Clinical presentation and outcomes in patients with antiphospholipid syndrome-associated adrenal hemorrhage. A multicenter cohort study and systematic literature review.

BACKGROUND: Adrenal hemorrhage (AH) can occur in patients with antiphospholipid Syndrome (APS). We aimed to characterize the clinical manifestations, treatments, and outcomes of patients presenting with APS-associated AH (APS-AH) through a retrospective cohort and a systematic literature review (SLR). METHODS: We performed a mixed-source approach combining a multicenter cohort with an SLR of patients with incident APS-AH. We included patients from Mayo Clinic and published cases with persistent positivity for antiphospholipid antibodies and presenting with AH, demonstrated by imaging or biopsy. We extracted demographics, clinical characteristics, laboratory findings, treatment strategies, and outcomes (primary adrenal insufficiency and mortality). We used Kaplan-Meier and Cox models for survival analysis. RESULTS: We included 256 patients in total, 61 (24%) from Mayo Clinic and 195 (76%) from the SLR. The mean age was 46.8 (SD 15.2) years, and 45% were female. 69% of patients had bilateral adrenal involvement and 64% presented adrenal insufficiency. The most common symptoms at presentation were abdominal pain in 79%, and nausea and vomiting 46%. Hyponatremia (77%) was the most common electrolyte abnormality. Factors associated with primary adrenal insufficiency were bilateral adrenal involvement at initial imaging (OR 3.73, CI; 95%, 1.47-9.46) and anticardiolipin IgG positivity (OR 3.80, CI; 95%, 1.30-11.09). The survival rate at five years was 82%. History of stroke was associated with 3.6-fold increase in mortality (HR 3.62, 95% CI; 1.33-9.85). CONCLUSION: AH is a severe manifestation of APS with increased mortality. Most patients developed permanent primary adrenal insufficiency, particularly those positive for anticardiolipin IgG and bilateral adrenal involvement.

Home and Community-Based Services: A Systematic Review and Evidence Map.

BACKGROUND: Many adults aged 60 years or older have functional limitations and require home and community-based services (HCBS) to support their independence and delay the transition to an institutionalized setting. This systematic review provides an evidence map of the existing literature on HCBS identifying evidence gaps for policy and research. METHODS: A comprehensive literature search of multiple databases including Medline, Embase, and Scopus was conducted through December 7, 2023. Interviews with various stakeholders were conducted to solicit additional perspectives. Narrative and thematic synthesis was conducted to evaluate HCBS in terms of populations, interventions, outcomes, person-centeredness, and relevant quality measures. RESULTS: We identified 27 primary studies and 29 quality measures. Populations of HCBS studies can be categorized as those with functional disability, cognitive impairment, high-risk/frail conditions, and disease-specific conditions (Parkinson's disease, Alzheimer's disease, and post-stroke). HCBS interventions targeted optimization of person-centered planning, nonpharmacological approaches for dementia care, physical rehabilitation, self-directed home care, geriatric resources for practical support at home, and interdisciplinary care coordination for high-risk conditions. Person-centered planning and self-direction of HCBS services were not explicitly described in many studies and very few studies focused on addressing health-related social needs, whereas the majority reported primary clinical outcomes. Numerous quality measures exist for HCBS, some of which were validated, addressed multiple person-centered domains, and may apply across various conditions and populations. Key challenges in the literature on HCBS include limited number of randomized trials, inadequate descriptions of interventions to determine person-centeredness, limited information on facilitators and barriers, and limited information on workforce challenges in recruiting, retaining, and training personnel delivering HCBS. DISCUSSION: This evidence map describes the current state of HCBS and identifies evidence gaps for future research and policy decisions.

Measuring Documentation Burden in Healthcare.

