Infection prophylaxis among patients with antineutrophil cytoplasmic antibody (ANCA) vasculitis: a scoping review.

Severe infections associated with the use of strong immunosuppressive medication are a leading cause of morbidity and mortality in patients with ANCA vasculitis (AV). While guidelines conditionally recommend trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia in AV patients, robust evidence on prophylaxis strategies is lacking. This scoping review aimed to assess the existing evidence on infection prophylaxis in AV patients, identify knowledge gaps, and guide future study design. A comprehensive search of six databases and relevant references identified original studies in English from January 1, 2000, to July 31, 2020. Inclusion criteria encompassed studies evaluating the impact of any antimicrobial prophylaxis strategy on infection-related outcomes in AV patients receiving immunosuppressive treatment. Studies were screened by four researchers using a blinded approach. Data was extracted by two reviewers, with differences resolved via consensus in consultation with a third reviewer. Nineteen studies met inclusion criteria, including two randomized trials and 17 cohort studies, with TMP-SMX being the most commonly assessed prophylactic strategy. The studies varied in sample sizes, outcomes measured, prophylactic strategies employed, and proportion of patients who received the regimen. Most cohort studies included no or limited control of potential confounding factors. This scoping review suggests significant variation in AV patients' receipt of TMP-SMX and alternative infection prophylaxis approaches. Observational studies using large secondary healthcare databases with rigorous designs are needed to provide high-quality evidence of the real-world effectiveness of antimicrobial prophylactic regimens, to improve clinical decision-making and quality of care for AV patients receiving immunosuppressive treatment.

Validation of an interprofessional education search strategy in PubMed to optimize IPE literature searching.

Objective: With exponential growth in the publication of interprofessional education (IPE) research studies, it has become more difficult to find relevant literature and stay abreast of the latest research. To address this gap, we developed, evaluated, and validated search strategies for IPE studies in PubMed, to improve future access to and synthesis of IPE research. These search strategies, or search hedges, provide comprehensive, validated sets of search terms for IPE publications. Methods: The search strategies were created for PubMed using relative recall methodology. The research methods followed the guidance of previous search hedge and search filter validation studies in creating a gold standard set of relevant references using systematic reviews, having expert searchers identify and test search terms, and using relative recall calculations to validate the searches' performance against the gold standard set. Results: The three recommended search hedges for IPE studies presented had recall of 71.5%, 82.7%, and 95.1%; the first more focused for efficient literature searching, the last with high recall for comprehensive literature searching, and the remaining hedge as a middle ground between the other two options. Conclusion: These validated search hedges can be used in PubMed to expedite finding relevant scholarships, staying up to date with IPE research, and conducting literature reviews and evidence syntheses.

The effects of prenatal exposure to opioids on early childhood development: context matters most.

INTRODUCTION: The opioid crisis has brought an increasing focus on the long-term outcomes of children following prenatal opioid exposure. Evidence to date has been conflicting, which has caused confusion and concern amongst parents, caregivers, social service providers, medical providers and policy makers. METHODS: This review systematically evaluated the highest quality studies relating prenatal exposure to opioids with early childhood developmental outcomes. It focused on developmental outcomes as measured by the Bayley Scales of Infant and Toddler Development, encompassing cognitive, motor, and psychosocial domains of child development. RESULTS: Although several articles reported correlations between prenatal opioid exposure and poor early childhood developmental outcomes, these relationships were no longer statistically significant after adjusting for socio-environmental factors. CONCLUSION: Additional research is needed to determine the extent of any relationship of socio-environmental factors with early childhood development in children prenatally exposed to opioids. This review suggests that socio-environmental factors may be significantly related to poor early childhood outcomes in the presence of prenatal opioid exposure.

Practice-enhancing publications about the medication-use process in 2022.

