Pharmacological interventions for antipsychotic-related sialorrhea: a systematic review and network meta-analysis of randomized trials.

Antipsychotic-induced sialorrhea carries a significant burden, but evidence-based treatment guidance is incomplete, warranting network meta-analysis (NMA) of pharmacological interventions for antipsychotic-related sialorrhea. PubMed Central/PsycInfo/Cochrane Central database/Clinicaltrials.gov/WHO-ICTRP and the Chinese Electronic Journal Database (Qikan.cqvip.com) were searched for published/unpublished RCTs of antipsychotic-induced sialorrhea (any definition) in adults, up to 06/12/2023. We assessed global/local inconsistencies, publication bias, risk of bias (RoB2), and confidence in the evidence, conducting subgroup/sensitivity analyses. Co-primary efficacy outcomes were changes in saliva production (standardized mean difference/SMD) and study-defined response (risk ratios/RRs). The acceptability outcome was all-cause discontinuation (RR). Primary nodes were molecules; the mechanism of action (MoA) was secondary. Thirty-four RCTs entered a systematic review, 33 NMA (n = 1958). All interventions were for clozapine-induced sialorrhea in subjects with mental disorders. Regarding individual agents and response, metoclopramide (RR = 3.11, 95% C.I. = 1.39-6.98), cyproheptadine, (RR = 2.76, 95% C.I. = 2.00-3.82), sulpiride (RR = 2.49, 95% C.I. = 1.65-3.77), propantheline (RR = 2.39, 95% C.I. = 1.97-2.90), diphenhydramine (RR = 2.32, 95% C.I. = 1.88-2.86), benzhexol (RR = 2.32, 95% C.I. = 1.59-3.38), doxepin (RR = 2.30, 95% C.I. = 1.85-2.88), amisulpride (RR = 2.23, 95% C.I. = 1.30-3.81), chlorpheniramine (RR = 2.20, 95% C.I. = 1.67-2.89), amitriptyline (RR = 2.09, 95% C.I. = 1.34-3.26), atropine, (RR = 2.03, 95% C.I. = 1.22-3.38), and astemizole, (RR = 1.70, 95% C.I. = 1.28-2.26) outperformed placebo, but not glycopyrrolate or ipratropium. Across secondary nodes (k = 28, n = 1821), antimuscarinics (RR = 2.26, 95% C.I. = 1.91-2.68), benzamides (RR = 2.23, 95% C.I. = 1.75-3.10), TCAs (RR = 2.23, 95% C.I. = 1.83-2.72), and antihistamines (RR = 2.18, 95% C.I. = 1.83-2.59) outperformed placebo. In head-to-head comparisons, astemizole and ipratropium were outperformed by several interventions. All secondary nodes, except benzamides, outperformed the placebo on the continuous efficacy outcome. For nocturnal sialorrhea, neither benzamides nor atropine outperformed the placebo. Active interventions did not differ significantly from placebo regarding constipation or sleepiness/drowsiness. Low-confidence findings prompt caution in the interpretation of the results. Considering primary nodes' co-primary efficacy outcomes and head-to-head comparisons, efficacy for sialorrhea is most consistent for the following agents, decreasing from metoclopramide through cyproheptadine, sulpiride, propantheline, diphenhydramine, benzhexol, doxepin, amisulpride, chlorpheniramine, to amitriptyline, and atropine (the latter not for nocturnal sialorrhea). Shared decision-making with the patient should guide treatment decisions regarding clozapine-related sialorrhea.

Economic Evaluations of Chimeric Antigen Receptor T-Cell Therapies for Hematologic and Solid Malignancies: A Systematic Review.

OBJECTIVES: This study aimed to systematically review evidence on the cost-effectiveness of chimeric antigen receptor T-cell (CAR-T) therapies for patients with cancer. METHODS: Electronic databases were searched in October 2022 and updated in September 2023. Systematic reviews, health technology assessments, and economic evaluations that compared costs and effects of CAR-T therapy in patients with cancer were included. Two reviewers independently screened studies, extracted data, synthesized results, and critically appraised studies using the Philips checklist. Cost data were presented in 2022 US dollars. RESULTS: Our search yielded 1809 records, 47 of which were included. Most of included studies were cost-utility analysis, published between 2018 and 2023, and conducted in the United States. Tisagenlecleucel, axicabtagene ciloleucel, idecabtagene vicleucel, ciltacabtagene autoleucel, lisocabtagene maraleucel, brexucabtagene autoleucel, and relmacabtagene autoleucel were compared with various standard of care chemotherapies. The incremental cost-effectiveness ratio (ICER) for CAR-T therapies ranged from $9424 to $4 124 105 per quality-adjusted life-year (QALY) in adults and from $20 784 to $243 177 per QALY in pediatric patients. Incremental cost-effectiveness ratios were found to improve over longer time horizons or when an earlier cure point was assumed. Most studies failed to meet the Philips checklist due to a lack of head-to-head comparisons and uncertainty surrounding CAR-T costs and curative effects. CONCLUSIONS: CAR-T therapies were more expensive and generated more QALYs than comparators, but their cost-effectiveness was uncertain and dependent on patient population, cancer type, and model assumptions. This highlights the need for more nuanced economic evaluations and continued research to better understand the value of CAR-T therapies in diverse patient populations.

