Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Face Feature Change Detection Ability in Developmental Prosopagnosia and Super-Recognisers.

In non-clinical populations, facial features (eyes, nose, mouth) may vary in their contribution to face identity perception. Changes to whole faces are easier to detect than changes to individual features, and eye changes are typically easier to detect than mouth changes, which in turn are easier to detect than nose changes. However, how this differs for people with face recognition difficulties (developmental prosopagnosia; DP) and for individuals with superior face recognition abilities (super-recognisers; SR) is not clear; although findings from previous studies have suggested differences, the nature of this difference is not understood. The aim of this study was to examine whether differences in the ability to detect feature changes in DPs and SRs were (a) quantitative, meaning that the pattern across feature changes remained the same but there was an overall upwards or downwards shift in performance, or (b) qualitative, meaning that the pattern across feature changes was different. Using a change detection task in which individual face features (eyes, nose, mouth) changed between sequentially presented faces, we found that while prosopagnosics showed a quantitative difference in performance with a downwards shift across all conditions, super-recognisers only showed qualitative differences: they were better able to detect when the face was the same and were marginally (but not non-significantly) worse at detecting when the eyes changed. Further, the only condition which distinguished between the three groups was the ability to identify when the same face was presented, with SRs being better than controls, and controls being better than DPs. Our findings suggest that, in feature-matching tasks, differences for DPs are due to them being overall worse at the task, while SRs use a qualitatively different strategy.

Developing and conducting a language inclusivity assessment on a health science library's website, LibGuides, and signage.

Background: A Diversity, Equity, and Inclusion (DEI) Team at a university health science library created a checklist for inclusive language and conducted an assessment of their library's website, LibGuides, and physical and digital signage. Inclusive language was defined as "language that is free from words, phrases or tones that reflect prejudiced, stereotyped or discriminatory views of particular people or groups". Case Presentation: The 32-item checklist facilitated the identification of gendered language, stereotypes, ableist language, racist language, stigmatizing language, slang, acronyms, and out-of-date terminology regarding physical and mental health conditions. From the library's website, 20 instances were noted for which improvements were necessary. Out of the 130 LibGuides reviewed, 23 LibGuides had no changes needed and 107 had changes identified relating to language inclusivity (14 strongly recommended changes and 116 suggested changes). Regarding the signage, one flyer was removed for reprinting. Conclusion: The checklist enabled the team to implement a number of improvements to the library's website and LibGuides. The checklist has been shared with Library Technology Services and the wider campus libraries' Usability Committee for future use, and has also been added to the DEI Team's LibGuide for use by others outside of the university.

Psychological Constructs From the Fear Avoidance Model and Beyond as Predictors for Persisting Symptoms After Concussion: An Integrative Review.

OBJECTIVES: To identify the range of evidence for relationships between psychological factors using the Fear Avoidance Model (FAM) as a guiding framework and relevant clinical outcomes in adult patients with persisting symptoms after concussion (PSaC), develop a comprehensive understanding of psychological factors that have been identified as predictors of clinical outcomes for PSaC, and contribute to the theoretical framework of the FAM for PSaC. DATA SOURCES: Six databases (CINAHL, Embase, PsycINFO, PubMed, SportDiscus, and Web of Science) were searched by a librarian for empirical and theoretical publications and experimental and quasi-experimental study designs. The literature search was not limited by publication date restrictions. Gray literature, with the exception of doctoral dissertations, was excluded. STUDY SELECTION: We included studies in the English language consisting of human participants aged ≥18 years. Articles must have included both outcomes pertaining to PSaC (≥3mo after injury) and psychological constructs. DATA EXTRACTION: One reviewer extracted data from the resulting studies using a standardized data extraction form designed for this review. Two reviewers independently assessed risk of bias using the Quality in Prognosis Studies tool. DATA SYNTHESIS: This review found numerous psychological constructs, some directly linked to the FAM, that have potential prognostic relationships with PSaC. However, research remains limited and some psychological factors central to FAM were only identified in a small number of studies (catastrophizing, cogniphobia, and avoidance), whereas other psychological factors were studied more extensively (anxiety and depression). CONCLUSIONS: There is the need for additional evidence, and this integrative review provides an adaptation of the FAM for PSaC to be used as a guiding preliminary framework for future research. Future research should aim to include psychological factors proposed in this modified FAM to fully understand PSaC.

The importance of pharmacist engagement in diagnostic stewardship.

Diagnostic stewardship is increasingly recognized as a powerful tool to improve patient safety. Given the close relationship between diagnostic testing and antimicrobial misuse, antimicrobial stewardship (AMS) pharmacists should be key members of the diagnostic team. Pharmacists practicing in AMS already frequently engage with clinicians to improve the diagnostic process and have many skills needed for the implementation of diagnostic stewardship initiatives. As diagnostic stewardship becomes more broadly used, all infectious disease clinicians, including pharmacists, must collaborate to optimize patient care.