BACKGROUND: The enactment of the Health Information Technology for Economic and Clinical Health Act and the wide adoption of electronic health record (EHR) systems have ushered in increasing documentation burden, frequently cited as a key factor affecting the work experience of healthcare professionals and a contributor to burnout. This systematic review aims to identify and characterize measures of documentation burden. METHODS: We integrated discussions with Key Informants and a comprehensive search of the literature, including MEDLINE, Embase, Scopus, and gray literature published between 2010 and 2023. Data were narratively and thematically synthesized. RESULTS: We identified 135 articles about measuring documentation burden. We classified measures into 11 categories: overall time spent in EHR, activities related to clinical documentation, inbox management, time spent in clinical review, time spent in orders, work outside work/after hours, administrative tasks (billing and insurance related), fragmentation of workflow, measures of efficiency, EHR activity rate, and usability. The most common source of data for most measures was EHR usage logs. Direct tracking such as through time-motion analysis was fairly uncommon. Measures were developed and applied across various settings and populations, with physicians and nurses in the USA being the most frequently represented healthcare professionals. Evidence of validity of these measures was limited and incomplete. Data on the appropriateness of measures in terms of scalability, feasibility, or equity across various contexts were limited. The physician perspective was the most robustly captured and prominently focused on increased stress and burnout. DISCUSSION: Numerous measures for documentation burden are available and have been tested in a variety of settings and contexts. However, most are one-dimensional, do not capture various domains of this construct, and lack robust validity evidence. This report serves as a call to action highlighting an urgent need for measure development that represents diverse clinical contexts and support future interventions.

Metabolomic biomarkers for (R, S)-ketamine and (S)-ketamine in treatment-resistant depression and healthy controls: A systematic review.

BACKGROUND: Ketamine is increasingly used for treatment-resistant depression (TRD) while its mechanism of action is still being investigated. In this systematic review, we appraise the current evidence of metabolomic biomarkers for racemic ketamine and esketamine in patients with TRD and healthy controls (HCs). METHODS: A comprehensive search of several databases (Ovid MEDLINE®, Embase, and Epub Ahead of Print) was performed from each database's inception to June 29, 2022, in any language, was conducted. We included studies wherein the metabolomic biomarkers for racemic ketamine or esketamine were investigated in TRD or HCs. Our main outcomes were to examine changes in metabolites among patients treated with ketamine/esketamine and explore the association with response to ketamine/esketamine. RESULTS: A total of 1859 abstracts were screened of which 11 were included for full-text review. Of these, a total of five articles were included (N = 147), including three RCTs (n = 129) and two open-label trials (n = 18). All studies used racemic ketamine; one study additionally used esketamine. The included studies evaluated patients with treatment-resistant bipolar depression (n = 22), unipolar depression (n = 91), and HCs (n = 34). The included studies reported alteration in several metabolites including acylcarnitines, lipids, kynurenine (KYN), and arginine with ketamine in TRD. Studies suggest the involvement of energy metabolism, KYN, and arginine pathways. In HCs, acetylcarnitine decreased post-infusion, whereas inconsistent findings were observed after the ketamine infusion in TRD patients. CONCLUSIONS: This systematic review provides preliminary evidence that ketamine may cause changes in several important pathways involved in energy metabolism and inflammation. Larger and more rigorous studies are needed.

Association Between Tranexamic Acid and Decreased Periprosthetic Joint Infection Risk in Patients Undergoing Total Hip and Knee Arthroplasty: A Systematic Review and Meta-Analysis of Over 2 Million Patients.

BACKGROUND: The purpose of this study was to perform a systematic review and meta-analysis to evaluate the association between tranexamic acid (TXA) use during primary total hip arthroplasty (THA) and primary total knee arthroplasty (TKA), and the risk of developing periprosthetic joint infection (PJI) after these procedures. METHODS: A systematic review was carried out from inception to October 17, 2022. There were 6 studies that were ultimately included in the meta-analysis. The association between the development of PJI and TXA was analyzed using odds ratios (ORs) with 95% confidence intervals (CIs) and estimates of risk difference (RD). Subgroup analysis was performed to evaluate only studies reporting out to 90 days of follow-up versus more than 90 days of follow-up. RESULTS: Among 2,098,469 arthroplasties, TXA utilization was associated with an overall lower risk of PJI (OR = 0.63 [95% CI 0.42 to 0.96], P < .001) and a 0.4% lower incidence of PJI (RD = -0.0038, 95% CI [-0.005 to -0.002], P < .001). When subgrouping the studies according to length of follow-up, TXA was associated with a lower risk of PJI (OR = 0.43 [95% CI 0.35 to 0.53], P < .001) and a 1% lower incidence of PJI (RD = -0.0095 [95% CI -0.013 to -0.005], P < .001) in patients followed for more than 90 days. CONCLUSIONS: This meta-analysis demonstrates that TXA use is associated with a reduced risk of PJI, with our RD analysis identifying an approximately 0.4% reduction in PJI rates with TXA use. These findings provide even more data to support the routine use of TXA during primary THA and primary TKA.

