Where Have All the Rodents Gone? The Effects of Attrition in Experimental Research on Cancer and Stroke.

Given small sample sizes, loss of animals in preclinical experiments can dramatically alter results. However, effects of attrition on distortion of results are unknown. We used a simulation study to analyze the effects of random and biased attrition. As expected, random loss of samples decreased statistical power, but biased removal, including that of outliers, dramatically increased probability of false positive results. Next, we performed a meta-analysis of animal reporting and attrition in stroke and cancer. Most papers did not adequately report attrition, and extrapolating from the results of the simulation data, we suggest that their effect sizes were likely overestimated.

Quality of Life after Deep Brain Stimulation in Parkinson's Disease: Does the Target Matter?

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) and globus pallidus internus (GPi) is an accepted therapy for Parkinson's disease (PD) with disabling motor complications. For elderly patients with poorer cognition and postural instability, GPi has been proposed as the preferable DBS target based on expert opinion, arguing GPi-DBS may be less complicated by depression, apathy, worsened verbal fluency, and executive dysfunction, resulting in greater improvement in quality of life (QoL). However, data supporting such patient-tailored approach are lacking. OBJECTIVES: The aims were to analyze whether the DBS target influences QoL in a PD cohort and a matched subgroup of frail patients with poor cognitive status and reduced postural stability, and whether other factors affect the QoL outcomes. METHODS: In this retrospective study, we analyzed a single-center cohort of 138 PD patients who received bilateral STN-DBS (117) or GPi-DBS (21) using the mentioned approach for target selection. All patients underwent standardized clinical evaluations of motor- and nonmotor signs as well as QoL before and 1 year after surgery. RESULTS: DBS of both targets improved motor signs, dyskinesias, and pain. QoL improved without significant difference between the targets, but with a trend for greater improvement across all QoL domains in favor of the STN, even in an STN subgroup matched to the GPi group. CONCLUSION: Our results contradict the prevailing belief that GPi-DBS is superior in frail PD patients with cognitive decline and postural instability, questioning the proposed patient-tailored approach of DBS target selection. Further studies are needed for a data-driven approach.

Subthalamic stimulation has acute psychotropic effects and improves neuropsychiatric fluctuations in Parkinson's disease.

Background: Subthalamic nucleus deep brain stimulation (STN-DBS) is a well-established treatment for motor complications in Parkinson's disease (PD). However, its effects on neuropsychiatric symptoms remain disputed. The aim of this study was to evaluate the effects of STN-DBS on neuropsychiatric symptoms in PD. Methods: We retrospectively assessed 26 patients with PD who underwent a preoperative levodopa challenge and postoperative levodopa and stimulation challenges 1 year after STN-DBS. Based on the Neuropsychiatric Fluctuations Scale, Neuropsychiatric State Scores and Neuropsychiatric Fluctuation Indices (NFIs) were calculated. Mixed-effects models with random effects for intercept were used to examine the association of Neuropsychiatric State Score and NFI with the different assessment conditions. Results: In acute challenge conditions, there was an estimated increase of 15.9 points in the Neuropsychiatric State Score in stimulation ON conditions (95% CI 11.4 to 20.6, p<0.001) and 7.6 points in medication ON conditions (95% CI 3.3 to 11.9, p<0.001). Neuropsychiatric fluctuations induced by levodopa, quantified with NFI, decreased by 35.54% (95% CI 49.3 to 21.8, p<0.001) 1 year after STN-DBS. Conclusions: Bilateral STN-DBS at therapeutic parameters has acute psychotropic effects similar to levodopa and can modulate and decrease levodopa-induced neuropsychiatric fluctuations.

Nutrition in early life and risk of childhood leukemia: a case-control study in Greece.

PURPOSE: There is a paucity of findings concerning the role of diet in childhood leukemogenesis, whereas the results are equivocal and the studies heterogeneous with regard to food items examined. This case-control study investigates the association of childhood leukemia with food groups, macronutrient consumption, total energy intake and adherence to Mediterranean diet among children aged 5-14 years in Greece. METHODS: A total of 139 consecutive, incident leukemia cases out of which 121 were acute lymphoblastic leukemia were derived from the Nationwide Registry for Childhood Hematological Malignancies along with one : one age- and gender-matched hospital controls. Information on socio-demographic, maternal and child variables and dietary habits was obtained through in-person interviews with the guardians/children. Multiple logistic regression was performed with adjustment for birth weight and possible confounding variables. RESULTS: Higher consumption of added lipids was associated with an increased risk of childhood leukemia, whereas consumption of milk and dairy products with reduced risk. From the macronutrient analysis, a borderline trend linking high protein intake with reduced childhood leukemia risk was observed. CONCLUSION: Consumption of milk and dairy products in the first year of life may protect against childhood leukemia possibly through vitamin D actions, while added lipids may increase the risk through various mechanisms. These results offer a holistic evaluation of children's nutrition and suggest that dietary habits in the early years of life may contribute to the prevention of childhood leukemia.

