The Impact of a High Sensitivity Troponin HEART Pathway Based Clinical Decision Protocol on Observation Visits.

BACKGROUND: Use of high-sensitivity troponin (hs-cTn) might lead to an increase in hospital observation visits due to higher number of abnormal troponin levels. STUDY OBJECTIVES: To determine the impact of incorporating hs-cTn into a chest pain clinical decision protocol (CDP) on observation visits in a large academic health system. METHODS: This is a retrospective observational cohort study of all chest pain observation patients in four hospitals in an academic health system over 24 months. All hospitals used the Beckman Coulter Unicel Dxi instrument, and all shared the same emergency department (ED) chest pain protocol, which used the HEART pathway and serial troponins and directed ED dispositions to either an observation stay, ED discharge, or inpatient admission. Outcomes studied before and after introduction of a hs-cTn protocol included daily chest pain observation census, cost, observation hours, and inpatient admit rate. Census was reported as the daily chest pain observation census and as a proportion of all observation visits. Data was retrieved from a health system data warehouse and a cost accounting program. RESULTS: There were 6,712 chest pain observation visits over 24-months, with 4,087 visits before and 2,634 visits after the hs-cTn protocol implementation. Comparison groups were similar in terms of age, gender, and type of insurance. There were 10.59 (95% CI: 10.24 - 10.95) daily chest pain observation visits before and 7.66 (95% CI: 7.34 - 7.97) visits after implementation, with a 28% (95% CI: 35% - 20%) decrease in the total daily census. As a portion of all observation visits, there was a 22% drop in the proportion that were observed for chest pain. The daily number of chest pain patients requiring inpatient admission was unchanged. The daily total direct cost for chest pain observation decreased with an effective daily cost savings of $4,313 USD (95% CI: $1,534 - $6,998). The total daily number of chest pain observation bed hours also decreased by 41.5 hours (95% CI 13.4 - 96.4 hr). CONCLUSION: Implementation of a hs-cTn chest pain protocol was associated with a significant decrease in the number and proportion of observation visits, a decrease in total daily cost and bed hours used, and no increase in inpatient admissions.

The feasibility of emergency department observation units in the management of mild to moderate hyponatremia.

OBJECTIVE: To describe the feasibility of managing hyponatremia patients under outpatient observation status in an academic medical center, and compare outcomes based on the use of an emergency department observation unit (EDOU). METHODS: This is a retrospective cohort study of emergency department hyponatremic patients managed in four hospitals within a large urban academic medical center over 27 months. All patients had an admit-to-observation order, ICD-10 codes for hyponatremia, and mild (130-135 mmol/L) to moderate (121-129 mmol/L) hyponatremia. Observation settings were divided into two groups: EDOU and Non-Observation Unit (NOU) inpatient beds. Severe hyponatremia (≤120 mmol/L) was excluded. Primary clinical outcomes were inpatient admit rate, length of stay (LOS), total direct cost, the rate of adverse events and 30-day recidivism. RESULTS: 188 patients were managed as an observation patient, with 64 managed in an EDOU setting (age 74.0 yr, 70.3% female) and 124 managed in a NOU setting (age 71.5 yr, 64.5% female). Patient subgroups were similar in terms of presenting complaints, comorbidities, and medication histories. Initial and final sodium levels were similar between settings: EDOU (125.1 to 132.6 mmol/L) vs NOU (123.5 to 132.0 mmol/L). However, outcomes differed by setting for observation to inpatient admit rate (EDOU 28.1% vs NOU 37.9%, adjusted effect 0.70), overall length of stay (EDOU 19.2 h vs NOU 31.9 h; adjusted effect -10.5 h and total direct cost ($1230 vs $1531; adjusted effect -$167). EDOU sodium correction rates were faster (EDOU 0.44 mmol/L/h vs 0.24 mmol/L/h; adjusted effect 0.15 mmol/L/h) and 30-day recidivism rate was similar (EDOU 13% vs NOU 15%). There were no index visit deaths or intensive care unit admissions. CONCLUSION: Management of selected hyponatremia patients under observation status is feasible, with the EDOU setting demonstrating lower admit rates, shorter length of stay, and lower total direct costs with similar clinical outcomes.

The use of ICSI in ART: evidence for practice.