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: This article identifies, prioritizes, and summarizes published literature on the medication-use process (MUP) from calendar year 2022 that can impact health-system pharmacy daily practice. The MUP is the foundational system that provides the framework for safe medication utilization within the healthcare environment. The MUP is defined in this article as having the following components: prescribing/transcribing, dispensing, administration, and monitoring. Articles evaluating at least one step of the MUP were assessed for their usefulness toward practice improvement. SUMMARY: A PubMed search was conducted in January 2023 for articles published in calendar year 2022 using targeted Medical Subject Headings (MeSH) keywords, and searches of the table of contents of selected pharmacy journals were conducted, providing a total of 6,213 articles. A thorough review identified 69 potentially practice-enhancing articles: 13 for prescribing/transcribing, 13 for dispensing, 5 for administration, and 38 for monitoring. Practice trends discussed in the articles are briefly summarized, with a mention of their importance within health-system pharmacy. The articles are listed and summarized in tables for further review and evaluation. CONCLUSION: It is important to routinely review the published literature and to incorporate significant findings into daily practice. This article assists in identifying and summarizing the most impactful publications. Health-system pharmacists have an active role in improving the MUP in their institution, and awareness of the significant published studies can assist in changing practice at the institutional level.

Usability, Acceptability, and Implementation of Artificial Intelligence (AI) and Machine Learning (ML) Techniques in Surgical Coaching and Training: A Scoping Review.

OBJECTIVE: To define the current state of peer-reviewed literature demonstrating the usability, acceptability, and implementation of artificial intelligence (AI) and machine learning (ML) techniques in surgical coaching and training. DESIGN: We conducted a literature search with defined inclusion and exclusion criteria. We searched five scholarly databases: MEDLINE via PubMed, Embase via Elsevier, Scopus via Elsevier, Cochrane Central Register of Controlled Trials, and the Healthcare Administration Database via ProQuest. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. RESULTS: Only 4 articles met the inclusion criteria and used standardized methods for performance evaluation with expert observation. We found no literature examining the impact on performance, user acceptance, or implementation of AI/ML techniques used for surgical coaching and training. We highlight the need for qualitative and quantitative research demonstrating these techniques' effectiveness before broad implementation. CONCLUSION AND RELEVANCE: We emphasize the need for research to specifically evaluate performance, impact, user acceptance, and implementation of AI/ML techniques. Incorporating these facets of research when developing AI/ML techniques for surgical training is crucial to ensure emerging technology meets user needs without increasing cognitive burden or frustrating users.

Policy Approaches for Increasing Adolescent HPV Vaccination Coverage: A Systematic Review.

CONTEXT: US jurisdictions have enacted a wide range of policies to address low human papillomavirus (HPV) vaccination coverage among adolescents, but it is unclear which policies are effective. OBJECTIVE: To systematically review the impact of governmental policies on adolescent HPV vaccination coverage. DATA SOURCES: PubMed, Embase, and Scopus databases. STUDY SELECTION: Eligible studies, published from 2009 to 2022, evaluated the impact of governmental policies on HPV vaccination coverage among adolescents ages 9 to 18. DATA EXTRACTION: Two investigators independently extracted data on study sample, study design and quality, policy characteristics, and HPV vaccination outcomes. We summarized findings by policy type: school-entry requirements (SERs), federally-funded policies related to the Vaccines for Children program and Medicaid, educational requirements, and others. RESULTS: Our search yielded 36 eligible studies. A majority of studies evaluating HPV vaccine SERs found positive associations between SERs and HPV vaccination coverage (8 of 14), particularly for SERs in Rhode Island and Washington, DC. All studies evaluating SERs for other adolescent vaccines observed positive spillover effects for HPV vaccination (7 of 7). Federally-funded policies related to Vaccines for Children and Medicaid were consistently associated with higher HPV vaccination coverage (7 of 9). Relatively few studies found associations between educational requirements and HPV vaccination coverage (2 of 8). LIMITATIONS: Studies used limited vaccination data sources and non- or quasi-experimental designs. Some studies had no or poorly matched comparison groups. CONCLUSIONS: Our findings suggest promise for SERs and federally-funded policies, but not educational requirements, for increasing HPV vaccination coverage among adolescents.

Classification and functional characterization of regulators of intracellular STING trafficking identified by genome-wide optical pooled screening.

