USP17 is required for peripheral trafficking of lysosomes.

Expression of the deubiquitinase USP17 is induced by multiple stimuli, including cytokines (IL-4/6), chemokines (IL-8, SDF1), and growth factors (EGF), and several studies indicate it is required for cell proliferation and migration. However, the mechanisms via which USP17 impacts upon these cellular functions are unclear. Here, we demonstrate that USP17 depletion prevents peripheral lysosome positioning, as well as trafficking of lysosomes to the cell periphery in response to EGF stimulation. Overexpression of USP17 also increases secretion of the lysosomal protease cathepsin D. In addition, USP17 depletion impairs plasma membrane repair in cells treated with the pore-forming toxin streptolysin O, further indicating that USP17 is required for lysosome trafficking to the plasma membrane. Finally, we demonstrate that USP17 can deubiquitinate p62, and we propose that USP17 can facilitate peripheral lysosome trafficking by opposing the E3 ligase RNF26 to untether lysosomes from the ER and facilitate lysosome peripheral trafficking, lysosome protease secretion, and plasma membrane repair.

Recommendations for Choosing Wisely in Pediatric Emergency Medicine: Five Opportunities to Improve Value.

Unnecessary diagnostic tests and treatments in children cared for in emergency departments (EDs) do not benefit patients, increase costs, and may result in harm. To address this low-value care, a taskforce of pediatric emergency medicine (PEM) physicians was formed to create the first PEM Choosing Wisely recommendations. Using a systematic, iterative process, the taskforce collected suggested items from an interprofessional group of 33 ED clinicians from 6 academic pediatric EDs. An initial review of 219 suggested items yielded 72 unique items. Taskforce members independently scored each item for its extent of overuse, strength of evidence, and potential for harm. The 25 highest-rated items were sent in an electronic survey to all 89 members of the American Academy of Pediatrics PEM Committee on Quality Transformation (AAP COQT) to select their top ten recommendations. The AAP COQT survey had a 63% response rate. The five most selected items were circulated to over 100 stakeholder and specialty groups (within the AAP, CW Canada, and CW USA organizations) for review, iterative feedback, and approval. The final 5 items were simultaneously published by Choosing Wisely United States and Choosing Wisely Canada on December 1, 2022. All recommendations focused on decreasing diagnostic testing related to respiratory conditions, medical clearance for psychiatric conditions, seizures, constipation, and viral respiratory tract infections. A multinational PEM taskforce developed the first Choosing Wisely recommendation list for pediatric patients in the ED setting. Future activities will include dissemination efforts and interventions to improve the quality and value of care specific to recommendations.

TBX2 acts as a potent transcriptional silencer of tumour suppressor genes through interaction with the CoREST complex to sustain the proliferation of breast cancers.

Chromosome 17q23 amplification occurs in 20% of primary breast tumours and is associated with poor outcome. The TBX2 gene is located on 17q23 and is often over-expressed in this breast tumour subset. TBX2 is an anti-senescence gene, promoting cell growth and survival through repression of Tumour Suppressor Genes (TSGs), such as NDRG1 and CST6. Previously we found that TBX2 cooperates with the PRC2 complex to repress several TSGs, and that PRC2 inhibition restored NDRG1 expression to impede cellular proliferation. Here, we now identify CoREST proteins, LSD1 and ZNF217, as novel interactors of TBX2. Genetic or pharmacological targeting of CoREST emulated TBX2 loss, inducing NDRG1 expression and abolishing breast cancer growth in vitro and in vivo. Furthermore, we uncover that TBX2/CoREST targeting of NDRG1 is achieved by recruitment of TBX2 to the NDRG1 promoter by Sp1, the abolishment of which resulted in NDRG1 upregulation and diminished cancer cell proliferation. Through ChIP-seq we reveal that 30% of TBX2-bound promoters are shared with ZNF217 and identify novel targets repressed by TBX2/CoREST; of these targets a lncRNA, LINC00111, behaves as a negative regulator of cell proliferation. Overall, these data indicate that inhibition of CoREST proteins represents a promising therapeutic intervention for TBX2-addicted breast tumours.

Pediatric croup with COVID-19.

