Aromatase Inhibitor Increases the Height of Patients with Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

Objective: Patients with 21-hydroxylase deficiency (21OHD) typically suffer from short stature due to early exposure to adrenal-derived androgen. The aim of this study was to investigate whether adding aromatase inhibitor (AI) to gonadotropin-releasing hormone (GnRH) analogue (GnRHa) and recombinant human growth hormone (rhGH) therapy would increase the height of patients with 21OHD.Methods: This retrospective study included 15 patients with 21OHD. The AI/GnRHa/rhGH group consisted of 9 patients, who were treated with AI for at least 12 months in addition to GnRHa/rhGH therapy. The other 6 patients, who received GnRHa/rhGH therapy only, were defined as the GnRHa/rhGH group.Results: Patients were 6.3 ± 1.7 years old, and 7/15 of patients were male. Among them, 12 patients exhibited simple virilization type, and 3 patients were salt-wasting type. In the AI/GnRHa/rhGH group, patients were 6.6 ± 2.0 years old when AI therapy was initiated. Their bone age was 5.9 ± 2.2 years ahead of their chronological age. They received the AI letrizole for an average of 25.1 months (range, 12 to 37 months). In the GnRHa/rhGH group, the patients were 5.9 ± 0.9 years old when they started GnRHa/rhGH therapy, and their bone age was 6.2 ± 1.7 years ahead of their chronological age. Patients received GnRHa/rhGH therapy for an average of 24.5 months (range, 12 to 41 months). The predicted final height increased from 145.9 ± 7.9 to 158.0 ± 8.4 cm in the AI/GnRHa/rhGH group (P = .001, compared with the baseline) and from 141.7 ± 2.7 to 150.7 ± 4.7 cm in the GnRHa/rhGH group (P = .001, compared with the baseline). Bone age progression was 0.15 ± 0.05 per year versus 0.44 ± 0.13 per year in the two groups, respectively (P = .032).Conclusion: Addition of letrizole to GnRHa/rhGH therapy significantly delays bone maturation and may increase the final height.     

The Clinical and Biochemical Spectrum of Congenital Adrenal Hyperplasia Secondary to 21-Hydroxylase Deficiency

21-Hydroxylase Deficiency (21-OH Deficiency) represents the most common form of Congenital Adrenal Hyperplasia (CAH), a complex and heterogenous group of conditions, characterised by defects in one of the five enzymes involved in adrenal steroidogenesis. Defects in this steroidogenic enzyme, the product of the CYP21A2 gene, cause disruption in the pathway involved in cortisol and aldosterone production and consequently, the accumulation of their steroid precursors as well as a resulting adrenocorticotrophic hormone (ACTH)-driven overproduction of adrenal androgens. Treatment with glucocorticoid, with or without mineralocorticoid and salt replacement, is directed at preventing adrenal crises and ensuring normal childhood growth by alleviating hyperandrogenism. Conventionally, two clinical forms of 21-OH Deficiency are described - the classical form, separated into salt-wasting and simple-virilising phenotypes, and the non-classical form. They are differentiated by their hormonal profile, predominant clinical features and age of presentation. A greater understanding of the genotype-phenotype correlation supports the view that 21-OH Deficiency is a continuum of phenotypes as opposed to a number of distinct phenotypical entities. Significant advancements in technologies such as Tandem Mass Spectrometry (TMS) and improvements in gene analysis, such as complete PCR-based sequencing of the involved gene, have resulted in remarkable developments in the areas of diagnosis, treatment and treatment monitoring, neonatal screening, prenatal diagnosis and prenatal therapy.     

