Farah, Magdoleen H

Abstract Background Community-acquired pneumonia (CAP) is a significant public health concern associated with increased rates of hospital admissions and mortality. The purpose of the current study was to compare beta-lactam plus azithromycin or doxycycline vs fluoroquinolones in adults hospitalized with CAP. Methods We searched several databases from inception to 10 June 2024. Two reviewers independently screened, selected, and extracted data. Disagreements were resolved by consensus or a third reviewer. Study quality was assessed in duplicate with the Cochrane Risk of Bias 2 for randomized studies and the Newcastle-Ottawa Scale for nonrandomized studies. Meta-analysis was conducted by a random effect model when feasible. Network meta-analysis was performed to compare direct and indirect evidence. The GRADE approach (Grading of Recommendations Assessment, Development, and Evaluation) was followed to rate the certainty of evidence. Results Twenty studies were included (20 beta-lactam + azithromycin, 7 beta-lactam + doxycycline, 12 levofloxacin, and 4 moxifloxacin): 6 were randomized, enrolling 861 participants (mean age, 61.8 years; 43.2% women), and 14 were nonrandomized, enrolling 185 928 participants (mean age, 65.2 years; 42.9% women). Direct comparison and network meta-analysis results showed no statistically significant differences and likely equal effectiveness between beta-lactam + azithromycin and beta-lactam + doxycycline in terms of in-hospital mortality, need for intensive care unit admission or invasive mechanical ventilation, or safety outcomes including Clostridioides difficile infection and QT prolongation. Conclusions The current evidence demonstrated no likely difference in outcomes between azithromycin and doxycycline in adults hospitalized with CAP receiving beta-lactam. Head-to-head randomized clinical trials are needed to validate these results.

Objective: The objective of this investigation was to evaluate the agreement rate on judgments made using the Murad tool by different systematic review teams. Introduction: Evaluating the methodological quality of case reports and case series is challenging but some tools do exist for this purpose. We leveraged the presence of studies that have been evaluated by different systematic review teams to assess the inter-consensus agreement among different teams on Murad tool domains. Methods: Using a back-citation method, we identified systematic reviews that used the Murad tool and retrieved all the included primary studies. We selected studies that were assessed by more than 1 systematic review team. We calculated observed agreement and Gwet’s agreement coefficient on judgments made about each signaling question. Results: We identified 982 systematic reviews that cited the Murad tool and collectively cited 59,080 references. The final data comprised of 81 duplicated case reports and series assessed by more than 1 systematic review team. Overall, the signaling questions had very high observed agreement with 5 of the 8 questions having agreement over 75%. The signaling questions with the highest agreement addressed the adequacy of the ascertainment of the exposure (coefficient 0.959), ascertainment of the outcome (coefficient 0.829), presence of a dose-response gradient (perfect agreement), and clarity of reporting (coefficient 0.755). Conclusion: The current study demonstrates overall high agreement among different systematic review teams that used the Murad tool for appraisal of the same case series and case reports. Leveraging duplicated studies across systematic reviews is a feasible way to retrospectively assess the reliability of the tool.

Abstract Background Partial breast irradiation (PBI) is an effective treatment for early-stage breast cancer. However, evidence comparing different PBI modalities is limited. Methods This trial emulation uses electronic health records from a multi-state large tertiary health system. Three PBI modalities were compared: proton radiation therapy, photon radiation therapy, and applicator-based brachytherapy. Inverse probability weighting (IPW) was used to balance confounders. The primary outcome was ipsilateral breast recurrence (IBR). Results Between 2013 and 2023, 1041 women with early-stage breast cancer were treated with PBI. Of these, 1026 patients were included in the analyses. The median age was 66 years; 22.51% had ductal carcinoma in situ (DCIS), and 97.56% were estrogen receptor positive. With median follow-up of 38.2 months, the rate of IBR in the overall group was 3.05% (95% confidence interval [CI] = 1.99% to 4.65%) at 3 years. After IPW, compared with photon PBI, the hazard ratio for IBR for proton PBI was 2.11 (95% CI = 0.70 to 6.33) and for brachytherapy, 3.86 (95% CI = 1.39 to 10.69). Compared with proton PBI, the hazard ratio for IBR for brachytherapy was 1.83 (95% CI = 0.88 to 3.81). IBR risk was similar across PBI modalities for patients with tumor size ≤ 10 mm and in patients treated for DCIS. Among patients with tumor size >10 mm, the hazard ratio for IBR for brachytherapy was 7.64 (95% CI = 1.64 to 35.58) and 3.59 (95% CI = 1.22 to 10.56) relative to photons and protons, respectively. Conclusion PBI with applicator-based brachytherapy was associated with higher IBR than photon or proton PBI in patients with tumor size > 10 mm, suggesting the need for more careful PBI patient selection for this modality.

