Antisense oligonucleotide targeting DMPK in patients with myotonic dystrophy type 1: a multicentre, randomised, dose-escalation, placebo-controlled, phase 1/2a trial.

BACKGROUND: Myotonic dystrophy type 1 results from an RNA gain-of-function mutation, in which DM1 protein kinase (DMPK) transcripts carrying expanded trinucleotide repeats exert deleterious effects. Antisense oligonucleotides (ASOs) provide a promising approach to treatment of myotonic dystrophy type 1 because they reduce toxic RNA levels. We aimed to investigate the safety of baliforsen (ISIS 598769), an ASO targeting DMPK mRNA. METHODS: In this dose-escalation phase 1/2a trial, adults aged 20-55 years with myotonic dystrophy type 1 were enrolled at seven tertiary referral centres in the USA and randomly assigned via an interactive web or phone response system to subcutaneous injections of baliforsen 100 mg, 200 mg, or 300 mg, or placebo (6:2 randomisation at each dose level), or to baliforsen 400 mg or 600 mg, or placebo (10:2 randomisation at each dose level), on days 1, 3, 5, 8, 15, 22, 29, and 36. Sponsor personnel directly involved with the trial, participants, and all study personnel were masked to treatment assignments. The primary outcome measure was safety in all participants who received at least one dose of study drug up to day 134. This trial is registered with ClinicalTrials.gov (NCT02312011), and is complete. FINDINGS: Between Dec 12, 2014, and Feb 22, 2016, 49 participants were enrolled and randomly assigned to baliforsen 100 mg (n=7, one patient not dosed), 200 mg (n=6), 300 mg (n=6), 400 mg (n=10), 600 mg (n=10), or placebo (n=10). The safety population comprised 48 participants who received at least one dose of study drug. Treatment-emergent adverse events were reported for 36 (95%) of 38 participants assigned to baliforsen and nine (90%) of ten participants assigned to placebo. Aside from injection-site reactions, common treatment-emergent adverse events were headache (baliforsen: ten [26%] of 38 participants; placebo: four [40%] of ten participants), contusion (baliforsen: seven [18%] of 38; placebo: one [10%] of ten), and nausea (baliforsen: six [16%] of 38; placebo: two [20%] of ten). Most adverse events (baliforsen: 425 [86%] of 494; placebo: 62 [85%] of 73) were mild in severity. One participant (baliforsen 600 mg) developed transient thrombocytopenia considered potentially treatment related. Baliforsen concentrations in skeletal muscle increased with dose. INTERPRETATION: Baliforsen was generally well tolerated. However, skeletal muscle drug concentrations were below levels predicted to achieve substantial target reduction. These results support the further investigation of ASOs as a therapeutic approach for myotonic dystrophy type 1, but suggest improved drug delivery to muscle is needed. FUNDING: Ionis Pharmaceuticals, Biogen.

Hypoxia Does Not Change Performance and Psychophysiological Responses During Repeated Cycling Sprints to Exhaustion With Short Exercise-to-Rest Ratio.

PURPOSE: To compare the acute performance and psychophysiological responses of repeated cycling sprints to exhaustion with a short exercise-to-rest ratio (1:6), between different effort durations and inspired oxygen fractions. METHODS: On separate visits, 10 active participants completed 6 repeated cycling sprint exercises to exhaustion with 3 different effort durations (5, 10, and 20 s) and 2 conditions of inspired oxygen (20.9% and 13.6%). Exercise-to-rest ratio was 1:6 for all trials (ie, 5:30, 10:60, and 20:120). Vastus lateralis muscle oxygenation (near-infrared spectroscopy), blood lactate concentration, and lower-limb and breathing discomfort, using ratings of perceived exertion, were measured. RESULTS: Number of sprints and peak power output decreased while blood lactate increased (all P < .001) during 5:30 compared with 10:60 or 20:120. No condition or interaction effects were reported for blood lactate and exercise-related sensation. Muscle deoxyhemoglobin increased (P < .001) and total hemoglobin decreased (P = .002) during sprint with increasing sprint duration (no condition or interaction). CONCLUSION: During repeated-sprint exercise to exhaustion with a short exercise-to-rest ratio, the psychophysiological responses did not differ between normoxia and moderate hypoxia, probably due to an extended recovery period. It means that hypoxia did not modify repeated-sprint exercise performance with a short exercise-to-rest ratio. The sprint duration was the primary underlying factor of the observed differences in performance and muscle oxygenation reported between the repeated-sprint exercise sessions.

