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Introduction-Aim: Adopting a lifestyle that incorporates regular physical activity confers substantial benefits to both physical and mental health and is recommended for prediabetic individuals. The aim of this study is to investigate the impact of activity tracking apps on increasing physical activity and its effect on glycemic control in people with prediabetes., Materials and Methods: This pilot study included 37 participants, 18 in the prediabetic group and 19 in the normoglycemic group matched for age and gender (mean age 53 years, 40% males). Participants used the Google Fit app for 3 months. The number of daily steps was recorded via the app, and blood and urine tests as well as body fat measurements were conducted before and following 3 months of app use. The co-primary outcome was the change in steps, and the change in HbA1c in both groups. Secondary outcomes were the change in fasting plasma glucose (FPG) (main secondary outcome), as well as lipid parameters, body mass index, visceral fat, and kidney function indices among the two groups., Results: Both groups increased the daily step count following the app intervention, without any statistically significant difference when we compared the steps change between the two groups. We found a statistically significant difference between HbA1c levels in favor of the prediabetic compared to the normoglycemic group [mean difference (MD) 0.16, 95%CI 0.04, 0.28, p -value 0.01)], following the 3-month intervention. Additionally, there was a statistically significant difference between FPG levels in favor of the prediabetic compared to the normoglycemic group (MD 9.06, 95%CI 4.16, 13.96, p -value 0.001)., Conclusions: The present study suggests that the use of activity tracking apps, combined with tailored activity goals and monthly supportive phone calls, may contribute to improved glycemic control among individuals with prediabetes.

Background/objectives: Lifestyle interventions such as dietary changes have been proposed to control the cardiometabolic risk factors and thus prevent cardiovascular (CV) disease (CVD). We performed an umbrella review to investigate whether different dietary patterns affect CV risk in individuals with at least one cardiometabolic risk factor (hypertension, dyslipidemia, obesity, diabetes, metabolic syndrome) but not established CVD., Methods: We systematically searched the PubMed and Scopus databases (up to August 2024) for the systematic reviews and meta-analyses of randomized controlled trials (RCTs). Articles should be written in English and refer to a specific dietary pattern (such as Mediterranean diet, etc.). The population studied referred to adults with at least one cardiovascular (CV) risk factor., Results: From 4512 records identified, we finally included 25 meta-analyses with a total of 329 associations. Strong evidence for a benefit was found for LCD with reductions in BW [MD: -4.79 (95% CI -5.85, -3.72) kg, p ≤ 0.001], SBP [MD: -6.38 (95% CI -7.84, -4.93) mmHg, p ≤ 0.001], TG [WMD: -5.81 (95% CI -7.96, -3.66) mg/dL, p ≤ 0.001], and fasting plasma insulin [MD: -15.35 (95% CI -19.58, -11.12) pmol/L, p ≤ 0.001], as well as for low-GI diet for the reduction of BW [SMD: -0.66 (95% CI -0.90, -0.43) kg, p ≤ 0.001]., Conclusions: Across many dietary patterns, LCD showed strong or highly suggestive evidence for a benefit on SBP, BW reduction, and lipid profile improvement. Secondarily, low-GI, DASH, and Portfolio and Nordic diets suggested beneficial effects on controlling CV risk.

Youths with type 1 diabetes (T1D) exhibits higher levels of pulse wave velocity (PWV) compared to healthy controls. Higher PWV in T1D subjects is associated with increased hazard of progression in albuminuria, decline in eGFR, cardiovascular (CV) events and mortality. In the recently published work by Georeli et al., increased PWV was associated with poor glycemic control as expressed by time-in-range (TIR) < 50 % in T1D children, adolescents and young adults. This finding is of great interest, since it is well known that glycemic control, as measured by TIR, is an important contributor of CV risk. The duration of TIR < 50 % is not reported by the authors, but is of importance, knowing that CGM provide data for the last 3-6 months, depending on the CGM model. In conclusion, PWV looks promising for risk stratification in T1D, but its exact role in T1D still remains to be fully explored., Competing Interests: Declaration of competing interest None related to this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Fertilizers are widely used to supply nutrients to crops, thereby increasing yields and soil fertility. However, the effects of their production and application on human health through occupational, residential, and environmental exposure remain unclear., Objective: To conduct a systematic review of epidemiological studies on the association between exposure to fertilizers and health-related outcomes., Methods: We searched in PubMed, Scopus, and Web of Science for cohort, case-control, cross-sectional, and ecological studies (up to May 2024) related to exposure to fertilizers and any reported human health endpoints across all age groups, without language or geographical limitations. Data were extracted for population and study characteristics, type of fertilizer used, exposure assessment, sample size, outcome and its definition, effect estimate, and quality characteristics from the eligible studies, and they were descriptively synthesized., Results: We found 65 eligible publications, with 407 postulated associations. Forty-six publications (321 associations) assessed exposure to inorganic fertilizers, and nineteen studies (93 associations) assessed organic fertilizers. Exposure assessed was related to occupation, residence, and/or proximity. The assessed outcomes were diverse, with considerable harmonization challenges. Inorganic fertilizers have been associated with an increased risk of cancerous outcomes in a small number of studies with methodological limitations and low replication validity, while organic fertilizers have been associated with infections and diarrhea., Conclusions: The epidemiological evidence suggests possible associations between inorganic fertilizers with solid organ tumors and hematological malignancies and organic fertilizers with infections and diarrhea. However, the available evidence is limited, and heterogeneity prevails. Further research is needed to enlarge the evidence base and increase the replication validity and robustness of the results.