Diagnostic Stewardship for Urine Cultures.

Urinary tract infections are among the most common infectious diagnoses in health care, but most urinary tract infections are diagnosed inappropriately in patients without signs or symptoms of infection. Asymptomatic bacteriuria leads to inappropriate antibiotic prescribing and negative downstream effects, including antimicrobial resistance, health care-associated infections, and adverse drug events. Diagnostic stewardship is the process of modifying the ordering, performing, or reporting of test results to improve clinical care. Diagnostic stewardship impacts the diagnostic pathway to decrease inappropriate detection and treatment of asymptomatic bacteriuria. This article reviews diagnostic stewardship methods and closes with a case study illustrating these principles in practice.

Risk Compensation After Initiation of Daily Oral Pre-exposure Prophylaxis Among Sexual and Gender Minorities in Nigeria.

Pre-exposure prophylaxis (PrEP) use may be associated with risk compensation. We enrolled and provided PreP to sexual and gender minorities (SGM) in Abuja, Nigeria between April 2018 and May 2019. Behavioral information and samples for urogenital and anorectal Chlamydia trachomatis and Neisseria gonorrhoeae sexually transmitted infections (STIs) were collected at baseline. Blood samples for PrEP assay and self-reported adherence were collected at three-monthly follow-up visits. STIs were detected using Aptima Combo2 assay. We estimated the odds ratios (ORs) of PCR-diagnosed bacterial STIs and self-reported behavioral outcomes (condomless anal intercourse [CAI] and concurrent sexual relationships) with conditional logistic regression. Of 400 SGM who initiated PrEP, 206 were eligible for analysis, and had a median age of 24 years (IQR 22-27). In multivariable analysis, participants in the PrEP period had decreased odds of CAI (adjusted OR: 0.49, 95% CI 0.28, 0.84). PrEP use was not associated with risk compensation.

MetaQuad: shared informative variants discovery in metagenomic samples.

Motivation: Strain-level analysis of metagenomic data has garnered significant interest in recent years. Microbial single nucleotide polymorphisms (SNPs) are genomic variants that can reflect strain-level differences within a microbial species. The diversity and emergence of SNPs in microbial genomes may reveal evolutionary history and environmental adaptation in microbial populations. However, efficient discovery of shared polymorphic variants in a large collection metagenomic samples remains a computational challenge. Results: MetaQuad utilizes a density-based clustering technique to effectively distinguish between shared variants and non-polymorphic sites using shotgun metagenomic data. Empirical comparisons with other state-of-the-art methods show that MetaQuad significantly reduces the number of false positive SNPs without greatly affecting the true positive rate. We used MetaQuad to identify antibiotic-associated variants in patients who underwent Helicobacter pylori eradication therapy. MetaQuad detected 7591 variants across 529 antibiotic resistance genes. The nucleotide diversity of some genes is increased 6 weeks after antibiotic treatment, potentially indicating the role of these genes in specific antibiotic treatments. Availability and implementation: MetaQuad is an open-source Python package available via https://github.com/holab-hku/MetaQuad.

Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19: Serologic Testing.

BACKGROUND: The role of serologic testing for SARS-CoV-2 has evolved during the pandemic as seroprevalence in global populations has increased. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the coronavirus disease 2019 (COVID-19) serology literature and construct updated best practice guidance related to SARS-CoV-2 serologic testing. This guideline is an update to the fourth in a series of rapid, frequently updated COVID-19 guidelines developed by IDSA. OBJECTIVE: To develop evidence-based recommendations and identify unmet research needs pertaining to the use of anti-SARS-CoV-2 antibody tests for diagnosis, decisions related to vaccination and administration of monoclonal antibodies or convalescent plasma in immunocompromised patients, and identification of a serologic correlate of immunity. METHODS: A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists and experts in systematic literature reviewed, identified, and prioritized clinical questions related to the use of SARS-CoV-2 serologic tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. RESULTS: The panel recommends against serologic testing to diagnose SARS-CoV-2 infection in the first two weeks after symptom onset (strong recommendations, low certainty of evidence). Serologic testing should not be used to provide evidence of COVID-19 in symptomatic patients with a high clinical suspicion and repeatedly negative nucleic acid amplification test results (strong recommendation, very low certainty of evidence). Serologic testing may assist with the diagnosis of multisystem inflammatory syndrome in children (strong recommendation, very low certainty of evidence). To seek evidence for prior SARS-CoV-2 infection, the panel suggests testing for IgG, IgG/IgM, or total antibodies to nucleocapsid protein three to five weeks after symptom onset (conditional recommendation, low certainty of evidence). In individuals with previous SARS-CoV-2 infection or vaccination, we suggest against routine serologic testing given no demonstrated benefit to improving patient outcomes (conditional recommendation, very low certainty of evidence.) The panel acknowledges further that a negative spike antibody test may be a useful metric to identify immunocompromised patients who are candidates for immune therapy. CONCLUSIONS: The high seroprevalence of antibodies against SARS-CoV-2 worldwide limits the utility of detecting anti-SARS CoV-2 antibody. The certainty of available evidence supporting the use of serology for diagnosis was graded as very low to low. Future studies should use serologic assays calibrated to a common reference standard.

