Is biochemical pregnancy loss associated with embryo or endometrium? A retrospective cohort study in frozen single embryo transfer of own and donated oocytes.

STUDY QUESTION: Does the use of preimplantation genetic testing for aneuploidies (PGT-A), personalized embryo transfer with endometrial receptivity assay (pET-ERA), or the use of donated oocytes modify the incidence of biochemical pregnancy loss (BPL) in frozen single embryo transfer (FSET)? SUMMARY ANSWER: Following FSET, BPL incidence does not differ between own and donated oocytes, and the use of PGT-A with euploid embryo transfer or pET-ERA results in a similar incidence of BPL compared to cycles without embryo or endometrial analysis. WHAT IS KNOWN ALREADY: BPL occurs frequently after IVF, and many factors have been associated with its incidence. The etiology of BPL is not well known, but the most probable cause seems to be either a low-quality embryo or impaired endometrial maintenance. The impact of techniques diagnosing embryonic ploidy or endometrial receptivity on BPL incidence and the BPL incidence between own and donated oocytes have not been analyzed. STUDY DESIGN, SIZE, DURATION: This is a retrospective cohort study analyzing the incidence of BPL over 3741 cycles of FSET derived from own (2399 cycles) and donated (1342 cycles) oocytes between January 2013 and January 2022 in 1736 of which PGT-A, pET-ERA, or both were applied. PARTICIPANTS/MATERIALS, SETTING, METHODS: We defined BPL as a pregnancy diagnosed only by serum ß-hCG > 10 UI/l followed by a decrease that does not result in a clinical pregnancy. Clinical pregnancy was defined as the presence of gestational sac on transvaginal ultrasound. We compared BPL rates among patients undergoing 2399 FSETs from own oocytes, which comprised 1310 cycles of embryos analyzed by PGT-A, 950 cycles of untested embryos, 30 cycles of untested embryos with pET-ERA, and a subgroup of 109 cycles analyzed by both PGT-A and pET-ERA. We also included a total of 1342 FSET cycles from donated oocytes comprising 132, 1055, 140, and 15 cycles in the same groups, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: In FSET from own oocytes, the overall BPL rate per embryo transfer was 8.2% (95% CI [7.09-9.33]). In untested embryo transfers, the BPL rate was 7.5% [5.91-9.37]. In the PGT-A group, the BPL rate was 8.8% [7.32-10.47]. In the pET-ERA group, the rate was 6.7% [0.82-22.07]. In the PGT-A+ERA group, the rate was 6.5% [2.65-12.90]. No significant differences were found (P = 0.626). A multivariate analysis considering clinically meaningful variables that were significantly different among groups, taking the untested embryos/endometrium group as a reference, showed comparable incidences among groups. For PGT-A, the adjusted odds ratio (AdjOR) was 1.154 [0.768-1.735] (P = 0.49) and for PGT-A+ERA 0.885 [0.330-2.375] (P = 0.808). Because of a low number of registered cases in the pET-ERA group, and to prevent statistical errors and convergence issues, this group was excluded from further analysis. In FSET of donated oocytes, the overall BPL rate per embryo transfer was 4.9% [3.76-6.14]. In the PGT-A group, the BPL rate was 6.8% [3.16-12.55]. In the pET-ERA group, the rate was 5.0% [2.03-10.03]. In untested embryo transfers, the rate was 4.7% [3.46-6.10]. No cases occurred in the PGT-A+ERA group, and no significant differences were found (P = 0.578). The multivariate analysis showed comparable incidences among groups. For PGT-A the AdjOR was 1.669 [0.702-3.972] (P = 0.247) and for pET-ERA 1.189 [0.433-3.265] (P = 0.737). The PGT-A+ERA group was eliminated from the model to prevent statistical errors and convergence issues because no BPL cases were registered in this group. In the multivariate analysis, when the sources of oocytes were compared, own versus donated, no significant differences were found in the incidence of BPL. LIMITATIONS, REASONS FOR CAUTION: This was a retrospective cohort study with potential biases. In addition, we were unable to control differences among groups due to modifications in medical or laboratory protocols during this long time period, which may modify the relationships being addressed. Factors previously associated with BPL, such as immunological conditions other than thyroid autoimmunity, were not considered in this study. Limited sample sizes of some groups may limit the statistical power for finding differences that can be present in the general population. WIDER IMPLICATIONS OF THE FINDINGS: BPL may be related to a mechanism not associated with the chromosomal constitution of the embryo or the transcriptome of the endometrium. More studies are needed to explore the factors associated with this reproductive issue. STUDY FUNDING/COMPETING INTEREST(S): No specific funding was available for this study. None of the authors have a conflict of interest to declare with regard to this study. TRIAL REGISTRATION NUMBER: This trial was registered at clinicaltrials.gov (NCT04549909).

