Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Lymphangioleiomyomatosis in lymph node cytology: Another "Floating Island" to visit.

Lymphangioleiomyomatosis (LAM) is a rare disease with variable presentations. The neoplastic cells in LAM demonstrate a unique and diagnostically important "myomelanocytic" phenotype. Cytologic reports of LAM are infrequent and have not in the past emphasized the floating island pattern in which circumscribed aggregates of lesional cells are rimmed by appliques of flattened endothelium. This case illustrates the cytology of LAM and emphasizes that the floating island cytoarchitectural pattern more classically associated with entities such as hepatocellular carcinomas may be seen in cytological preparations of LAM at unanticipated body sites.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guideline for the Management of Hyperglycemia in Adults Hospitalized for Noncritical Illness or Undergoing Elective Surgical Procedures.

CONTEXT: Individuals with diabetes or newly recognized hyperglycemia account for over 30% of noncritically ill hospitalized patients. Management of hyperglycemia in these patients is challenging. OBJECTIVE: To support development of the Endocrine Society Clinical Practice Guideline for management of hyperglycemia in adults hospitalized for noncritical illness or undergoing elective surgical procedures. METHODS: We searched several databases for studies addressing 10 questions provided by a guideline panel from the Endocrine Society. Meta-analysis was conducted when feasible. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess certainty of evidence. RESULTS: We included 94 studies reporting on 135 553 patients. Compared with capillary blood glucose, continuous glucose monitoring increased the number of patients identified with hypoglycemia and decreased mean daily blood glucose (BG) (very low certainty). Data on continuation of insulin pump therapy in hospitalized adults were sparse. In hospitalized patients receiving glucocorticoids, combination neutral protamine hagedorn (NPH) and basal-bolus insulin was associated with lower mean BG compared to basal-bolus insulin alone (very low certainty). Data on NPH insulin vs basal-bolus insulin in hospitalized adults receiving enteral nutrition were inconclusive. Inpatient diabetes education was associated with lower HbA1c at 3 and 6 months after discharge (moderate certainty) and reduced hospital readmissions (very low certainty). Preoperative HbA1c level < 7% was associated with shorter length of stay, lower postoperative BG and a lower number of neurological complications and infections, but a higher number of reoperations (very low certainty). Treatment with glucagon-like peptide-1 agonists or dipeptidyl peptidase-4 inhibitors in hospitalized patients with type 2 diabetes and mild hyperglycemia was associated with lower frequency of hypoglycemic events than insulin therapy (low certainty). Caloric oral fluids before surgery in adults with diabetes undergoing surgical procedures did not affect outcomes (very low certainty). Counting carbohydrates for prandial insulin dosing did not affect outcomes (very low certainty). Compared with scheduled insulin (basal-bolus or basal insulin + correctional insulin), correctional insulin was associated with higher mean daily BG and fewer hypoglycemic events (low certainty). CONCLUSION: The certainty of evidence supporting many hyperglycemia management decisions is low, emphasizing importance of shared decision-making and consideration of other decisional factors.

Association of study design features and treatment effects in trials of chronic medical conditions: a meta-epidemiological study.

OBJECTIVES: To evaluate the association of study design features and treatment effects in randomised controlled trials (RCTs) evaluating therapies for individuals with chronic medical conditions. DESIGN: Meta-epidemiological study. SETTING: RCTs from meta-analyses published in the 10 general medical journals with the highest impact factor published between 1 January 2007 and 10 June 2019 and evaluated a drug, procedure or device treatment of chronic medical conditions. MAIN OUTCOME MEASURES: The association between trial design features and the effect size, reporting a ratio of ORs (ROR) and 95% confidence interval (CI). RESULTS: We included 1098 trials from 86 meta-analyses. The most common outcome in the trials was mortality (52%), followed by disease progression (16%) and adverse events (12%). Lack of blinding of patients and study personnel was associated with a larger treatment effect (ROR 1.12; 95% CI 1.00 to 1.25). There was no statistically significant association with random sequence generation, allocation concealment, blinding of outcome assessors, incomplete outcome data, whether trials were stopped early, study funding, type of interventions or with type of outcomes (objective vs subjective). CONCLUSION: The meta-epidemiological study did not demonstrate a clear pattern of association between risk of bias indicators and treatment effects in RCTs in chronic medical conditions. The unpredictability of the direction of bias emphasises the need to make every attempt to adhere to blinding, allocation concealment and reduce attrition bias. TRIAL REGISTRATION NUMBER: Not applicable.

Induction and maintenance of remission with mycophenolate mofetil in ANCA-associated vasculitis: a systematic review and meta-analysis.

BACKGROUND: Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. METHODS: Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV, granulomatosis with polyangiitis and microscopic polyangiitis (MPA). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to 5 May 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. RESULTS: From 565 articles captured, 10 met the predefined criteria, 5 phase II and 5 III trials; 4 assessed remission-induction, 3 remission maintenance and 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% confidence interval 0.74, 1.52), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA positivity, newly diagnosed disease) (P > 0.05). The overall ES for remission maintenance at the end of follow-up ranged between 51% and 91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92%, 76-100%) versus those enrolling patients with and without kidney involvement (56%, 45-66%). Results were similar in multiple sensitivity analyses. During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. CONCLUSIONS: In AAV, MMF use was significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.