Indoor Radon Levels in Homes and Schools in the Western Cape, South Africa-Results from a Schools Science Outreach Initiative and Corresponding Model Predictions.

We describe a school science outreach initiative that introduced learners to applied nuclear physics research by means of a two-day workshop that involved learners and teachers from 5 schools in the Western Cape province of South Africa. During this workshop, the participants were introduced to the naturally occurring, inert, colorless, and tasteless radioactive gas radon (222Rn). During the first day of the workshop, the participants were informed about the detrimental health impacts of inhaling radon and its daughter radionuclides and were shown how indoor radon activity concentrations can be measured using the electret ion chamber (EIC) technology. The learners were then each supplied with a short-term electret (E-PERM, Radelec, Frederick, MD, USA) and associated ion chamber to enable them to make radon measurements in their homes. The teachers in turn were supplied with EICs to enable them make radon measurements in their schools. The participants returned the EICs on the second day of the workshop, one week later. Here, the drop in the potential difference across each electret was measured in order to calculate the average indoor radon activity concentration. A total of 49 indoor radon concentrations were measured. The average indoor radon concentrations were 36 ± 26 Bqm-3 in homes and 41 ± 36 Bqm-3 in schools, while the highest concentration was found to be 144 Bqm-3. These levels were compared to predictions from a model that uses input information about the uranium content associated with the surface geology at each measurement location. The predictions compared well with the measured values.

The Oxidative-Glycolytic Balance Influenced by Sprint Duration Is Key during Repeated Sprint in Hypoxia.

PURPOSE: This study investigates the effects of normobaric hypoxia on repeated sprint exercise (RSE) with different balance between oxidative (phosphocreatine and oxidative pathway) and glycolytic contributions. Therefore, performance and psychophysiological responses were compared during RSE to exhaustion with the same exercise-to-rest ratio (1:2) but different sprint durations (5, 10, or 20 s) either in normoxic (RSN) or hypoxic (RSH; F io2 = 0.13) conditions. METHODS: On separate visits, 10 active participants completed in random order three cycling RSN (5:10; 10:20 and 20:40) and three similar RSH sessions to exhaustion. Vastus lateralis muscle oxygenation was recorded by near-infrared spectroscopy. Blood lactate concentration, limb and breathing discomfort, and ratings of perceived exertion were measured. RESULTS: Total sprint number was smaller in hypoxia than in normoxia for 5:10 (20.8 ± 8.6 vs 14.7 ± 3.4; P = 0.014) and 10:20 (13.7 ± 6.3 vs 8.8 ± 2.5; P = 0.018) but not 20:40 (5.6 ± 1.9 vs 5.6 ± 2.5). The fatigue index was larger in hypoxia only for 5:10 (-43.5%, P < 0.001). Irrespective of condition, blood lactate concentration increased with the sprint duration with higher values for 20:40 than 5:10 (13.1 ± 2.7 vs 11.5 ± 2.2 mmoL·L -1 ; P = 0.027). Limb and breathing discomfort and ratings of perceived exertion did not differ in all RSE. Muscle oxygenation was mainly impacted by sprint duration (i.e., main effect of sprint duration on [HHb] min, [tHb] max, Δ[HHb], and Δ[tHb]) but not by hypoxia. The normoxia-to-hypoxia percentage decrease for total sprint number for 5:10 was correlated with the highest power output over 5 s ( R2 = 0.55; P = 0.013) and 10 s ( R2 = 0.53; P = 0.016). CONCLUSIONS: Hypoxia impairs repeated sprint ability when the oxidative but not the glycolytic contribution is substantial. The oxidative-glycolytic balance, influenced partly by sprint duration, is key during repeated sprint in hypoxia.