Associations between food portion sizes, insulin resistance, VO2 max and metabolic syndrome in European adolescents: The HELENA study.

BACKGROUND AND AIMS: This study aims to examine the associations of food portion size (PS) with markers of insulin resistance (IR) and clustered of metabolic risk score in European adolescents. METHODS: A total of 495 adolescents (53.5% females) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study were included. The association between PS from food groups and homeostasis model assessment of insulin resistance (HOMA-IR) index, VO2 max, and metabolic risk score was assessed by multilinear regression analysis adjusting for several confounders. Analysis of covariance (ANCOVA) was used to determine the mean differences of food PS from food groups by HOMA-IR cutoff categories by using maternal education as a covariable. RESULTS: Larger PS from vegetables in both gender and milk, yoghurt, and milk beverages in males were associated with higher VO2 max, while larger PS from margarines and vegetable oils were associated with lower VO2 max (p < 0.05). Males who consumed larger PS from fish and fish products; meat substitutes, nuts, and pulses; cakes, pies, and biscuits; and sugar, honey, jams, and chocolate have a higher metabolic risk score (p < 0.05). Males with lower HOMA-IR cutoff values consumed larger PS from vegetables, milk, yoghurt, and milk beverages (p < 0.05). Females with lower HOMA-IR cutoff values consumed larger PS from breakfast cereals, while those with higher HOMA-IR cutoff values consumed larger PS from butter and animal fats (p = 0.018). CONCLUSION: The results show that larger PS from dairy products, cereals, and high energy dense foods are a significant determinant of IR and VO2 max, and larger PS from food with higher content of sugar were associated with higher metabolic risk score.

Biomarker analyses in the phase III ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer.

BACKGROUND: The pivotal phase III ASCENT trial demonstrated improved survival outcomes associated with sacituzumab govitecan (SG), an anti-trophoblast cell-surface antigen 2 (anti-Trop-2) antibody-drug conjugate linked with the topoisomerase-inhibitor SN-38, over single-agent chemotherapy treatment of physician's choice (TPC) in previously treated metastatic triple-negative breast cancer (mTNBC). This prespecified, exploratory biomarker analysis from the ASCENT trial evaluates the association between tumor Trop-2 expression and germline BRCA1/2 mutation status with clinical outcomes. PATIENTS AND METHODS: Patients with mTNBC refractory to or progressing after two or more prior chemotherapies, with one or more in the metastatic setting, were randomized to receive SG (10 mg/kg intravenously days 1 and 8, every 21 days) or TPC (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression/unacceptable toxicity. Biopsy or surgical specimens were collected at study entry to determine Trop-2 expression level using a validated immunohistochemistry assay and histochemical scoring. Germline BRCA1/2 mutation status was collected at baseline. RESULTS: Of 468 assessable patients, 290 had Trop-2 expression data [64% (n = 151 SG) versus 60% (n = 139 TPC)] and 292 had known BRCA1/2 mutation status [63% (n = 149 SG) versus 61% (n = 143 TPC)]. Median progression-free survival in SG- versus TPC-treated patients was 6.9, 5.6, and 2.7 months versus 2.5, 2.2, and 1.6 months for high, medium, and low Trop-2 expression, respectively. Median overall survival (14.2, 14.9, and 9.3 months versus 6.9, 6.9, and 7.6 months) and objective response rates (44%, 38%, and 22% versus 1%, 11%, and 6%) were numerically higher with SG versus TPC in patients with high, medium, and low Trop-2 expression, respectively. Efficacy outcomes were numerically higher with SG versus TPC in patients with and without germline BRCA1/2 mutations. CONCLUSIONS: SG benefits patients with previously treated mTNBC expressing high/medium Trop-2 compared with standard-of-care chemotherapy and regardless of germline BRCA1/2 mutation status. The small number of patients with low Trop-2 expression precludes definitive conclusions on the benefit of SG in this subgroup.