We describe three previously healthy children, admitted from our emergency department (ED) to our free-standing children's hospital, as the first documented cases of croup as a manifestation of SARS-CoV-2 infection. All three cases (ages 11 months, 2 years, and 9 years old) presented with non-specific upper-respiratory-tract symptoms that developed into a barky cough with associated stridor at rest and respiratory distress. All were diagnosed with SARS-CoV-2 by polymerase chain reaction testing from nasopharyngeal samples that were negative for all other pathogens including the most common etiologies for croup. Each received multiple (≥3) doses of nebulized racemic epinephrine with minimal to no improvement shortly after medication. All had a prolonged period of time from ED presentation until the resolution of their stridor at rest (13, 19, and 21 h). All received dexamethasone early in their ED treatment and all were admitted. All three received at least one additional dose of dexamethasone, an atypical treatment occurrence in our hospital, due to each patient's prolonged duration of symptoms. One child required heliox therapy and admission to intensive care. All patients were eventually discharged. Pathogen testing is usually not indicated in croup, but with "COVID-19 croup," SARS-CoV-2 testing should be considered given the prognostic significance and prolonged quarantine implications. Our limited experience with this newly described COVID-19 croup condition suggests that cases can present with significant pathology and might not improve as rapidly as those with typical croup.

Evaluation of an Online Educational Tool to Improve Postresuscitation Debriefing in the Emergency Department.

OBJECTIVE: Postresuscitation debriefing (PRD) addresses Accreditation Council for Graduate Medical Education core competencies and is recommended by the American Heart Association. Postresuscitation debriefing improves resuscitation outcomes, promotes team morale, supports emotional well-being, and reduces burnout. Despite these benefits, PRD occurs infrequently. Commonly cited barriers to PRD include lack of training and comfort in facilitating PRD. We are unaware of any video-based educational tools that train physicians in PRD. We aimed to evaluate the impact of an educational tool on the frequency of PRD using a before- and after-study design. METHODS: We created and distributed a 20-minute, video-based educational tool via youtube.com on PRD to pediatric emergency medicine (EM) fellows, pediatric EM attendings, senior EM residents, and EM attending physicians. Participants completed web-based surveys before, immediately after, and 3 months after watching the tool. We analyzed the effects of participation on PRD knowledge, comfort conducting PRD, and frequency of PRD performance. RESULTS: Thirty-five (63%) of 56 participants completed all 3 surveys. Participation in our study showed significant improvements in reported frequency of performing PRD (23% presurvey, 38% follow-up survey; 95% confidence interval [CI], 2%-29%; P = 0.03), perceived knowledge of PRD (odds ratio, 6.1; 95% CI, 3.05-12.29; P < 0.001), and comfort in conducting PRD (odds ratio, 3.7; 95% CI, 1.96-7.03; P < 0.001). Most respondents (94%) reported that the tool was worthwhile. Most (83%) would recommend the tool to colleagues, and 86% reported positive effects on their teams with PRD. CONCLUSIONS: Implementation of a video-based educational tool on PRD in the emergency department was associated with increased provider report of PRD frequency, knowledge, and comfort level.

A Pulse Check on Leadership and Teamwork: An Evaluation of the First 5 Minutes of Emergency Department Resuscitation During Pediatric Cardiopulmonary Arrests.

OBJECTIVES: Effective leadership and teamwork are imperative during pediatric cardiopulmonary resuscitations (CPR). The initial phase of pediatric CPR, termed the "first 5 minutes," has significant care delivery gaps in both leadership and team performance. The aim of the study was to describe the performance data of emergency department (ED) teams who performed CPR in a pediatric ED. METHODS: We conducted a retrospective video review of resuscitations involving pediatric patients younger than 21 years who presented in cardiac arrest to a tertiary pediatric ED. Descriptive statistics were used for data analysis. RESULTS: Twenty events met study inclusion criteria. Prearrival task completion included the following: estimated weight (90%), airway set-up (85%), epinephrine dose prepared (84%), defibrillator ready (75%), and intraosseous kit ready (50%). Median prearrival notification time was 5 minutes 34 seconds (interquartile range = 4:44-7:13) with no significant relationship between prearrival time and task completion. Within the first 5 minutes, the team leader provided a care summary in 84%, prioritized tasks in 95%, and assigned roles for airway management (90%), intravenous/intravenous access (63%), and CPR/pulse check (63%). Most critical tasks were completed within 1 minute; however, only 25% had defibrillator pads placed within the 5-minute window. CONCLUSIONS: Our study of leadership and teamwork during the first 5 minutes of pediatric CPR care noted wide variation in team performance. Opportunities for improvements in CPR readiness can be incorporated into education and quality programs to drive improvements in the care of future pediatric patients experiencing cardiac arrest.

