Background
Non‐invasive ventilation (NIV) with bi‐level positive airway pressure (BiPAP) is commonly used to treat patients admitted to hospital with acute hypercapnic respiratory failure (AHRF) ...secondary to an acute exacerbation of chronic obstructive pulmonary disease (AECOPD).
Objectives
To compare the efficacy of NIV applied in conjunction with usual care versus usual care involving no mechanical ventilation alone in adults with AHRF due to AECOPD. The aim of this review is to update the evidence base with the goals of supporting clinical practice and providing recommendations for future evaluation and research.
Search methods
We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Allied and Complementary Medicine Database (AMED), and PsycINFO, and through handsearching of respiratory journals and meeting s. This update to the original review incorporates the results of database searches up to January 2017.
Selection criteria
All randomised controlled trials that compared usual care plus NIV (BiPAP) versus usual care alone in an acute hospital setting for patients with AECOPD due to AHRF were eligible for inclusion. AHRF was defined by a mean admission pH < 7.35 and mean partial pressure of carbon dioxide (PaCO2) > 45 mmHg (6 kPa). Primary review outcomes were mortality during hospital admission and need for endotracheal intubation. Secondary outcomes included hospital length of stay, treatment intolerance, complications, changes in symptoms, and changes in arterial blood gases.
Data collection and analysis
Two review authors independently applied the selection criteria to determine study eligibility, performed data extraction, and determined risk of bias in accordance with Cochrane guidelines. Review authors undertook meta‐analysis for data that were both clinically and statistically homogenous, and analysed data as both one overall pooled sample and according to two predefined subgroups related to exacerbation severity (admission pH between 7.35 and 7.30 vs below 7.30) and NIV treatment setting (intensive care unit‐based vs ward‐based). We reported results for mortality, need for endotracheal intubation, and hospital length of stay in a 'Summary of findings' table and rated their quality in accordance with GRADE criteria.
Main results
We included in the review 17 randomised controlled trials involving 1264 participants. Available data indicate that mean age at recruitment was 66.8 years (range 57.7 to 70.5 years) and that most participants (65%) were male. Most studies (12/17) were at risk of performance bias, and for most (14/17), the risk of detection bias was uncertain. These risks may have affected subjective patient‐reported outcome measures (e.g. dyspnoea) and secondary review outcomes, respectively.
Use of NIV decreased the risk of mortality by 46% (risk ratio (RR) 0.54, 95% confidence interval (CI) 0.38 to 0.76; N = 12 studies; number needed to treat for an additional beneficial outcome (NNTB) 12, 95% CI 9 to 23) and decreased the risk of needing endotracheal intubation by 65% (RR 0.36, 95% CI 0.28 to 0.46; N = 17 studies; NNTB 5, 95% CI 5 to 6). We graded both outcomes as 'moderate' quality owing to uncertainty regarding risk of bias for several studies. Inspection of the funnel plot related to need for endotracheal intubation raised the possibility of some publication bias pertaining to this outcome. NIV use was also associated with reduced length of hospital stay (mean difference (MD) ‐3.39 days, 95% CI ‐5.93 to ‐0.85; N = 10 studies), reduced incidence of complications (unrelated to NIV) (RR 0.26, 95% CI 0.13 to 0.53; N = 2 studies), and improvement in pH (MD 0.05, 95% CI 0.02 to 0.07; N = 8 studies) and in partial pressure of oxygen (PaO2) (MD 7.47 mmHg, 95% CI 0.78 to 14.16 mmHg; N = 8 studies) at one hour. A trend towards improvement in PaCO2 was observed, but this finding was not statistically significant (MD ‐4.62 mmHg, 95% CI ‐11.05 to 1.80 mmHg; N = 8 studies). Post hoc analysis revealed that this lack of benefit was due to the fact that data from two studies at high risk of bias showed baseline imbalance for this outcome (worse in the NIV group than in the usual care group). Sensitivity analysis revealed that exclusion of these two studies resulted in a statistically significant positive effect of NIV on PaCO2. Treatment intolerance was significantly greater in the NIV group than in the usual care group (risk difference (RD) 0.11, 95% CI 0.04 to 0.17; N = 6 studies). Results of analysis showed a non‐significant trend towards reduction in dyspnoea with NIV compared with usual care (standardised mean difference (SMD) ‐0.16, 95% CI ‐0.34 to 0.02; N = 4 studies). Subgroup analyses revealed no significant between‐group differences.