Clinical decision support for gastrointestinal panel testing.

Objective: This study aimed to assess the impact of clinical decision support (CDS) to improve ordering of multiplex gastrointestinal polymerase chain reaction (PCR) testing panel ("GI panel"). Design: Single-center, retrospective, before-after study. Setting: Tertiary care Veteran's Affairs (VA) Medical Center provides inpatient, outpatient, and residential care. Patients: All patients tested with a GI panel between June 22, 2022 and April 20, 2023. Intervention: We designed a CDS questionnaire in the electronic medical record (EMR) to guide appropriate ordering of the GI panel. A "soft stop" reminder at the point of ordering prompted providers to confirm five appropriateness criteria: 1) documented diarrhea, 2) no recent receipt of laxatives, 3) C. difficile is not the leading suspected cause of diarrhea, 4) time period since a prior test is >14 days or prior positive test is >4 weeks and 5) duration of hospitalization <72 hours. The CDS was implemented in November 2022. Results: Compared to the pre-implementation period (n = 136), fewer tests were performed post-implementation (n = 92) with an IRR of 0.61 (p = 0.003). Inappropriate ordering based on laxative use or undocumented diarrhea decreased (IRR 0.37, p = 0.012 and IRR 0.25, p = 0.08, respectively). However, overall inappropriate ordering and outcome measures did not significantly differ before and after the intervention. Conclusions: Implementation of CDS in the EMR decreased testing and inappropriate ordering based on use of laxatives or undocumented diarrhea. However, inappropriate ordering of tests overall remained high post-intervention, signaling the need for continued diagnostic stewardship efforts.

Using methylation data to improve transcription factor binding prediction.

Modelling the regulatory mechanisms that determine cell fate, response to external perturbation, and disease state depends on measuring many factors, a task made more difficult by the plasticity of the epigenome. Scanning the genome for the sequence patterns defined by Position Weight Matrices (PWM) can be used to estimate transcription factor (TF) binding locations. However, this approach does not incorporate information regarding the epigenetic context necessary for TF binding. CpG methylation is an epigenetic mark influenced by environmental factors that is commonly assayed in human cohort studies. We developed a framework to score inferred TF binding locations using methylation data. We intersected motif locations identified using PWMs with methylation information captured in both whole-genome bisulfite sequencing and Illumina EPIC array data for six cell lines, scored motif locations based on these data, and compared with experimental data characterizing TF binding (ChIP-seq). We found that for most TFs, binding prediction improves using methylation-based scoring compared to standard PWM-scores. We also illustrate that our approach can be generalized to infer TF binding when methylation information is only proximally available, i.e. measured for nearby CpGs that do not directly overlap with a motif location. Overall, our approach provides a framework for inferring context-specific TF binding using methylation data. Importantly, the availability of DNA methylation data in existing patient populations provides an opportunity to use our approach to understand the impact of methylation on gene regulatory processes in the context of human disease.

Diagnostic stewardship to improve patient outcomes and healthcare-associated infection (HAI) metrics.

Diagnostic stewardship seeks to improve ordering, collection, performance, and reporting of tests. Test results play an important role in reportable HAIs. The inclusion of HAIs in public reporting and pay for performance programs has highlighted the value of diagnostic stewardship as part of infection prevention initiatives. Inappropriate testing should be discouraged, and approaches that seek to alter testing solely to impact a reportable metric should be avoided. HAI definitions should be further adapted to new testing technologies, with focus on actionable and clinically relevant test results that will improve patient care.

AI-Generated Clinical Summaries Require More Than Accuracy.

This Viewpoint discusses AI-generated clinical summaries and the necessity of transparent development of standards for their safe rollout.

Game-based learning to improve diagnostic accuracy: a pilot randomized-controlled trial.