Mâmawihitowin (bringing the camps together): Perinatal healthcare provider and staff participation in an Indigenous-led experiential intervention for enhancing culturally informed care-a mixed methods study.

BACKGROUND: In partnership with a Nehiyawak (Plains Cree) community of Maskwacîs,central Alberta (Canada), we implemented an Indigenous-led intervention to provide experiential learning opportunities for perinatal health care providers (HCPs) and staff. Our objective was to capture the impact of participating in cultural safety learning opportunities on perceived self-awareness for HCPs and staff to provide enhanced culturally informed care. METHODS: Perinatal HCPs and staff who work regularly with Indigenous women from our partnering community took part in a series of experiential learning activities designed by a Community Advisory Committee. We used an explanatory sequential mixed methods approach informed by community-based participatory research. We compared Cultural Intelligence Scale (CQS) and Maskwacîs-Specific Cultural Scale (MSCS) scores pre- and post-intervention using non-parametrical statistical analysis (Wilcoxon signed rank test). Post-intervention, we conducted a qualitative description study using semi-structured interviews. Qualitative data was analyzed using thematic analysis. RESULTS: A total of 17 participants completed pre- and post-intervention questionnaires. Responses indicated a shift in perceived cultural and community knowledge and comfort levels, with positive gains in overall mean scores for both the CQS (p = 0.01) and MSCS (p = 0.01). Nine participants completed qualitative interviews. Overall, participants felt better equipped to provide more culturally informed care to their patients post-intervention. CONCLUSION: An Indigenous-led experiential learning intervention was effective in enhancing overall perceived cultural awareness and preparedness to provide culturally informed care for perinatal HCPs and staff. This study provides evidence for fostering relationships between Indigenous communities and health systems toward enhanced perinatal care.

Increasing Cases of SARS-CoV-2 Omicron Reinfection Reveals Ineffective Post-COVID-19 Immunity in Denmark and Conveys the Need for Continued Next-Generation Sequencing

SARS-CoV-2 has extensively mutated creating variants of concern (VOC) resulting in global infection surges. The Omicron VOC reinfects individuals exposed to earlier variants of SARS-CoV-2 at a higher frequency than previously seen for non-Omicron VOC. An analysis of the sub-lineages associated with an Omicron primary infection and Omicron reinfection reveals that the incidence of Omicron-Omicron reinfections is occurring over a shorter time interval than seen after a primary infection with a non-Omicron VOC. Our analysis suggests that a single infection from SARS-CoV-2 may not generate the protective immunity required to defend against reinfections from emerging Omicron lineages. This analysis was made possible by Next-generation sequencing (NGS), specifically of a Danish cohort with clinical metadata on both infections occurring in the same individual. We suggest that the continuation of COVID-19 NGS and inclusion of clinical metadata is necessary to ensure effective surveillance of SARS-CoV-2 genomics, assist in treatment and vaccine development, and guide public health recommendations.

Impacts of the COVID-19 pandemic on pharmaceuticals in wastewater treated for beneficial reuse: Two case studies in central Pennsylvania.

