Claire Friedemann Smith

Quantifying the Association Between Physical Activity and Cardiovascular Disease and Diabetes: A Systematic Review and Meta‐Analysis

Background The relationships between physical activity (PA) and both cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) have predominantly been estimated using categorical measures of PA, masking the shape of the dose‐response relationship. In this systematic review and meta‐analysis, for the very first time we are able to derive a single continuous PA metric to compare the association between PA and CVD/T2DM, both before and after adjustment for a measure of body weight. Methods and Results The search was applied to MEDLINE and EMBASE electronic databases for all studies published from January 1981 to March 2014. A total of 36 studies (3 439 874 participants and 179 393 events, during an average follow‐up period of 12.3 years) were included in the analysis (33 pertaining to CVD and 3 to T2DM). An increase from being inactive to achieving recommended PA levels (150 minutes of moderate‐intensity aerobic activity per week) was associated with lower risk of CVD mortality by 23%, CVD incidence by 17%, and T2DM incidence by 26% (relative risk [RR], 0.77 [0.71–0.84]), (RR, 0.83 [0.77–0.89]), and (RR, 0.74 [0.72–0.77]), respectively, after adjustment for body weight. Conclusions By using a single continuous metric for PA levels, we were able to make a comparison of the effect of PA on CVD incidence and mortality including myocardial infarct (MI), stroke, and heart failure, as well as T2DM. Effect sizes were generally similar for CVD and T2DM, and suggested that the greatest gain in health is associated with moving from inactivity to small amounts of PA.

Improved neuroprotection using miglustat, curcumin and ibuprofen as a triple combination therapy in Niemann-Pick disease type C1 mice.

OBJECTIVES Niemann-Pick disease type C (NPC) is a neurodegenerative lysosomal storage disorder characterised by the storage of multiple lipids, reduced lysosomal calcium levels, impaired late endosome:lysosome fusion and neuroinflammation. NPC is caused by mutations in either of the two genes, NPC1 or NPC2, which are believed to function in a common cellular pathway, the function of which remains unclear. The complexity of the pathogenic cascade in NPC disease provides a number of potential clinical intervention points. To date, drugs that target pivotal stages in the pathogenic cascade have been tested as monotherapies or in combination with a second agent, showing additive or synergistic benefit. In this study, we have investigated whether we can achieve greater therapeutic benefit in the Npc1(-/-) mouse by combining three therapies that each targets unique aspects of the pathogenic cascade. METHODS We have treated Npc1(-/-) mice with miglustat that targets sphingolipid synthesis and storage, curcumin that compensates for the lysosomal calcium defect by elevating cytosolic calcium, and the non-steroidal anti-inflammatory drug ibuprofen to reduce central nervous system inflammation. RESULTS/INTERPRETATION We have found that triple combination therapy has a greater neuroprotective benefit compared with single and dual therapies, increasing the time period that Npc1(-/-) mice maintained body weight and motor function and maximally delaying the onset of Purkinje cell loss. In addition, ibuprofen selectively reduced microglial activation, while curcumin had no anti-inflammatory effects, indicating differential mechanisms of action for these two therapies. When taken together, these results demonstrate that targeting multiple unique steps in the pathogenic cascade maximises the clinical benefit in a mouse model of NPC1 disease.

What prompts help-seeking for cancer ‘alarm' symptoms? A primary care based survey

Background:Encouraging prompt help-seeking for cancer symptoms can help shorten the patient interval and improve timely diagnosis. We explored factors associated with help-seeking in a primary care sample reporting ‘alarm’ symptoms.Methods:A questionnaire was mailed to 9771 adults (⩾50 years of age and no cancer diagnosis) and 3766 (39%) returned it. Our sample included 1732 adults reporting at least one cancer ‘alarm’ symptom; with a total of 2726 symptoms. Respondents completed questions relating to help-seeking, demographic and symptom characteristics (e.g., type, knowledge, concern, interference and attribution).Results:Over a third of people who reported a cancer ‘alarm’ symptom in the past 3 months had not sought help from a doctor. An unexplained lump (odds ratio (OR) 2.46, 1.42–4.26) and persistent unexplained pain (OR 1.79, 1.19–2.69) were associated with increased likelihood of help-seeking. Symptom concern (OR 3.10, 2.19–4.39) and interference (OR 3.06, 2.15–4.36) were associated with an increased likelihood of seeking help independently of symptom type. People who were not working (OR 1.41, 1.09–1.83), were married/cohabiting rather than single (OR 1.38, 1.10–1.74) and were older (60–69 years) rather than younger (50–59 years; OR 1.33, 1.02–1.75) were more likely to have sought help.Conclusions:Our findings highlighted symptom type and symptom characteristics as key drivers of help-seeking. We also found that there may be specific demographic groups where encouraging help-seeking might be warranted.

