Multisystem Progeroid Syndrome With Lipodystrophy, Cardiomyopathy, and Nephropathy Due to an LMNA p.R349W Variant.

BACKGROUND: Pathogenic variants in lamin A/C (LMNA) cause a variety of progeroid disorders including Hutchinson-Gilford progeria syndrome, mandibuloacral dysplasia, and atypical progeroid syndrome. Six families with 11 patients harboring a pathogenic heterozygous LMNA c.1045C>T; p.R349W variant have been previously reported to have partial lipodystrophy, cardiomyopathy, and focal segmental glomerulosclerosis (FSGS), suggesting a distinct progeroid syndrome. METHODS: We report 6 new patients with a heterozygous LMNA p.R349W variant and review the phenotype of previously reported patients to define their unique characteristics. We also performed functional studies on the skin fibroblasts of a patient to seek the underlying mechanisms of various clinical manifestations. RESULTS: Of the total 17 patients, all 14 adults with the heterozygous LMNA p.R349W variant had peculiar lipodystrophy affecting the face, extremities, palms, and soles with variable gain of subcutaneous truncal fat. All of them had proteinuric nephropathy with FSGS documented in 7 of them. Ten developed cardiomyopathy, and 2 of them died early at ages 33 and 45 years. Other common features included premature graying, alopecia, high-pitched voice, micrognathia, hearing loss, and scoliosis. Metabolic complications, including diabetes mellitus, hypertriglyceridemia, and hepatomegaly, were highly prevalent. This variant did not show any abnormal splicing, and no abnormal nuclear morphology was noted in the affected fibroblasts. CONCLUSIONS: The heterozygous LMNA p.R349W variant in affected individuals has several distinct phenotypic features, and these patients should be classified as having multisystem progeroid syndrome (MSPS). MSPS patients should undergo careful assessment at symptom onset and yearly metabolic, renal, and cardiac evaluation because hyperglycemia, hypertriglyceridemia, FSGS, and cardiomyopathy cause major morbidity and mortality.

A Genetic Approach to the Association Between PCSK9 and Sepsis.

Importance: Whether the PCSK9 gene is associated with the progress from infection to sepsis is unknown to date. Objective: To test the associations between PCSK9 genetic variants, a PCSK9 genetic risk score (GRS), or genetically estimated PCSK9 expression levels and the risk of sepsis among patients admitted to a hospital with infection. Design, Setting, and Participants: This retrospective cohort study used deidentified electronic health records to identify patients admitted to Vanderbilt University Medical Center, Nashville, Tennessee, with infection. Patients were white adults, had a code indicating infection from the International Classification of Diseases, Ninth Revision, Clinical Modification, or the International Statistical Classification of Diseases, Tenth Revision, Clinical Modification, and received an antibiotic within 1 day of hospital admission (N = 61 502). Data were collected from January 1, 1993, through December 31, 2017, and analyzed from April 1, 2018, to March 16, 2019. Exposures: Four known PCSK9 functional variants, a GRS for PCSK9, and genetically estimated PCSK9 expression. Main Outcomes and Measures: The primary outcome was sepsis; secondary outcomes included cardiovascular failure and in-hospital death. Results: Of patients with infection, genotype information was available in 10 922 white patients for PCSK9 functional variants (5628 men [51.5%]; mean [SD] age, 60.1 [15.7] years), including 7624 patients with PCSK9 GRS and 6033 patients with estimated PCSK9 expression. Of these, 3391 developed sepsis, 835 developed cardiovascular failure, and 366 died during hospitalization. None of the 4 functional PCSK9 variants were significantly associated with sepsis, cardiovascular failure, or in-hospital death, with or without adjustment for (1) age and sex or (2) age, sex, and Charlson-Deyo comorbidities (in model adjusted for age, sex, and comorbidities, odds ratios for any loss-of function variant were 0.96 [95% CI, 0.88-1.04] for sepsis, 1.05 [95% CI, 0.90-1.22] for cardiovascular failure, and 0.89 [95% CI, 0.72-1.11] for death). Similarly, neither the PCSK9 GRS nor genetically estimated PCSK9 expression were significantly associated with sepsis, cardiovascular failure, or in-hospital death in any of the analysis models. For GRS, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.96-1.06; P = .70), 1.03 for cardiovascular failure (95% CI, 0.95-1.12; P = .48), and 1.05 for in-hospital death (95% CI, 0.92-1.19; P = .50). For genetically estimated PCSK9 expression, in the full model adjusted for age, sex, and comorbidities, the odds ratios were 1.01 for sepsis (95% CI, 0.95-1.06; P = .86), 0.96 for cardiovascular failure (95% CI, 0.88-1.05; P = .41), and 0.99 for in-hospital death (95% CI, 0.87-1.14; P = .94). Conclusions and Relevance: In this study, PCSK9 genetic variants were not significantly associated with risk of sepsis or the outcomes of sepsis in patients hospitalized with infection.

