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  • Adjuvant treatment for breast cancer

    16 October 2018

    © 2015 Elsevier Ltd. All rights reserved. Adjuvant treatment for breast cancer is given following primary surgical management and aims to reduce the risk of recurrence (both local and distant) as well as improve survival rates. Radiotherapy is delivered to reduce local recurrence risk. Whole breast radiotherapy is considered standard treatment following breast-conserving surgery for invasive cancer and is also considered after mastectomy depending on pathological risk factors. Systemic therapies (such as chemotherapy, endocrine treatment and biological therapy) reduce the risk of distant metastases and improve overall survival. The decision to advise adjuvant treatment is complex (taking into account both prognostic and patient factors) and is made with the patient following a multidisciplinary team meeting. It is now common practice to employ benefit-risk calculators in the clinical setting to aid treatment decision making. Recent major advances in both systemic treatments and radiotherapy techniques have led to more personalized treatment for patients with the aim to reduce breast cancer mortality even further.

  • [Associations between season of birth and age both at menarche and at menopause].

    16 October 2018

    Objective: To examine the associations between season of birth and factors as age at menarche, age at menopause and reproductive span. Methods: A total of 285 186 female from the China Kadoorie Biobank, with complete data on critical variables and had menarche at 9-18 years old, were included. A total of 132 373 female with natural menopause were included for the analysis on age at menopause and reproductive span. Multiple linear regression models were used to assess the associations of birth season and the age at menarche, menopause, and reproductive span. Subgroup analyses were performed on birth cohorts and urban/rural residence. Results: Compared with the Spring-born (March, April, and May), participants who were born in Summer (June, July, and August), Autumn (September, October, and November), and Winter (December, January, and February) appeared late on both age at menarche and menopause. Multivariable-adjusted coefficients (95% CI) appeared as 0.14 (95% CI: 0.13-0.16), 0.26(95% CI: 0.24-0.27), 0.10 (95% CI: 0.08-0.12) for age at menarche respectively and 0.14 (95%CI: 0.08-0.20), 0.18 (95%CI: 0.12-0.24), 0.09 (95%CI: 0.03-0.16) for age at menopause respectively. No statistically significant association was found between the season of birth and reproductive span. The association was consistent between urban and rural residents and across the birth cohorts. Conclusions: female born in spring showed both earlier age on both menarche and menopause, compared to the ones born in other seasons. Our findings suggested that exposures in early life with some degree of seasonal variation might influence the development of female reproductive system.

  • Differential effects of PCSK9 variants on risk of coronary disease and ischaemic stroke.

    16 October 2018

    Aims: PCSK9 genetic variants that have large effects on low-density lipoprotein cholesterol (LDL-C) and coronary heart disease (CHD) have prompted the development of therapeutic PCSK9-inhibition. However, there is limited evidence that PCSK9 variants are associated with ischaemic stroke (IS). Methods and results: Associations of the loss-of-function PCSK9 genetic variant (rs11591147; R46L), and five additional PCSK9 variants, with IS and IS subtypes (cardioembolic, large vessel, and small vessel) were estimated in a meta-analysis involving 10 307 IS cases and 19 326 controls of European ancestry. They were then compared with the associations of these variants with LDL-C levels (in up to 172 970 individuals) and CHD (in up to 60 801 CHD cases and 123 504 controls). The rs11591147 T allele was associated with 0.5 mmol/L lower LDL-C level (P = 9 × 10-143) and 23% lower CHD risk [odds ratio (OR): 0.77, 95% confidence interval (CI): 0.69-0.87, P = 7 × 10-6]. However, it was not associated with risk of IS (OR: 1.04, 95% CI: 0.84-1.28, P = 0.74) or IS subtypes. Information from additional PCSK9 variants also indicated consistently weaker effects on IS than on CHD. Conclusion: PCSK9 genetic variants that confer life-long lower PCSK9 and LDL-C levels appear to have significantly weaker, if any, associations with risk of IS than with risk of CHD. By contrast, similar proportional reductions in risks of IS and CHD have been observed in randomized trials of therapeutic PCSK9-inhibition. These findings have implications for our understanding of when Mendelian randomization can be relied upon to predict the effects of therapeutic interventions.

