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Effect of tocilizumab, sarilumab, and baricitinib on mortality among patients hospitalized for COVID-19 treated with corticosteroids: a systematic review and meta-analysis.
Albuquerque, AM, Eckert, I, Tramujas, L, Butler-Laporte, G, McDonald, EG, Brophy, JM, Lee, TC
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2023;(1):13-21
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Abstract
BACKGROUND Randomized controlled trials (RCT) established the mortality reduction by tocilizumab (Actemra), baricitinib (Olumiant), and sarilumab (Kevzara) in hospitalized COVID-19 patients. However, uncertainty remains about which treatment performs best in patients receiving corticosteroids. OBJECTIVES To estimate probabilities of noninferiority between baricitinib and sarilumab compared to tocilizumab in patients treated with corticosteroids. DATA SOURCES PubMed, Embase, Cochrane Library, and MedRxiv. STUDY ELIGIBILITY CRITERIA Eligible RCTs assigning hospitalized adults with COVID-19 treated with corticosteroids to tocilizumab or baricitinib or sarilumab versus standard of care or placebo (control). METHODS Reviewers independently abstracted published data and assessed study quality with the Risk of Bias 2 tool. Unpublished data, if required, were requested from authors of included studies. The outcome of interest was all-cause mortality at 28 days. PARTICIPANTS Twenty-seven RCTs with 13 549 patients were included. Overall, the risk of bias was low. Bayesian pairwise meta-analyses were used to aggregate results of each treatment versus control. The average odds ratio for mortality was 0.78 (95% credible interval [CrI]: 0.65, 0.94) for tocilizumab; 0.78 (95% CrI: 0.56, 1.03) for baricitinib; and 0.91 (95% CrI: 0.60, 1.40) for sarilumab. The certainty of evidence (GRADE) ranged from moderate to low. Bayesian meta-regressions with multiple priors were used to estimate probabilities of noninferiority (margin of 13% greater effect by tocilizumab). Compared to tocilizumab, there were ≤94% and 90% probabilities of noninferiority with baricitinib and sarilumab, respectively. RESULTS All but two studies included data with only indirect evidence for the comparison of interest. CONCLUSIONS Among hospitalized COVID-19 treated with corticosteroids, there are high probabilities that both baricitinib and sarilumab are associated with similar mortality reductions in comparison to tocilizumab.
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Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials.
Eljaaly, K, Bidell, MR, Gandhi, RG, Alshehri, S, Enani, MA, Al-Jedai, A, Lee, TC
Open forum infectious diseases. 2021;(2):ofab026
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BACKGROUND Nephrotoxicity is a known adverse effect of polymyxin antibiotics, including colistin. Although previous meta-analyses have aimed to characterize colistin-associated nephrotoxicity risk relative to other antibiotics, included studies were observational in nature with high risk of confounding and heterogeneity. We conducted this systematic review and meta-analysis of exclusively randomized controlled trials (RCTs) to evaluate the incidence of nephrotoxicity associated with colistin versus minimally nephrotoxic antibiotics. METHODS We searched PubMed, EMBASE, Cochrane Library, and 3 trial registries for RCTs comparing the nephrotoxicity of colistin to nonpolymyxin antibiotics. Randomized controlled trials that used aminoglycosides were excluded. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models. The study outcome was the rate of nephrotoxicity. RESULTS Five RCTs with a total of 377 patients were included. Most patients received colistin for pneumonia in the intensive care unit, and the comparators were β-lactam-based regimens. Colistimethate sodium was dosed at 9 million units/day (300 mg/day of colistin base activity), with administration of a loading dose in 4 studies. The nephrotoxicity incidence in patients who received colistin was 36.2% (95% CI, 23.3% to 51.3%). The nephrotoxicity rate was significantly higher in the colistin arm than comparators (RR, 2.40; 95% CI, 1.47 to 3.91; P ≤ .001; I2 = 0%), and the number needed to harm was 5. Findings persisted upon one-study-removed-analysis. CONCLUSIONS This meta-analysis of RCTs found a colistin-associated nephrotoxicity rate of 36.2% and an increase in this risk compared with β-lactam-based regimens by 140%. Colistin should be regarded as a last-line agent and safer alternatives should be considered when possible.
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Efficacy, Safety, and Exposure of Apixaban in Patients with High Body Weight or Obesity and Venous Thromboembolism: Insights from AMPLIFY.