Using an eLearning Module to Facilitate Sepsis Knowledge Acquisition Across Multiple Institutions and Learner Disciplines.

OBJECTIVE: Guidelines exist for care of pediatric sepsis, but no study has assessed the benefit of electronic learning (eLearning) in this topic area. The objective of this multicenter study was to assess knowledge acquisition and retention for pediatric sepsis across multiple health care provider roles, using an adaptive and interactive eLearning module. METHODS: The study used pretest, posttest, and 90-day delayed test scores to evaluate provider knowledge after an adaptive and interactive eLearning module intervention. The eLearning module contained conditional logic-based assessments that allowed real-time adjustments of the displayed content according to each participant's demonstrated knowledge. Physicians, nurses, and advanced practice providers, primarily emergency department based, at 9 pediatric institutions were included. Changes in test scores were stratified by provider role. RESULTS: A total of 574 participants completed the posttest, and 296 (51.6%) of those completed the delayed test. Across all providers, there was an increase in test scores of 15.7% between the pretest and posttest (P < 0.001) with a large effect size as measured by Cramer's V. Across all providers, there was an overall test score increase of 5.2% (P < 0.001) between the pretest and delayed test, with a small effect size. CONCLUSIONS: An eLearning module improved immediate and delayed pediatric sepsis knowledge in pediatric health care providers across multiple institutions and provider roles. Immediate knowledge gain was meaningful as indicated by effect sizes, although by the time of the delayed test, the effect was smaller. This module fills an important gap in currently available pediatric sepsis education.

Development, Validation, and Implementation of a Guideline to Improve Clinical Event Debriefing at a Level-I Adult and Level-II Pediatric Trauma Center.

OBJECTIVE: Clinical event debriefing is recommended by the American Heart Association and the European Resuscitation Council, because debriefings improve team performance. The purpose here was to develop and validate tools needed to overcome barriers to debriefing in the emergency department. METHOD: This quality improvement project was conducted in 4 phases. Phase 1: Current evidence related to debriefing in the emergency department was reviewed and synthesized to inform an iterative process for drafting the debriefing guideline and instrument for documentation. Phase 2: Content Validity Index of the tools was evaluated by obtaining ratings of items' clarity and relevance from 5 national experts in 2 rounds of review. On the basis of experts' feedback, tools were revised, and a Facilitators' Guide was created. Phase 3: The validated debriefing tools were implemented. Phase 4: Debriefing facilitators completed a survey about their experience with using the new tools. RESULTS: The Content Validity Index of 71 debriefing tool items (guideline, instrument, Facilitators' Guide) was 0.93 and 0.96 for clarity and relevance, respectively. Of the 32 debriefings conducted during the first 8 weeks of implementation, 53% described patient safety concerns, and 97% described recommendations to improve performance. Most (94%) facilitators agreed that the guideline clarified debriefing requirements. CONCLUSION: The use of debriefing tools validated by computation of the Content Validity Index led to the identification of safety threats and recommendations to improve care processes. These tools can be used in ED settings to promote team learning and aid in identifying and resolving safety concerns.

Identifying Nonprovider Factors Affecting Pediatric Emergency Medicine Provider Efficiency.