Authors' conclusions
Data from good quality randomised controlled trials show that NIV is beneficial as a first‐line intervention in conjunction with usual care for reducing the likelihood of mortality and endotracheal intubation in patients admitted with acute hypercapnic respiratory failure secondary to an acute exacerbation of chronic obstructive pulmonary disease (COPD). The magnitude of benefit for these outcomes appears similar for patients with acidosis of a mild (pH 7.30 to 7.35) versus a more severe nature (pH < 7.30), and when NIV is applied within the intensive care unit (ICU) or ward setting.
The role of fatty acid synthesis in endothelial cells (ECs) remains incompletely characterized. We report that fatty acid synthase knockdown (FASNKD) in ECs impedes vessel sprouting by reducing ...proliferation. Endothelial loss of FASN impaired angiogenesis in vivo, while FASN blockade reduced pathological ocular neovascularization, at >10-fold lower doses than used for anti-cancer treatment. Impaired angiogenesis was not due to energy stress, redox imbalance, or palmitate depletion. Rather, FASNKD elevated malonyl-CoA levels, causing malonylation (a post-translational modification) of mTOR at lysine 1218 (K1218). mTOR K-1218 malonylation impaired mTOR complex 1 (mTORC1) kinase activity, thereby reducing phosphorylation of downstream targets (p70S6K/4EBP1). Silencing acetyl-CoA carboxylase 1 (an enzyme producing malonyl-CoA) normalized malonyl-CoA levels and reactivated mTOR in FASNKD ECs. Mutagenesis unveiled the importance of mTOR K1218 malonylation for angiogenesis. This study unveils a novel role of FASN in metabolite signaling that contributes to explaining the anti-angiogenic effect of FASN blockade.
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•Fatty acid synthase inhibition impairs physiological and pathological angiogenesis•FASN inhibition selectively reduces endothelial cell proliferation, not migration•By elevating malonyl-CoA levels, FASN inhibition promotes mTOR lysine malonylation•The resultant decrease in mTORC1 kinase activity contributes to angiogenic defects
Bruning et al. report that blocking fatty acid synthase (FASN) in endothelial cells (ECs) reduces angiogenesis by impairing EC proliferation. Mechanistically, FASN inhibition elevates the malonyl-CoA substrate pool, thereby increasing post-translational malonylation of mTOR and decreasing the pro-angiogenic mTORC1 activity.
Several prospective studies have shown a moderate positive association between increasing circulating insulin‐like growth factor‐I (IGF‐I) levels and colorectal cancer risk. However, the associations ...were often statistically nonsignificant, and the relationship of cancer risk with IGF‐I's major binding protein, IGFBP‐3, showed major discrepancies between studies. We investigated the association of colorectal cancer risk with serum IGF‐I, total and intact IGFBP‐3, in a case‐control study nested within the EPIC cohort (1,121 cases of colorectal cancer and 1,121 matched controls). Conditional logistic regression was used to adjust for possible confounders. Our present study results were combined in a meta‐analysis with those from 9 previous prospective studies to examine the overall evidence for a relationship of prediagnostic serum IGF‐I with colorectal cancer risk. In the EPIC study, serum concentrations of IGF‐I and IGFBP‐3 showed no associations with risk of colorectal cancer overall. Only in subgroup analyses did our study show moderate positive associations of IGF‐I levels with risk, either among younger participants only (and only for colon cancer) or among participants whose milk intakes were in the lowest tertile of the population distribution (RR for an increase of 100 ng/ml = 1.43 95% CI = 1.13–1.93). Nevertheless, in the meta‐analysis a modest positive association remained between serum IGF‐I and colorectal cancer risk overall (RR = 1.07 1.01–1.14 for 1 standard deviation increase in IGF‐I). Overall, data from our present study and previous prospective studies combined indicate a relatively modest association of colorectal cancer risk with serum IGF‐I.
