Effect of Combination Therapy on Joint Destruction in Rheumatoid Arthritis: A Network Meta-Analysis of Randomized Controlled Trials

Background

Despite significant cost differences, the comparative effect of combination treatments of disease modifying anti-rheumatic drugs (DMARDs) with and without biologic agents has rarely been examined. Thus we performed a network meta-analysis on the effect of combination therapies on progression of radiographic joint erosions in patients with rheumatoid arthritis (RA).

Methods and Findings

The following combination drug therapies compared versus single DMARD were investigated: Double DMARD: 2 DMARDs (methotrexate, sulfasalazine, leflunomide, injectable gold, cyclosporine, chloroquine, azathioprin, penicillamin) or 1 DMARD plus low dose glucocorticoid (LDGC); triple DMARD: 3 DMARDs or 2 DMARDs plus LDGC; biologic combination: 1 DMARD plus biologic agent (tumor necrosis factor α inhibitor (TNFi) or abatacept or tocilizumab or CD20 inhibitor (CD20i)). Randomized controlled trials were identified in a search of electronic archives of biomedical literature and included in a star-shaped network meta-analysis and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement protocol. Effects are reported as standardized mean differences (SMD). The effects of data from 39 trials published in the period 1989–2012 were as follows: Double DMARD: −0.32 SMD (CI: −0.42, −0.22); triple DMARD: −0.46 SMD (CI: −0.60, −0.31); 1 DMARD plus TNFi: −0.30 SMD (CI: −0.36, −0.25); 1 DMARD plus abatacept: −0.20 SMD (CI: −0.33, −0.07); 1 DMARD plus tocilizumab: −0.34 SMD (CI: −0.48, −0.20); 1 DMARD plus CD20i: −0.32 SMD (CI: −0.40, −0.24). The indirect comparisons showed similar effects between combination treatments apart from triple DMARD being significantly better than abatacept plus methotrexate (−0.26 SMD (CI: −0.45, −0.07)) and TNFi plus methotrexate (−0.16 SMD (CI: −0.31, −0.01)).

Conclusion

Combination treatment of a biologic agent with 1 DMARD is not superior to 2–3 DMARDs including or excluding LDGC in preventing structural joint damage. Future randomized studies of biologic agents should be compared versus a combination of DMARDs.     

Advice to use topical or oral ibuprofen for chronic knee pain in older people: randomised controlled trial and patient preference study

Objective To determine whether older patients with chronic knee pain should be advised to use topical or oral non-steroidal anti-inflammatory drugs (NSAIDs).Design Randomised controlled trial and patient preference study.Setting 26 general practices.Participants People aged ≥50 with knee pain: 282 in randomised trial and 303 in preference study. Interventions Advice to use topical or oral ibuprofen.Primary outcome measures WOMAC (Western Ontario and McMaster Universities) osteoarthritis index, major and minor adverse effects.Results Changes in global WOMAC scores at 12 months were equivalent. In the randomised trial the difference (topical minus oral) was two points (95% confidence interval −2 to 6); in the preference study, it was one point (−4 to 6). There were no differences in major adverse effects in the trial or study. The only significant differences in secondary outcomes were in the randomised trial. The oral group had more respiratory adverse effects (17% v 7%,95% confidence interval for difference −17% to −2%), the change in serum creatinine was 3.7 mmol/l less favourable (0.9 µmol/l to 6.5 µmol/l); and more participants changed treatments because of adverse effects (16% v 1%, −16% to −5%). In the topical group more participants had chronic pain grade III or IV at three months, and more participants changed treatment because of ineffectiveness.Conclusions Advice to use oral or topical preparations has an equivalent effect on knee pain over one year, and there are more minor side effects with oral NSAIDs. Topical NSAIDs may be a useful alternative to oral NSAIDs.Trial registration ISRCTN 79353052.     

Simultaneous analysis of several non-steroidal anti-inflammatory drugs in human urine by high-performance liquid chromatography with normal solid-phase extraction

A practical and reproducible high-performance liquid chromatographic method using normal solid-phase extraction has been developed for the simultaneous analysis of twelve non-steroidal anti-inflammatory drugs (NSAIDs) in human urine. A urine specimen mixed with acetate buffer pH 5.0 was purified by solid-phase extraction on a Sep-Pak Silica cartridge. The analyte was chromatographed by a reversed-phase Inertsil ODS-2 column using a phosphate buffer-acetonitrile at pH 5.0 as the mobile phase, and the effluent from the column was monitored at 230 or 320 nm. Absolute recoveries were greater than 73% for all of the twelve NSAIDs. The present method enabled simple manipulation and isocratic HPLC with UV analysis as well as high sensivity of 0.005 μg/ml for naproxen, and 0.05 μg/ml for sulindac, piroxicam, loxoprofen, ketoprofen, felbinac, fenbufen, flurbiprofen, diclofenac, ibuprofen and mefanamic acid as the quantitation limit in human urine using indomethacin as an internal standard.     

