Reimagining How We Synthesize Information to Impact Clinical Care, Policy, and Research Priorities in Real Time: Examples and Lessons Learned from COVID-19.

Real-time clinical care, policy, and research decisions need real-time evidence synthesis. However, as we found during the COVID-19 pandemic, it is challenging to rapidly address key clinical and policy questions through rigorous, relevant, and usable evidence. Our objective is to present three exemplar cases of rapid evidence synthesis products from the Veterans Healthcare Administration Evidence Synthesis Program (ESP) and, in the context of these examples, outline ESP products, challenges, and lessons learned. We faced challenges in (1) balancing scientific rigor with the speed in which evidence synthesis was needed, (2) sorting through rapidly evolving large bodies of evidence, and (3) assessing the impact of evidence synthesis products on clinical care, policy, and research. We found solutions in (1) engaging stakeholders early, (2) utilizing artificial intelligence capabilities, (3) building infrastructure to establish living reviews, and (4) planning for dissemination to maximize impact.

Direct organocatalytic transfer hydrogenation and C-H oxidation: high-yielding synthesis of 3-hydroxy-3-alkyloxindoles.

Readily available 3-alkylideneoxindoles were effectively reduced to 3-alkyloxindoles through transfer hydrogenation using Hantzsch ester as a reducing agent at ambient temperature and the greenness/sustainability of this protocol was assessed by correlation with Pd/C-mediated hydrogenation with hydrogen gas. Furthermore, an organocatalytic method was developed to access drug-like 3-alkyl-3-hydroxyoxindoles by C-H oxidation of 3-alkyl-indolin-2-one, using a catalytic amount of 1,1,3,3-tetramethylguanidine (TMG) as an organic base and dissolved oxygen in THF as an oxidant at room temperature. Key reaction intermediates were observed by controlled on-line ESI-HRMS experiments and identified by their corresponding mass (m/z) analysis. This two-step high-yielding transfer hydrogenation/C-H oxidation protocol was used for the total synthesis of medicinally important 3-cyanomethyl-3-hydroxyoxindole and formal total synthesis of (±)-alline and (±)-CPC-I in very good overall yields compared to previous methods.

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.

[Inactivation of Ras1 in Fission Yeast Aggravates the Oxidative Stress Response Induced by Tert Butyl Hydroperoxide (tBHP)].

Ras proteins are small GTPases and function as molecular switches to regulate cellular homeostasis. Ras-dependent signalling pathways regulate several essential processes such as cell cycle progression, growth, migration, apoptosis, and senescence. The dysregulation of Ras signaling pathway has been linked to several pathological outcomes. A potential role of RAS in regulating the redox signalling pathway has been established that includes the manipulation of ROS levels to provide a redox milieu that might be conducive to carcinogenesis. Reactive oxygen species (ROS) and mitochondrial impairment have been proposed as major factors affecting the physiology of cells and implicated in several pathologies. The present study was conducted to evaluate the role of Ras1, tert Butyl hydroperoxide (tBHP), and antimycin A in oxidative stress response in Schizosaccharomyces pombe cells. We observed decreased cell survival, higher levels of ROS, and mitochondrial dysfunctionality in ras1Δ cells and tBHP as well as respiratory inhibitor, antimycin A treated wild type cells. Furthermore, these defects were more profound in ras1Δ cells treated with tBHP or antimycin A. Additionally, Ras1 also has been shown to regulate the expression and activity of several antioxidant enzymes like glutathione peroxidase (GSH-Px), glutathione-S-transferase (GST), and catalase. Together, these results suggest the potential role of S. pombe Ras1 in mitigating oxidative stress response.

Remdesivir for Adults With COVID-19 : A Living Systematic Review for American College of Physicians Practice Points.

