Developing Evidence to Support Policy: Protocol for the StrAtegic PoLicy EvIdence-Based Evaluation CeNTer (SALIENT).

BACKGROUND: All federal agencies are required to support appropriation requests with evidence and evaluation (US Public Law 115-435; the Evidence Act). The StrAtegic PoLicy EvIdence-Based Evaluation CeNTer (SALIENT) is 1 of 6 centers that help the Department of Veterans Affairs (VA) meet this requirement. OBJECTIVE: Working with the existing VA evaluation structure, SALIENT evaluations will contribute to (1) optimize policies and programs for veteran populations; (2) improve outcomes regarding health, equity, cost, and provider well-being; (3) advance the science of dissemination and knowledge translation; and (4) expand the implementation and dissemination science workforce. METHODS: We leverage the Lean Sprint methodology (iterative, incremental, rule-governed approach to clearly defined, and time-boxed work) and 3 cores to develop our evaluation plans collaboratively with operational partners and key stakeholders including veterans, policy experts, and clinicians. The Operations Core will work with evaluation teams to develop timelines, facilitate work, monitor progress, and guide quality improvement within SALIENT. The Methods Core will work with evaluation teams to identify the most appropriate qualitative, quantitative, and mixed methods approaches to address each evaluation, ensure that the analyses are conducted appropriately, and troubleshoot when problems with data acquisition and analysis arise. The Knowledge Translation (KT) Core will target key partners and decision makers using a needs-based market segmentation approach to ensure that needs are incorporated in the dissemination of knowledge. The KT Core will create communications briefs, playbooks, and other materials targeted at these market segments to facilitate implementation of evidence-based practices and maximize the impact of evaluation results. RESULTS: The SALIENT team has developed a center infrastructure to support high-priority evaluations, often to be responsive to shifting operational needs and priorities. Our team has engaged in our core missions and operations to rapidly evaluate a high-priority areas, develop a comprehensive Lean Sprint systems redesign approach to training, and accelerate rapid knowledge translation. CONCLUSIONS: With an array of interdisciplinary expertise, operational partnerships, and integrated resources, SALIENT has an established and evolving infrastructure to rapidly develop and implement high-impact evaluations. Projects are developed with sustained efficiency approaches that can pivot to new priorities as needed and effectively translate knowledge for key stakeholders and policy makers, while creating a learning health system infrastructure to foster the next generation of evaluation and implementation scientists. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/59830.

Progress on nonculture based diagnostic tests for invasive mould infection.

PURPOSE OF REVIEW: This review describes the current status of diagnosing invasive mould disease and Pneumocystis pneumonia using nonconventional diagnostics methods. RECENT FINDINGS: There has been significant development in the range of nonculture mycological tests. Lateral flow tests (LFTs) for diagnosing aspergillosis complement galactomannan ELISA testing, and LFTs for other fungal diseases are in development. Rapid and low through-put B-D-Glucan assays increase access to testing and there has been significant progress in the standardization/development of molecular tests. Despite this, no single perfect test exists and combining tests (e.g., antigen and molecular testing) is likely required for the optimal diagnosis of most fungal diseases. SUMMARY: Based on established clinical performance few mycological tests can be used alone for optimal diagnosis of fungal disease (FD) and combining tests, including classical approaches is the preferred route for confirming and excluding disease. Next-generation sequencing will likely play an increasing role in how we diagnose disease, but optimization, standardization and validation of the entire molecular process is needed and we must consider how host biomarkers can stratify risk. Given the burden of FD in low- and medium-income countries, improved access to novel but more so existing diagnostic testing is critical along with simplification of testing processes.

Genetic Re-assessment of Population Subdivision in Yellowstone National Park Bison.

Yellowstone National Park is home to the only plains bison population that has continually existed as wildlife, on the same landscape, through the population bottleneck of the late 19th century. Nevertheless, by the early 1900s, only 23 wild bison were known to have survived poaching. Salvation efforts included the addition of 18 females from Montana and 3 bulls from Texas to augment this population. A century later, nuclear microsatellite-based population level assessment revealed two genetically distinct bison sub-populations. However, in 2016 an analysis of mitochondrial haplotypes showed the two founding lineages were distributed throughout the park. This study is designed to delineate any current sub-structure in the Yellowstone bison population by strategically sampling the two major summer breeding herds and the two major winter ranges. Population level metrics were derived using the same microsatellite loci as the original study along with a newly developed set of highly informative bison specific Single Nucleotide Polymorphisms (SNPs). Our analyses reveal that the modern bison in Yellowstone National Park currently consist of one interbreeding population, comprised of two subunits.

