Randomized Phase II Trial of Imiquimod with or without 9-Valent HPV Vaccine versus Observation in Patients with High-grade Pre-neoplastic Cervical Lesions (NCT02864147).

PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.

Use of point-of-care ultrasound in rural British Columbia: Scale, training, and barriers.

OBJECTIVE: To determine the scale and scope of use of point-of-care ultrasound (POCUS) in rural British Columbia (BC). DESIGN: Online survey. SETTING: Rural BC. PARTICIPANTS: Physicians practising in rural BC communities. MAIN OUTCOME MEASURES: Practitioner demographic and practice characteristics, locations and frequency of POCUS use, POCUS education and training, and practitioner attitudes about and barriers to POCUS use. RESULTS: Two hundred twenty-seven surveys were completed in fall 2021, corresponding to a response rate of 11.9% of all rural practitioners in BC. A total of 52.1% of respondents worked in communities with less than 10,000 people, while 24.9% had practices with relatively large proportions of Indigenous patients (more than 20% of the practice population). Respondents reported ease of access to local POCUS devices, with use highest in emergency departments (87.2%) followed by ambulatory care clinic (54.7%) and inpatient (50.3%) settings. Use of POCUS influenced clinical decision making in half the occasions in which it was employed, including a range of diagnostic and procedural applications. Barriers to use included lack of training, limited time to perform POCUS scans, and absence of image review or consultative support. Needed support for POCUS identified by respondents included real-time image acquisition advice and funding for both device acquisition and training. Recommendations for including POCUS training in undergraduate and residency education were strongly supported. CONCLUSION: Use of POCUS in BC is expanding in frequency, scope, and scale in practices serving rural areas and in rural communities with large Indigenous populations, with practitioners reporting important improvements in clinical care as a result. Future research could help improve systemic support for POCUS use, guide needed curriculum changes in medical school and postgraduate training, and be used to inform continuing professional development needs.

Test Characteristics of Emergency Medicine-Performed Point-of-Care Ultrasound for the Diagnosis of Acute Cholecystitis: A Systematic Review and Meta-analysis.

Acute cholecystitis accounts for up to 9% of hospital admissions for acute abdominal pain, and best practice entails early surgical management. Ultrasound is the standard modality used to confirm diagnosis. Our objective was to perform a systematic review and meta-analysis to determine the diagnostic accuracy of emergency physician-performed point-of-care ultrasound for the diagnosis of acute cholecystitis when compared with a reference standard of final diagnosis (informed by available surgical pathology, discharge diagnosis, and radiology-performed ultrasound). We completed a systematic review and meta-analysis, registered in PROSPERO, in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched 7 databases as well as gray literature in the form of select conference abstracts from inception to February 8, 2023. Two independent reviewers completed study selection, data extraction, and risk of bias (QUADAS-2) assessment. Disagreements were resolved by consensus with a third reviewer. Data were extracted from eligible studies to create 2 × 2 tables for diagnostic accuracy meta-analysis. Hierarchical Summary Receiver Operating Characteristic models were constructed. Of 1855 titles/abstracts, 40 were selected for full-text review. Ten studies (n=2356) were included. Emergency physician-performed point-of-care ultrasound with final diagnosis as the reference standard (7 studies, n=1,772) had a pooled sensitivity of 70.9% (95% confidence interval [CI] 62.3 to 78.2), specificity of 94.4% (95% CI 88.2 to 97.5), positive likelihood ratio of 12.7 (5.8 to 27.5), and negative likelihood ratio of 0.31 (0.23 to 0.41) for the diagnosis of acute cholecystitis. Emergency physician-performed point-of-care ultrasound has high specificity and moderate sensitivity for the diagnosis of acute cholecystitis in patients with clinical suspicion. This review supports the use of emergency physician-performed point-of-care ultrasound to rule in a diagnosis of acute cholecystitis in the emergency department, which may help expedite definitive management.

POCUS literature primer: key papers on POCUS in cardiac arrest and shock.