During the COVID-19 pandemic, wastewater surveillance was leveraged as a powerful tool for monitoring community-scale health. Further, the well-known persistence of some pharmaceuticals through wastewater treatment plants spurred concerns that increased usage of pharmaceuticals during the pandemic would increase the concentrations in wastewater treatment plant effluent. We collected weekly influent and effluent samples from May 2020 through May 2021 from two wastewater treatment plants in central Pennsylvania, the Penn State Water Reclamation Facility and the University Area Joint Authority, that provide effluent for beneficial reuse, including for irrigation. Samples were analyzed for severe acute respiratory syndrome coronavirus 2 (influent only), two over-the-counter medicines (acetaminophen and naproxen), five antibiotics (ampicillin, doxycycline, ofloxacin, sulfamethoxazole, and trimethoprim), two therapeutic agents (remdesivir and dexamethasone), and hydroxychloroquine. Although there were no correlations between pharmaceutical and virus concentration, remdesivir detection occurred when the number of hospitalized patients with COVID-19 increased, and dexamethasone detection co-occurred with the presence of patients with COVID-19 on ventilators. Additionally, Penn State decision-making regarding instruction modes explained the temporal variation of influent pharmaceutical concentrations, with detection occurring primarily when students were on campus. Risk quotients calculated for pharmaceuticals with known effective and lethal concentrations at which 50% of a population is affected for fish, daphnia, and algae were generally low in the effluent; however, some acute risks from sulfamethoxazole were high when students returned to campus. Remdesivir and dexamethasone persisted through the wastewater treatment plants, thereby introducing novel pharmaceuticals directly to soils and surface water. These results highlight connections between human health and water quality and further demonstrate the broad utility of wastewater surveillance.

Paediatric Gastrointestinal, Hepatic and Pancreatic Inflammatory Myofibroblastic Tumours, A Single Centre Experience.

ABSTRACT: Inflammatory myofibroblastic tumours (IMTs) are rare soft tissue tumours. Reports of gastrointestinal tract, liver and pancreas tumours are limited. The objective of this study is to identify presenting features, contributing prognostic / etiological factors and any variability in outcomes in the context of different historical treatments. We retrospectively reviewed the records of seven children treated at our hospital between 2006 and 2019 and assessed the demographic, presentation, treatment, immunohistochemistry, and outcomes of their tumours. Age range at presentation was 4 months-15 years with a male predominance. Presentations were typically due to local mass effect or incidental discovery. Systemic symptoms were rare. Outcomes were good with six out of seven stable or in remission irrespective of treatment. Surgical resection where possible is the treatment of choice. Medical therapy had good outcomes with chemotherapy acting as first line treatment when required. The only negative prognostic factor identified was local spread at the time of presentation.

B-cell lymphoma 6 expression is not associated with live birth in a normal responder in vitro fertilization population.

OBJECTIVE: To determine whether increased endometrial B-cell lymphoma 6 (BCL6) expression is associated with live birth in a normal responder in vitro fertilization (IVF) population. DESIGN: Case-control study. SETTING: University-affiliated infertility center. PATIENT(S): Two groups of women undergoing IVF with preimplantation genetic testing for aneuploidy followed by warmed, single, euploid embryo transfer. Group 1 consisted of women who failed to achieve live birth, and group 2 consisted of women who achieved live birth. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometrial BCL6 expression measured by immunohistochemistry in endometrial tissue samples. Overexpression was defined by mean HSCORE with a cutoff of positivity of >1.4, as previously described in the literature. RESULT(S): Twenty-seven patients who achieved live birth and 23 patients who failed to achieve live birth were included. B-cell lymphoma 6 expression/HSCORE and live birth rate were not associated (Odds ratio [OR], 0.78 [0.24-2.55]). Using a cutoff of >1.4 for positivity, 8 of 23 samples were positive for BCL6 in the no live birth group, whereas 7 of 27 were positive in the live birth group. There was no significant association between BCL6 positivity and live birth (OR, 0.66 [0.19-2.21]). CONCLUSION(S): The proportion of patients with BCL6 positivity did not significantly differ between those who achieved live birth and those who did not. In the population of patients at our center, who compromise of women who respond normally to IVF stimulation, BCL6 overexpression was not associated with IVF success. Physicians implementing BCL6 testing as a diagnostic tool for clinical decision making should counsel patients that results may have limited utility in predicting IVF outcomes in this population.

Precision Medicine for Rheumatoid Arthritis: The Right Drug for the Right Patient-Companion Diagnostics.