Risk Factors for Surgical Site Infection after Lower Limb Revascularisation Surgery: a Systematic Review and Meta-Analysis of Prognostic Studies.

OBJECTIVE: To systematically review and meta-analyse adjusted risk factors for surgical site infection (SSI) after lower limb revascularisation surgery. DATA SOURCES: MEDLINE, Embase, Evidence Based Medicine Reviews, and the Cochrane Central Register of Controlled Trials (inception to 28 April 2022). REVIEW METHODS: Systematic review and meta-analysis conducted according to PRISMA guidelines. After protocol registration, databases were searched. Studies reporting adjusted risk factors for SSI in adults who underwent lower limb revascularisation surgery for peripheral artery disease were included. Adjusted odds ratios (ORs) were pooled using random effects models. GRADE was used to assess certainty. RESULTS: Among 6 377 citations identified, 50 studies (n = 271 125 patients) were included. The cumulative incidence of SSI was 12 (95% confidence interval [CI] 10 - 13) per 100 patients. Studies reported 139 potential SSI risk factors adjusted for a median of 12 (range 1 - 69) potential confounding factors. Risk factors that increased the pooled adjusted odds of SSI included: female sex (pooled OR 1.41, 95% CI 1.20 - 1.64; high certainty); dependent functional status (pooled OR 1.18, 95% CI 1.03 - 1.35; low certainty); being overweight (pooled OR 1.82, 95% CI 1.29 - 2.56; moderate certainty), obese (pooled OR 2.20, 95% CI 1.44 - 3.36; high certainty), or morbidly obese (pooled OR 1.65, 95% CI 1.08 - 2.52; moderate certainty); chronic obstructive pulmonary disease (pooled OR 1.42, 95% CI 1.17 - 1.71; high certainty); chronic limb threatening ischaemia (pooled OR 1.67, 95% CI 1.22 - 2.29; moderate certainty); chronic kidney disease (pooled OR 2.13, 95% CI 1.18 - 3.83; moderate certainty); intra-operative (pooled OR 1.23, 95% CI 1.02 - 1.49), peri-operative (pooled OR 1.92, 95% CI 1.27 - 2.90), or post-operative (pooled OR 2.21, 95% CI 1.44 - 3.39) blood transfusion (moderate certainty for all); urgent or emergency surgery (pooled OR 2.12, 95% CI 1.22 - 3.70; moderate certainty); vein bypass and or patch instead of endarterectomy alone (pooled OR 1.86, 95% CI 1.33 - 2.59; moderate certainty); an operation lasting ≥ 3 hours (pooled OR 1.86, 95% CI 1.33 - 2.59; moderate certainty) or ≥ 5 hours (pooled OR 1.60, 95% CI 1.18 - 2.17; moderate certainty); and early or unplanned re-operation (pooled OR 4.50, 95% CI 2.18 - 9.32; low certainty). CONCLUSION: This systematic review identified evidence informed SSI risk factors following lower limb revascularisation surgery. These may be used to develop improved SSI risk prediction tools and to identify patients who may benefit from evidence informed SSI prevention strategies.

Test Characteristics of Emergency Medicine-Performed Point-of-Care Ultrasound for the Diagnosis of Acute Cholecystitis: A Systematic Review and Meta-analysis.

Acute cholecystitis accounts for up to 9% of hospital admissions for acute abdominal pain, and best practice entails early surgical management. Ultrasound is the standard modality used to confirm diagnosis. Our objective was to perform a systematic review and meta-analysis to determine the diagnostic accuracy of emergency physician-performed point-of-care ultrasound for the diagnosis of acute cholecystitis when compared with a reference standard of final diagnosis (informed by available surgical pathology, discharge diagnosis, and radiology-performed ultrasound). We completed a systematic review and meta-analysis, registered in PROSPERO, in adherence to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched 7 databases as well as gray literature in the form of select conference abstracts from inception to February 8, 2023. Two independent reviewers completed study selection, data extraction, and risk of bias (QUADAS-2) assessment. Disagreements were resolved by consensus with a third reviewer. Data were extracted from eligible studies to create 2 × 2 tables for diagnostic accuracy meta-analysis. Hierarchical Summary Receiver Operating Characteristic models were constructed. Of 1855 titles/abstracts, 40 were selected for full-text review. Ten studies (n=2356) were included. Emergency physician-performed point-of-care ultrasound with final diagnosis as the reference standard (7 studies, n=1,772) had a pooled sensitivity of 70.9% (95% confidence interval [CI] 62.3 to 78.2), specificity of 94.4% (95% CI 88.2 to 97.5), positive likelihood ratio of 12.7 (5.8 to 27.5), and negative likelihood ratio of 0.31 (0.23 to 0.41) for the diagnosis of acute cholecystitis. Emergency physician-performed point-of-care ultrasound has high specificity and moderate sensitivity for the diagnosis of acute cholecystitis in patients with clinical suspicion. This review supports the use of emergency physician-performed point-of-care ultrasound to rule in a diagnosis of acute cholecystitis in the emergency department, which may help expedite definitive management.