Efficacy of intravenous ketamine and intranasal esketamine with dose escalation for Major depression: A systematic review and meta-analysis.

OBJECTIVE: Intravenous (IV) racemic ketamine and intranasal (IN) esketamine have demonstrated rapid antidepressant effects in treatment-resistant depression (TRD). This systematic review aims to evaluate the efficacy and safety of ketamine and esketamine at various dosages for depression. METHODS: We included randomized controlled trials (RCTs) with parallel group dose comparison of ketamine and esketamine for depression/TRD. Ovid Medline, Embase, PsycINFO, Scopus and Cochrane databases were searched. Standardized mean differences were calculated using Hedges'-g to complete random effects meta-analysis. The efficacy outcomes were changes in depression outcomes for IV ketamine and IN esketamine respectively. Safety was assessed by reported adverse effects. RESULTS: A random effects meta-analysis of studies (n = 12) showed efficacy in reducing depression symptoms with IV ketamine (Hedges'g = 1.52 [0.98-2.22], Z = 4.23, p < 0.001) and IN esketamine (Hedges' g = 0.31 [0.18-0.44], Z = 4.53, P < 0.001) compared to control/placebo. Treatment response was observed at IV ketamine doses ≤0.2 mg/kg, >0.2-0.5 mg/kg and > 0.5 mg/kg. Higher IV ketamine doses (>0.5 mg/kg) did not lead to greater treatment response. Esketamine doses of 56-84 mg were superior to 28 mg dose. LIMITATIONS: Overall quality of evidence was low and limited by small number of studies. Publication bias was high. CONCLUSIONS: This meta-analysis suggests that IV ketamine may be efficacious at doses as low as 0.2 mg/kg, with increasing dose response at 0.5 mg/kg, without demonstrable increased benefit at 1 mg/kg, based on a small number of studies. Efficacy for IN esketamine increases with doses above 28 mg with best response being found between 56 and 84 mg for reducing depressive symptoms.

Outcome-based Risk Assessment of Non-HLA Antibodies in Heart Transplantation: A Systematic Review.

BACKGROUND: Current monitoring after heart transplantation (HT) employs repeated invasive endomyocardial biopsies (EMB). Although positive EMB confirms rejection, EMB fails to predict impending, subclinical, or EMB-negative rejection events. While non-human leukocyte antigen (non-HLA) antibodies have emerged as important risk factors for antibody-mediated rejection after HT, their use in clinical risk stratification has been limited. A systematic review of the role of non-HLA antibodies in rejection pathologies has the potential to guide efforts to overcome deficiencies of EMB in rejection monitoring. METHODS: Databases were searched to include studies on non-HLA antibodies in HT recipients. Data collected included the number of patients, type of rejection, non-HLA antigen studied, association of non-HLA antibodies with rejection, and evidence for synergistic interaction between non-HLA antibodies and donor-specific anti-human leukocyte antigen antibody (HLA-DSA) responses. RESULTS: A total of 56 studies met the inclusion criteria. Strength of evidence for each non-HLA antibody was evaluated based on the number of articles and patients in support versus against their role in mediating rejection. Importantly, despite previous intense focus on the role of anti-major histocompatibility complex class I chain-related gene A (MICA) and anti-angiotensin II type I receptor antibodies (AT1R) in HT rejection, evidence for their involvement was equivocal. Conversely, the strength of evidence for other non-HLA antibodies supports that differing rejection pathologies are driven by differing non-HLA antibodies. CONCLUSIONS: This systematic review underscores the importance of identifying peri-HT non-HLA antibodies. Current evidence supports the role of non-HLA antibodies in all forms of HT rejection. Further investigations are required to define the mechanisms of action of non-HLA antibodies in HT rejection.

Temporal Relationship and Clinical Outcomes of Acute Kidney Injury Following Acute Respiratory Distress Syndrome: A Systematic Review and Meta-Analysis.