Corrigendum to "Yield responses of arable crops to liming - An evaluation of relationships between yields and soil pH from a long-term liming experiment" [Eur. J. Agron. 105 (2019) 176-188].

[This corrects the article DOI: 10.1016/j.eja.2019.02.016.].

Dose-related Mutagenic and Clastogenic Effects of Benzo[b]fluoranthene in Mouse Somatic Tissues Detected by Duplex Sequencing and the Micronucleus Assay.

Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants that originate from the incomplete combustion of organic materials. We investigated the clastogenicity and mutagenicity of benzo[ b ]fluoranthene (BbF), one of 16 priority PAHs, in MutaMouse males after a 28-day oral exposure. BbF causes robust dose-dependent increases in micronucleus frequency in peripheral blood, indicative of chromosome damage. Duplex Sequencing (DS), an error-corrected sequencing technology, reveals that BbF induces dose-dependent increases in mutation frequencies in bone marrow (BM) and liver. Mutagenicity is increased in intergenic relative to genic regions, suggesting a role for transcription-coupled repair of BbF-induced DNA damage. At higher doses, the maximum mutagenic response to BbF is higher in liver, which has a lower mitotic index but higher metabolic capacity than BM; however, mutagenic potency is comparable between the two tissues. BbF induces primarily C:G>A:T mutations, followed by C:G>T:A and C:G>G:C, indicating that BbF metabolites mainly target guanines and cytosines. The mutation spectrum of BbF correlates with cancer mutational signatures associated with tobacco exposure, supporting its contribution to the carcinogenicity of combustion-derived PAHs in humans. Overall, BbF's mutagenic effects are similar to benzo[ a ]pyrene, a well-studied mutagenic PAH. Our work showcases the utility of DS for effective mutagenicity assessment of environmental pollutants. Synopsis: We used Duplex Sequencing to study the mutagenicity of benzo[ b ]fluoranthene across the mouse genome. Dose-dependent changes in mutation frequency and spectrum quantify its role in PAH-induced carcinogenicity.

The Impact of the Fungal Priority Pathogens List on Medical Mycology: A Northern European Perspective.

Fungal diseases represent a considerable global health concern, affecting >1 billion people annually. In response to this growing challenge, the World Health Organization introduced the pivotal fungal priority pathogens list (FPPL) in late 2022. The FPPL highlights the challenges in estimating the global burden of fungal diseases and antifungal resistance (AFR), as well as limited surveillance capabilities and lack of routine AFR testing. Furthermore, training programs should incorporate sufficient information on fungal diseases, necessitating global advocacy to educate health care professionals and scientists. Established international guidelines and the FPPL are vital in strengthening local guidance on tackling fungal diseases. Future iterations of the FPPL have the potential to refine the list further, addressing its limitations and advancing our collective ability to combat fungal diseases effectively. Napp Pharmaceuticals Limited (Mundipharma UK) organized a workshop with key experts from Northern Europe to discuss the impact of the FPPL on regional clinical practice.

Substance Use Screening in a Large Pediatric Primary Care Network: A Quality Improvement Project.

Background: This project aimed to introduce substance use screening, using the CRAFFT (Car, Relax, Alone, Forget, Family/Friends, Trouble) screening tool, into the routine care of adolescents using quality improvement strategies and tools. Methods: We expanded a single-site project showing the successful introduction of CRAFFT screening into adolescent care to include the entire 34-site primary care network of a children's hospital in Northeastern Ohio. We deployed quality improvement methodology to facilitate the acceptance and use of the screener. Data showing the percentage of eligible adolescents screened were collected and shared monthly with network providers. Results: The single-site phase increased the screening rate from 3.5% to 72%. The percentage screened for the network phase rose from 0% to >90% in the first 2 months of the project and remained at that level. Of those screened, 85% were low risk, 3% were medium risk, and 2% were high risk. Ten percent of the results were not recorded in a way that allowed for post hoc risk assessment. During the network phase, 35,750 of 38,427 (93%) eligible patients completed the screening form. Conclusions: This project resulted in the highly reliable use of the CRAFFT screener in a large primary care network.

Polymerase Chain Reaction on Respiratory Tract Specimens of Immunocompromised Patients to Diagnose Pneumocystis Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations. METHODS: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined. RESULTS: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients. CONCLUSIONS: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested.

Universal digital high-resolution melting for the detection of pulmonary mold infections.

