Yeast life span extension by depletion of 60s ribosomal subunits is mediated by Gcn4.

In nearly every organism studied, reduced caloric intake extends life span. In yeast, span extension from dietary restriction is thought to be mediated by the highly conserved, nutrient-responsive target of rapamycin (TOR), protein kinase A (PKA), and Sch9 kinases. These kinases coordinately regulate various cellular processes including stress responses, protein turnover, cell growth, and ribosome biogenesis. Here we show that a specific reduction of 60S ribosomal subunit levels slows aging in yeast. Deletion of genes encoding 60S subunit proteins or processing factors or treatment with a small molecule, which all inhibit 60S subunit biogenesis, are each sufficient to significantly increase replicative life span. One mechanism by which reduced 60S subunit levels leads to life span extension is through induction of Gcn4, a nutrient-responsive transcription factor. Genetic epistasis analyses suggest that dietary restriction, reduced 60S subunit abundance, and Gcn4 activation extend yeast life span by similar mechanisms.

Evaluation and guide for embedding opioid use disorder education in health professions' curricula.

BACKGROUND: Morbidity and mortality from Opioid Use Disorder is a health crisis in the United States. During the COVID-19 pandemic, there was a devastating increase of 38.4% in overdose deaths from the 12-month period leading up to June 2019 compared with the 12-month period leading up to May 2020, primarily driven by synthetic opioids. Buprenorphine is an effective medication for opioid use disorder but uptake is slow due in part to lack of provider knowledge, confidence, and negative attitudes/stigma toward patients with OUD. Addressing these barriers in academic training is a promising approach to building workforce able to effectively treat opioid use disorder. METHODS: Our university developed a training for pre-licensure physicians, physician assistants and psychiatric nurse practitioners that included the DATA Waiver training and a shadowing experience. Expected outcomes included improved knowledge, skills and attitudes about persons with OUD and buprenorphine treatment, plans to provide this treatment post-graduation, for pre-licensure learners to have completed all requirements to prescribe buprenorphine post-graduation, and for the training to be embedded into school's curricula. RESULTS: Results were positive overall including improved knowledge and attitudes toward persons with OUD, better understanding of the benefits of this treatment for patients, increased confidence and motivation to provide this treatment post-graduation. The training is now embedded in each program's graduation requirements. CONCLUSION: Developing a didactic and experiential training on buprenorphine treatment for opioid use disorder and embedding it into medical, physician assistant, and psychiatric nurse practitioner licensure programs can help prepare future providers to treat opioid use disorder in a range of settings. Key to replicating this program in other university settings is to engage faculty members who actively provide treatment to persons with OUD to ensure shadowing opportunities and serve as role models for learners.

Brain swelling and death in children with cerebral malaria.

BACKGROUND: Case fatality rates among African children with cerebral malaria remain in the range of 15 to 25%. The key pathogenetic processes and causes of death are unknown, but a combination of clinical observations and pathological findings suggests that increased brain volume leading to raised intracranial pressure may play a role. Magnetic resonance imaging (MRI) became available in Malawi in 2009, and we used it to investigate the role of brain swelling in the pathogenesis of fatal cerebral malaria in African children. METHODS: We enrolled children who met a stringent definition of cerebral malaria (one that included the presence of retinopathy), characterized them in detail clinically, and obtained MRI scans on admission and daily thereafter while coma persisted. RESULTS: Of 348 children admitted with cerebral malaria (as defined by the World Health Organization), 168 met the inclusion criteria, underwent all investigations, and were included in the analysis. A total of 25 children (15%) died, 21 of whom (84%) had evidence of severe brain swelling on MRI at admission. In contrast, evidence of severe brain swelling was seen on MRI in 39 of 143 survivors (27%). Serial MRI scans showed evidence of decreasing brain volume in the survivors who had had brain swelling initially. CONCLUSIONS: Increased brain volume was seen in children who died from cerebral malaria but was uncommon in those who did not die from the disease, a finding that suggests that raised intracranial pressure may contribute to a fatal outcome. The natural history indicates that increased intracranial pressure is transient in survivors. (Funded by the National Institutes of Health and Wellcome Trust U.K.).