  • Clinicodemographic Profile of Children with Seizures in a Tertiary Care Hospital: A Cross-Sectional Observational Study.

    16 October 2018

    Seizures are one of the common causes for hospital admissions in children with significant mortality and morbidity. This study was conducted to study the prevalence and clinicodemographic profile of children with seizures in a tertiary care hospital of western Nepal. This prospective cross-sectional study conducted over a period of 2 years included all admitted children (2 months-16 years) with seizures. Among 4962 admitted children, seizures were present in 3.4% (n = 168) of children, with male preponderance. 138 (82.1%) children had generalized tonic-clonic seizures (GTCS) and 30 (17.9%) children had partial seizures. GTCS were more common than partial seizures in both sexes (male = 82.7%; female = 81.2%) and age groups. There was no statistical significance in the distribution of seizures (GTCS and partial seizures) with sexes (P = 0.813) and age groups (P = 0.955). Mean ages of children having GTCS and partial seizures were 8.2 ± 4.6 years and 8.2 ± 4.2 years, respectively. Loss of consciousness (55.4%), fever (39.9%), vomiting (35.1%), and headache (16.1%) were common complaints in seizure patients. Significant number of GTCS cases had fever (P = 0.041) and neurocysticercosis (n = 72; 43%) was the most common etiology in seizure patients. Idiopathic epilepsy (38 (22.6%)), meningoencephalitis (26 (15.5%)), and febrile convulsions (14 (8.33%)) were other leading disorders in children with seizures.

  • Association of Body Mass Index With Cardiometabolic Disease in the UK Biobank: A Mendelian Randomization Study.

    16 October 2018

    Importance: Higher body mass index (BMI) is a risk factor for cardiometabolic disease; however, the underlying causal associations remain unclear. Objectives: To use UK Biobank data to report causal estimates of the association between BMI and cardiometabolic disease outcomes and traits, such as pulse rate, using mendelian randomization. Design, Setting, and Participants: Cross-sectional baseline data from a population-based cohort study including 119 859 UK Biobank participants with complete phenotypic (medical and sociodemographic) and genetic data. Participants attended 1 of 22 assessment centers across the United Kingdom between 2006 and 2010. The present study was conducted from May 1 to July 11, 2016. Main Outcomes and Measures: Prevalence of hypertension, coronary heart disease, and type 2 diabetes were determined at assessment, based on self-report. Blood pressure was measured clinically. Participants self-reported sociodemographic information pertaining to relevant confounders. A polygenic risk score comprising 93 single-nucleotide polymorphisms associated with BMI from previous genome-wide association studies was constructed, and the genetic risk score was applied to derive causal estimates using a mendelian randomization approach. Results: Of the 119 859 individuals included in the study, 56 816 (47.4%) were men; mean (SD) age was 56.87 (7.93) years. Mendelian randomization analysis showed significant positive associations between genetically instrumented higher BMI and risk of hypertension (odds ratio [OR] per 1-SD higher BMI, 1.64; 95% CI, 1.48-1.83; P = 1.1 × 10-19), coronary heart disease (OR, 1.35; 95% CI, 1.09-1.69; P = .007) and type 2 diabetes (OR, 2.53; 95% CI, 2.04-3.13; P = 1.5 × 10-17), as well as systolic blood pressure (β = 1.65 mm Hg; 95% CI, 0.78-2.52 mm Hg; P = 2.0 × 10-04) and diastolic blood pressure (β  = 1.37 mm Hg; 95% CI, 0.88-1.85 mm Hg; P = 3.6 × 10-08). These associations were independent of age, sex, Townsend deprivation scores, alcohol intake, and smoking history. Conclusions and Relevance: The results of this study add to the burgeoning evidence of an association between higher BMI and increased risk of cardiometabolic diseases. This finding has relevance for public health policies in many countries with increasing obesity levels.

