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Producing living guidelines requires making important decisions about methods for evidence identification, appraisal and integration to allow the living mode to function. Clarifying what these decisions are and the trade-offs between options is necessary. This paper provides Living Guideline developers with a framework to enable them to choose the most suitable model for their living guideline topic, question or context.We developed this guidance through an iterative process informed by interviews, feedback and a consensus process with an international group of Living Guideline developers.Several key decisions need to be made both before commencing and throughout the continual process of Living Guideline development and maintenance. These include deciding what approach is taken to the systematic review process; decisions about methods to be applied for the evidence appraisal process, including the use of unpublished data; and selection of "triggers" to incorporate new studies into Living Guideline recommendations. In each case, there are multiple options and trade-offs.We identify trade-offs and important decisions to be considered throughout the Living Guideline development process. The most appropriate, and most sustainable, mode of development and updating will be dependent on the choices made in each of these areas.

History and physical exam are key features to narrow the differential diagnosis of central versus peripheral causes in patients presenting with acute vertigo. We conducted a systematic review and meta-analysis of the diagnostic test accuracy of physical exam findings.Patient-intervention-control-outcome (PICO) question, (P) adult ED patients with vertigo/dizziness; (I) presence/absence of specific physical exam findings; (O) central (ischemic stroke, hemorrhage, others) versus peripheral etiology. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was assessed.From 6,309 titles, 460 articles were retrieved, and 43 met the inclusion criteria. General Neurologic Exam: 5 studies, 869 patients, pooled sensitivity 46.8% (CI 32.3%-61.9%, moderate certainty) and specificity 92.8% (CI 75.7%-98.1%, low certainty). Limb weakness/Hemiparesis: 4 studies, 893 patients, sensitivity 11.4% (5.1%-23.6%, high) and specificity 98.5% (97.1%-99.2%, high). Truncal/Gait Ataxia: 10 studies, 1,810 patients. Increasing severity of truncal ataxia had an increasing sensitivity for central etiology. Sensitivity 69.7% (43.3%-87.9%, low) and specificity 83.7% (52.1%-96.0%, low). Dysmetria signs: 4 studies, 1,135 patients, sensitivity 24.6% (15.6%-36.5%, high) and specificity 97.8% (94.4%-99.2%, high). Head Impulse Test (HIT): 17 studies, 1,366 patients, sensitivity 76.8% (64.4%-85.8%, low) and specificity 89.1% (75.8%-95.6%, moderate). Spontaneous Nystagmus: 6 studies, 621 patients, sensitivity 52.3% (29.8%-74.0%, moderate) and specificity 42.0% (15.5%-74.1%, moderate). Nystagmus Type: 16 studies, 1,366 patients. Bidirectional, vertical, direction changing, or pure torsional nystagmus are consistent with a central cause of vertigo. Sensitivity 50.7% (41.1%-60.2%, moderate) and specificity 98.5% (91.7%-99.7%, moderate). Test of Skew: 15 studies, 1,150 patients. Skew deviation is abnormal and consistent with central etiology. Sensitivity was 23.7% (15%-35.4%, moderate) and specificity 97.6% (96%-98.6%, moderate). HINTS (Head Impulse, Nystagmus, Test of Skew): 14 studies, 1,781 patients, sensitivity 92.9% (79.1%-97.9%, high), specificity 83.4% (69.6%-91.7%, moderate). HINTS+: 5 studies, 342 patients, sensitivity 99.0% (73.6%-100%, high) and specificity 84.8% (70.1%-93.0%, high).Most neurological exam findings have low sensitivity and high specificity for a central cause in patients with acute vertigo or dizziness. In acute vestibular syndrome (monophasic, continuous, persistent dizziness), HINTS and HINTS+ have high sensitivity when performed by trained clinicians.

The COVID-19 pandemic has led to a boom in the use of V-V ECMO for ARDS secondary to COVID. Comparisons of outcomes of ECMO for COVID to ECMO for influenza have emerged. Very few comparisons of ECMO for COVID to ECMO for ARDS of all etiologies are available.To compare clinically important outcome measures in recipients of ECMO for COVID to those observed in recipients of ECMO for ARDS of other etiologies.V-V ECMO recipients between March 2020 and March 2022 consisted exclusively of COVID patients and formed the COVID ECMO group. All patients who underwent V-V ECMO for ARDS between January 2014 and March 2020 were eligible for analysis as the non-COVID ECMO comparator group. The primary outcome was survival to hospital discharge. Secondary outcomes included ECMO decannulation, ECMO duration30 days, and serious complications.Thirty-six patients comprised the COVID ECMO group and were compared to 18 non-COVID ECMO patients. Survival to hospital discharge was not significantly different between the two groups (33% in COVID vs. 50% in non-COVID; p = 0.255) nor was there a significant difference in the rate of non-palliative ECMO decannulation. The proportion of patients connected to ECMO for30 days was significantly higher in the COVID ECMO group: 69% vs. 17%; p = 0.001. There was no significant difference in serious complications.This study could not identify a statistically significant difference in hospital survival and rate of successful ECMO decannulation between COVID ECMO and non-COVID ECMO patients. Prolonged ECMO may be more common in COVID. Complications were not significantly different.