Importance Suicide is a leading cause of death among young people and an escalating public health crisis. Objective To assess the effectiveness and harms of available treatments for suicidal thoughts and behaviors among youths at heightened risk for suicide. Evidence Review A systematic review was conducted searching databases including MEDLINE, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and various gray literature sources from January 1, 2000, to September 26, 2024. We included randomized clinical trials, comparative observational studies, and before-after studies of psychosocial interventions, pharmacologic interventions, neurotherapeutics, emerging therapies, and combination therapies. Eligible patients were youths (aged 5-24 years) with heightened risk for suicide, adolescents from racial and ethnic minority groups known to be at increased risk of suicide, or those exposed to crime or violence. Pairs of independent reviewers selected and appraised studies. Findings This review included 65 studies (33 randomized clinical trials, 13 comparative observational studies, and 19 before-after studies) reporting on 14 534 patients (median age, 15.1 years; 75.1% female patients). Psychosocial interventions comprised psychotherapy interventions (33 studies; cognitive behavioral therapy, dialectical behavioral therapy, collaborative assessment and management of suicidality, dynamic deconstructive psychotherapy, attachment-based family therapy, and family-focused therapy), acute (ie, 1-4 sessions or contacts) psychosocial interventions (19 studies; safety planning, family-based crisis management, motivational interviewing crisis interventions, continuity of care after crisis, and brief adjunctive treatments), and school- or community-based psychosocial interventions (13 studies; social network interventions, school-based skills interventions, suicide awareness or gatekeeper programs, and community-based, culturally tailored adjunct programs). Dialectical behavior therapy showed moderate strength of evidence for reducing suicidal ideation. Other categories of psychosocial treatments showed insufficient to low strength of evidence for reducing suicidal outcomes. None of the studies evaluated adverse events. The evidence base on pharmacologic treatment for youths at risk of suicide was largely nonexistent. Conclusions and Relevance This systematic review found that the current evidence on available interventions targeting youths at heightened risk of suicide is uncertain. Medication, neurotherapeutics, and emerging therapies remain unstudied among this population. The limited evidence base calls for the development of novel, developmentally and trauma-informed treatments, as well as multilevel interventions to target the increasing suicide risk among youths.

Abstract Context Primary aldosteronism (PA) is a leading endocrine cause of secondary hypertension. Objective To support the development of the Endocrine Society Clinical Practice Guideline on managing PA. Data Source MEDLINE, Embase, Scopus, and others were searched on October 4, 2024. Study Selection Studies were selected by pairs of independent reviewers. Data Extraction Data were extracted and appraised by pairs of independent reviewers. Data Synthesis We included 95 studies (7 randomized trials and 88 observational studies). We did not identify trials that evaluated the outcomes of PA screening. One observational study suggested that screening was associated with higher rates of using PA-specific medical therapies and better blood pressure control. Patients managed with adrenal venous sampling (vs computed tomography alone) may have a better post-adrenalectomy biochemical cure rate, but with an increased risk of adrenal hemorrhage. Two small observational studies suggested that PA-specific medical or surgical therapy was likely associated with better blood pressure control than nonspecific therapy. Small randomized trials suggested that surgical therapy may be associated with better blood pressure control than medical therapy, with a lower number and dosage of antihypertensive medications. Compared to eplerenone, spironolactone may be associated with better control of hypokalemia and a lower number and dosage of antihypertensive agents. Unsuppressed plasma renin activity was associated with better control of hypokalemia, while suppression was associated with higher risk of mortality, atrial fibrillation, and stroke (very low certainty). Conclusion This systematic review addresses various aspects of managing PA and will support the development of the Endocrine Society guidelines.