Battlefield acupuncture to treat low back pain in the emergency department.

INTRODUCTION: Battlefield acupuncture (BFA) is an ear acupuncture protocol used by the military for immediate pain relief. This is a pilot feasibility study of BFA as a treatment for acute low back pain (LBP) in the emergency department (ED). METHODS: Thirty acute LBP patients that presented to ED were randomized to standard care plus BFA or standard care alone. In the BFA group, outcomes were assessed at the time of randomization, 5 min after intervention, and again within 1 h after intervention. In the standard care group outcomes were assessed at the time of randomization and again an hour later. Primary outcomes included post-intervention LBP on a 10-point numeric pain rating scale (NRS) and the timed get-up-and-go test (GUGT). t-Test and chi squared tests were used to compare differences between groups demographics to evaluate randomization, and Analysis of Covariance (ANCOVA) was used to assess differences in primary/secondary outcomes. RESULTS: We randomized 15 patients to BFA plus standard care, and 15 patients to standard care alone. Demographics were similar between groups. Post-intervention LBP NRS was significantly lower in the BFA group compared with the standard care group (5.2 vs. 6.9, ANCOVA p = 0.04). GUGT was similar between groups (21.3 s vs. 19.0 s, ANCOVA p = 0.327). No adverse events from acupuncture were reported. DISCUSSION: This pilot study demonstrates that BFA is feasible as a therapy for LBP in the ED. Furthermore, our data suggest that BFA may be efficacious to improve LBP symptoms, and thus further efficacy studies are warranted. (Clinicaltrials.gov registration number NCT02399969).

Auricular Acupuncture in Emergency Department Treatment of Acute Pain.

The National Institutes of Health and the World Health Organization note that acupuncture is a safe and effective treatment for pain. Nonopioid treatment options for moderate to severe acute pain in the emergency department (ED) are limited. Additional strategies for managing acute pain in the ED are needed. Auricular Battlefield Acupuncture has been described as a simple, safe, rapid, and effective analgesic option to opioid medications in managing acute pain. We describe 4 cases in which emergency physicians with brief training performed this auricular acupuncture protocol to treat patients with acute pain in EDs when opioid analgesia was not an acceptable option.

Histidine-rich protein 2 plasma levels predict progression to cerebral malaria in Malawian children with Plasmodium falciparum infection.

Some children with uncomplicated malaria progress to cerebral malaria despite appropriate treatment; identifying them in advance might improve their care. The objective of this study was to determine if plasma concentrations of a malaria protein, HRP2 (histidine-rich protein 2) would serve this purpose. Cases and controls were children presenting with uncomplicated malaria; the cases (n = 25) developed cerebral malaria, and the controls (n = 125) did not. Mean plasma HRP2 concentrations were significantly higher in the cases, and an HRP2 cutoff was identified that could predict disease progression (sensitivity and specificity, 88% for each). Quantitative measurements of HRP2 may be a useful screening tool.

Genomic mapping of single-stranded DNA in hydroxyurea-challenged yeasts identifies origins of replication.

During DNA replication one or both strands transiently become single stranded: first at the sites where initiation of DNA synthesis occurs (known as origins of replication) and subsequently on the lagging strands of replication forks as discontinuous Okazaki fragments are generated. We report a genome-wide analysis of single-stranded DNA (ssDNA) formation in the presence of hydroxyurea during DNA replication in wild-type and checkpoint-deficient rad53 Saccharomyces cerevisiae cells. In wild-type cells, ssDNA was first observed at a subset of replication origins and later 'migrated' bi-directionally, suggesting that ssDNA formation is associated with continuously moving replication forks. In rad53 cells, ssDNA was observed at virtually every known origin, but remained there over time, suggesting that replication forks stall. Telomeric regions seemed to be particularly sensitive to the loss of Rad53 checkpoint function. Replication origins in Schizosaccharomyces pombe were also mapped using our method.