To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures.This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database's inception to July 16, 2020. Meta-analyses were conducted when possible.In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE).This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.

Patients presenting to the emergency department (ED) with acute vertigo or dizziness represent a diagnostic challenge. Neuroimaging has variable indications and yield. We aimed to conduct a systematic review and meta-analysis of the diagnostic test accuracy of neuroimaging for patients presenting with acute vertigo or dizziness.An electronic search was designed following patient-intervention-control-outcome (PICO) question-(P) adult patients with acute vertigo or dizziness presenting to the ED; (I) neuroimaging including computed tomography (CT), CT angiography (CTA), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and ultrasound (US); (C) MRI/clinical criterion standard; and (O) central causes (stroke, hemorrhage, tumor, others) versus peripheral causes of symptoms. Articles were assessed in duplicate. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was used to assess certainty of evidence in pooled estimates.We included studies that reported diagnostic test accuracy. From 6309 titles, 460 articles were retrieved, and 12 were included: noncontrast CT scan-six studies, 771 patients, pooled sensitivity 28.5% (95% confidence interval [CI] 14.4%-48.5%, moderate certainty) and specificity 98.9% (95% CI 93.4%-99.8%, moderate certainty); MRI-five studies, 943 patients, sensitivity 79.8% (95% CI 71.4%-86.2%, high certainty) and specificity 98.8% (95% CI 96.2%-100%, high certainty); CTA-one study, 153 patients, sensitivity 14.3% (95% CI 1.8%-42.8%) and specificity 97.7% (95% CI 93.8%-99.6%), CT had higher sensitivity than CTA (21.4% and 14.3%) for central etiology; MRA-one study, 24 patients, sensitivity 60.0% (95% CI 26.2%-87.8%) and specificity 92.9% (95% CI 66.1%-99.8%); US-three studies, 258 patients, sensitivity ranged from 30% to 53.6%, specificity from 94.9% to 100%.Noncontrast CT has very low sensitivity and MRI will miss approximately one in five patients with stroke if imaging is obtained early after symptom onset. The evidence does not support neuroimaging as the only tool for ruling out stroke and other central causes in patients with acute dizziness or vertigo presenting to the ED.

Intensive interdisciplinary pain treatment (IIPT) for youth with high impact chronic pain has been found to be effective in improving child symptoms and functioning. However, it remains unclear how these interventions impact the parents' own well-being, as well as cognitions and behaviours which are known to influence child pain and functioning. Thus, the current study sought to determine the effect of IIPT on parent mental health, cognitions and behaviours in parents of youth attending IIPT with their child.A search of the electronic databases CINAHL, Ovid EBM Reviews, Embase, Medline, APA PsychINFO, Scopus and web of Science was conducted. Studies were included if they comprised at least 10 parents of patients aged 9-22 with nonmalignant chronic pain attending an IIPT and were written in English.A random-effects model was used to pool the standardized mean change (SMC) across seven prepost studies. At discharge, IIPT participation was associated with small to moderate improvements in direct parental outcomes (general mental health, anxiety, depression and parenting stress), a moderate improvement in pain catastrophizing and large improvements in psychological flexibility and parenting behaviours. Most improvements were maintained at follow-up. The risk of bias of all studies was rated as serious and the certainty of the evidence as low, suggesting limited confidence in the estimates.Although parents appear to benefit from attending an IIPT with their child, RCTs are needed to substantiate the effect of these interventions on important aspects of parent well-being and functioning.

BackgroundAdult patients with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. These patients are at increased risk for adverse clinical outcomes in the absence of defined approaches to glycemic management.ObjectiveTo review and update the 2012 Management of Hyperglycemia in Hospitalized Patients in Non-Critical Care Settings: An Endocrine Society Clinical Practice Guideline and to address emerging areas specific to the target population of noncritically ill hospitalized patients with diabetes or newly recognized or stress-induced hyperglycemia.MethodsA multidisciplinary panel of clinician experts, together with a patient representative and experts in systematic reviews and guideline development, identified and prioritized 10 clinical questions related to inpatient management of patients with diabetes and/or hyperglycemia. The systematic reviews queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations.ResultsThe panel agreed on 10 frequently encountered areas specific to glycemic management in the hospital for which 15 recommendations were made. The guideline includes conditional recommendations for hospital use of emerging diabetes technologies including continuous glucose monitoring and insulin pump therapy; insulin regimens for prandial insulin dosing, glucocorticoid, and enteral nutrition–associated hyperglycemia; and use of noninsulin therapies. Recommendations were also made for issues relating to preoperative glycemic measures, appropriate use of correctional insulin, and diabetes self-management education in the hospital. A conditional recommendation was made against preoperative use of caloric beverages in patients with diabetes.ConclusionThe recommendations are based on the consideration of important outcomes, practicality, feasibility, and patient values and preferences. These recommendations can be used to inform system improvement and clinical practice for this frequently encountered inpatient population.