OBJECTIVE: The aim of this study was to create a multivariable model of standardized relative value units per hour by adjusting for nonprovider factors that influence efficiency. METHODS: We obtained productivity data based on billing records measured in emergency relative value units for (1) both evaluation and management of visits and (2) procedures for 16 pediatric emergency medicine providers with more than 750 hours worked per year. Eligible shifts were in an urban, academic pediatric emergency department (ED) with 2 sites: a tertiary care main campus and a satellite community site. We used multivariable linear regression to adjust for the impact of shift and pediatric ED characteristics on individual-provider efficiency and then removed variables from the model with minimal effect on productivity. RESULTS: There were 2998 eligible shifts for the 16 providers during a 3-year period. The resulting model included 4 variables when looking at both ED sites combined. These variables include the following: (1) number of procedures billed by provider, (2) season of the year, (3) shift start time, and (4) day of week. Results were improved when we separately modeled each ED location. A 3-variable model using procedures billed by provider, shift start time, and season explained 23% of the variation in provider efficiency at the academic ED site. A 3-variable model using procedures billed by provider, patient arrivals per hour, and shift start time explained 45% of the variation in provider efficiency at the satellite ED site. CONCLUSIONS: Several nonprovider factors affect provider efficiency. These factors should be considered when designing productivity-based incentives.

An Evaluation of a New Debriefing Framework: REFLECT.

BACKGROUND: Postresuscitation debriefing (PRD) is recommended by the American Heart Association guidelines but is infrequently performed. Prior studies have identified barriers for pediatric emergency medicine (PEM) fellows including lack of a standardized curriculum. OBJECTIVE: Our objective was to create and assess the feasibility of a time-limited, structured PRD framework entitled REFLECT: Review the event, Encourage team participation, Focused feedback, Listen to each other, Emphasize key points, Communicate clearly, and Transform the future. METHODS: Each PEM fellow (n = 9) at a single center was a team leader of a pre-intervention and post-intervention videotaped, simulated resuscitation followed by a facilitated team PRD. Our intervention was a 2-hour interactive, educational workshop on debriefing and the use of the REFLECT debriefing aid. Videos of the pre-intervention and post-intervention debriefings were blindly analyzed by video reviewers to assess for the presence of debriefing characteristics contained in the REFLECT debriefing aid. PEM fellow and team member assessments of the debriefings were completed after each pre-intervention and post-intervention simulation, and written evaluations by PEM fellows and team members were analyzed. RESULTS: All 9 PEM fellows completed the study. There was an improvement in the pre-intervention and post-intervention assessment of the REFLECT debriefing characteristics as determined by fellow perception (63% to 83%, P < 0.01) and team member perception (63% to 82%, P < 0.001). All debriefings lasted less than 5 minutes. There was no statistical difference between pre-intervention and post-intervention debriefing time (P = 1.00). CONCLUSIONS: REFLECT is a feasible debriefing aid designed to incorporate evidence-based characteristics into a PRD.

Implementation of an Innovative, Multiunit, Postevent Debriefing Program in a Children's Hospital.

BACKGROUND: Postevent debriefing has been associated with improved resuscitation outcomes and is recommended by the American Heart Association and the American Academy of Pediatrics to improve clinical performance. OBJECTIVE: Despite the benefits of postevent debriefing, published debriefing programs have focused on single areas within a hospital. We are unaware of any hospital-wide debriefing programs implemented in a pediatric setting. METHODS: We established a multidisciplinary, interprofessional debriefing collaborative at the Children's Hospital of Philadelphia to implement postevent debriefings in multiple areas of the hospital. The collaborative created a standardized debriefing form to capture data about the postevent debriefings. RESULTS: From July 23, 2015 to December 31, 2017, the emergency department performed 153 debriefings (18%) for 850 resuscitations. The neonatal intensive care unit conducted 10 debriefings (9%) for 107 resuscitations, and the pediatric intensive care unit performed 5 debriefings (7%) for 73 resuscitations. CONCLUSIONS: Several departments at the Children's Hospital of Philadelphia have incorporated hot and cold debriefings into their clinical practice as part of their continuous quality improvement programs. By disseminating the tools and lessons learned from the implementation process, the collaborative hopes that other institutions will benefit from their lessons learned to successfully create their own debriefing programs. Widespread adoption of debriefing programs will enable a more scientific approach to studying the outcomes of debriefing.

NUP98 - a novel predictor of response to anthracycline-based chemotherapy in triple negative breast cancer.

