The impact of social media influencers on health outcomes: Systematic review.

A fast emerging area of public health interest is the potential role of social media influencers in spreading health information and affecting health behaviour. The aim of this research was to systematically synthesise evidence on the impact of social media influencers on health outcomes. A systematic search of six databases (Medline, Embase, PsycINFO, CINAHL, Science Citation Index and Sociology Collection) was conducted in October 2021, with an update search in January 2023. Two reviewers independently screened titles and abstracts. We included interventional study designs which examined the effect of social media influencer as the primary or only exposure on a quantified health outcome. We used narrative synthesis to summarise the characteristics and main findings of studies within each of four main topic areas. We assessed quality using a critical appraisal checklist for quasi-experimental studies. We identified twelve studies across four areas that met the inclusion criteria: children's dietary behaviour (n = 5), body image dissatisfaction (n = 4), influenza and COVID-19 (n = 2), and social comparison and anxiety (n = 1). Influencer marketing of unhealthy foods had a statistically significant effect on increasing children's immediate energy intake, but no effect was found for influencer promotion of vegetables. When an unhealthy food is marketed by an influencer of unhealthy appearance, this led to an increased preference for healthy snacks. Exposure to idealised influencer body imagery had statistically significant negative impacts on body image and mood. Anxiety caused by viewing idealised portrayals of motherhood was the same whether or not the portrayal was by an influencer. Public health campaigns harnessing influencers to promote hygiene habits in the context of COVID-19 and influenza showed some positive changes in health behaviours. Most of the published studies are of poor methodological quality with poor generalisability and statistical weaknesses. We conclude that social media influencers have both negative and positive impacts on health outcomes, with negative impacts seen consistently in studies of body image dissatisfaction. Further research is needed to harness the potential positive health impact of social media influencers, while mitigating against harmful effects.

Assessing Trans-Inhibition of OATP1B1 and OATP1B3 by Calcineurin and/or PPIase Inhibitors and Global Identification of OATP1B1/3-Associated Proteins.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are key determinants of drug-drug interactions (DDIs). Various drugs including the calcineurin inhibitor (CNI) cyclosporine A (CsA) exert preincubation-induced trans-inhibitory effects upon OATP1B1 and/or OATP1B3 (abbreviated as OATP1B1/3) by unknown mechanism(s). OATP1B1/3 are phosphoproteins; calcineurin, which dephosphorylates and regulates numerous phosphoproteins, has not previously been investigated in the context of preincubation-induced trans-inhibition of OATP1B1/3. Herein, we compare the trans-inhibitory effects exerted on OATP1B1 and OATP1B3 by CsA, the non-analogous CNI tacrolimus, and the non-CNI CsA analogue SCY-635 in transporter-overexpressing human embryonic kidney (HEK) 293 stable cell lines. Preincubation (10-60 min) with tacrolimus (1-10 µM) rapidly and significantly reduces OATP1B1- and OATP1B3-mediated transport up to 0.18 ± 0.03- and 0.20 ± 0.02-fold compared to the control, respectively. Both CsA and SCY-635 can trans-inhibit OATP1B1, with the inhibitory effects progressively increasing over a 60 min preincubation time. At each equivalent preincubation time, CsA has greater trans-inhibitory effects toward OATP1B1 than SCY-635. Preincubation with SCY-635 for 60 min yielded IC50 of 2.2 ± 1.4 µM against OATP1B1, which is ~18 fold greater than that of CsA (0.12 ± 0.04 µM). Furthermore, a proteomics-based screening for protein interactors was used to examine possible proteins and processes contributing to OATP1B1/3 regulation and preincubation-induced inhibition by CNIs and other drugs. A total of 861 and 357 proteins were identified as specifically associated with OATP1B1 and OATP1B3, respectively, including various protein kinases, ubiquitin-related enzymes, the tacrolimus (FK506)-binding proteins FKBP5 and FKBP8, and several known regulatory targets of calcineurin. The current study reports several novel findings that expand our understanding of impaired OATP1B1/3 function; these include preincubation-induced trans-inhibition of OATP1B1/3 by the CNI tacrolimus, greater preincubation-induced inhibition by CsA compared to its non-CNI analogue SCY-635, and association of OATP1B1/3 with various proteins relevant to established and candidate OATP1B1/3 regulatory processes.

OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005.