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements—many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development—in addition to the rationale for such changes. Improvements to the Society’s guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice.

Background & Aims The latitudinal gradient effect is described for several autoimmune diseases including celiac disease in the United States. However, the association between latitude and global celiac disease prevalence is unknown. We aimed to explore the association between latitude and serology-based celiac disease prevalence through meta-analysis. Methods We searched MEDLINE, Embase, Cochrane, and Scopus databases from their beginning through June 29, 2018, to identify screening studies that targeted a general population sample, used serology-based screening tests, and provided a clear location from which we could assign a latitude. Studies were excluded if sampling was based on symptoms, risk factors, or referral. Study selection and data extraction were performed by independent reviewers. The association measures between latitude and prevalence of serology-based celiac disease were evaluated with random-effects meta-analyses and meta-regression. Results Of the identified 4667 unique citations, 128 studies were included, with 155 prevalence estimates representing 40 countries. Celiac disease was more prevalent at the higher latitudes of 51° to 60° (relative risk [RR], 1.62; 95% CI, 1.09–2.38) and 61° to 70° (RR, 2.30; 95% CI, 1.36–3.89) compared with the 41° to 50° reference level. No statistically significant difference was observed at lower latitudes. When latitude was treated as continuous, we found a statistically significant association between CD prevalence and latitude overall in the world (RR, 1.03, 95% CI, 1.01–1.05) and a subregional analysis of Europe (RR, 1.05; 95% CI, 1.02–1.07) and North America (RR, 1.1; 95% CI, 1.0–1.2). Conclusions In this comprehensive review of screening studies, we found that a higher latitude was associated with greater serology-based celiac disease prevalence.

Background: Antidiabetic medications (ADM) may modify colorectal cancer risk in patients with diabetes mellitus. We performed a systematic review and meta-analysis, evaluating the effect of metformin, thiazolidinediones (TZD), sulfonylureas, and insulin on colorectal cancer risk in diabetic patients.Methods: We conducted a systematic search of multiple bibliographic databases, up to September 2012, for articles that evaluated exposure to metformin, TZD, sulfonylureas, and insulin, reported colorectal cancer risk in patients with diabetes mellitus, and reported OR or provided data for their estimation. Summary OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model.Results: Fifteen studies reporting 13,871 cases of colorectal cancer in 840,787 patients with diabetes mellitus were included. Meta-analysis of observational studies showed an 11% reduction in colorectal cancer risk associated with metformin use (n = 9 studies; OR, 0.89; 95% CI, 0.81–0.99), whereas TZD use was not associated with colorectal cancer risk (n = 5 studies; OR, 0.96; 95% CI, 0.87–1.05). Conversely, a trend toward higher colorectal cancer risk was observed with sulfonylurea (n = 7 studies; OR, 1.11; 95% CI, 0.97–1.26) and insulin (n = 9 studies; OR, 1.33; 95% CI, 0.91–1.94) use, although these associations were not statistically significant. There was considerable heterogeneity across studies, partly explained by study location and adjustment for concomitant use of other ADMs. Post-hoc analysis of randomized controlled trials did not reveal any significant association between ADM and colorectal cancer risk.Conclusions: Meta-analysis of published studies supports a protective association between metformin use and colorectal cancer risk in patients with diabetes mellitus.Impact: Clinical trials on the chemopreventive effect of metformin against colorectal cancer are warranted. Cancer Epidemiol Biomarkers Prev; 22(12); 2258–68. ©2013 AACR.

PDF - 44KB, The figures report the Forest plots for the association between anti-diabetic medications and risk of colorectal cancer.

PDF - 98KB, Newcastle-Ottawa scale for assessment of quality of included studies - Cohort studies and Case-Control studies. Supplementary Tables 1-2 and Supplementary Figure Legends.