Intravitreal chemotherapy is used as a salvage therapy for retinoblastoma with persistent or recurrent vitreous seeding after primary treatment. To assess the safety of this technique, we conducted a systematic review of all studies reporting ocular toxicity data. Forty-eight trials involving 2751 eyes were included. The most common complications were cataract, retinal toxicity, and vitreous hemorrhage. However, severe and permanent adverse events were limited, while the risk of extraocular dissemination, a significant concern, was practically eliminated through preventive techniques. Globe salvage rates ranged from 29 % to 100 %. In conclusion, intravitreal chemotherapy seems to improve prognosis of eyes with advanced disease, with an acceptable safety profile. Nevertheless, most relevant studies are retrospective, and no randomized trials have been performed. Recognizing the challenges regarding the conduct of randomized studies for such a rare pediatric cancer, we believe that multicenter trials through international collaborations can significantly enhance the available information., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We evaluated the effect of sodium glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA) on arterial stiffness indices., Methods: We searched PubMed (up to January 2024) for RCTs assessing the effect of SGLT2i or GLP1-RA on arterial stiffness with reporting outcomes PWV and AIx. Effect sizes of the included studies were expressed as weighted mean difference (WMD) and 95 % confidence interval. Subgroup analyses were performed based on comparator (placebo vs. active comparator), design (RCT vs. crossover), population (diabetic vs. all) and blindness (yes vs. no)., Results: A total of 19 studies (SGLT2i, 12 studies; GLP1-RA, 5 studies; SGLT2i/GLP1-RA combination, 2 studies) assessing 1212 participants were included. We did not find any statistically significant association between GLP1-RA or SGLT2i and PWV or AIx. None of the subgroup analyses showed any statistically significant result., Conclusion: No evidence of a favorable change in arterial stiffness indices (PWV, AIx) was found following the administration of SGLT2i or GLP1-RA., Competing Interests: Declaration of competing interest ER has received speaker honoraria and consulting fees for clinical trials unelated to this work (Novartis, Sanofi, NovoNordisk, Pfizer, AstraZeneca/BMS, Eli Lilly, MSD/Vianex, Boehringer Ing, Amgen, GSK, Plus Pharmaceuticals, WinMedica, Servier). The rest of the authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The 5-year overall survival of children and adolescents with osteosarcoma has been in plateau during the last 30 years. The present systematic review (1976-2023) and meta-analysis aimed to explore factors implicated in the prognosis of children and young adults with high-grade osteosarcoma. Original studies including patients ≤30 years and the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST) data (2010-2021) referred to children ≤14 years were analysed. Individual participant data (IPD) and summary estimates were used to assess the n-year survival rates, as well as the association of risk factors with overall survival (OS) and event-free survival (EFS). IPD and the n-year survival rates were pooled using Kaplan-Meier and Cox regression models, and random effects models, respectively. Data from 8412 patients, including 46 publications, NARECHEM-ST data, and 277 IPD from 10 studies were analysed. The summary 5-year OS rate was 64% [95% confidence interval (95%CI): 62%-66%, 37 studies, 6661 patients] and the EFS was 52% (95%CI: 49%-56%, 30 studies, 5010 patients). The survival rates generally differed in the pre-specified subgroups. Limb-salvage surgery showed a higher 5-year OS rate (69%) versus amputation (47%). Good responders had higher OS rates at 3 years (94%) and 5 years (81%), compared to poor responders at 3 years (66%), and 5 years (56%). Patients with metastatic disease had a higher risk of death [Hazard Ratio (HR): 3.60, 95%CI: 2.52, 5.15, 11 studies]. Sex did not have an impact on EFS (HR females/males : 0.90, 95%CI: 0.54, 1.48, 3 studies), whereas age>18 years seems to adversely affect EFS (HR 18+/<10 years : 1.36, 95%CI: 1.09, 1.86, 3 studies). Our results summarize the collective experience on prognostic factors of high-grade osteosarcoma among children and young adults. Poor response to neoadjuvant chemotherapy and metastatic disease at diagnosis were confirmed as primary risk factors of poor outcome. International collaboration of osteosarcoma study groups is essential to improve survival., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Comprehensive characteristics of the glycemic profile for prediabetes derived by continuous glucose monitoring (CGM) are unknown. We evaluate the difference of CGM profiles between individuals with prediabetes and normoglycemic individuals, including the response to oral glucose tolerance test (OGTT)., Methods: Individuals with prediabetes matched for age, sex, and BMI with normoglycemic individuals were instructed to use professional CGM for 1 week. OGTT was performed on the second day. The primary outcomes were percentages of glucose readings time below range (TBR): <54 or <70 mg/dL, time in range (TIR): 70 to 180 mg/dL, and time above range (TAR): >180 or >250 mg/dL. Area under the curve (AUC) was calculated following the OGTT. Glucose variability was depicted by coefficient of variation (CV), SD, and mean amplitude of glucose excursion (MAGE). Wilcoxon sign-ranked test, McNemar mid P -test and linear regression models were employed., Results: In all, 36 participants (median age 51 years; median body mass index [BMI] = 26.4 kg/m 2 ) formed 18 matched pairs. Statistically significant differences were observed for 24-hour time in range (TIR; median 98.5% vs. 99.9%, P = .013), time above range (TAR) >180 mg/dl (0.4% vs. 0%, P = .0062), and 24-hour mean interstitial glucose (113.8 vs. 108.8 mg/dL, P = .0038) between people with prediabetes compared to normoglycemic participants. Statistically significant differences favoring the normoglycemic group were found for glycemic variability indexes (median CV 15.2% vs. 11.9%, P = .0156; median MAGE 44.3 vs. 33.3 mg/dL, P = 0.0043). Following OGTT, the AUC was significantly lower in normoglycemic compared to the prediabetes group (median 18615.3 vs. 16370.0, P = .0347 for total and 4666.5 vs. 2792.7, P = .0429 for incremental 2-hour post OGTT)., Conclusion: Individuals with prediabetes have different glucose profiles compared to normoglycemic individuals. CGM might be helpful in individuals with borderline glucose values for a more accurate reclassification., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Beau's lines are transverse grooves in the nail plate that result from transient interruption of the growth of the proximal nail matrix. These rare nail disorders can be triggered mostly by infections or systemic diseases., Case Description: We describe a 65-year-old man who presented with nail changes on all fingernails. The patient, a non-smoker with no medication history, had severe immune responses during two hospitalisations, 9 and 4 months ago, for COVID-19. Both hospitalisations were accompanied by markedly elevated interleukin-6 levels, and treatment with tocilizumab on top of dexamethasone was required. The present examination revealed Beau's lines which were associated with both prior COVID-19 infections., Conclusions: Although nail changes look harmless, seeking Beau's lines during the physical examination might indicate past severe COVID-19 infection and a higher probability for reinfection and rehospitalisation., Learning Points: Beau's lines are grooves that traverse the nail plate horizontally.The appearance of Beau's lines may indicate past severe COVID-19 infection.Beau's lines can potentially indicate a higher probability of COVID-19 reinfection and rehospitalisation., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Congenital cryptorchidism is a well-established risk factor of testicular malignancies. However, there is still remarkable variability in the measures of associations between of these two clinical entities. The current meta-analysis investigates the up-to-date risk of testicular cancer in adults with a history of surgically corrected congenital cryptorchidism until adolescence. The meta-analysis was conducted with strict criteria for the identification of the congenital cryptorchidism cases that underwent surgery before adulthood. The study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A search of the PubMed and the Scopus databases was conducted, using a defined strategy, from inception to February 2023. Two independent authors screened the literature and extracted the data, using inclusion and exclusion criteria. Of the 2176 articles identified, 93 articles were fully retrieved, and 6 articles met all the inclusion criteria. The Newcastle-Ottawa scale was applied for the studies' quality assessment. The random-effects model in RevMan 5.4 program was used for the meta-analysis. Three case-control studies and three cohort studies were selected. They included 371,681 patients and 1786 incidents of testicular cancer. The pooled odds ratio (OR) was 3.99 (95% confidence intervals (CI): 2.80-5.71). The heterogeneity was moderate and estimated at 51% with the I-squared statistic. A forest plot and a funnel plot were produced to evaluate the ORs and the probable publication bias, respectively. The mean Newcastle-Ottawa score was 8/9 for all the included reports.  Conclusion: This systematic review and meta-analysis verifies, with an updated estimate, the increased risk of testicular cancer in adults with an orchidopexy history. New evidence on the maldescent laterality supports that the cancer risk remains increased and for the contralateral, unaffected testicle, although to a lesser extent. The orchidopexy in the first year of life prevents the testicular damage and decreases the overall cancer risk. What is Known: • Congenital cryptorchidism is the commonest genitourinary abnormality and a risk factor for testicular cancer. • The most recent meta-analysis reporting this association was in 2013. What is New: • After reviewing literature until February 2023, the association of congenital cryptorchidism with testicular cancer risk in adulthood was verified: odds ratio=3.99 [2.80-5.71], 95% CI. • The meta-analysis highlights the protective role of early orchidopexy and the controversial data about maldescent and testicular cancer laterality., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Pulse wave velocity (PWV) and augmentation index (AIx) are indices used to assess arterial stiffness. We aim to compare the effect of empagliflozin, liraglutide and their sequential combination on arterial stiffness indices in patients with type 2 diabetes (T2D)., Methods: This was a randomized single blind study evaluating the effect of empagliflozin vs liraglutide in adult patients with T2D. Patients were randomized to liraglutide titrated gradually to 1.8 mg or empagliflozin 25 mg in 1:1 ratio. Three months later empagliflozin was added to the liraglutide group, and liraglutide was added to the empagliflozin group. Patients were assessed with non-invasive tests for arterial stiffness (i.e., carotid-femoral PWV and AIx of aortic pressure) at baseline, 3-month and 9-month visits (final visit was extended for 3 months from the initial design due to Covid 19 pandemic). The primary outcome was the between-group difference of PWV change (ΔPWV) and ΔAIx at 3 months. Secondary outcomes included the between-group difference of ΔPWV and ΔAIx at 9 months, as well as the ΔPWV and ΔAIx between baseline and 9-month visit when total study population was assessed., Results: A total of 62 patients with T2D (30 started liraglutide; 32 empagliflozin, mean age 63 years, 25 % with established cardiovascular disease) participated in the study. We failed to show any significant between-group differences of ΔPWV and ΔΑΙx at 3 and 9 months, as well as between-group difference of ΔPWV and ΔAIx for the total study population between baseline and 9-month visit. In contrast, systemic vascular resistance and lipoprotein(a) levels improved, showing better results with liraglutide than empagliflozin. Favorable effects were also observed on body weight, body mass index, body and visceral fat, blood pressure, HbA1c, and uric acid levels., Conclusion: No evidence of a favorable change in arterial stiffness indices was seen with empagliflozin or liraglutide or their combination in this study. Well-designed powerful studies are needed to address any potential effects on arterial stiffness in selected populations., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Rationale: Pragmatic design may facilitate the generalizability of effectiveness of randomized controlled trials (RCTs) in primary health care (PHC)., Aims and Objectives: The aim of this study was to investigate whether published protocols in PHC were designed pragmatically and to explore whether specific trial characteristics may be related to a pragmatic design., Methods: Using the Pragmatic Explanatory Continuum Indicator Summary-2 (PRECIS-2), we assessed pragmatism for 123 published RCT protocols. For each domain, we calculated the mean score with the 95% confidence interval (95% CI). Interrater reliability was assessed by weighted κ-coefficient with 95% CI. We examined potential associations of published protocol characteristics with overall pragmatism by performing univariate and multivariate analyses., Results: We observed the highest score for primary analysis (4.66, 95% CI: 4.51, 4.82). The eligibility score was intermediate (3.16, 95% CI: 3.01, 3.32). Domains with scores towards the explanatory side included organization (2.50, 95% CI: 2.36, 2.63), flexibility of delivery (2.74, 95% CI: 2.60, 2.88) and flexibility of adherence (3.00, 95% CI: 2.83, 3.17). Interrater agreement was good (κ = 0.61; 95% CI: 0.34, 0.80; p < 0.001). Higher sample sizes were correlated to a pragmatic design (odds ratio: 6.86, 95% CI: 1.64, 28.75; p = 0.04)., Conclusion: Most RCT protocols were rated as intermediate in the pragmatic-explanatory continuum. Future research may guide all stakeholders on how best to incorporate the level of pragmatism in the interpretation of the results so that the trials are more likely to be applicable in real-world settings., (© 2022 John Wiley & Sons Ltd.)