Intraoperative pharmacologic opioid minimisation strategies and patient-centred outcomes after surgery: a scoping review.

BACKGROUND: Postoperative patient-centred outcome measures are essential to capture the patient's experience after surgery. Although a large number of pharmacologic opioid minimisation strategies (i.e. opioid alternatives) are used for patients undergoing surgery, it remains unclear which strategies are most promising in terms of patient-centred outcome improvements. This scoping review had two main objectives: (1) to map and describe evidence from clinical trials assessing the patient-centred effectiveness of pharmacologic intraoperative opioid minimisation strategies in adult surgical patients, and (2) to identify promising pharmacologic opioid minimisation strategies. METHODS: We searched MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases from inception to February 2023. We included trials investigating the use of opioid minimisation strategies in adult surgical patients and reporting at least one patient-centred outcome. Study screening and data extraction were conducted independently by at least two reviewers. RESULTS: Of 24,842 citations screened for eligibility, 2803 trials assessed the effectiveness of intraoperative opioid minimisation strategies. Of these, 457 trials (67,060 participants) met eligibility criteria, reporting at least one patient-centred outcome. In the 107 trials that included a patient-centred primary outcome, patient wellbeing was the most frequently used domain (55 trials). Based on aggregate findings, dexmedetomidine, systemic lidocaine, and COX-2 inhibitors were promising strategies, while paracetamol, ketamine, and gabapentinoids were less promising. Almost half of the trials (253 trials) did not report a protocol or registration number. CONCLUSIONS: Researchers should prioritise and include patient-centred outcomes in the assessment of opioid minimisation strategy effectiveness. We identified three potentially promising pharmacologic intraoperative opioid minimisation strategies that should be further assessed through systematic reviews and multicentre trials. Findings from our scoping review may be influenced by selective outcome reporting bias. STUDY REGISTRATION: OSF - https://osf.io/7kea3.

A systematic review of the efficacy and safety of turmeric in the treatment of digestive disorders.

Turmeric has been gaining popularity as a treatment option for digestive disorders, although a rigorous synthesis of efficacy has not been conducted. This study aimed to summarize the evidence for the efficacy and safety of turmeric in the treatment of digestive disorders, including inflammatory bowel diseases (IBD), irritable bowel syndrome (IBS), dyspepsia, gastroesophageal reflux disease, and peptic ulcers. Literature searches were conducted in Medline, EMBASE, AMED, the Cochrane Central Register of Control Trials, and Dissertation Abstracts from inception to November 15, 2021. Dual independent screening of citations and full texts was conducted and studies meeting inclusion criteria were retained: randomized controlled trials (RCT) and comparative observational studies evaluating turmeric use in people of any age with one of the digestive disorders of interest. Extraction of relevant data and risk of bias assessments were performed by two reviewers independently. Meta-analysis was not conducted due to high heterogeneity. From 1136 citations screened, 26 eligible studies were retained. Most studies were assessed to have a high risk of bias, and many had methodological limitations. Descriptive summaries suggest that turmeric is safe, with possible efficacy in patients with IBD or IBS, but its effects were inconsistent for other conditions. The efficacy of turmeric in digestive disorders remains unclear due to the high risk of bias and methodological limitations of the included studies. Future studies should be designed to include larger sample sizes, use rigorous statistical methods, employ core outcome sets, and adhere to reporting guidance for RCTs of herbal interventions to facilitate more meaningful comparisons and robust conclusions.

Should Cell Salvage Be Used in Liver Resection and Transplantation? A Systematic Review and Meta-analysis.

OBJECTIVE: To evaluate the effect of intraoperative blood cell salvage and autotransfusion (IBSA) use on red blood cell (RBC) transfusion and postoperative outcomes in liver surgery. BACKGROUND: Intraoperative RBC transfusions are common in liver surgery and associated with increased morbidity. IBSA can be utilized to minimize allogeneic transfusion. A theoretical risk of cancer dissemination has limited IBSA adoption in oncologic surgery. METHODS: Electronic databases were searched from inception until May 2021. All studies comparing IBSA use with control in liver surgery were included. Screening, data extraction, and risk of bias assessment were conducted independently, in duplicate. The primary outcome was intraoperative allogeneic RBC transfusion (proportion of patients and volume of blood transfused). Core secondary outcomes included: overall survival and disease-free survival, transfusion-related complications, length of hospital stay, and hospitalization costs. Data from transplant and resection studies were analyzed separately. Random effects models were used for meta-analysis. RESULTS: Twenty-one observational studies were included (16 transplant, 5 resection, n=3433 patients). Seventeen studies incorporated oncologic indications. In transplant, IBSA was associated with decreased allogeneic RBC transfusion [mean difference -1.81, 95% confidence interval (-3.22, -0.40), P =0.01, I 2 =86%, very-low certainty]. Few resection studies reported on transfusion for meta-analysis. No significant difference existed in overall survival or disease-free survival in liver transplant [hazard ratio (HR)=1.12 (0.75, 1.68), P =0.59, I 2 =0%; HR=0.93 (0.57, 1.48), P =0.75, I 2 =0%] and liver resection [HR=0.69 (0.45, 1.05), P =0.08, I 2 =0%; HR=0.93 (0.59, 1.45), P =0.74, I 2 =0%]. CONCLUSION: IBSA may reduce intraoperative allogeneic RBC transfusion without compromising oncologic outcomes. The current evidence base is limited in size and quality, and high-quality randomized controlled trials are needed.