Introduction Acute stroke patients presenting with large vessel occlusion secondary to intracranial atherosclerosis (ICAS‐LVO) may require rescue therapy (RT) in addition to mechanical thrombectomy (MT) to achieve and maintain successful recanalization. We performed a systematic review and meta‐analysis of comparative studies that reported outcomes of RT in ICAS‐LVO patients to evaluate its safety and efficacy. Methods Databases searched include PubMed, CINAHL Complete, and Scopus from database date of inception through August 17, 2021. We included comparative studies that reported the outcomes of ICAS‐LVO RT compared to outcomes of ICAS‐LVO patients who did not undergo RT or to those presenting with embolic LVO patients (non‐ICAS LVO). Meta‐analysis using the random effects model was used to combine estimates reporting odds ratios (OR) and 95% confidence intervals (CI). Results Total of 9 nonrandomized studies were included: 5 studies in ICAS‐LVO RT vs. ICAS‐LVO non‐RT analysis and 5 ICAS‐LVO RT vs. non‐ICAS LVO analysis. Rescue treatments included intra‐arterial antiplatelets, angioplasty, stenting or combination of treatments. Compared to non‐RT ICAS LVO, RT was associated with increased favorable 90‐day outcome (OR 3.19, 95% CI 1.91‐5.32, I2 14%) and decreased 90‐day mortality (OR 0.35, 95% CI 0.16‐0.76, I2 21%) (Figure 1). In the analysis of ICAS LVO vs embolic LVO, the incidence of favorable 90‐day outcome and 90‐day mortality did not differ between the ICAS‐LVO RT and non‐ICAS LVO (OR 0.97, 95% CI 0.58‐1.64, I2 50%) and (OR 1.22, 95% CI 0.90‐1.66, I2 0%), respectively. Conclusions Rescue treatment is associated with better outcomes in ICAS‐LVO patients. The outcomes of ICAS‐LVO patients who receive RT may be comparable to embolic LVO patients (non‐ICAS LVO).

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC). OBJECTIVE: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). METHODS: We searched MEDLINE, Embase, Scopus and other sources. 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. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15–1.82) and all-cause mortality 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: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

Objectives. To evaluate the comparative effectiveness and harms of partial breast irradiation (PBI) compared with whole breast irradiation (WBI) for early-stage breast cancer, and how differences in effectiveness and harms may be influenced by patient, tumor, and treatment factors, including treatment modality, target volume, dose, and fractionation. We also evaluated the relative financial toxicity of PBI versus WBI. Data sources. MEDLINE®, Embase®, Cochrane Central Registrar of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various grey literature sources from database inception to June 30, 2022. Review methods. We included randomized clinical trials (RCTs) and observational studies that enrolled adult women with early-stage breast cancer who received one of six PBI modalities: multi-catheter interstitial brachytherapy, single-entry catheter brachytherapy (also known as intracavitary brachytherapy), 3-dimensional conformal external beam radiation therapy (3DCRT), intensity-modulated radiation therapy (IMRT), proton radiation therapy, intraoperative radiotherapy (IORT). Pairs of independent reviewers screened and appraised studies. Results. Twenty-three original studies with 17,510 patients evaluated the comparative effectiveness of PBI, including 14 RCTs, 6 comparative observational studies, and 3 single-arm observational studies. PBI was not significantly different from WBI in terms of ipsilateral breast recurrence (IBR), overall survival, or cancer-free survival at 5 and 10 years (high strength of evidence [SOE]). Evidence for cosmetic outcomes was insufficient. Results were generally consistent when PBI modalities were compared with WBI, whether compared individually or combined. These PBI approaches included 3DCRT, IMRT, and multi-catheter interstitial brachytherapy. Compared with WBI, 3DCRT showed no difference in IBR, overall survival, or cancer-free survival at 5 and 10 years (moderate to high SOE); IMRT showed no difference in IBR or overall survival at 5 and 10 years (low SOE); multi-catheter interstitial brachytherapy showed no difference in IBR, overall survival, or cancer-free survival at 5 years (low SOE). Compared with WBI, IORT was associated with a higher IBR rate at 5, 10, and over 10 years (high SOE), with no difference in overall survival, cancer-free survival, or mastectomy-free survival (low to high SOE). There were significantly fewer acute adverse events (AEs) with PBI compared with WBI, with no apparent difference in late AEs (moderate SOE). Data about quality of life were limited. Head-to-head comparisons between the different PBI modalities showed insufficient evidence to estimate an effect on main outcomes. There were no significant differences in IBR or other outcomes according to patient, tumor, and treatment characteristics; however, data for subgroups were insufficient to draw conclusions. Eight studies addressed concepts closely related to financial toxicity. Compared with conventionally fractionated WBI, accelerated PBI was associated with lower transportation costs and days away from work. PBI was also associated with less subjective financial difficulty at various time points after radiotherapy. Conclusions. Clinical trials that compared PBI with WBI demonstrate no significant difference in the risk of IBR. PBI is associated with fewer acute AEs and may be associated with less financial toxicity. The current evidence supports the use of PBI in appropriately selected patients with early-stage breast cancer. Further investigation is needed to evaluate the outcomes of PBI in patients with various clinical and tumor characteristics, and to define optimal radiation treatment dose and technique for PBI.