Therapeutic advancements have improved pediatric cancer prognosis, shifting the interest towards the management of psychosocial burden and treatment-related morbidity. To critically appraise the available evidence, we conducted an umbrella review of meta-analyses of randomized controlled trials on supportive interventions for childhood cancer. Thirty-four publications (92 meta-analyses, 1 network, 14,521 participants) were included. The most concrete data showed a reduction in procedure-related pain and distress through hypnosis. Moreover, exercise improved the functional mobility of the patients. Regarding pharmacological interventions, most of the meta-analyses pertained to the treatment of nausea/vomiting (ondansetron was effective) and infections/febrile neutropenia [granulocyte-(macrophage) colony-stimulating factors showed benefits]. Substantial heterogeneity was detected in 31 associations. Conclusively, supportive interventions for pediatric cancer are being thoroughly evaluated. However, most of the studies are small and of moderate quality, highlighting the need for more randomized evidence in order to increase precision in improving the quality of life of patients, survivors and their families., Competing Interests: Conflict of interest Dr. Panagiotou reports personal fees from International Consulting Associates, Inc. outside the scope of the submitted work. Dr. Trikalinos is the PI for pharmaceutical sponsored trials at his institution. None includes the interventions or population addressed in our paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Atopic dermatitis (AD) is a type 2 chronic skin disorder associated with systemic and psychosocial comorbidities decreasing the quality of life for many patients. Dupilumab, a human monoclonal antibody that blocks interleukins IL-4 and IL-13, is a recently added systematic treatment option with an emerging evidence base. Here, we assessed the safety and efficacy of dupilumab in patients with AD. We conducted a systematic review and meta-analysis of placebo-controlled randomized clinical trials evaluating the safety and efficacy of dupilumab on AD-related outcomes including clinical symptoms, quality of life and adverse events (AE). Subgroup analysis was further performed in adults and children/adolescents. Fourteen trials were included: twelve in adults (n = 3,817) and two in children/adolescents (n = 618). Dupilumab decreased the Eczema Area Severity Index (EASI) score [standardized mean difference (SMD) = -0.98; 95% confidence interval (95% CI) = (-1.09, -0.88)], the percent change difference in Scoring Atopic Dermatitis (SCORAD) [mean difference (MD) = -31.56, 95% CI = (-33.75, -29.36)], and in pruritus Numeric Rating Scale (pNRS) [MD = -29.24, 95% CI = (-32.11, -26.37)]. It also achieved a reduction of at least ≥75% in the EASI score [Risk Ratio (RR) = 2.89, 95% CI = (2.47, 3.38)], the Investigator's Global Assessment (IGA) score ≤1 [RR = 3.47, 95% CI = (2.96, 4.06)] and eight additional endpoints with no signs of increased AE compared to placebo. In subgroup analysis, the results were concordant for both groups. Dupilumab improved clinical symptoms and quality of life in adults and children/adolescents with a safety profile comparable to placebo.

Few studies so far have examined the impact of nutritional status on the survival of children with cancer, with the majority of them focusing on hematological malignancies. We summarized published evidence reporting the association of nutritional status at diagnosis with overall survival (OS), event-free survival (EFS), relapse, and treatment-related toxicity (TRT) in children with cancer. Published studies on children with leukemia, lymphoma, and other solid tumors have shown that both under-nourished and over-nourished children at cancer diagnosis had worse OS and EFS. Particularly, the risk of death and relapse increased by 30-50% among children with leukemia with increased body mass index at diagnosis. Likewise, the risk of TRT was higher among malnourished children with osteosarcoma and Ewing sarcoma. Nutritional status seems to play a crucial role in clinical outcomes of children with cancer, thus providing a significant modifiable prognostic tool in childhood cancer management. Future studies with adequate power and longitudinal design are needed to further evaluate the association of nutritional status with childhood cancer outcomes using a more standardized definition to measure nutritional status in this population. The use of new technologies is expected to shed further light on this understudied area and give room to person-targeted intervention strategies.

