation in the Canadian setting.

To estimate the incremental cost-effectiveness of a liver transplant program that utilizes normothermic machine perfusion (NMP) alongside static cold storage (SCS) compared to SCS alone (control). A Markov model compared strategies (NMP vs. control) using 1-year cycle lengths over a 5-year time horizon from the public healthcare payer perspective. Primary micro-costing data from a single center retrospective trial were applied along with utility values from literature sources. Transition probabilities were deduced using the retrospective trial cohort, local transplant data, and supplemented with literature values. Scenario and probabilistic sensitivity analysis (PSA) were conducted. The NMP strategy was cost-effective in comparison to the control strategy, which was dominated. The mean cost for NMP was $456 455 (2021 US$) and the control was $519 222. The NMP strategy had greater incremental quality-adjusted life years (QALYs) gains over 5 years compared to the control, with 3.48 versus 3.17, respectively. The overarching results remained unchanged in scenario analysis. In PSA, NMP was cost-effective in 63% of iterations at a willingness-to-pay threshold of $40 941. The addition of NMP to a liver transplant program results in greater QALY gains and is cost-effective from the public healthcare payer perspective.

Inducible Pluripotent Stem Cells as a Potential Cure for Diabetes.

Over the last century, diabetes has been treated with subcutaneous insulin, a discovery that enabled patients to forego death from hyperglycemia. Despite novel insulin formulations, patients with diabetes continue to suffer morbidity and mortality with unsustainable costs to the health care system. Continuous glucose monitoring, wearable insulin pumps, and closed-loop artificial pancreas systems represent an advance, but still fail to recreate physiologic euglycemia and are not universally available. Islet cell transplantation has evolved into a successful modality for treating a subset of patients with 'brittle' diabetes but is limited by organ donor supply and immunosuppression requirements. A novel approach involves generating autologous or immune-protected islet cells for transplant from inducible pluripotent stem cells to eliminate detrimental immune responses and organ supply limitations. In this review, we briefly discuss novel mechanisms for subcutaneous insulin delivery and define their shortfalls. We describe embryological development and physiology of islets to better understand their role in glycemic control and, finally, discuss cell-based therapies for diabetes and barriers to widespread use. In response to these barriers, we present the promise of stem cell therapy, and review the current gaps requiring solutions to enable widespread use of stem cells as a potential cure for diabetes.

Clinical islet transplantation: Current progress and new frontiers.

Islet transplantation (IT) is now a robust treatment for selected patients with type 1 diabetes suffering from recurrent hypoglycemia and impaired awareness of hypoglycemia. A global soar of clinical islet transplant programs attests to the commitment of many institutions and researchers to advance IT as a potential cure for this devastating disease. However, many challenges limiting the widespread applicability of clinical IT remain. In this review, we will touch on the milestones in the history of IT and its path to clinical success, discuss the current challenges around IT, propose some possible solutions, and elaborate on the frontiers envisioned in the future of clinical IT.

Two-year outcomes of the ARTISAN-SNM study for the treatment of urinary urgency incontinence using the Axonics rechargeable sacral neuromodulation system.

AIMS: Sacral neuromodulation (SNM) is a guideline-recommended treatment with proven therapeutic benefit for urinary urgency incontinence (UUI) patients. The Axonics® System is the first Food and Drug Administration-approved rechargeable SNM system and is designed to deliver therapy for a minimum of 15 years. The ARTISAN-SNM study was designed to evaluate UUI participants treated with the Axonics System. Two-year follow-up results are presented. METHODS: One hundred and twenty-nine UUI participants underwent implantation with the Axonics System. Therapeutic response rate, participant quality of life (QoL), and satisfaction were determined using 3-day voiding diaries, ICIQ-OABqol, and satisfaction questionnaires. Participants were considered responders if they had a 50% or greater reduction in UUI episodes post-treatment. As-treated and Completers analyses are presented. RESULTS: At 2 years, 93% of the participants (n = 121 Completers at 2 years) were therapy responders, of which 82% achieved ≥ 75% reduction in UUI episodes and 37% were dry (100% reduction). Daily UUI episodes reduced from 5.6 ± 0.3 at baseline to 1.0 ± 0.2 at 2 years. Statistically significant improvements in ICIQ-OABqol were reported. All participants were able to recharge their device and 94% of participants reported that the recharging frequency and duration were acceptable. Participant demographics nor condition severity were correlated with clinical outcomes or recharging experience. No unanticipated or serious device-related adverse events occurred. CONCLUSIONS: At 2 years, participants treated with the Axonics System demonstrated sustained safety and efficacy, high levels of satisfaction with therapy and recharging. Participant-related factors were not associated with efficacy or recharging outcomes, indicating the reported results are applicable to a diverse population.