Cohen, AT, Pan, S, Byon, W, Ilyas, BS, Taylor, T, Lee, TC
Advances in therapy. 2021;(6):3003-3018
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INTRODUCTION As a result of limited clinical data, guidelines do not recommend the use of non-vitamin K antagonist oral anticoagulants in patients who weigh > 120 kg or have a body mass index (BMI) > 40 kg/m2. METHODS This post hoc analysis of the AMPLIFY trial evaluated the efficacy (venous thromboembolism [VTE]/VTE-related death), safety (major and composite of major and clinically relevant non-major [CRNM] bleeding), and exposure of apixaban compared with enoxaparin followed by warfarin for the treatment of VTE by body weight (≤ 60, > 60 to < 100, ≥ 100 to < 120, ≥ 120 kg) and BMI (≤ 25, > 25 to 30, > 30 to 35, > 35 to 40, > 40 kg/m2). RESULTS Among the AMPLIFY safety population, 5384 and 5359 patients had recorded body weight (range 28.9 to 222.0 kg; ≥ 120 kg, n = 290) and BMI (range 12.5-71.8 kg/m2; > 40 kg/m2, n = 263), respectively. The rates of recurrent VTE/VTE-related death for apixaban versus enoxaparin/warfarin were similar across body weight subgroups: relative risks (RR; 95% confidence intervals [CI]) were 0.63 (0.23, 1.72), 0.99 (0.65, 1.50), 0.77 (0.34, 1.72), and 0.20 (0.02, 1.72) for the ≤ 60, > 60 to < 100, ≥ 100 to < 120, and ≥ 120 kg groups, respectively (Pinteraction = 0.44). The rates of major bleeding were lower with apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.15 (0.02, 1.15), 0.41 (0.21, 0.77), not estimable, and 0.34 (0.04, 3.22), respectively (Pinteraction = not estimable). The rates of major/CRNM bleeding were significantly lower for apixaban versus enoxaparin/warfarin; RRs (95% CI) were 0.46 (0.24, 0.89), 0.49 (0.38, 0.63), 0.30 (0.16, 0.58), and 0.28 (0.12, 0.66), respectively (Pinteraction = 0.36). Similar trends were seen in the BMI subgroups. There was a modest, not clinically meaningful, decrease (< 30%) in the median predicted exposure with increasing body weight (n = 281). CONCLUSIONS The findings of this post hoc analysis support the use of apixaban in patients with body weight ≥ 120 kg or BMI > 40 kg/m2. TRIAL REGISTRATION NUMBER NCT00643201.
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Development of a multidisciplinary colorectal and pelvic health program: Program implementation and clinical impact.
Style, CC, Hsu, DM, Verla, MA, Mittal, AG, Austin, P, Seth, A, Dietrich, JE, Adeyemi-Fowode, OA, Bercaw-Pratt, JL, Chiou, EH, et al
Journal of pediatric surgery. 2020;(11):2397-2402
Abstract
INTRODUCTION Pediatric patients with complex colorectal and genitourinary conditions often require coordinated multidisciplinary care; however, this coordinated care can be hard to structure and deliver. The purpose of this paper is to review the development and implementation of a multidisciplinary colorectal and pelvic health program, one year after the program's initiation. METHODS This is an observational retrospective 1-year study (10/1/2017 to 9/30/2018). In fiscal year (FY) 2018, a multidisciplinary colorectal and pelvic health program was initiated. The program development incorporated bimonthly team meetings, educational conferences, and initiation of three clinics: a complex colorectal and genitourinary reconstruction clinic, a bowel management clinic, and a colonic motility clinic. Conditions treated included complex anorectal and cloacal malformations, Hirschsprung disease, and idiopathic constipation. The fiscal year was selected to provide comparative administrative data after program implementation. RESULTS During the study period, 121 patients underwent comprehensive collaborative evaluation of which 58 (47%) were new to the institution compared to 12 (19%) new patients in the previous year (p < 0.001). In FY 2018, there were 130 procedures performed and 512 collaborative visits with an average of 47 visits per month. This was a 3.4-fold increase in visits compared to FY2017 (171 visits). Of the new patients, 60% (35/58), traveled a median of 181 miles, representing 33 statewide counties, and 4 states compared to a median of 93 miles in the previous fiscal year (p = 0.004). CONCLUSION The development of a colorectal and pelvic health program is feasible and requires a collaborative approach, necessitating multiple service lines within an institution. Program creation and implementation can result in rapid institutional clinical growth by filling a local and regional need through coordinated multidisciplinary care. LEVEL OF EVIDENCE IV.
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Diagnostic accuracy of serum (1-3)-β-D-glucan for Pneumocystis jirovecii pneumonia: a systematic review and meta-analysis.