BACKGROUND: Few treatments exist for coronavirus disease 2019 (COVID-19). PURPOSE: To evaluate the effectiveness and harms of remdesivir for COVID-19. DATA SOURCES: Several databases, tables of contents of journals, and U.S. Food and Drug Administration and company websites were searched from 1 January through 31 August 2020. STUDY SELECTION: English-language, randomized trials of remdesivir treatments for adults with suspected or confirmed COVID-19. New evidence will be incorporated using living review methods. DATA EXTRACTION: Single-reviewer abstraction and risk-of-bias assessment verified by a second reviewer; GRADE (Grading of Recommendations Assessment, Development and Evaluation) methods used for certainty-of-evidence assessments. DATA SYNTHESIS: Four randomized trials were included. In adults with severe COVID-19, remdesivir compared with placebo probably improves recovery by a large amount (absolute risk difference [ARD] range, 7% to 10%) and may result in a small reduction in mortality (ARD range, -4% to 1%) and a shorter time to recovery or clinical improvement. Remdesivir may have little to no effect on hospital length of stay. Remdesivir probably reduces serious adverse events by a moderate amount (ARD range, -6% to -8%). Compared with a 10-day remdesivir course, a 5-day course may reduce mortality, increase recovery or clinical improvement by small to moderate amounts, reduce time to recovery, and reduce serious adverse events among hospitalized patients not requiring mechanical ventilation. Recovery due to remdesivir may not vary by age, sex, symptom duration, or disease severity. LIMITATIONS: Low-certainty evidence with few published trials, including 1 preliminary report and 2 open-label trials. Trials excluded pregnant women and adults with severe kidney or liver disease. CONCLUSION: In hospitalized adults with COVID-19, remdesivir probably improves recovery and reduces serious adverse events and may reduce mortality and time to clinical improvement. For adults not receiving mechanical ventilation or extracorporeal membrane oxygenation, a 5-day course of remdesivir may provide similar benefits to and fewer harms than a 10-day course. PRIMARY FUNDING SOURCE: U.S. Department of Veterans Affairs, Veterans Health Administration Office of Research and Development, Health Services Research and Development Service, and Evidence Synthesis Program.

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.

"I want to live, but " the desire to live and its physical, psychological, spiritual, and social factors among advanced cancer patients: evidence from the APPROACH study in India.

BACKGROUND: The limited access to palliative care resources along with the social stigma around cancer largely explains the poor quality of life (QoL) of Indian advanced cancer patients. As advanced cancer patients with poor QoL often harbour a desire for hastened death (DHD), it is imperative to understand factors affecting DHD, or the desire to live (DTL) among advanced cancer patients in India. We aim to examine the relationship between DTL and physical, psychological, spiritual, and social factors measuring patients' QoL alongside their awareness of their late cancer stage. METHODS: We surveyed 200 patients from a tertiary cancer hospital in India to collect their DTL, awareness of cancer stage, demographic characteristics, and standardized measures for patients' QoL. We used a linear probability regression model to quantify the association between these factors and patients' DTL among the final sample of 192 patients with no missing information for the variables of interest. RESULTS: Among the various domains affecting cancer patients' QoL, we found that the pain severity score (ranging from 0 to 10) and psychological distress score (ranging from 0 to 42) are negatively associated with the DTL. One point increase in each score reduced the DTL by 2.2% (p < 0.05) and 0.7% (p < 0.05), respectively. Our results also showed that patients whose perceived socio-economic status (SES) is poor have a 16% (p < 0.05) lower probability of DTL, compared to those with higher SES (lower middle class, upper middle class, and wealthy). Controlling for caste, religion, gender, age, marital status and years of education, we found psychological distress is statistically higher among patients belonging to this bottom SES. CONCLUSIONS: We found that pain severity, psychological distress and perceived low SES are negatively associated with the desire to live in advanced cancer patients. Future research should focus on developing interventions to improve physical pain and psychological distress, particularly for patients who are socially and economically disadvantaged.

Green synthesis of silver, iron and gold nanoparticles of lycopene extracted from tomato: their characterization and cytotoxicity against COLO320DM, HT29 and Hella cell.

