The 2.4 Å structure of Zymomonas mobilis pyruvate kinase: Implications for stability and regulation.

Human liver pyruvate kinase (hlPYK) catalyzes the final step in glycolysis, the formation of pyruvate (PYR) and ATP from phosphoenolpyruvate (PEP) and ADP. Fructose 1,6-bisphosphate (FBP), a pathway intermediate of glycolysis, serves as an allosteric activator of hlPYK. Zymomonas mobilis pyruvate kinase (ZmPYK) performs the final step of the Entner-Doudoroff pathway, which is similar to glycolysis in that energy is harvested from glucose and pyruvate is generated. The Entner-Doudoroff pathway does not have FBP as a pathway intermediate, and ZmPYK is not allosterically activated. In this work, we solved the 2.4 Å X-ray crystallographic structure of ZmPYK. The protein is dimeric in solution as determined by gel filtration chromatography, but crystallizes as a tetramer. The buried surface area of the ZmPYK tetramerization interface is significantly smaller than that of hlPYK, and yet tetramerization using the standard interfaces from higher organisms provides an accessible low energy crystallization pathway. Interestingly, the ZmPYK structure showed a phosphate ion in the analogous location to the 6-phosphate binding site of FBP in hlPYK. Circular Dichroism (CD) was used to measure melting temperatures of hlPYK and ZmPYK in the absence and presence of substrates and effectors. The only significant difference was an additional phase of small amplitude for the ZmPYK melting curves. We conclude that the phosphate ion plays neither a structural or allosteric role in ZmPYK under the conditions tested. We hypothesize that ZmPYK does not have sufficient protein stability for activity to be tuned by allosteric effectors as described for rheostat positions in the allosteric homologues.

Systematic review and meta-analysis on the effect of self-assembling peptide P11-4 on arrest, cavitation, and progression of initial caries lesions.

BACKGROUND: Simple noninvasive evidence-based interventions for caries are needed to overcome limitations in the restorative paradigm. The self-assembling peptide P11-4 is a noninvasive intervention that regenerates enamel in initial caries lesions. STUDIES REVIEWED: The authors conducted a systematic review and meta-analysis on the effectiveness of the P11-4 products Curodont Repair (Credentis; now manufactured by vVARDIS) (CR) and Curodont Repair Fluoride Plus (Credentis; now manufactured by vVARDIS) on initial caries lesions. Primary outcomes were lesion progression after 24 months, caries arrest, and cavitation. Secondary outcomes were changes in merged International Caries Detection and Assessment System score categories, quantitative light-induced fluorescence (QLF; Inspektor Research System), esthetic appearance, and lesion size. RESULTS: Six clinical trials met the inclusion criteria. Results of this review represent 2 primary and 2 secondary outcomes. When compared with parallel groups, use of CR likely results in a large increase in caries arrest (relative risk [RR], 1.82 [95% CI, 1.32 to 2.50]; 45% attributable risk [95% CI, 24% to 60%]; number needed to treat [NNT], 2.8) and likely decreases lesion size by a mean (SD) of 32% (28%). The evidence also suggests that use of CR results in a large reduction in cavitation (RR, 0.32 [95% CI, 0.10 to 1.06]; NNT, 6.9) and is uncertain about lowering merged International Caries Detection and Assessment System score (RR, 3.68 [95% CI, 0.42 to 32.3]; NNT, 19). No studies used Curodont Repair Fluoride Plus. No studies reported adverse esthetic changes. PRACTICAL IMPLICATIONS: CR likely has clinically important effects on caries arrest and decreased lesion size. Two trials had nonmasked assessors, and all trials had elevated risks of bias. The authors recommend conducting longer trials. CR is a promising treatment for initial caries lesions. The protocol for this systematic review was registered a priori with PROSPERO (304794).

COVID-19 Evidence Reviews website: a VA effort to catalog and curate COVID-19 evidence reviews.