Background: We used, for the first time, data registered in the Nationwide Registry for Childhood Hematological Malignancies and Solid Tumors (NARECHEM-ST)-Greece to estimate incidence/time trends of the rare childhood (0-14 years) non-Wilms tumors (non-WT), and compared the results of malignant non-WT to those from the Surveillance, Epidemiology, and End Results Program (SEER)-USA., Methods: Fifty-five cases (n = 33 malignant-only) were extracted from NARECHEM-ST (2001-2020) and 332 malignant cases from SEER (1990-2017). To allow between-country comparisons, age-standardized incidence rates (AIR) of malignant-only non-WT were calculated, and temporal trends were evaluated using Poisson and joinpoint regressions., Results: In NARECHEM-ST, malignant and non-malignant non-WT accounted for 22.6% of all renal tumors. Among malignant tumors, the AIR was 1.0/10 6 children in Greece, similar to that calculated for SEER, USA (AIR=0.9/10 6 ). The proportion of infant malignant and non-malignant non-WT was 27% (20% before 6 months) in NARECHEM-ST. Most common non-WT in Greece were congenital mesoblastic nephromas (CMN) diagnosed mainly in infancy (CIR=7.2/10 6 ). The proportion of infant malignant non-WT was 20% in SEER (AIR infancy =2.5/10 6 ), mainly attributed to rhabdoid tumors (CIR=1.6/10 6 ). The male-to-female (M:F) ratio of malignant non-WT was 0.9 in NARECHEM-ST vs. 1.2 in SEER, whereas boys outnumbered girls with clear cell sarcoma in NARECHEM-ST (M:F=4.0). Lastly, significantly increasing trends in incidence rates were noted in NARECHEM-ST [+ 6.8%, 95% confidence intervals (CI): 0.5, 13.3] and in SEER (+7.3%, 95%CI: 5.6, 9.0)., Conclusions: Observed incidence, time trends and sociodemographic variations of non-WT may reflect differential registration practices and healthcare delivery patterns including differences regarding surveillance, coding and treatment practices., (Copyright © 2022. Published by Elsevier Ltd.)

Background & Aims: Omega-3 supplements are widely used for cardiovascular (CV) protection. We performed an updated meta-analysis for omega-3 and CV outcomes., Methods: Random-effects meta-analysis including double-blind RCTs with duration ≥1 year, evaluating omega-3 supplements in 4 a priori defined categories (<1, 1, 2, ≥3 of 1g capsules/day) on all-cause mortality, cardiac death, myocardial infarction and stroke, reporting the relative risk (RR) as the measure of interest. Complementary approaches were Trial Sequential Analysis (TSA) and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid (EPA), sample size, statin use and study duration., Results: Nineteen randomized controlled trials (RCTs) with 97,709 participants were included. Omega-3 supplements were not statistically significantly associated with reduced all-cause mortality, cardiac death, MI, or stroke, with the exception of reduced cardiac mortality only for the equivalent dose of 2 capsules/day (RR 0.55, 95%CI 0.33, 0.90, p = 0.0169, I 2  = 0%). TSA reached the required information size only for the lower doses regarding all-cause and cardiac mortality, where they show no significant association. Meta-regression on EPA dose, as well as the majority of sensitivity analyses did not show any statistically significant association., Conclusion: Compared to the robust evidence for low doses, higher doses and particularly for the unique type of omega-3 icosapent ethyl ester should be further addressed., Competing Interests: Conflict of interest ER has received speaker honoraria and consulting fees for clinical trials unelated to this work (Novartis, Sanofi, NovoNordisk, Pfizer, AstraZeneca/BMS, Eli Lilly, MSD/Vianex, Boehringer Ing, Amgen, GSK, Plus Pharmaceuticals, WinMedica, Servier). NK has received support for attending meetings unelated to this work (Bayer-Novagem, Pfizer, Boehringer-Ingelheim). IP is implicated in clinical studies using omega-3 intervention for neurodegenerative diseases unrelated to this work (PALUPA Medical Ltd). The rest of the coauthors declare no competing interests., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Nation-wide SARS-CoV-2 seroprevalence surveys provide valuable insights into the course of the pandemic, including information often not captured by routine surveillance of reported cases., Methods: A serosurvey of IgG antibodies against SARS-CoV-2 was conducted in Greece between March and December 2020. It was designed as a cross-sectional survey repeated at monthly intervals. The leftover sampling methodology was used and a geographically stratified sampling plan was applied., Results: Of 55,947 serum samples collected, 705 (1.26%) were found positive for anti-SARS-CoV-2 antibodies, with higher seroprevalence (9.09%) observed in December 2020. Highest seropositivity levels were observed in the "0-29" and "30-49" year age groups. Seroprevalence increased with age in the "0-29" age group. Highly populated metropolitan areas were characterized with elevated seroprevalence levels (11.92% in Attica, 12.76% in Thessaloniki) compared to the rest of the country (5.90%). The infection fatality rate (IFR) was estimated at 0.451% (95% CI: 0.382-0.549%) using aggregate data until December 2020, and the ratio of actual to reported cases was 9.59 (7.88-11.33)., Conclusions: The evolution of seroprevalence estimates aligned with the course of the pandemic and varied widely by region and age group. Young and middle-aged adults appeared to be drivers of the pandemic during a severe epidemic wave under strict policy measures.

A Knowledge, Attitudes and Practices (KAP) study was conducted at the end of May 2021 engaging 1456 healthcare workers (HCWs) from 20 hospitals throughout Greece. Acceptance of vaccination against coronavirus disease 2019 (COVID-19) was estimated at 77.7%, with lower vaccine acceptance identified in nurses compared to physicians. Fears related to vaccine safety, lack of information and general knowledge about vaccinations, influenza vaccine acceptance, education level and years of practice were among the factors independently associated with vaccine acceptance. A strong association was identified between vaccination of HCWs in each health region and the population coverage, indicating that HCWs may be role models for the general population. Information campaigns should continue despite decisions taken regarding mandatory vaccinations.

Background and Aims: To systematically address all the relevant evidence of the association between high-density lipoprotein cholesterol (HDL-C) and COVID-19 infection., Methods: We searched PubMed, PubMed Central and medRxiv databases (up to May 2021) for studies related to HDL-C and COVID-19 infection. A qualitative synthesis of published prospective and retrospective studies for the role of low HDL-C levels on COVID-19 infection severity was performed., Results: Thirty-three studies (6 prospective, 27 retrospective) including 11,918 COVID-19 patients were eligible for the systematic review. Twelve studies compared HDL-C levels on admission in COVID-19 patients with healthy controls. In these 12 studies, COVID-19 patients had significantly lower HDL-C levels on admission compared with that of healthy controls. Twenty-eight studies observed the HDL-C levels among COVID-19 diagnosed patients, to establish the role of low HDL-C values in the prognosis of the infection. Twenty-four studies showed a correlation between low HDL-C levels with disease severity, while only 4 studies showed no association., Conclusions: Low HDL-C levels should be added in the list of the others well-known risk factors for COVID-19 severity., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors.)