  • Intratumoral stromal morphometry predicts disease recurrence but not response to 5-fluorouracil-results from the QUASAR trial of colorectal cancer.

    16 October 2018

    The biological importance of tumour-associated stroma is becoming increasingly apparent, but its clinical utility remains ill-defined. For stage II/Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC.Relative proportions of tumour epithelium (PoT) or stroma (PoS) were morphometrically quantified on digitised haematoxylin and eosin (H&E) sections derived from 1800 patients enrolled in QUASAR, which randomised 3239 (91% stage II) CRC patients between adjuvant fluorouracil/folinic acid (FUFA) chemotherapy and observation. The prognostic and predictive values of PoT/PoS measurements were determined by the use of stratified log-rank analyses. A high proportion of tumour stroma (≥50%) was associated with an increased recurrence risk: 31.3% (143/457) recurrence for ≥50% versus 21.9% (294/1343) for <50% [rate ratio (RR) 1.62; 95% confidence interval (CI) 1.30-2.02; P < 0.0001]. Of patients with stromal proportions of ≥65%, 40% (46/115) had recurrent disease within 10 years. The adverse prognostic effect of a high stromal proportion was independent of established prognostic variables, and was maintained in stage II/Dukes B patients (RR 1.62; 95% CI 1.26-2.08; P = 0.0002). KRAS mutation in the presence of a high stromal proportion augmented recurrence risk (RR 2.93; 95% CI 1.87-4.59; P = 0.0005). Stromal morphometry did not predict response to FUFA chemotherapy.Simple digital morphometry applied to a single representative H&E section identifies CRC patients with a >50% higher risk of disease recurrence. This technique can reliably partition patients into subpopulations with different risks of tumour recurrence in a simple and cost-effective manner. Further prospective validation is warranted.

  • Core outcome measures for interventions to prevent or slow the progress of dementia for people living with mild to moderate dementia: Systematic review and consensus recommendations.

    16 October 2018

    BACKGROUND: There are no disease-modifying treatments for dementia. There is also no consensus on disease modifying outcomes. We aimed to produce the first evidence-based consensus on core outcome measures for trials of disease modification in mild-to-moderate dementia. METHODS AND FINDINGS: We defined disease-modification interventions as those aiming to change the underlying pathology. We systematically searched electronic databases and previous systematic reviews for published and ongoing trials of disease-modifying treatments in mild-to-moderate dementia. We included 149/22,918 of the references found; with 81 outcome measures from 125 trials. Trials involved participants with Alzheimer's disease (AD) alone (n = 111), or AD and mild cognitive impairment (n = 8) and three vascular dementia. We divided outcomes by the domain measured (cognition, activities of daily living, biological markers, neuropsychiatric symptoms, quality of life, global). We calculated the number of trials and of participants using each outcome. We detailed psychometric properties of each outcome. We sought the views of people living with dementia and family carers in three cities through Alzheimer's society focus groups. Attendees at a consensus conference (experts in dementia research, disease-modification and harmonisation measures) decided on the core set of outcomes using these results. Recommended core outcomes were cognition as the fundamental deficit in dementia and to indicate disease modification, serial structural MRIs. Cognition should be measured by Mini Mental State Examination or Alzheimer's Disease Assessment Scale-Cognitive Subscale. MRIs would be optional for patients. We also made recommendations for measuring important, but non-core domains which may not change despite disease modification. LIMITATIONS: Most trials were about AD. Specific instruments may be superseded. We searched one database for psychometric properties. INTERPRETATION: This is the first review to identify the 81 outcome measures the research community uses for disease-modifying trials in mild-to-moderate dementia. Our recommendations will facilitate designing, comparing and meta-analysing disease modification trials in mild-to-moderate dementia, increasing their value. TRIAL REGISTRATION: PROSPERO no. CRD42015027346.