OBJECTIVE: The objective of this study is to identify the top five most influential papers published on the use of point-of-care ultrasound (POCUS) in cardiac arrest and the top five most influential papers on the use of POCUS in shock in adult patients. METHODS: An expert panel of 14 members was recruited from the Canadian Association of Emergency Physicians (CAEP) Emergency Ultrasound Committee and the Canadian Ultrasound Fellowship Collaborative. The members of the panel are ultrasound fellowship trained or equivalent, are engaged in POCUS research, and are leaders in POCUS locally and nationally in Canada. A modified Delphi process was used, consisting of three rounds of sequential surveys and discussion to achieve consensus on the top five most influential papers for the use of POCUS in cardiac arrest and shock. RESULTS: The panel identified 39 relevant papers on POCUS in cardiac arrest and 42 relevant papers on POCUS in shock. All panel members participated in all three rounds of the modified Delphi process, and we ultimately identified the top five most influential papers on POCUS in cardiac arrest and also on POCUS in shock. Studies include descriptions and analysis of safe POCUS protocols that add value from a diagnostic and prognostic perspective in both populations during resuscitation. CONCLUSION: We have developed a reading list of the top five influential papers on the use of POCUS in cardiac arrest and shock to better inform residents, fellows, clinicians, and researchers on integrating and studying POCUS in a more evidence-based manner.

RéSUMé: OBJECTIF: L'objectif de cette étude est d'identifier les cinq articles les plus influents publiés sur l'utilisation de l'échographie au point de soin (POCUS) dans l'arrêt cardiaque et les cinq articles les plus influents sur l'utilisation de POCUS dans le choc chez les patients adultes. MéTHODES: Un comité d'experts composé de 14 membres a été recruté par le Comité d'échographie d'urgence de l'Association canadienne des médecins d'urgence (ACMU) et le Canadian Ultrasound Fellowship Collaborative. Les membres du comité sont formés en échographie ou l'équivalent, participent à la recherche sur le POCUS et sont des chefs de file du POCUS à l'échelle locale et nationale au Canada. Un processus Delphi modifié a été utilisé, consistant en trois séries de sondages séquentiels et de discussions pour parvenir à un consensus sur les cinq articles les plus influents pour l'utilisation de POCUS dans les arrêts cardiaques et les chocs. RéSULTATS: Le panel a identifié 39 articles pertinents sur le POCUS en arrêt cardiaque et 42 articles pertinents sur le POCUS en état de choc. Tous les membres du panel ont participé aux trois cycles du processus Delphi modifié, et nous avons finalement identifié les cinq articles les plus influents sur le POCUS en arrêt cardiaque et aussi sur le POCUS en état de choc. Les études comprennent des descriptions et des analyses de protocoles POCUS sûrs qui ajoutent de la valeur d'un point de vue diagnostique et pronostique dans les deux populations pendant la réanimation. CONCLUSION: Nous avons dressé une liste de lecture des cinq principaux articles influents sur l'utilisation du POCUS en cas d'arrêt cardiaque et de choc afin de mieux informer les résidents, les boursiers, les cliniciens et les chercheurs sur l'intégration et l'étude du POCUS d'une manière plus factuelle.

Recommendations for POCUS Curriculum in Canadian Undergraduate Medical Education: Consensus from the Inaugural Seguin Canadian POCUS Education Conference.

Point of care ultrasound (POCUS) in Canadian undergraduate medical education (UGME) is limited. To address this paucity, the inaugural Seguin Canadian POCUS Education Conference hosted 14 of the 17 Canadian medical schools to develop a list of recommendations for POCUS education in Canadian UGME. Attending schools were divided into delegations consisting of a pre-clerkship student, a clerkship student and a staff physician. Recommendations were developed via a modified consensus development panel. Delegations submitted school-specific POCUS education summary documents for roundtable discussions, which yielded an initial set of recommendations. These were then summarized in a large group setting and voted upon for adoption with an a priori agreement threshold of 80%. Conference attendees developed 14 recommendations which 87% of participants agreed to adopt. Conference recommendations reflect the opinions of Canadian trainees and POCUS education experts thus serving as a framework for UGME POCUS education in Canada.