Invasive mold infections (IMIs) are associated with high morbidity, particularly in immunocompromised patients, with mortality rates between 40% and 80%. Early initiation of appropriate antifungal therapy can substantially improve outcomes, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive mycological findings. Universal digital high-resolution melting (U-dHRM) analysis may enable rapid and robust diagnoses of IMI. A universal fungal assay was developed for U-dHRM and used to generate a database of melt curve signatures for 19 clinically relevant fungal pathogens. A machine learning algorithm (ML) was trained to automatically classify these pathogen curves and detect novel melt curves. Performance was assessed on 73 clinical bronchoalveolar lavage samples from patients suspected of IMI. Novel curves were identified by micropipetting U-dHRM reactions and Sanger sequencing amplicons. U-dHRM achieved 97% overall fungal organism identification accuracy and a turnaround time of ~4 hrs. U-dHRM detected pathogenic molds (Aspergillus, Mucorales, Lomentospora, and Fusarium) in 73% of 30 samples classified as IMI, including mixed infections. Specificity was optimized by requiring the number of pathogenic mold curves detected in a sample to be >8 and a sample volume to be 1 mL, which resulted in 100% specificity in 21 at-risk patients without IMI. U-dHRM showed promise as a separate or combination diagnostic approach to standard mycological tests. U-dHRM's speed, ability to simultaneously identify and quantify clinically relevant mold pathogens in polymicrobial samples, and detect emerging opportunistic pathogens may aid treatment decisions, improving patient outcomes. IMPORTANCE: Improvements in diagnostics for invasive mold infections are urgently needed. This work presents a new molecular detection approach that addresses technical and workflow challenges to provide fast pathogen detection, identification, and quantification that could inform treatment to improve patient outcomes.

Age difference of patients with and without invasive aspergillosis: a systematic review and meta-analysis.

BACKGROUND: Invasive Aspergillosis (IA) is a life-threatening fungal disease with significant mortality rates. Timely diagnosis and treatment greatly enhance patient outcomes. This study aimed to explore the association between patient age and the development of IA, as well as the potential implications for risk stratification strategies. METHODS: We searched National Center for Biotechnology Information (NCBI) databases for publications until October 2023 containing age characteristics of patients with and without IA. A random-effects model with the application of inverse-variance weighting was used to pool reported estimates from each study, and meta-regression and subgroup analyses were utilized to assess sources of heterogeneity. RESULTS: A systematic review was conducted, resulting in the inclusion of 55 retrospective observational studies with a total of 13,983 patients. Meta-analysis revealed that, on average, patients with IA were approximately two and a half years older (95% Confidence Interval [CI] 1.84-3.31 years; I2 = 26.1%) than those without the disease (p < 0.0001). No significant moderators could explain the observed heterogeneity in age difference. However, subgroup analysis revealed that age differences were more pronounced within particular patient groups compared to others. For example, patients with and without IA who had primary severe lung infections exhibited a greater difference in mean age than other patient cohorts. CONCLUSIONS: Further research, such as individual patient data meta-analysis, is necessary to better understand the potential relationship between increasing age and the likelihood of IA. Improved risk stratification strategies based on patient age could potentially enhance the early detection and treatment of IA, ultimately improving patient outcomes.

Knowledge, Attitudes, Practices, and Prevention Barriers Related to Childhood Lead Poisoning Among Nepali-Speaking Bhutanese Parents in Northeast Ohio, United States.

The study objectives were: (i) to develop and administer a survey to assess childhood lead poisoning (CLP) knowledge, attitudes, practices and prevention barriers (KAP-B) among the Nepali-Speaking Bhutanese (NSB) community in Northeast Ohio; and (ii) to examine the association between socio-demographic characteristics of NSB parents and their understanding of CLP as measured by the constructs of knowledge and attitudes. A Nepali language KAP-B questionnaire was developed and 200 NSB parents with at least one child ≤ 7 years of age from the Akron Metropolitan Area, Ohio were interviewed. NSB parents demonstrated a low level of knowledge about CLP prevention measures. While 82% lived in pre-1978 houses, only 27.5% perceived their house/neighborhood to be potentially lead contaminated. Only 33% of the parents reported understanding lead-related information provided by their child's healthcare provider. Low-level CLP awareness among NSB community emphasizes a need for culturally tailored and linguistically appropriate community-level CLP educational intervention programs in this vulnerable community.

An Evaluation of the OLM PneumID Real-Time Polymerase Chain Reaction to Aid in the Diagnosis of Pneumocystis Pneumonia.