American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but ...without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events.
We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH <0.45 mIU/L, the last two with normal free thyroxine levels. Among 25 390 participants, 2068 (8.1%) had subclinical hypothyroidism and 648 (2.6%) had subclinical hyperthyroidism. In age- and sex-adjusted analyses, risks of heart failure events were increased with both higher and lower TSH levels (P for quadratic pattern <0.01); the hazard ratio was 1.01 (95% confidence interval, 0.81-1.26) for TSH of 4.5 to 6.9 mIU/L, 1.65 (95% confidence interval, 0.84-3.23) for TSH of 7.0 to 9.9 mIU/L, 1.86 (95% confidence interval, 1.27-2.72) for TSH of 10.0 to 19.9 mIU/L (P for trend <0.01) and 1.31 (95% confidence interval, 0.88-1.95) for TSH of 0.10 to 0.44 mIU/L and 1.94 (95% confidence interval, 1.01-3.72) for TSH <0.10 mIU/L (P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors.
Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and <0.10 mIU/L.
Endometrial cancer risk has been associated with reproductive factors (age at menarche, age at menopause, parity, age at first and last birth, time since last birth and use of oral contraceptives ...(OCs). However, these factors are closely interrelated and whether they act independently still requires clarification. We conducted a study to examine the association of menstrual and reproductive variables with the risk of endometrial cancer among the European Prospective Investigation into Cancer and Nutrition (EPIC). Among the 302,618 women eligible for the study, 1,017 incident endometrial cancer cases were identified. A reduction in endometrial cancer risk was observed in women with late menarche, early menopause, past OC use, high parity and a shorter time since last full‐term pregnancy (FTP). No association was observed for duration of breast feeding after adjustment for number of FTP or for abortion (spontaneous or induced). After mutual adjustment, late age at menarche, early age at menopause and duration of OC use showed similar risk reductions of 7–8% per year of menstrual life, whereas the decreased risk associated with cumulative duration of FTPs was stronger (22% per year). In conclusion, our findings confirmed a reduction in risk of endometrial cancer with factors associated with a lower cumulative exposure to estrogen and/or higher exposure to progesterone, such as increasing number of FTPs and shorter menstrual lifespan and, therefore, support an important role of hormonal mechanisms in endometrial carcinogenesis.
The reluctance of young adults to seek mental health treatment has been attributed to poor mental health literacy, stigma, preference for self-reliance and concerns about confidentiality. The purpose ...of this study was to examine the potential impact of an anti-stigma intervention that includes education about depression, information about help-seeking as well as contact with a person with lived experience, on help seeking attitudes.
A pre-post study design was employed. Changes in help-seeking attitudes were measured using the Inventory of Attitudes towards Seeking Mental Health Services (IASMHS) immediately post-intervention and after 3 months. Sociodemographic data, information on past experiences in the mental health field and contact with people with mental illness were collated. Three hundred ninety university students enrolled in the study. Linear mixed models were used to examine the effects of the intervention.
Scores on all subscales of the IASMHS, Psychological Openness (PO), Help-seeking Propensity (HP) and Indifference to Stigma improved significantly post-intervention and at 3-month follow-up compared to pre-intervention, with HP demonstrating the highest effect size. However, a significant decline was observed on all three scales at 3-month follow-up compared to post-intervention. Gender, having friends/family with mental illness, and previous experience in the mental health field moderated the intervention effects for the PO and HP subscales.
The study showed that the brief anti-stigma intervention was associated with improvements in help-seeking attitudes among university students with differential effects among certain sub-groups. As the beneficial outcomes appeared to decrease over time, booster sessions or opportunities to participate in mental health-related activities post-intervention may be required to maintain the desired changes in help-seeking attitudes.
This study aimed to assess the frequency of anxiety and depression in a cohort of adult patients with atopic dermatitis (AD) in a tertiary dermatological centre, using the Hospital Anxiety and ...Depression Scale (HADS). We looked for any correlation between anxiety and depression with skin disease severity.
