Murad, M. Hassan

Abstract Immunoassays designed to detect SARS-CoV-2 protein antigens are now commercially available. The most widely used tests are rapid lateral flow assays that generate results in ~15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 antigen (Ag) assays have also been developed. The overall accuracy of SARS-CoV-2 Ag tests, however, is not well defined. The Infectious Diseases Society of America (IDSA) convened an expert panel to perform a systematic review of the literature and develop best-practice guidance related to SARS-CoV-2 Ag testing. This guideline is the third in a series of rapid, frequently updated COVID-19 diagnostic guidelines developed by IDSA. IDSA’s goal was to develop evidence-based recommendations or suggestions that assist clinicians, clinical laboratories, patients, public health authorities, administrators, and policymakers in decisions related to the optimal use of SARS-CoV-2 Ag tests in both medical and nonmedical settings. A multidisciplinary panel of infectious diseases clinicians, clinical microbiologists, and experts in systematic literature review identified and prioritized clinical questions related to the use of SARS-CoV-2 Ag tests. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. The panel agreed on 5 diagnostic recommendations. These recommendations address Ag testing in symptomatic and asymptomatic individuals as well as assess single versus repeat testing strategies. Data on the clinical performance of US Food and Drug Administration SARS-CoV-2 Ag tests with Emergency Use Authorization are mostly limited to single, one-time testing versus standard nucleic acid amplification testing (NAAT) as the reference standard. Rapid Ag tests have high specificity and low to modest sensitivity compared with reference NAAT methods. Antigen test sensitivity is heavily dependent on viral load, with differences observed between symptomatic compared with asymptomatic individuals and the time of testing post-onset of symptoms. Based on these observations, rapid reverse transcriptase–polymerase chain reaction (RT-PCR) or laboratory-based NAAT remain the diagnostic methods of choice for diagnosing SARS-CoV-2 infection. However, when molecular testing is not readily available or is logistically infeasible, Ag testing can help identify some individuals with SARS-CoV-2 infection. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.

AbstractRegenerative, cell-based therapy is a promising treatment option for diabetic kidney disease (DKD), which has no cure. To prepare for clinical translation, this systematic review and meta-analysis summarized the effect of cell-based interventions in DKD animal models and treatment-related factors modifying outcomes. Electronic databases were searched for original investigations applying cell-based therapy in diabetic animals with kidney endpoints (January 1998-May 2019). Weighted or standardized mean differences were estimated for kidney outcomes and pooled using random-effects models. Subgroup analyses tested treatment-related factor effects for outcomes (creatinine, urea, urine protein, fibrosis, and inflammation). In 40 studies (992 diabetic rodents), therapy included mesenchymal stem/stromal cells (MSC; 61%), umbilical cord/amniotic fluid cells (UC/AF; 15%), non-MSC (15%), and cell-derived products (13%). Tissue sources included bone marrow (BM; 65%), UC/AF (15%), adipose (9%), and others (11%). Cell-based therapy significantly improved kidney function while reducing injury markers (proteinuria, histology, fibrosis, inflammation, apoptosis, epithelial-mesenchymal-transition, oxidative stress). Preconditioning, xenotransplantation, and disease-source approaches were effective. MSC and UC/AF cells had greater effect on kidney function while cell products improved fibrosis. BM and UC/AF tissue sources more effectively improved kidney function and proteinuria vs adipose or other tissues. Cell dose, frequency, and administration route also imparted different benefits. In conclusion, cell-based interventions in diabetic animals improved kidney function and reduced injury with treatment-related factors modifying these effects. These findings may aid in development of optimal repair strategies through selective use of cells/products, tissue sources, and dose administrations to allow for successful adaptation of this novel therapeutic in human DKD.

e16522 Background: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC) in cisplatin-eligible patients. This systematic review and meta-analysis provide an updated efficacy and safety comparison between the two most commonly used cisplatin-based regimens; dose-dense (dd) or conventional MVAC versus GC. Methods: We searched different databases for studies comparing MVAC versus GC in the neoadjuvant setting. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model. Results: We identified 24 studies from inception to March 2020; among them 17 were peer reviewed and 7 were only reported as abstracts in national or international meetings, including a phase 3, randomized-controlled clinical trial. Among peer-reviewed published studies, efficacy outcomes such as OS, downstaging and pCR were comparable between conventional MVAC and GC for MIBC. If including non-peer-reviewed studies, dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95% CI 1.15–1.82), and OS at longest follow-up (OR 0.63; 95% CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95% CI 0.13–0.80), anemia (OR 0.32; 95% CI 0.18–0.54), nausea and vomiting (OR 0.27; 95% CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95% CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95% CI 0.01-0.31). Certainty in the estimates was very low for most outcomes. Conclusions: Among peer-reviewed published studies, efficacy and safety outcomes were comparable between conventional MVAC and GC for MIBC. However, If including non-peer-reviewed studies, this analysis showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice

PURPOSE Multiple large clinical trials have investigated adjuvant tyrosine kinase inhibitors (TKIs) to reduce the risk of cancer recurrence and progression to metastasis in high-risk renal cell carcinoma. We sought to maintain living and interactive evidence on this topic, until a high level of certainty is reached for key clinical outcomes such that further updates become unnecessary and unlikely to change clinical practice. METHODS We created a living interactive evidence synthesis platform to maintain a continuously updated meta-analysis on TKI monotherapy in adjuvant renal cell carcinoma. We implemented an automated search strategy with weekly updates to identify randomized phase 2 and 3 clinical trials. Study selection, appraisal, and data extraction were done in duplicate. Cumulative meta-analysis was performed using Analyzer Module in Living Interactive Evidence platform. For each outcome (overall survival [OS], disease-free survival [DFS], and all-cause and treatment-related adverse events), we assessed certainty of evidence using GRADE approach and conducted trial sequential analysis. RESULTS This final update includes five randomized trials including recently updated data from PROTECT trial. Meta-analysis shows that adjuvant TKI monotherapy offers no benefit in OS (hazard ratio, 1.01; 95% CI, 0.91 to 1.12, high certainty) or DFS (hazard ratio, 0.92; 95% CI, 0.86 to 1.00, high certainty) and significantly increases adverse event risk. Lack of benefit was consistent across subgroups including highest-risk patients (test for subgroup differences: P = .32). Optimal information size criteria were met, and there was high certainty of evidence for lack of DFS and OS benefit for adjuvant TKIs. CONCLUSION There is no guidance on when to stop maintaining a living review. In this example, we used trial sequential analysis and high certainty of evidence (future clinical trials unlikely to change current conclusions) as a benchmark to conclude a living review in view of convincing evidence.

Abstract Introduction: The inconsistent use of standardized approaches for classifying postamputation pain (PAP) has been a barrier to establishing its prevalence. Objectives: The primary objective of this systematic review and meta-analysis is to determine the prevalence of nontraumatic lower-extremity PAP using an established taxonomy. The secondary objective is to determine the prevalence of PAP subtypes, including phantom limb pain and residual limb pain (RLP). Methods: An a priori protocol was registered, and a database search was conducted by a reference librarian. Randomized trials and uncontrolled studies were eligible for inclusion. The risk of bias was assessed using a tool developed for uncontrolled studies. A total of 2679 studies were screened, and 13 studies met inclusion criteria (n = 1063). Results: The sources of risk of bias included selection bias and, to a lesser extent, whether the outcome was adequately ascertained. Two studies reported the prevalence of PAP and the pooled prevalence was 61% (95% confidence interval [CI], 33%–86%) with high heterogeneity (I2 = 93%). Thirteen studies reported the prevalence of phantom limb pain and the pooled prevalence was 53% (95% CI, 40%–66%) with high heterogeneity (I2 = 93%). Eight studies reported the prevalence of RLP and the pooled prevalence was 32% (95% CI 24%–41%) with high heterogeneity (I2 = 76%). Clinical subtypes of RLP were not reported. Conclusions: The prevalence of PAP is high in patients with nontraumatic lower-extremity amputations. Ongoing research that uses a taxonomy for PAP is needed to fully delineate the prevalence of PAP subtypes.

Abstract In a large cohort of United States healthcare personnel without prior coronavirus disease 2019 (COVID-19) infection, 94 382 doses of messenger RNA (mRNA) COVID-19 vaccine were administered to 49 220 individuals. The adjusted vaccine effectiveness following 2 doses of each of the 2 available brands of mRNA vaccine exceeded 96%.

Objective To characterise the potential association of hyperlipidaemia (HLP) versus no HLP with all-cause mortality among patients hospitalised for pneumonia. Design Propensity score matched retrospective study. Participants The study cohort consisted of consecutive 8553 adults hospitalised at a large academic centre with a discharge diagnosis of pneumonia from 1996 through 2015, followed until death or end of the study period, 17 August 2017. Outcomes The outcome was HR for mortality at 28 days and in the long term in patients with pneumonia with concurrent HLP compared with those with no HLP. We first constructed multivariable Cox proportional regression models to estimate the association between concurrent HLP versus no HLP and mortality after pneumonia hospitalisation for the entire cohort. We then identified 1879 patients with pneumonia with concurrent HLP and propensity score matched in a 1:1 ratio to 1879 patients with no HLP to minimise the imbalance from measured covariates for further analysis. Results Among 8553 unmatched patients with pneumonia, concurrent HLP versus no HLP was independently associated with lower mortality at 28 days (HR 0.52, 95% CI 0.41 to 0.66) and at a median follow-up of 3.9 years (HR 0.75, 95% CI 0.70 to 0.80). The risk difference in mortality was consistent between 1879 propensity score matched pairs both at 28 days (HR 0.65, 95% CI 0.49 to 0.86) and at a median follow-up of 4 years (HR 0.88, 95% CI 0.81 to 0.96). In the subgroup of patients with clinically measured low-density lipoprotein cholesterol (LDL-C), graded inverse associations between LDL-C levels and mortality were found in both unmatched and matched cohorts. Conclusions Among hospitalised patients with pneumonia, a diagnosis of HLP is protective against both short-term and long-term risk of death after adjustment for other major contributors to mortality in both unmatched and propensity score matched cohorts. These findings should be further investigated.