Abstract Context Low vitamin D status is common and is associated with various common medical conditions. Objective To support the development of the Endocrine Society's Clinical Practice Guideline on Vitamin D for the Prevention of Disease. Methods We searched multiple databases for studies that addressed 14 clinical questions prioritized by the guideline panel. Of the 14 questions, 10 clinical questions assessed the effect of vitamin D vs no vitamin D in the general population throughout the lifespan, during pregnancy, and in adults with prediabetes; 1 question assessed dosing; and 3 questions addressed screening with serum 25-hydroxyvitamin D (25[OH]D). The Grading of Recommendations Assessment, Development and Evaluation approach was used to assess certainty of evidence. Results Electronic searches yielded 37 007 citations, from which we included 151 studies. In children and adolescents, low-certainty evidence suggested reduction in respiratory tract infections with empiric vitamin D. There was no significant effect on select outcomes in healthy adults aged 19 to 74 years with variable certainty of evidence. There was a very small reduction in mortality among adults older than 75 years with high certainty of evidence. In pregnant women, low-certainty evidence suggested possible benefit on various maternal, fetal, and neonatal outcomes. In adults with prediabetes, moderate certainty of evidence suggested reduction in the rate of progression to diabetes. Administration of high-dose intermittent vitamin D may increase falls, compared to lower-dose daily dosing. We did not identify trials on the benefits and harms of screening with serum 25(OH)D. Conclusion The evidence summarized in this systematic review addresses the benefits and harms of vitamin D for the prevention of disease. The guideline panel considered additional information about individuals’ and providers’ values and preferences and other important decisional and contextual factors to develop clinical recommendations.

Abstract Background Early-stage breast cancer is among the most common cancer diagnoses. Adjuvant radiotherapy is an essential component of breast-conserving therapy, and several options exist for tailoring its extent and duration. This study assesses the comparative effectiveness of partial-breast irradiation (PBI) compared with whole-breast irradiation (WBI). Methods A systematic review was completed to identify relevant randomized clinical trials and comparative observational studies. Independent reviewers working in pairs selected studies and extracted data. Randomized trial results were pooled using a random effects model. Prespecified main outcomes were ipsilateral breast recurrence (IBR), cosmesis, and adverse events (AEs). Results Fourteen randomized clinical trials and 6 comparative observational studies with 17 234 patients evaluated the comparative effectiveness of PBI. PBI was not statistically significantly different from WBI for IBR at 5 years (RR = 1.34, 95% CI = 0.83 to 2.18; high strength of evidence [SOE]) and 10 years (RR = 1.29, 95% CI = 0.87 to 1.91; high SOE). Evidence for cosmetic outcomes was insufficient. Statistically significantly fewer acute AEs were reported with PBI compared with WBI, with no statistically significant difference in late AEs. Data from subgroups according to patient, tumor, and treatment characteristics were insufficient. Intraoperative radiotherapy was associated with higher IBR at 5, 10, and over than 10 years (high SOE) compared with WBI. Conclusions Ipsilateral breast recurrence was not statistically significantly different between PBI and WBI. Acute AEs were less frequent with PBI. This evidence supports the effectiveness of PBI among selected patients with early-stage, favorable-risk breast cancer who are similar to those represented in the included studies.