Despite the abundance of epidemiological evidence concerning the association between pesticide exposure and adverse health outcomes including acute childhood leukemia (AL), evidence remains inconclusive, and is inherently limited by heterogeneous exposure assessment and multiple statistical testing. We performed a literature search of peer-reviewed studies, published until January 2021, without language restrictions. Summary odds ratios (OR) and 95% confidence intervals (CI) were derived from stratified random-effects meta-analyses by type of exposure and outcome, exposed populations and window of exposure to address the large heterogeneity of existing literature. Heterogeneity and small-study effects were also assessed. We identified 55 eligible studies (n = 48 case-control and n = 7 cohorts) from over 30 countries assessing >200 different exposures of pesticides (n = 160,924 participants). The summary OR for maternal environmental exposure to pesticides (broad term) during pregnancy and AL was 1.88 (95%CI: 1.15-3.08), reaching 2.51 for acute lymphoblastic leukemia (ALL; 95%CI: 1.39-4.55). Analysis by pesticide subtype yielded an increased risk for maternal herbicide (OR: 1.41, 95%CI: 1.00-1.99) and insecticide (OR: 1.60, 95%CI: 1.11-2.29) exposure during pregnancy and AL without heterogeneity (p = 0.12-0.34). Meta-analyses of infant leukemia were only feasible for maternal exposure to pesticides during pregnancy. Higher magnitude risks were observed for maternal pesticide exposure and infant ALL (OR: 2.18, 95%CI: 1.44-3.29), and the highest for infant acute myeloid leukemia (OR: 3.42, 95%CI: 1.98-5.91). Overall, the associations were stronger for maternal exposure during pregnancy compared to childhood exposure. For occupational or mixed exposures, parental, and specifically paternal, pesticide exposure was significantly associated with increased risk of AL (OR parental : 1.75, 95%CI: 1.08-2.85; OR paternal : 1.20, 95%CI: 1.07-1.35). The epidemiological evidence, supported by mechanistic studies, suggests that pesticide exposure, mainly during pregnancy, increases the risk of childhood leukemia, particularly among infants. Sufficiently powered studies using repeated biomarker analyses are needed to confirm whether there is public health merit in reducing prenatal pesticide exposure., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

We assessed event-free (EFS) and overall (OS) survival in 676 incident cases of childhood Hodgkin (HL) and non-Hodgkin (NHL) lymphoma actively registered in Greece (1996-2019). HL-OS 5-year was 96% and NHL-OS 5-year 85%, whereas HL-EFS 5-year was 86% and NHL-EFS 5-year was 81%, notably similar to the respective OS rates (HL: 95%, NHL: 85%) in developed countries. For HL, older age at diagnosis, high maternal education and close proximity to treatment centers were linked to remarkably favorable outcomes. By contrast, stage IV patients showed worse OS and EFS. HL patients with low levels of hemoglobin were associated with worse EFS (hazard ratio: 2.81, 95% confidence intervals: 1.09-7.22). OS (76%) and EFS (73%) were poor among high-risk NHL patients and those with increased LDH (71%). The identified predictors of poor disease outcome point to the need for intensification of individualized treatments. Ongoing clinical cancer registration entailing clinical components could contribute to use of state-of-the-art treatments.

Objective: To conduct a bibliometric analysis using a large sample of overviews of systematic reviews (OoSRs) and reveal research trends and areas of interest about these studies., Study Design and Setting: We searched MEDLINE, Scopus and Cochrane Database of Systematic Reviews from 1/1/2000 to 15/10/2020. We used Scopus meta-data and two authors recorded supplementary information independently. We summarized the data using frequencies with percentages., Results: A total of 1558 studies were considered eligible for analysis. We found that the publications have been increasing yearly and their nomenclature was not uniform (the most frequent label in the title was "overview of systematic reviews"). The largest number of papers and the most cited ones were published by corresponding authors from the UK. The publications were distributed across 737 scholarly journals and many of them were published in the field of complementary/alternative medicine, psychiatry/psychology, nutrition/dietetics, and pediatrics. The co-authorship analysis revealed collaborations among countries. The most common clinical conditions were depression, diabetes, cancer, dementia, pain, cardiovascular disease, stroke, obesity, and schizophrenia., Conclusion: OoSRs have recently become a popular approach of evidence synthesis. International collaborations between overview authors from countries with increased research productivity and countries with less research activity should be encouraged., Competing Interests: Conflict of interest All authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Treatment advancements in pediatric cancer have improved prognosis, but the strength of supporting evidence has not been thoroughly evaluated. To critically appraise it, we performed an umbrella review of meta-analyses of randomized controlled trials examining the efficacy and safety of therapeutic interventions for pediatric malignancies. Fourteen publications (68 meta-analyses, 31,496 participants) were eligible. Acute lymphoblastic leukemia (ALL) was investigated at most. Substantial heterogeneity was detected in 10 associations, with limited indications for small-study effects and excess-significance bias. The most concrete evidence pertained to the use of methotrexate and vincristine-prednisone pulses for ALL, improving event-free survival. Evidence regarding other cancers was relatively weak. Conclusively, we found few small meta-analyses focusing mainly on ALL. Randomized evidence stemming from adult populations still seems to serve as valuable indirect evidence backup. More randomized evidence and individual patient data meta-analyses are needed to increase certainty and precision in the care of pediatric cancer patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Genetic and environmental factors during early development may influence lung growth and impact lung function. We performed a meta-analysis of epidemiological studies examining the association between conception history of assisted reproduction techniques (ART) and childhood asthma. We searched PubMed and Embase up to November 2020 for relevant observational studies and synthesized data data under a fixed or random effects model as appropriate. Heterogeneity was assessed using the I 2 metric. We identified 13 individual studies including 3,226,386 participants. We did not observe a statistically significant association between ART and physician-diagnosed asthma (n = 9, random OR 1.16; 95% CI 0.94-1.43; I 2 61%). We observed a statistically significant association between ART and prescription of asthma medications (n = 6, fixed OR 1.27; 95% CI 1.23-1.32; I 2 0%). Wheezing was also associated with ART (n = 4, fixed OR 1.71; 95% CI 1.08-2.72; I 2 0%). When we combined studies using any asthma definition, a statistically significant association was observed (random OR 1.19; 95% CI 1.05-1.34; I 2 80%).Conclusion: The available observational evidence suggests that the risk of asthma is higher among children born after ART. The mechanism and potential sources of bias behind this association are under scrutiny, and further work is needed to establish causality. What is Known: • "Positive" epidemiological signals for the association between assisted reproduction techniques and asthma stemming from large studies were not replicated by subsequent research. • Any available research synthesis effort so far bears no quantitative aspect. What is New: • The available observational evidence suggests that the risk of asthma is higher among children born after ART. • The mechanism and potential sources of bias behind this association are under scrutiny.

A serosurvey of IgG antibodies against SARS-CoV-2 was conducted in Greece between May and August 2020. It was designed as a cross-sectional survey and was repeated at monthly intervals. The leftover sampling methodology was used and a geographically stratified sampling plan was applied. Of 20,110 serum samples collected, 89 (0.44%) were found to be positive for anti-SARS-CoV-2 antibodies, with higher seroprevalence (0.35%) observed in May 2020. The highest seroprevalence was primarily observed in the "30-49" year age group. Females presented higher seroprevalence compared to males in May 2020 (females: 0.58% VS males: 0.10%). This difference reversed during the study period and males presented a higher proportion in August 2020 (females: 0.12% VS males: 0.58%). Differences in the rate of seropositivity between urban areas and the rest of the country were also observed during the study period. The four-month infection fatality rate (IFR) was estimated to be 0.47%, while the respective case fatality rate (CFR) was at 1.89%. Our findings confirm low seroprevalence of COVID-19 in Greece during the study period. The young adults are presented as the most affected age group. The loss of the cumulative effect of seropositivity in a proportion of previous SARS-CoV-2 infections was indicated.