Metformin-Responsive Classic Salt-Losing Congenita L Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency: a Case Report

ObjectiveTo study the effect of adding metformin to standard steroid replacement therapy in a patient with classic salt-losing congenital adrenal hyperplasia due to 21- hydroxylase deficiency with suboptimal biochemical and clinical control.MethodsWe present the clinical and laboratory findings before and after the addition of metformin to the therapeutic regimen of the study patient.ResultsA 17-year-old girl had been diagnosed as a neonate with classic salt-losing congenital adrenal hyperplasia caused by 21-hydroxylase deficiency (CYP21A2 deficiency). She was treated with hydrocortisone, 20 mg in the morning and 10 mg at bedtime, and fludrocortisone, 50 mcg daily. While on steroid replacement, she maintained normal serum electrolytes, glucose, blood pressure, and external genitalia, but she continued to express clinical features of obesity, hirsutism, amenorrhea, and acanthosis nigricans. Elevated laboratory measurements included the following: fasting 17-hydroxyprogesterone, 3410 ng/dL; total testosterone, 326 ng/dL; and androstenedione, 390 ng/dL. She was initiated on metformin, 500 mg twice daily after meals. After 3 months, the patient lost 2 kg, amenorrhea resolved, 17-hydroxyprogesterone decreased to 1539 ng/dL, total testosterone decreased to 163 ng/dL, and androstenedione levels remained unchanged.ConclusionsMetformin, an agent known to reduce insulin resistance, further suppressed the 17-hydroxyprogesterone concentration in a patient with classic congenital adrenal hyperplasia on steroid replacement therapy. Metformin may improve clinical and biochemical outcomes in classic congenital adrenal hyperplasia without the risk of iatrogenic Cushing syndrome. (Endocr Pract. 2008;14:889-891)     

Prevalence and Characteristics of Adrenal Tumors and Myelolipomas in Congenital Adrenal Hyperplasia: A Systematic Review and Meta-Analysis

Objective: The prevalence of adrenal tumors in congenital adrenal hyperplasia (CAH) is uncertain. Our objective was to estimate the prevalence and characteristics of adrenal tumors and myelolipoma in CAH, and investigate clinical features of this population.Methods: We carried out systematic searches in Medline Ovid and Embase for articles published until January, 2020. Studies with confirmed CAH, biochemically and/or genetically, were included. The two authors independently extracted data from each study.Results: Six cohort studies were included in the prevalence calculation. In addition, 32 case reports on adrenal myelolipomas and CAH were included. The prevalence of adrenal tumors in CAH was 29.3%. When only studies with genetically verified cytochrome P450, Family 21, subfamily A, polypeptide 2 gene (CYP21A2) mutations were included the prevalence was 23.6%. The prevalence of myelolipoma in CAH was 7.4% (verified CYP21A2 mutations 8.6%). The proportion of myelolipoma in the adrenal tumors was 25.4% (genetically verified 36.6%). The median (range) age at tumor diagnosis was 36.0 (12 to 60) years and there were more tumors in males than in females (37.9% versus 22.1%; P<.05). In patients with myelolipomas, 93.5% had an undiagnosed or poorly managed CAH.Conclusion: Patients with CAH had a high prevalence of adrenal tumors, particularly myelolipomas. Those with myelolipomas had a high frequency of late-diagnosed or poorly controlled CAH. Adrenal imaging may be considered in patients with CAH, especially if abdominal pain is present.     

HLA Typing of Patients with 21-Hydroxylase Deficiency in Iranian Children with Congenital Adrenal Hyperplasia

Congenital adrenal hyperplasia (CAH) is a group of potentially life-threatening disorders, most often caused by deficiency of steroid 21-hydroxylase. Children with ambiguous genitalia, hermaphroditism, or signs and symptoms of CAH admitted to Children's Medical Center were enrolled in the survey, and 101 patients were found. Karyotyping, clinical examination, and paraclinical tests were done. HLA typing was done in patients with proven classical CAH and their parents. HLA antigens were typed in children with CAH-type 21-hydroxylase deficiency. The antigen frequencies were compared with those of the control population. The studies revealed that two HLA antigens, HLA-B18 and HLA-B21, showed a significant increase in frequency. The calculated relative risk value was high, distinguishing the population of patients and their parents. The relative risk among patients was 11.82 for HLA-B18 and 1.75 for HLA-B21 antigens. There was no relationship between HLA-DR antigens and CAH. Studies on the correlation between HLA and CAH indicate an association with HLA-B18 and HLA-B21 antigens, and they can be used as genetic markers of the disorder in the Iranian population, if they are restricted to Iranian patients.     