Plasma concentrations of parasite histidine-rich protein 2 distinguish between retinopathy-positive and retinopathy-negative cerebral malaria in Malawian children.

BACKGROUND: Brain histology and ophthalmoscopy suggest that approximately 25% of children with World Health Organization-defined cerebral malaria (CM) have a nonmalarial cause of death. Misclassification complicates clinical care, confounds studies of association, and may obfuscate successes in malaria control. Retinopathy predicts intracerebral parasite sequestration with >90% sensitivity and specificity, but detecting retinopathy requires well-trained personnel and expensive equipment. METHODS: We investigated the utility of plasma concentrations of parasite histidine-rich protein 2 (pHRP2), a Plasmodium-specific protein, as a predictor of intracerebral parasite sequestration at autopsy and of malaria retinopathy on clinical examination in patients with clinically defined CM. RESULTS: In 64 autopsy cases, 47 of whom had histological evidence of sequestration, the sensitivity and specificity of a plasma pHRP2 level of >1700 ng/mL were 98% and 94%, respectively, and the area under the receiver operating characteristic (AUROC) curve was 0.98. In a separate, prospectively studied group of 101 children with clinically defined CM, of whom 71 had retinopathy, the same pHRP2 cutoff predicted retinopathy-positivity with a sensitivity of 90% and specificity of 87% (AUROC, 0.90). CONCLUSIONS: Elevated plasma pHRP2 concentrations can identify Malawian children with histologically confirmed or retinopathy-positive CM and is a more field-friendly approach to confirming the diagnosis than post mortem sampling or ophthalmoscopy.

Pilot survey of prescription opioid use patterns and engagement with harm-reduction strategies in emergency department patients.

Background: The United States is experiencing an opioid epidemic. The aim of this pilot study was to describe patterns of prescription opioid medication (POM) use, examine factors associated with opioid misuse and overdose, and assess knowledge of take-home naloxone, and other harm-reduction strategies as well as participation in medications for opioid use disorder (MOUD) among emergency department (ED) patients that have been prescribed opioid medications. Methods: This was a pilot survey of a convenience sample of adult ED patients with a past opioid prescription at one urban tertiary care hospital. The survey asked participants about patterns of opioid consumption, risk factors associated with opioid misuse, and knowledge of harm-reduction strategies. The survey tool consisted of mixed open- and closed-ended questions. Reported daily POM consumption was converted to milligram morphine equivalents (MME). Responses to survey questions were compared with daily MME in order to generate hypotheses for future research. Results: 50 individuals completed a survey. Of these, 56% reported taking opioids daily, and 24% reported greater than 100 MME daily opioid consumption. Many subjects reported history of psychiatric illness (34%) and previous substance abuse treatment (24%). The majority of patients (66%) were not aware of take-home naloxone programs to treat opioid overdose. Conclusions: In this pilot survey of ED patients with a pain-related chief complaint, many respondents reported risk factors for opioid misuse, and the majority of participants were unaware of the existence of important harm-reduction strategies, such as take-home naloxone programs, even among those with the highest daily POM use.

Emergency Department Initiation of Buprenorphine for Opioid Use Disorder: Current Status, and Future Potential.

Patients experiencing the consequences of opioid use often present to the emergency department (ED) at times of crisis, such as following overdose or when in withdrawal. This highlights the important role of the ED in recognizing opioid use disorder and engaging these patients into ongoing treatment. Given the limited ability of the healthcare system to provide timely addiction treatment, initiation of therapy in the ED, with referral to long-term care, is associated with improved outcomes. The primary evidence-based treatment used in EDs for this indication is buprenorphine. Although clinicians may find the initiation of buprenorphine therapy daunting, it is straightforward and well-tolerated, and many of the barriers are surmountable. This article addresses these barriers, which include stigma, complicated pharmacology, and confusing regulations, and provides a basis for the use of buprenorphine in acute care clinical practice.