Association of maternal and index child's diet with subsequent leukemia risk: A systematic review and meta analysis.

BACKGROUND: Exploring the effect of maternal and/or childhood diet on offspring leukemogenesis is challenging, given differences in food group categories, their potentially variable impact depending on time window of exposure and the multiple leukemia subtypes. We opted to quantitatively synthesize published data on the association of maternal/child diet with leukemia risk. METHODS: Medline was searched until June 30th, 2016 for eligible articles on the association of childhood leukemia with consumption of (i) food groups, excluding alcoholic and non-alcoholic beverages, and (ii) specific dietary supplements before/during index pregnancy and childhood. RESULTS: Eighteen studies of case-control design (N=11,720 cases/18,721 controls) were included, of which nine assessed maternal dietary components, five index child's and four both, mainly focusing on acute lymphoblastic leukemia (ALL). Statistically significant inverse estimates for ALL were found (2 studies, 413 cases, 490 controls) for fruit (OR: 0.81, 95% CI: 0.67, 0.99); vegetables (OR: 0.51, 95% CI: 0.28, 0.94); legumes (OR: 0.76, 95% CI: 0.62, 0.94); fish (OR: 0.27, 95% CI: 0.14, 0.53, among the 0-4year old; 2 studies 215 cases, 215 controls); preconception folic acid supplementation (OR: 0.69, 95%CI: 0.50-0.95; published meta analysis plus 2 studies, 3511 cases, 6816 controls); and use of vitamins during pregnancy (OR: 0.81, 95%CI: 0.74-0.88; published meta analysis plus one study, 5967 cases, 8876 controls). The associations (2 studies) of the remaining food groups and maternal dietary supplements consumption during pregnancy as well as of childhood diet and supplements intake (2-4 studies) were non significant. CONCLUSIONS: Maternal consumption of specific food groups comprising"healthy" items of the Mediterranean diet, preconception use of folic acid and intake of vitamins during pregnancy were associated with decreased ALL risk. Further research is needed, however preferably with homogeneous dietary information and data on immunophenotypic/cytogenetic subtypes to also explore the interaction of specific macro- and micronutrients intake with gene polymorphisms.

Parental alcohol consumption and risk of leukemia in the offspring: a systematic review and meta-analysis.

Parental alcohol consumption before and during pregnancy has been linked to adverse outcomes in the offspring including leukemogenesis. We, therefore, aimed to systematically assess and quantitatively synthesize published data on the association of paternal consumption during preconception and maternal consumption during pregnancy with leukemia risk in childhood (0-14 years). Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we searched PubMed (until February 2016) and the reference lists of the relevant studies. Observational studies examining the association between parental alcohol consumption and childhood leukemia were considered eligible. Data extracted from 39 case-control studies (over 16 000 leukemia cases and 30 000 controls) were pooled and summary-effect estimates were calculated. Subgroup analyses were carried out by main acute leukemia type [lymphoblastic or myeloid), cytogenetics/genetic polymorphisms, and specific alcohol beverages. We found a statistically significant dose-response association of any level of maternal alcohol consumption compared with nondrinking during pregnancy exclusively with acute myeloid leukemia (AML) [odds ratio (OR)moderate consumption: 1.64, 95% confidence intervals (CIs): 1.23-2.17 and ORhigh consumption: 2.36, 95% CI: 1.60-3.49]. In contrast, no association of paternal preconception consumption with any leukemia type was noted. In beverage-specific analyses, only a positive association of maternal wine drinking with childhood AML was found, which was more pronounced in analyses including only studies on infant leukemia (ORwine: 2.12, 95% CI: 1.16-3.90). The largest ever meta-analysis shows a sizeable, statistically significant dose-response association of maternal alcohol consumption during index pregnancy with AML risk. Future research exploring the role of genetic polymorphisms is anticipated to shed light on the underlying pathophysiology.