Search for Lepton Number and Flavor Violation in K

Searches for the lepton number violating K^{+}→π^{-}µ^{+}e^{+} decay and the lepton flavor violating K^{+}→π^{+}µ^{-}e^{+} and π^{0}→µ^{-}e^{+} decays are reported using data collected by the NA62 experiment at CERN in 2017-2018. No evidence for these decays is found and upper limits of the branching ratios are obtained at 90% confidence level: B(K^{+}→π^{-}µ^{+}e^{+})<4.2×10^{-11}, B(K^{+}→π^{+}µ^{-}e^{+})<6.6×10^{-11} and B(π^{0}→µ^{-}e^{+})<3.2×10^{-10}. These results improve by 1 order of magnitude over previous results for these decay modes.

In children and adolescents with temporomandibular disorder assembled with juvenile idiopathic arthritis - no association were found between pain and TMJ deformities using CBCT.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer from temporomandibular disorder (TMD). Due to this, imaging diagnosis is crucial in JIA with non-symptomatic TM joint (TMJ) involvement. The aim of the study was to examine the association between clinical TMD signs/symptoms and cone-beam computed tomography (CBCT) findings of TMJ structural deformities in children and adolescents with JIA. METHODS: This cross-sectional study is part of a longitudinal prospective multi-centre study performed from 2015-2020, including 228 children and adolescents aged 4-16 years diagnosed with JIA, according to the International League of Associations for Rheumatology (ILAR). For this sub-study, we included the Bergen cohort of 72 patients (32 female, median age 13.1 years, median duration of JIA 4.5 years). Clinical TMD signs/symptoms were registered as pain on palpation, pain on jaw movement, and combined pain of those two. The severity of TMJ deformity was classified as sound (no deformity), mild, or moderate/severe according to the radiographic findings of CBCT. RESULTS: Of 72 patients, 21 (29.2%) had pain on palpation at and around the lateral pole, while 41 (56.9%) had TMJ pain upon jaw movement and 26 (36.1%) had pain from both. Of 141 TMJs, 18.4% had mild and 14.2% had moderate/severe structural deformities visible on CBCT. CBCT findings were not significantly associated with either the pain on palpation or the pain on jaw movement. A significant difference was found between structural deformities in CBCT and the combined pain outcome (pain at both palpation and movement) for both TMJs for the persistent oligoarticular subtype (p = 0.031). CONCLUSIONS: There was no association between painful TMD and CBCT imaging features of the TMJ in patients with JIA, but the oligoarticular subtype of JIA, there was a significant difference associated with TMJ pain and structural CBCT deformities.

Patient self-management of oral anticoagulation with vitamin K antagonists in everyday practice: clinical outcomes in a single centre cohort after long-term follow-up.