Despite the growing number of biologic and JAK inhibitor therapeutic agents available to treat various systemic autoimmune illnesses, the lack of a validated companion diagnostic (CDx) to accurately predict drug responsiveness for an individual results in many patients being treated for years with expensive, ineffective, or toxic drugs. This review will focus primarily on rheumatoid arthritis (RA) therapeutics where the need is greatest due to poor patient outcomes if the optimum drug is delayed. We will review current FDA-approved biologic and small molecule drugs and why RA patients switch these medications. We will discuss the sampling of various tissues for potential CDx and review early results from studies investigating drug responsiveness utilizing advanced technologies including; multiplex testing of cytokines and proteins, autoantibody profiling, genomic analysis, proteomics, miRNA analysis, and metabolomics. By using these new technologies for CDx the goal is to improve RA patient outcomes and achieve similar successes like those seen in oncology using precision medicine guided therapeutics.

Recurrent implantation failure: how common is it?

PURPOSE OF REVIEW: To clarify a lingering issue, the true incidence of repeated implantation failures (RIF) in women undergoing successive frozen euploid single embryo transfers (FE-SET). RECENT FINDINGS: As not all Assisted reproductive techinique (ART) attempts are crowned by success, it has been questioned since incept of ART whether failures resulted from an embryonic or endometrial cause. RIF has received no precise definition but a trend has existed toward setting a more stringent definition, as reproductive biology has become more effective and ART success rates improved. No scientific society has yet convened on a universally accepted definition. The advent of effective and well tolerated pregestational testing of embryos for aneuploidy (PGT-A) has allowed to not transfer aneuploid embryos, which are bound not to succeed. This, therefore, justify revisiting the concept of RIF when only euploid embryos are transferred. SUMMARY: Contrary to lingering beliefs, the results of our study indicate that RIF following three successive euploid embryo transfers in a morphologically normal endometrium is a rare occurrence (<5%). This supports the concept that ART failures mainly result from embryonic causes. Our data also propose a new - functional - definition of RIF being an ART failure following 3 successive FE-SET attempts. Our findings, therefore seriously question the soundness of prescribing the often complex and expensive endometrial testing procedures that largely publicized for treating RIF.

Reaching the summit of discharge summaries: a quality improvement project.

BACKGROUND: Discharge summaries need to be completed in a timely manner, to improve communication between primary and secondary care, and evidence suggests that delays in discharge summary completion can lead to patient harm.Following a hospital health and safety review due to the sheer backlog of notes in the doctor's room and wards, urgent action had to be undertaken to improve the discharge summary completion process at our hospital's paediatric assessment unit. It was felt that the process would best be carried out within a quality improvement (QI) project. METHODS: Kotter's 'eight-step model for change' was implemented in this QI project with the aim to clear the existing backlog of pending discharge summaries and improve the timeliness of discharge summary completion from the hospital's paediatric assessment unit. A minimum target of 10% improvement in the completion rate of discharge summaries was set as the primary goal of the project. RESULTS: Following the implementation of the QI processes, we were able to clear the backlog of discharge summaries within 9 months. We improved completion within 24 hours, from <10% to 84%, within 2 months. The success of our project lies in the sustainability of the change process; to date we have consistently achieved the target completion rates since the inception of the project. As a result of the project, we were able to modify the junior doctor rota to remove discharge summary duty slots and bolster workforce on the shop floor. This is still evident in November 2020, with consistently improved discharge summary rates. CONCLUSION: QI projects when conducted successfully can be used to improve patient care, as well as reduce administrative burden on junior doctors. Our QI project is an example of how Kotter's eight-step model for change can be applied to clinical practice.

The regulatory technology "RegTech" and money laundering prevention in Islamic and conventional banking industry.