STING is an innate immune sensor that traffics across many cellular compartments to carry out its function of detecting cyclic di-nucleotides and triggering defense processes. Mutations in factors that regulate this process are often linked to STING-dependent human inflammatory disorders. To systematically identify factors involved in STING trafficking, we performed a genome-wide optical pooled screen and examined the impact of genetic perturbations on intracellular STING localization. Based on subcellular imaging of STING protein and trafficking markers in 45 million cells perturbed with sgRNAs, we defined 464 clusters of gene perturbations with similar cellular phenotypes. A higher-dimensional focused optical pooled screen on 262 perturbed genes which assayed 11 imaging channels identified 73 finer phenotypic clusters. In a cluster containing USE1, a protein that mediates Golgi to ER transport, we found a gene of unknown function, C19orf25. Consistent with the known role of USE1, loss of C19orf25 enhanced STING signaling. Other clusters contained subunits of the HOPS, GARP and RIC1-RGP1 complexes. We show that HOPS deficiency delayed STING degradation and consequently increased signaling. Similarly, GARP/RIC1-RGP1 loss increased STING signaling by delaying STING exit from the Golgi. Our findings demonstrate that genome-wide genotype-phenotype maps based on high-content cell imaging outperform other screening approaches, and provide a community resource for mining for factors that impact STING trafficking as well as other cellular processes observable in our dataset.

Single-cell image-based genetic screens systematically identify regulators of Ebola virus subcellular infection dynamics.

Ebola virus (EBOV) is a high-consequence filovirus that gives rise to frequent epidemics with high case fatality rates and few therapeutic options. Here, we applied image-based screening of a genome-wide CRISPR library to systematically identify host cell regulators of Ebola virus infection in 39,085,093 million single cells. Measuring viral RNA and protein levels together with their localization in cells identified over 998 related host factors and provided detailed information about the role of each gene across the virus replication cycle. We trained a deep learning model on single-cell images to associate each host factor with predicted replication steps, and confirmed the predicted relationship for select host factors. Among the findings, we showed that the mitochondrial complex III subunit UQCRB is a post-entry regulator of Ebola virus RNA replication, and demonstrated that UQCRB inhibition with a small molecule reduced overall Ebola virus infection with an IC50 of 5 µM. Using a random forest model, we also identified perturbations that reduced infection by disrupting the equilibrium between viral RNA and protein. One such protein, STRAP, is a spliceosome-associated factor that was found to be closely associated with VP35, a viral protein required for RNA processing. Loss of STRAP expression resulted in a reduction in full-length viral genome production and subsequent production of non-infectious virus particles. Overall, the data produced in this genome-wide high-content single-cell screen and secondary screens in additional cell lines and related filoviruses (MARV and SUDV) revealed new insights about the role of host factors in virus replication and potential new targets for therapeutic intervention.

Identifying Healthcare Professionals With Lower Human Papillomavirus (HPV) Vaccine Recommendation Quality: A Systematic Review.

PURPOSE: Strengthening healthcare professionals' (HCPs) communication is an evidence-based approach to increasing human papillomavirus (HPV) vaccine uptake among adolescents. To better target future interventions, we sought to synthesize evidence on HCP subgroups who most need to improve their HPV vaccine recommendation quality. METHODS: We searched five databases for quantitative studies published from 2012 to 2022 on HPV vaccine recommendation quality, including recommendation consistency and strength, for United States adolescents. Two coders independently abstracted data from each eligible study, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We summarized variation in recommendation quality by clinical and HCP characteristics. RESULTS: The 28 eligible studies indicated that relatively low proportions of HCPs used higher-quality recommendation practices (median: 61% across 30 measures) and that recommendation quality varied across HCP subgroups. The most consistent findings were that more pediatric HCPs used higher-quality recommendations than family medicine HCPs (8 of 11 studies, 2-60 percentage point difference) and that HPV-related knowledge was associated with higher recommendation quality (four of seven studies). Most studies observed no differences in recommendation quality by clinical role (e.g., provider vs. nurse) or HCP demographics (e.g., gender, age, race/ethnicity). DISCUSSION: Studies suggest a substantial need to improve HCPs' recommendation quality, with opportunities for targeting future interventions.