BACKGROUND: Patient self-management (PSM) of vitamin K antagonists (VKA) seems a very promising model of care for oral anticoagulation in terms of efficacy and safety. In comparison with other management models of VKA therapy, the number of scientific publications supporting the advantages of PSM is more limited. Currently, most of the scarce information comes from randomized clinical trials. Moreover, a small number of studies have assessed PSM of VKA therapy in real life conditions. METHODS: We analyzed clinical outcomes of 927 patients in a single center (6018.6 patient-years of follow-up). Recruitment took place between 2002 and 2017. All patients followed a structured training program, conducted by specialized nurses. RESULTS: Fifty percent of individuals had a mechanical heart valve (MHV), 23% suffered from recurrent venous thromboembolism (VTE) or high-risk thrombophilia, and 13% received VKA therapy because of atrial fibrillation (AF). Median follow-up was 6.5 years (range 0.1-15.97 years), median age was 58.1 years (IQR 48-65.9) and 46.5% were women. The incidence of major complications (either hemorrhagic or thromboembolic) was 1.87% patient-years (pt-ys) with a 95% CI of 1.54-2.27. The incidence of major thromboembolic events was 0.86% pt-ys (95% CI 0.64-1.13) and that of major hemorrhagic events was 1.01% pt-ys (95% CI 0.77-1.31). The incidence of intracranial bleeding was 0.22% pt-ys (95% CI 0.12-0.38). In terms of clinical indication for VKA therapy, the incidence of total major complications was 2.4% pt-ys, 2.0% pt-ys, 0.9% pt-ys and 1.34% pt-ys for MHV, AF, VTE and other (including valvulopathies and myocardiopathies), respectively. Clinical outcomes were worse in patients with multiple comorbidities, previous major complications during conventional VKA therapy, and in older individuals. The percentage of time in therapeutic range (TTR) was available in 861 (93%) patients. Overall, the mean (SD) of TTR was 63.6 ± 13.4%, being higher in men (66.2 ± 13.1%) than women (60.6 ± 13.2%), p < 0.05. CONCLUSIONS: In terms of clinically relevant outcomes (incidence of major complications and mortality), PSM in real life setting seems to be a very good alternative in properly trained patients.

Prevalence of temporomandibular disorder in children and adolescents with juvenile idiopathic arthritis - a Norwegian cross- sectional multicentre study.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer pain from temporomandibular disorder (TMD). Still, routines for the assessment of temporomandibular joint (TMJ) pain in health and dental care are lacking. The aims of this study were to examine the prevalence of TMD in children and adolescents with JIA compared to their healthy peers and to investigate potential associations between JIA and TMD. METHODS: This comparative cross-sectional study is part of a longitudinal multicentre study performed during 2015-2020, including 228 children and adolescents aged 4-16 years with a diagnosis of JIA according to the ILAR criteria. This particular substudy draws on a subset of data from the first study visit, including assessments of TMD as part of a broader oral health examination. Children and adolescents with JIA were matched with healthy controls according to gender, age, and centre site. Five calibrated examiners performed the clinical oral examinations according to a standardised protocol, including shortened versions of the diagnostic criteria for TMD (DC/TMD) and the TMJaw Recommendations for Clinical TMJ Assessment in Patients Diagnosed with JIA. Symptoms were recorded and followed by a clinical examination assessing the masticatory muscles and TMJs. RESULTS: In our cohort of 221 participants with JIA and 221 healthy controls, 88 (39.8%) participants with JIA and 25 (11.3%) healthy controls presented with TMD based on symptoms and clinical signs. Painful TMD during the last 30 days was reported in 59 (26.7%) participants with JIA vs. 10 (5.0%) of the healthy controls (p <  0.001). Vertical unassisted jaw movement was lower in participants with JIA than in controls, with means of 46.2 mm vs. 49.0 mm, respectively (p <  0.001). Among participants with JIA, a higher proportion of those using synthetic disease-modifying antirheumatic-drugs and biologic disease-modifying antirheumatic-drugs presented with painful masticatory muscles and TMJs at palpation. CONCLUSION: Symptoms and clinical signs of TMD were seen in approximately half of the JIA patients compared to about one fourth of their healthy peers. Painful palpation to masticatory muscles and decreased vertical unassisted jaw movement were more frequent in participants with JIA than among healthy controls and should be part of both medical and dental routine examinations in patients with JIA.

Mediterranean diet, diet quality, and bone mineral content in adolescents: the HELENA study.