Background: Omega-3 supplements are popular for cardiovascular disease (CVD) prevention. We aimed to assess the association between dose-specific omega-3 supplementation and CVD outcomes., Design: We included double-blind randomised clinical trials with duration ≥1 year assessing omega-3 supplementation and estimated the relative risk (RR) for all-cause mortality, cardiac death, sudden death, myocardial infarction and stroke. Primary analysis was a stratified random-effects meta-analysis by omega-3 dose in 4 a priori defined categories (<1, 1, 2, ≥3 of 1 g capsules/day). Complementary approaches were trial sequential analysis and sensitivity analyses for triglycerides, prevention setting, intention-to-treat analysis, eicosapentaenoic acid, sample size, statin use, study duration., Results: Seventeen studies (n=83 617) were included. Omega-3 supplementation as ≤1 capsule/day was not associated with any outcome under study; futility boundaries were crossed for all-cause mortality and cardiac death. For two capsules/day, we observed a statistically significant reduction of cardiac death (n=3, RR 0.55, 95% CI 0.33 to 0.90, I 2 =0%); for ≥3 capsules/day we observed a statistically significant reduction of cardiac death (n=3, RR 0.82, 95% CI 0.68 to 0.99, I 2 =0%), sudden death (n=1, RR 0.70, 95% CI 0.51 to 0.97) and stroke (n=2, RR 0.74, 95% CI 0.57 to 0.95, I 2 =0%)., Conclusion: Omega-3 supplementation at <2 1 g capsules/day showed no association with CVD outcomes; this seems unlikely to change from future research. Compared with the robust scientific evidence available for low doses, the evidence for higher doses (2-4 1 g capsules/day) is weak. The emerging postulated benefit from high-dose supplementation needs replication and further evaluation as to the precise formulation and indication., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

There is a growing recognition that social support can potentially exert consistent or opposing effects in influencing health behaviours. The present paper presents a cross-sectional study, including 2,064 adults from Italy, Spain and Greece, who were participants in a multi-centre randomised controlled trial (C4H study), aiming to examine whether social support is correlated with adherence to a healthy Mediterranean diet and physical activity. Social support data were available for 1,572 participants. The majority of the sample reported emotional support availability (84·5 %), financial support availability (72·6 %) and having one or more close friends (78·2 %). Mediterranean diet adherence was significantly associated with emotional support ( P = 0·009) and social network support ( P = 0·021). No statistically significant associations were found between participant physical activity and the social support aspects studied. In conclusion, emotional and social network support may be associated with increased adherence to the Mediterranean diet. However, further research is needed to evaluate the role of social support in adherence to healthy Mediterranean diet., (© The Author(s) 2020.)

Season of birth, a surrogate of seasonal variation of environmental exposures, has been associated with increased risk of several cancers. In the context of a Southern-Eastern Europe (SEE) consortium, we explored the potential association of birth seasonality with childhood (0-14 years) central nervous system (CNS) tumors. Primary CNS tumor cases (n = 6,014) were retrieved from 16 population-based SEE registries (1983-2015). Poisson regression and meta-analyses on birth season were performed in nine countries with available live birth data (n = 4,987). Subanalyses by birth month, age, gender and principal histology were also conducted. Children born during winter were at a slightly increased risk of developing a CNS tumor overall [incidence rate ratio (IRR): 1.06, 95% confidence intervals (CI): 0.99-1.14], and of embryonal histology specifically (IRR: 1.13, 95% CI: 1.01-1.27). The winter peak of embryonal tumors was higher among boys (IRR: 1.24, 95% CI: 1.05-1.46), especially during the first 4 years of life (IRR: 1.33, 95% CI: 1.03-1.71). In contrast, boys <5 years born during summer seemed to be at a lower risk of embryonal tumors (IRR: 0.73, 95% CI: 0.54-0.99). A clustering of astrocytomas was also found among girls (0-14 years) born during spring (IRR: 1.23, 95% CI: 1.03-1.46). Although the present exploratory results are by no means definitive, they provide some indications for age-, gender- and histology-related seasonal variations of CNS tumors. Expansion of registration and linkage with cytogenetic reports could refine if birth seasonality is causally associated with CNS tumors and shed light into the complex pathophysiology of this lethal disease., (© 2020 UICC.)

Tuberculosis (TB) can manifest prolonged fever or fever of unknown origin, especially when it is located extrapulmonary. We report a case of disseminated TB complicated by iliac bone osteolysis and a gluteal abscess in a 75-year-old female patient with fever and bone marrow dysplasia. Diagnosis of TB was made despite transient false-positive high-titer agglutination tests and ELISA antibodies to Brucella. The case presented shows that in a highly suggestive case of TB, positive agglutination tests or ELISA antibodies to Brucella should be interpreted with caution, and repeated testing should be performed to assess their persistence and fluctuation over time.

A serosurvey of IgG antibodies against severe acute respiratory coronavirus 2 (SARS-CoV-2) was performed during March and April 2020. Among 6,586 leftover sera, 24 (0.36%) were positive, with higher prevalence in females, older individuals and residents of large urban areas. Seroprevalence was estimated at 0.02% and 0.25%, respectively, in March and April, infection fatality rate at 2.66% and 0.54%. Our findings confirm low COVID-19 incidence in Greece and possibly the effectiveness of early measures.

Osteoporosis is the most common metabolic bone disorder globally and is characterized by skeletal fragility and microarchitectural deterioration. Genetic pleiotropy occurs when a single genetic element is associated with more than one phenotype. We aimed to identify pleiotropic loci associated with bone mineral density (BMD) and nonbone phenotypes in genome-wide association studies. In the discovery stage, the NHGRI-EBI Catalog was searched for genome-wide significant associations ( P value < 5 × 10 -8 ), excluding bone-related phenotypes. SNiPA was used to identify proxies of the significantly associated single nucleotide polymorphisms (SNPs) ( r 2  = 1). We then assessed putative genetic associations of this set of SNPs with femoral neck (FN) and lumbar spine (LS) BMD data from the GEFOS Consortium. Pleiotropic variants were claimed at a false discovery rate < 1.4 × 10 -3 for FN-BMD and < 1.5 × 10 -3 for LS-BMD. Replication of these genetic markers was performed among more than 400 000 UK Biobank participants of European ancestry with available genetic and heel bone ultrasound data. In the discovery stage, 72 BMD-related pleiotropic SNPs were identified, and 12 SNPs located in 11 loci on 8 chromosomes were replicated in the UK Biobank. These SNPs were associated, in addition to BMD, with 14 different phenotypes. Most pleiotropic associations were exhibited by rs479844 ( AP5B1, OVOL1 genes), which was associated with dermatological and allergic diseases, and rs4072037 ( MUC1 gene), which was associated with magnesium levels and gastroenterological cancer. In conclusion, 12 BMD-related genome-wide significant SNPs showed pleiotropy with nonbone phenotypes. Pleiotropic associations can deepen the genetic understanding of bone-related diseases by identifying shared biological mechanisms with other diseases or traits., Competing Interests: Competing interestsDr. Kiel’s time was supported by a grant from NIAMS R01 AR041398. All remaining authors declare no competing interests., (© The Author(s) 2020.)