Association of Individual Non-Steroidal Anti-Inflammatory Drugs and Chronic Kidney Disease: A Population-Based Case Control Study

Background

Non-steroidal anti-inflammatory agents (NSAIDs) are known to be associated with renal damage. No clear evidence exists regarding differential risk of chronic kidney disease (CKD), specifically, across various NSAIDs.

Aim

The aim of this population-based case-control study was to evaluate the association between use of individual NSAIDs and risk of CKD in a general population of Southern Italy.

Methods

A nested case-control study was carried out using the general practice Arianna database, identifying incident CKD patients as cases and matched controls from 2006 to 2011. The date of first CKD diagnosis was defined as the index date (ID). Conditional logistic regressions were performed to estimate the risk of CKD associated with NSAIDs by class and individual drugs as compared to non-use during different time windows (within one year, six or three months prior to ID), with the latter being defined as current users. Among current users, the effect of cumulative exposure to these drugs was evaluated.

Results

Overall, 1,989 CKD cases and 7,906 matched controls were identified. A statistically significant increase in the risk of CKD was found for current users of oxicams (adjusted OR: 1.68; 95% CI: 1.15-2.44) and concerning individual compounds, for ketorolac (adj. OR: 2.54; 95% CI: 1.45-4.44), meloxicam (adj. OR: 1.98; 95% CI: 1.01-3.87) and piroxicam (adj. OR: 1.95; 95% CI: 1.19-3.21).

Conclusions

The risk of CKD varies across individual NSAIDs. Increased risk has been found for ketorolac, which may precipitate subclinical CKD through acute renal damage, and long-term exposure to oxicams, especially meloxicam and piroxicam.     

Managing postoperative pain in adult outpatients: a systematic review and meta-analysis comparing codeine with NSAIDs

BACKGROUND:Analgesics that contain codeine are commonly prescribed for postoperative pain, but it is unclear how they compare with nonopioid alternatives. We sought to compare the effectiveness of codeine and nonsteroidal anti-inflammatory drugs (NSAIDs) for adults who underwent outpatient surgery.METHODS:We conducted a systematic review and meta-analysis of randomized controlled trials comparing codeine and NSAIDs for postoperative pain in outpatient surgery. We searched MEDLINE and Embase from inception to October 2019 for eligible studies. Our primary outcome was the patient pain score, converted to a standard 10-point intensity scale. Our secondary outcomes were patient-reported global assessments and adverse effects. We used random-effects models and grading of recommendations assessment, development and evaluation (GRADE) to assess the quality of evidence.RESULTS:Forty studies, including 102 trial arms and 5116 patients, met inclusion criteria. The studies had low risk of bias and low-to-moderate heterogeneity. Compared with codeine, NSAIDs were associated with better pain scores at 6 hours (weighted mean difference [WMD] 0.93 points, 95% confidence interval [CI] 0.71 to 1.15) and at 12 hours (WMD 0.79, 95% CI 0.38 to 1.19). Stronger NSAID superiority at 6 hours was observed among trials where acetaminophen was coadministered at equivalent doses between groups (WMD 1.18, 95% CI 0.87 to 1.48). NSAIDs were associated with better global assessments at 6 hours (WMD −0.88, 95% CI −1.04 to −0.72) and at 24 hours (WMD −0.67, 95% CI −0.95 to −0.40), and were associated with fewer adverse effects, including bleeding events.INTERPRETATION:We found that adult outpatients report better pain scores, better global assessments and fewer adverse effects when their postoperative pain is treated with NSAIDs than with codeine. Clinicians across all specialties can use this information to improve both pain management and opioid stewardship.