Del Corpo, O, Butler-Laporte, G, Sheppard, DC, Cheng, MP, McDonald, EG, Lee, TC
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2020;(9):1137-1143
Abstract
BACKGROUND Pneumocystis jirovecii pneumonia (PJP) can be a life-threatening opportunistic infection in immunocompromised hosts. The diagnosis can be challenging, often requiring semi-invasive respiratory sampling. The serum 1,3-β-D-glucan (BDG) assay has been proposed as a minimally invasive test for the presumptive diagnosis of PJP. METHOD We carried out a systematic review and meta-analysis using articles in the English language published between January 1960 and September 2019. We estimated the pooled sensitivity and specificity of BDG testing using a bivariate random effects approach and compared test performance in human immunodeficiency virus (HIV) and non-HIV subgroups with meta-regression. Data from the pooled sensitivity and specificity were transformed to generate pre- and post-test probability curves. RESULTS Twenty-three studies were included. The pooled sensitivity and specificity of serum BDG testing for PJP were 91% (95%CI 87-94%) and 79% (95%CI 72-84%) respectively. The sensitivity in patients with HIV was better than in patients without (94%, 95%CI 91-96%) versus 86% (95%CI 78-91%) (p 0.02), with comparable specificity (83%, 95%CI 69-92% versus 83%, 95%CI 72-90%) (p 0.10). A negative BDG was only associated with a low post-test probability of PJP (≤5%) when the pre-test probability was low to intermediate (≤20% in non-HIV and ≤50% in HIV). CONCLUSIONS Among patients with a higher likelihood of PJP, the pooled sensitivity of BDG is insufficient to exclude infection. Similarly, for most cases, the pooled specificity is inadequate to diagnose PJP. Understanding the performance of BDG in the population being investigated is therefore essential to optimal clinical decision-making.
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COVID-19 and anatomy: Stimulus and initial response.
Brassett, C, Cosker, T, Davies, DC, Dockery, P, Gillingwater, TH, Lee, TC, Milz, S, Parson, SH, Quondamatteo, F, Wilkinson, T
Journal of anatomy. 2020;(3):393-403
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The outbreak of COVID-19, resulting from widespread transmission of the SARS-CoV-2 virus, represents one of the foremost current challenges to societies across the globe, with few areas of life remaining untouched. Here, we detail the immediate impact that COVID-19 has had on the teaching and practice of anatomy, providing specific examples of the varied responses from several UK, Irish and German universities and medical schools. Alongside significant issues for, and suspension of, body donation programmes, the widespread closure of university campuses has led to challenges in delivering anatomy education via online methods, a particular problem for a practical, experience-based subject such as anatomy. We discuss the short-term consequences of COVID-19 for body donation programmes and anatomical education, and highlight issues and challenges that will need to be addressed in the medium to long term in order to restore anatomy education and practice throughout the world.
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Structural and Functional Characterization of Human Stem-Cell-Derived Retinal Organoids by Live Imaging.
Browne, AW, Arnesano, C, Harutyunyan, N, Khuu, T, Martinez, JC, Pollack, HA, Koos, DS, Lee, TC, Fraser, SE, Moats, RA, et al
Investigative ophthalmology & visual science. 2017;(9):3311-3318
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PURPOSE Human pluripotent stem cell (hPSC)-derived retinal organoids are a platform for investigating retinal development, pathophysiology, and cellular therapies. In contrast to histologic analysis in which multiple specimens fixed at different times are used to reconstruct developmental processes, repeated analysis of the same living organoids provides a more direct means to characterize changes. New live imaging modalities can provide insights into retinal organoid structure and metabolic function during in vitro growth. This study employed live tissue imaging to characterize retinal organoid development, including metabolic changes accompanying photoreceptor differentiation. METHODS Live hPSC-derived retinal organoids at different developmental stages were examined for microanatomic organization and metabolic function by phase contrast microscopy, optical coherence tomography (OCT), fluorescence lifetime imaging microscopy (FLIM), and hyperspectral imaging (HSpec). Features were compared to those revealed by histologic staining, immunostaining, and microcomputed tomography (micro-CT) of fixed organoid tissue. RESULTS We used FLIM and HSpec to detect changes in metabolic activity as organoids differentiated into organized lamellae. FLIM detected increased glycolytic activity and HSpec detected retinol and retinoic acid accumulation in the organoid outer layer, coinciding with photoreceptor genesis. OCT enabled imaging of lamellae formed during organoid maturation. Micro-CT revealed three-dimensional structure, but failed to detect lamellae. CONCLUSIONS Live imaging modalities facilitate real-time and nondestructive imaging of retinal organoids as they organize into lamellar structures. FLIM and HSpec enable rapid detection of lamellar structure and photoreceptor metabolism. Live imaging techniques may aid in the continuous evaluation of retinal organoid development in diverse experimental and cell therapy settings.