The safety, tolerability, immunogenicity, and pharmacokinetic (PK) profile of an anti-OX40L monoclonal antibody (KY1005, currently amlitelimab) were evaluated. Pharmacodynamic (PD) effects were explored using keyhole limpet hemocyanin (KLH) and tetanus toxoid (TT) immunizations. Sixty-four healthy male subjects (26.5 ± 6.0 years) were randomized to single doses of 0.006, 0.018, or 0.05 mg/kg, or multiple doses of 0.15, 0.45, 1.35, 4, or 12 mg/kg KY1005, or placebo (6:2). Serum KY1005 concentrations were measured. Antibody responses upon KLH and TT immunizations and skin response upon intradermal KLH administration were performed. PD data were analyzed using repeated measures analysis of covariances (ANCOVAs) and post hoc exposure-response modeling. No serious adverse events occurred and all adverse events were temporary and of mild or moderate severity. A nonlinear increase in mean serum KY1005 concentrations was observed (median time to maximum concentration (Tmax ) ~ 4 hours, geometric mean terminal half-life (t½) ~ 24 days). Cutaneous blood perfusion (estimated difference (ED) -13.4 arbitrary unit (AU), 95% confidence interval (CI) -23.0 AU to -3.8 AU) and erythema quantified as average redness (ED -0.23 AU, 95% CI -0.35 AU to -0.11 AU) decreased after KY1005 treatment at doses of 0.45 mg/kg and above. Exposure-response analysis displayed a statistically significant treatment effect on anti-KLH antibody titers (IgG maximum effect (Emax ) -0.58 AU, 95% CI -1.10 AU to -0.06 AU) and skin response (erythema Emax -0.20 AU, 95% CI -0.29 AU to -0.11 AU). Administration of KY1005 demonstrated an acceptable safety and tolerability profile and PK analyses displayed a nonlinear profile of KY1005. Despite the observed variability, skin challenge response after KY1005 treatment indicated pharmacological activity of KY1005. Therefore, KY1005 shows potential as a novel pharmacological treatment in immune-mediated disorders.

Lack of uniformity in reporting autoimmune gastritis among a diverse group of pathologists.

Autoimmune gastritis (AIG) is a clinicopathologic diagnosis requiring characteristic histopathology and correlation with laboratory work-up. To better understand how the diagnosis of AIG is made and reported in the pathology community, we conducted an anonymous web-based survey which was circulated among a diverse group of pathologists. Excluding trainees there were 64 respondents: 25 academic gastrointestinal pathologists (AGI, 39%), 22 academic general pathologists (AGP, 34%), 17 private general pathologists (PP, 27%). Our survey results highlighted variations in work-up and sign-out practices. The type of metaplasia needed to diagnose AIG lacked consensus. There was variation in accurate interpretation of immunostains with a trend towards more accurate diagnosis of enterochromaffin-like (ECL) cell hyperplasia by AGI (92%) and AGP (95%) than PP (71%) (p = 0.07). G-cells in antrum on neuroendocrine immunostain, a mimicker of ECL cell hyperplasia, was more frequently misdiagnosed by PP/ AGP (44%), versus AGI (12%) (p = 0.02). A triple immunostain panel (H. pylori, neuroendocrine, gastrin) was used in the work-up of AIG by 72% of AGI versus 23% AGP and 12% PP (p = 0.000061). The less-specific term "atrophic gastritis" was used in the diagnostic line more by respondents with >10 years sign-out experience compared with others (p = 0.04). In conclusion, the survey results highlighted deficiencies in the interpretation of neuroendocrine immunostains which is crucial for AIG diagnosis, as well as variation in reporting practices and definitions. Uniform criteria and terminology are needed in this field to improve communication with clinicians, resulting in appropriate testing and follow-up.

Radiation Therapy for Treatment of Soft Tissue Sarcoma in Adults: Executive Summary of an ASTRO Clinical Practice Guideline.