Energy Expenditure in 21-Hydroxylase Congenital Adrenal Hyperplasia Patients and Comparison with Predictive Equations

Objective: To characterize resting energy expenditure (REE) in patients with classic 21-hydroxylase congenital adrenal hyperplasia (21-OH CAH) using indirect calorimetry and compare it to the most commonly used REE predictive equations.Methods: This case-control study comprised 29 post-pubertal 21-OH CAH patients regularly followed at the University of Campinas. Elevated serum 17-hydroxyprogesterone and CYP21 gene molecular analysis confirmed the diagnosis. A healthy control group paired by age, gender, and body mass index was examined. Dual-energy X-ray absorptiometry (DEXA) measured body compositions. A bioimpedance analyzer determined fat-free mass, and indirect calorimetry using a metabolic cart measured REE.Results: Unlike our initial hypothesis, REE was similar between the groups (18.7 ± 3.1 kcal/kg/day in CAH vs. 20.3 ± 3.5 kcal/kg/day in controls; P = .728). No predictive equations reached the stipulated accuracy criteria, thus lacking validity in REE assessment in adults with the characteristics of the group studied. DEXA analysis revealed higher body fat and diminished nonbone lean mass in 21-OH CAH. Anthropometric and bioelectrical impedance parameters were not significantly different.Conclusion: Classic 21-OH CAH is generally followed in reference centers, which may facilitate indirect calorimetry use for REE measurement. Alternatively, considering our REE findings in adult 21-OH CAH patients, nutrition management based on 25 kcal/body weight/day (measured REE × activity factor 1.2 to 1.3) may be reasonable for current body weight maintenance in these patients.Abbreviations: 17-OHP = 17-hydroxyprogesterone; 21-OH CAH = classic 21-hydroxylase deficiency congenital adrenal hyperplasia; BMI = body mass index; REE = resting energy expenditure; VO2 = volume of oxygen; VCO₂ = volume of carbon dioxide     

Adrenal Myelolipomas in Patients with Congenital Adrenal Hyperplasia: Review of the Literature and A Case Report

ObjectiveTo review the association between congenital adrenal hyperplasia (CAH) and adrenal myelolipomas and report a case of bilateral, giant adrenal myelolipomas in a patient with untreated CAH due to 21-hydroxylase deficiency.MethodsWe describe the patient’s clinical presentation, imaging findings, and laboratory test results and review the relevant English-language literature concerning patients with both CAH and myelolipomas.ResultsA 45-year-old man with untreated CAH due to 21-hydroxylase deficiency presented with increasing abdominal girth and abdominal pain. Computed tomography of the abdomen demonstrated very low-density adrenal masses (22 × 11 cm on the left side and 6 × 5.5-cm on the right side) consistent with adrenal myelolipomas. The left adrenal myelolipoma was resected (24.4 × 19.0 × 9.5 cm; 2557 g). The mass was composed of mature adipose tissue with areas of hematopoietic cells of myeloid, erythroid, and megakaryocytic cell lines. Islands of adrenal cortical cells were scattered between the adipose and hematopoietic tissue. Including the present case, we identified 31 patients with both CAH and myelolipomas who have been described in the English-language literature. The details of these cases were reviewed.ConclusionsPersons with CAH may be at increased risk of developing adrenal myelolipomas, particularly if their CAH is poorly controlled. How and whether chronic exposure of the adrenal glands to high corticotropin levels increases the risk of developing myelolipomas remains a matter of speculation. (Endocr Pract. 2011;17:441-447)     

Serum MicroRNA-21 as a Diagnostic Marker for Lung Carcinoma: A Systematic Review and Meta-Analysis

Objectives

MicroRNA-21 in serum is a promising marker for the diagnosis of lung carcinoma. A meta-analysis was performed to assess the diagnostic accuracy and clinical value of serum microRNA-21 in patients with lung carcinoma.

Methods

PubMed, EMBASE, Web of Knowledge (ISI), the Cochrane Library, Scopus, BioMed Central, Science Direct, China National Knowledge Infrastructure (CNKI), Wan Fang data and Technology of Chongqing (VIP) databases were searched to identify studies in English and Chinese that assessed the diagnostic value of serum miR-21 for lung carcinoma, from inception to 9 April 2014. Two independent investigators identified and extracted the study characteristics from all articles according to defined inclusion and exclusion criteria. Quality assessment of diagnostic accuracy studies (QUADAS) was used to score the quality of the eligible studies. Stata12 and Meta-DiSc software were used to test the heterogeneity and to perform the meta-analysis.