Self-Measured vs Professionally Measured Waist Circumference.

PURPOSE: Although waist circumference can provide important metabolic risk information, logistic issues inhibit its routine use in outpatient practice settings. We assessed whether self-measured waist circumference is sufficiently accurate to replace professionally measured waist circumference for identifying high-risk patients. METHODS: Medical outpatients and research participants self-measured their waist circumference at the same visit during which a professionally measured waist circumference was obtained. Participants were provided with standardized pictorial instructions on how to measure their waist circumference, and professionals underwent standard training. RESULTS: Self- and professionally measured waist circumference data were collected for 585 women (mean ± SD age = 40 ± 14 years, mean ± SD body mass index = 27.7 ± 6.0 kg/m(2)) and 165 men (mean ± SD age = 41 ± 14 years, mean ± SD body mass index = 29.3 ± 4.6 kg/m(2)). Although self- and professionally measured waist circumference did not differ significantly, we found a clinically important false-negative rate for the self-measurements. Eleven percent of normal-weight and 52% of overweight women had a professionally measured waist circumference putting them in a high-risk category for metabolic syndrome (ie, greater than 88 cm); however, 57% and 18% of these women, respectively, undermeasured their waist circumference as falling below that cutoff. Fifteen percent and 84% of overweight and class I obese men, respectively, had a professionally measured waist circumference putting them in the high-risk category (ie, greater than 102 cm); however, 23% and 16% of these men, respectively, undermeasured their waist circumference as falling below that cutoff. CONCLUSIONS: Despite standardized pictorial instructions for self-measured waist circumference, the false-negative rate of self-measurements approached or exceeded 20% for some groups at high risk for poor health outcomes.

LINGUAL THYROID: 35-YEAR EXPERIENCE AT A TERTIARY CARE REFERRAL CENTER.

OBJECTIVE: Lingual thyroid (LT) results from a developmental abnormality due to failure of the thyroid gland to descend to its pretracheal position. Given the low incidence of this disease, standardized management recommendations are lacking. We aimed to describe our institution's experience in LT management and to suggest a practice algorithm. METHODS: We conducted a retrospective review of LT diagnosed at Mayo Clinic, Rochester, Minnesota, between 1976 and 2010. Demographics, clinical presentation, laboratory data, treatment received, and outcomes were collected. RESULTS: We identified 29 patients with LT. Eighty-three percent were female; age at diagnosis ranged from 2 weeks to 68 years. Almost one-third of patients were symptomatic, with the most common symptoms being cough and hoarseness. The diagnosis of LT was incidental in 9 patients (31%). Seventy-two percent of patients developed hypothyroidism. Levothyroxine was the treatment of choice, followed by thyroidectomy. Two asymptomatic euthyroid patients were followed without any intervention. CONCLUSION: Management of patients with LT should be individualized and guided by the patient's symptoms and thyroid hormone status.

PREDICTORS OF BIOCHEMICAL REMISSION AND RECURRENCE AFTER SURGICAL AND RADIATION TREATMENTS OF CUSHING DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

OBJECTIVE: We conducted a systematic review and meta-analysis to synthesize the evidence about predictors that may affect biochemical remission and recurrence after transsphenoidal surgery (TSS), radiosurgery (RS), and radiotherapy (RT) in Cushing disease. METHODS: We searched multiple databases through December 2014 including original controlled and uncontrolled studies that enrolled patients with Cushing disease who received TSS (first-line), RS, or RT. We extracted data independently, in duplicates. Outcomes of interest were biochemical remission and recurrence. A meta-analysis was conducted using the random-effects model to estimate event rates with 95% confidence intervals (CIs). RESULTS: First-line TSS was associated with high remission (76% [95% CI, 72 to 79%]) and low recurrence rates (10% [95% CI, 6 to 16%]). Remission after TSS was higher in patients with microadenomas or positive-adrenocorticotropic hormone tumor histology. RT was associated with a high remission rate (RS, 68% [95% CI, 61 to 77%]; RT, 66% [95% CI, 58 to 75%]) but also with a high recurrence rate (RS, 32% [95% CI, 16 to 60%]; RT, 26% [95% CI, 14 to 48%]). Remission after RS was higher at short-term follow-up (≤2 years) and with high-dose radiation, while recurrence was higher in women and with lower-dose radiation. Remission was after RT in adults who received TSS prior to RT, and with lower radiation doses. There was heterogeneity (nonstandardization) in the criteria and cutoff points used to define biochemical remission and recurrence. CONCLUSION: First-line TSS is associated with high remission and low recurrence, while RS and RT are associated with reasonable remission rates but important recurrence rates. The current evidence warrants low confidence due to the noncomparative nature of the studies, high heterogeneity, and imprecision.