This study aims to illustrate the impact of adopting Regulatory technology (RegTech) innovations in banks on money laundering prevention effectiveness using Bahrain as a case study. Bahrain has strived to position itself as the banking center of the Arabian Gulf, hence the results of this novel research are informative of the practices in the region. The primary data for this study was collected through a survey instrument distributed to 100 bankers working in Bahrain with expertise in compliance. The results of multivariate analysis indicate that transactions monitoring through RegTech and cost- and time-saving aspects of RegTech, drive money laundering prevention effectiveness to a highly statistically significant extent. However, electronic know your customer (KYC) technologies are insignificant as drivers. This research not only sheds light on the efficacy of RegTech but also raises general awareness concerning the adoption and integration of RegTech platforms for fighting money laundering. In particular, the findings provide specific insights about the deployment of RegTech capabilities in banks in regional banking centers of modest scale.

anti-IL-6 versus anti-IL-6R Blocking Antibodies to Treat Acute Ebola Infection in BALB/c Mice with Potential Implications for Treating Patients Presenting with COVID-19

Cytokine release syndrome (CRS) is known to be a factor in morbidity and mortality associated with acute viral infections including those caused by filoviruses and coronaviruses. IL-6 has been implicated as a cytokine negatively associated with survival after filovirus and coronavirus infection. However, IL-6 has also been shown to be an important mediator of innate immunity and important for the host response to an acute viral infection. Clinical studies are now being conducted by various researchers to evaluate the possible role of IL-6 blockers to improve outcomes in critically ill patients with CRS. Most of these studies involve the use of anti-IL-6R monoclonal antibodies (-IL-6R mAbs). We present data showing that direct neutralization of IL-6 with an -IL-6 mAb in a BALB/c Ebolavirus (EBOV) challenge model produced a statistically significant improvement in outcome compared with controls when administered within the first 24 hours of challenge and repeated every 72 hours. A similar effect was seen in mice treated with the same dose of -IL-6R mAb when the treatment was delayed 48 hrs post-challenge. These data suggest that direct neutralization of IL-6, early during the course of infection, may provide additional clinical benefits to IL-6 receptor blockade alone during treatment of patients with virus-induced CRS.

Correlation of Fentanyl Positive Drug Screens with Other Medications in Patients from Pain, Rehabilitation and Behavioral Programs.

Fentanyl has been associated with many drug overdose deaths; its presence in many street drugs has been postulated to be increasing. We examined 1.3 million urine drug tests from April 2016 to April 2019 for fentanyl and other drugs. The highest relationship was observed with heroin. Approximately 30%-40% of the drug tests positive for the heroin metabolite 6-monacetylmorphine (6-MAM) were also positive for fentanyl. There was a large variance over time, but the percent positive in 2016 and 2019 were similar. In contrast, there was a definite increase in the presence of fentanyl with cocaine and methamphetamine. There was not a large increase over time associated with methadone, buprenorphine, and marijuana.

Enzyme immunoassay for SARS-CoV-2 antibodies in dried blood spot samples: A minimally-invasive approach to facilitate community- and population-based screening

BackgroundSerological testing for SARS-CoV-2 IgG antibodies is needed to document the community prevalence and distribution of the virus, particularly since many individuals have mild symptoms and cannot access molecular diagnostic testing of naso-pharyngeal swabs. However, the requirement for serum/plasma limits serological testing to clinical settings where it is feasible to collect and process venous blood. To address this problem we developed a serological test for SARS-CoV-2 IgG antibodies that requires only a single drop of capillary whole blood, collected from a simple finger prick and dried on filter paper (dried blood spot, DBS). MethodsEnzyme linked immunosorbent assay (ELISA) was optimized to detect SARS-CoV-2 IgG antibodies against the receptor-binding domain (RBD) of the spike protein. DBS samples were eluted overnight and transferred to a 96-well plate coated with antigen, and anti-human IgG-HRP was used to generate signal in proportion to bound antibody. DBS samples spiked with anti-SARS IgG antibody, and samples from known positive and negative cases, were compared to evaluate assay performance. ResultsAnalysis of samples with known concentrations of anti-SARS IgG produced the expected pattern of dose-response. Optical density (OD) values were significantly elevated for known positive cases in comparison with samples from unexposed individuals. DiscussionDBS ELISA provides a minimally-invasive alternative to venous blood collection that combines the convenience of sample collection in the home or non-clinical setting with the quantitation of ELISA in the lab. Serological testing for SARS-CoV-2 IgG antibodies in DBS samples should facilitate research across a wide range of community- and population-based settings on seroprevalence, predictors and duration of antibody responses, as well as correlates of protection from reinfection, each of which is critically important for pandemic control.