Background Immunoassays designed to detect SARS-CoV-2 protein antigens (Ag) are commonly used to diagnose COVID-19. The most widely used tests are lateral flow assays that generate results in approximately 15 minutes for diagnosis at the point-of-care. Higher throughput, laboratory-based SARS-CoV-2 Ag assays have also been developed. The number of commercially available SARS-CoV-2 Ag detection tests has increased rapidly, as has the COVID-19 diagnostic literature. 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 an update to the third in a series of frequently updated COVID-19 diagnostic guidelines developed by the IDSA. Objective The 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 non-medical settings. Methods 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. A review of relevant, peer-reviewed published literature was conducted through April 1, 2022. Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make testing recommendations. Results The panel made ten diagnostic recommendations. These recommendations address Ag testing in symptomatic and asymptomatic individuals and assess single versus repeat testing strategies. Conclusions U.S. Food and Drug Administration (FDA) SARS-CoV-2 Ag tests with Emergency Use Authorization (EUA) have high specificity and low to moderate sensitivity compared to nucleic acid amplification testing (NAAT). Ag test sensitivity is dependent on the presence or absence of symptoms, and in symptomatic patients, on timing of testing after symptom onset. In contrast, Ag tests have high specificity, and, in most cases, positive Ag results can be acted upon without confirmation. Results of point-of-care testing are comparable to those of laboratory-based testing, and observed or unobserved self-collection of specimens for testing yields similar results. Modeling suggests that repeat Ag testing increases sensitivity compared to testing once, but no empirical data were available to inform this question. Based on these observations, rapid RT-PCR or laboratory-based NAAT remains the testing method of choice for diagnosing SARS-CoV-2 infection. However, when timely molecular testing is not readily available or is logistically infeasible, Ag testing helps identify individuals with SARS-CoV-2 infection. Data were insufficient to make a recommendation about the utility of Ag testing to guide release of patients with COVID-19 from isolation. The overall quality of available evidence supporting use of Ag testing was graded as very low to moderate.

There is no clear consensus regarding the optimal approach for secondary prophylaxis of gastric variceal bleeding (GVB) in patients with cirrhosis. We conducted a systematic review and network meta-analysis (NMA) to compare the efficacy of available treatments. A comprehensive search of several databases from each database's inception to March 23, 2021, was conducted to identify relevant randomized controlled trials (RCTs). Outcomes of interest were rebleeding and mortality. Results were expressed as relative risk (RR) and 95% confidence interval (CI). We followed the Grading of Recommendations Assessment, Development, and Evaluation approach to rate the certainty of evidence. We included 9 RCTs with 647 patients who had histories of GVB and follow-ups6 weeks. A total of 9 interventions were included in the NMA. Balloon-occluded retrograde transvenous obliteration (BRTO) was associated with a lower risk of rebleeding when compared with β-blockers (RR, 0.04; 95% CI, 0.01-0.26; low certainty), and endoscopic injection sclerotherapy (EIS)-cyanoacrylate (CYA) (RR, 0.18; 95% CI, 0.04-0.77; low certainty). β-blockers were associated with a higher risk of rebleeding compared with most interventions and with increased mortality compared with EIS-CYA (RR, 4.12, 95% CI, 1.50-11.36; low certainty), and EIS-CYA + nonselective β-blockers (RR, 5.61; 95% CI, 1.91-16.43; low certainty). Analysis based on indirect comparisons suggests that BRTO may be the best intervention in preventing rebleeding, whereas β-blocker monotherapy is likely the worst in preventing rebleeding and mortality. Head-to-head RCTs are needed to validate these results.

Objective To measure well-being at a community level using a valid instrument. Patients and Methods Written surveys were mailed to a random sample of residents in Olmsted County, Minnesota, in 2015 and 2019 including the 5-item World Health Organization Well-being Index (0-100; for which 100 is the best imaginable well-being or quality of life). Multivariable hierarchical regression was used to evaluate the association between well-being and demographic characteristics, comorbid conditions, and environmental factors. Results The survey was returned by 1232 of 4000 individuals (response rate, 30.80%). The average well-being score was 70.02. Impaired well-being was identified in 223/1187 individuals (18.79%). Adjusted regression models showed that impaired well-being was independently associated with household poverty, financial stress, reduced access to medical or mental health care, ever having depression diagnosed, living in an unsafe community, or being socially isolated. Conclusion One in 5 people in a county in the US Midwest have impaired well-being. Well-being was associated with several modifiable factors. Data provide a rationale for policies that align transportation and housing and create opportunities for community members to connect and interact in a safe environment.