An Electronic Search Algorithm for Early Disseminated Intravascular Coagulopathy Diagnosis in the Intensive Care Unit: A Derivation and Validation Study.

AIM: We aim to create and validate an electronic search algorithm for accurate detection of disseminated intravascular coagulopathy (DIC) from medical records. METHODS: Patients with DIC in Mayo Clinic's intensive care units (ICUs) from Jan 1, 2007, to May 4, 2018, were included in the study. An algorithm was developed based on clinical notes and ICD diagnosis codes. A cohort of 50 patients was included with DIC diagnosis, its variations, and no diagnosis of DIC. Then, the next set of 50 patients was used to refine the algorithm. Results were compared with a manual reviewer and the disagreements were resolved by the third reviewer. The same process was repeated with 'revised clinical note search' for the first and second derivation cohort with additional exclusion terms. The obtained sensitivity and specificity were reported. The generated algorithm was applied to another set of 50 patients for validation. RESULTS: In the first derivation cohort- DIC search by clinical notes and diagnosis codes had 92% sensitivity and 100% specificity. Sensitivity dropped to 71% in the second cohort although specificity remains the same. Therefore, the algorithm was refined to clinical notes search only. The revised search was reapplied to first and second derivation cohorts and results obtained for the first derivation were the same but 91.3% sensitive and 100% specific for the second derivation. The search was locked and applied in the validation cohort with 95.8% sensitivity and 100% specificity, respectively. CONCLUSION: The revised clinical note based electronic search algorithm was found to be highly sensitive and specific for DIC during the corresponding ICU duration.

Anticoagulation in COVID-19: A Systematic Review, Meta-analysis, and Rapid Guidance From Mayo Clinic.

A higher risk of thrombosis has been described as a prominent feature of coronavirus disease 2019 (COVID-19). This systematic review synthesizes current data on thrombosis risk, prognostic implications, and anticoagulation effects in COVID-19. We included 37 studies from 4070 unique citations. Meta-analysis was performed when feasible. Coagulopathy and thrombotic events were frequent among patients with COVID-19 and further increased in those with more severe forms of the disease. We also present guidance on the prevention and management of thrombosis from a multidisciplinary panel of specialists from Mayo Clinic. The current certainty of evidence is generally very low and continues to evolve.

A Framework for Evidence Synthesis Programs to Respond to a Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic requires making rapid decisions based on sparse and rapidly changing evidence. Evidence synthesis programs conduct systematic reviews for guideline developers, health systems clinicians, and decision-makers that usually take an average 6 to 8 months to complete. We present a framework for evidence synthesis programs to respond to pandemics that has proven feasible and practical during the COVID-19 response in a large multistate health system employing more than 78,000 people. The framework includes four components: an approach for conducting rapid reviews, a repository of rapid reviews, a registry for all original studies about COVID-19, and twice-weekly prioritized update of new evidence sent to key stakeholders. As COVID-19 will not be our last pandemic, we share the details of this framework to allow replication in other institutions and re-implementation in future pandemics.

Frequency and Associated Factors of Parental Refusal to Perform Lumbar Puncture in Children with Suspected Central Nervous System Infection: A Cross-sectional Study.

Objective Lumbar puncture (LP) is a useful procedure which is performed for both diagnosis and treatment of numerous conditions affecting children and adults. The purpose of this study was to determine the frequency and cause of increased parental refusal to perform LP in the pediatric population. Method A cross-sectional study was conducted from January 2018 to June 2019 at the Civil Hospital, Dow University of Health Sciences, pediatric department, Civil Hospital, Karachi. Over the 18-month time period, a total of 215 patients who had indications of LP were selected from the in-patient pediatrics department; the age range was between newborn to 12 years of age. The mode of research was a questionnaire and interview-based method that was conducted with guardians of minor patients to understand the extent of their knowledge and awareness about the LP procedure as well as its complication and the role of culture, education background, and financial status of the families which may lead to an increased likelihood of refusal. Result The frequency of LP refusal amongst the 215 families of the patients that were interviewed was found to be 32.6%. Mean age of the respondents was 30.98 years. The decision for LP was not significantly affected by the subjects' gender (p=0.1), by the religious communities to which the families belonged (p=0.9), their ethnicities (0.52), or by the families' financial status (p=0.4). It was observed that when indications for performing LP were appropriately explained, there was a significantly greater number of consents given as compared to when they were not made clear (p=0.009). Explaining the complications of the procedure did not considerably impact the decision for refusal of the procedure (p=0.1). The multi-variable logistic regression analysis model was applied to determine the likelihood of variables affecting refusal of LP and the logistic regression model was found to be statistically significant, χ2 (8) = 38.2 p < 0. 001. Conclusion Lack of knowledge about the LP procedure and fear of ramification plays a conspicuous role in the denial of LP procedure by the guardians of minor patients. A better, simpler approach using standardized consent forms by the doctors may lead to the removal of the information gaps and can provide a better understanding about the concerned risks, the primary indications, and the benefits of this procedure to the guardians.