This article reviews the evidence regarding the safety and efficacy of intra-cytoplasmic sperm injection (ICSI). It provides evidence-based clinical and laboratory guidelines and recommendations for use of ICSI within an assisted reproductive technology (ART) service. The guidelines address the evidence for the use of ICSI rather than conventional IVF (cIVF); the use of ART techniques supplementary to ICSI; and risks associated with ICSI. This article is not intended to be the only approved standard of practice or to dictate an exclusive course of treatment. Other plans of management may be appropriate, taking into account the needs and medical history of the patient, available resources, and institutional or clinical practice limitations.

The Impact of Virtual Care in an Emergency Department Observation Unit.

STUDY OBJECTIVE(S): We report the impact of telemedicine virtual rounding in emergency department observation units (EDOU) on the effectiveness, safety, and cost relative to traditional observation care. METHODS: In this retrospective diff-in-diff study, we compared observation visit outcomes from 2 EDOUs before (pre) and after (post) full adoption of telemedicine rounding tele-observation (tele-obs) with usual care in control EDOU and care in a hospital bed in an integrated health system without tele-obs. Tele-obs physicians did not work at the control hospital. Outcomes were the length of stay, total direct costs, admission status, and adverse events (ICU and death). Difference-in-differences modeling evaluated outcomes with covariates including age, sex, payer type, and clinical classification software diagnostic category. Data from a system data warehouse and a cost accounting database were used. RESULTS: Of the 20,861 EDOU visits, 15,630 (74.9%) were seen in the preperiod and 6,657 (31.9%) in control EDOU. Of 23,055 non-EDOU inpatient visits assigned to observation status (nonobservation unit), 76% were seen in the preperiod. Adjusted length of stay was not significantly different for tele-obs and control EDOUs (26.4 hours versus 23.5 hours), which remained lower than in hospital settings (37.9 hours). The pre-post diff-in-diff was not significant (P=.78). Inpatient admission status was similar for tele-obs and control EDOUs (20.9% versus 22.4.%) and lower than in hospital settings (30.3%). Prepost odds ratios for inpatient admission and adverse outcomes did not change significantly for all study groups. Adjusted costs increased over time for all settings; however, the prepost median cost change was not significantly different between tele-obs EDOUs and control EDOUs ($162.5 versus $235) and was lower than the change for control hospital settings ($783). Median tele-obs EDOU cost over both periods ($1,541) remained significantly lower than hospital costs ($2,413). CONCLUSION: Using tele-obs to manage observation patients in an ED observation unit was not associated with significant differences in length of stay, admission status, measured adverse events, or total direct cost.

Sperm cryopreservation for impaired spermatogenesis.

Sperm cryopreservation for men with severely impaired spermatogenesis is one of the commonest reasons for short-term sperm storage, usually in advance of fertility treatment. Cryopreservation is generally very effective, although not all spermatozoa survive the process of freezing and thawing. This review considers various aspects of freezing sperm, including an overview of methods, appropriate use of cryoprotectants and practical considerations, as well as oxidative stress and mechanisms of cell cryodamage.

Virtual Screening in the Cloud Identifies Potent and Selective ROS1 Kinase Inhibitors.

ROS1 rearrangements account for 1-2% of non-small cell lung cancer patients, yet there are no specifically designed, selective ROS1 therapies in the clinic. Previous knowledge of potent ROS1 inhibitors with selectivity over TrkA, a selected antitarget, enabled virtual screening as a hit finding approach in this project. The ligand-based virtual screening was focused on identifying molecules with a similar 3D shape and pharmacophore to the known actives. To that end, we turned to the AstraZeneca virtual library, estimated to cover 1015 synthesizable make-on-demand molecules. We used cloud computing-enabled FastROCS technology to search the enumerated 1010 subset of the full virtual space. A small number of specific libraries were prioritized based on the compound properties and a medicinal chemistry assessment and further enumerated with available building blocks. Following the docking evaluation to the ROS1 structure, the most promising hits were synthesized and tested, resulting in the identification of several potent and selective series. The best among them gave a nanomolar ROS1 inhibitor with over 1000-fold selectivity over TrkA and, from the preliminary established SAR, these have the potential to be further optimized. Our prospective study describes how conceptually simple shape-matching approaches can identify potent and selective compounds by searching ultralarge virtual libraries, demonstrating the applicability of such workflows and their importance in early drug discovery.

Stock market response to COVID-19 pandemic: A comparative evidence from two emerging markets.