Outpatient surgical procedures are now more common than inpatient procedures, given the development of less invasive techniques, the drive for health care efficiency, and improvements in anesthesia and pain management. ^1–4 Postoperative pain management after outpatient procedures often includes low-potency or low-dose opioids.⁵ Codeine use is widespread in this setting and codeine remains the most commonly prescribed opioid in many countries, including Canada.^6–9 However, its efficacy is variable, its potency is low and its use is associated with risks of severe adverse effects and misuse.¹⁰ Amid the ongoing opioid crisis, management of pain and potential opioid misuse is important across all medical and dental specialties.¹¹Nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to low-potency opioids. The potency, effects and toxicity of NSAIDs depend on the degree to which they inhibit cyclooxygenase 1 and 2 activity. Their main adverse effects are gastrointestinal bleeding, renal impairment and myocardial infarction with long-term use.^12–15 Postoperative pain can be effectively managed with NSAIDs, and NSAIDs have been shown to reduce opioid consumption in postoperative patients.¹⁶Given how commonly these medications are used, and the uncertainty in their comparative efficacy and safety, we sought to compare pain and safety outcomes for codeine-based medications and NSAIDs among adults who underwent outpatient surgery through a systematic review and meta-analysis of randomized controlled trials (RCTs).     

The sugar content of foods in the UK by category and company: A repeated cross-sectional study, 2015-2018

BackgroundConsumption of free sugars in the UK greatly exceeds dietary recommendations. Public Health England (PHE) has set voluntary targets for industry to reduce the sales-weighted mean sugar content of key food categories contributing to sugar intake by 5% by 2018 and 20% by 2020. The aim of this study was to assess changes in the sales-weighted mean sugar content and total volume sales of sugar in selected food categories among UK companies between 2015 and 2018.Methods and findingsWe used sales data from Euromonitor, which estimates total annual retail sales of packaged foods, for 5 categories—biscuits and cereal bars, breakfast cereals, chocolate confectionery, sugar confectionery, and yoghurts—for 4 consecutive years (2015–2018). This analysis includes 353 brands (groups of products with the same name) sold by 99 different companies. These data were linked with nutrient composition data collected online from supermarket websites over 2015–2018 by Edge by Ascential. The main outcome measures were sales volume, sales-weighted mean sugar content, and total volume of sugar sold by category and company. Our results show that between 2015 and 2018 the sales-weighted mean sugar content of all included foods fell by 5.2% (95% CI −9.4%, −1.4%), from 28.7 g/100 g (95% CI 27.2, 30.4) to 27.2 g/100 g (95% CI 25.8, 28.4). The greatest change seen was in yoghurts (−17.0% [95% CI −26.8%, −7.1%]) and breakfast cereals (−13.3% [95% CI −19.2%, −7.4%]), with only small reductions in sugar confectionery (−2.4% [95% CI −4.2%, −0.6%]) and chocolate confectionery (−1.0% [95% CI −3.1, 1.2]). Our results show that total volume of sugars sold per capita fell from 21.4 g/d (95% CI 20.3, 22.7) to 19.7 g/d (95% CI 18.8, 20.7), a reduction of 7.5% (95% CI −13.1%, −2.8%). Of the 50 companies representing the top 10 companies in each category, 24 met the 5% reduction target set by PHE for 2018. The key limitations of this study are that it does not encompass the whole food market and is limited by its use of brand-level sales data, rather than individual product sales data.ConclusionsOur findings show there has been a small reduction in total volume sales of sugar in the included categories, primarily due to reductions in the sugar content of yoghurts and breakfast cereals. Additional policy measures may be needed to accelerate progress in categories such as sugar confectionery and chocolate confectionery if the 2020 PHE voluntary sugar reduction targets are to be met.

In a multi-year cross sectional study of sales and nutrient data, Lauren Kate Bandy and colleagues investigate the sugar content and volume of sugar sales of select foods in the UK from 2015-2018.     

Leucine-rich Repeat Kinase 2 (LRRK2) Pharmacological Inhibition Abates α-Synuclein Gene-induced Neurodegeneration