PURPOSE: This guideline provides evidence-based recommendations addressing the indications for radiation therapy (RT), sequencing of local therapies, and appropriate dose and planning techniques for management of primary, operable, localized, soft tissue sarcoma (STS) in adults. METHODS: The American Society for Radiation Oncology convened a task force to address 5 key questions focused on the use of RT for management of STS. These questions included indications for RT for STS of the extremity and superficial trunk; considerations for sequencing of RT with respect to surgery, dose of RT, appropriate treatment volumes and techniques; and the role of RT in management of retroperitoneal sarcoma. Recommendations were based on a systematic literature review and created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: Multidisciplinary evaluation and decision making are recommended for all cases of STS. RT is recommended for patients in whom there is increased risk of local recurrence of resected STS, particularly if close or microscopically positive margins are anticipated or have occurred. When RT is indicated, preoperative RT is strongly recommended over postoperative RT. Postoperative RT is conditionally recommended in specific clinical circumstances (eg, uncontrolled pain or bleeding) or when the risk of wound complications outweighs that of late toxicity from RT. Routine use of RT in addition to oncologic resection for retroperitoneal sarcoma is conditionally not recommended. When RT is used for retroperitoneal sarcoma, preoperative RT is recommended, whereas postoperative RT is not recommended. CONCLUSIONS: Based on currently published data, the American Society for Radiation Oncology task force has proposed evidence-based recommendations regarding the use of RT for STS in adults. Future studies will ascertain whether alterations in dosing and sequencing may optimize outcomes and quality of life.

The Ovarian Transcriptome of Reproductively Aged Multiparous Mice: Candidate Genes for Ovarian Cancer Protection.

In middle-aged women, the decline of ovarian follicle reserve below a critical threshold marks menopause, leading to hormonal, inflammatory, and metabolic changes linked to disease. The highest incidence and mortality of sporadic ovarian cancer (OC) occur at post-menopause, while OC risk is reduced by full-term pregnancies during former fertile life. Herein, we investigate how parity history modulates the ovarian transcriptome related to such declining follicle pool and systemic inflammation in reproductively-aged mice. Female C57BL/6 mice were housed under multiparous and virgin (nulliparous) breeding regimens from adulthood until estropause. The ovaries were then subjected to follicle count and transcriptional profiling, while a cytokine panel was determined in the sera. As expected, the follicle number was markedly decreased just by aging. Importantly, a significantly higher count of primordial and total follicles was observed in aged multiparous relative to aged virgin ovaries. Consistently, among the 65 genes of higher expression in aged multiparous ovaries, 27 showed a follicle count-like pattern, 21 had traceable evidence of roles in follicular/oocyte homeostasis, and 7 were transforming-growth factor beta (TGF-ß)/bone morphogenetic protein (BMP) superfamily members. The remaining genes were enriched in cell chemotaxis and innate-immunity, and resembled the profiles of circulating CXCL1, CXCL2, CXCL5, CSF3, and CCL3, chemokines detected at higher levels in aged multiparous mice. We conclude that multiparity during reproductive life promotes the retention of follicle remnants while improving local (ovarian) and systemic immune-innate surveillance in aged female mice. These findings could underlie the mechanisms by which pregnancy promotes the long-term reduced OC risk observed at post-menopause.

Publisher Correction: Pattern of Altered Plasma Elemental Phosphorus, Calcium, Zinc, and Iron in Alzheimer's Disease.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Pattern of Altered Plasma Elemental Phosphorus, Calcium, Zinc, and Iron in Alzheimer's Disease.

Metal/mineral dyshomeostasis has been implicated in the development of Alzheimer's disease (AD). The aim of the study was to investigate the difference in absolute and percentage levels of plasma phosphorus, calcium, iron, zinc, copper, selenium in cognitively normal (CN) and AD subjects. Total reflection X-ray fluorescence (TXRF) spectroscopy was used to detect plasma metals/minerals in CN and AD subjects (n = 44 per group). TXRF detected significantly increased plasma levels of phosphorus (p = 1.33 × 10-12) and calcium (p = 0.025) in AD compared to CN subjects, with higher phosphorus/calcium (p = 2.55 × 10-14) ratio in the former. Percentage concentrations calculated for phosphorus, calcium, iron, zinc, copper, selenium by dividing the concentration of each element by the total concentration of these elements and multiplying by 100%, demonstrated phosphorus was higher in AD compared to CN subjects, while calcium, iron, zinc, copper and selenium were lower in AD subjects, with area under the curves as high as 0.937 (p = 6 × 10-5) computed from receiver operating curves. With exclusion of high levels of phosphorus and calcium from percentage calculations, iron levels remained low in AD whereas zinc was higher in AD, and copper and selenium levels were similar. We demonstrate altered distribution of elements in the plasma of AD subjects with high interdependencies between elemental levels and propose the potential of TXRF measurements for disease monitoring.

Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma.