Outcomes in Obese Adult Veno-Venous Extracorporeal Membrane Oxygenation: A Systematic Review.

Obesity is associated with an overall increased risk of morbidity and mortality. However, in patients with critical illness, sepsis, and acute respiratory distress syndrome, obesity may be protective, termed "the obesity paradox." This is a systematic literature review of articles published from 2000 to 2022 evaluating complications and mortality in adults with respiratory failure on veno-venous extracorporeal membrane oxygenation (VV ECMO) based on body mass index (BMI). Eighteen studies with 517 patients were included. Common complications included acute renal failure (175/377, 46.4%), venous thrombosis (175/293, 59.7%), and bleeding (28/293, 9.6%). Of the six cohort studies, two showed improved mortality among obese patients, two showed a trend toward improved mortality, and two showed no difference. Comparing all patients in the studies with BMI of less than 30 to those with BMI of greater than or equal to 30, we noted decreased mortality with obesity (92, 37.1% of BMI <30 vs. 30, 11% of BMI ≥30, p ≤ 0.0001). Obesity may be protective against mortality in adult patients undergoing VV ECMO. Morbid and super morbid obesity should not be considered a contraindication to cannulation, with patients with BMI ≥ 80 surviving to discharge. Complications may be high, however, with higher rates of continuous renal replacement therapy and thrombosis among obese patients.

Bacille Calmette-Guérin preparation and intravesical administration to patients with bladder cancer: Risks to healthcare personnel and patients, and mitigation strategies.

Intravesical Bacillus Calmette-Guérin (BCG) is a standard therapy for non-muscle-invasive bladder cancer used in urology clinics and inpatient settings. We present a review of infection risks to patients receiving intravesical BCG, healthcare personnel who prepare and administer BCG, and other patients treated in facilities where BCG is prepared and administered. Knowledge of these risks and relevant regulations informs appropriate infection prevention measures.

Human STING is a proton channel.

Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of interferon genes (STING) activation. On the basis of structural analysis, we hypothesized that human STING is a proton channel. Indeed, we found that STING activation induced a pH increase in the Golgi and that STING reconstituted in liposomes enabled transmembrane proton transport. Compound 53 (C53), a STING agonist that binds the putative channel interface, blocked STING-induced proton flux in the Golgi and in liposomes. STING-induced LC3B lipidation and inflammasome activation were also inhibited by C53, suggesting that STING's channel activity is critical for these two processes. Thus, STING's interferon-induction function can be decoupled from its roles in LC3B lipidation and inflammasome activation.

The OpenMolcas Web: A Community-Driven Approach to Advancing Computational Chemistry.

The developments of the open-source OpenMolcas chemistry software environment since spring 2020 are described, with a focus on novel functionalities accessible in the stable branch of the package or via interfaces with other packages. These developments span a wide range of topics in computational chemistry and are presented in thematic sections: electronic structure theory, electronic spectroscopy simulations, analytic gradients and molecular structure optimizations, ab initio molecular dynamics, and other new features. This report offers an overview of the chemical phenomena and processes OpenMolcas can address, while showing that OpenMolcas is an attractive platform for state-of-the-art atomistic computer simulations.

A genome-wide optical pooled screen reveals regulators of cellular antiviral responses.