Therapeutic approaches to slow or block the progression of Parkinson disease (PD) do not exist. Genetic and biochemical studies implicate α-synuclein and leucine-rich repeat kinase 2 (LRRK2) in late-onset PD. LRRK2 kinase activity has been linked to neurodegenerative pathways. However, the therapeutic potential of LRRK2 kinase inhibitors is not clear because significant toxicities have been associated with one class of LRRK2 kinase inhibitors. Furthermore, LRRK2 kinase inhibitors have not been tested previously for efficacy in models of α-synuclein-induced neurodegeneration. To better understand the therapeutic potential of LRRK2 kinase inhibition in PD, we evaluated the tolerability and efficacy of a LRRK2 kinase inhibitor, PF-06447475, in preventing α-synuclein-induced neurodegeneration in rats. Both wild-type rats as well as transgenic G2019S-LRRK2 rats were injected intracranially with adeno-associated viral vectors expressing human α-synuclein in the substantia nigra. Rats were treated with PF-06447475 or a control compound for 4 weeks post-viral transduction. We found that rats expressing G2019S-LRRK2 have exacerbated dopaminergic neurodegeneration and inflammation in response to the overexpression of α-synuclein. Both neurodegeneration and neuroinflammation associated with G2019S-LRRK2 expression were mitigated by LRRK2 kinase inhibition. Furthermore, PF-06447475 provided neuroprotection in wild-type rats. We could not detect adverse pathological indications in the lung, kidney, or liver of rats treated with PF-06447475. These results demonstrate that pharmacological inhibition of LRRK2 is well tolerated for a 4-week period of time in rats and can counteract dopaminergic neurodegeneration caused by acute α-synuclein overexpression.     

The Ca2+ Sensor Protein Swiprosin-1/EFhd2 Is Present in Neurites and Involved in Kinesin-Mediated Transport in Neurons

Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca²⁺ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2^−/−/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb. Immunohistochemistry and western blotting confirmed this pattern and revealed expression of EFhd2 during neuronal maturation. In cortical neurons, EFhd2 was detected in neurites marked by MAP2 and co-localized with pre- and post-synaptic markers. Approximately one third of EFhd2 associated with a biochemically isolated synaptosome preparation. There, EFhd2 was mostly confined to the cytosolic and plasma membrane fractions. Both synaptic endocytosis and exocytosis in primary hippocampal EFhd2^−/− neurons were unaltered but transport of synaptophysin-GFP containing vesicles was enhanced in EFhd2^−/− primary hippocampal neurons, and notably, EFhd2 inhibited kinesin mediated microtubule gliding. Therefore, we found that EFhd2 is a neuronal protein that interferes with kinesin-mediated transport.     

Gender Differences in the Association between Socioeconomic Status and Subclinical Atherosclerosis

Objectives

This study explored the pattern of associations between socioeconomic status (SES) and atherosclerosis progression (as indicated by carotid intima media thickness, CIMT) across gender.

Design

Cross-sectional analysis of a sample of 5474 older persons (mean age 73 years) recruited between 1999 and 2001 in the 3C study (France). We fitted linear regression models including neighborhood SES, individual SES and cardiovascular risk factors.

Results

CIMT was on average 24 µm higher in men (95% CI: 17 to 31). Neighborhood SES was inversely associated with CIMT in women only (highest versus lowest tertiles: −12.2 µm, 95%CI −22 to −2.4). This association persisted when individual SES and risk factors were accounted for. High individual education was associated with lower CIMT in men (−21.4 µm 95%CI −37.5 to −5.3) whereas high professional status was linked to lower CIMT among women (−15.7 µm 95%CI: −29.2 to −2.2). Adjustment for cardiovascular risk factors resulted in a slightly more pronounced reduction of the individual SES-CIMT association observed in men than in women.

Conclusion

In this sample, neighborhood and individual SES displayed different patterns of associations with subclinical atherosclerosis across gender. This suggests that the causal pathways leading to SES variations in atherosclerosis may differ among men and women.     

Milk Consumption and Cardiovascular Risk Factors in Older Chinese: The Guangzhou Biobank Cohort Study

Background

Dairy products consumption is increasingly common globally. Most of the evidence concerning dairy products comes from observational studies in western populations which are inevitably open to confounding. To triangulate the evidence concerning dairy products, we examined the associations of whole cow''s milk consumption with cardiovascular risk factors in a non-Western setting with a different pattern of milk consumption and cardiovascular diseases from Western populations.

Methods

We used multivariable censored linear or logistic regression to examine cross-sectionally the adjusted associations of whole cow''s milk consumption (none (n = 14892), 1–3/week (n = 2689) and 3+/week (n = 2754)) with cardiovascular risk factors in Chinese (≥50 years) in the Guangzhou Biobank Cohort Study.

Results

Whole cow''s milk consumption was negatively associated with systolic blood pressure (3+/week compared to none −2.56 mmHg, 95% confidence interval (CI) −3.63 to −1.49), diastolic blood pressure (−1.32 mmHg, 95% CI −1.87 to −0.77) and triglycerides (−0.06 mmol/L, 95% CI −0.11 to −0.002), but was positively associated with HDL-cholesterol (0.02 mmol/L,95% CI 0.01 to 0.04) and fasting glucose (0.08 mmol/L, 95% CI 0.01 to 0.16) adjusted for age, sex, phase of study, socio-economic position, lifestyle (smoking, alcohol use and physical activity) and adiposity, but had no obvious association with LDL-cholesterol or the presence of diabetes.