Our study aimed at development of Silver, Iron and Gold nanoparticles of Lycopene isolated from tomato by using green synthesis technique and to evaluate its anticancer potential against colorectal and cervical cancer. Lycopene was extracted by benzene extraction method and the silver, iron and gold nanoparticles were developed by green synthesis method. 1% aqueous extract of isolated Lycopene was mixed with 1% solutions of AgNO3, FeCl3 and HAuCl4 solutions and incubated at ambient temperature for 3-4 h separately and observed for the color change which is an indicative of formation of the nanoparticles. The prepared nanoparticles were characterized by FTIR, SEM, XRD analysis and evaluated for their antimicrobial potential. The cytotoxicity studies were carried out by in vitro assay like MTT, SRB and Tryphan blue method against Colo 320 DM, HT 29, and Hella. SEM showed nanosized particles of 50-100 nm range, whereas no antimicrobial activity was exhibited by the prepared nanoparticles. In MTT assay the LyAgNP showed maximum 41.41 ± 0.4124% inhibition against COLO320DM, whereas LyGNP exhibited 41.47 ± 0.4469% inhibition against HT 29 and LyAgNP showed 40.9 ± 0.6908% inhibition against Hella cells. In SRB assay LyAgNP showed maximum 82.68 ± 1.1798% inhibition against COLO320DM, whereas LyGNP exhibited maximum 91.21 ± 0.2372% inhibition against HT29 and 87.98 ± 0.5878% inhibition against Hella cells. In tryphan blue assay against COLO320DM, HT29 and Hella cells, the maximum inhibition exhibited by the prepared nanoparticles were observed as LyGNP 83.45 ± 0.4694%, LyAgNP 88.05 ± 0.1870% and LyAgNP65.47 ± 0.4766%. We conclude that the developed nanoparticles of Lycopene exhibited potential anticancer activity against Colorectal and cervical cancer cell as compared with pure Lycopene.

A possible direct action of oxytocin on spermatogenesis and steroidogenesis in pre-pubertal mouse.

The aim of this study was to evaluate the effects of in vivo and in vitro treatments of oxytocin (OT) on the testis of pre-pubertal mice. The OT treatment produced significant changes in the spermatogenic and steroidogenic activity by increasing expression of OT-receptor in the testis of pre-pubertal mice. Treatment with OT showed increased proliferation of germ cells as indicated by increased number of spermatocytes and round spermatids. Dose-dependent increase in expression of PCNA, Bcl-2 and AR proteins was observed in the testis of OT-treated mice as compared with the control and further supports the role of OT in germ cell proliferation and survival. The pre-pubertal mice treated with increasing dose of OT showed significant increase in testosterone synthesis due to dose-dependent stimulatory effects on 3ß-HSD activity and increased expression of STAR, LH-receptor (LH-R) and gonadotrophin-releasing hormone receptor (GnRH-R) proteins in the testis. The in vitro study has confirmed in vivo finding showing direct action of OT on testicular steroidogenesis. Thus, OT stimulates testicular spermatogenesis and steroidogenesis by directly acting on testis in mice.

Investigation of high optical gain in complex type-II InGaAs/InAs/GaAsSb nano-scale heterostructure for MIR applications.

This paper reports a comprehensive theoretical study of W-shaped complex type-II InGaAs/InAs/GaAsSb nano-scale heterostructure consisting of two quantum wells of InAs material using the six-band k.p theory. The entire structure has been supposed to be grown on InP substrate. In order to optimize the optical gain, the probability densities of electrons and holes were optimized in the heterostructure. Following these calculations, dispersion relations for electron and hole energies, and transverse electric and transverse magnetic polarizations dependent dipole matrix elements and momentum matrix elements were calculated and, finally, the optical gain in both polarization modes was calculated. For this optimized complex heterostructure, a very high optical gain of the order of ∼4500 cm-1 in the regime of mid-infrared wavelength ∼3.2 µm has been achieved. The results suggest that the designed nano-heterostructure may be utilized for mid-infrared region (MIR) applications such as chemical and bio-molecular sensing of molecules, for the applications of spectroscopy in the "fingerprint region" of molecular science, and for detection of atmospheric gases that respond to 3.2 µm wavelength.

