Recently, we developed a transgenic mouse with cardiac-specific Gsalpha overexpression (TG mouse), which exhibits enhanced postsynaptic beta-adrenergic receptor signaling, ultimately developing a cardiomyopathy. The goal of the present study was to determine whether cardiac Gsalpha overexpression alters autonomic cardiovascular control, which could shed light on the mechanism responsible for the later development of cardiomyopathy. Mean arterial pressure was increased (P<.05) in conscious, chronically instrumented TG mice (123+/-1 mm Hg) compared with age-matched wild-type (WT) control mice (103+/-1 mm Hg). Respiratory frequency was increased (P<.05) in TG mice (269+/-26/min) compared with WT mice (210+/-20/min). By use of telemetric techniques, baseline heart rate (HR) was elevated (P<.05) in conscious, untethered TG mice (696+/-13 bpm) compared with WT mice (568+/-28 bpm). Intrinsic HR, after propranolol and atropine or after ganglionic blockade with hexamethonium, was not different between TG and WT mice. Both the normal minute-to-minute and circadian variations of HR observed in WT mice were markedly blunted in TG mice. HR variability was assessed by the time-domain and frequency-domain methods. At baseline, time-domain analysis indices were reduced (P<.05) in TG mice compared with WT mice. Although the low frequency (LF) component was higher (P<.05) than the high frequency (HF) component in WT mice, the LF component was less (P<.05) than the HF component in TG mice. In addition, arterial baroreflex regulation of HR was markedly blunted in TG mice in response to both nitroglycerin-induced hypotension and phenylephrine-induced hypertension. The reduced LF/HF ratio in TG mice was surprising in view of enhanced beta-adrenergic signaling and may be due to reduced neural tone secondary to the elevated arterial pressure or alterations in arterial baroreflex control. Dobutamine infusion in WT mice also resulted in depressed HR variability. The combination of elevated baseline HR, arterial pressure, and respiratory frequency suggests that enhanced beta-adrenergic signaling in TG mice results in reduced HR variability, in terms of both minute-to-minute variability and the lack of circadian variations in HR. The lack of normal HR variability in general and the failure of HR to decline, even during sleep, may actually be critical mechanisms contributing to the ultimate development of cardiomyopathy in these animals.
ObjectiveTo synthesise evidence from exclusively primary prevention data on the effectiveness of statins for prevention of cardiovascular disease (CVD), including stroke, and outcomes stratified by baseline risk and gender.DesignOverview of systematic reviews (SRs) using Revised-AMSTAR approach to assess quality.Data sourcesCochrane Database of Systematic Reviews, MEDLINE, Embase, PubMed, Scopus and PROSPERO to June 2017.Eligibility criteria for selecting studiesSRs of randomised control trials (RCTs) or individual patient data (IPD) from RCTs, examining the effectiveness of statins versus placebo or no treatment on all-cause mortality, coronary heart disease, CVD (including stroke) and composite endpoints, with stratification by baseline risk and gender.Data extraction and synthesisTwo independent reviewers extracted data and assessed methodological quality. A narrative synthesis was conducted.ResultsThree SRs were included. Quality of included SRs was mixed, and none reported on the risk of bias of included trials.We found trends towards reduced all-cause mortality in all SRs (RR 0.91 [95% CI 0.85 to 0.97]), (RR 0.91 [95% CI 0.83 to 1.01]) and (RR 0.78 [95% CI 0.53 to 1.15]) though it was not statistically significant in two SRs. When stratified by baseline risk, the effect on all-cause mortality was no longer statistically significant except in one medium risk category. One review reported significant reductions (RR 0.85 [95% CI 0.77 to 0.95]) in vascular deaths and non-significant reductions in non-vascular deaths (RR 0.97 [95% CI 0.88 to 1.07]). There were significant reductions in composite outcomes overall, but mixed results were reported in these when stratified by baseline risk. These reviews included studies with participants considered risk equivalent to those with established CVD.ConclusionsThere is limited evidence on the effectiveness of statins for primary prevention with mixed findings from studies including participants with widely ranging baseline risks. Decision making for the use of statins should consider individual baseline risk, absolute risk reduction and whether risk reduction justifies potential harms and taking a daily medicine for life.Trial registration numberCRD42017064761.