Adult T cell leukemia/lymphoma (ATLL) is a frequently incurable disease associated with the human lymphotropic virus type I (HTLV-I). RNAi screening of ATLL lines revealed that their proliferation depends on BATF3 and IRF4, which cooperatively drive ATLL-specific gene expression. HBZ, the only HTLV-I encoded transcription factor that is expressed in all ATLL cases, binds to an ATLL-specific BATF3 super-enhancer and thereby regulates the expression of BATF3 and its downstream targets, including MYC. Inhibitors of bromodomain-and-extra-terminal-domain (BET) chromatin proteins collapsed the transcriptional network directed by HBZ and BATF3, and were consequently toxic for ATLL cell lines, patient samples, and xenografts. Our study demonstrates that the HTLV-I oncogenic retrovirus exploits a regulatory module that can be attacked therapeutically with BET inhibitors.

Efficacy and safety of prostate artery embolization for benign prostatic hyperplasia: an observational study and propensity-matched comparison with transurethral resection of the prostate (the UK-ROPE study).

OBJECTIVES: To assess the efficacy and safety of prostate artery embolization (PAE) for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) and to conduct an indirect comparison of PAE with transurethral resection of the prostate (TURP). PATIENTS AND METHODS: As a joint initiative between the British Society of Interventional Radiologists, the British Association of Urological Surgeons and the National Institute for Health and Care Excellence, we conducted the UK Register of Prostate Embolization (UK-ROPE) study, which recruited 305 patients across 17 UK urological/interventional radiology centres, 216 of whom underwent PAE and 89 of whom underwent TURP. The primary outcomes were International Prostate Symptom Score (IPSS) improvement in the PAE group at 12 months post-procedure, and complication data post-PAE. We also aimed to compare IPSS score improvements between the PAE and TURP groups, using non-inferiority analysis on propensity-score-matched patient pairs. The clinical results and urological measurements were performed at clinical sites. IPSS and other questionnaire-based results were mailed by patients directly to the trial unit managing the study. All data were uploaded centrally to the UK-ROPE study database. RESULTS: The results showed that PAE was clinically effective, producing a median 10-point IPSS improvement from baseline at 12 months post-procedure. PAE did not appear to be as effective as TURP, which produced a median 15-point IPSS score improvement at 12 months post-procedure. These findings are further supported by the propensity score analysis, in which we formed 65 closely matched pairs of patients who underwent PAE and patients who underwent TURP. In terms of IPSS and quality-of-life (QoL) improvement, there was no evidence of PAE being non-inferior to TURP. Patients in the PAE group had a statistically significant improvement in maximum urinary flow rate and prostate volume reduction at 12 months post-procedure. PAE had a reoperation rate of 5% before 12 months and 15% after 12 months (20% total rate), and a low complication rate. Of 216 patients, one had sepsis, one required a blood transfusion, four had local arterial dissection and four had a groin haematoma. Two patients had non-target embolization that presented as self-limiting penile ulcers. Additional patient-reported outcomes, pain levels and return to normal activities were very encouraging for PAE. Seventy-one percent of PAE cases were performed as outpatient or day cases. In contrast, 80% of TURP cases required at least 1 night of hospital stay, and the majority required 2 nights. CONCLUSION: Our results indicate that PAE provides a clinically and statistically significant improvement in symptoms and QoL, although some of these improvements were greater in the TURP arm. The safety profile and quicker return to normal activities may be seen as highly beneficial by patients considering PAE as an alternative treatment to TURP, with the concomitant advantages of reduced length of hospital stay and need for admission after PAE. PAE is an advanced embolization technique demanding a high level of expertise, and should be performed by experienced interventional radiologists who have been trained and proctored appropriately. The use of cone-beam computed tomography is encouraged to improve operator confidence and minimize non-target embolizations. The place of PAE in the care pathway is between that of drugs and surgery, allowing the clinician to tailor treatment to individual patients' symptoms, requirements and anatomical variation.

No Genetic Overlap Between Circulating Iron Levels and Alzheimer's Disease.

Iron deposition in the brain is a prominent feature of Alzheimer's disease (AD). Recently, peripheral iron measures have also been shown to be associated with AD status. However, it is not known whether these associations are causal: do elevated or depleted iron levels throughout life have an effect on AD risk? We evaluate the effects of peripheral iron on AD risk using a genetic profile score approach by testing whether variants affecting iron, transferrin, or ferritin levels selected from GWAS meta-analysis of approximately 24,000 individuals are also associated with AD risk in an independent case-control cohort (n∼10,000). Conversely, we test whether AD risk variants from a GWAS meta-analysis of approximately 54,000 account for any variance in iron measures (n∼9,000). We do not identify a genetic relationship, suggesting that peripheral iron is not causal in the initiation of AD pathology.