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The Mechanism of Diarrhetic Shellfish Poisoning Toxin Production in Prorocentrum spp.: Physiological and Molecular Perspectives.
Lee, TC, Fong, FL, Ho, KC, Lee, FW
Toxins. 2016;(10)
Abstract
Diarrhetic shellfish poisoning (DSP) is a gastrointestinal disorder caused by the consumption of seafood contaminated with okadaic acid (OA) and dinophysistoxins (DTXs). OA and DTXs are potent inhibitors of protein phosphatases 2A, 1B, and 2B, which may promote cancer in the human digestive system. Their expression in dinoflagellates is strongly affected by nutritional and environmental factors. Studies have indicated that the level of these biotoxins is inversely associated with the growth of dinoflagellates at low concentrations of nitrogen or phosphorus, or at extreme temperature. However, the presence of leucine or glycerophosphate enhances both growth and cellular toxin level. Moreover, the presence of ammonia and incubation in continuous darkness do not favor the toxin production. Currently, studies on the mechanism of this biotoxin production are scant. Full genome sequencing of dinoflagellates is challenging because of the massive genomic size; however, current advanced molecular and omics technologies may provide valuable insight into the biotoxin production mechanism and novel research perspectives on microalgae. This review presents a comprehensive analysis on the effects of various nutritional and physical factors on the OA and DTX production in the DSP toxin-producing Prorocentrum spp. Moreover, the applications of the current molecular technologies in the study on the mechanism of DSP toxin production are discussed.
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Utilising inorganic nanocarriers for gene delivery.
Loh, XJ, Lee, TC, Dou, Q, Deen, GR
Biomaterials science. 2016;(1):70-86
Abstract
The delivery of genetic materials into cells to elicit cellular responses has been extensively studied by biomaterials scientists globally. Many materials such as lipids, peptides, viruses, synthetically modified cationic polymers and certain inorganic nanomaterials could be used to complex the negatively charged plasmids and deliver the formed package into cells. The recent literature on the delivery of genetic materials utilising inorganic nanoparticles is carefully examined in this review. We have picked out the most relevant references and concisely summarised the findings with illustrated examples. We further propose alternative approaches and suggest future pathways towards the practical use of multifunctional nanocarriers.
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Two-year safety and effectiveness of the platinum chromium everolimus-eluting stent for the treatment of small vessels and longer lesions.
Teirstein, PS, Meredith, IT, Feldman, RL, Rabinowitz, AC, Cannon, LA, Lee, TC, Dens, J, Dubois, CL, Mooney, MR, Pompili, VJ, et al
Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions. 2015;(2):207-15
Abstract
OBJECTIVES To report 1- and 2-year clinical outcomes of patients receiving platinum chromium everolimus-eluting stents (PtCr-EES) in the prospective, single-arm PLATINUM small vessel (SV) and long lesion (LL) studies. BACKGROUND Small vessel diameter and long lesion length are independently associated with increased risk of adverse cardiac events after drug-eluting stent implantation. METHODS The PLATINUM SV study enrolled 94 patients with coronary artery lesions in vessels ≥2.25 mm to <2.50 mm in diameter and ≤28 mm in length. The PLATINUM LL study enrolled 102 patients with lesions >24 to ≤34 mm long in vessels ≥2.50 to ≤4.25 mm in diameter. The primary endpoint for both studies was target lesion failure (TLF) at 1 year compared to a prespecified performance goal based on outcomes with the TAXUS Express paclitaxel-eluting stent in small vessels and long lesions. RESULTS One-year TLF rates with the PtCr-EES were significantly (P < 0.001) lower than the predetermined performance goals: 2.4% versus 21.1% in the SV cohort and 3.2% versus 19.4% in the LL cohort. Cumulative rates of TLF to 2 years were 4.7% in the SV cohort and 8.8% in the LL cohort. No myocardial infarction or ARC definite/probable stent thromboses occurred in either cohort through 2-year follow-up. CONCLUSIONS The clinical efficacy and safety outcomes observed in these small vessel and long lesion cohorts support the use of the PtCr-EES in the treatment of small diameter vessels and long lesions.