Single-inhaler triple therapy in patients with chronic obstructive pulmonary disease:a systematic review

Abstract Background Guidelines recommend that treatment with a long-acting β2 agonist (LABA), a long-acting muscarinic antagonist (LAMA), and inhaled corticosteroids (ICS), i.e. triple therapy, is reserved for a select group of symptomatic patients with chronic obstructive pulmonary disease (COPD) who continue to exacerbate despite treatment with dual therapy (LABA/LAMA). A number of single-inhaler triple therapies are now available and important clinical questions remain over their role in the patient pathway. We compared the efficacy and safety of single-inhaler triple therapy to assess the magnitude of benefit and to identify patients with the best risk-benefit profile for treatment. We also evaluated and compared study designs and population characteristics to assess the strength of the evidence base. Methods We conducted a systematic search, from inception to December 2018, of randomised controlled trials (RCTs) of single-inhaler triple therapy in patients with COPD. The primary outcome was the annual rate of moderate and severe exacerbations. Results We identified 523 records, of which 15 reports/abstracts from six RCTs were included. Triple therapy resulted in the reduction of the annual rate of moderate or severe exacerbations in the range of 15–52% compared with LAMA/LABA, 15–35% compared to LABA/ICS and 20% compared to LAMA. The patient-based number needed to treat for the moderate or severe exacerbation outcome ranged between approximately 25–50 (preventing one patient from having an event) and the event-based number needed to treat of around 3–11 (preventing one event). The absolute benefit appeared to be greater in patients with higher eosinophil counts or historical frequency of exacerbations and ex-smokers. In the largest study, there was a significantly higher incidence of pneumonia in the triple therapy arm. There were important differences in study designs and populations impacting the interpretation of the results and indicating there would be significant heterogeneity in cross-trial comparisons. Conclusion The decision to prescribe triple therapy should consider patient phenotype, magnitude of benefit and increased risk of adverse events. Future research on specific patient phenotype thresholds that can support treatment and funding decisions is now required from well-designed, robust, clinical trials. Trial registration PROSPERO #CRD42018102125 .https://deepblue.lib.umich.edu/bitstream/2027.42/152151/1/12931_2019_Article_1213.pd

Systemic lupus erythematosus; stroke and myocardial infarction risk: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the risk of stroke and myocardial infarction (MI) in adult patients with systemic lupus erythematosus (SLE) through a systematic review and meta-analysis. METHODS: We searched MEDLINE and EMBASE from inception to May 2020 to identify observational studies (cohort and cross-sectional) that evaluated risk of stroke and MI in adult patients with SLE compared with the general population or healthy controls. Studies were included if they reported effect-size estimates that could be used for calculating pooled-effect estimates. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% CIs for stroke and MI. Heterogeneity quantified by the I2 test and sensitivity analyses assessed bias. RESULTS: In total, 26 studies were included in this meta-analysis: 14, 5 and 7 studies on stroke, MI and both stroke and MI, respectively. The pooled RR for ischaemic stroke was 2.18 (95% CI 1.78 to 2.67; I2 75%), intracerebral haemorrhage 1.84 (95% CI 1.16 to 2.90; I2 67%), subarachnoid haemorrhage 1.95 (95% CI 0.69 to 5.52; I2 94%), composite stroke 2.13 (95% CI 1.73 to 2.61; I2 88%) and MI 2.99 (95% CI 2.34 to 3.82; I2 85%). There was no evidence for publication bias, and sensitivity analyses confirmed the robustness of the results. CONCLUSIONS: Overall, patients with SLE were identified to have a twofold to threefold higher risk of stroke and MI. Future research on the interaction between known SLE-specific modifiable risk factors and risk of stroke and MI to support development of prevention and treatment strategies are needed. PROSPERO REGISTRATION NUMBER: CRD42018098690

Feasibility trial of an early therapy in perinatal stroke (eTIPS)