Aim: To investigate which metabolic factors increase the risk of incident diabetes (T2D) in statin-treated patients., Methods: A retrospective study conducted in Greece including 1241 consecutive individuals with dyslipidemia attending a lipid clinic for ≥3 years. After defining associations with incident T2D, we assessed the risk of new-onset T2D based on the presence of impaired fasting glucose (IFG), atherogenic dyslipidemia, and overweight/obesity., Results: After excluding 166 patients with baseline T2D and 193 subjects taking lipid-lowering therapy at the baseline visit, 882 participants were included in the study. Eleven percent (n=94) developed T2D during their follow-up (median 6 years; IQR: 4-10). Baseline patients' age (OR: 1.05; 95% CI: 1.02-1.08, p<0.01), family history of diabetes (OR: 3.58; 95% CI: 1.86-6.91, p<0.01), IFG (OR: 6.56; 95% CI: 3.53-12.12, p<0.01), overweight/obesity (OR: 2.65; 95% CI: 1.39-5.05, p<0.01), atherogenic dyslipidemia (OR: 3.27; 95% CI: 1.50-7.15, p<0.01), and treatment with high-intensity statins (OR: 3.51; 95% CI: 1.89-6.51, p<0.01) were independently associated with increased risk of T2D in statin-treated patients. Among the IFG subjects, atherogenic dyslipidemia (OR: 3.44; 95% CI: 1.31-9.04, p=0.01) and overweight/obesity (OR: 2.54; 95% CI: 1.14-5.66, p<0.05) independently increased the risk of T2D. Among the overweight/obese ones, atherogenic dyslipidemia independently increased the risk of T2D (adjusted OR: 5.60; 95% CI: 2.19-14.30, p<0.01)., Conclusion: Atherogenic dyslipidemia appears to be an independent risk factor for new-onset T2D in statin-treated patients, while IFG, overweight/obesity and family history of diabetes remain risk factors for new-onset T2D in this group., (Copyright © 2019 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

With the exception of renal cell carcinoma, studies assessing the association between hypertension and other cancers are inconsistent. We conducted a meta-analysis to assess this evidence. We included observational studies investigating the association between any definition of hypertension or systolic and diastolic blood pressure and risk of any cancer, after searching PubMed until November 2017. We calculated summary relative risks (RR) and 95% confidence intervals (CI) using inverse-variance weighted random effects methods. A total of 148 eligible publications were identified out of 39,891 initially screened citations. Considering only evidence from 85 prospective studies, positive associations were observed between hypertension and kidney, colorectal and breast cancer. Positive associations between hypertension and risk of oesophageal adenocarcinoma and squamous cell carcinoma, liver and endometrial cancer were also observed, but the majority of studies did not perform comprehensive multivariable adjustments. Systolic and diastolic blood pressure were positively associated with risk of kidney cancer but not with other cancers. In addition to the previously well-described association between hypertension and risk of kidney cancer, the current meta-analysis suggested that hypertensive individuals may also be at higher risk of colorectal and breast cancer. However, careful interpretation is required as most meta-analyses included relatively small number of studies, several relative risks had weak or moderate magnitude and maybe affected by residual confounding.

In the version of this article initially published, in Fig. 5a, the data in the right column of 'DAAM2 gRNA1' were incorrectly plotted as circles indicating 'untreated' rather than as squares indicating 'treated'. The error has been corrected in the HTML and PDF versions of the article.

Aims: To assess the association between atrial fibrillation (AF) and all-cause mortality and implantable cardioverter-defibrillators (ICDs) therapies in heart failure (HF) patients with reduced ejection fraction and an ICD implanted., Methods and Results: A systematic MEDLINE search performed from inception through November 2016, supplemented by hand searching of reference lists, identified 62 eligible studies (227 998 patients) reporting on the association between AF and outcomes in HF patients; 36 studies included data on all-cause mortality, 30 on appropriate, and 17 on inappropriate ICD interventions. Hazard ratio, risk ratio, or odds ratio estimates were used based on data availability. Effect estimates were synthesized under a random-effects model. Implantable cardioverter-defibrillator-implanted HF patients with a history of AF had a 42% {combined effect estimate (cEE) 1.42 [95% confidence interval (CI) 1.28-1.57]} higher risk of all-cause mortality compared with patients with no AF history. Furthermore, AF patients had a higher risk of appropriate [cEE 1.44 (95% CI 1.27-1.64)] and inappropriate ICD interventions [cEE 2.05 (95% CI 1.75-2.44)]., Conclusion: Atrial fibrillation history is statistically significantly associated with adverse major clinical outcomes in ICD-implanted HF patients. Patients with AF have a higher risk of all-cause mortality, appropriate, and inappropriate ICD interventions compared with patients with no AF history. Whether AF may have an independent deleterious effect on HF prognosis or may simply be a marker of HF severity should be further investigated., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10 -75 ) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.

Rationale: COPD has been perceived as being a disease of older men. However, >7 million women are estimated to live with COPD in the USA alone. Despite a growing body of literature suggesting an increasing burden of COPD in women, the evidence is limited., Objectives: To assess and synthesize the available evidence among population-based epidemiologic studies and calculate the global prevalence of COPD in men and women., Materials and Methods: A systematic review and meta-analysis reporting gender-specific prevalence of COPD was undertaken. Gender-specific prevalence estimates were abstracted from relevant studies. Associated patient characteristics as well as custom variables pertaining to the diagnostic method and other important epidemiologic covariates were also collected. A Bayesian random-effects meta-analysis was performed investigating gender-specific prevalence of COPD stratified by age, geography, calendar time, study setting, diagnostic method, and disease severity., Measurements and Main Results: Among 194 eligible studies, summary prevalence was 9.23% (95% credible interval [CrI]: 8.16%-10.36%) in men and 6.16% (95% CrI: 5.41%-6.95%) in women. Gender prevalences varied widely by the World Health Organization Global Burden of Disease subregions, with the highest female prevalence found in North America (8.07% vs 7.30%) and in participants in urban settings (13.03% vs 8.34%). Meta-regression indicated that age ≥40 and bronchodilator testing contributed most significantly to heterogeneity of prevalence estimates across studies., Conclusion: We conducted the largest ever systematic review and meta-analysis of global prevalence of COPD and the first large gender-specific review. These results will increase awareness of COPD as a critical woman's health issue., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objectives: To identify genetic determinants of susceptibility to clinical vertebral fractures, which is an important complication of osteoporosis., Methods: Here we conduct a genome-wide association study in 1553 postmenopausal women with clinical vertebral fractures and 4340 controls, with a two-stage replication involving 1028 cases and 3762 controls. Potentially causal variants were identified using expression quantitative trait loci (eQTL) data from transiliac bone biopsies and bioinformatic studies., Results: A locus tagged by rs10190845 was identified on chromosome 2q13, which was significantly associated with clinical vertebral fracture (P=1.04×10 -9 ) with a large effect size (OR 1.74, 95% CI 1.06 to 2.6). Bioinformatic analysis of this locus identified several potentially functional SNPs that are associated with expression of the positional candidate genes TTL (tubulin tyrosine ligase) and SLC20A1 (solute carrier family 20 member 1). Three other suggestive loci were identified on chromosomes 1p31, 11q12 and 15q11. All these loci were novel and had not previously been associated with bone mineral density or clinical fractures., Conclusion: We have identified a novel genetic variant that is associated with clinical vertebral fractures by mechanisms that are independent of BMD. Further studies are now in progress to validate this association and evaluate the underlying mechanism., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors., Methods: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods., Findings: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75-79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2-9·7) followed by physical inactivity (5·5%, 2·1-8·5), history of diabetes (2·8%, 2·1-4·0), and low to average BMI (2·0%, 1·4-2·7), whereas low alcohol consumption (0·01-2·5 g per day) and high BMI had a protective effect., Interpretation: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle., Funding: European Community's Seventh Framework Programme., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND license. Published by Elsevier Ltd.. All rights reserved.)