BACKGROUND: The COVID-19 pandemic has sparked a wave of SARS-CoV-2 and COVID-19 research that organizations around the world have been synthesizing in evidence reviews to provide high-quality evidence to support policymakers and clinicians. The urgency of these efforts opens these organizations to the risk of duplicated efforts, which could waste valuable time and resources. CASE PRESENTATION: The VA Evidence Synthesis Program (VA ESP) formed a COVID Response Team that launched an online catalog of COVID-19 evidence reviews in March 2020 (https://www.covid19reviews.org/). The goal of this website is to capture the work of evidence synthesis groups in the US and around the world to maximize their collective contributions to patients, frontline clinicians, researchers, and policymakers during the COVID-19 pandemic and avoid duplicating efforts. CONCLUSIONS: This ongoing and evolving project provides a helpful catalog of evidence reviews at various stages of production; in addition, the website provides further value with informational icons, review collections, and links to similar resources. The VA ESP will maintain this website to continue to support the needs of policymakers, clinicians, and researchers both within the VA and around the world throughout the COVID-19 pandemic.

Mental health outcomes of adults hospitalized for COVID-19: A systematic review.

BACKGROUND: Patients hospitalized for COVID-19 may be at high risk of mental health (MH) disorders. This systematic review assesses MH outcomes among adults during and after hospitalization for COVID-19 and ascertains MH care utilization and resource needs. METHODS: We searched multiple medical literature databases for studies published December 2019 to March 2021. Studies of ≥ 200 participants were synthesized. One reviewer completed article selection, data abstraction and assessed study quality and strength of evidence, with verification by a second. RESULTS: Fifty articles met preliminary inclusion criteria; 19 articles that included ≥ 200 participants were synthesized. Evidence from these primarily fair-quality studies suggests many patients experience symptoms of depression (9-66%), anxiety (30-39%), and insomnia (24-40%) during and 3 months after hospitalization for COVID-19. However, patients infrequently receive a new MH disorder diagnosis 6 months after hospitalization (5% are diagnosed with a new mood disorder, 7% anxiety disorder, and 3% insomnia). Some hospitalized patients - including women and those with more severe COVID-19 - may be at higher risk of poor MH outcomes. Data on MH care utilization and resource needs are currently limited. LIMITATIONS: Most included studies were small, did not report the proportion of participants with preexisting MH disorders, and did not use comparison groups. CONCLUSIONS: While many patients experience MH symptoms after hospitalization for COVID-19, most do not go on to develop a new MH disorder. Future studies should report whether participants have preexisting MH disorders and compare patients hospitalized for COVID-19 to patients hospitalized for other causes.

Major Update 2: Remdesivir for Adults With COVID-19: A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is approved for the treatment of adults hospitalized with COVID-19. PURPOSE: To update a living review of remdesivir for adults with COVID-19. DATA SOURCES: Several electronic U.S. Food and Drug Administration, company, and journal websites from 1 January 2020 through 19 October 2021. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. DATA EXTRACTION: One reviewer abstracted, and a second reviewer verified data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: Since the last update (search date 9 August 2021), 1 new RCT and 1 new subtrial comparing a 10-day course of remdesivir with control (placebo or standard care) were identified. This review summarizes and updates the evidence on the cumulative 5 RCTs and 2 subtrials for this comparison. Our updated results confirm a 10-day course of remdesivir, compared with control, probably results in little to no mortality reduction (5 RCTs). Updated results also confirm that remdesivir probably results in a moderate increase in the proportion of patients recovered by day 29 (4 RCTs) and may reduce time to clinical improvement (2 RCTs) and hospital length of stay (4 RCTs). New RCTs, by increasing the strength of evidence, lead to an updated conclusion that remdesivir probably results in a small reduction in the proportion of patients receiving ventilation or extracorporeal membrane oxygenation at specific follow-up times (4 RCTs). New RCTs also alter the conclusions for harms-remdesivir, compared with control, may lead to a small reduction in serious adverse events but may lead to a small increase in any adverse event. LIMITATION: The RCTs differed in definitions of COVID-19 severity and outcomes reported. CONCLUSION: In hospitalized adults with COVID-19, the findings confirm that remdesivir probably results in little to no difference in mortality and increases the proportion of patients recovered. Remdesivir may reduce time to clinical improvement and may lead to small reductions in serious adverse events but may result in a small increase in any adverse event. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Major Update: Remdesivir for Adults With COVID-19 : A Living Systematic Review and Meta-analysis for the American College of Physicians Practice Points.