Oral vs Transdermal Estrogen Therapy and Vascular Events: A Systematic Review and Meta-Analysis.

BACKGROUND: Menopausal hormone therapy is widely used to alleviate climacteric symptoms but may increase the risk of venous and arterial vascular events. OBJECTIVE: The objective was to synthesize the evidence about the risk of vascular events in postmenopausal women who use oral estrogen therapy (ET) and transdermal ET. METHODS: We searched bibliographical databases through August 2013 for longitudinal comparative studies that enrolled postmenopausal women using either oral or transdermal ET and reported the outcomes of interest: venous thromboembolism (VTE), pulmonary embolism, deep venous thrombosis (DVT), myocardial infarction (MI), and stroke. Two reviewers independently selected and appraised studies. Outcomes were pooled using random effects meta-analysis and were reported as risk ratio (RR) and 95% confidence interval (CI). RESULTS: We included 15 observational studies at moderate risk of bias with follow-up of 3 to 20.25 years. When compared to transdermal ET, oral ET was associated with increased risk of a first episode of VTE (RR, 1.63; 95% CI, 1.40-1.90; I(2) = 53%), DVT (RR, 2.09; 95% CI, 1.35-3.23; I(2) = 0 %), and possibly stroke (RR, 1.24; 95% CI, 1.03-1.48; a single case-controlled study), but not MI (RR, 1.17; 95% CI, 0.80-1.71; I(2) = 74%). CONCLUSION: Observational evidence warranting low confidence suggests that compared to transdermal ET, oral ET may be associated with increased risk of VTE and DVT, but not MI.

Menopausal Hormone Therapy and Mortality: A Systematic Review and Meta-Analysis.

OBJECTIVES: The objective was to assess the effect of menopausal hormonal therapy (MHT) on all-cause and cause-specific mortality. METHODS: We conducted a comprehensive search of several databases (MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus) from inception until August 2013. We included randomized controlled trials (RCTs) of more than 6 months of duration comparing MHT with no treatment. Pairs of independent reviewers selected trials, assessed risk of bias and extracted data. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) using the random-effects model. RESULTS: We included 43 RCTs at moderate risk of bias. Meta-analysis showed no effect on mortality (RR 0.99 [95% CI, 0.94-1.05]), regardless of MHT type or history of preexisting heart disease. No association was found between MHT and cardiac death (RR 1.04 [95% CI 0.87-1.23]) or stroke (RR 1.49 [95% CI 0.95-2.31]). Estrogen plus progesterone use was associated with a likely increase in breast cancer mortality (RR 1.96 [95% CI 0.98-3.94]), whereas estrogen use was not. MHT use was not associated with mortality of other types of cancer. In 5 trials, MHT was likely started at a younger age: 2 RCTs with mean age less than 60 and 3 RCTs with MHT started less than 10 years after menopause. Meta-analysis of these 5 RCTs showed a reduction of mortality with MHT (RR 0.70 [95% CI 0.52-0.95]). CONCLUSION: The current evidence suggests that MHT does not affect the risk of death from all causes, cardiac death and death from stroke or cancer. These data may be used to support clinical and policy deliberations about the role of MHT in the care of symptomatic postmenopausal women.

Randomized controlled trial of rituximab in patients with Graves' orbitopathy.

CONTEXT: Graves' orbitopathy (GO) is a potentially sight-threatening disease for which available medical therapy is not uniformly successful. Multiple case series suggest that rituximab (RTX) may be effective therapy for GO patients. OBJECTIVE: To determine the efficacy of RTX in GO. DESIGN: It is a prospective, randomized, double-masked, placebo-controlled trial. SETTING: The study was conducted at a large academic private practice. PATIENTS: Twenty five patients with active moderate to severe GO were enrolled, and 21 completed the study to the primary endpoint. INTERVENTIONS: Two RTX infusions (1000 mg each) or two saline infusions were given 2 weeks apart. MAIN OUTCOME MEASURES: The primary endpoint was a reduction in clinical activity score (CAS) assessed as a continuum and separately as improvement by ≥ 2 points at 24 weeks. Secondary endpoints included success and failure rates, proportions showing clinically significant improvement in proptosis, lid fissure width, diplopia score, lagophthalmos and disease severity, and changes in those parameters, orbital fat/ muscle volume and quality-of-life. RESULTS: The treatment groups were similar in all parameters at baseline. The last observation was carried forward if the patient discontinued prematurely. No differences were found in the proportions of patients showing CAS improvement at 24 weeks (25% placebo; 31% RTX, P = .75) or in CAS decrease from baseline to 24 or 52 weeks [mean 1.5 points (1.8 SD) placebo; 1.2 (2 SD) RTX at 24 weeks, P = .73]. Similarly, there were no differences between groups in any of the secondary endpoints at either 24 or 52 weeks. There were four adverse events (AE) in 3/12 placebo patients and 11 AE in 8/13 RTX-treated patients; 5/6 moderate or severe AE occurred in the RTX group. CONCLUSION: RTX offered no additional benefit over placebo to our patients with active and moderate to severe GO and carried with it non-negligible adverse effects.