Recipient Outcomes Following Transplantation of Allografts From Live Kidney Donors Who Subsequently Developed End-Stage Renal Disease.

Live kidney donors have an increased risk of end-stage renal disease (ESRD) compared with nondonors; however, it is unknown whether undetected, subclinical kidney disease exists at donation that subsequently contributes to this risk. To indirectly test this hypothesis, the authors followed the donated kidneys, by comparing the outcomes of 257 recipients whose donors subsequently developed ESRD with a matched cohort whose donors remained ESRD free. The compared recipients were matched on donor (age, sex, race/ethnicity, donor-recipient relationship), transplant (HLA mismatch, peak panel-reactive antibody, previous transplantation, year of transplantation), and recipient (age, sex, race/ethnicity, body mass index, cause of ESRD, and time on dialysis) risk factors. Median recipient follow-up was 12.5 years (interquartile range 7.4-17.9, maximum 20 years). Recipients of allografts from donors who developed ESRD had increased death-censored graft loss (74% versus 56% at 20 years; adjusted hazard ratio [aHR] 1.7; 95% confidence interval [CI] 1.5-2.0; p < 0.001) and mortality (61% versus 46% at 20 years; aHR 1.5; 95% CI 1.2-1.8; p < 0.001) compared with matched recipients of allografts from donors who did not develop ESRD. This association was similar among related, spousal, and unrelated nonspousal donors. These findings support a novel view of the mechanisms underlying donor ESRD: that of pre-donation kidney disease. However, biopsy data may be required to confirm this hypothesis.

Changes in Discard Rate After the Introduction of the Kidney Donor Profile Index (KDPI).

Since March 26, 2012, the Kidney Donor Profile Index (KDPI) has been provided with all deceased-donor kidney offers, with the goal of improving the expanded criteria donor (ECD) indicator. Although an improved risk index may facilitate identification and transplantation of marginal yet viable kidneys, a granular percentile system may reduce provider-patient communication flexibility, paradoxically leading to more discards ("labeling effect"). We studied the discard rates of the kidneys recovered for transplantation between March 26, 2010 and March 25, 2012 ("ECD era," N = 28 636) and March 26, 2012 and March 25, 2014 ("KDPI era," N = 29 021) using Scientific Registry of Transplant Recipients (SRTR) data. There was no significant change in discard rate from ECD era (18.1%) to KDPI era (18.3%) among the entire population (adjusted odds ratio [aOR] = 0.97 1.041.10 , p = 0.3), or in any KDPI stratum. However, among kidneys in which ECD and KDPI indicators were discordant, "high risk" standard criteria donor (SCD) kidneys (with KDPI > 85) were at increased risk of discard in the KDPI era (aOR = 1.07 1.421.89 , p = 0.02). Yet, recipients of these kidneys were at much lower risk of death (adjusted Risk Ratio [aRR] = 0.56 0.770.94 at 2 years posttransplant) compared to those remaining on dialysis waiting for low-KDPI kidneys. Our findings suggest that there might be an unexpected, harmful labeling effect of reporting a high KDPI for SCD kidneys, without the expected advantage of providing a more granular risk index.

Where the Sun Shines: Industry's Payments to Transplant Surgeons.

The Open Payments Program (OPP) was recently implemented to publicly disclose industry payments to physicians, with the goal of enabling patient awareness of potential conflicts of interests. Awareness of OPP, its data, and its implications for transplantation are critical. We used the first wave of OPP data to describe industry payments made to transplant surgeons. Transplant surgeons (N = 297) received a total of $759 654. The median (interquartile range [IQR]) payment to a transplant surgeon was $125 ($39-1018), and the highest payment to an individual surgeon was $83 520; 122 surgeons received <$100, and 17 received >$10 000. A higher h-index was associated with 30% higher chance of receiving >$1000 (relative risk/10 unit h-index increase = 1.18 1.301.44 , p < 0.001). The highest payment category was consulting fees, with a total of $314 448 paid in this reported category. Recipients of consulting fees had higher h-indices, median (IQR) of 20 (10-35) versus nine (3-17) (p < 0.001). Ten of 122 companies accounted for 62% of all payments. Kidney transplant and liver transplant (LT) centers that received >$1000 had higher center volumes (p < 0.001). LT centers that received payments of >$1000 had a higher percentage of private-insurance/self-pay patients (p < 0.01). Continued surveillance of industry payments may further elucidate the relationship between industry payments and physician practices.