OBJECTIVES: Conduct a systematic review and meta-analysis to assess prevalence and timing of acute kidney injury (AKI) development after acute respiratory distress syndrome (ARDS) and its association with mortality. DATA SOURCES: Ovid MEDLINE(R), Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Ovid PsycINFO database, Scopus, and Web of Science thought April 2023. STUDY SELECTION: Titles and abstracts were screened independently and in duplicate to identify eligible studies. Randomized controlled trials and prospective or retrospective cohort studies reporting the development of AKI following ARDS were included. DATA EXTRACTION: Two reviewers independently extracted data using a pre piloted abstraction form. We used Review Manager 5.4 software (Cochrane Library, Oxford, United Kingdom) and Open Meta software (Brown University, Providence, RI) for statistical analyses. DATA SYNTHESIS: Among the 3646 studies identified and screened, 17 studies comprising 9359 ARDS patients met the eligibility criteria and were included in the meta-analysis. AKI developed in 3287 patients (40%) after the diagnosis of ARDS. The incidence of AKI at least 48 hours after ARDS diagnosis was 20% (95% CI, 0.18-0.21%). The pooled risk ratio (RR) for the hospital (or 30-d) mortality among ARDS patients who developed AKI was 1.93 (95% CI, 1.71-2.18). AKI development after ARDS was identified as an independent risk factor for mortality in ARDS patients, with a pooled odds ratio from multivariable analysis of 3.69 (95% CI, 2.24-6.09). Furthermore, two studies comparing mortality between patients with late vs. early AKI initiation after ARDS revealed higher mortality in late AKI patients with RR of 1.46 (95% CI, 1.19-1.8). However, the certainty of evidence for most outcomes was low to very low. CONCLUSIONS: While our findings highlight a significant association between ARDS and subsequent development of AKI, the low to very low certainty of evidence underscores the need for cautious interpretation. This systematic review identified a significant knowledge gap, necessitating further research to establish a more definitive understanding of this relationship and its clinical implications.

Machine learning for predicting mortality in adult critically ill patients with Sepsis: A systematic review.

INTRODUCTION: Various Machine Learning (ML) models have been used to predict sepsis-associated mortality. We conducted a systematic review to evaluate the methodologies employed in studies to predict mortality among patients with sepsis. METHODS: Following a pre-established protocol registered at the International Prospective Register of Systematic Reviews, we performed a comprehensive search of databases from inception to February 2024. We included peer-reviewed articles reporting predicting mortality in critically ill adult patients with sepsis. RESULTS: Among the 1822 articles, 31 were included, involving 1,477,200 adult patients with sepsis. Nineteen studies had a high risk of bias. Among the diverse ML models, Logistic regression and eXtreme Gradient Boosting were the most frequently used, in 22 and 16 studies, respectively. Nine studies performed internal and external validation. Compared with conventional scoring systems such as SOFA, the ML models showed slightly higher performance in predicting mortality (AUROC ranges: 0.62-0.90 vs. 0.47-0.86). CONCLUSIONS: ML models demonstrate a modest improvement in predicting sepsis-associated mortality. The certainty of these findings remains low due to the high risk of bias and significant heterogeneity. Studies should include comprehensive methodological details on calibration and hyperparameter selection, adopt a standardized definition of sepsis, and conduct multicenter prospective designs along with external validations.

Inclusion of Rurality and Social Determinants of Health in Documents for the Primary Prevention of Type 2 Diabetes: A Systematic Review.

Purpose: The type 2 diabetes (T2D) burden is disproportionately concentrated in low- and middle-income economies, particularly among rural populations. The purpose of the systematic review was to evaluate the inclusion of rurality and social determinants of health (SDOH) in documents for T2D primary prevention. Methods: This systematic review is reported following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. We searched 19 databases, from 2017-2023, for documents on rurality and T2D primary prevention. Furthermore, we searched online for documents from the 216 World Bank economies, categorized by high, upper-middle, lower-middle, and low income status. We extracted data on rurality and the ten World Health Organization SDOH. Two authors independently screened documents and extracted data. Findings: Based on 3318 documents (19 databases and online search), we selected 15 documents for data extraction. The 15 documents applied to 32 economies; 12 of 15 documents were from nongovernment sources, none was from low-income economies, and 10 of 15 documents did not define or describe rurality. Among the SDOH, income and social protection (SDOH 1) and social inclusion and nondiscrimination (SDOH 8) were mentioned in documents for 25 of 29 high-income economies, while food insecurity (SDOH 5) and housing, basic amenities, and the environment (SDOH 6) were mentioned in documents for 1 of 2 lower-middle-income economies. For U.S. documents, none of the authors was from institutions in noncore (most rural) counties. Conclusions: Overall, documents on T2D primary prevention had sparse inclusion of rurality and SDOH, with additional disparity based on economic status. Inclusion of rurality and/or SDOH may improve T2D primary prevention in rural populations.