AbstractContextHypercalcemia is a common complication of malignancy that is associated with high morbidity and mortality.ObjectiveTo support development of the Endocrine Society Clinical Practice Guideline for the treatment of hypercalcemia of malignancy in adults.MethodsWe searched multiple databases for studies that addressed 8 clinical questions prioritized by a guideline panel from the Endocrine Society. Quantitative and qualitative synthesis was performed. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess certainty of evidence.ResultsWe reviewed 1949 citations, from which we included 21 studies. The risk of bias for most of the included studies was moderate. A higher proportion of patients who received bisphosphonate achieved resolution of hypercalcemia when compared to placebo. The incidence rate of adverse events was significantly higher in the bisphosphonate group. Comparing denosumab to bisphosphonate, there was no significant difference in the rate of patients who achieved resolution of hypercalcemia. Two-thirds of patients with refractory/recurrent hypercalcemia of malignancy who received denosumab following bisphosphonate therapy achieved resolution of hypercalcemia. Addition of calcitonin to bisphosphonate therapy did not affect the resolution of hypercalcemia, time to normocalcemia, or hypocalcemia. Only indirect evidence was available to address questions on the management of hypercalcemia in tumors associated with high calcitriol levels, refractory/recurrent hypercalcemia of malignancy following the use of bisphosphonates, and the use of calcimimetics in the treatment of hypercalcemia associated with parathyroid carcinoma. The certainty of the evidence to address all 8 clinical questions was low to very low.ConclusionThe evidence summarized in this systematic review addresses the benefits and harms of treatments of hypercalcemia of malignancy. Additional information about patients’ values and preferences, and other important decisional and contextual factors is needed to facilitate the development of clinical recommendations.

AbstractBackgroundHistory and physical examination 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 examination findings.MethodsThis study involved a patient–intervention–control–outcome (PICO) question: (P) adult ED patients with vertigo/dizziness; (I) presence/absence of specific physical examination findings; and (O) central (ischemic stroke, hemorrhage, others) versus peripheral etiology. Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) was assessed.ResultsFrom 6309 titles, 460 articles were retrieved, and 43 met the inclusion criteria: general neurologic examination—five studies, 869 patients, pooled sensitivity 46.8% (95% confidence interval [CI] 32.3%–61.9%, moderate certainty) and specificity 92.8% (95% CI 75.7%–98.1%, low certainty); limb weakness/hemiparesis—four studies, 893 patients, sensitivity 11.4% (95% CI 5.1%–23.6%, high) and specificity 98.5% (95% CI 97.1%–99.2%, high); truncal/gait ataxia—10 studies, 1810 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% [95% CI 52.1%–96.0%, low]); dysmetria signs—four studies, 1135 patients, sensitivity 24.6% (95% CI 15.6%–36.5%, high) and specificity 97.8% (94.4%–99.2%, high); head impulse test (HIT)—17 studies, 1366 patients, sensitivity 76.8% (64.4%–85.8%, low) and specificity 89.1% (95% CI 75.8%–95.6%, moderate); spontaneous nystagmus—six studies, 621 patients, sensitivity 52.3% (29.8%–74.0%, moderate) and specificity 42.0% (95% CI 15.5%–74.1%, moderate); nystagmus type—16 studies, 1366 patients (bidirectional, vertical, direction changing, or pure torsional nystagmus are consistent with a central cause of vertigo, sensitivity 50.7% [95% CI 41.1%–60.2%, moderate] and specificity 98.5% [95% CI 91.7%–99.7%, moderate]); test of skew—15 studies, 1150 patients (skew deviation is abnormal and consistent with central etiology, sensitivity was 23.7% [95% CI 15%–35.4%, moderate] and specificity 97.6% [95% CI 96%–98.6%, moderate]); HINTS (head impulse, nystagmus, test of skew)—14 studies, 1781 patients, sensitivity 92.9% (95% CI 79.1%–97.9%, high) and specificity 83.4% (95% CI 69.6%–91.7%, moderate); and HINTS+ (HINTS with hearing component)—five studies, 342 patients, sensitivity 99.0% (95% CI 73.6%–100%, high) and specificity 84.8% (95% CI 70.1%–93.0%, high).ConclusionsMost neurologic examination 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.

AbstractBackgroundPatients 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.MethodsAn 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.ResultsWe 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%.ConclusionsNoncontrast 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.