Point-of-Care Ultrasound (POCUS) Literature Primer: Key Papers on Renal and Biliary POCUS.

Objective The objective of this study is to identify the top five influential papers published on renal point-of-care ultrasound (POCUS) and the top five influential papers on biliary POCUS in adult patients. Methods A 14-member expert panel was recruited from the Canadian Association of Emergency Physicians (CAEP) Emergency Ultrasound Committee and the Canadian Ultrasound Fellowship Collaborative. All panel members have had ultrasound fellowship training or equivalent, are actively engaged in POCUS scholarship, and are involved with POCUS at their local site and nationally in Canada. We used a modified Delphi process consisting of three rounds of sequential surveys and discussion to achieve consensus on the top five influential papers for renal POCUS and biliary POCUS. Results The panel identified 27 relevant papers on renal POCUS and 30 relevant papers on biliary POCUS. All panel members participated in all three rounds of the modified Delphi process, and after completing this process, we identified the five most influential papers on renal POCUS and the five most influential papers on biliary POCUS. Conclusion We have developed a list, based on expert opinion, of the top five influential papers on renal and biliary POCUS to better inform all trainees and clinicians on how to use these applications in a more evidence-based manner. This list will also be of interest to clinicians and researchers who strive to further advance the field of POCUS.

A Narrative Review of Point of Care Ultrasound Assessment of the Optic Nerve in Emergency Medicine.

Point of care ultrasound (POCUS) of the optic nerve is easy to learn and has great diagnostic potential. Within emergency medicine, research has primarily focused on its use for the assessment of increased intracranial pressure, but many other applications exist, though the literature is heterogeneous and largely observational. This narrative review describes the principles of POCUS of the optic nerve including anatomy and scanning technique, as well as a summary of its best studied clinical applications of relevance in emergency medicine: increased intracranial pressure, idiopathic intracranial hypertension, optic neuritis, acute mountain sickness, and pediatric intracranial pressure assessment. In many of these applications, sonographic optic nerve sheath diameter (ONSD) has moderately high sensitivity and specificity, but the supporting studies are heterogeneous. Further studies should focus on standardization of the measurement of ONSD, establishment of consistent diagnostic thresholds for elevated intracranial pressure, and automation of ONSD measurement.

Test characteristics of ultrasound for the diagnosis of peritonsillar abscess: A systematic review and meta-analysis.

BACKGROUND: Distinguishing peritonsillar abscess (PTA) from peritonsillar cellulitis using clinical assessment is challenging as many features overlap for both conditions, and physical examination is only about 75% sensitive and 50% specific for diagnosing PTA. The primary objective of this systematic review was to determine the test characteristics of ultrasound for diagnosing PTA when compared to a reference standard of computed tomography or acquisition of pus via needle aspiration or incision and drainage. METHODS: This systematic review was performed in accordance with the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy (PRISMA-DTA) guidelines. We searched seven databases from 1960 to November 2022. Two independent reviewers completed study selection, data extraction, and QUADAS-2 risk-of-bias assessment. We used a bivariate random-effects model to calculate pooled sensitivity, specificity, positive likelihood ratio (LR+), and negative likelihood ratio (LR-). We also conducted subgroup analyses on radiology ultrasound compared to point-of-care ultrasound (POCUS) and intraoral compared to transcervical scanning techniques. RESULTS: From 339 citations, we identified 18 studies for inclusion. Because one study only reported positive cases of PTA (thereby preventing the calculation of specificity), it was excluded from the analysis, so the analysis included a total of 17 studies with 812 patients, of whom 541 had PTA. Pooled bivariate sensitivity was 86% (95% confidence interval [CI] 78%-91%), specificity 76% (95% CI 67%-82%), LR+ 3.51 (95% CI 2.59-4.89), and LR- 0.19 (95% CI 0.12-0.30). On subgroup analysis, radiology-performed ultrasound had a sensitivity and specificity of 89% and 71%, compared to POCUS, which had a sensitivity and specificity of 74% and 79%. Comparing the two different techniques, intraoral had a sensitivity and specificity of 91% and 75% while transcervical had a sensitivity and specificity of 80% and 81%. CONCLUSIONS: Ultrasound demonstrates high sensitivity for ruling out PTA, but it only has moderate specificity for ruling in the diagnosis.