A novel experience-based internet intervention for smoking cessation: feasibility randomised controlled trial.

BACKGROUND: The internet is frequently used to share experiences of health and illness, but this phenomenon has not been harnessed as an intervention to achieve health behaviour change. The aim of this study was to determine the feasibility of a randomised trial assessing the effects of a novel, experience-based website as a smoking cessation intervention. The secondary aim was to measure the potential impact on smoking behaviour of both the intervention and a comparator website. METHODS: A feasibility randomised controlled single-blind trial assessed a novel, experience-based website containing personal accounts of quitting smoking as a cessation intervention, and a comparator website providing factual information. Feasibility measures including recruitment, and usage of the interventions were recorded, and the following participant-reported outcomes were also measured: Smoking Abstinence Self-Efficacy Questionnaire, the single-item Motivation to Stop Scale, self-reported abstinence, quit attempts and health status outcomes. Eligible smokers from two English regions were entered into the trial and given access to their allocated website for two weeks. RESULTS: Eighty-seven smokers were randomised, 65 completed follow-up (75 %). Median usage was 15 min for the intervention, and 5 min for the comparator (range 0.5-213 min). Median logins for both sites was 2 (range 1-20). All participant-reported outcomes were similar between groups. CONCLUSIONS: It was technically feasible to deliver a novel intervention harnessing the online sharing of personal experiences as a tool for smoking cessation, but recruitment was slow and actual use was relatively low, with attrition from the trial. Future work needs to maximize engagement and to understand how best to assess the value of such interventions in everyday use, rather than as an isolated 'dose of information'. TRIAL REGISTRATION: ISRCTN29549695 DOI 10.1186/ISRCTN29549695 . Registered 17/05/2013.

Informational and emotional elements in online support groups: a Bayesian approach to large-scale content analysis.

OBJECTIVE: This research examines the extent to which informational and emotional elements are employed in online support forums for 14 purposively sampled chronic medical conditions and the factors that influence whether posts are of a more informational or emotional nature. METHODS: Large-scale qualitative data were obtained from Dailystrength.org. Based on a hand-coded training dataset, all posts were classified into informational or emotional using a Bayesian classification algorithm to generalize the findings. Posts that could not be classified with a probability of at least 75% were excluded. RESULTS: The overall tendency toward emotional posts differs by condition: mental health (depression, schizophrenia) and Alzheimer's disease consist of more emotional posts, while informational posts relate more to nonterminal physical conditions (irritable bowel syndrome, diabetes, asthma). There is no gender difference across conditions, although prostate cancer forums are oriented toward informational support, whereas breast cancer forums rather feature emotional support. Across diseases, the best predictors for emotional content are lower age and a higher number of overall posts by the support group member. DISCUSSION: The results are in line with previous empirical research and unify empirical findings from single/2-condition research. Limitations include the analytical restriction to predefined categories (informational, emotional) through the chosen machine-learning approach. CONCLUSION: Our findings provide an empirical foundation for building theory on informational versus emotional support across conditions, give insights for practitioners to better understand the role of online support groups for different patients, and show the usefulness of machine-learning approaches to analyze large-scale qualitative health data from online settings.

Internet-based interventions for the secondary prevention of coronary heart disease.