BACKGROUND: Triple Negative breast cancer (TNBC) is a poor outcome subgroup of breast cancer defined based on the absence of expression of ERα and PR and HER2 amplification. These hard to treat cancers lack targeted treatment options and are therefore treated with a standard of care (SoC) generic cocktail of DNA damaging chemotherapy, with a wide range of clinical responses. While a subset of TNBC patients respond very well to this treatment, others receive no clinical benefit and die from their disease within a short time period. We currently lack biomarkers to prospectively identify patients likely to relapse and we lack alternate treatment options. METHODS: NUP98 protein expression was investigated in patient samples using two independent tissue microarrays (TMAs), as well as a normal breast TMA. Correlation with pathological response to various chemotherapy regimens was investigated. RESULTS: We have shown that high NUP98 is significantly associated with poor outcome in TNBC patient samples both by gene expression and IHC-based protein analysis. While trends linking NUP98 expression with poorer outcomes were observed in breast cancer overall (and more specifically in the LuminalB Her2- subgroup), significant correlations were observed in TNBC. This appeared to be specific to anthracycline based regimens as the association between NUP98 and response was not observed in patients treated with taxane-based chemotherapy. CONCLUSIONS: We have identified a novel biomarker, NUP98, that can predict response to anthracycline based chemotherapy in TNBC. The ability to prospectively identify patients who are less likely to respond to SoC chemotherapy is a vital step in improving the overall survival of these patients.

Defining the molecular evolution of extrauterine high grade serous carcinoma.

OBJECTIVE: High grade serous carcinoma (HGSC) is the most common and most aggressive, subtype of epithelial ovarian cancer. It presents as advanced stage disease with poor prognosis. Recent pathological evidence strongly suggests HGSC arises from the fallopian tube via the precursor lesion; serous tubal intraepithelial carcinoma (STIC). However, further definition of the molecular evolution of HGSC has major implications for both clinical management and research. This study aims to more clearly define the molecular pathogenesis of HGSC. METHODS: Six cases of HGSC were identified at the Northern Ireland Gynaecological Cancer Centre (NIGCC) that each contained ovarian HGSC (HGSC), omental HGSC (OMT), STIC, normal fallopian tube epithelium (FTE) and normal ovarian surface epithelium (OSE). The relevant formalin-fixed paraffin embedded (FFPE) tissue samples were retrieved from the pathology archive via the Northern Ireland Biobank following attaining ethical approval (NIB11:005). Full microarray-based gene expression profiling was performed on the cohort. The resulting data was analysed bioinformatically and the results were validated in a HGSC-specific in-vitro model. RESULTS: The carcinogenesis of HGSC was investigated and showed the molecular profile of HGSC to be more closely related to normal FTE than OSE. STIC lesions also clustered closely with HGSC, indicating a common molecular origin. CONCLUSION: This study provides strong evidence suggesting that extrauterine HGSC arises from the fimbria of the distal fallopian tube. Furthermore, several potential pathways were identified which could be targeted by novel therapies for HGSC. These findings have significant translational relevance for both primary prevention and clinical management of the disease.

Identification and SAR exploration of a novel series of Legumain inhibitors.

This letter describes the development of a series of potent and selective small molecule Legumain inhibitors suitable as chemical probes for in vitro experiments. Our previous research had identified a dipeptide inhibitor utilizing a semi-reversible cyano warhead that generated 2, a cell active inhibitor. This work explores an alternative P2-P3 linker and further SAR exploration of the P3 group which led to the identification of 16i, a highly potent inhibitor with excellent physiochemical properties.

Videographic Assessment of the Quality of EMS to ED Handoff Communication During Pediatric Resuscitations.