Conclusions

Whole cow''s milk consumption had heterogeneous associations with cardiovascular risk factors. Higher whole cow''s milk consumption was associated with lower levels of specific cardiovascular risk factors which might suggest risk factor specific biological pathways with different relations to blood pressure and lipids than glucose.     

Pathways of Economic Inequalities in Maternal and Child Health in Urban India: A Decomposition Analysis

Background/Objective

Children and women comprise vulnerable populations in terms of health and are gravely affected by the impact of economic inequalities through multi-dimensional channels. Urban areas are believed to have better socioeconomic and maternal and child health indicators than rural areas. This perception leads to the implementation of health policies ignorant of intra-urban health inequalities. Therefore, the objective of this study is to explain the pathways of economic inequalities in maternal and child health indicators among the urban population of India.

Methods

Using data from the third wave of the National Family Health Survey (NFHS, 2005–06), this study calculated relative contribution of socioeconomic factors to inequalities in key maternal and child health indicators such as antenatal check-ups (ANCs), institutional deliveries, proportion of children with complete immunization, proportion of underweight children, and Infant Mortality Rate (IMR). Along with regular CI estimates, this study applied widely used regression-based Inequality Decomposition model proposed by Wagstaff and colleagues.

Results

The CI estimates show considerable economic inequalities in women with less than 3 ANCs (CI  = −0.3501), institutional delivery (CI  = −0.3214), children without fully immunization (CI  = −0.18340), underweight children (CI  = −0.19420), and infant deaths (CI  = −0.15596). Results of the decomposition model reveal that illiteracy among women and her partner, poor economic status, and mass media exposure are the critical factors contributing to economic inequalities in maternal and child health indicators. The residuals in all the decomposition models are very less; this implies that the above mentioned factors explained maximum inequalities in maternal and child health of urban population in India.

Conclusion

Findings suggest that illiteracy among women and her partner, poor economic status, and mass media exposure are the critical pathways through which economic factors operate on inequalities in maternal and child health outcomes in urban India.     

A Role for the p75 Neurotrophin Receptor in Axonal Degeneration and Apoptosis Induced by Oxidative Stress

The p75 neurotrophin receptor (p75^NTR) mediates the death of specific populations of neurons during the development of the nervous system or after cellular injury. The receptor has also been implicated as a contributor to neurodegeneration caused by numerous pathological conditions. Because many of these conditions are associated with increases in reactive oxygen species, we investigated whether p75^NTR has a role in neurodegeneration in response to oxidative stress. Here we demonstrate that p75^NTR signaling is activated by 4-hydroxynonenal (HNE), a lipid peroxidation product generated naturally during oxidative stress. Exposure of sympathetic neurons to HNE resulted in neurite degeneration and apoptosis. However, these effects were reduced markedly in neurons from p75^NTR−/− mice. The neurodegenerative effects of HNE were not associated with production of neurotrophins and were unaffected by pretreatment with a receptor-blocking antibody, suggesting that oxidative stress activates p75^NTR via a ligand-independent mechanism. Previous studies have established that proteolysis of p75^NTR by the metalloprotease TNFα-converting enzyme and γ-secretase is necessary for p75^NTR-mediated apoptotic signaling. Exposure of sympathetic neurons to HNE resulted in metalloprotease- and γ-secretase-dependent cleavage of p75^NTR. Pharmacological blockade of p75^NTR proteolysis protected sympathetic neurons from HNE-induced neurite degeneration and apoptosis, suggesting that cleavage of p75^NTR is necessary for oxidant-induced neurodegeneration. In vivo, p75^NTR−/− mice exhibited resistance to axonal degeneration associated with oxidative injury following administration of the neurotoxin 6-hydroxydopamine. Together, these data suggest a novel mechanism linking oxidative stress to ligand-independent cleavage of p75^NTR, resulting in axonal fragmentation and neuronal death.     

Partial Deletion of eNOS Gene Causes Hyperinsulinemic State,Unbalance of Cardiac Insulin Signaling Pathways and Coronary Dysfunction Independently of High Fat Diet

Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD), affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT), eNOS^−/− and eNOS^+/− mice were studied. WT and eNOS^+/− mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS^−/−. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR) was measured at baseline and during infusions of acetylcholine (Ach) or sodium-nitroprusside (SNP) to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS^−/−) showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS^−/− and eNOS^+/− mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS^−/−. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels, consistent with a shift towards a vasoconstrictive pattern.     