Association of Age at Menopause and Duration of Reproductive Period With Depression After Menopause: A Systematic Review and Meta-analysis.

IMPORTANCE: Estrogens have neuroprotective and antidepressive effects; however, associations between indices of reduced endogenous estrogens and risk for postmenopausal depression have not been systematically explored. OBJECTIVE: To investigate the association of age at menopause and the duration of the reproductive period with the risk for depression among postmenopausal women with naturally occurring menopause. DATA SOURCES: A search strategy for use of MEDLINE was developed (through January 1, 2015) using the key terms menopause, climacteric, reproductive period, depression, and mood disorders. References of included studies and reviews were also screened; authors were contacted to maximize synthesized evidence. STUDY SELECTION: A total of 12,323 articles, without language restriction, were screened by pairs of reviewers to identify observational studies related to the study hypothesis; 14 studies were eligible for meta-analysis. DATA EXTRACTION AND SYNTHESIS: Pairs of reviewers independently extracted information on study design and type of analysis by participants' characteristics and methods of depression ascertainment. Study quality was assessed using the Newcastle-Ottawa Scale, and fixed- or random-effects models were implemented. MAIN OUTCOMES AND MEASURES: Pooled-effect estimates for depression, defined by psychiatric evaluation or validated instruments, by age at menopause and duration of the reproductive period. RESULTS: The 14 studies included in the meta-analysis represented 67,714 women. An inverse association (reported as odds ratio [OR]; 95% CI of 2-year increments) with depression in postmenopausal women was shown for increasing age at menopause (0.98; 0.96-0.99 [67,434 unique participants; 13 studies]) and duration of the reproductive period (0.98; 0.96-0.99 [54,715 unique participants; 5 studies]). Menopause at age 40 or more years compared with premature menopause was associated with a 50% decreased risk for depression (3033 unique participants; 4 studies). Pooling of studies examining severe depression showed a 5% decrease in risk of severe depression with increasing (2-year increment) age at menopause (52,736 unique participants; 3 studies); sensitivity analysis of studies controlling for past depression revealed similar results for age at menopause (0.98; 0.96-1.00 [48,894 unique participants; 3 studies). No heterogeneity or publication bias was evident in the main analyses. CONCLUSIONS AND RELEVANCE: Longer exposure to endogenous estrogens, expressed as older age at menopause and longer reproductive period, is associated with a lower risk of depression in later life. Identifying women at higher risk for depression due to early menopause who could benefit from psychiatric intervention or estrogen-based therapies could be useful in the clinical setting.

Age at menopause and duration of reproductive period in association with dementia and cognitive function: A systematic review and meta-analysis.

INTRODUCTION: The preponderance of dementia among postmenopausal women compared with same-age men and the female sex hormones neuroprotective properties support a tentative role of their deficiency in the dementia pathogenesis. METHODS: Pairs of independent reviewers screened 12,323 publications derived from a search strategy for MEDLINE to identify articles investigating the association of age at menopause/reproductive period with (i) dementia and (ii) cognitive function; a snowball of eligible articles and reviews was conducted and authors were contacted for additional information. Random-effect models were used for the meta-analysis. RESULTS: Age at menopause (13 studies; 19,449 participants) and reproductive period (4 studies; 9916 participants) in the highest categories were not associated with odds of dementia (effect size [ES]: 0.97 [0.78-1.21]) and Alzheimer's disease (ES: 1.06 [0.71-1.58]). Significant heterogeneity was however noted in both analyses (I2: 63.3%, p=0.003 and I2: 72.6%, p=0.01, respectively). Subgroup analyses by outcome assessment, study design, level of adjustment and study quality did not materially change the findings. In 9/13 studies assessing cognitive function, advanced age at menopause/longer reproductive period was significantly associated with better cognitive performance/lower decline. Due to statistical differences, no meta-analysis was possible for cognitive function. CONCLUSIONS: Existing evidence does not support an association between indices of prolonged exposure to female hormones and lower dementia risk. There are indications, however, for better cognitive performance and delayed cognitive decline, supporting a link between female hormone deficiency and cognitive aging. Current literature limitations, indicated by the heterogeneous study-set, point towards research priorities in this clinically relevant area.

Maternal and childhood consumption of coffee, tea and cola beverages in association with childhood leukemia: a meta-analysis.