EFSUMB Clinical Practice Guidelines for Point-of-Care Ultrasound: Part One (Common Heart and Pulmonary Applications) SHORT VERSION.

OBJECTIVE: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendations were produced, including assigning levels of evidence (LoE) and grading of recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement of the summary and recommendation for each question (using a 5-point Likert scale), which was approved in the case of a level of agreement of greater than 75 %. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1), the remaining 9 questions achieved broad agreement with an assigned LoE of 4 and a weak GRADE recommendation (question 2), three achieved an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8) and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.

EFSUMB Clinical Practice Guidelines for Point-of-Care Ultrasound: Part One (Common Heart and Pulmonary Applications) LONG VERSION.

AIMS: To evaluate the evidence and produce a summary and recommendations for the most common heart and lung applications of point-of-care ultrasound (PoCUS). METHODS: We reviewed 10 clinical domains/questions related to common heart and lung applications of PoCUS. Following review of the evidence, a summary and recommendation were produced, including assignment of levels of evidence (LoE) and grading of the recommendation, assessment, development, and evaluation (GRADE). 38 international experts, the expert review group (ERG), were invited to review the evidence presented for each question. A level of agreement of over 75 % was required to progress to the next section. The ERG then reviewed and indicated their level of agreement regarding the summary and recommendation for each question (using a 5-point Likert scale), which was approved if a level of agreement of greater than 75 % was reached. A level of agreement was defined as a summary of "strongly agree" and "agree" on the Likert scale responses. FINDINGS AND RECOMMENDATIONS: One question achieved a strong consensus for an assigned LoE of 3 and a weak GRADE recommendation (question 1). The remaining 9 questions achieved broad agreement with one assigned an LoE of 4 and weak GRADE recommendation (question 2), three achieving an LoE of 3 with a weak GRADE recommendation (questions 3-5), three achieved an LoE of 3 with a strong GRADE recommendation (questions 6-8), and the remaining two were assigned an LoE of 2 with a strong GRADE recommendation (questions 9 and 10). CONCLUSION: These consensus-derived recommendations should aid clinical practice and highlight areas of further research for PoCUS in acute settings.

Point of Care Ultrasound Literature Primer: Key Papers on Focused Assessment With Sonography in Trauma (FAST) and Extended FAST.

Objective The objective of this study is to identify the top five most influential papers published on focused assessment with sonography in trauma (FAST) and the top five most influential papers on the extended FAST (E-FAST) in adult patients. Methods An expert panel was recruited from the Canadian Association of Emergency Physicians (CAEP) Emergency Ultrasound Committee and the Canadian Ultrasound Fellowship Collaborative. These experts are ultrasound fellowship-trained or equivalent, are involved with point-of-care ultrasound (POCUS) research and scholarship, and are leaders in both the POCUS program at their local site and within the national Canadian POCUS community. This 14-member expert group used a modified Delphi process consisting of three rounds of sequential surveys and discussion to achieve consensus on the top five most influential papers for FAST and E-FAST. Results The expert panel identified 56 relevant papers on FAST and 40 relevant papers on E-FAST. After completing all three rounds of the modified Delphi process, the authors identified the top five most influential papers on FAST and the top five most influential papers on E-FAST. Conclusion We have developed a reading list of the top five influential papers for FAST and E-FAST that will benefit residents, fellows, and clinicians who are interested in using POCUS in an evidence-informed manner.

Biomarkers of Tretinoin Precursors and Tretinoin Efficacy in Patients With Moderate to Severe Facial Photodamage: A Randomized Clinical Trial.