Systematic review and meta-analysis of randomized controlled trials of mesenchymal stromal cells to treat coronavirus disease 2019: is it too late?

BACKGROUND AIMS: Evidence regarding the extent that mesenchymal stromal cells (MSCs) may improve clinical outcomes in patients with coronavirus disease 2019 (COVID-19) has been limited by marked inter-study heterogeneity, inconsistent product characterization and appreciable risk of bias (RoB). Given the evolution of treatment options and trajectory of the pandemic, an updated analysis of high-quality evidence from randomized controlled trials is needed for a timely and conclusive understanding of the effectiveness of MSCs. METHODS: A systematic literature search through March 30, 2022, identified all English language, full-text randomized controlled trials examining the use of MSCs in the treatment of COVID-19. RESULTS: Eight studies were identified (316 patients, 165 administered MSCs and 151 controls). Controls evolved significantly over time with a broad range of comparison treatments. All studies reported mortality at study endpoint. Random effects meta-analysis revealed that MSCs decreased relative risk of death (risk ratio, 0.63, 95% confidence interval, 0.42-0.94, P = 0.02, I2 = 14%) with no significant difference in absolute risk of death. MSCs decreased length of hospital stay and C-reactive protein levels and increased odds of clinical improvement at study endpoint compared with controls. Rates of adverse events and severe adverse events were similar between MSC and control groups. Only two (25%) studies reported all four International Society for Cell & Gene Therapy criteria for MSC characterization. Included studies had low (n = 7) or some (n = 1) concerns regarding RoB. CONCLUSIONS: MSCs may reduce risk of death in patients with severe or critical COVID-19 and improve secondary clinical outcomes. Variable outcome reporting, inconsistent product characterization and variable control group treatments remain barriers to higher-quality evidence and may constrain clinical usage. A master protocol is proposed and appears necessary for accelerated translation of higher-quality evidence for future applications of MSC therapy.

Management of genitourinary symptoms in patients with breast cancer: an updated systematic review of available evidence from randomized trials.

PURPOSE: The purpose of this systematic review update is to synthesize available data on management of genitourinary symptoms (GUS) in breast cancer patients, a common and challenging clinical scenario. METHODS: EMBASE, Ovid Medline, and the Cochrane Library were searched from September 2014 to December 2021 for randomized controlled trials which examined various interventions for GUS in breast cancer patients. Outcomes of interest included improvements in vaginal symptoms (e.g., dryness, pain, dyspareunia, itching), vaginal hormone response measured by validated scales (e.g., Vaginal Health Index, and Vaginal Maturation Index), and Female Sexual Function Index (FSFI). A team of reviewers participated in the processes of study selection, data collection, and risk of bias appraisal. A descriptive approach to synthesis was used. RESULTS: Of 842 unique citations identified (412 from this update, 430 from previous review), eight studies (n = 539) met inclusion criteria. Interventions included 0.005% estriol gel (EG; n = 50), intravaginal testosterone (IVT; n = 21), intravaginal prebiotic (n = 13), hyaluronic acid (HA; n = 12), polyacrylic acid (PA; n = 25), pH-balanced gel (n = 118), Replens® (n = 24), and Lidocaine (n = 22). These were compared to placebo/saline/lubricants/usual care (n = 228). FSFI total score was significantly improved by all interventions except IVT and lidocaine, and not measured for Replens®. Significant improvements in vaginal hormone responses were reported for EG and pH-balanced gel; however, no significant effects were found for IVT, HA, or prebiotics. Vaginal symptoms were significantly improved by EG, IVT, PA, and PH-balanced gel. CONCLUSION: Treatment of GUS remains a challenging issue. It is evident that more prospective trials are needed.

Cervical spine injuries in adults ≥ 65 years after low-level falls - A systematic review and meta-analysis.