Effects of continuous positive airway pressure on plasma fibrinogen levels in obstructive sleep apnea patients: a systemic review and meta-analysis

Objective: Fibrinogen has been implicated to play a role in the pathophysiology of obstructive sleep apnea (OSA). Many studies have evaluated the effect of continuous positive airway pressure (CPAP) on plasma fibrinogen levels in OSA patients. However, results from different reports were not consistent. To assess the effect of CPAP treatment on plasma fibrinogen levels of patients with OSA, a meta-analysis was performed.Methods: A systematic search of Pubmed, Embase, Cochrane, Wanfang Database and Chinese National Knowledge Infrastructure was performed. Data were extracted, and then weighted mean difference (WMD) and 95% confidence intervals (CIs) were calculated using a random-effects model.Results: Twenty-two studies involving 859 patients were included in this meta-analysis. Combined data showed that plasma fibrinogen concentrations decreased after CPAP therapy (WMD = −0.38 g/l, 95% CI [−0.54 to −0.22 g/l], P<0.001). In the subgroup analyses by therapy duration, plasma fibrinogen concentrations declined significantly in the long-term (≥1 month) CPAP therapy subgroup (WMD = −0.33 g/l, 95% CI [−0.49 to −0.16 g/l], P<0.001) but not in the short-term (<1 month) CPAP therapy subgroup (WMD = −0.84 g/l, 95% CI [−1.70 to 0.03 g/l], P=0.058). Moreover, in patients with long-term CPAP therapy duration, plasma fibrinogen levels decreased with good CPAP compliance (≥4 h/night) (WMD = −0.37 g/l, 95% CI [−0.55 to −0.19 g/l], P<0.001) but not with poor CPAP compliance (<4 h/night) (WMD = 0.12 g/l, 95% CI [−0.09 to 0.33 g/l], P=0.247).Conclusion: Long-term CPAP treatment with good compliance can reduce the plasma fibrinogen levels in patients with OSA.     

Non-Steroidal Anti-Inflammatory Drugs Use Is Associated with Reduced Risk of Inflammation-Associated Cancers: NIH-AARP Study

Background

Chronic inflammation has been linked to cancers, and use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of several cancers. To further refine the magnitude of NSAID-related associations, in particular for cancers related to inflammation, such as alcohol-, infection-, obesity-, and smoking-related cancers, as well as for less common cancers, we evaluated the use of NSAIDs and cancer risk in a very large cohort. We used propensity scores to account for potential selection bias and hypothesized that NSAID use is associated with decreased cancer incidence.

Methods

We conducted a prospective study among 314,522 participants in the NIH-AARP Diet and Health Study. Individuals who completed the lifestyle questionnaire, which included NSAID use, in 1996–1997 were followed through 2006. Information on cancer incidence was ascertained by linking to cancer registries and vital status databases.

Findings

During 2,715,994 person-years of follow-up (median 10.1 person-years), there were 51,894 incident cancers. Compared with non-users of NSAIDs, individuals who reported use in the 12 months prior to interview had a significantly lower risk of all inflammation-related cancer, alcohol-related, infection-related, obesity-related, and smoking-related cancers [hazard ratio (HR) (95% CI)) 0.90 (0.87–0.93), 0.80 (0.74–0.85), 0.82 (0.78–0.87), 0.88 (0.84–0.92), and 0.88 (0.85–0.92) respectively)].

Conclusions

After accounting for potential selection bias, our data showed an inverse association between NSAID use and alcohol-related, infection-related, obesity-related, and smoking-related cancers and support the hypothesis that inflammation is related to an increased risk of certain cancers.     

Mindfulness-Based Therapies in the Treatment of Somatization Disorders: A Systematic Review and Meta-Analysis

Background

Mindfulness-based therapy (MBT) has been used effectively to treat a variety of physical and psychological disorders, including depression, anxiety, and chronic pain. Recently, several lines of research have explored the potential for mindfulness-therapy in treating somatization disorders, including fibromyalgia, chronic fatigue syndrome, and irritable bowel syndrome.

Methods

Thirteen studies were identified as fulfilling the present criteria of employing randomized controlled trials to determine the efficacy of any form of MBT in treating somatization disorders. A meta-analysis of the effects of mindfulness-based therapy on pain, symptom severity, quality of life, depression, and anxiety was performed to determine the potential of this form of treatment.