OBJECTIVE: To systematically review studies and meta-analyze the literature on the association of maternal and/or index child's coffee, tea, and cola consumption with subsequent development of childhood leukemia and its major subtypes. METHODS: Eligible studies were identified through a detailed algorithm and hand-search of eligible articles' references; thereafter, summary-effect estimates were calculated by leukemia subtype and dose-response meta-analyses were performed. RESULTS: Twelve case-control studies, comprising a total of 3649 cases and 5705 controls, were included. High maternal coffee consumption was positively associated with acute lymphoblastic leukemia (ALL; OR: 1.43, 95%CI: 1.22-1.68) and acute myeloid leukemia (AML; OR: 2.52, 95%CI: 1.59-3.57). Any or low to moderate maternal cola consumption was also positively associated with overall leukemia (AL) and ALL, A linear trend between coffee and cola consumption and childhood leukemia was observed in the dose-response analyses. On the contrary, low to moderate tea consumption was inversely associated with AL (OR: 0.85, 95%CI: 0.75-0.97), although the trend was non-significant. A null association between offspring's cola consumption and leukemia was noted. CONCLUSIONS: Our findings confirm the detrimental association between maternal coffee consumption and childhood leukemia risk and provide indications for a similar role of maternal cola intake. In contrast, an inverse association with tea was found, implying that other micronutrients contained in this beverage could potentially counterbalance the deleterious effects of caffeine. Further research should focus on the intake of specific micronutrients, different types of coffee and tea, specific immunophenotypes of the disease, and the modifying effect of genetic polymorphisms.

IVF and breast cancer: a systematic review and meta-analysis.

BACKGROUND: The effects of controlled ovarian hyperstimulation (COH) for IVF in terms of breast cancer risk remain controversial, despite the hormone-dependent nature of the latter. METHODS: Eligible studies up to 15 February 2013 were identified and pooled effect estimates for relative risk (RR) were calculated separately for the investigations using the general population and those using infertile women, as a reference group. Fixed- or random-effects models were implemented and subgroup analyses were performed, as appropriate. RESULTS: Eight cohort studies were synthesized, yielding a total cohort size of 1,554,332 women among whom 14,961 incident breast cancer cases occurred, encompassing 576 incident breast cancer cases among women exposed to IVF. No significant association between IVF and breast cancer was observed either in the group of studies treating the general population (RR = 0.91, 95% confidence interval (CI): 0.74-1.11) or infertile women (RR = 1.02, 95% CI: 0.88-1.18), as a reference group. Of note were the marginal associations, protective for pregnant and/or parous women after IVF (pooled effect estimate = 0.86, 95% CI: 0.73-1.01) and adverse for women <30 years at first IVF treatment (pooled effect estimate = 1.64, 95% CI: 0.96-2.80). CONCLUSIONS: At present, COH for IVF does not seem to impart increased breast cancer risk. Longer follow-up periods, comparisons versus infertile women, subgroup analyses aiming to trace vulnerable subgroups, adjustment for various confounders and larger informative data sets are needed before conclusive statements for the safety of the procedure are reached.

Cognitive impairment and dietary habits among elders: the Velestino Study.

To investigate the association of dietary habits with cognitive function among elders (>65 years). Complete sociodemographic, dietary information, serum measurements, and Mini-Mental State Examination (MMSE) assessments were available for 237 elderly men and 320 women residing in Velestino, Greece (a rural Greek town). All models were adjusted for age, education, social activity, smoking, depression symptomatology (using the Geriatric Depression Scale), MedDietScore (range 0-55), and metabolic syndrome. About 49.8% men and 66.6% women had MMSE scores <24, with a mean MMSE score of 22.7±4.43 and 21.1±4.73, respectively. Adherence to the Mediterranean diet was moderate (mean MedDietScore of 34.1±3.25 in men and 35.1±2.48 in women). Indicative cognitive impairment (MMSE score <24) was positively associated with age and low education in women and with depressive symptoms, low education status, and low social activity in men. Adherence to the Mediterranean diet was positively associated with MMSE score in men (P=.02), but inversely associated in women (P=.04). Concerning the food groups studied, intake of pulses, nuts, and seeds was associated with lower likelihood of having MMSE score<24 in men (P=.04). Only the Mediterranean dietary pattern showed a significant association with MMSE score positive for cognitive impairment (i.e., protective in men, but not in women), while individual food groups or nutrients did not achieve significance. The latter findings support the role of whole diet in the prevention of mental disorders, and state a research hypothesis for a sex-diet interaction on cognitive function among elders.