Risk factors for severe respiratory depression from prescription opioid overdose.

BACKGROUND AND AIMS: Prescription opioid overdose is a leading cause of injury-related morbidity and mortality in the United States. We aimed to identify characteristics associated with clinical severity in emergency department patients with prescription opioid overdose. DESIGN: This was a secondary data analysis of adult prescription opioid overdoses from a large prospective cohort of acute overdoses. We examined elements of a typical emergency department evaluation using a multivariable model to determine which characteristics were associated with clinical severity, specifically severe respiratory depression (SRD). SETTING: This study was conducted at two urban academic emergency departments in New York City, USA. PARTICIPANTS: Adult patients who presented with acute prescription opioid overdose between 2009 and 2013 were included in the current study. We analyzed 307 patients (mean age = 44.7, 42% female, 2.0% mortality). MEASUREMENTS: Patient demographics, reported substances ingested, suspected intent for ingesting the substance, vital signs, laboratory data, treatments including antidotes and intubation and outcome of death were recorded by trained research assistants. Intent was categorized into four mutually exclusive categories: suicide, misuse, therapeutic error and undetermined. The primary outcome was SRD, defined as administration of either (a) naloxone or (b) endotracheal intubation (ETI). FINDINGS: A total of 109 patients suffered SRD with 90 patients receiving naloxone alone, nine ETI alone and 10 both naloxone and ETI. The most common opioids were oxycodone (n = 124) and methadone (n = 116). Mean age was higher in patients with SRD (51.1 versus 41.1, P < 0.001). Opioid misuse was associated with SRD in the multivariable analysis [odds ratio (OR) = 2.07, 95% confidence interval (CI) = 1.21-3.55]. The unadjusted relative risk of SRD was high for fentanyl (83.3% SRD) and lowest for codeine (3.6% SRD). CONCLUSION: In emergency department patients in the United States with prescription opioid overdose, worse clinical severity was associated with opioid misuse, increased with age and was widely variable, depending on the specific opioid medication involved.

The Creation of a Pediatric Hospital Medicine Dashboard: Performance Assessment for Improvement.

BACKGROUND AND OBJECTIVES: Leaders of pediatric hospital medicine (PHM) recommended a clinical dashboard to monitor clinical practice and make improvements. To date, however, no programs report implementing a dashboard including the proposed broad range of metrics across multiple sites. We sought to (1) develop and populate a clinical dashboard to demonstrate productivity, quality, group sustainability, and value added for an academic division of PHM across 4 inpatient sites; (2) share dashboard data with division members and administrations to improve performance and guide program development; and (3) revise the dashboard to optimize its utility. METHODS: Division members proposed a dashboard based on PHM recommendations. We assessed feasibility of data collection and defined and modified metrics to enable collection of comparable data across sites. We gathered data and shared the results with division members and administrations. RESULTS: We collected quarterly and annual data from October 2011 to September 2013. We found comparable metrics across all sites for descriptive, productivity, group sustainability, and value-added domains; only 72% of all quality metrics were tracked in a comparable fashion. After sharing the data, we saw increased timeliness of nursery discharges and an increase in hospital committee participation and grant funding. CONCLUSIONS: PHM dashboards have the potential to guide program development, mobilize faculty to improve care, and demonstrate program value to stakeholders. Dashboard implementation at other institutions and data sharing across sites may help to better define and strengthen the field of PHM by creating benchmarks and help improve the quality of pediatric hospital care.

A Comprehensive Analysis of Replicative Lifespan in 4,698 Single-Gene Deletion Strains Uncovers Conserved Mechanisms of Aging.