BACKGROUND: Adults ≥ 65 are at risk of cervical spine (C-spine) injury, even after low-level falls. The objectives of this systematic review were to determine the prevalence of C-spine injury in this population and explore the association of unreliable clinical exam with C-spine injury. METHODS: We conducted this systematic review according to PRISMA guidelines. We searched MEDLINE, PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Database of Systematic reviews to include studies reporting on C-spine injury in adults ≥ 65 years after low-level falls. Two reviewers independently screened articles, abstracted data, and assessed bias. Discrepancies were resolved by a third reviewer. A meta-analysis was performed to estimate overall prevalence and the pooled odds ratio for the association between C-spine injury and an unreliable clinical exam. RESULTS: The search identified 2044citations, 138 full texts were screened, and 21 studies were included in the systematic review. C-spine injury prevalence in adults ≥ 65 years after low-level falls was 3.8% (95% CI: 2.8-5.3). The odds of c-spine injury in those with altered level of consciousness (aLOC) v/s not aLOC was 1.21 (0.90-1.63) and in those with GCS < 15 v/s GCS 15 was 1.62 (0.37-6.98). Studies were at a low-risk of bias, although some had low recruitment and significant loss to follow-up. CONCLUSIONS: Adults ≥ 65 years are at risk of cervical spine injury after low-level falls. More research is needed to determine whether there is an association between cervical spine injury and GCS < 15 or altered level of consciousness.

A Systematic Review and Meta-analysis of Randomized Controlled Trials Comparing Intraoperative Red Blood Cell Transfusion Strategies.

OBJECTIVE: The objective of this work was to carry out a meta-analysis of RCTs comparing intraoperative RBC transfusion strategies to determine their impact on postoperative morbidity, mortality, and blood product use. SUMMARY OF BACKGROUND DATA: RBC transfusions are common in surgery and associated with widespread variability despite adjustment for casemix. Evidence-based recommendations guiding RBC transfusion in the operative setting are limited. METHODS: The search strategy was adapted from a previous Cochrane Review. Electronic databases were searched from January 2016 to February 2021. Included studies from the previous Cochrane Review were considered for eligibility from before 2016. RCTs comparing intraoperative transfusion strategies were considered for inclusion. Co-primary outcomes were 30-day mortality and morbidity. Secondary outcomes included intraoperative and perioperative RBC transfusion. Meta-analysis was carried out using random-effects models. RESULTS: Fourteen trials (8641 patients) were included. One cardiac surgery trial accounted for 56% of patients. There was no difference in 30-day mortality [relative risk (RR) 0.96, 95% confidence interval (CI) 0.71-1.29] and pooled postoperative morbidity among the studied outcomes when comparing restrictive and liberal protocols. Two trials reported worse composite outcomes with restrictive triggers. Intraoperative (RR 0.53, 95% CI 0.43-0.64) and perioperative (RR 0.70, 95% CI 0.62-0.79) blood transfusions were significantly lower in the restrictive group compared to the liberal group. CONCLUSIONS: Intraoperative restrictive transfusion strategies decreased perioperative transfusions without added postoperative morbidity and mortality in 12/14 trials. Two trials reported worse outcomes. Given trial design and generalizability limitations, uncertainty remains regarding the safety of broad application of restrictive transfusion triggers in the operating room. Trials specifically designed to address intraoperative transfusions are urgently needed.

Association Between Endoscopist Specialty and Colonoscopy Quality: A Systematic Review and Meta-analysis.

BACKGROUND & AIMS: Colonoscopy quality indicators provide measurable assessments of performance, but significant provider-level variations exist. We performed a systematic review and meta-analysis to assess whether endoscopist specialty is associated with adenoma detection rate (ADR) - the primary outcome - or cecal intubation rate, adverse event rates, and post-colonoscopy colorectal cancer rates. METHODS: We searched EMBASE, Google Scholar, MEDLINE, and the Cochrane Central Registry of Controlled Trials from inception to December 14, 2020. Two reviewers independently screened titles and abstracts. Citations underwent duplicate full-text review, with disagreements resolved by a third reviewer. Data were abstracted in duplicate. The DerSimonian and Laird random effects model was used to calculate pooled odds ratios (ORs) with respective 95% confidence intervals (CIs). Risk of bias was assessed using Risk of Bias in Non-randomised Studies of Interventions. RESULTS: Of 11,314 citations, 36 studies representing 3,500,832 colonoscopies were included. Compared with colonoscopies performed by gastroenterologists, those by surgeons were associated with lower ADRs (OR, 0.81; 95% CI, 0.74-0.88) and lower cecal intubation rates (OR, 0.76; 95% CI, 0.63-0.92). Compared with colonoscopies performed by gastroenterologists, those by other (non-gastroenterologist, non-surgeon) endoscopists were associated with lower ADRs (OR, 0.91; 95% CI, 0.87-0.96), higher perforation rates (OR, 3.02; 95% CI, 1.65-5.51), and higher post-colonoscopy colorectal cancer rates (OR, 1.23; 95% CI, 1.14-1.33). Substantial to considerable heterogeneity existed for most analyses, and overall certainty in the evidence was low according to the Grading of Recommendations, Assessment, Development, and Evaluations framework. CONCLUSION: Colonoscopies performed by surgeons or other endoscopists were associated with poorer quality metrics and outcomes compared with those performed by gastroenterologists. Targeted quality improvement efforts may be warranted.