BACKGROUND: The National Association of Emergency Medical Services (EMS) Physicians emphasizes the importance of high quality communication between EMS providers and emergency department (ED) staff for providing safe, effective care. The Joint Commission has identified ineffective handoff communication as a contributing factor in 80% of serious medical errors. The quality of handoff communication from EMS to ED teams for critically ill pediatric patients needs further exploration. OBJECTIVE: This study assessed the quality of handoff communication between EMS and ED staff during pediatric medical resuscitations. METHODS/DESIGN: We conducted a retrospective review of video recordings of pediatric patients who required critical care ("resuscitation") in the ED between January 2014 and February 2016 at a Level 1 pediatric trauma center. Handoff quality between EMS and emergency department teams was assessed for completeness, timeliness, and efficiency. Institutional review board approval was obtained. RESULTS: Sixty-eight resuscitations were reviewed; 28% presented in cardiac arrest, requiring cardiopulmonary resuscitation (CPR). Completeness of information communicated was variable and included chief complaint (88%), prehospital interventions (81%), physical exam findings (63%), medical history (59%), age (56%), and weight (20%). Completeness of specific vital sign reporting included: respiratory rate (53%), heart rate (43%), oxygen saturation (39%), and blood pressure (31%). Timeliness of communication included median patient handoff and report times of 50 seconds [IQR 30,74] and 108 seconds [IQR 62,252], respectively. Inefficient communication occurred in 87% of handoffs, including interruptions by ED staff (51%), questions from the ED physician team leader asking for information already communicated (40%), and questions by ED physician team leader requesting information not yet communicated (65%). When comparing non-CPR to CPR cases, only timeliness of patient handoff was significantly different for those patients receiving prehospital CPR. CONCLUSION: Handoff communication between EMS and ED teams during pediatric resuscitation was frequently incomplete and inefficient. Future educational and quality improvement interventions could aim to improve the quality of handoff communication for this patient population.

Evaluating the Implementation Barriers of an Intranasal Fentanyl Pain Pathway for Pediatric Long-Bone Fractures.

OBJECTIVES: This study aimed to assess physician comfort, knowledge, and implementation barriers regarding the use of intranasal fentanyl (INF) for pain management in patients with long-bone fractures in a pediatric emergency department (ED) with an INF pain pathway. METHODS: A retrospective chart review was conducted of patients, 3 to 21 years old, in our ED with an International Classification of Diseases-9th Revision code for a long-bone fracture from September 1, 2013, to August 31, 2015. Patients were divided into 4 groups: (1) received INF on the pathway appropriately; (2) "missed opportunities" to receive INF, defined as either INF was ordered and then subsequently canceled (for pain ratings, ≥6/10), or INF was ordered, cancelled, and intravenous (IV) morphine given, or INF was not ordered and a peripheral IV line was placed to give IV morphine as first-line medication; (3) peripheral IV established upon ED arrival; (4) no pain medication required. Additionally, a survey regarding practice habits for pain management was completed to evaluate physician barriers to utilization of the pathway. RESULTS: A total of 1374 patients met the inclusion criteria. Missed opportunities were identified 41% of the time. Neither younger patient age nor more years of physician experience in the ED were associated with increased rates of missed opportunities. The survey (95% response rate) revealed greater comfort with and preference for IV morphine over INF. CONCLUSIONS: The high rate of missed opportunities, despite the implementation of an INF pain pathway, indicates the need for further exploration of the barriers to utilization of the INF pain pathway.

Secondary imaging for suspected appendicitis after equivocal ultrasound: time to disposition of MRI compared to CT.

PURPOSE: The purpose of this study was to compare MRI to CT as a secondary imaging modality for children age 5 years and older with suspected appendicitis after an equivocal abdominal ultrasound in terms of (1) the time to ED disposition decision, (2) surgery consultation rate, and (3) imaging test accuracy. METHODS: We retrospectively studied children with suspected appendicitis and equivocal ultrasound results who underwent MR or CT as secondary imaging in a pediatric emergency department over two-consecutive 9-month periods. No oral or intravenous contrast was utilized for MRI. No sedation was utilized for any modality. Time of disposition is the time to admission or discharge order. RESULTS: Twenty-five patients underwent CT and 30 underwent MRI, with no significant difference in the median time from ultrasound to disposition between the CT (5.9 h, IQR 4.5, 8.4) and the MRI (5.9 h, IQR 4.6, 6.9) groups (p = 0.65). Fifteen patients had appendicitis. Of the 40 negative or equivocal studies, surgery was consulted for 79% in the CT and 48% in the MRI group (odds ratio 4.12, 95% CI 1.02-16.67). Diagnostic accuracy was as follows: MRI: sensitivity of 90%, specificity of 97.1%, positive predictive value of 90%, and negative predictive value of 97.1%. Abdominal CT: sensitivity of 88%, specificity of 98.6%, positive predictive value of 95.7%, and negative predictive value of 95.8%. CONCLUSION: MRI is a feasible alternative to CT for secondary imaging in acute appendicitis for showing comparable ED throughput metrics and diagnostic accuracy, with added benefits of reduced radiation and avoidance of intravenous contrast.