Results

Our search returned 1008 articles, of which seven fulfilled the inclusion criteria, accounting for 500 patients and 386 controls. Using random-effect model analysis, the summary assessments revealed that the mean sensitivity was 0.71% (95%CI: 57–82%) and specificity was 0.84% (95%CI: 76–89%). The area under the receiver operating characteristic curve was 0.86 (95%CI: 0.83–0.89). In addition, heterogeneity was clearly apparent but was not caused by the threshold effect, as shown by Meta-DiSc analysis.

Conclusion

The current evidence suggests that serum miR-21 can be rapidly measured in lung carcinoma patients and has potential diagnostic value with moderate sensitivity and specificity. Further prospective studies to assess the early stage diagnostic value are needed in the future.     

Analysis of the Association between the HLA-DQA1 Alleles and the Steroid 21-Hydroxylase Gene Mutations in the Patients with Congenital Adrenal Hyperplasia

In 96 patients with congenital adrenal hyperplasia (CAH) and 50 healthy donors from northwestern Russia the distribution of the HLA-DQA1 alleles and the mutation spectrum and frequency at the CYP21B gene were examined. In the patients with nonclassical (NC) CAH, the distribution of the HLA-DQA1 polymorphic alleles was similar to that in the population sample. In the patients with the salt-wasting form of the disease a statistically significant decrease of the *0401 or *0501major allele frequency was observed. The prevalence of certain HLA-DQA1 genotypes, namely, HLA5, HLA3, and HLA4, was observed in the patients with the NC, salt-wasting (SW), and simple virilizing CAH, respectively. Each clinical group was characterized by a specific spectrum of clinically valuable mutations. An association between theCYP21B mutations most frequently found in case of SW and SV CAH (delB, I2splice, and I172N) and certain HLA-DQA1alleles was demonstrated. The necessity of more precise clinical diagnostics of the NC CAH cases along with detailed examination of this group for determination of the major mutations typical of the NC CAH cases from northwestern Russia is discussed.     

C-peptide as a Therapy for Kidney Disease: A Systematic Review and Meta-Analysis

C-peptide has intrinsic biological activity and may be renoprotective. We conducted a systematic review to determine whether C-peptide had a beneficial effect on renal outcomes. MEDLINE, EMBASE, and the Cochrane Central Databases were searched for human and animal studies in which C-peptide was administered and renal endpoints were subsequently measured. We identified 4 human trials involving 74 patients as well as 18 animal studies involving 35 separate experiments with a total of 641 animals. In humans, the renal effects of exogenously delivered C-peptide were only studied in type 1 diabetics with either normal renal function or incipient nephropathy. Pooled analysis showed no difference in GFR (mean difference, -1.36 mL/min/1.73 m2, p = 0.72) in patients receiving C-peptide compared to a control group, but two studies reported a reduction in glomerular hyperfiltration (p<0.05). Reduction in albuminuria was also reported in the C-peptide group (p<0.05). In diabetic rodent models, C-peptide led to a reduction in GFR (mean difference, -0.62 mL/min, p<0.00001) reflecting a partial reduction in glomerular hyperfiltration. C-peptide also reduced proteinuria (mean difference, -186.25 mg/day, p = 0.05), glomerular volume (p<0.00001), and mesangial matrix area (p<0.00001) in diabetic animals without affecting blood pressure or plasma glucose. Most studies were relatively short-term in duration, ranging from 1 hour to 3 months. Human studies of sufficient sample size and duration are needed to determine if the beneficial effects of C-peptide seen in animal models translate into improved long-term clinical outcomes for patients with chronic kidney disease. (PROSPERO CRD42014007472)     