Trends in late and advanced HIV diagnoses among migrants in Australia; implications for progress on Fast-Track targets: A retrospective observational study.

Achieving the Joint United Nations Program on human immunodeficiency virus (HIV)/AIDS Fast-Track targets requires additional strategies for mobile populations. We examined trends and socio-demographics of migrants (overseas-born) and Australian-born individuals presenting with late and advanced HIV diagnoses between 2008 and 2017 to help inform public health approaches for HIV testing coverage and linkage to care and treatment.We conducted a retrospective population-level observational study of individuals diagnosed with HIV in Australia and reported to the National HIV Registry. Annual proportional trends in late (CD4+ T-cell count <350 cells/µL) and advanced (CD4+ T-cell count <200 cells/µL). HIV diagnoses were determined using Poisson regression.Of 9926 new HIV diagnoses from 2008 to 2017, 84% (n = 8340) were included in analysis. Overall, 39% (n = 3267) of diagnoses were classified as late; 52% (n = 1688) of late diagnoses were advanced. Of 3317 diagnoses among migrants, 47% were late, versus 34% of Australian-born diagnoses (P < .001).The annual proportions of late (incidence rate ratio [IRR] 1.00; 95% confidence interval [CI] 0.99-1.01) and advanced HIV diagnoses (IRR 1.01; 95% CI 0.99-1.02) remained constant. Among migrants with late HIV diagnosis, the proportion reporting male-to-male sex exposure (IRR 1.05; 95% CI 1.03-1.08), non-English speaking (IRR 1.03; 95% CI 1.01-1.05), and individuals born in countries in low HIV-prevalence (IRR 1.02; 95% CI 1.00-1.04) increased. However, declines were noted among some migrants' categories such as females, heterosexual exposure, English speaking, and those born in high HIV-prevalence countries.Late HIV diagnosis remains a significant public health concern in Australia. Small declines in late diagnosis among some migrant categories are offset by increases among male-to-male exposures. Reaching the Fast-Track targets in Australia will require targeted testing and linkage to care strategies for all migrant populations, especially men who have sex with men.

An Effective CTL Peptide Vaccine for Ebola Zaire Based on Survivors' CD8+ Targeting of a Particular Nucleocapsid Protein Epitope with Potential Implications for COVID-19 Vaccine Design

The 2013-2016 West Africa EBOV epidemic was the biggest EBOV outbreak to date. An analysis of virus-specific CD8+ T-cell immunity in 30 survivors showed that 26 of those individuals had a CD8+ response to at least one EBOV protein. The dominant response (25/26 subjects) was specific to the EBOV nucleocapsid protein (NP). It has been suggested that epitopes on the EBOV NP could form an important part of an effective T-cell vaccine for Ebola Zaire. We show that a 9-amino-acid peptide NP44-52 (YQVNNLEEI) located in a conserved region of EBOV NP provides protection against morbidity and mortality after mouse adapted EBOV challenge. A single vaccination in a C57BL/6 mouse using an adjuvanted microsphere peptide vaccine formulation containing NP44-52 is enough to confer immunity in mice. Our work suggests that a peptide vaccine based on CD8+ T-cell immunity in EBOV survivors is conceptually sound and feasible. Nucleocapsid proteins within SARS-CoV-2 contain multiple class I epitopes with predicted HLA restrictions consistent with broad population coverage. A similar approach to a CTL vaccine design may be possible for that virus.

Development of an Emergency Department Trigger Tool Using a Systematic Search and Modified Delphi Process.