The infection of mammalian cells by viruses and innate immune responses to infection are spatiotemporally organized processes. Cytosolic RNA sensors trigger nuclear translocation of the transcription factor interferon regulatory factor 3 (IRF3) and consequent induction of host immune responses to RNA viruses. Previous genetic screens for factors involved in viral sensing did not resolve changes in the subcellular localization of host or viral proteins. Here, we increased the throughput of our optical pooled screening technology by over fourfold. This allowed us to carry out a genome-wide CRISPR knockout screen using high-resolution multiparameter imaging of cellular responses to Sendai virus infection coupled with in situ cDNA sequencing by synthesis (SBS) to identify 80,408 single guide RNAs (sgRNAs) in 10,366,390 cells-over an order of magnitude more genomic perturbations than demonstrated previously using an in situ SBS readout. By ranking perturbations using human-designed and deep learning image feature scores, we identified regulators of IRF3 translocation, Sendai virus localization, and peroxisomal biogenesis. Among the hits, we found that ATP13A1, an ER-localized P5A-type ATPase, is essential for viral sensing and is required for targeting of mitochondrial antiviral signaling protein (MAVS) to mitochondrial membranes where MAVS must be localized for effective signaling through retinoic acid-inducible gene I (RIG-I). The ability to carry out genome-wide pooled screens with complex high-resolution image-based phenotyping dramatically expands the scope of functional genomics approaches.

Pre-therapeutic molecular biomarkers of pathological response to neoadjuvant chemotherapy in gastric and esophago-gastric junction adenocarcinoma: A systematic review and meta-analysis.

PURPOSE: Multimodal treatment is the standard of care in patients with locally advanced gastric cancer. Unfortunately, the response rate after neoadjuvant treatment remains limited. The ability to predict the response has a potential to improve patient outcomes by promoting a more individualized approach. We sought to describe the current state of research in pre-treatment molecular biomarkers of response to neoadjuvant therapy in gastric adenocarcinoma available for testing before the initiation of treatment and to perform a systematic review and meta-analysis in order to summarize and evaluate the potential methods. METHODS: A systematic MEDLINE, EMBASE and CENTRAL literature search was conducted to extract articles on potentially predictive molecular biomarkers of pathological response to neoadjuvant therapy in patients with gastric- and esophago-gastric junction adenocarcinoma. Fixed and random effects models were used to undertake the meta-analysis when appropriate. RESULTS: Data on predictive biomarkers was reported in 38 studies. These articles described 47 biomarkers showing statistical significance. After evaluation of all reported biomarkers, 3 of them met the inclusion criteria for meta-analysis. The meta-analysis results indicate that >5 â€‹ng/mL pre-therapeutic serum concentration of carcinoembryonic antigen (CEA; norm <5 â€‹ng/mL) is significantly associated with tumor response (RR â€‹= â€‹5.13, 95% CI 2.53-10.43, P â€‹= â€‹0.026). CONCLUSION: Previous studies describe a large number of candidate biomarkers. Our meta-analysis indicated pre-therapeutic serum concentration of CEA >5 â€‹ng/mL as a potential and easy-accessible biomarker available for use before initiation of treatment. However, it could be only an additional tool for complex qualification for neoadjuvant therapy.

ESCRT-dependent STING degradation inhibits steady-state and cGAMP-induced signalling.

Stimulator of interferon genes (STING) is an intracellular sensor of cyclic di-nucleotides involved in the innate immune response against pathogen- or self-derived DNA. STING trafficking is tightly linked to its function, and its dysregulation can lead to disease. Here, we systematically characterize genes regulating STING trafficking and examine their impact on STING-mediated responses. Using proximity-ligation proteomics and genetic screens, we demonstrate that an endosomal sorting complex required for transport (ESCRT) complex containing HGS, VPS37A and UBAP1 promotes STING degradation, thereby terminating STING-mediated signaling. Mechanistically, STING oligomerization increases its ubiquitination by UBE2N, forming a platform for ESCRT recruitment at the endosome that terminates STING signaling via sorting in the lysosome. Finally, we show that expression of a UBAP1 mutant identified in patients with hereditary spastic paraplegia and associated with disrupted ESCRT function, increases steady-state STING-dependent type I IFN responses in healthy primary monocyte-derived dendritic cells and fibroblasts. Based on these findings, we propose that STING is subject to a tonic degradative flux and that the ESCRT complex acts as a homeostatic regulator of STING signaling.

Scoping Review to Inform the Future Development of a Measure for Team-Based Care in Oncology.