BACKGROUND: Remdesivir is being studied and used for treatment of coronavirus disease 2019 (COVID-19). PURPOSE: To update a previous review of remdesivir for adults with COVID-19, including new meta-analyses of patients with COVID-19 of any severity compared with control. DATA SOURCES: Several sources from 1 January 2020 through 7 December 2020. STUDY SELECTION: English-language, randomized controlled trials (RCTs) of remdesivir for COVID-19. New evidence is incorporated by using living review methods. DATA EXTRACTION: 1 reviewer abstracted data; a second reviewer verified the data. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. DATA SYNTHESIS: The update includes 5 RCTs, incorporating data from a new large RCT and the final results of a previous RCT. Compared with control, a 10-day course of remdesivir probably results in little to no reduction in mortality (risk ratio [RR], 0.93 [95% CI, 0.82 to 1.06]; 4 RCTs) but may result in a small reduction in the proportion of patients receiving mechanical ventilation (RR, 0.71 [CI, 0.56 to 0.90]; 3 RCTs). Remdesivir probably results in a moderate increase in the percentage of patients who recovered and a moderate decrease in serious adverse events and may result in a large reduction in time to recovery. Effect on hospital length of stay or percentage remaining hospitalized is mixed. Compared with a 10-day course for those not requiring ventilation at baseline, a 5-day course may reduce mortality, the need for ventilation, and serious adverse events while increasing the percentage of patients who recovered or clinically improved. LIMITATION: Summarizing findings was challenging because of varying disease severity definitions and outcomes. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably results in little to no mortality difference but probably improves the percentage recovered and reduces serious harms and may result in a small reduction in the proportion receiving ventilation. For patients not receiving ventilation, a 5-day course may provide greater benefits and fewer harms with lower drug costs than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs.

Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review.

BACKGROUND: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) susceptibility, severity, and treatment is unclear. PURPOSE: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment. DATA SOURCES: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance. STUDY SELECTION: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality. DATA EXTRACTION: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence. DATA SYNTHESIS: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case-control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19. LIMITATION: Half the studies were small and did not adjust for important confounding variables. CONCLUSION: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain. PRIMARY FUNDING SOURCE: None. (PROSPERO: registration number pending).

The Research Role of the Librarian at a Community Health Hackathon - A Technical Report.

A hackathon is a social event that is focused on building small and innovative technology projects. The 2018 Hackathon hosted by the Washington State University (WSU) Elson S. Floyd College of Medicine aimed to solve rural health problems in Washington state. One major modification to the regular format of a healthcare hackathon was the inclusion of research librarians. Librarians with health sciences and business expertise provided research and library services at a designated Research Station, which included literature, patent, and internet searches. Participant and hackathon librarian observations, verbal feedback, and librarian survey results demonstrate the positive value/outcome of library services to the health hackathon winners. The winning hackathon teams used the services by the Research Station extensively. Areas of strength for this event included collaboration between librarians, promotion of library services, and efficient information retrieval. Areas for improvement included making regular contact with hackathon teams during the event and clearer signage and marketing.

Increasing rural nurses' awareness of a statewide health information resource: an educational outreach initiative.

BACKGROUND: HEALWA is an online library of evidence-based health information resources that are available to Washington state health practitioners. To increase awareness and use of HEALWA among health practitioners in rural areas, the National Network of Libraries of Medicine Pacific Northwest Region and Washington State University Spokane co-funded an outreach librarian position to provide instruction on using HEALWA. CASE PRESENTATION: After attempts at frequent in-person workshops failed due to lack of attendance, a one-hour-long webinar targeted at rural nurses was developed to be delivered once a month. These webinars introduced participating health professionals to HEALWA, including how to set up their access and how to navigate the resource. To accommodate the busy schedules and different learning styles of the target audience, the workshops occurred both as monthly webinars and in-person, when available, in addition to an online self-guided tutorial. Continuing education credit was obtained through the Washington State Nurses Association, and a partnership with the Washington State Nursing Commission improved promotion of the webinars. Evaluations for both the webinars and workshops have been largely positive. CONCLUSIONS: The webinar series, coupled with in-person workshops and an online tutorial, reached nurses in rural areas of Washington state to increase awareness of HEALWA. To further facilitate access to HEALWA instruction, a recorded version of the live webinar is in development.

Using Slack to communicate with medical students.

Academic libraries often make use of social networks like Facebook and Twitter to connect with their student users. While the Spokane Academic Library at Washington State University also employs this outreach strategy, the health sciences librarian was able to use a new type of social network called Slack to communicate more directly with the inaugural class of the Elson S. Floyd College of Medicine. As a digital workspace for communication and collaboration, Slack provided the medical librarian with an effective medium through which to post library announcements and updates, as well as have individual conversations with students about library-related questions and concerns.