This paper presents the first comparative study of emerging stock markets' response to the COVID-19 pandemic with evidence from Ghana and Botswana. Using daily time-series data from March 1, 2020, to September 30, 2021, the study estimates parametric, semi-parametric and non-parametric models, and provides evidence to support the negative effects of the COVID-19 pandemic (i.e., the total number of reported COVID-19 cases and deaths) on the stock market performances of Ghana and Botswana. Interestingly, the study shows that the impact of the pandemic on Ghana's stock market is quantitatively greater than the stock market of Botswana. The study calls for fiscal and monetary policies to help firms on the stock market to survive the shock. Going forward, measures aimed at building a robust stock market to withstand such external shocks are critical.

Feasibility study of a novel digital health platform for patients undergoing transcatheter aortic valve replacement.

INTRODUCTION: Despite abundant evidence indicating that digital health solutions improve outcomes in chronic medical conditions, there are few validated solutions for acute surgical episodes. Transcatheter aortic valve replacement (TAVR) is a less invasive alternative to open surgery that is becoming more prevalent. We assessed the feasibility of ManageMySurgery (MMS), a smartphone application that combines patient education and outcomes tracking for patients undergoing TAVR procedures. METHODS: MMS was offered to patients receiving TAVR at an academic health center. Pre- and postoperatively, patients completed app-based tasks and reported clinical results using validated NYHA and KCCQ-12 surveys. Additionally, users reported levels of satisfaction with the digital platform. RESULTS: Sixty-nine patients were invited to use MMS, of which 43 (62%) downloaded and used the platform. The median age of patients was 77 years and 66.7% were male. The platform was accessed at an average of 2.6 times per user, with 79.1% of patients logging in one to three times. On average, 5.2 frequently asked questions were viewed. Of the 37 patients who completed the feedback survey (86%), 73.0% said it was helpful in preparation for surgery and 86.5% would recommend MMS to others. DISCUSSION: It is possible to utilize a digital health platform to guide patients undergoing TAVR through their interventional journey. Additional research is warranted to assess whether digital patient navigation tools provide an added benefit over traditional perioperative care alone, in terms of long-term patient engagement and outcomes.

Preparedness, Adaptation, and Innovation: Approach to the COVID-19 Pandemic at a Decentralized, Quaternary Care Department of Emergency Medicine.

The COVID-19 pandemic has required healthcare systems to be creative and adaptable in response to an unprecedented crisis. Below we describe how we prepared for and adapted to this pandemic at our decentralized, quaternary-care department of emergency medicine, with specific recommendations from our experience. We discuss our longstanding history of institutional preparedness, as well as adaptations in triage, staffing, workflow, and communications. We also discuss innovation through working with industry on solutions in personal protective equipment, as well as telemedicine and methods for improving morale. These preparedness and response solutions and recommendations may be useful moving forward as we transition between response and recovery in this pandemic as well as future pandemics.

Ligand-centred redox activation of inert organoiridium anticancer catalysts.

Organometallic complexes with novel activation mechanisms are attractive anticancer drug candidates. Here, we show that half-sandwich iodido cyclopentadienyl iridium(iii) azopyridine complexes exhibit potent antiproliferative activity towards cancer cells, in most cases more potent than cisplatin. Despite their inertness towards aquation, these iodido complexes can undergo redox activation by attack of the abundant intracellular tripeptide glutathione (GSH) on the chelated azopyridine ligand to generate paramagnetic intermediates, and hydroxyl radicals, together with thiolate-bridged dinuclear iridium complexes, and liberate reduced hydrazopyridine ligand. DFT calculations provided insight into the mechanism of this activation. GS- attack on the azo bond facilitates the substitution of iodide by GS-, and leads to formation of GSSG and superoxide if O2 is present as an electron-acceptor, in a largely exergonic pathway. Reactions of these iodido complexes with GSH generate Ir-SG complexes, which are catalysts for GSH oxidation. The complexes promoted elevated levels of reactive oxygen species (ROS) in human lung cancer cells. This remarkable ligand-centred activation mechanism coupled to redox reactions adds a new dimension to the design of organoiridium anticancer prodrugs.

Pharmaco-genomic investigations of organo-iridium anticancer complexes reveal novel mechanism of action.