Pharmacologic interventions for painful diabetic neuropathy: An umbrella systematic review and comparative effectiveness network meta-analysis.

BACKGROUND: Multiple treatments for painful diabetic peripheral neuropathy are available. PURPOSE: To evaluate the comparative effectiveness of oral and topical analgesics for diabetic neuropathy. DATA SOURCES: Multiple electronic databases between January 2007 and April 2014, without language restriction. STUDY SELECTION: Parallel or crossover randomized, controlled trials that evaluated pharmacologic treatments for adults with painful diabetic peripheral neuropathy. DATA EXTRACTION: Duplicate extraction of study data and assessment of risk of bias. DATA SYNTHESIS: 65 randomized, controlled trials involving 12 632 patients evaluated 27 pharmacologic interventions. Approximately one half of these studies had high or unclear risk of bias. Nine head-to-head trials showed greater pain reduction associated with serotonin-norepinephrine reuptake inhibitors (SNRIs) than anticonvulsants (standardized mean difference [SMD], -0.34 [95% credible interval {CrI}, -0.63 to -0.05]) and with tricyclic antidepressants (TCAs) than topical capsaicin 0.075%. Network meta-analysis showed that SNRIs (SMD, -1.36 [CrI, -1.77 to -0.95]), topical capsaicin (SMD, -0.91 [CrI, -1.18 to -0.08]), TCAs (SMD, -0.78 [CrI, -1.24 to -0.33]), and anticonvulsants (SMD, -0.67 [CrI, -0.97 to -0.37]) were better than placebo for short-term pain control. Specifically, carbamazepine (SMD, -1.57 [CrI, -2.83 to -0.31]), venlafaxine (SMD, -1.53 [CrI, -2.41 to -0.65]), duloxetine (SMD, -1.33 [CrI, -1.82 to -0.86]), and amitriptyline (SMD, -0.72 [CrI, -1.35 to -0.08]) were more effective than placebo. Adverse effects included somnolence and dizziness with TCAs, SNRIs, and anticonvulsants; xerostomia with TCAs; and peripheral edema and burning sensation with pregabalin and capsaicin. LIMITATION: Confidence in findings was limited because most evidence came from indirect comparisons of trials with short (≤3 months) follow-up and unclear or high risk of bias. CONCLUSION: Several medications may be effective for short-term management of painful diabetic neuropathy, although their comparative effectiveness is unclear. PRIMARY FUNDING SOURCE: Mayo Foundation for Medical Education and Research.

Glucose targets in pregnant women with diabetes: a systematic review and meta-analysis.

BACKGROUND: Glucose-lowering treatments are used during pregnancy to reduce the risk for complications in the mother and offspring, yet treatment targets have not been established. OBJECTIVE: Our objective was to appraise and summarize the available evidence regarding the association between different blood glucose targets during pregnancy and fetal and maternal outcomes. METHODS: We searched Medline, EMBASE, Cochrane Library, Web of Science, Scopus, PsycInfo, and CINAHL through May 2011 for randomized trials and observational studies that enrolled women with diabetes during pregnancy and reported planned or achieved glucose targets. We used random-effects meta-regression models to estimate the odds ratio for the association of outcomes of interest and glucose targets. When possible, we adjusted for diabetes type, trimester, and diabetes treatment. RESULTS: We included 34 studies enrolling 9433 women. The studies had moderate to high risk of bias due to evidence of reporting bias and insufficient adjustment for important covariates, particularly maternal body mass index. A fasting glucose target of <90 mg/dL was the most commonly reported and the one most strongly associated with reduced risk of macrosomia (odds ratio = 0.53, 95% confidence interval = 0.31-0.90, P = .02) for women with gestational diabetes during the third trimester. For type 1 and type 2 diabetes, and for pre- and postprandial targets, data were sparse and inconclusive. CONCLUSIONS: Evidence warranting very low confidence in the estimates suggests that a fasting glucose target of <90 mg/dL is associated with a lower risk of macrosomia and other outcomes of different importance in women with gestational diabetes. Whether this target can be extrapolated to women with pregestational diabetes or whether targets above or below this threshold offer a better benefit/risk balance remains unclear.