Parathyroid Cystic Adenoma: A Systematic Review and Meta-Analysis

ObjectiveTo review diagnostic imaging modalities for parathyroid cystic adenomas (PCA). Since PCAs are a rare (0.5%-1%) subclass of parathyroid adenomas, and due to their cystic component, imaging modalities known to be efficient for diagnosing solid adenomas might fail in localizing them.MethodsWe conducted a systematic review using the PubMed and Cochrane databases for English articles on PCAs published between 1995 and 2020. A meta-analysis of the retrieved data was performed.ResultsOverall, 39 studies, reporting on a total of 160 patients, were included in the analysis. Two thirds (68%) of the patients were female, with a mean age of 53.9 years. A single cystic adenoma was detected in 98.1% of cases. The mean blood calcium corrected for albumin level was 12.6 ± 2.7 mg/dL, and the mean parathyroid hormone level was 565.5 ± 523.8 pg/mL. The mean PCA sizes as measured by ultrasound (US), computed tomography (CT), and ex vivo measurement were 4.8 ± 3.6, 5.2 ± 3.2, and 3.5 cm, respectively. The median weight was 8.1 g. PCA was detected in 86% of US examinations; 100% of US-guided fine needle aspiration, 4-dimensional computed tomography (4D-CT), or magnetic resonance imaging examinations; and 61% of 99m-technetium sestamibi scan with single-photon emission computed tomography ((99m)Tc-SPECT). (99m)Tc-SPECT showed a significantly lower diagnostic rate than US (odds ratio, 3.589), US-guided fine needle aspiration, CT combined with 4D-CT, and the combination of US, CT, 4D-CT, and magnetic resonance imaging (P < .001).ConclusionAlthough US and 4D-CT showed a significantly high rate in diagnosing PCA, (99m)Tc-SPECT showed a lower PCA diagnostic rate. These findings suggest that larger cystic lesions suspected as PCAs should be further evaluated using 4D-CT rather than (99m)Tc-SPECT.     

Metamizole-Associated Adverse Events: A Systematic Review and Meta-Analysis

Background

Metamizole is used to treat pain in many parts of the world. Information on the safety profile of metamizole is scarce; no conclusive summary of the literature exists.

Objective

To determine whether metamizole is clinically safe compared to placebo and other analgesics.

Methods

We searched CENTRAL, MEDLINE, EMBASE, CINAHL, and several clinical trial registries. We screened the reference lists of included trials and previous systematic reviews. We included randomized controlled trials that compared the effects of metamizole, administered to adults in any form and for any indication, to other analgesics or to placebo. Two authors extracted data regarding trial design and size, indications for pain medication, patient characteristics, treatment regimens, and methodological characteristics. Adverse events (AEs), serious adverse events (SAEs), and dropouts were assessed. We conducted separate meta-analyses for each metamizole comparator, using standard inverse-variance random effects meta-analysis to pool the estimates across trials, reported as risk ratios (RRs). We calculated the DerSimonian and Laird variance estimate T² to measure heterogeneity between trials. The pre-specified primary end point was any AE during the trial period.

Results

Of the 696 potentially eligible trials, 79 trials including almost 4000 patients with short-term metamizole use of less than two weeks met our inclusion criteria. Fewer AEs were reported for metamizole compared to opioids, RR = 0.79 (confidence interval 0.79 to 0.96). We found no differences between metamizole and placebo, paracetamol and NSAIDs. Only a few SAEs were reported, with no difference between metamizole and other analgesics. No agranulocytosis or deaths were reported. Our results were limited by the mediocre overall quality of the reports.

Conclusion

For short-term use in the hospital setting, metamizole seems to be a safe choice when compared to other widely used analgesics. High-quality, adequately sized trials assessing the intermediate- and long-term safety of metamizole are needed.     

Physical Activity and Asthma: A Systematic Review and Meta-Analysis

Introduction

This review aims to give an overview of available published evidence concerning the association between physical activity and asthma in children, adolescents and adults.

Methods

We included all original articles in which both physical activity and asthma were assessed in case-control, cross-sectional or longitudinal (cohort) studies. Excluded were studies concerning physical fitness, studies in athletes, therapeutic or rehabilitation intervention studies such as physical training or exercise in asthma patients. Methodological quality of the included articles was assessed according to the Newcastle-Ottawa Scale (NOS).