PURPOSE: Team-based care is the delivery of health services to an individual by at least two health care providers working collaboratively to achieve optimal care. Participants on the National Cancer Institute and the ASCO Teams in the Cancer Care Delivery Project have defined 13 key principles to serve as the foundation for a successful team; however, it is unclear whether there exist measures of these key principles. METHODS: A scoping literature search was conducted for each key principle on PubMed and Embase to identify existing measures for key principles. Articles of interest were exported to a citation manager, Sciwheel, cataloged by the key principle. Existing measures were extracted via a two-stage screening process, with an abstract review followed by a full-text review. RESULTS: Fifteen unique measures were identified, with items extrapolated for 12 of the 13 key principles. Measures were not exclusive and could represent more than one key principle. The number of measures varied per principle from zero to five, with Team Composition and Diversity yielding no existing measure. CONCLUSION: The long-term goal is to compile and edit these measures, to create a comprehensive measure to be used in various team-based oncology care settings, and to address areas for improvement, ultimately optimizing patient care.

The role of extracorporeal membrane oxygenation in adult kidney transplant patients: A qualitative systematic review of literature.

BACKGROUND: A paucity of evidence exists regarding the risks and benefits of Extracorporeal Membrane Oxygenation (ECMO) in adult kidney transplantation. METHODS: This was a systematic review conducted from Jan 1, 2000 to April 24, 2020 of adult kidney transplant recipients (pre- or post- transplant) and donors who underwent veno-arterial or veno-venous ECMO cannulation. Death and graft function were the primary outcomes, with complications as secondary outcomes. RESULTS: Twenty-three articles were identified that fit inclusion criteria. 461 donors were placed on ECMO, with an overall recipient 12-month mortality rate of 1.3% and a complication rate of 61.5%, the majority of which was delayed graft function. Fourteen recipients were placed on ECMO intraoperatively or postoperatively, with infection as the most common indication for ECMO. The 90-day mortality rate for recipients on ECMO was 42.9%, with multisystem organ failure and infection as the ubiquitous causes of death. 35.7% of patients experienced rejection within 6 months of decannulation, yet all were successfully treated. CONCLUSIONS: ECMO use in adult kidney transplantation is a useful adjunct. Recipient morbidity and mortality from donors placed on ECMO mirrors that of recipients from standard criteria donors. The morbidity and mortality of recipients placed on ECMO are also similar to other patient populations requiring ECMO.

Barriers and Facilitators for Population Genetic Screening in Healthy Populations: A Systematic Review.

Studies suggest that 1-3% of the general population in the United States unknowingly carry a genetic risk factor for a common hereditary disease. Population genetic screening is the process of offering otherwise healthy patients in the general population testing for genomic variants that predispose them to diseases that are clinically actionable, meaning that they can be prevented or mitigated if they are detected early. Population genetic screening may significantly reduce morbidity and mortality from these diseases by informing risk-specific prevention or treatment strategies and facilitating appropriate participation in early detection. To better understand current barriers, facilitators, perceptions, and outcomes related to the implementation of population genetic screening, we conducted a systematic review and searched PubMed, Embase, and Scopus for articles published from date of database inception to May 2020. We included articles that 1) detailed the perspectives of participants in population genetic screening programs and 2) described the barriers, facilitators, perceptions, and outcomes related to population genetic screening programs among patients, healthcare providers, and the public. We excluded articles that 1) focused on direct-to-consumer or risk-based genetic testing and 2) were published before January 2000. Thirty articles met these criteria. Barriers and facilitators to population genetic screening were organized by the Social Ecological Model and further categorized by themes. We found that research in population genetic screening has focused on stakeholder attitudes with all included studies designed to elucidate individuals' perceptions. Additionally, inadequate knowledge and perceived limited clinical utility presented a barrier for healthcare provider uptake. There were very few studies that conducted long-term follow-up and evaluation of population genetic screening. Our findings suggest that these and other factors, such as prescreen counseling and education, may play a role in the adoption and implementation of population genetic screening. Future studies to investigate macro-level determinants, strategies to increase provider buy-in and knowledge, delivery models for prescreen counseling, and long-term outcomes of population genetic screening are needed for the effective design and implementation of such programs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020198198.