Dietary scores, rather than individual nutrients, allow exploring associations between overall diet and bone health. The aim of the present study was to assess the associations between the Mediterranean Diet Score for Adolescents (MDS-A) and the Diet Quality Index for Adolescents (DQI-A) and bone mineral content (BMC) among Spanish adolescents. Our results do not support an association between dietary scores or indices and BMC in adolescents. INTRODUCTION: To assess the associations between the MDS-A and a DQI-A with the BMC measured with dual-energy X-ray absorptiometry. METHODS: The MDS-A and the DQI-A were calculated in 179 Spanish adolescents, based on two 24-h dietary recalls from the HELENA cross-sectional study. The associations between the diet scores and the BMC outcomes [total body less head (TBLH), femoral neck (FN), lumbar spine (LS), and hip] were analyzed using logistic regression models adjusting for several confounders. RESULTS: Four hundred ninety-two models were included and only fruits and nuts and cereal and roots were found to provide significant ORs with regard to BMC. The risk of having low BMC reduced by 32% (OR 0.684; CI 0.473-0.988) for FN when following the ideal MDS-A, but this association lost significance when adjusting for lean mass and physical activity. For every 1-point increase in the cereal and root and the fruit and nut components, the risk of having low FN diminished by 56% (OR 0.442; CI 0.216-0.901) and by 67% (OR 0.332; CI 0.146-0.755), respectively. CONCLUSION: An overall dietary score or index is not associated with BMC in our adolescent Spanish sample.

Inflammation in metabolically healthy and metabolically abnormal adolescents: The HELENA study.

BACKGROUND AND AIMS: Inflammation may influence the cardio-metabolic profile which relates with the risk of chronic diseases. This study aimed to assess the inflammatory status by metabolic health (MH)/body mass index (BMI) category and to assess how inflammatory markers can predict the cardio-metabolic profile in European adolescents, considering BMI. METHODS AND RESULTS: A total of 659 adolescents (295 boys) from a cross-sectional European study were included. Adolescents were classified by metabolic health based on age- and sex-specific cut-off points for glucose, blood pressure, triglycerides, high density cholesterol and BMI. C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin (IL-6), complement factors (C3, C4) and cell adhesion molecules were assessed. RESULTS: Metabolically abnormal (MA) adolescents had higher values of C3 (p < 0.001) and C4 (p = 0.032) compared to those metabolically healthy (MHy). C3 concentrations significantly increased with the deterioration of the metabolic health and BMI (p < 0.001). Adolescents with higher values of CRP had higher probability of being in the overweight/obese-MH group than those allocated in other categories. Finally, high C3 and C4 concentrations increased the probability of having an unfavorable metabolic/BMI status. CONCLUSIONS: Metabolic/BMI status and inflammatory biomarkers are associated, being the CRP, C3 and C4 the most related inflammatory markers with this condition. C3 and C4 were associated with the cardio-metabolic health consistently.

Folate and vitamin B12 concentrations are associated with plasma DHA and EPA fatty acids in European adolescents: the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study.

This study aimed to examine the association between vitamin B6, folate and vitamin B12 biomarkers and plasma fatty acids in European adolescents. A subsample from the Healthy Lifestyle in Europe by Nutrition in Adolescence study with valid data on B-vitamins and fatty acid blood parameters, and all the other covariates used in the analyses such as BMI, Diet Quality Index, education of the mother and physical activity assessed by a questionnaire, was selected resulting in 674 cases (43 % males). B-vitamin biomarkers were measured by chromatography and immunoassay and fatty acids by enzymatic analyses. Linear mixed models elucidated the association between B-vitamins and fatty acid blood parameters (changes in fatty acid profiles according to change in 10 units of vitamin B biomarkers). DHA, EPA) and n-3 fatty acids showed positive associations with B-vitamin biomarkers, mainly with those corresponding to folate and vitamin B12. Contrarily, negative associations were found with n-6:n-3 ratio, trans-fatty acids and oleic:stearic ratio. With total homocysteine (tHcy), all the associations found with these parameters were opposite (for instance, an increase of 10 nmol/l in red blood cell folate or holotranscobalamin in females produces an increase of 15·85 µmol/l of EPA (P value <0·01), whereas an increase of 10 nmol/l of tHcy in males produces a decrease of 2·06 µmol/l of DHA (P value <0·05). Positive associations between B-vitamins and specific fatty acids might suggest underlying mechanisms between B-vitamins and CVD and it is worth the attention of public health policies.