Many genes that affect replicative lifespan (RLS) in the budding yeast Saccharomyces cerevisiae also affect aging in other organisms such as C. elegans and M. musculus. We performed a systematic analysis of yeast RLS in a set of 4,698 viable single-gene deletion strains. Multiple functional gene clusters were identified, and full genome-to-genome comparison demonstrated a significant conservation in longevity pathways between yeast and C. elegans. Among the mechanisms of aging identified, deletion of tRNA exporter LOS1 robustly extended lifespan. Dietary restriction (DR) and inhibition of mechanistic Target of Rapamycin (mTOR) exclude Los1 from the nucleus in a Rad53-dependent manner. Moreover, lifespan extension from deletion of LOS1 is nonadditive with DR or mTOR inhibition, and results in Gcn4 transcription factor activation. Thus, the DNA damage response and mTOR converge on Los1-mediated nuclear tRNA export to regulate Gcn4 activity and aging.

Toxin-induced cardiovascular failure.

Adverse cardiovascular events comprise a large portion of the morbidity and mortality in drug overdose emergencies. Adverse cardiovascular events encountered by emergency physicians treating poisoned patients include myocardial injury, hemodynamic compromise with shock, tachydysrhythmias, and cardiac arrest. Early signs of toxin-induced cardiovascular failure include bradycardia, tachycardia, and specific ECG findings. Treatment of toxicologic tachycardia relies on rapid supportive care along with proper use of benzodiazepines for sedation. Treatment of toxicologic bradycardia consists of the use of isotonic fluids, atropine, calcium salts, and glucagon. High-dose insulin euglycemia should be used early in the course of suspected severe poisoning and intravenous lipid emulsion given to patients who suffer cardiac arrest.

Primary liver tumors in pediatric patients: proper imaging technique for diagnosis and staging.

Liver tumors in children are rare and comprise a diverse set of both benign and malignant lesions, most of which are not clinically detected until they are large and often difficult to resect. Technological advances in diagnostic imaging have greatly influenced the surgical planning of these lesions and ultimately the clinical outcome. The intent of this article is to present an imaging algorithm for the effective and efficient workup of liver tumors in pediatric patients. This includes the appropriate timing and use of various imaging modalities, such as conventional radiographs, ultrasound, computed tomography, and magnetic resonance imaging. This article also addresses the use of sedation, intravenous contrast agents, and the benefits and limitations of specific imaging modalities. An overview of the radiologic and pathologic findings in common liver lesions in pediatric patients, as well as individual case examples demonstrating the use of the proposed workup algorithm, is provided.

Shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity.

BACKGROUND: Identification of genes that modulate longevity is a major focus of aging-related research and an area of intense public interest. In addition to facilitating an improved understanding of the basic mechanisms of aging, such genes represent potential targets for therapeutic intervention in multiple age-associated diseases, including cancer, heart disease, diabetes, and neurodegenerative disorders. To date, however, targeted efforts at identifying longevity-associated genes have been limited by a lack of predictive power, and useful algorithms for candidate gene-identification have also been lacking. METHODOLOGY/PRINCIPAL FINDINGS: We have utilized a shortest-path network analysis to identify novel genes that modulate longevity in Saccharomyces cerevisiae. Based on a set of previously reported genes associated with increased life span, we applied a shortest-path network algorithm to a pre-existing protein-protein interaction dataset in order to construct a shortest-path longevity network. To validate this network, the replicative aging potential of 88 single-gene deletion strains corresponding to predicted components of the shortest-path longevity network was determined. Here we report that the single-gene deletion strains identified by our shortest-path longevity analysis are significantly enriched for mutations conferring either increased or decreased replicative life span, relative to a randomly selected set of 564 single-gene deletion strains or to the current data set available for the entire haploid deletion collection. Further, we report the identification of previously unknown longevity genes, several of which function in a conserved longevity pathway believed to mediate life span extension in response to dietary restriction. CONCLUSIONS/SIGNIFICANCE: This work demonstrates that shortest-path network analysis is a useful approach toward identifying genetic determinants of longevity and represents the first application of network analysis of aging to be extensively validated in a biological system. The novel longevity genes identified in this study are likely to yield further insight into the molecular mechanisms of aging and age-associated disease.