Results

A literature search was performed until June 2011 and resulted in 6,951 publications derived from PubMed and 1,978 publications from EMBASE. In total, 39 studies met the inclusion criteria: 5 longitudinal studies (total number of subjects n = 85,117) with physical activity at baseline as exposure, and asthma incidence as outcome. Thirty-four cross-sectional studies (n = 661,222) were included. Pooling of the longitudinal studies showed that subjects with higher physical activity levels had lower incidence of asthma (odds ratio 0.88 (95% CI: 0.77–1.01)). When restricting pooling to the 4 prospective studies with moderate to good study quality (defined as NOS≥5) the pooled odds ratio only changed slightly (0.87 (95% CI: 0.77–0.99)). In the cross-sectional studies, due to large clinical variability and heterogeneity, further statistical analysis was not possible.

Conclusions

The available evidence indicates that physical activity is a possible protective factor against asthma development. The heterogeneity suggests that possible relevant effects remain hidden in critical age periods, sex differences, or extremes of levels of physical activity (e.g. sedentary). Future longitudinal studies should address these issues.     

c-Met as a Prognostic Marker in Gastric Cancer: A Systematic Review and Meta-Analysis

Background

c-Met has been recognized as an important therapeutic target in gastric cancer, but the prognostic property of the c-Met status is still unclear. We aimed to characterize the prognostic effect of c-Met by systematic review and meta-analysis.

Methods

We identified 15 studies assessing survival in gastric cancer by c-Met status. Effect measure of interest was hazard ratio (HR) for survival. Meta-regression was performed to estimate the relationship between HR and disease stage. Random-effects meta-analyses were used to account for heterogeneity.

Results

15 eligible studies provided outcome data stratified by c-Met status in 2210 patients. Meta-analysis of the HRs indicated a significantly poorer Os in patients with high c-Met expression (average HR=2.112, 95%CI: 1.622–2.748). Subgroup analysis showed the prognostic effect of c-Met was identical in protein-level and gene-level based methodology. The same effect was also seen in Asian and Western ethnicity subgroup analysis. Meta-regression showed HR was not associated with disease stage.

Conclusions

Patients with tumors that harbor high c-Met expression are more likely to have a worse Os, with this prognostic effect independent of disease stage. c-Met status should be evaluated in clinical prognosis.     

iStent as a Solo Procedure for Glaucoma Patients: A Systematic Review and Meta-Analysis

BackgroundGlaucoma is a leading cause of irreversible blindness. It is firmly entrenched in the traditional treatment paradigm to start with pharmacotherapy. However, pharmacotherapy is not benign and has been well documented to have a number of significant challenges. Minimally invasive glaucoma surgery (MIGS) that targets the outflow pathway with minimal to no scleral dissection has resulted in the need to reconsider the glaucoma treatment paradigm.PurposeTo perform a systematic review and meta-analysis to evaluate and quantify the effect on post-operative intraocular pressure (IOP) and number of topical glaucoma medications, in patients receiving the iStent MIGS device as the solo procedure without concurrent cataract surgery.MethodsA systematic review was conducted by searching various databases between January 1, 2000, and June 30, 2014. Studies reporting up to a maximum follow-up period of 24 months were retrieved and screened using the EPPI-Reviewer 4 gateway. Percentage reduction in IOP (IOPR%), and mean reduction in topical glaucoma medications after surgery were computed. Meta-analysis was performed using STATA v. 13.0. The standardized mean difference (SMD) was calculated as the effect size for continuous scale outcomes. Heterogeneity was determined using the I² statistics, Z-value, and χ² statistics. Fixed-effect and random-effect models were developed based on heterogeneity. Sub-group analysis was performed based on the number of iStents implanted and the follow-up period. The outcome measures were changes in the IOP and number of glaucoma medications.ResultsThe search strategy identified 105 records from published literature and 9 records from the grey literature. Five studies with 248 subjects were included for quantitative synthesis. A 22% IOP reduction (IOPR%) from baseline occurred at 18-months after one iStent implant, 30% at 6-months after two iStents implantations, and 40% at 6-months after implantation of three iStents. A mean reduction of 1.2 bottles per patient of topical glaucoma medications occurred at 18-months after one iStent implant, 1.45 bottles per patient at 6-months after two iStents, and one bottle of medication per patient was reduced at 6-months following placement of three iStents implants. Meta-analysis results showed a significant reduction in the IOP after one iStent (SMD = -1.68, 95% CI: [-2.7, -0.61]), two iStents (SMD = -1.88, 95% CI: [-2.2, -1.56]), and three iStents (SMD = -2, 95% CI: [-2.62, -1.38]) implantation. Results showed a significant drop in the topical glaucoma medications after one iStent (SMD = -2.11, CI: [-3.95, -0.27]), two iStent (SMD = -1.88, CI: [-2.20, -1.56]), and three iStents (SMD = -2.00, CI: [-2.62, -1.38]) implantation. The maximum reduction in IOP occurred at 12-months (SMD = -2.21, CI: [-2.53, -1.88]) and a significant reduction in post-operative topical glaucoma medications occurred even after 18-months of iStent implantation (SMD = -0.71, CI: [-1.15, -0.26]).ConclusioniStent implantation as a solo procedure without concurrent cataract extraction does lower IOP, and reduces the dependency on glaucoma medications. This effect seems to last at least 18 months.     