Resistance to platinum drugs (used in >50% of cancer chemotherapies) is a clinical problem. Other precious metal complexes with distinct mechanisms of action might overcome this. Half-sandwich organometallic complexes containing arene or cyclopentadienyl (Cp) ligands show promise. We screened two iridium(iii) complexes [Ir(CpXbiph)(ppy)Cl] (ZL49, 1, ppy = phenylpyridine) and [Ir(CpXph)(azpyNMe2)Cl]PF6 (ZL109, 2, azpyNMe2 = N,N-dimethylphenylazopyridine) in 916 cancer cell lines from 28 tissue types. On average, complex 2 was 78× more potent than 1, 36× more active than cisplatin (CDDP), and strongly active (nanomolar) in patient-derived ovarian cancer cell lines. RNA sequencing of A2780 ovarian cells revealed upregulation of antioxidant responses (NRF2, AP-1) consistent with observed induction of reactive oxygen species (ROS). Protein microarrays, high content imaging and cell cycle analysis showed S/G2 arrest, and late-stage DNA damage response without p53 requirement. The triple-negative breast cancer cell line OCUB-M was highly sensitive to 2 as were cell lines with KIT mutations. Complex 2 exhibits a markedly different pattern of antiproliferative activity compared to the 253 drugs in the Sanger Cancer Genome database, but is most similar to osmium(ii) arene complexes which share the same azopyridine ligand. Redox modulation and DNA damage can provide a multi-targeting strategy, allowing compounds such as 2 to overcome cellular resistance to platinum anticancer drugs.

ALiEM Blog and Podcast Watch: Toxicology.

INTRODUCTION: The WestJEM Blog and Podcast Watch presents high-quality open-access educational blogs and podcasts in emergency medicine based on the ongoing Academic Life in Emergency Medicine (ALiEM) Approved Instructional Resources (AIR) and AIR-Professional (Pro) series. Both series critically appraise open-access educational blogs and podcasts in EM using an objective scoring instrument. This installment of the blog and podcast watch series curated and scored relevant posts in the specific topic of toxicology emergencies from the AIR-Pro Series. METHODS: The AIR-Pro Series is a continuously building curriculum covering a new subject area every two months. For each area, eight EM chief residents identify 3-5 advanced clinical questions. Using FOAMsearch.net and FOAMSearcher to search blogs and podcasts, relevant posts are scored by eight reviewers from the AIR-Pro editorial board, which is comprised of EM faculty and chief residents at various institutions across North America. The scoring instrument contains five measurement outcomes based on seven-point Likert scales: recency, accuracy, educational utility, evidence based, and references. The AIR-Pro label is awarded to posts with a score of ≥28 (out of 35) points. An "honorable mention" label is awarded if board members collectively felt that the blogs were valuable and the scores were > 25. RESULTS: A total of 31 blog posts and podcasts were included. Key educational pearls from the six high-quality AIR-Pro posts and four honorable mentions are summarized. CONCLUSION: The WestJEM ALiEM Blog and Podcast Watch series is based on the AIR and AIR-Pro Series, which attempts to identify high-quality educational content on open-access blogs and podcasts. This series provides an expert-based, crowdsourced approach towards critically appraising educational social media content for EM clinicians. This installment focuses on toxicology emergencies.

Are coastal protected areas always effective in achieving population recovery for nesting sea turtles?

Sea turtles are highly migratory and usually dispersed, but aggregate off beaches during the nesting season, rendering them vulnerable to coastal threats. Consequently, coastal Marine Protection Areas (MPAs) have been used to facilitate the recovery of turtle populations, but the effectiveness of these programs is uncertain as most have been operating for less than a single turtle generation (or<20 yr). South Africa, however, hosts one of the longest running conservation programs, protecting nesting loggerhead (Caretta caretta) and leatherback (Dermochelys coriacea) turtles since 1963 in a series of coastal MPAs. This provides a unique opportunity to evaluate the long-term effect of spatial protection on the abundance of two highly migratory turtle species with different life history characteristics. Population responses were assessed by modeling the number of nests over time in an index area (13 km) and an expanded monitoring area (53 km) with varying survey effort. Loggerhead abundance increased dramatically from∼250 to>1700 nests pa (index area) especially over the last decade, while leatherback abundance increased initially∼10 to 70 nests pa (index area), but then stabilized. Although leatherbacks have higher reproductive output per female and comparable remigration periods and hatching success to loggerheads, the leatherback population failed to expand. Our results suggest that coastal MPAs can work but do not guarantee the recovery of sea turtle populations as pressures change over time. Causes considered for the lack of population growth include factors in the MPA (expansion into unmonitored areas or incubation environment) of outside of the MPA (including carrying capacity and fishing mortality). Conservation areas for migratory species thus require careful design to account for species-specific needs, and need to be monitored to keep track of changing pressures.