BACKGROUND: The use of the PCR to aid in the diagnosis of Pneumocystis pneumonia (PcP) has demonstrated excellent clinical performance, as evidenced through various systematic reviews and meta-analyses, yet there are concerns over the interpretation of positive results due to the potential presence of Pneumocystis colonization of the airways. While this can be overcome by applying designated positivity thresholds to PCR testing, the shear number of assays described limits the development of a universal threshold. Commercial assays provide the opportunity to overcome this problem, provided satisfactory performance is determined through large-scale, multi-centre evaluations. METHODS: Retrospective case/control and consecutive cohort performance evaluations of the OLM PneumID real-time PCR assay were performed on DNA eluates from a range of samples sent from patients where "in-house" PCR had been performed as part of routine diagnostic testing. The clinical performance of the PneumID assay was determined before including it in a diagnostic algorithm to provide the probability of PcP (dependent on diagnostic evidence). RESULTS: After being used to test 317 patients (32 with PcP), the overall performance of the PneumID assay was found to be excellent (Sensitivity/Specificity: 96.9%/95.1%). False positivity could be removed by applying a threshold specific to sample type (<33.1 cycles for BAL fluid; <37.0 cycles for throat swabs), whereas considering any positive respiratory samples as significant generated 100% sensitivity, making absolute negativity sufficient to exclude PcP. Incorporating the PneumID assay into diagnostic algorithms alongside (1-3)-ß-D-Glucan testing provided high probabilities of PcP (up to 85.2%) when both were positive and very low probabilities (<1%) when both were negative. CONCLUSIONS: The OLM PneumID qPCR provides a commercial option for the accurate diagnosis of PcP, generating excellent sensitivity and specificity, particularly when testing respiratory specimens. The combination of PcP PCR with serum (1-3)-ß-D-Glucan provides excellent clinical utility for diagnosing PcP.

Universal Digital High Resolution Melt for the detection of pulmonary mold infections.

Background: Invasive mold infections (IMIs) such as aspergillosis, mucormycosis, fusariosis, and lomentosporiosis are associated with high morbidity and mortality, particularly in immunocompromised patients, with mortality rates as high as 40% to 80%. Outcomes could be substantially improved with early initiation of appropriate antifungal therapy, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive mycological findings. Universal digital high resolution melting analysis (U-dHRM) may enable rapid and robust diagnosis of IMI. This technology aims to accomplish timely pathogen detection at the single genome level by conducting broad-based amplification of microbial barcoding genes in a digital polymerase chain reaction (dPCR) format, followed by high-resolution melting of the DNA amplicons in each digital reaction to generate organism-specific melt curve signatures that are identified by machine learning. Methods: A universal fungal assay was developed for U-dHRM and used to generate a database of melt curve signatures for 19 clinically relevant fungal pathogens. A machine learning algorithm (ML) was trained to automatically classify these 19 fungal melt curves and detect novel melt curves. Performance was assessed on 73 clinical bronchoalveolar lavage (BAL) samples from patients suspected of IMI. Novel curves were identified by micropipetting U-dHRM reactions and Sanger sequencing amplicons. Results: U-dHRM achieved an average of 97% fungal organism identification accuracy and a turn-around-time of 4hrs. Pathogenic molds (Aspergillus, Mucorales, Lomentospora and Fusarium) were detected by U-dHRM in 73% of BALF samples suspected of IMI. Mixtures of pathogenic molds were detected in 19%. U-dHRM demonstrated good sensitivity for IMI, as defined by current diagnostic criteria, when clinical findings were also considered. Conclusions: U-dHRM showed promising performance as a separate or combination diagnostic approach to standard mycological tests. The speed of U-dHRM and its ability to simultaneously identify and quantify clinically relevant mold pathogens in polymicrobial samples as well as detect emerging opportunistic pathogens may provide information that could aid in treatment decisions and improve patient outcomes.

Boyle's Law ignores dynamic processes in governing barotrauma in fish.

The expansion and potential rupture of the swim bladder due to rapid decompression, a major cause of barotrauma injury in fish that pass through turbines and pumps, is generally assumed to be governed by Boyle's Law. In this study, two swim bladder expansion models are presented and tested in silico. One based on the quasi-static Boyle's Law, and a Modified Rayleigh Plesset Model (MRPM), which includes both inertial and pressure functions and was parametrised to be representative of a fish swim bladder. The two models were tested using a range of: (1) simulated and (2) empirically derived pressure profiles. Our results highlight a range of conditions where the Boyle's Law model (BLM) is inappropriate for predicting swim bladder size in response to pressure change and that these conditions occur in situ, indicating that this is an applied and not just theoretical issue. Specifically, these conditions include any one, or any combination, of the following factors: (1) when rate of pressure change is anything but very slow compared to the resonant frequency of the swim bladder; (2) when the nadir pressure is near or at absolute zero; and (3) when a fish experiences liquid tensions (i.e. negative absolute pressures). Under each of these conditions, the MRPM is more appropriate tool for predicting swim bladder size in response to pressure change and hence it is a better model for quantifying barotrauma in fish.