Background: Perinatal stroke (PS) affects up to 1/2300 infants and frequently leads to unilateral cerebral palsy (UCP). Preterm-born infants affected by unilateral haemorrhagic parenchymal infarction (HPI) are also at risk of UCP. To date no standardised early therapy approach exists, yet early intervention could be highly effective, by positively influencing processes of activity-dependent plasticity within the developing nervous system including the corticospinal tract. Our aim was to test feasibility and acceptability of an "early Therapy In Perinatal Stroke" (eTIPS) intervention, aiming ultimately to improve motor outcome. Methods: Design: Feasibility trial, North-East England, August 2015-September 2017. Participants were infants with PS or HPI, their carers and therapists. The intervention consisted of a parent-delivered lateralised therapy approach starting from term equivalent age and continuing until 6 months corrected age. The outcome measures were feasibility (recruitment and retention rates) and acceptability of the intervention (parental questionnaires including the Warwick-Edinburgh Mental Wellbeing Scale (WEBWMS), qualitative observations and in-depth interviews with parents and therapists). We also reviewed clinical imaging data and undertook assessments of motor function, including the Hand Assessment for Infants (HAI). Assessments were also piloted in typically developing (TD) infants, to provide further information on their ease of use and acceptability. Results: Over a period of 18 months we screened 20 infants referred as PS/HPI: 14 met the inclusion criteria and 13 took part. At 6 months, 11 (85%) of those enrolled had completed the final assessment. Parents valued the intervention and found it acceptable and workable. There were no adverse events related to the intervention. We recruited 14 TD infants, one of whom died prior to undertaking any assessments and one of whom was subsequently found to have a condition affecting neurodevelopmental progress: thus, data for 12 TD infants was analysed to 6 months. The HAI was well tolerated by infants and highly valued by parents. Completion rates for the WEBWMS were high and did not suggest any adverse effect of engagement in eTIPS on parental mental wellbeing. Conclusion: The eTIPS intervention was feasible to deliver and acceptable to families. We plan to investigate efficacy in a multicentre randomised controlled trial

Risk of malignancy in patients with systemic lupus erythematosus: Systematic review and meta-analysis.

BACKGROUND: Malignancy is a potential comorbidity in patients with systemic lupus erythematosus (SLE). However, risk by malignancy type remains to be fully elucidated. We evaluated the risk of malignancy type in SLE patients in a systematic review and meta-analysis. METHODS: MEDLINE and EMBASE were searched from inception to July 2018 to identify observational studies that evaluated malignancy risk in adult SLE patients compared with the general population. Random-effects models were used to calculate pooled risk ratios (RRs) and 95% confidence intervals (CIs). Heterogeneity was quantified using the I2 test. FINDINGS: Forty-one studies reporting on 40 malignancies (one overall, 39 site-specific) were included in the meta-analysis. The pooled RR for all malignancies from 3694 events across 80 833 patients was 1.18 (95% CI: 1.00-1.38). The risk of 24 site-specific malignancies (62%) was increased in SLE patients. For malignancies with ≥6 studies, non-Hodgkin lymphoma and Hodgkin lymphoma risk was increased >3-fold; myeloma and liver >2-fold; cervical, lung, bladder, and thyroid ≥1.5-fold; stomach and brain >1.3-fold. The risk of four malignancies (breast, uterine, melanoma, prostate) was decreased, whereas risk of 11 other malignancies did not differ between SLE patients and the general population. Heterogeneity ranged between 0% and 96%, and 63% were non-significant. INTERPRETATION: The risk of overall and some site-specific malignancies is increased in SLE compared with the general population. However, the risk for some site-specific malignancies is decreased or did not differ. Further examination of risk profiles and SLE patient phenotypes may support guidelines aimed at reducing malignancy risk. FUNDING: AstraZeneca. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number: CRD42018110433

The risk of infections in adult patients with systemic lupus erythematosus: systematic review and meta-analysis.

OBJECTIVES: We conducted a systematic review and meta-analysis to determine the magnitude of infection risk in patients with SLE and evaluate the effect of general and SLE-related factors on infection risk. METHODS: We searched MEDLINE and Embase from inception to July 2018, screening for observational studies that evaluated infection risk in patients with SLE compared with the general population/healthy controls. Outcomes of interest included overall severe infection, herpes zoster infection/reactivation, opportunistic infections, pneumonia and tuberculosis. Random-effects models were used to calculate pooled risk ratios (RRs) for each type of infection. Sensitivity analysis assessed the impact of removing studies with high risk of bias. RESULTS: Eleven retrospective or prospective cohort studies were included in the meta-analysis: overall severe infection (n = 4), pneumonia (n = 6), tuberculosis (n = 3) and herpes zoster (n = 2). Pooled RRs for overall severe infection significantly increased for patients with SLE compared with the general population/healthy controls [RR 2.96 (95% CI 1.28, 6.83)]. Pooled RRs for pneumonia, herpes zoster and tuberculosis showed significantly increased risk compared with the general population/healthy controls [RR 2.58 (1.80, 3.70), 2.50 (2.36, 2.65) and 6.11 (3.61, 10.33), respectively]. Heterogeneity and evidence of publication bias were present for all analyses, except herpes zoster. Sensitivity analyses confirmed robustness of the results. CONCLUSION: Patients with SLE have significantly higher risk of infection compared with the general population/healthy controls. Efforts to strengthen strategies aimed at preventing infections in SLE are needed. PROTOCOL REGISTRATION: PROSPERO number: CRD42018109425