Mesenchymal stem/stromal cell-based therapies for COVID-19: First iteration of a living systematic review and meta-analysis: MSCs and COVID-19.

BACKGROUND: Mesenchymal stem/stromal cells (MSCs) and their secreted products are a promising therapy for COVID-19 given their immunomodulatory and tissue repair capabilities. Many small studies were launched at the onset of the pandemic, and repeated meta-analysis is critical to obtain timely and sufficient statistical power to determine efficacy. METHODS AND FINDINGS: All English-language published studies identified in our systematic search (up to February 3, 2021) examining the use of MSC-derived products to treat patients with COVID-19 were identified. Risk of bias (RoB) was assessed for all studies. Nine studies were identified (189 patients), four of which were controlled (93 patients). Three of the controlled studies reported on mortality (primary analysis) and were pooled through random-effects meta-analysis. MSCs decreased the risk of death at study endpoint compared with controls (risk ratio, 0.18; 95% confidence interval [CI], 0.04 to 0.74; P = .02; I2 = 0%), although follow-up differed. Among secondary outcomes, interleukin-6 levels were most commonly reported and were decreased compared with controls (standardized mean difference, -0.69; 95% CI, -1.15 to -0.22; P = .004; I2 = 0%) (n = 3 studies). Other outcomes were not reported consistently, and pooled estimates of effect were not performed. Substantial heterogeneity was observed between studies in terms of study design. Adherence to published ISCT criteria for MSC characterization was low. In two of nine studies, RoB analysis revealed a low to moderate risk of bias in controlled studies, and uncontrolled case series were of good (3 studies) or fair (2 studies) quality. CONCLUSION: Use of MSCs to treat COVID-19 appears promising; however, few studies were identified, and potential risk of bias was detected in all studies. More controlled studies that report uniform clinical outcomes and use MSC products that meet standard ISCT criteria should be performed. Future iterations of our systematic search should refine estimates of efficacy and clarify potential adverse effects.

Use of CRISPR/Cas9 gene editing to improve chimeric antigen-receptor T cell therapy: A systematic review and meta-analysis of preclinical studies.

BACKGROUND: Chimeric antigen-receptor T (CAR-T) cells represent great promise in cancer treatment. CRISPR/Cas9 gene editing in preclinical studies has enabled the development of enhanced CAR-T products with improved function and reduced toxicity. METHODS: A systematic review of preclinical animal studies was conducted to determine the efficacy and safety of this approach. RESULTS: 3753 records were identified (to September 9, 2020), with 11 studies using CRISPR/Cas9 gene editing in combination with CAR-T therapy against human cells in animal models of acute leukemia (four studies), glioma (two studies), melanoma (two studies), and other cancers (three studies). Compared with unedited controls, gene-edited CAR-T cells reduced tumor volume in treated animals and improved survival. No adverse side effects were reported. Use of allogeneic "third-party" CAR-T cells appears feasible. Improved efficacy was achieved through both knock-in and knockout gene editing of various targets implicated in immune function. Targeting multiple genes also appears feasible. Significant heterogeneity in study design and outcome reporting was observed, and potential bias was identified in all studies. CONCLUSION: CRISPR/Cas9 gene editing enables manufacturing of CAR-T cells with improved anti-cancer effects. Future studies should reduce unintentional bias and heterogeneity of study designs and strive to augment long-term persistence of edited cells. PROTOCOL REGISTRATION: PROSPERO; registration number CRD42020220313 registered November 30, 2020.

Effectiveness of Peripheral Nerve Blocks for the Treatment of Primary Headache Disorders: A Systematic Review and Meta-Analysis.

STUDY OBJECTIVE: Primary headache disorders are prevalent and account for 2% of all emergency department visits. Current treatment options are effective; however, time to pain relief is suboptimal. Alternatives such as peripheral nerve blocks have shown promising results. The objective of this systematic review is to examine the effectiveness of peripheral nerve blocks for timely pain relief. METHODS: We searched Ovid MEDLINE, EMBASE, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials and included randomized controlled trials comparing peripheral nerve blocks to placebo or active therapy. The primary outcome was pain within 120 minutes. Secondary outcomes were pain after 120 minutes, adverse events, need for rescue medications, and relapse of headache. Two reviewers screened and extracted data independently; mean differences (MDs) were calculated, and results were pooled using a random-effects model. RESULTS: Eleven studies met our eligibility criteria (n=860), of which 9 were included in the meta-analysis. Pain scores were significantly lower in patients treated with peripheral nerve blocks than with placebo at 15 minutes (MD: -1.17; 95% confidence interval: -1.82 to -0.51) and 30 minutes (MD: -0.99; 95% confidence interval: -1.66 to -0.32), and no serious adverse events were reported. Pain scores for peripheral nerve blocks versus active therapy and secondary outcomes were not pooled due to clinical heterogeneity. CONCLUSION: Our review shows peripheral nerve blocks are effective as a rapid treatment option when compared to placebo; however, we were unable to assess effectiveness against standard treatment. Emergency physicians should consider peripheral nerve blocks as an adjunct therapy for patients with primary headache disorders.