Organic Solvents as Risk Factor for Autoimmune Diseases: A Systematic Review and Meta-Analysis

Background

Genetic and epigenetic factors interacting with the environment over time are the main causes of complex diseases such as autoimmune diseases (ADs). Among the environmental factors are organic solvents (OSs), which are chemical compounds used routinely in commercial industries. Since controversy exists over whether ADs are caused by OSs, a systematic review and meta-analysis were performed to assess the association between OSs and ADs.

Methods and Findings

The systematic search was done in the PubMed, SCOPUS, SciELO and LILACS databases up to February 2012. Any type of study that used accepted classification criteria for ADs and had information about exposure to OSs was selected. Out of a total of 103 articles retrieved, 33 were finally included in the meta-analysis. The final odds ratios (ORs) and 95% confidence intervals (CIs) were obtained by the random effect model. A sensitivity analysis confirmed results were not sensitive to restrictions on the data included. Publication bias was trivial. Exposure to OSs was associated to systemic sclerosis, primary systemic vasculitis and multiple sclerosis individually and also to all the ADs evaluated and taken together as a single trait (OR: 1.54; 95% CI: 1.25–1.92; p-value<0.001).

Conclusion

Exposure to OSs is a risk factor for developing ADs. As a corollary, individuals with non-modifiable risk factors (i.e., familial autoimmunity or carrying genetic factors) should avoid any exposure to OSs in order to avoid increasing their risk of ADs.     

Yoga for Multiple Sclerosis: A Systematic Review and Meta-Analysis

While yoga seems to be effective in a number of neuropsychiatric disorders, the evidence of efficacy in multiple sclerosis remains unclear. The aim of this review was to systematically assess and meta-analyze the available data on efficacy and safety of yoga in patients with multiple sclerosis. Medline/PubMed, Scopus, the Cochrane Central Register of Controlled Trials, PsycINFO, CAM-Quest, CAMbase, and IndMED were searched through March 2014. Randomized controlled trials (RCTs) of yoga for patients with multiple sclerosis were included if they assessed health-related quality of life, fatigue, and/or mobility. Mood, cognitive function, and safety were defined as secondary outcome measures. Risk of bias was assessed using the Cochrane tool. Seven RCTs with a total of 670 patients were included. Evidence for short-term effects of yoga compared to usual care were found for fatigue (standardized mean difference [SMD] = −0.52; 95% confidence intervals (CI) = −1.02 to −0.02; p = 0.04; heterogeneity: I² = 60%; Chi² = 7.43; p = 0.06) and mood (SMD = −0.55; 95%CI = −0.96 to −0.13; p = 0.01; heterogeneity: I² = 0%; Chi² = 1.25; p = 0.53), but not for health-related quality of life, muscle function, or cognitive function. The effects on fatigue and mood were not robust against bias. No short-term or longer term effects of yoga compared to exercise were found. Yoga was not associated with serious adverse events. In conclusion, since no methodological sound evidence was found, no recommendation can be made regarding yoga as a routine intervention for patients with multiple sclerosis. Yoga might be considered a treatment option for patients who are not adherent to recommended exercise regimens.     