The Warnie volcanic province : Jurassic intraplate volcanism in Central Australia

We wish to thank Santos Ltd. for providing us with the Snowball 3D seismic survey. In particular we wish to thank Jenni Clifford and Lance Holmes who provided helpful feedback and 2D seismic lines covering the Lambda 1, Orientos 2 and Warnie East 1 wells. We also wish to thank Beach Energy, in particular Rob Menpes, for the helpful discussions and feedback on the manuscript in addition to helping us with the analysis of the magnetic data. The work contained in this paper contains work conducted during a PhD study undertaken as part of the Natural Environment Research Council (NERC) Centre for Doctoral Training (CDT) in Oil & Gas [grant number NEM00578X/1] and is fully funded by NERC whose support is gratefully acknowledged. Lastly, the two anonymous reviews of the manuscript are thanked for their insightful and constructive comments that significantly improved the work presented.Peer reviewedPostprin

Admixture Mapping Scans Identify a Locus Affecting Retinal Vascular Caliber in Hypertensive African Americans: the Atherosclerosis Risk in Communities (ARIC) Study

Retinal vascular caliber provides information about the structure and health of the microvascular system and is associated with cardiovascular and cerebrovascular diseases. Compared to European Americans, African Americans tend to have wider retinal arteriolar and venular caliber, even after controlling for cardiovascular risk factors. This has suggested the hypothesis that differences in genetic background may contribute to racial/ethnic differences in retinal vascular caliber. Using 1,365 ancestry-informative SNPs, we estimated the percentage of African ancestry (PAA) and conducted genome-wide admixture mapping scans in 1,737 African Americans from the Atherosclerosis Risk in Communities (ARIC) study. Central retinal artery equivalent (CRAE) and central retinal vein equivalent (CRVE) representing summary measures of retinal arteriolar and venular caliber, respectively, were measured from retinal photographs. PAA was significantly correlated with CRVE (ρ = 0.071, P = 0.003), but not CRAE (ρ = 0.032, P = 0.182). Using admixture mapping, we did not detect significant admixture association with either CRAE (genome-wide score = −0.73) or CRVE (genome-wide score = −0.69). An a priori subgroup analysis among hypertensive individuals detected a genome-wide significant association of CRVE with greater African ancestry at chromosome 6p21.1 (genome-wide score = 2.31, locus-specific LOD = 5.47). Each additional copy of an African ancestral allele at the 6p21.1 peak was associated with an average increase in CRVE of 6.14 µm in the hypertensives, but had no significant effects in the non-hypertensives (P for heterogeneity <0.001). Further mapping in the 6p21.1 region may uncover novel genetic variants affecting retinal vascular caliber and further insights into the interaction between genetic effects of the microvascular system and hypertension

Exploring Human Milk, Nutrition, Growth, and Breastfeeding Rates at Discharge(HUMMINGBIRD Study): a protocol for a pilot randomised controlled trial