Various pharmacotherapies exist for heart failure with preserved ejection fraction (HFpEF), but with unclear comparative efficacy. We searched EMBASE, Medline, and Cochrane Library from inception through August 2021 for all randomized clinical trials in HFpEF (EF40%) that evaluated beta-blockers, mineralocorticoid receptor antagonist (MRA), angiotensin-converting enzyme inhibitors (ACE), angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor (ARNI), and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Outcomes assessed were cardiovascular mortality, all-cause mortality, and HF hospitalization. A frequentist network meta-analysis was performed with a random-effects model. We included 22 randomized clinical trials (30,673 participants; mean age = 71.7 ± 4.2 years; females = 49.3 ± 7.7%; median follow-up = 24.4 ± 11.1 months). Compared with placebo, there was no statistically significant difference in cardiovascular mortality [beta-blockers; odds ratio (OR) 0.79 (0.46-1.34), MRA; OR 0.90 (0.70-1.14), ACE OR 0.95 (0.59-1.53), ARB; OR 1.02 (0.87-1.19), ARNI; OR 0.97 (0.74-1.26) and SGLT2i; OR 1.00 (0.84-1.18)] or all-cause mortality [beta blockers; OR 0.75 (0.54-1.04), MRA; OR 0.90 (0.75-1.08) ACE; OR 1.05 (0.71-1.54), ARB; OR 1.03 (0.91-1.15), ARNI; OR 0.99 (0.82-1.20) and SGLT2i; OR 1.00 (0.89-1.13)]. The certainty in these estimates was low or very low. There was a significantly reduction in HF hospitalization with the use of SGLT2i [OR 0.71 (0.62-0.82), moderate certainty], ARNI [OR 0.77 (0.63-0.94), low certainty], and MRA [OR 0.81 (0.66-0.98), moderate certainty]; with corresponding P scores of 0.84, 0.68, and 0.58, respectively. In HFpEF, the use of beta-blockers, MRA, ACE/ARB/ARNI, or SGLT2i was not associated with improved cardiovascular or all-cause mortality. SGLT2i, ARNI, and MRA reduced the risk of HF hospitalizations.

Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough. Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms. Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance. Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management.

Corticosteroid dosing in the range of 0.5–2 mg/kg/day of methylprednisolone equivalents has become a standard part of the management of intensive care unit (ICU) patients with COVID‐19 pneumonia based on positive results of randomized trials and a meta‐analysis. Alongside such conventional dosing, administration of 1 gm of methylprednisolone daily (pulse dosing) has also been reported in the literature with claims of favorable outcomes. Comparisons between such disparate approaches to corticosteroids for Coronavirus disease 2019 (COVID‐19) pneumonia are lacking. In this retrospective study of patients admitted to the ICU with COVID‐19 pneumonia, we compared patients treated with 0.5–2 mg/kg/day in methylprednisolone equivalents (high‐dose corticosteroids) and patients treated with 1 gm of methylprednisolone (pulse‐dose corticosteroids) to those who did not receive any corticosteroids. The endpoints of interest were hospital mortality, ICU‐free days at Day 28, and complications potentially attributable to corticosteroids. Pulse‐dose corticosteroid therapy was associated with a significant increase in ICU‐free days at Day 28 compared to no receipt: adjusted relative risk (aRR): 1.45 (95% confidence interval [CI]: 1.05–2.02; p = 0.03) and compared with high‐dose corticosteroid administration (p = 0.003). Nonetheless, receipt of high‐dose corticosteroids—but not of pulse‐dose corticosteroids—significantly reduced the odds of hospital mortality compared to no receipt: adjusted Odds ratio (aOR) 0.31 (95% CI: 0.12–0.77; p = 0.01). High‐dose corticosteroids reduced mortality compared to pulse‐dose corticosteroids (p = 0.04). Pulse‐dose corticosteroids—but not high‐dose corticosteroids—significantly increased the odds of acute kidney injury requiring renal replacement therapy compared to no receipt: aOR 3.53 (95% CI: 1.27–9.82; p = 0.02). The odds of this complication were also significantly higher in the pulse‐dose group when compared to the high‐dose group (p = 0.05 for the comparison). In this single‐center study, pulse‐dose corticosteroid therapy for COVID‐19 pneumonia in the ICU was associated with an increase in ICU‐free days but failed to impact hospital mortality, perhaps because of its association with development of severe renal failure. In line with existing trial data, the effect of high‐dose corticosteroids on mortality was favorable.

Background: Sickle cell disease (SCD) is a life-limiting inherited hemoglobinopathy that results in significant complications and affects quality of life. Hematopoietic stem cell transplantation (HSCT) is currently the only curative intervention for SCD; however, guidelines are needed to inform how to apply HSCT in clinical practice. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and health professionals in their decisions about HSCT for SCD. Methods: The multidisciplinary guideline panel formed by ASH included 2 patient representatives and was balanced to minimize potential bias from conflicts of interest. The Mayo Evidence-Based Practice Research Program supported the guideline development process, including performing systematic evidence reviews (through 2019). The panel prioritized clinical questions and outcomes according to their importance for clinicians and patients. The panel used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 8 recommendations to help patients and providers assess how individuals with SCD should consider the timing and type of HSCT. Conclusions: The evidence review yielded no randomized controlled clinical trials for HSCT in SCD; therefore, all recommendations are based on very low certainty in the evidence. Key recommendations include considering HSCT for those with neurologic injury or recurrent acute chest syndrome at an early age and to improve nonmyeloablative regimens. Future research should include the development of a robust SCD registry to serve as a comparator for HSCT studies.