Charting the next century of insulin replacement with cell and gene therapies.

The discovery of insulin a century ago changed the lives of millions of individuals suffering from diabetes, paving the way for long-term survival. While the availability of recombinant insulin for hormone replacement therapy has served extremely well to help control blood glucose in diabetes, there remains significant room for further improvements for an ultimate "cure" for diabetes patients. In this review, we celebrate the 100th anniversary of the discovery of insulin and consolidate the key milestones and advances in the development of recombinant human insulin. We then summarize recent and current technological developments in terms of insulin gene- and cell-replacement therapies that are promising in greater therapeutic potential. We envision that the next era of insulin replacement therapies will effectively treat diabetes and serve our patients even better for the next century to come.

Safety and immunogenicity of an adjuvanted Escherichia coli adhesin vaccine in healthy women with and without histories of recurrent urinary tract infections: results from a first-in-human phase 1 study.

Antibiotic resistance among gram-negative bacteria continues to rise globally at an alarming rate. New vaccines that prevent bacterial infections and reduce antibiotic use could provide a potential solution to these problems. This study focused on development of an investigational vaccine to prevent recurrent urinary traction infections (UTI) caused by gram-negative bacteria that use type 1 pili to adhere to, invade, and colonize human bladders. The vaccine antigen is FimH, an adhesin protein on the tip of type 1 pili with a lectin binding domain that enables attachment to glycoproteins on mammalian bladders. This was a phase 1, open-label, dose escalation study evaluating the vaccine in 67 healthy women with and without histories of recurrent UTI. The objectives of the study were to evaluate the safety, tolerability, and immunogenicity of different dosages of the antigen and adjuvant of the vaccine. All dosages were well-tolerated and a low incidence of systemic reactions occurred. No serious adverse events related to the vaccine were reported. The vaccine induced both binding and functional antibodies. The women with histories of recurrent UTI demonstrated greater than 150-fold increases in antibodies against the N-terminal region of FimH. Based on the results of this phase 1 study, this vaccine is proceeding to a double-blind, randomized, placebo-controlled phase 2 study. If this vaccine is successful in future studies, it could potentially prevent millions of recurrent UTI globally and reduce the development of antibiotic resistance.

Knowledge Organization Systems for Systematic Chemical Assessments.

BACKGROUND: Although the implementation of systematic review and evidence mapping methods stands to improve the transparency and accuracy of chemical assessments, they also accentuate the challenges that assessors face in ensuring they have located and included all the evidence that is relevant to evaluating the potential health effects an exposure might be causing. This challenge of information retrieval can be characterized in terms of "semantic" and "conceptual" factors that render chemical assessments vulnerable to the streetlight effect. OBJECTIVES: This commentary presents how controlled vocabularies, thesauruses, and ontologies contribute to overcoming the streetlight effect in information retrieval, making up the key components of Knowledge Organization Systems (KOSs) that enable more systematic access to assessment-relevant information than is currently achievable. The concept of Adverse Outcome Pathways is used to illustrate what a general KOS for use in chemical assessment could look like. DISCUSSION: Ontologies are an underexploited element of effective knowledge organization in the environmental health sciences. Agreeing on and implementing ontologies in chemical assessment is a complex but tractable process with four fundamental steps. Successful implementation of ontologies would not only make currently fragmented information about health risks from chemical exposures vastly more accessible, it could ultimately enable computational methods for chemical assessment that can take advantage of the full richness of data described in natural language in primary studies. https://doi.org/10.1289/EHP6994.