Gender Differences in Autonomy Granted to Residents and Fellows During Procedural Training: A Systematic Review and Meta-Analysis.

PURPOSE: Supervisors may be prone to implicit (unintentional) bias when granting procedural autonomy to trainees due to the subjectivity of autonomy decisions. The authors aimed to conduct a systematic review and meta-analysis to assess the differences in perceptions of procedural autonomy granted to physician trainees based on gender and/or race. METHOD: MEDLINE, Embase, CENTRAL, Scopus, and Web of Science were searched (search date: January 5, 2022) for studies reporting quantitative gender- or race-based differences in perceptions of procedural autonomy of physician trainees. Reviewers worked in duplicate for article selection and data abstraction. Primary measures of interest were self-reported and observer-rated procedural autonomy. Meta-analysis pooled differences in perceptions of procedural autonomy based on trainee gender. RESULTS: The search returned 2,714 articles, of which 16 were eligible for inclusion. These reported data for 6,109 trainees (median, 90 per study) and 2,763 supervisors (median, 54 per study). No studies investigated differences in perceptions of autonomy based on race. In meta-analysis of disparities between genders in autonomy ratings (positive number favoring female trainees), pooled standardized mean differences were -0.12 (95% confidence interval [CI], -0.19 to -0.04; P = .003; n = 10 studies) for trainee self-rated autonomy and -0.05 (95% CI, -0.11 to 0.01; P = .07; n = 9 studies) for supervisor ratings of autonomy. CONCLUSIONS: Limited evidence suggests that female trainees perceived that they received less procedural autonomy than did males. Further research exploring the degree of gender- and race-based differences in procedural autonomy, and factors that influence these differences is warranted.

Functional neuroimaging in patients with catatonia: A systematic review.

BACKGROUND: Catatonia is a challenging and heterogeneous neuropsychiatric syndrome of motor, affective and behavioral dysregulation which has been associated with multiple disorders such as structural brain lesions, systemic diseases, and psychiatric disorders. This systematic review summarized and compared functional neuroimaging abnormalities in catatonia associated with psychiatric and medical conditions. METHODS: Using PRISMA methods, we completed a systematic review of 6 databases from inception to February 7th, 2024 of patients with catatonia that had functional neuroimaging performed. RESULTS: A total of 309 studies were identified through the systematic search and 62 met the criteria for full-text review. A total of 15 studies reported patients with catatonia associated with a psychiatric disorder (n = 241) and one study reported catatonia associated with another medical condition, involving patients with N-methyl-d-aspartate receptor antibody encephalitis (n = 23). Findings varied across disorders, with hyperactivity observed in areas like the prefrontal cortex (PFC), the supplementary motor area (SMA) and the ventral pre-motor cortex in acute catatonia associated to a psychiatric disorder, hypoactivity in PFC, the parietal cortex, and the SMA in catatonia associated to a medical condition, and mixed metabolic activity in the study on catatonia linked to a medical condition. CONCLUSION: Findings support the theory of dysfunction in cortico-striatal-thalamic, cortico-cerebellar, anterior cingulate-medial orbitofrontal, and lateral orbitofrontal networks in catatonia. However, the majority of the literature focuses on schizophrenia spectrum disorders, leaving the pathophysiologic characteristics of catatonia in other disorders less understood. This review highlights the need for further research to elucidate the pathophysiology of catatonia across various disorders.

Impact of Glucocorticoid Dose on Complete Response, Serious Infections, and Mortality During the Initial Therapy of Lupus Nephritis: A Systematic Review and Meta-Analysis of the Control Arms of Randomized Controlled Trials.