The development of rigorous, high-quality clinical guidelines increases the need for resources and skilled personnel within guideline-producing organizations. While collaboration between organizations provides a unique opportunity to pool resources and save time and effort, the collaboration presents its own unique challenges. To assess the perceived needs and current challenges of guideline producers worldwide related to guideline development and collaboration efforts. Survey questions were developed by the Guidelines International Network and the US GRADE Network, pilot-tested among attendees of a guideline development workshop, and disseminated electronically using convenience and snowball sampling methods. A total of 171 respondents representing 30 countries and more than 112 unique organizations were included in this analysis. The survey included free-response, multiple-choice, and seven-point Likert-scale questions. Questions assessed respondents’ perceived value of guidelines, resource availability and needs, guideline development processes, and collaboration efforts of their organization. Time required to develop high-quality systematic reviews and guidelines was the most relevant need (median=7; IQR=5.5–7). In-house resources to conduct literature searches (median=4; IQR=3–6) and the resources to develop rigorous guidelines rapidly (median=4; IQR=2–5) were perceived as the least available resources. Difficulties reconciling differences in guideline methodology (median=6; IQR=4–7) and the time required to establish collaborative agreements (median=6; IQR=5–6) were the most relevant barriers to collaboration between organizations. Results also indicated a general need for improvement in conflict of interest (COI) disclosure policies. The survey identified organizational challenges in supporting rigorous guideline development, including the time, resources, and personnel required. Connecting guideline developers to existing databases of high-quality systematic reviews and the use of freely available online platforms may facilitate guideline development. Guideline-producing organizations may also consider allocating resources to hiring or training personnel with expertise in systematic review methodologies or utilizing resources more effectively by establishing collaborations with other organizations.

Schistosomiasis is a helminthiasis infecting approximately 250 million people worldwide. In 2001, the World Health Assembly (WHA) 54.19 resolution defined a new global strategy for control of schistosomiasis through preventive chemotherapy programmes. This resolution culminated in the 2006 WHO guidelines that recommended empirical treatment by mass drug administration with praziquantel, predominately to school-aged children in endemic settings at regular intervals. Since then, school-based and community-based preventive chemotherapy programmes have been scaled-up, reducing schistosomiasis-associated morbidity. Over the past 15 years, new scientific evidence-combined with a more ambitious goal of eliminating schistosomiasis and an increase in the global donated supply of praziquantel-has highlighted the need to update public health guidance worldwide. In February, 2022, WHO published new guidelines with six recommendations to update the global public health strategy against schistosomiasis, including expansion of preventive chemotherapy eligibility from the predominant group of school-aged children to all age groups (2 years and older), lowering the prevalence threshold for annual preventive chemotherapy, and increasing the frequency of treatment. This Review, written by the 2018-2022 Schistosomiasis Guidelines Development Group and its international partners, presents a summary of the new WHO guideline recommendations for schistosomiasis along with their historical context, supporting evidence, implications for public health implementation, and future research needs.

Background Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. Objective To develop guidelines for the treatment of adults with HCM. Methods A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. Results The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. Conclusions The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

ContextHypoglycemia in people with diabetes is common, especially in those taking medications such as insulin and sulfonylureas (SU) that place them at higher risk. Hypoglycemia is associated with distress in those with diabetes and their families, medication nonadherence, and disruption of life and work, and it leads to costly emergency department visits and hospitalizations, morbidity, and mortality.ObjectiveTo review and update the diabetes-specific parts of the 2009 Evaluation and Management of Adult Hypoglycemic Disorders: Endocrine Society Clinical Practice Guideline and to address developing issues surrounding hypoglycemia in both adults and children living with diabetes. The overriding objectives are to reduce and prevent hypoglycemia.MethodsA multidisciplinary panel of clinician experts, together with a patient representative, and methodologists with expertise in evidence synthesis and guideline development, identified and prioritized 10 clinical questions related to hypoglycemia in people living with diabetes. Systematic reviews were conducted to address all the questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations.ResultsThe panel agreed on 10 questions specific to hypoglycemia risk and prevention in people with diabetes for which 10 recommendations were made. The guideline includes conditional recommendations for use of real-time continuous glucose monitoring (CGM) and algorithm-driven insulin pumps in people with type 1 diabetes (T1D), use of CGM for outpatients with type 2 diabetes at high risk for hypoglycemia, use of long-acting and rapid-acting insulin analogs, and initiation of and continuation of CGM for select inpatient populations at high risk for hypoglycemia. Strong recommendations were made for structured diabetes education programs for those at high risk for hypoglycemia, use of glucagon preparations that do not require reconstitution vs those that do for managing severe outpatient hypoglycemia for adults and children, use of real-time CGM for individuals with T1D receiving multiple daily injections, and the use of inpatient glycemic management programs leveraging electronic health record data to reduce the risk of hypoglycemia.ConclusionThe recommendations are based on the consideration of critical outcomes as well as implementation factors such as feasibility and values and preferences of people with diabetes. These recommendations can be used to inform clinical practice and health care system improvement for this important complication for people living with diabetes.