Association Between Time to Colonoscopy After Positive Fecal Testing and Colorectal Cancer Outcomes: A Systematic Review.

BACKGROUND & AIMS: Colonoscopy is required following a positive fecal screening test for colorectal cancer (CRC). It remains unclear to what extent time to colonoscopy is associated with CRC-related outcomes. We performed a systematic review to elucidate this relationship. METHODS: An electronic search was performed through April 2020 for studies reporting associations between time from positive fecal testing to colonoscopy and outcomes including CRC incidence (primary outcome), CRC stage at diagnosis, and/or CRC-specific mortality. Our primary objective was to quantify these relationships following positive fecal immunochemical testing (FIT). Two authors independently performed screening, abstraction, and risk of bias assessments. RESULTS: From 1,612 initial studies, 8 were included in the systematic review, with 5 reporting outcomes for FIT. Although meta-analysis was not possible, consistent trends between longer time delays and worse outcomes were apparent in all studies. Colonoscopy performed beyond 9 months from positive FIT compared to within 1 month was significantly associated with a higher incidence of CRC, with adjusted odds ratios (AORs) of 1.75 and 1.48 in the two largest studies. These studies also reported significant associations between colonoscopy performed beyond 9 months and higher incidence of advanced stage CRC (stage III or IV) at diagnosis, with AORs of 2.79 and 1.55, respectively. CONCLUSIONS: Colonoscopy for positive FIT should not be delayed beyond 9 months. Given the additional time required for urgent referrals and surgical planning for CRC, colonoscopy should ideally be performed well in advance of 9 months following a positive FIT.

A scoping review characterizing "Choosing Wisely®" recommendations for breast cancer management.

PURPOSE: Choosing Wisely (CW)® was created by the American Board of Internal Medicine (ABIM) to promote patient-physician conversations about unnecessary medical interventions. Similarly, other countries created their own panels of experts called "CW® campaigns" which review recommendations submitted by that country's oncology societies. We performed a scoping review to consolidate CW® recommendations from different groups with respect to breast cancer care. METHODS: A systematic search of Medline and Embase was designed by an information specialist for publications presenting CW® recommendations for breast cancer care practices from 2011-2020. We also reviewed the websites of all CW® campaigns and reference sections of each CW® recommendation. Two reviewers independently screened studies for inclusion and performed data extraction. Findings were summarized narratively. RESULTS: Review of ABIM CW® recommendations showed 19 breast cancer-related recommendations pertaining to; screening (n = 4), radiological staging (n = 2), treatment (n = 10), surveillance (n = 2), and miscellaneous (genetic testing; n = 1). Of 22 countries with CW® campaigns, 10 published recommendations for breast cancer. Over half (57%) of recommendations were supported by more than one country. No recommendations were refuted between campaigns. Two campaigns developed 3 novel recommendations on new topics, including chemotherapy in ductal carcinoma in situ (Italy) and comparison of screening imaging modalities (Portugal). CONCLUSIONS: CW® recommendations focus on reducing overutilization of investigations and treatments. There was a high rate of consensus between different CW® campaigns. As health care systems globally move attention to reduce low-value care, further studies are required to address adherence to these current recommendations and develop new recommendations.

Safety and efficacy of autologous whole cell vaccines in hematologic malignancies: A systematic review and meta-analysis.

Autologous cell vaccines use a patient's tumor cells to stimulate a broad antitumor response in vivo. This approach shows promise for treating hematologic cancers in early phase clinical trials, but overall safety and efficacy remain poorly described. We conducted a systematic review assessing the use of autologous cell vaccination in treating hematologic cancers. Primary outcomes of interest were safety and clinical response, with secondary outcomes including survival, relapse rate, correlative immune assays and health-quality related metrics. We performed a search of MEDLINE, Embase and the Cochrane Register of Controlled Trials including any interventional trial employing an autologous, whole cell product in any hematologic malignancy. Risk of bias was assessed using a modified Institute of Health Economics tool. Across 20 single arm studies, only 341 of 592 enrolled participants received one or more vaccinations. Primary reasons for not receiving vaccination included rapid disease progression/death and manufacturing challenges. Overall, few high-grade adverse events were observed. One death was reported and attributed to a GM-CSF producing allogeneic cell line co-administered with the autologous vaccine. Of 58 evaluable patients, the complete response rate was 21.0% [95% CI, 10.4%-37.8%)] and overall response rate was 35.8% (95% CI, 24.4%-49.0%). Of 97 evaluable patients for survival, the 5-years overall survival rate was 64.9% (95% CI, 52.6%-77.2%) and disease-free survival was 59.7% (95% CI, 47.7%-71.7%). We conclude that, in hematologic malignancies, based on limited available data, autologous cell vaccines are safe and display a trend towards efficacy but that challenges exist in vaccine manufacture and administration.

Impact of Exercise Training on Hematological Outcomes Following Hematopoietic Cell Transplantation: A Scoping Review.