OBJECTIVE: Our objective was to evaluate the effect of glucocorticoid regimens on renal response, infections, and mortality among patients with lupus nephritis (LN). METHODS: We performed a systematic review and meta-analysis of the control arms of randomized clinical trials (RCTs). We included RCTs of biopsy-proven LN that used a protocolized regimen of glucocorticoids in combination with mycophenolic acid analogs or cyclophosphamide and reported the outcomes of complete response (CR), serious infections, and death. The starting dosage of glucocorticoids, tapering method, and administration of glucocorticoid pulses were abstracted. Meta-analysis of proportions, meta-regression, and subgroup meta-analysis were performed at 6 and 12 months for all outcomes. RESULTS: Fifty RCT arms (3,231 patients with LN) were included. The predicted rates of CR, serious infections, and death when starting on oral prednisone at 25 mg/day without pulses were 19.5% (95% confidence interval [CI] 7.3-31.5), 3.2% (95% CI 2.4-4.0), and 0.2% (95% CI 0.0-0.4), respectively. Starting on prednisone at 60 mg/day (without pulses) increased the rates to 34.6% (95% CI 16.9-52.3), 12.1% (95% CI 9.3-14.9), and 2.7% (95% CI 0.0-5.3), respectively. Adding glucocorticoid pulses increased the rates of CR and death but not serious infections. We observed a dose-response gradient between the initial glucocorticoid dosage and all the outcomes at six months after accounting for the administration of glucocorticoid pulses, underlying immunosuppressant, and baseline proteinuria. CONCLUSION: A higher exposure to glucocorticoids during the initial therapy of LN was associated with better renal outcomes at the cost of increased infections and death.

An Update on the Efficacy of Single and Serial Intravenous Ketamine Infusions and Esketamine for Bipolar Depression: A Systematic Review and Meta-Analysis.

Ketamine has shown rapid antidepressant and anti-suicidal effects in treatment-resistant depression (TRD) with single and serial intravenous (IV) infusions, but the effectiveness for depressive episodes of bipolar disorder is less clear. We conducted an updated systematic review and meta-analysis to appraise the current evidence on the efficacy and tolerability of ketamine/esketamine in bipolar depression. A search was conducted to identify randomized controlled trials (RCTs) and non-randomized studies examining single or multiple infusions of ketamine or esketamine treatments. A total of 2657 articles were screened; 11 studies were included in the systematic review of which 7 studies were included in the meta-analysis (five non-randomized, N = 159; two RCTs, N = 33) with a mean age of 42.58 ± 13.1 years and 54.5% females. Pooled analysis from two RCTs showed a significant improvement in depression symptoms measured with MADRS after receiving a single infusion of ketamine (1-day WMD = -11.07; and 2 days WMD = -12.03). Non-randomized studies showed significant response (53%, p < 0.001) and remission rates (38%, p < 0.001) at the study endpoint. The response (54% vs. 55%) and remission (30% vs. 40%) rates for single versus serial ketamine infusion studies were similar. The affective switch rate in the included studies approximated 2.4%. Esketamine data for bipolar depression are limited, based on non-randomized, small sample-sized studies. Further studies with larger sample sizes are required to strengthen the evidence.

Industry involvement in rheumatology consensus-based recommendations: a systematic review.

Consensus-based recommendations guide standards of care for clinical practice. Pharmaceutical industry involvement in producing such recommendations might undermine their objectivity. We did a systematic review of rheumatology consensus-based recommendations that were published in English from 2000 to 2020. We compared those that were endorsed by major professional societies to those that were sponsored by industry using the validated Appraisal of Guidelines for Research & Evaluation (AGREE) II instrument. Of 234 consensus-based recommendation projects, 51 (22%) were endorsed by major societies and 74 (32%) were sponsored by the pharmaceutical industry. Among industry-sponsored projects, the sponsor was involved in the consensus-based process in 21 (28%), provided a medical writer in 12 (16%), offered honoraria for participation in five (7%), and was allowed to approve the final draft of one project. When compared with projects endorsed by major societies, industry-sponsored projects were less likely to have a high quality assessment on the AGREE II instrument. These results suggest that industry sponsorship of consensus-based recommendations is common in projects that do not receive endorsement by major societies. Such projects are often of lower quality than guidelines endorsed by major professional societies. Medical journals should consider steps to encourage greater rigour of development and to limit undue influence by industry sponsors.