Acute myeloid leukaemia secondary to treatment with capecitabine for metastatic colorectal cancer.

A 63-year-old woman was diagnosed with acute myelo-monocytic leukaemia, associated with MLL gene rearrangement, 16 months after completion of oral capecitabine for metastatic colon cancer. Capecitabine, recommended for use in metastatic breast and colon cancer and more recently as adjuvant treatment of colon cancer, has not previously been reported to be associated with secondary cancer.

Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders.

Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs.

Novel translocations that disrupt the platelet-derived growth factor receptor beta (PDGFRB) gene in BCR-ABL-negative chronic myeloproliferative disorders.

The BCR-ABL-negative chronic myeloproliferative disorders (CMPD) and myelodysplastic/myeloproliferative diseases (MDS/MPD) are a spectrum of related conditions for which the molecular pathogenesis is poorly understood. Translocations that disrupt and constitutively activate the platelet-derived growth factor receptor beta(PDGFRB) gene at chromosome band 5q33 have been described in some patients, the most common being the t(5;12)(q33;p13). An accurate molecular diagnosis of PDGFRB-rearranged patients has become increasingly important since recent data have indicated that they respond very well to imatinib mesylate therapy. In this study, we have tested nine patients with a CMPD or MDS/MPD and a translocation involving 5q31-33 for disruption of PDGFRB by two-colour fluorescence in situ hybridization (FISH) using differentially labelled, closely flanking probes. Normal control interphase cells gave a false positive rate of 3% (signals more than one signal width apart). Six patients showed a pattern of one fused signal (from the normal allele) and one pair of signals separated by more than one signal width in > 85% of interphase cells, indicating that PDGFRB was disrupted. These individuals had a t(1;5)(q21;q33), t(1;5)(q22;q31), t(1;3;5)(p36;p21;q33), t(2;12;5)(q37;q22;q33), t(3;5) (p21;q31) and t(5;14)(q33;q24) respectively. The remaining three patients with a t(1;5)(q21;q31), t(2;5)(p21;q33) and t(5;6)(q33;q24-25) showed a normal pattern of hybridization, with > or = 97% interphase cells with two fusion signals. We conclude that two-colour FISH is useful to determine the presence of a PDGFRB rearrangement, although, as we have shown previously, this technique may not detect subtle complex translocations at this locus. Our data indicate that several PDGFRB partner genes remain to be characterized.

GLOBAL PHYLOGEOGRAPHY OF THE LOGGERHEAD TURTLE (CARETTA CARETTA) AS INDICATED BY MITOCHONDRIAL DNA HAPLOTYPES.

Restriction-site analyses of mitochondrial DNA (mtDNA) from the loggerhead sea turtle (Caretta caretta) reveal substantial phylogeographic structure among major nesting populations in the Atlantic, Indian, and Pacific oceans and the Mediterranean sea. Based on 176 samples from eight nesting populations, most breeding colonies were distinguished from other assayed nesting locations by diagnostic and often fixed restriction-site differences, indicating a strong propensity for natal homing by nesting females. Phylogenetic analyses revealed two distinctive matrilines in the loggerhead turtle that differ by a mean estimated sequence divergence p = 0.009, a value similar in magnitude to the deepest intraspecific mtDNA node (p = 0.007) reported in a global survey of the green sea turtle Chelonia mydas. In contrast to the green turtle, where a fundamental phylogenetic split distinguished turtles in the Atlantic Ocean and the Mediterranean Sea from those in the Indian and Pacific oceans, genotypes representing the two primary loggerhead mtDNA lineages were observed in both Atlantic-Mediterranean and Indian-Pacific samples. We attribute this aspect of phylogeographic structure in Caretta caretta to recent interoceanic gene flow, probably mediated by the ability of this temperate-adapted species to utilize habitats around southern Africa. These results demonstrate how differences in the ecology and geographic ranges of marine turtle species can influence their comparative global population structures.