PURPOSE: Hematopoietic cell transplantation (HCT) is associated with significant risk prior to hematopoietic engraftment. Endurance exercise can modify the bone marrow microenvironment, alter hematopoiesis and accelerate hematopoietic regeneration in mouse models of transplantation. METHODS: A systematic review was conducted to clarify the impact of exercise on clinically relevant hemato-logical outcomes in patients following HCT. RESULTS: A systematic search of the literature identified 13 studies (total of 615 participants; 313 in study arms). Studies included exercise regimens that were primarily low-to-moderate intensity. A total of five studies re-ported on engraftment and length of stay, which were largely unchanged with intervention. Rates of graft-ver-sus host disease were reported in six studies whereas red cell and platelet transfusion needs were reported in four studies, neither of which was different with exercise. Survival was reported in four studies and was significantly improved by exercise in one study. CONCLUSIONS: Exercise in patients receiving HCT appears feasible and safe. Heterogeneity in type and intensity of exercise was observed and few studies examined high intensity exercise. Outcome reporting was inconsis-tent regarding transplant-related outcomes. Standardized hematological outcome measures are needed to clarify the impact of higher intensity exercise on HCT.

What Is the Best Evidence to Guide Management of Acute Achilles Tendon Ruptures? A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Uncertainty exists regarding the best treatment for acute Achilles tendon ruptures. Simultaneous comparison of the multiple treatment options using traditional study designs is problematic; multiarm clinical trials often are logistically constrained to small sample sizes, and traditional meta-analyses are limited to comparisons of only two treatments that have been compared in head-to-head trials. Network meta-analyses allow for simultaneous comparison of all existing treatments utilizing both direct (head-to-head comparison) and indirect (not previously compared head-to-head) evidence. QUESTIONS/PURPOSES: We performed a network meta-analysis of randomized controlled trials (RCTs) to answer the following questions: Considering open repair, minimally invasive surgery (MIS) repair, functional rehabilitation, or primary immobilization for acute Achilles tendon ruptures, (1) which intervention is associated with the lowest risk of rerupture? (2) Which intervention is associated with the lowest risk of complications resulting in surgery? METHODS: This study was conducted with methods guided by the Cochrane Handbook for Systematic Reviews of Interventions and is reported in adherence with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension statement for incorporating network meta-analysis. Five databases and grey literature sources (such as major orthopaedic meeting presentation lists) were searched from inception to September 30, 2019. Included studies were RCTs comparing treatment of acute Achilles tendon ruptures using two or more of the following interventions: primary immobilization, functional rehabilitation, open surgical repair, or MIS repair. We excluded studies enrolling patients with chronic ruptures, reruptures, and preexisting Achilles tendinopathy as well as studies with more than 20% loss to follow-up or less than 6 months of follow-up. Nineteen RCTs (1316 patients) were included in the final analysis. The mean number of patients per study treatment arm was 35 ± 16, mean age was 41 ± 5 years, mean sex composition was 80% ± 10% males, and mean follow-up was 22 ± 12 months. The four treatment groups were compared for the main outcomes of rerupture and complications resulting in operation. The analysis was conducted using random-effects Bayesian network meta-analysis with vague priors. Evidence quality was evaluated using Grades of Recommendation, Assessment, Development, and Evaluation methodology. We found risk of selection, attrition, and reporting bias to be low across treatments, and we found the risk of performance and detection bias to be high. Overall risk of bias between treatments appeared similar. RESULTS: We found that treatment with primary immobilization had a greater risk of rerupture than open surgery (odds ratio 4.06 [95% credible interval {CrI} 1.47 to 11.88]; p < 0.05). There were no other differences between treatments for risk of rerupture. Minimally invasive surgery was ranked first for fewest complications resulting in surgery and was associated with a lower risk of complications resulting in surgery than functional rehabilitation (OR 0.16 [95% CrI 0.02 to 0.90]; p < 0.05), open surgery (OR 0.22 [95% CrI 0.04 to 0.93]; p < 0.05), and primary immobilization (OR < 0.01 [95% CrI < 0.01 to 0.01]; p < 0.05). Risk of complications resulting in surgery was no different between primary immobilization and open surgery (OR 1.46 [95% CrI 0.35 to 5.36]). Data for patient-reported outcome scores and return to activity were inappropriate for pooling secondary to considerable clinical heterogeneity and imprecision associated with small sample sizes. CONCLUSION: Faced with acute Achilles tendon rupture, patients should be counseled that, based on the best-available evidence, the risk of rerupture likely is no different across contemporary treatments. Considering the possibly lower risk of complications resulting in surgery associated with MIS repair, patients and surgeons must balance any benefit with the potential risks of MIS techniques. As treatments continue to evolve, consistent reporting of validated patient-reported outcome measures is critically important to facilitate analysis with existing RCT evidence. Infrequent but serious complications such as rerupture and deep infection should be further explored to determine whether meaningful differences exist in specific patient populations. LEVEL OF EVIDENCE: Level I, therapeutic study.