ObjectiveTo conduct a systematic review investigating the normal age-related changes in lung function in adults without known lung disease.DesignSystematic review.Data sourcesMEDLINE, Embase and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for eligible studies from inception to February 12, 2019, supplemented by manual searches of reference lists and clinical trial registries.Eligibility criteriaWe planned to include prospective cohort studies and randomised controlled trials (control arms) that measured changes in lung function over time in asymptomatic adults without known respiratory disease.Data extraction and synthesisTwo authors independently determined the eligibility of studies, extracted data and assessed the risk of bias of included studies using the modified Newcastle–Ottawa Scale.ResultsFrom 4385 records screened, we identified 16 cohort studies with 31 099 participants. All included studies demonstrated decline in lung function—forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow rate (PEFR) with age. In studies with longer follow-up (>10 years), rates of FEV1decline ranged from 17.7 to 46.4 mL/year (median 22.4 mL/year). Overall, men had faster absolute rates of decline (median 43.5 mL/year) compared with women (median 30.5 mL/year). Differences in relative FEV1change, however, were not observed between men and women. FEV1/FVC change was reported in only one study, declining by 0.29% per year. An age-specific analysis suggested the rate of FEV1function decline may accelerate with each decade of age.ConclusionsLung function—FEV1, FVC and PEFR—decline with age in individuals without known lung disease. The definition of chronic airway disease may need to be reconsidered to allow for normal ageing and ensure that people likely to benefit from interventions are identified rather than healthy people who may be harmed by potential overdiagnosis and overtreatment. The first step would be to apply age, sex and ethnicity-adjusted FEV1/FVC thresholds to the disease definition of chronic obstructive pulmonary disease.PROSPERO registration numberCRD42018087066.

ObjectiveTo assess the benefits and harms of pregabalin in the management of neuropathic pain.DesignRapid review and meta-analysis of phase III, randomised, placebo-controlled trials.ParticipantsAdults aged 18 years and above with neuropathic pain defined according to the International Association for the Study of Pain criteria.InterventionsPregabalin or placebo.Primary and secondary outcome measuresOur primary outcomes were pain (as measured using validated scales) and adverse events. Our secondary outcomes were sleep disturbance, quality of life, Patient Global Impression of Change, Clinician Global Impression scale, anxiety and depression scores, overall discontinuations and discontinuations because of adverse events.ResultsWe included 28 trials comprising 6087 participants. The neuropathic pain conditions studied were diabetic peripheral neuropathy, postherpetic neuralgia, herpes zoster, sciatica (radicular pain), poststroke pain and spinal cord injury-related pain. Patients who took pregabalin reported significant reductions in pain (numerical rating scale (NRS)) compared with placebo (standardised mean difference (SMD) −0.49 (95% CI −0.66 to −0.32, p<0.00001), very low quality evidence). Pregabalin significantly reduced sleep interference scores (NRS) compared with placebo (SMD −0.38 (95% CI −0.50 to −0.26, p<0.00001), moderate quality evidence. Pregabalin significantly increased the risk of adverse events compared with placebo (RR 1.33 (95% CI 1.23 to 1.44, p<0.00001, low quality evidence)). The risks of experiencing weight gain, somnolence, dizziness, peripheral oedema, fatigue, visual disturbances, ataxia, non-peripheral oedema, vertigo and euphoria were significantly increased with pregabalin. Pregabalin was significantly more likely than placebo to lead to discontinuation of the drug because of adverse events (RR 1.91 (95% CI 1.54 to 2.37, p<0.00001), low quality evidence).ConclusionPregabalin has beneficial effects on some symptoms of neuropathic pain. However, its use significantly increases the risk of a number of adverse events and discontinuation due to adverse events. The quality of the evidence from journal publications is low.

BackgroundAutopsy studies demonstrate the prevalence pool of incidental breast cancer in the population, but estimates are uncertain due to small numbers in any primary study. We aimed to conduct a systematic review of autopsy studies to estimate the prevalence of incidental breast cancer and precursors.MethodsRelevant articles were identified through searching PubMed and Embase from inception up to April 2016, and backward and forward citations. We included autopsy studies of women with no history of breast pathology, which included systematic histological examination of at least one breast, and which allowed calculation of the prevalence of incidental breast cancer or precursor lesions. Data were pooled using logistic regression models with random intercepts (non-linear mixed models).ResultsWe included 13 studies from 1948 to 2010, contributing 2363 autopsies with 99 cases of incidental cancer or precursor lesions. More thorough histological examination (≥20 histological sections) was a strong predictor of incidental in-situ cancer and atypical hyperplasia (OR = 126·8 and 21·3 respectively, p < 0·001), but not invasive cancer (OR = 1·1, p = 0·75). The estimated mean prevalence of incidental cancer or precursor lesion was 19·5% (0·85% invasive cancer + 8·9% in-situ cancer + 9·8% atypical hyperplasia).ConclusionOur systematic review in ten countries over six decades found that incidental detection of cancer in situ and breast cancer precursors is common in women not known to have breast disease during life. The large prevalence pool of undetected cancer in-situ and atypical hyperplasia in these autopsy studies suggests screening programs should be cautious about introducing more sensitive tests that may increase detection of these lesions.

Background: Unwanted anticholinergic effects are both underestimated and frequently overlooked. Failure to identify adverse drug reactions (ADRs) can lead to prescribing cascades and the unnecessary use of over-thecounter products. The objective of this systematic review and meta-analysis is to explore and quantify the frequency and severity of ADRs associated with amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults with any indication, as well as healthy individuals. Methods: A systematic search in six electronic databases, forward/backward searches, manual searches, and searches for Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval studies, will be performed. Placebo-controlled RCTs evaluating amitriptyline in any dosage, regardless of indication and without restrictions on the time and language of publication, will be included, as will healthy individuals. Studies of topical amitriptyline, combination therapies, or including < 100 participants, will be excluded. Two investigators will screen the studies independently, assess methodological quality, and extract data on design, population, intervention, and outcomes ((non-)anticholinergic ADRs, e.g., symptoms, test results, and adverse drug events (ADEs) such as falls). The primary outcome will be the frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Anticholinergic ADRs will be defined by an experienced clinical pharmacologist, based on literature and data from Martindale: The Complete Drug Reference. Secondary outcomes will be frequency and severity of (non-)anticholinergic ADRs and ADEs. The information will be synthesized in meta-analyses and narratives. We intend to assess heterogeneity using metaregression (for indication, outcome, and time points) and I 2 statistics. Binary outcomes will be expressed as odds ratios, and continuous outcomes as standardized mean differences. Effect measures will be provided using 95% confidence intervals. We plan sensitivity analyses to assess methodological quality, outcome reporting etc., and subgroup analyses on age, dosage, and duration of treatment. Discussion: We will quantify the frequency of anticholinergic and other ADRs/ADEs in adults taking amitriptyline for any indication by comparing rates for amitriptyline vs. placebo, hence, preventing bias from disease symptoms and nocebo effects. As no standardized instrument exists to measure it, our overall estimate of anticholinergic ADRs may have limitations.