Patients with AD were recruited from the National Skin Centre, Singapore, from 2008 to 2009 for a prospective cross-sectional study. The scoring atopic dermatitis (SCORAD) grade was determined and the HADS was administered via interviews.
A total of 100 patients (78 males, 22 females) were enrolled (92% Chinese, 4% Malays and 4% Indians). Their average age was 25.7 years. Sixty-five percent used topical steroids, 14% had previously taken oral prednisolone for the control of disease flares, and 20% were on concurrent systemic therapy. The mean SCORAD was 55.0, with 99% of patients having moderate or severe AD. The mean HADS anxiety score was 7.2 and the mean depression score was 5.0. The level of anxiety correlated well with that of depression (Spearman's rank correlation coefficient, ρ = 0.59,
<0.05); 18% were considered as cases of anxiety and 5% as cases of depression. These patients also had higher SCORAD values compared to other patients with lower scores for anxiety or depression (
<0.05). Linear regression demonstrated a statistically significant positive relationship between anxiety and depression scores, and SCORAD scores.
Our study identified, by means of the HADS, the frequency of anxiety and depression amongst a cohort of Singaporean patients with AD. More severe skin disease correlated to greater psychological burden. The HADS is a useful screening tool that can constitute part of the overall holistic management of patients with AD so as to improve patient care.
Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by an expanded CAG repeat in the HTT gene. It is diagnosed following a standardized examination of motor control and often ...presents with cognitive decline and psychiatric symptoms. Recent studies have detected genetic loci modifying the age at onset of motor symptoms in HD, but genetic factors influencing cognitive and psychiatric presentations are unknown.
We tested the hypothesis that psychiatric and cognitive symptoms in HD are influenced by the same common genetic variation as in the general population by 1) constructing polygenic risk scores from large genome-wide association studies of psychiatric and neurodegenerative disorders and of intelligence and 2) testing for correlation with the presence of psychiatric and cognitive symptoms in a large sample (n = 5160) of patients with HD.
Polygenic risk score for major depression was associated specifically with increased risk of depression in HD, as was schizophrenia risk score with psychosis and irritability. Cognitive impairment and apathy were associated with reduced polygenic risk score for intelligence.
Polygenic risk scores for psychiatric disorders, particularly depression and schizophrenia, are associated with increased risk of the corresponding psychiatric symptoms in HD, suggesting a common genetic liability. However, the genetic liability to cognitive impairment and apathy appears to be distinct from other psychiatric symptoms in HD. No associations were observed between HD symptoms and risk scores for other neurodegenerative disorders. These data provide a rationale for treatments effective in depression and schizophrenia to be used to treat depression and psychotic symptoms in HD.
Menopausal hormone therapy (MHT) is characterized by use of different constituents, regimens and routes of administration. We investigated the association between the use of different types of MHT ...and breast cancer risk in the EPIC cohort study. The analysis is based on data from 133,744 postmenopausal women. Approximately 133,744 postmenopausal women contributed to this analysis. Information on MHT was derived from country‐specific self‐administered questionnaires with a single baseline assessment. Incident breast cancers were identified through population cancer registries or by active follow‐up (mean: 8.6 yr). Overall relative risks (RR) and 95% confidence interval (CI) were derived from country‐specific Cox proportional hazard models estimates. A total of 4312 primary breast cancers were diagnosed during 1,153,747 person‐years of follow‐up. Compared with MHT never users, breast cancer risk was higher among current users of estrogen only (RR: 1.42, 95% CI 1.23–1.64) and higher still among current users of combined MHT (RR: 1.77, 95% CI 1.40–2.24; p = 0.02 for combined vs. estrogen‐only). Continuous combined regimens conferred a 43% (95% CI: 19–72%) greater risk compared with sequential regimens. There was no significant difference between progesterone and testosterone derivatives in sequential regimens. There was no significant variation in risk linked to the estrogenic component of MHT, neither for oral vs. cutaneous administration nor for estradiol compounds vs. conjugated equine estrogens. Estrogen‐only and combined MHT uses were associated with increased breast cancer risk. Continuous combined preparations were associated with the highest risk. Further studies are needed to disentangle the effects of the regimen and the progestin component.
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