One-year outcomes of the ARTISAN-SNM study with the Axonics System for the treatment of urinary urgency incontinence.

AIMS: Sacral neuromodulation (SNM) is a guideline-recommended treatment for voiding dysfunction including urgency, urge incontinence, and nonobstructive retention as well as fecal incontinence. The Axonics® System is a miniaturized, rechargeable SNM system designed to provide therapy for at least 15 years, which is expected to significantly reduce revision surgeries as it will not require replacement as frequently as the non-rechargeable SNM system. The ARTISAN-SNM study is a pivotal study designed to treat patients with urinary urgency incontinence (UUI). Clinical results at 1-year are presented. METHODS: A total of 129 eligible UUI patients were treated. All participants were implanted with a quadripolar tined lead and neurostimulator in a single procedure. Efficacy data were collected using a 3-day bladder diary, a validated quality of life questionnaire (ICIQ-OABqol), and a participant satisfaction questionnaire. Therapy responders were defined as participants with ≥50% reduction in UUI episodes compared to baseline. Data were analyzed on all 129 participants. RESULTS: At 1 year, 89% of the participants were therapy responders. The average UUI episodes per day reduced from 5.6 ± 0.3 at baseline to 1.4 ± 0.2. Participants experienced an overall clinically meaningful improvement of 34 points on the ICIQ-OABqol questionnaire. All study participants (100%) were able to recharge their device at 1 year, and 96% of participants reported that the frequency and duration of recharging was acceptable. There were no serious device-related adverse events. CONCLUSIONS: The Axonics System is safe and effective at 1 year, with 89% of participants experiencing clinically and statistically significant improvements in UUI symptoms.

ORSO (Online Resource for Social Omics): A data-driven social network connecting scientists to genomics datasets.

High-throughput sequencing has become ubiquitous in biomedical sciences. As new technologies emerge and sequencing costs decline, the diversity and volume of available data increases exponentially, and successfully navigating the data becomes more challenging. Though datasets are often hosted by public repositories, scientists must rely on inconsistent annotation to identify and interpret meaningful data. Moreover, the experimental heterogeneity and wide-ranging quality of high-throughput biological data means that even data with desired cell lines, tissue types, or molecular targets may not be readily interpretable or integrated. We have developed ORSO (Online Resource for Social Omics) as an easy-to-use web application to connect life scientists with genomics data. In ORSO, users interact within a data-driven social network, where they can favorite datasets and follow other users. In addition to more than 30,000 datasets hosted from major biomedical consortia, users may contribute their own data to ORSO, facilitating its discovery by other users. Leveraging user interactions, ORSO provides a novel recommendation system to automatically connect users with hosted data. In addition to social interactions, the recommendation system considers primary read coverage information and annotated metadata. Similarities used by the recommendation system are presented by ORSO in a graph display, allowing exploration of dataset associations. The topology of the network graph reflects established biology, with samples from related systems grouped together. We tested the recommendation system using an RNA-seq time course dataset from differentiation of embryonic stem cells to cardiomyocytes. The ORSO recommendation system correctly predicted early data point sources as embryonic stem cells and late data point sources as heart and muscle samples, resulting in recommendation of related datasets. By connecting scientists with relevant data, ORSO provides a critical new service that facilitates wide-ranging research interests.

Focal arm weakness following intradetrusor botulinum toxin administration in spinal cord injury: Report of two cases.

Context: Outpatient Spinal Cord Injury follow-up practice Findings: We present two cases of individuals with tetraplegia who experienced proximal arm weakness temporally related to the administration of intradetrusor onabotulinumtoxinA without other systemic effects. This arm weakness lasted approximately three months in both cases, whereas the effect of the toxin on the bladder lasted for over six months. In one of the cases, the pattern of proximal arm weakness after intravesicular botulinum toxin injection recurred after repeat injection. Conclusion: These cases represent a previously unreported phenomenon of proximal focal weakness associated with the use of intradetrusor chemodenervation. Possible mechanisms for these cases are discussed.