BACKGROUND: The Internet could provide a means of delivering secondary prevention programmes to people with coronary heart disease (CHD). OBJECTIVES: To determine the effectiveness of Internet-based interventions targeting lifestyle changes and medicines management for the secondary prevention of CHD. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, in December 2014. We also searched six other databases in October 2014, and three trials registers in January 2015 together with reference checking and handsearching to identify additional studies. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating Internet-delivered secondary prevention interventions aimed at people with CHD. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed risk of bias and extracted data according to the Cochrane Handbook for Systematic Reviews of Interventions. We assessed evidence quality using the GRADE approach and presented this in a 'Summary of findings' table. MAIN RESULTS: Eighteen trials met our inclusion criteria. Eleven studies are complete (1392 participants), and seven are ongoing. Of the completed studies, seven interventions are broad, targeting the lifestyle management of CHD, and four focused on physical activity promotion. The comparison group in trials was usual care (n = 6), minimal intervention (n = 3), or traditional cardiac rehabilitation (n = 2).We found no effects of Internet-based interventions for all-cause mortality (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.04 to 1.63; participants = 895; studies = 6; low-quality evidence). There was only one case of cardiovascular mortality in a control group (participants = 895; studies = 6). No incidences of non-fatal re-infarction were reported across any of the studies. We found no effects for revascularisation (OR 0.69, 95% CI 0.37 to 1.27; participants = 895; studies = 6; low-quality evidence).We found no effects for total cholesterol (mean difference (MD) 0.00, 95% CI -0.27 to 0.28; participants = 439; studies = 4; low-quality evidence), high-density lipoprotein (HDL) cholesterol (MD 0.01, 95% CI -0.06 to 0.07; participants = 437; studies = 4; low-quality evidence), or triglycerides (MD 0.01, 95% CI -0.17 to 0.19; participants = 439; studies = 4; low-quality evidence). We did not pool the data for low-density lipoprotein (LDL) cholesterol due to considerable heterogeneity. Two out of six trials measuring LDL cholesterol detected favourable intervention effects, and four trials reported no effects. Seven studies measured systolic and diastolic blood pressure; we did not pool the data due to substantial heterogeneity. For systolic blood pressure, two studies showed a reduction with the intervention, but the remaining studies showed no effect. For diastolic blood pressure, two studies showed a reduction with the intervention, one study showed an increase with the intervention, and the remaining four studies showed no effect.Five trials measured health-related quality of life (HRQOL). We could draw no conclusions from one study due to incomplete reporting; one trial reported no effect; two studies reported a short- and medium-term effect respectively; and one study reported both short- and medium-term effects.Five trials assessed dietary outcomes: two reported favourable effects, and three reported no effects. Eight studies assessed physical activity: five of these trials reported no physical activity effects, and three reported effectiveness. Trials are yet to measure the impact of these interventions on compliance with medication.Two studies measured healthcare utilisation: one reported no effects, and the other reported increased usage of healthcare services compared to a control group in the intervention group at nine months' follow-up. Two trials collected cost data: both reported that Internet-delivered interventions are likely to be cost-effective.In terms of the risk of bias, the majority of studies reported appropriate randomisation and appropriate concealment of randomisation processes. A lack of blinding resulted in a risk of performance bias in seven studies, and a risk of detection bias in five trials. Two trials were at risk of attrition bias, and five were at risk for reporting bias. AUTHORS' CONCLUSIONS: In general, evidence was of low quality due to lack of blinding, loss to follow-up, and uncertainty around the effect size. Few studies measured clinical events, and of those that did, a very small number of events were reported, and therefore no firm conclusions can be made. Similarly, there was no clear evidence of effect for cardiovascular risk factors, although again the number of studies reporting these was small. There was some evidence for beneficial effects on HRQOL, dietary outcomes, and physical activity, although firm conclusions cannot yet be made. The effects on healthcare utilisation and cost-effectiveness are also inconclusive, and trials are yet to measure the impact of Internet interventions on compliance with medication. The comparison groups differed across trials, and there were insufficient studies with usable data for subgroup analyses. We intend to study the intensity of comparison groups in future updates of this review when more evidence is available. The completion of the ongoing trials will add to the evidence base.

Associations between Potentially Modifiable Risk Factors and Alzheimer Disease: A Mendelian Randomization Study.

BACKGROUND: Potentially modifiable risk factors including obesity, diabetes, hypertension, and smoking are associated with Alzheimer disease (AD) and represent promising targets for intervention. However, the causality of these associations is unclear. We sought to assess the causal nature of these associations using Mendelian randomization (MR). METHODS AND FINDINGS: We used SNPs associated with each risk factor as instrumental variables in MR analyses. We considered type 2 diabetes (T2D, NSNPs = 49), fasting glucose (NSNPs = 36), insulin resistance (NSNPs = 10), body mass index (BMI, NSNPs = 32), total cholesterol (NSNPs = 73), HDL-cholesterol (NSNPs = 71), LDL-cholesterol (NSNPs = 57), triglycerides (NSNPs = 39), systolic blood pressure (SBP, NSNPs = 24), smoking initiation (NSNPs = 1), smoking quantity (NSNPs = 3), university completion (NSNPs = 2), and years of education (NSNPs = 1). We calculated MR estimates of associations between each exposure and AD risk using an inverse-variance weighted approach, with summary statistics of SNP-AD associations from the International Genomics of Alzheimer's Project, comprising a total of 17,008 individuals with AD and 37,154 cognitively normal elderly controls. We found that genetically predicted higher SBP was associated with lower AD risk (odds ratio [OR] per standard deviation [15.4 mm Hg] of SBP [95% CI]: 0.75 [0.62-0.91]; p = 3.4 × 10(-3)). Genetically predicted higher SBP was also associated with a higher probability of taking antihypertensive medication (p = 6.7 × 10(-8)). Genetically predicted smoking quantity was associated with lower AD risk (OR per ten cigarettes per day [95% CI]: 0.67 [0.51-0.89]; p = 6.5 × 10(-3)), although we were unable to stratify by smoking history; genetically predicted smoking initiation was not associated with AD risk (OR = 0.70 [0.37, 1.33]; p = 0.28). We saw no evidence of causal associations between glycemic traits, T2D, BMI, or educational attainment and risk of AD (all p > 0.1). Potential limitations of this study include the small proportion of intermediate trait variance explained by genetic variants and other implicit limitations of MR analyses. CONCLUSIONS: Inherited lifetime exposure to higher SBP is associated with lower AD risk. These findings suggest that higher blood pressure--or some environmental exposure associated with higher blood pressure, such as use of antihypertensive medications--may reduce AD risk.