Background: Inhabitants of Metsovo, NW Greece, had been domestically exposed to asbestos from a gradually abandoned whitewash ("luto") that resulted in a declining epidemic of malignant mesothelioma., Objectives: We aimed to evaluate whether other sources of asbestos exposure exist following "luto" abandonment., Methods: Chest computed tomography (CT) and bronchoalveolar lavage (BAL) were used to evaluate residual asbestos exposure in younger Metsovites through the identification of pleural calcifications and asbestos bodies, respectively. In order to provide a historical universally exposed group for comparison, we used the accumulated chest CTs and chest roentgenograms of our previous studies, performed in Metsovites with confirmed exposure but negative chest roentgenogram. As an additional external comparison group, we also assessed CT scans and chest roentgenograms of Metsovites being older than our target group obtained from the records of the Radiology Department between 2009 and 2011. In order to be able to compare our BAL findings, we sought historical controls among BAL studies performed in Metsovites with known exposure to "luto," in the 1980s-1990s, mainly to evaluate alveolitis. Those belonging to individuals of the same age range were used for further comparison., Results: Twenty-two Metsovites born between 1960 and 1980 consented to undergo a chest CT scan, while another 14 CTs were retrieved from the records of the Radiology Department (among 86 of all ages), thus increasing the number of individuals studied to 36. Five of the 36 Metsovites studied were former "luto" users for a short period of time. Minimal pleural calcifications were present in 2 of them, while all chest CTs of nonusers were negative. All 8 BAL studies were negative for asbestos bodies., Conclusion: "Luto" use seems to have been the only source of considerable asbestos exposure in Metsovo., (© 2017 S. Karger AG, Basel.)

Background: Diabetes mellitus has a multifactorial pathogenesis with a strong genetic component as well as many environmental and lifestyle influences. Emerging evidence suggests that environmental contaminants, including pesticides, might play an important role in the pathogenesis of diabetes., Objectives: We performed a systematic review and meta-analysis of observational studies that assessed the association between exposure to pesticides and diabetes and we examined the presence of heterogeneity and biases across available studies., Methods: A comprehensive literature search of peer-reviewed original research pertaining to pesticide exposure and diabetes, published until 30st May 2015, with no language restriction, was conducted. Eligible studies were those that investigated potential associations between pesticides and diabetes without restrictions on diabetes type. We included cohort studies, case-control studies and cross-sectional studies. We extracted information on study characteristics, type of pesticide assessed, exposure assessment, outcome definition, effect estimate and sample size., Results: We identified 22 studies assessing the association between pesticides and diabetes. The summary OR for the association of top vs. bottom tertile of exposure to any type of pesticide and diabetes was 1.58 (95% CI: 1.32-1.90, p=1.21×10(-6)), with large heterogeneity (I(2)=66.8%). Studies evaluating Type 2 diabetes in particular (n=13 studies), showed a similar summary effect comparing top vs. bottom tertiles of exposure: 1.61 (95% CI 1.37-1.88, p=3.51×10(-9)) with no heterogeneity (I(2)=0%). Analysis by type of pesticide yielded an increased risk of diabetes for DDE, heptachlor, HCB, DDT, and trans-nonachlor or chlordane., Conclusions: The epidemiological evidence, supported by mechanistic studies, suggests an association between exposure to organochlorine pesticides and Type 2 diabetes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Conversion to mammalian target of rapamycin inhibitors (mTORi) is often used in liver transplantation to overcome calcineurin inhibitor (CNI) nephrotoxicity but the evidence base for this approach is not well defined. To summarize the evidence, from randomized clinical trials (RCTs), for conversion from CNI to mTORi-based immunosuppression after liver transplantation., Methods: Databases and conference abstracts were searched up to August 2015. The RCTs evaluating conversion from CNI to mTORi-based maintenance immunosuppression after adult liver transplantation. Descriptive and quantitative information was extracted; summary mean difference and risk ratio (RR) estimates were synthesized under a random-effects model. Heterogeneity was assessed using the Q statistic and I., Results: Ten RCTs, with a total of 1927 patients, met the final inclusion criteria. Patients converted to mTORi had significantly better renal function at 1 year after randomization compared with patients remaining on CNI (mean difference, 7.48 mL/min per 1.73 m; 95% confidence interval [95% CI], 3.18-11.8). The risks of graft loss (RR, 0.77; 95% CI, 0.29-2.09; I, 31%) and patient death (RR, 1.05; 95% CI, 0.63-1.73; I, 0%) were similar for patients converted to mTORi and patients remaining on CNI. However, conversion to mTORi was associated with a higher risk of acute rejection (RR, 1.76; 95% CI, 1.33-2.34; I, 0%) and study discontinuation due to adverse events (RR, 2.17; 95% CI, 1.38-3.44; I, 63%) up to 1 year after randomization., Conclusions: Conversion from CNI to mTORi after liver transplantation is associated with improved renal function after 1 year but increases the risk of acute rejection and may be poorly tolerated.

The extent to which low-frequency (minor allele frequency (MAF) between 1-5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n = 2,882 from UK10K (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes reference panel (n = 26,534), and de novo replication genotyping (n = 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., Pmeta = 1 × 10(-11)). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Objectives: To summarise the evidence and evaluate the validity of the associations between type 2 diabetes and the risk of developing or dying from cancer., Design: An umbrella review of the evidence across meta-analyses of observational studies of type 2 diabetes with risk of developing or dying from any cancer., Data Sources: PubMed, Embase, Cochrane database of systematic reviews, and manual screening of references., Eligibility Criteria: Meta-analyses or systematic reviews of observational studies in humans that examined the association between type 2 diabetes and risk of developing or dying from cancer., Results: Eligible meta-analyses assessed associations between type 2 diabetes and risk of developing cancer in 20 sites and mortality for seven cancer sites. The summary random effects estimates were significant at P=0.05 in 20 meta-analyses (74%); and all reported increased risks of developing cancer for participants with versus without diabetes. Of the 27 meta-analyses, eventually only seven (26%) compiled evidence on more than 1000 cases, had significant summary associations at P ≤ 0.001 for both random and fixed effects calculations, and had neither evidence of small study effects nor evidence for excess significance. Of those, only six (22%) did not have substantial heterogeneity (I(2)>75%), pertaining to associations between type 2 diabetes and risk of developing breast, cholangiocarcinoma (both intrahepatic and extrahepatic), colorectal, endometrial, and gallbladder cancer. The 95% prediction intervals excluded the null value for four of these associations (breast, intrahepatic cholangiocarcinoma, colorectal, and endometrial cancer)., Conclusions: Though type 2 diabetes has been extensively studied in relation to risk of developing cancer and cancer mortality and strong claims of significance exist for most of the studied associations, only a minority of these associations have robust supporting evidence without hints of bias., (© Tsilidis et al 2014.)

Objectives: Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects., Methods: We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used., Results: We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis)., Conclusions: Novel genetic loci for hip OA were found in this meta-analysis of GWAS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Parkinson's disease is a neurodegenerative disease, with a constantly increasing prevalence and a high global financial impact arising from direct and indirect costs. Large-scale, observational studies provide data that support the better comprehension of disease aspects, constitute a baseline reference for future studies and assist comparisons among different patient populations, allowing the recognition of distinctive characteristics and special needs. The present study is the first to depict the clinical characteristics and their interplay in a large sample of Parkinson's disease (PD) patients in Greece. Nine hundred eighty six consecutive PD outpatients were recruited from 17 centers around Greece in the time period from 8/2007 to 7/2009 and were examined and interviewed by movement disorders experts. Multiple clinical characteristics were recorded including age at diagnosis, disease severity, patients' self classification of PD symptoms and their relevance to physician's global clinical impression, smoking, alcohol consumption, presence of family history for PD, dementia, depression, hypertension, cancer and other comorbidities. Associations of high clinical significance were found between certain clinical characteristics., (Copyright © 2014 Elsevier B.V. All rights reserved.)