OBJECTIVES: Perform a pilot study of online game-based learning (GBL) using natural frequencies and feedback to teach diagnostic reasoning. METHODS: We conducted a multicenter randomized-controlled trial of computer-based training. We enrolled medical students, residents, practicing physicians and nurse practitioners. The intervention was a 45 min online GBL training vs. control education with a primary outcome of score on a scale of diagnostic accuracy (composed of 10 realistic case vignettes, requesting estimates of probability of disease after a test result, 0-100 points total). RESULTS: Of 90 participants there were 30 students, 30 residents and 30 practicing clinicians. Of these 62 % (56/90) were female and 52 % (47/90) were white. Sixty were randomized to GBL intervention and 30 to control. The primary outcome of diagnostic accuracy immediately after training was better in GBL (mean accuracy score 59.4) vs. control (37.6), p=0.0005. The GBL group was then split evenly (30, 30) into no further intervention or weekly emails with case studies. Both GBL groups performed better than control at one-month and some continued effect at three-month follow up. Scores at one-month GBL (59.2) GBL plus emails (54.2) vs. control (33.9), p=0.024; three-months GBL (56.2), GBL plus emails (42.9) vs. control (35.1), p=0.076. Most participants would recommend GBL to colleagues (73 %), believed it was enjoyable (92 %) and believed it improves test interpretation (95 %). CONCLUSIONS: In this pilot study, a single session with GBL nearly doubled score on a scale of diagnostic accuracy in medical trainees and practicing clinicians. The impact of GBL persisted after three months.

Diagnostic stewardship and the coronavirus disease 2019 (COVID-19) pandemic: Lessons learned for prevention of emerging infectious diseases in acute-care settings.

The coronavirus disease 2019 (COVID-19) pandemic has demonstrated the importance of stewardship of viral diagnostic tests to aid infection prevention efforts in healthcare facilities. We highlight diagnostic stewardship lessons learned during the COVID-19 pandemic and discuss how diagnostic stewardship principles can inform management and mitigation of future emerging pathogens in acute-care settings. Diagnostic stewardship during the COVID-19 pandemic evolved as information regarding transmission (eg, routes, timing, and efficiency of transmission) became available. Diagnostic testing approaches varied depending on the availability of tests and when supplies and resources became available. Diagnostic stewardship lessons learned from the COVID-19 pandemic include the importance of prioritizing robust infection prevention mitigation controls above universal admission testing and considering preprocedure testing, contact tracing, and surveillance in the healthcare facility in certain scenarios. In the future, optimal diagnostic stewardship approaches should be tailored to specific pathogen virulence, transmissibility, and transmission routes, as well as disease severity, availability of effective treatments and vaccines, and timing of infectiousness relative to symptoms. This document is part of a series of papers developed by the Society of Healthcare Epidemiology of America on diagnostic stewardship in infection prevention and antibiotic stewardship.1.

Assessing Dose- and Sex-Dependent Antinociceptive Effects of Cannabidiol and Amitriptyline, Alone and in Combination, and Exploring Mechanism of Action Involving Serotonin 1A Receptors.

Inflammatory pain is caused by tissue hypersensitization and is a component of rheumatic diseases, frequently causing chronic pain. Current guidelines use a multimodal approach to pain and sociocultural changes have renewed interest in cannabinoid use, particularly cannabidiol (CBD), for pain. The tricyclic antidepressant amitriptyline (AT) is approved for use in pain-related syndromes, alone and within a multimodal approach. Therefore, we investigated sex- and dose-dependent effects of CBD and AT antinociception in the 2.5% formalin inflammatory pain model. Male and female C57BL/6J mice were pretreated with either vehicle, CBD (0.3-100 mg/kg), or AT (0.1-30 mg/kg) prior to formalin testing. In the acute phase, CBD induced antinociception after administration of 30-100 mg/kg in males and 100 mg/kg in females and in the inflammatory phase at doses of 2.5-100 mg/kg in males and 10-100 mg/kg in females. In the acute phase, AT induced antinociception at 10 mg/kg for all mice, and at 0.3 mg/kg in males and 3 mg/kg in female mice in the inflammatory phase. Combining the calculated median effective doses of CBD and AT produced additive effects for all mice in the acute phase and for males only in the inflammatory phase. Use of selective serotonin 1A receptor antagonist N-[2-[4-(2-methoxyphenyl)-1 piperazinyl]ethyl]-N-2-pyridinylcyclohexanecarboxamide (WAY-100635) maleate (0.1 mg/kg) before co-administration of CBD and AT reversed antinociception in the acute and partially reversed antinociception in the inflammatory phase. Administration of AT was found to enhance cannabinoid receptor type 1mRNA expression only in female mice. These results suggest a role for serotonin and sex in mediating cannabidiol and amitriptyline-induced antinociception in inflammatory pain. SIGNIFICANCE STATEMENT: Inflammatory pain is an important component of both acute and chronic pain. We have found that cannabidiol (CBD) and amitriptyline (AT) show dose-dependent, and that AT additionally shows sex-dependent, antinociceptive effects in an inflammatory pain model. Additionally, the combination of CBD and AT was found to have enhanced antinociceptive effects that is partially reliant of serotonin 1A receptors and supports the use of CBD within a multimodal approach to pain.