Stratified gene expression analysis identifies major amyotrophic lateral sclerosis genes.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons resulting in progressive paralysis. Gene expression studies of ALS only rarely identify the same gene pathways as gene association studies. We hypothesized that analyzing tissues by matching on degree of disease severity would identify different patterns of gene expression from a traditional case-control comparison. We analyzed gene expression changes in 4 postmortem central nervous system regions, stratified by severity of motor neuron loss. An overall comparison of cases (n = 6) and controls (n = 3) identified known ALS gene, SOX5, as showing differential expression (log2 fold change = 0.09, p = 5.5 × 10(-5)). Analyses stratified by disease severity identified expression changes in C9orf72 (p = 2.77 × 10(-3)), MATR3 (p = 3.46 × 10(-3)), and VEGFA (p = 8.21 × 10(-4)), all implicated in ALS through genetic studies, and changes in other genes in pathways involving RNA processing and immune response. These findings suggest that analysis of gene expression stratified by disease severity can identify major ALS genes and may be more efficient than traditional case-control comparison.

Identifying complications of interventional procedures from UK routine healthcare databases: a systematic search for methods using clinical codes.

BACKGROUND: Several authors have developed and applied methods to routine data sets to identify the nature and rate of complications following interventional procedures. But, to date, there has been no systematic search for such methods. The objective of this article was to find, classify and appraise published methods, based on analysis of clinical codes, which used routine healthcare databases in a United Kingdom setting to identify complications resulting from interventional procedures. METHODS: A literature search strategy was developed to identify published studies that referred, in the title or abstract, to the name or acronym of a known routine healthcare database and to complications from procedures or devices. The following data sources were searched in February and March 2013: Cochrane Methods Register, Conference Proceedings Citation Index - Science, Econlit, EMBASE, Health Management Information Consortium, Health Technology Assessment database, MathSciNet, MEDLINE, MEDLINE in-process, OAIster, OpenGrey, Science Citation Index Expanded and ScienceDirect. Of the eligible papers, those which reported methods using clinical coding were classified and summarised in tabular form using the following headings: routine healthcare database; medical speciality; method for identifying complications; length of follow-up; method of recording comorbidity. The benefits and limitations of each approach were assessed. RESULTS: From 3688 papers identified from the literature search, 44 reported the use of clinical codes to identify complications, from which four distinct methods were identified: 1) searching the index admission for specified clinical codes, 2) searching a sequence of admissions for specified clinical codes, 3) searching for specified clinical codes for complications from procedures and devices within the International Classification of Diseases 10th revision (ICD-10) coding scheme which is the methodology recommended by NHS Classification Service, and 4) conducting manual clinical review of diagnostic and procedure codes. CONCLUSIONS: The four distinct methods identifying complication from codified data offer great potential in generating new evidence on the quality and safety of new procedures using routine data. However the most robust method, using the methodology recommended by the NHS Classification Service, was the least frequently used, highlighting that much valuable observational data is being ignored.

Transcriptome analysis of pancreatic cancer reveals a tumor suppressor function for HNF1A.