Moving Focus from Weight to Health. What Are the Components Used in Interventions to Improve Cardiovascular Health in Children

Introduction Obesity in childhood impacts on many areas of the child’s current and future health, including their cardiovascular health. To date many attempts have been made to design interventions to tackle excess childhood weight but with limited success. We aimed to establish the components common to interventions in children that improve cardiovascular health parameters. Methods We searched the following databases: EMBASE 1974-week 3 November 2014, Ovid Medline 1946 Present, and PsychINFO 1967-Present for studies reporting interventions in healthy young people under the age of 18. Included interventions had to contain an education component and have been carried out in a community, school, or clinical setting. Papers had to report on at least one of the pre-specified CVD risk parameters and at least one non-biological outcome from knowledge, attitudes or behaviours. Results We retrieved 2451 papers, from which 12 studies (18 papers) of 3046 participants were included. From the selected papers we identified four component themes; Health Behaviours, Self-Concept, Practical and Cognitive Tools, and Intervention Characteristics. The subcomponents that made up these themes were fairly consistent across the studies analysed although the studies varied in their duration, settings and children with which they were carried out. Nine of the studies were able to bring about positive change in at least one biological and one non-biological aspect of child cardiovascular health. Conclusion The component themes identified here were common to intervention studies that had success in improving parameters of cardiovascular health. We suggest that the focus of childhood health interventions be moved from weight onto cardiovascular health parameters and that future interventions use the lessons learned by their predecessors to incorporate those components that are associated with successful interventions.

General practitioner referrals to one-stop clinics for symptoms that could be indicative of cancer: a systematic review of use and clinical outcomes.

BACKGROUND One-stop clinics provide comprehensive diagnostic testing in one outpatient appointment. They could benefit patients with conditions, such as cancer, whose outcomes are improved by early diagnosis, and bring efficiency savings for health systems. OBJECTIVE To assess the use and outcomes of one-stop clinics for symptoms where cancer is a possible diagnosis. DESIGN AND SETTING Systematic review of studies reporting use and outcomes of one-stop clinics in primary care patients. METHOD We searched MEDLINE, Embase, and Cochrane Library for studies assessing one-stop clinics for adults referred after presenting to primary care with any symptom that could be indicative of cancer. Study selection was carried out independently in duplicate with disagreements resolved through discussion. RESULTS Twenty-nine studies were identified, most were conducted in the UK and observational in design. Few included a comparison arm. A pooled comparison of the cancer conversion rate of one-stop and multi-stop clinics was only possible for breast symptoms, and we found no significant difference. One-stop clinics were associated with significant reductions in the interval from referral to testing (15 versus 75 days) and more patients diagnosed on the same day (79% versus 25%) compared to multi-stop pathways. The majority of patients and GPs found one-stop clinics to be acceptable. CONCLUSION This review found one-stop clinics were associated with reduced time from referral to testing, increased same day diagnoses, and were acceptable to patients and GPs. Our conclusions are limited by high levels of heterogeneity, scarcity of comparator groups, and the overwhelmingly observational nature of included studies.

Direct access cancer testing in primary care: a systematic review of use and clinical outcomes

BACKGROUND Direct access (DA) testing allows GPs to refer patients for investigation without consulting a specialist. The aim is to reduce waiting time for investigations and unnecessary appointments, enabling treatment to begin without delay. AIM To establish the proportion of patients diagnosed with cancer and other diseases through DA testing, time to diagnosis, and suitability of DA investigations. DESIGN AND SETTING Systematic review assessing the effectiveness of GP DA testing in adults. METHOD MEDLINE, Embase, and the Cochrane Library were searched. Where possible, study data were pooled and analysed quantitatively. Where this was not possible, the data are presented narratively. RESULTS The authors identified 60 papers that met pre-specified inclusion criteria. Most studies were carried out in the UK and were judged to be of poor quality. The authors found no significant difference in the pooled cancer conversion rate between GP DA referrals and patients who first consulted a specialist for any test, except gastroscopy. There were also no significant differences in the proportions of patients receiving any non-cancer diagnosis. Referrals for testing were deemed appropriate in 66.4% of those coming from GPs, and in 80.9% of those from consultants; this difference was not significant. The time from referral to testing was significantly shorter for patients referred for DA tests. Patient and GP satisfaction with DA testing was consistently high. CONCLUSION GP DA testing performs as well as, and on some measures better than, consultant triaged testing on measures of disease detection, appropriateness of referrals, interval from referral to testing, and patient and GP satisfaction.

Galunisertib plus gemcitabine vs. gemcitabine for first-line treatment of patients with unresectable pancreatic cancer

BackgroundGalunisertib is the first-in-class, first-in-human, oral small-molecule type I transforming growth factor-beta receptor (ALK5) serine/threonine kinase inhibitor to enter clinical development. The effect of galunisertib vs. placebo in patients with unresectable pancreatic cancer was determined.MethodsThis was a two-part, multinational study: phase 1b was a non-randomised, open-label, multicentre, and dose-escalation study; phase 2 was a randomised, placebo- and Bayesian-augmented controlled, double-blind study in patients with locally advanced or metastatic pancreatic adenocarcinoma considered candidates for first-line chemotherapy with gemcitabine. Patients were randomised 2:1 to galunisertib–gemcitabine (N = 104) or placebo-gemcitabine (N = 52). Gemcitabine dose was 1000 mg/m2 QW. Primary endpoints for phases 1b and 2, respectively, were phase 2 dose and overall survival. Secondary objectives included tolerability and biomarkers.ResultsDose-escalation suggested a 300-mg/day dose. Primary objective was met: median survival times were 8.9 and 7.1 months for galunisertib and placebo, respectively (hazard ratio [HR] = 0.79 [95% credible interval: 0.59–1.09] and posterior probability HR < 1 = 0.93). Lower baseline biomarkers macrophage inflammatory protein-1-alpha and interferon-gamma-induced protein 10 were associated with galunisertib benefit.ConclusionsGalunisertib–gemcitabine combination improved overall survival vs. gemcitabine in patients with unresectable pancreatic cancer, with minimal added toxicity. Future exploration of galunisertib in pancreatic cancer is ongoing in combination with durvalumab.