Advanced Human Immunodeficiency Virus Disease in Botswana Following Successful Antiretroviral Therapy Rollout: Incidence of and Temporal Trends in Cryptococcal Meningitis.

Background: Botswana has a well-developed antiretroviral therapy (ART) program that serves as a regional model. With wide ART availability, the burden of advanced human immunodeficiency virus (HIV) and associated opportunistic infections would be expected to decline. We performed a nationwide surveillance study to determine the national incidence of cryptococcal meningitis (CM), and describe characteristics of cases during 2000-2014 and temporal trends at 2 national referral hospitals. Methods: Cerebrospinal fluid data from all 37 laboratories performing meningitis diagnostics in Botswana were collected from the period 2000-2014 to identify cases of CM. Basic demographic and laboratory data were recorded. Complete national data from 2013-2014 were used to calculate national incidence using UNAIDS population estimates. Temporal trends in cases were derived from national referral centers in the period 2004-2014. Results: A total of 5296 episodes of CM were observed in 4702 individuals; 60.6% were male, and median age was 36 years. Overall 2013-2014 incidence was 17.8 (95% confidence interval [CI], 16.6-19.2) cases per 100000 person-years. In the HIV-infected population, incidence was 96.8 (95% CI, 90.0-104.0) cases per 100000 person-years; male predominance was seen across CD4 strata. At national referral hospitals, cases decreased during 2007-2009 but stabilized during 2010-2014. Conclusions: Despite excellent ART coverage in Botswana, there is still a substantial burden of advanced HIV, with 2013-2014 incidence of CM comparable to pre-ART era rates in South Africa. Our findings suggest that a key population of individuals, often men, is developing advanced disease and associated opportunistic infections due to a failure to effectively engage in care, highlighting the need for differentiated care models.

Accuracy of Postresuscitation Team Debriefings in a Pediatric Emergency Department.

STUDY OBJECTIVE: Guideline committees recommend postresuscitation debriefings to improve performance. "Hot" postresuscitation debriefings occur immediately after the event and rely on team recall. We assessed the ability of resuscitation teams to recall their performance in team-based, hot debriefings in a pediatric emergency department (ED), using video review as the criterion standard. We hypothesized that debriefing accuracy will improve during the course of the study. METHODS: Resuscitation physician and nurse leaders cofacilitated debriefings after ED resuscitations involving cardiopulmonary resuscitation (CPR) or intubation. Debriefing teams recorded their self-assessments of clinical performance measures with standardized debriefing forms. The debriefing form data were compared with actual performance measured by video review at 2 pediatric EDs over 22 months. CPR performance measures included time to automated external defibrillator pad placement, epinephrine administration timing, and compression pause timing. Intubation measures included occurrences of oxygen desaturation, number of intubation attempts, and use of end-tidal carbon dioxide monitoring. RESULTS: We analyzed 100 resuscitations (14 cardiac arrests, 22 cardiac arrests with intubation, and 64 intubations). The accuracy of debriefing answers was 87%, increasing from 83% to 91% between the first and second halves of the study period (7.7% difference; 95% confidence interval 0.2% to 15%). Debriefings that acknowledged an error in certain performance measures (ie, automated external defibrillator pad placement delay, multiple intubation attempts, and occurrence of oxygen desaturation) had significantly worse performance in those specific measures on video review. CONCLUSION: Teams in postresuscitation debriefings had a higher degree of debriefing answer accuracy in the final 50 debriefings than in the first 50. Teams also distinguished various degrees of resuscitation performance.

Flat SAR of P3-methylsulphonamide based small molecule legumain inhibitors.

This letter describes the design, development and SAR exploration of a novel series of small legumain inhibitors. The SAR of a new small molecule legumain inhibitor chemotype was explored and found to have improved physiochemical properties compared to previously developed inhibitors within our group. However, further development of this series was found to be limited as the SAR was observed to be relatively flat.