Purpose: Significant increases in opioid utilisation have been reported in many countries in recent decades. This study investigated strong opioid prescribing in Irish General Medical Services (GMS) patients over a 10-year period.Methods: A retrospective repeated cross-sectional analysis of a national pharmacy claims database between January 2010 and December 2019 was conducted. Strong opioid prescribing in GMS patients was evaluated, including by route of administration, age (16-64 years and ≥65 years) and gender. Measures of consumption included prescribing prevalence and defined daily dose (DDD)/1000 population/day.Prevalence ratios (PRs) with 95% confidence intervals (CIs), and percentage and absolute changes were determined.Results: Strong opioid prescribing prevalence increased from 14.43% in 2010 to 16.28% in 2019, with the greatest increase in the ≥65 years age group. Tramadol was the most frequently prescribed product, constituting 63.9% of total strong opioid prescribing. The prescribing prevalence of oxycodone increased from 0.95% in 2010 to 2.68% in 2019 (PR 2.81, 95% CI 2.76, 2.87), with steep increases in oxycodone-naloxone since it became available (PR 5.23, 95% CI 4.98, 5.50). The prescribing prevalence of tapentadol increased from 0.18% to 1.58% between 2012 (first complete year available for reimbursement) and 2019 (PR 8.79, 95% CI 8.43, 9.16). Strong opioid prescribing was highest in females aged ≥65 years.Conclusions: This study found an overall increase in strong opioid prescribing in Ireland between 2010 and 2019, particularly in older adults. Tramadol was the most frequently prescribed product, with oxycodone and tapentadol prescribing increasing markedly over the study period.
Background:Recent meta-analyses suggest that pre-diagnostic statin use is associated with reduced breast cancer-specific mortality. Studies have shown that high breast tumour expression of the statin target (3-hydroxy-3-methylglutaryl coenzyme-A reductase) is associated with lymph-node negative cancer. Therefore, we examined the association between pre-diagnostic statin use and; lymph node status, breast cancer-specific and all-cause mortality.Methods:Women with stages I–III breast cancer were identified from the National Cancer Registry of Ireland (N=6314). Pre-diagnostic statin users were identified from linked prescription claims data (N=2082). Relative risks were estimated for associations between pre-diagnostic statin use and lymph node status. Hazard ratios (HR) were estimated for associations between pre-diagnostic statin use and breast cancer-specific and all-cause mortality.Results:Pre-diagnostic statin use was not associated with lymph node negative status at diagnosis. In multivariate analyses, pre-diagnostic statin use was associated with reduced all-cause (HR 0.78 95% confidence interval (CI) 0.69, 0.89) and breast cancer-specific mortality (HR 0.81 95% CI 0.68, 0.96). This reduction in cancer-specific mortality was greatest in statin-users with oestrogen (ER) receptor-positive tumours (HR 0.69 95% CI 0.55, 0.85).Conclusion:Patients with pre-diagnostic statin exposure had a significant reduction in breast cancer-specific mortality, which was even more pronounced in women with ER+ tumours.
Background:Prior evidence suggests a role for statins in the management of cancer. However, the benefit of statin use in the adjuvant setting remains uncertain. This study investigates associations between statin use initiated after a breast cancer diagnosis and mortality.Methods:Women with stage I–III breast cancer were identified from the National Cancer Registry of Ireland (N=4243). Post-diagnostic statin initiators were identified from pharmacy claims data (N=837). Multivariate models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for associations between de novo statin use and mortality.Results:The median duration of statin use was 6.7 years. No association was found between post-diagnostic statin use and breast cancer-specific (HR 0.88, 95% CI 0.66, 1.17) or all-cause mortality (HR 1.00, 95% CI 0.82, 1.21).Conclusions:The results from our study suggest that initiating statin use after a diagnosis of stage I–III breast cancer is not associated with a reduction in breast cancer-specific mortality.
We reviewed duration of illness in 26 children with severe pediatric Guillain-Barré syndrome (GBS) during two contiguous 8-year periods that represent a "non-treatment era" of supportive care alone or a "treatment era" of supportive care plus either plasma exchange or intravenous immunoglobulin intervention. Our findings of similar recovery times in each treatment group suggest that immunotherapy in severe pediatric GBS may be less effective than in adult GBS, or effective only when given to certain patients very early in the course of the illness.
PurposeCross-sectional studies show that statins, used in cardiovascular disease prevention, are often discontinued approaching death. Studies investigating associations between statin exposure and cancer outcomes, not accounting for these exposure changes, are prone to reverse causation bias. The aim of this study was to describe longitudinally the changes in statin initiation and continuation prior to death in patients with breast or colorectal cancer, thus establishing an appropriate exposure lag time.MethodsThis study was carried out using linked cancer registry and prescribing data. We identified patients who died of their cancer (cases) and cancer survivors were used as controls. The probability of initiating or continuing statin use was estimated up to 5 years prior to death (or index date). Conditional binomial models were used to estimate relative risks and risk differences for associations between approaching cancer death and statin use.ResultsCompared to controls, the probability of continued statin use in breast cancer cases was significantly lower 3 months prior to death (RR 0.86 95% CI 0.79, 0.94). Similarly, in colorectal cancer cases, the probability of continued statin use was significantly lower 3 months prior to colorectal cancer death (RR 0.77 95% CI 0.68, 0.88).ConclusionA significant proportion of patients will cease statin treatment in the months prior to a colorectal or breast cancer death.Electronic supplementary materialThe online version of this article (doi:10.1007/s00520-017-3576-0) contains supplementary material, which is available to authorized users.
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