An Overview of Systematic Reviews of Polymerase Chain Reaction (PCR) for the Diagnosis of Invasive Aspergillosis in Immunocompromised People: A Report of the Fungal PCR Initiative (FPCRI)-An ISHAM Working Group.

This overview of reviews (i.e., an umbrella review) is designed to reappraise the validity of systematic reviews (SRs) and meta-analyses related to the performance of Aspergillus PCR tests for the diagnosis of invasive aspergillosis in immunocompromised patients. The methodological quality of the SRs was assessed using the AMSTAR-2 checklist; the quality of the evidence (QOE) within each SR was appraised following the GRADE approach. Eight out of 12 SRs were evaluated for qualitative and quantitative assessment. Five SRs evaluated Aspergillus PCR on bronchoalveolar lavage fluid (BAL) and three on blood specimens. The eight SRs included 167 overlapping reports (59 evaluating PCR in blood specimens, and 108 in BAL), based on 107 individual primary studies (98 trials with a cohort design, and 19 with a case-control design). In BAL specimens, the mean sensitivity and specificity ranged from 0.57 to 0.91, and from 0.92 to 0.97, respectively (QOE: very low to low). In blood specimens (whole blood or serum), the mean sensitivity ranged from 0.57 to 0.84, and the mean specificity from 0.58 to 0.95 (QOE: low to moderate). Across studies, only a low proportion of AMSTAR-2 critical domains were unmet (1.8%), demonstrating a high quality of methodological assessment. Conclusions. Based on the overall methodological assessment of the reviews included, on average we can have high confidence in the quality of results generated by the SRs.

Co-design with Integrated Care Teams: Establishing Information Needs.

Introduction: Co-design has been cited as playing a major role in the future of effective integrated care, however, there is a lack of reporting and reflection on the methods used. Information sharing is fundamental when working in integrated care, however sharing across professions, service settings and localities can be complex. Through co-design, we seek to establish a shared understanding of information needs within a newly formed integrated care team. In doing so we aim to inform future practice in the understanding of co-design. Description: Co-design Workshop 1 (N = 24 participants, plus 6 facilitators), collected 'Current Position' understanding of service information needs. Co-design Workshop 2 (N = 18 participants, plus 6 facilitators) sought a 'Future Position' understanding, identifying solutions and next steps for establishing information-need solutions. Reflection on the co-design process was conducted to inform future co-design practices. Conclusion: Identified was a wide range of future service information needs under the themes of Culture Building, Health System Needs, and Processes. We conclude with 4 key learning points on co-designing. 1. Ensure simplicity in format. 2. Interdisciplinary co-design and co-facilitation of workshops are beneficial. 3. Planning and preparation are key. 4. Co-designing can enhance communication for service improvement.

An update on current and novel molecular diagnostics for the diagnosis of invasive fungal infections.

BACKGROUND: Invasive fungal infections cause millions of infections annually, but diagnosis remains challenging. There is an increased need for low-cost, easy to use, highly sensitive and specific molecular assays that can differentiate between colonized and pathogenic organisms from different clinical specimens. AREAS COVERED: We reviewed the literature evaluating the current state of molecular diagnostics for invasive fungal infections, focusing on current and novel molecular tests such as polymerase chain reaction (PCR), digital PCR, high-resolution melt (HRM), and metagenomics/next generation sequencing (mNGS). EXPERT OPINION: PCR is highly sensitive and specific, although performance can be impacted by prior/concurrent antifungal use. PCR assays can identify mutations associated with antifungal resistance, non-Aspergillus mold infections, and infections from endemic fungi. HRM is a rapid and highly sensitive diagnostic modality that can identify a wide range of fungal pathogens, including down to the species level, but multiplex assays are limited and HRM is currently unavailable in most healthcare settings, although universal HRM is working to overcome this limitation. mNGS offers a promising approach for rapid and hypothesis-free diagnosis of a wide range of fungal pathogens, although some drawbacks include limited access, variable performance across platforms, the expertise and costs associated with this method, and long turnaround times in real-world settings.