Introduction Mother’s own breast milk (MOM) is the optimal nutrition for preterm infants as it reduces the incidence of key neonatal morbidities and improves long-term outcomes. However, MOM shortfall is common and either preterm formula or pasteurised donor human milk (DHM) may be used, although practice varies widely. Limited data suggest that the use of DHM may impact maternal beliefs and behaviours and therefore breastfeeding rates. The aim of this pilot study is to determine if longer duration of DHM exposure increases breastfeeding rates, and if a randomised controlled trial (RCT) design is feasible.Methods and analysis The Human Milk, Nutrition, Growth, and Breastfeeding Rates at Discharge (HUMMINGBIRD) Study is a feasibility and pilot, non-blinded RCT with a contemporaneous qualitative evaluation. Babies born less than 33 weeks’ gestation or with birth weight &lt;1500 g whose mothers intend to provide MOM are randomly assigned to either control (DHM used to make up shortfall until full feeds and preterm formula thereafter) or intervention (DHM used for shortfall until 36 weeks’ corrected age or discharge if sooner). The primary outcome is breast feeding at discharge. Secondary outcomes include growth, neonatal morbidities, length of stay, breastfeeding self-efficacy and postnatal depression using validated questionnaires. Qualitative interviews using a topic guide will explore perceptions around use of DHM and analysed using thematic analysis.Ethics approval and dissemination Nottingham 2 Research Ethics Committee granted approval (IRAS Project ID 281071) and recruitment commenced on 7 June 2021. Results will be disseminated in peer-reviewed journals.Trial registration number ISRCTN57339063

Association of COPD exacerbations and acute cardiovascular events: a systematic review and meta-analysis

Background: The majority of patients with chronic obstructive pulmonary disease (COPD) suffer from comorbid cardiovascular (CV) disease. Accumulating evidence suggests a temporal association between COPD exacerbations and acute CV events, possibly due to lung hyperinflation, increased hypoxemia and systemic inflammation. The aims of the study were to estimate the risk of (1) acute CV events [acute myocardial infarction (AMI), CV-related death] or stroke in the months following a COPD exacerbation and (2) COPD exacerbation in the months following an acute CV event. Methods: A systematic literature review of observational studies published since 2000 was conducted by searching literature databases (Medline and Embase). Studies were eligible if conducted in adults with COPD, exposed to either COPD exacerbation or acute CV events, with outcomes of acute CV events or COPD exacerbation reported. Studies were appraised for relevance, bias and quality. Meta-analyses, using random-effect models, were performed for each outcome of interest, thus providing a pooled relative risk (RR) and its 95% confidence interval. Results: Eight studies were identified, of which seven were used for the meta-analyses examining the risk of CV events 1–3 months after an exacerbation compared with none. For stroke (six studies), RR was 1.68 (95% CI = 1.19–2.38). For AMI (six studies), RR was 2.43 (95% CI = 1.40–4.20). No studies exploring risk of exacerbation following an acute CV event were identified. Conclusion: This meta-analysis identified a markedly increased risk of stroke or AMI within a relatively short period of time following a COPD exacerbation. Although the underlying mechanisms are not fully elucidated, patients with COPD should be monitored for risk of CV outcomes after exacerbations. In addition, preventing exacerbations may decrease the risk of subsequent acute CV events. Registration: The study protocol was published via PROSPERO: International Prospective Register of Systematic Reviews (#CRD42020211055)

Characteristics of invasive staphylococcus aureus in United Kingdom neonatal units

BACKGROUND: In industrialized countries, Staphylococcus aureus (SA) is a leading cause of late-onset neonatal sepsis. METHODS: Culture-proven episodes were identified prospectively from neonatal units participating in the neonatal infection surveillance network. Demographic, risk factor, and outcome data were collected. RESULTS: Between 2004 and 2009, there were 117 episodes of SA infections (including 8 methicillin-resistant SA) in 116 infants from 13 units. The median gestational age and birth-weight were 27 weeks (90% ≤37 weeks, 85% ≤32 weeks) and 850 g (90% ≤2500 g), respectively. The overall incidence was 0.6 per 1000 live births and 23/1000 in infants <1500 g. Most episodes (94%) occurred more than 48 hours after birth (late onset). There were 7 early-onset episodes (<48 hours) (median gestational age, 38.5 weeks), all due to methicillin-susceptible SA. At the time of culture, 67 of 95 (71%) infants were receiving respiratory support and 47 of 94 (50%) had a central line in situ. The majority of infants had nonspecific clinical features although evidence of focal infection (skin, soft tissue, bone, joint, or pneumonia) was ultimately seen in 41 of 91 (45%). There were 18 deaths, 4 (all late onset) directly due to methicillin-susceptible SA sepsis (4.4%). CONCLUSIONS: SA is the second most common pathogen causing late-onset neonatal infections in this neonatal network. Infants who weigh <1500 g in intensive care settings are the most vulnerable group. Clinical signs are not sufficiently distinctive to allow targeted therapy, suggesting that an antistaphylococcal agent should be part of empiric therapy for late-onset sepsis in premature infants