There are many pharmacologic therapies that are being used or considered for treatment of coronavirus disease 2019 (COVID-19), with rapidly changing efficacy and safety evidence from trials. The objective was to develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19. In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations. Based on the most recent search conducted on 31 May 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and postexposure prophylaxis, ambulatory with mild-to-moderate disease, and hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at: https://idsociety.org/COVID19guidelines. At the inception of its work, the panel has expressed the overarching goal that patients be recruited into ongoing trials. Since then, many trials were conducted that provided much-needed evidence for COVID-19 therapies. There still remain many unanswered questions as the pandemic evolved, which we hope future trials can answer.

Clinicians regularly have to trade benefits and harms to choose between testing and treatment strategies. This process is often done by making global and implicit judgments. A decision analysis is an analytic method that makes this process more explicit, reproducible, and evidence-based. While clinicians are unlikely to conduct their own decision analysis, they will read publications of such analyses or use guidelines based on them. This review outlines the anatomy of a decision tree and provides clinicians with the tools to critically appraise a decision analysis and apply its results to medical decision making. Clinicians reading about a decision analysis can make two judgments. The first judgment is about the credibility of the methods, such as whether the decision analysis addressed a relevant clinical question, included all important outcomes, used the current best evidence to derive variables in the model, and adopted the appropriate time horizon. The second judgment is about rating confidence in the preferred course of action by determining the certainty in the model variables, whether the results are robust in sensitivity analyses and if the results are applicable to a specific patient. Results from a valid and robust decision analysis can inform both guideline panels and the patient-clinician dyad engaged in shared decision-making.

Objective : To identify and suggest strategies to make insufficient evidence ratings in systematic reviews more actionable. Study Design and Setting : A workgroup comprising members from the Evidence-Based Practice (EPC) Program of the Agency for Healthcare Research and Quality convened throughout 2020. We conducted iterative discussions considering information from three data sources: a literature review for relevant publications and frameworks, a review of a convenience sample of past systematic reviews conducted by the EPCs, and an audit of methods used in past EPC technical briefs. Results : We identified five strategies for supplementing systematic review findings when evidence on benefits or harms is expected to be, or found to be, insufficient: 1) reconsider eligible study designs, 2) summarize indirect evidence, 3) summarize contextual and implementation evidence, 4) consider modelling, and 5) incorporate unpublished health system data in the evidence synthesis. While these strategies may not increase the strength of evidence, they may improve the utility of reports for decisionmakers. Adopting these strategies depends on feasibility, timeline, funding, and expertise of the systematic reviewers. Conclusion : Throughout the process of evidence synthesis of early scoping, protocol development, review conduct, and review presentation, authors can consider these five strategies to supplement evidence with insufficient rating to make it more actionable for end-users.

Regenerative, 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., Cell‐based therapies improve diabetic kidney repair: a systematic review and meta‐analysis.

Objective: To evaluate the magnitude of the association between risk factors and premature myocardial infarction (MI) (men aged 18-55 years; women aged 18-65 years). Patients and Methods: We searched MEDLINE and other databases from inception through April 30, 2020, as well as bibliography of articles selected for data extraction. We selected observational studies reporting the magnitude of the association of at least 1 risk factor (demographic characteristics, lifestyle factors, clinical risk factors, or biomarkers) with premature MI and a control group. Pooled risk estimates (random effects) from all studies unadjusted and adjusted for risk factors were reported as summary odds ratios (ORs) with 95% CIs. Results: From 35,320 articles of 12.7 million participants, we extracted data on 19 risk factors from 77 studies across 58 countries. Men had a higher risk of premature MI (OR, 2.39; 95% CI, 1.71 to 3.35) than did women. Family history of cardiac disease was associated with a higher risk of premature MI (OR, 2.67; 95% CI, 2.29 to 3.27). Major modifiable risk factors associated with higher risk were current smoking (OR, 4.34; 95% CI, 3.68 to 5.12 vs no/former), diabetes mellitus (OR, 3.54; 95% CI, 2.69 to 4.65), dyslipidemia (OR, 2.94; 95% CI, 1.76 to 4.91), and hypertension (OR, 2.85; 95% CI, 2.48 to 3.27). Higher body mass index carried higher risk (OR, 1.46; 95% CI, 1.24 to 1.71 for ≥25 kg/m2 vs