OBJECTIVE: This study aimed to develop an emergency department (ED) trigger tool to improve the identification of adverse events in the ED and that can be used to direct patient safety and quality improvement. This work describes the first step toward the development of an ED all-cause harm measurement tool by experts in the field. METHODS: We identified a multidisciplinary group of emergency medicine safety experts from whom we solicited candidate triggers. We then conducted a modified Delphi process consisting of 4 stages as follows: (1) a systematic literature search and review, including an independent oversampling of review for inclusion, (2) solicitation of empiric triggers from participants, (3) a Web-based survey ranking triggers on specific performance constructs, and (4) a final in-person meeting to arrive at consensus triggers for testing. Results of each step were shared with participants between each stage. RESULTS: Among an initial 804 unique articles found using our search criteria, we identified 94 that were suitable for further review. Interrater reliability was high (κ = 0.80). Review of these articles yielded 56 candidate triggers. These were supplemented by 58 participant-submitted triggers yielding a total of 114 candidate triggers that were shared with team members electronically along with their definitions. Team members then voted on each measure via a Web-based survey, ranking triggers on their face validity, utility for quality improvement, and fidelity (sensitivity/specificity). Participants were also provided the ability to flag any trigger about which they had questions or they felt merited further discussion at the in-person meeting. Triggers were ranked by combining the first 2 categories (face validity and utility), and information on fidelity was reviewed for decision making at the in-person meeting. Seven redundant triggers were eliminated. At an in-person meeting including representatives from all facilities, we presented the 50 top-ranked triggers as well as those that were flagged on the survey by 2 or more participants. We reviewed each trigger individually, identifying 41 triggers about which there was a clear agreement for inclusion. Of the seven additional triggers that required subsequent voting via e-mail, 5 were adopted, arriving at a total of 46 consensus-derived triggers. CONCLUSIONS: Our modified Delphi process resulted in the identification of 46 final triggers for the detection of adverse events among ED patients. These triggers should be pilot field tested to quantify their individual and collective performance in detecting all-cause harm to ED patients.

Description and Yield of Current Quality and Safety Review in Selected US Academic Emergency Departments.

OBJECTIVES: Quality and safety review for performance improvement is important for systems of care and is required for US academic emergency departments (EDs). Assessment of the impact of patient safety initiatives in the context of increasing burdens of quality measurement compels standardized, meaningful, high-yield approaches for performance review. Limited data describe how quality and safety reviews are currently conducted and how well they perform in detecting patient harm and areas for improvement. We hypothesized that decades-old approaches used in many academic EDs are inefficient and low yield for identifying patient harm. METHODS: We conducted a prospective observational study to evaluate the efficiency and yield of current quality review processes at five academic EDs for a 12-month period. Sites provided descriptions of their current practice and collected summary data on the number and severity of events identified in their reviews and the referral sources that led to their capture. Categories of common referral sources were established at the beginning of the study. Sites used the Institute for Healthcare Improvement's definition in defining an adverse event and a modified National Coordinating Council for Medication Error Reporting and Prevention (MERP) Index for grading severity of events. RESULTS: Participating sites had similar processes for quality review, including a two-level review process, monthly reviews and conferences, similar screening criteria, and a grading system for evaluating cases. In 60 months of data collection, we reviewed a total of 4735 cases and identified 381 events. This included 287 near-misses, errors/events (MERP A-I) and 94 adverse events (AEs) (MERP E-I). The overall AE rate (event rate with harm) was 1.99 (95% confidence interval = 1.62%-2.43%), ranging from 1.24% to 3.47% across sites. The overall rate of quality concerns (events without harm) was 6.06% (5.42%-6.78%), ranging from 2.96% to 10.95% across sites. Seventy-two-hour returns were the most frequent referral source used, accounting for 47% of the cases reviewed but with a yield of only 0.81% in identifying harm. Other referral sources similarly had very low yields. External referrals were the highest yield referral source, with 14.34% (10.64%-19.03%) identifying AEs. As a percentage of the 94 AEs identified, external referrals also accounted for 41.49% of cases. CONCLUSIONS: With an overall adverse event rate of 1.99%, commonly used referral sources seem to be low yield and inefficient for detecting patient harm. Approximately 6% of the cases identified by these criteria yielded a near miss or quality concern. New approaches to quality and safety review in the ED are needed to optimize their yield and efficiency for identifying harm and areas for improvement.