Patterns of End-Stage Renal Disease Caused by Diabetes, Hypertension, and Glomerulonephritis in Live Kidney Donors.

Inferences about late risk of end-stage renal disease (ESRD) in live kidney donors have been extrapolated from studies averaging <10 years of follow-up. Because early (<10 years) and late (≥10 years) postdonation ESRD may differ by causal mechanism, it is possible that extrapolations are misleading. To better understand postdonation ESRD, we studied patterns of common etiologies including diabetes, hypertension and glomerulonephritis (GN; as reported by providers) using donor registry data linked to ESRD registry data. Overall, 125 427 donors were observed for a median of 11.0 years (interquartile range 5.3-15.7 years; maximum 25 years). The cumulative incidence of ESRD increased from 10 events per 10 000 at 10 years after donation to 85 events per 10 000 at 25 years after donation (late vs. early ESRD, adjusted for age, race and sex: incidence rate ratio [IRR] 1.3 1.72.3 [subscripts are 95% confidence intervals]). Early postdonation ESRD was predominantly reported as GN-ESRD; however, late postdonation ESRD was more frequently reported as diabetic ESRD and hypertensive ESRD (IRR 2.3 7.725.2 and 1.4 2.64.6 , respectively). These time-dependent patterns were not seen with GN-ESRD (IRR 0.4 0.71.2 ). Because ESRD in live kidney donors has traditionally been reported in studies averaging <10 years of follow-up, our findings suggest caution in extrapolating such results over much longer intervals.

Kinetic evaluation of glucose 1-phosphate analogues with a thymidylyltransferase using a continuous coupled enzyme assay.

Cps2L, a thymidylytransferase, is the first enzyme in Streptococcus pneumoniae L-rhamnose biosynthesis and an antibacterial target. We herein report the evaluation of six sugar phosphate analogues selected to further probe Cps2L substrate tolerance. A modified continuous spectrophotometric assay was employed for facile detection of pyrophosphate (PPi) released from nucleotidylyltransfase-catalysed condensation of sugar 1-phosphates and nucleoside triphosphates to produce sugar nucleotides. Additionally, experiments using waterLOGSY NMR spectroscopy were investigated as a complimentary method to evaluate binding affinity to Cps2L.

Comparative effect of fluoride, essential oil and chlorhexidine mouth rinses on dental plaque and gingivitis in patients with and without dental caries: a randomized controlled trial.

OBJECTIVES: The objective of this study was to compare the effectiveness of fluoride, essential oil (EO) and chlorhexidine (CHX)-containing mouth rinses on dental plaque and gingivitis and to compare their relative efficacy in patients with and without dental caries. MATERIAL AND METHODS: A randomized, controlled, double- blind, crossover clinical trial was conducted for a period of 8 weeks. Thiry-six qualifying subjects, aged 12-44 years, were included in the study. Subjects were divided into caries and caries-free groups and were randomly assigned to one of the following mouth rinse groups: fluoride; EO; CHX and saline as negative control. Subjects used their respective mouth rinse for a period of 7-days each with 1-week wash-out periods. Primary efficacy variables were Quigley-Hein plaque index (PI) and Loe and Silness gingival index. RESULTS: Fluoride and CHX mouth rinses showed significant reduction in plaque after use of mouth rinses (P < 0.05). However, no significant differences were observed with respect to each other in reducing gingivitis (P > 0.05). Further significant differences were found in reducing plaque and gingivitis in caries-free subjects in comparison to those with caries (P < 0.05). CONCLUSION: All the three mouth rinses significantly reduced plaque accumulation and gingivitis especially in caries-free subjects in comparison to those with caries, and amongst the three, fluoride and CHX proved to be more effective than EO mouth rinse.