Findings

While limited in power, the meta-analysis indicated a small to moderate positive effect of MBT (compared to wait-list or support group controls) in reducing pain (SMD  = −0.21, 95% CI: −0.37, −0.03; p<0.05), symptom severity (SMD  = −0.40, 95% CI: −0.54, −0.26; p<0.001), depression (SMD  = −0.23, 95% CI: −0.40, −0.07, p<0.01), and anxiety (SMD  = −0.20, 95% CI: −0.42, 0.02, p = 0.07) associated with somatization disorders, and improving quality of life (SMD  = 0.39, 95% CI: 0.19, 0.59; p<0.001) in patients with this disorder. Subgroup analyses indicated that the efficacy of MBT was most consistent for irritable bowel syndrome (p<0.001 for pain, symptom severity, and quality of life), and that mindfulness-based stress reduction (MBSR) and mindfulness-based cognitive therapy (MCBT) were more effective than eclectic/unspecified MBT.

Conclusions

Preliminary evidence suggests that MBT may be effective in treating at least some aspects of somatization disorders. Further research is warranted.     

Psychosocial Interventions for Perinatal Common Mental Disorders Delivered by Providers Who Are Not Mental Health Specialists in Low- and Middle-Income Countries: A Systematic Review and Meta-Analysis

Background

Perinatal common mental disorders (PCMDs) are a major cause of disability among women. Psychosocial interventions are one approach to reduce the burden of PCMDs. Working with care providers who are not mental health specialists, in the community or in antenatal health care facilities, can expand access to these interventions in low-resource settings. We assessed effects of such interventions compared to usual perinatal care, as well as effects of interventions based on intervention type, delivery method, and timing.

Methods and Findings

We conducted a systematic review, meta-analysis, and meta-regression. We searched databases including Embase and the Global Health Library (up to 7 July 2013) for randomized and non-randomized trials of psychosocial interventions delivered by non-specialist mental health care providers in community settings and antenatal health care facilities in low- and middle-income countries. We pooled outcomes from ten trials for 18,738 participants. Interventions led to an overall reduction in PCMDs compared to usual care when using continuous data for PCMD symptomatology (effect size [ES] −0.34; 95% CI −0.53, −0.16) and binary categorizations for presence or absence of PCMDs (odds ratio 0.59; 95% CI 0.26, 0.92). We found a significantly larger ES for psychological interventions (three studies; ES −0.46; 95% CI −0.58, −0.33) than for health promotion interventions (seven studies; ES −0.15; 95% CI −0.27, −0.02). Both individual (five studies; ES −0.18; 95% CI −0.34, −0.01) and group (three studies; ES −0.48; 95% CI −0.85, −0.11) interventions were effective compared to usual care, though delivery method was not associated with ES (meta-regression β coefficient −0.11; 95% CI −0.36, 0.14). Combined group and individual interventions (based on two studies) had no benefit compared to usual care, nor did interventions restricted to pregnancy (three studies). Intervention timing was not associated with ES (β 0.16; 95% CI −0.16, 0.49). The small number of trials and heterogeneity of interventions limit our findings.

Conclusions

Psychosocial interventions delivered by non-specialists are beneficial for PCMDs, especially psychological interventions. Research is needed on interventions in low-income countries, treatment versus preventive approaches, and cost-effectiveness. Please see later in the article for the Editors'' Summary     

Comparisons of GnRH Antagonist versus GnRH Agonist Protocol in Supposed Normal Ovarian Responders Undergoing IVF: A Systematic Review and Meta-Analysis

Objective

To evaluate the effectiveness and safety of GnRH antagonist and GnRH agonist in supposed normal ovarian responders undergoing IVF.

Methods

Data from 6 databases were retrieved for this study. The RCTs of GnRH agonist and GnRH antagonist use during IVF-EF therapy for patients with supposed normal ovarian response were included. A meta-analysis was performed with Revman 5.1software.

Results

Twenty-three RCTs met the inclusion criteria. The number of stimulation days (mean difference (MD): −0.66, 95% confidence interval (CI): −1.04∼−0.27), Gn amount (MD: −2.92, 95% CI: −5.0∼−0.85), E2 values on the day of HCG (MD: −330.39, 95% CI: −510.51∼−150.26), Number of oocytes retrieved (MD: −1.33, 95% CI: −2.02∼−0.64), clinical pregnancy rate (odds ratio (OR): 0.87, 95% CI: 0.75−1.0), and ovarian hyperstimulation syndrome (OHSS) incidence (OR: 0.59, 95% CI: 0.42∼0.82) were significantly lower in GnRH antagonist protocol than GnRH agonist protocol. However, the endometrial thickness on the day of HCG (MD: −0.04, 95% CI: −0.23∼0.14), the ongoing pregnancy rate (OR: 0.87, 95% CI: 0.74∼1.03), live birth rate (OR: 0.89, 95% CI: 0.64∼1.24), miscarriage rate (OR: 1.17, 95% CI: 0.85∼1.61), and cycle cancellation rate (OR: 1.11, 95% CI: 0.90∼1.37) did not significantly differ between the 2 groups.