Pancreatic ductal adenocarcinoma (PDAC) is driven by the accumulation of somatic mutations, epigenetic modifications and changes in the micro-environment. New approaches to investigating disruptions of gene expression networks promise to uncover key regulators and pathways in carcinogenesis. We performed messenger RNA-sequencing in pancreatic normal (n = 10) and tumor (n = 8) derived tissue samples, as well as in pancreatic cancer cell lines (n = 9), to determine differential gene expression (DE) patterns. Sub-network enrichment analyses identified HNF1A as the regulator of the most significantly and consistently dysregulated expression sub-network in pancreatic tumor tissues and cells (median P = 7.56×10(-7), median rank = 1, range = 1-25). To explore the effects of HNF1A expression in pancreatic tumor-derived cells, we generated stable HNF1A-inducible clones in two pancreatic cancer cell lines (PANC-1 and MIA PaCa-2) and observed growth inhibition (5.3-fold, P = 4.5×10(-5) for MIA PaCa-2 clones; 7.2-fold, P = 2.2×10(-5) for PANC-1 clones), and a G0/G1 cell cycle arrest and apoptosis upon induction. These effects correlated with HNF1A-induced down-regulation of 51 of 84 cell cycle genes (e.g. E2F1, CDK2, CDK4, MCM2/3/4/5, SKP2 and CCND1), decreased expression of anti-apoptotic genes (e.g. BIRC2/5/6 and AKT) and increased expression of pro-apoptotic genes (e.g. CASP4/9/10 and APAF1). In light of the established role of HNF1A in the regulation of pancreatic development and homeostasis, our data suggest that it also functions as an important tumor suppressor in the pancreas.

A web-based program improves physical activity outcomes in a primary care angina population: randomized controlled trial.

BACKGROUND: Angina affects more than 50 million people worldwide. Secondary prevention interventions such as cardiac rehabilitation are not widely available for this population. An Internet-based version could offer a feasible alternative. OBJECTIVE: Our aim was to examine the effectiveness of a Web-based cardiac rehabilitation program for those with angina. METHODS: We conducted a randomized controlled trial, recruiting those diagnosed with angina from general practitioners (GPs) in primary care to an intervention or control group. Intervention group participants were offered a 6-week Web-based rehabilitation program ("ActivateYourHeart"). The program was introduced during a face-to-face appointment and then delivered via the Internet (no further face-to-face contact). The program contained information about the secondary prevention of coronary heart disease (CHD) and set each user goals around physical activity, diet, managing emotions, and smoking. Performance against goals was reviewed throughout the program and goals were then reset/modified. Participants completed an online exercise diary and communicated with rehabilitation specialists through an email link/synchronized chat room. Participants in the control group continued with GP treatment as usual, which consisted of being placed on a CHD register and attending an annual review. Outcomes were measured at 6-week and 6-month follow-ups during face-to-face assessments. The primary outcome measure was change in daily steps at 6 weeks, measured using an accelerometer. Secondary outcome measures were energy expenditure (EE), duration of sedentary activity (DSA), duration of moderate activity (DMA), weight, diastolic/systolic blood pressure, and body fat percentage. Self-assessed questionnaire outcomes included fat/fiber intake, anxiety/depression, self-efficacy, and quality of life (QOL). RESULTS: A total of 94 participants were recruited and randomized to the intervention (n=48) or the usual care (n=46) group; 84 and 73 participants completed the 6-week and 6-month follow-ups, respectively. The mean number of log-ins to the program was 18.68 (SD 13.13, range 1-51), an average of 3 log-ins per week per participant. Change in daily steps walked at the 6-week follow-up was +497 (SD 2171) in the intervention group and -861 (SD 2534) in the control group (95% CI 263-2451, P=.02). Significant intervention effects were observed at the 6-week follow-up in EE (+43.94 kcal, 95% CI 43.93-309.98, P=.01), DSA (-7.79 minutes, 95% CI -55.01 to -7.01, P=.01), DMA (+6.31 minutes, 95% CI 6.01-51.20, P=.01), weight (-0.56 kg, 95% CI -1.78 to -0.15, P=.02), self-efficacy (95% CI 0.30-4.79, P=.03), emotional QOL score (95% CI 0.01-0.54, P=.04), and angina frequency (95% CI 8.57-35.05, P=.002). Significant benefits in angina frequency (95% CI 1.89-29.41, P=.02) and social QOL score (95% CI 0.05-0.54, P=.02) were also observed at the 6-month follow-up. CONCLUSIONS: An Internet-based secondary prevention intervention could be offered to those with angina. A larger pragmatic trial is required to provide definitive evidence of effectiveness and cost-effectiveness. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN): 90110503; http://www.controlled-trials.com/ISRCTN90110503/ISRCTN90110503 (Archived by WebCite at http://www.webcitation.org/6RYVOQFKM).