Importance: Topical formulations of tretinoin precursors (retinol and its ester derivatives) are widely available over the counter and may offer similar clinical benefits to those of tretinoin for treatment of photoaging. However, which of the many purported molecular effects of retinoids most strongly drives clinical improvements in tretinoin-treated skin remains unclear. Objectives: To evaluate the clinical efficacy of topical tretinoin precursors (TTP) vs tretinoin (RA) in treating moderate to severe facial photodamage and to identify potential biomarkers that correlate with clinical efficacy. Design, Setting, and Participants: This randomized, double-blind, single-center, parallel-arm study of 24 patients with moderate to severe facial photodamage was conducted at an academic referral center from November 2010 to December 2011, with data analysis performed from January 2012 to December 2021. Interventions: Daily topical application of 0.02% RA or 1.1% TTP formulation containing retinol, retinyl acetate, and retinyl palmitate for 24 weeks. Main Outcomes and Measures: Photoaging and tolerability were assessed by dermatologist evaluations and patient-reported outcomes. Target gene expression was assessed by real-time quantitative polymerase chain reaction of biopsied tissue from treated areas. Results: A total of 20 White women were ultimately analyzed (9 randomized to TTP, 11 randomized to RA). At week 24, there was no significant difference in Griffiths photoaging scores among patients receiving TTP vs RA (median, 4 vs 5) (TTP - RA difference: -1; 95% CI, -2 to 1; P = .27). Treatment with TTP was associated with erythema 6 times less frequently than RA (11% vs 64%) (TTP - RA difference: -0.53; 95% CI, -0.88 to -0.17; P = .01). Target gene analysis showed significant CRABP2 messenger RNA (mRNA) induction (confirming retinoic acid receptor signaling) but no significant changes in procollagen I or MMP1/3/9 mRNA in TTP-treated samples. Instead, MMP2 mRNA, which encodes a type IV collagenase, was significantly reduced in TTP-treated samples (week 24 - baseline mRNA difference: -5; 96% CI, -33 to 1.6; P = .02), and changes in MMP2 were strongly correlated with changes in fine wrinkles (r = 0.54; 95% CI, 0.12 to 0.80; P = .01). Interestingly, patients with severe baseline wrinkles exhibited greater improvements (r = -0.74; 95% CI, -0.89 to -0.43; P < .001). This trend was mirrored in MMP2 mRNA, with initial expression strongly predicting subsequent changes (r = -0.78; 95% CI, -0.89 to -0.43; P < .001). Conclusions and Relevance: In this randomized clinical trial, there was no significant difference in efficacy between this particular formulation of TTP and tretinoin 0.02%. However, the results of these mechanistic studies highlight MMP2 as a possible mediator of retinoid efficacy in photoaging. Trial Registration: ClinicalTrials.gov Identifier: NCT01283464.

Inhibition of type 1 immunity with tofacitinib is associated with marked improvement in longstanding sarcoidosis.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4+ T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity.

UVB-mediated DNA damage induces matrix metalloproteinases to promote photoaging in an AhR- and SP1-dependent manner.

It is currently thought that UVB radiation drives photoaging of the skin primarily by generating ROS. In this model, ROS purportedly activates activator protein-1 to upregulate MMPs 1, 3, and 9, which then degrade collagen and other extracellular matrix components to produce wrinkles. However, these MMPs are expressed at relatively low levels and correlate poorly with wrinkles, suggesting that another mechanism distinct from ROS and MMP1/3/9 may be more directly associated with photoaging. Here we show that MMP2, which degrades type IV collagen, is abundantly expressed in human skin, increases with age in sun-exposed skin, and correlates robustly with aryl hydrocarbon receptor (AhR), a transcription factor directly activated by UV-generated photometabolites. Through mechanistic studies with HaCaT human immortalized keratinocytes, we found that AhR, specificity protein 1 (SP1), and other pathways associated with DNA damage are required for the induction of both MMP2 and MMP11 (another MMP implicated in photoaging), but not MMP1/3. Last, we found that topical treatment with AhR antagonists vitamin B12 and folic acid ameliorated UVB-induced wrinkle formation in mice while dampening MMP2 expression in the skin. These results directly implicate DNA damage in photoaging and reveal AhR as a potential target for preventing wrinkles.