Conclusions

During IVF treatment for patients with supposed normal responses, the incidence of OHSS were significantly lower, whereas the ongoing pregnancy and live birth rates were similar in the GnRH antagonist compared with the standard long GnRH agonist protocols.     

Cathepsin E Deficiency Impairs Autophagic Proteolysis in Macrophages

Cathepsin E is an endosomal aspartic proteinase that is predominantly expressed in immune-related cells. Recently, we showed that macrophages derived from cathepsin E-deficient (CatE ^−/−) mice display accumulation of lysosomal membrane proteins and abnormal membrane trafficking. In this study, we demonstrated that CatE ^−/− macrophages exhibit abnormalities in autophagy, a bulk degradation system for aggregated proteins and damaged organelles. CatE ^−/− macrophages showed increased accumulation of autophagy marker proteins such as LC3 and p62, and polyubiquitinated proteins. Cathepsin E deficiency also altered autophagy-related signaling pathways such as those mediated by the mammalian target of rapamycin (mTOR), Akt, and extracellular signal-related kinase (ERK). Furthermore, immunofluorescence microscopy analyses showed that LC3-positive vesicles were merged with acidic compartments in wild-type macrophages, but not in CatE ^−/− macrophages, indicating inhibition of fusion of autophagosome with lysosomes in CatE ^−/− cells. Delayed degradation of LC3 protein was also observed under starvation-induced conditions. Since the autophagy system is involved in the degradation of damaged mitochondria, we examined the accumulation of damaged mitochondria in CatE ^−/− macrophages. Several mitochondrial abnormalities such as decreased intracellular ATP levels, depolarized mitochondrial membrane potential, and decreased mitochondrial oxygen consumption were observed. Such mitochondrial dysfunction likely led to the accompanying oxidative stress. In fact, CatE ^−/− macrophages showed increased reactive oxygen species (ROS) production and up-regulation of oxidized peroxiredoxin-6, but decreased antioxidant glutathione. These results indicate that cathepsin E deficiency causes autophagy impairment concomitantly with increased aberrant mitochondria as well as increased oxidative stress.     

Endothelial Dysfunction in Tristetraprolin-deficient Mice Is Not Caused by Enhanced Tumor Necrosis Factor-α Expression

Cardiovascular events are important co-morbidities in patients with chronic inflammatory diseases like rheumatoid arthritis. Tristetraprolin (TTP) regulates pro-inflammatory processes through mRNA destabilization and therefore TTP-deficient mice (TTP^−/− mice) develop a chronic inflammation resembling human rheumatoid arthritis. We used this mouse model to evaluate molecular signaling pathways contributing to the enhanced atherosclerotic risk in chronic inflammatory diseases. In the aorta of TTP^−/− mice we observed elevated mRNA expression of known TTP targets like tumor necrosis factor-α (TNF-α) and macrophage inflammatory protein-1α, as well as of other pro-atherosclerotic mediators, like Calgranulin A, Cathepsin S, and Osteopontin. Independent of cholesterol levels TTP^−/− mice showed a significant reduction of acetylcholine-induced, nitric oxide-mediated vasorelaxation. The endothelial dysfunction in TTP^−/− mice was associated with increased levels of reactive oxygen and nitrogen species (RONS), indicating an enhanced nitric oxide inactivation by RONS in the TTP^−/− animals. The altered RONS generation correlates with increased expression of NADPH oxidase 2 (Nox2) resulting from enhanced Nox2 mRNA stability. Although TNF-α is believed to be a central mediator of inflammation-driven atherosclerosis, genetic inactivation of TNF-α neither improved endothelial function nor normalized Nox2 expression or RONS production in TTP^−/− animals. Systemic inflammation caused by TTP deficiency leads to endothelial dysfunction. This process is independent of cholesterol and not mediated by TNF-α solely. Thus, other mediators, which need to be identified, contribute to enhanced cardiovascular risk in chronic inflammatory diseases.