Perioperative Use of Clevidipine: A Systematic Review and Meta-Analysis

Background

Clevidipine is an ultrashort-acting drug for rapid reduction of blood pressure by selectively acting on the L-type Ca2+ channels on arteriolar smooth muscle. The drug’s ultrashort action in reducing the blood pressure is due to its rapid hydrolysis by blood and extravascular tissue esterases, which does not depend on hepato-renal metabolism and excretion. An analysis of the perioperative management of blood pressure should be considered to compare with other intravenous antihypertensive agents.

Methods

Analyses of the available evidence in randomized clinical trials following the PRISMA methodology as well as clinical significance according to the GRADE system were conducted. Placebo versus other antihypertensive drugs studies were included. Statistical assessments were done using the X2 and I2 tests.

Results

Clevidipine was more effective in maintaining the blood pressure within pre-specified ranges compared with other antihypertensive drugs (MD, -17.87 CI 95%: -29.02 to -6.72; p = 0.02). The use of Clevidipine versus placebo and rescue antihypertensive intravenous drug showed a clear reduction in rates of treatment failure (RR 0.10; IC 95%; 0.05–0.18; p <0.0001). There was no difference in the incidence of adverse events compared with placebo (RR 1.47; 95% CI 0.89 to 2.43, p = 0.14) and with other antihypertensive drugs (RR 0.78, 95% CI 0.45 to 1.35; p = 0.37). In addition, there was no difference in the incidence of atrial fibrillation (AF) between clevidipine and control groups (RR 1.09, IC del 95%: 0.65 a 1.83; p = 0.73).

Conclusions

Clevidipine is an ultrafast-acting drug that is highly effective for management of perioperative arterial hypertension. It is devoid of adverse effects associated with the use of other IV antihypertensives. Its favorable pharmacodynamic and pharmacokinetic properties make clevidipine the drug of choice for the management of acute perioperative hypertension. It is important to emphasize the need for further studies with a larger number of patients to confirm these findings and increase the degree of evidence.     

Internet-Delivered Cognitive Behavioral Therapy to Treat Insomnia: A Systematic Review and Meta-Analysis

Background

Insomnia is of major public health importance. While cognitive behavioral therapy is beneficial, in-person treatment is often unavailable. We assessed the effectiveness of internet-delivered cognitive behavioral therapy for insomnia.

Objectives

The primary objectives were to determine whether online cognitive behavioral therapy for insomnia could improve sleep efficiency and reduce the severity of insomnia in adults. Secondary outcomes included sleep quality, total sleep time, time in bed, sleep onset latency, wake time after sleep onset, and number of nocturnal awakenings.

Data Sources

We searched PubMed/MEDLINE, the Cumulative Index to Nursing and Allied Health Literature, PsycInfo, Cochrane Library, Embase, and the Web of Science for randomized trials.

Methods

Studies were eligible if they were randomized controlled trials in adults that reported application of cognitive behavioral therapy for insomnia via internet delivery. Mean differences in improvement in sleep measures were calculated using the Hartung-Knapp-Sidik-Jonkman method for random effects meta-analysis.

Results

We found 15 trials, all utilizing a pretest-posttest randomized control group design. Sleep efficiency was 72% at baseline and improved by 7.2% (95% CI: 5.1%, 9.3%; p<0.001) with internet-delivered cognitive behavioral therapy versus control. Internet-delivered cognitive behavioral therapy resulted in a decrease in the insomnia severity index by 4.3 points (95% CI: -7.1, -1.5; p = 0.017) compared to control. Total sleep time averaged 5.7 hours at baseline and increased by 20 minutes with internet-delivered therapy versus control (95% CI: 9, 31; p = 0.004). The severity of depression decreased by 2.3 points (95% CI: -2.9, -1.7; p = 0.013) in individuals who received internet-delivered cognitive behavioral therapy compared to control. Improvements in sleep efficiency, the insomnia severity index and depression scores with internet-delivered cognitive behavioral therapy were maintained from 4 to 48 weeks after post-treatment assessment. There were no statistically significant differences between sleep efficiency, total sleep time, and insomnia severity index for internet-delivered versus in-person therapy with a trained therapist.

Conclusion

In conclusion, internet-delivered cognitive behavioral therapy is effective in improving sleep in adults with insomnia. Efforts should be made to educate the public and expand access to this therapy. Registration Number, Prospero: CRD42015017622