Analysis of the association of leptin and adiponectin concentrations with metabolic syndrome in children: Results from the IDEFICS study.

BACKGROUND AND AIMS: Adipokines may play a role in the pathogenesis of the metabolic syndrome (MetS) in children. We aimed to evaluate the association of leptin, adiponectin, and its ratio (L/A ratio) with the metabolic syndrome (MetS) in a subsample of the IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) cohort. METHODS AND RESULTS: Leptin, adiponectin and MetS parameters were measured in a subsample of 1253 children (3-9.9 years) participating to the IDEFICS study, grouped as: Non-OW (underweight/normal weight) and OW/Ob (overweight/obese). MetS was defined using the sex- and age-specific cut-offs based on the distribution of MetS components in the IDEFICS cohort. The prevalence of the MetS among OW/Ob was 24.8% and 27.1% in boys and girls respectively, whereas ≤2% among Non-OW. OW/Ob had significantly higher leptin and L/A ratio as compared to Non-OW. Significantly higher leptin was found in OW/Ob with MetS as compared with OW/Ob without MetS. Significantly lower adiponectin was observed only in OW/Ob girls as compared to Non-OW. A 1SD increase in leptin and L/A ratio z-scores or a 1SD decrease in adiponectin z-score were significantly associated with higher risk of MetS. After adjustment for BMI or body fat mass (BFM) the association remained significant only for leptin. CONCLUSION: We showed that in European children, higher leptin concentration is associated with MetS, even after adjusting for BMI or BFM, confirming an early role of leptin in MetS, while the association of adiponectin with MetS seems be mediated by body fat in this age range.

Ideal cardiovascular health and inflammation in European adolescents: The HELENA study.

BACKGROUND AND AIMS: Inflammation plays a key role in atherosclerosis and this process seems to appear in childhood. The ideal cardiovascular health index (ICHI) has been inversely related to atherosclerotic plaque in adults. However, evidence regarding inflammation and ICHI in adolescents is scarce. The aim is to assess the association between ICHI and inflammation in European adolescents. METHODS AND RESULTS: As many as 543 adolescents (251 boys and 292 girls) from the Healthy Lifestyle in Europe by Nutrition in Adolescence (HELENA) study, a cross-sectional multi-center study including 9 European countries, were measured. C-reactive protein (CRP), complement factors C3 and C4, leptin and white blood cell counts were used to compute an inflammatory score. Multilevel linear models and multilevel logistic regression were used to assess the association between ICHI and inflammation controlling by covariates. Higher ICHI was associated with a lower inflammatory score, as well as with several individual components, both in boys and girls (p < 0.01). In addition, adolescents with at least 4 ideal components of the ICHI had significantly lower inflammatory score and lower levels of the study biomarkers, except CRP. Finally, the multilevel logistic regression showed that for every unit increase in the ICHI, the probability of having an inflammatory profile decreased by 28.1% in girls. CONCLUSION: Results from this study suggest that a better ICHI is associated with a lower inflammatory profile already in adolescence. Improving these health behaviors, and health factors included in the ICHI, could play an important role in CVD prevention.

Glucocorticoid Receptors, Brain-Derived Neurotrophic Factor, Serotonin and Dopamine Neurotransmission are Associated with Interferon-Induced Depression.

BACKGROUND: The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. METHODS: We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. RESULTS: The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. CONCLUSIONS: The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders.

Dabigatran: A new oral anticoagulant. Guidelines to follow in oral surgery procedures. A systematic review of the literature.

BACKGROUND: Dabigatran is a newly commercialized drug that is replacing other anticoagulants in the prevention of venous thromboembolism, stroke and systemic arterial valve embolism. It acts directly on thrombin presenting in a dynamic and predictable way, which does not require monitoring these patients. Therefore, we consider the need to assess whether their use increases the risk of bleeding involved before any dental treatment. MATERIAL AND METHODS: We performed a systematic review with a bibliographic search in PubMed/Medline along with the Cochrane Library. We excluded articles dealing with all anticoagulants other than dabigatran, and works about surgical treatments in anatomical locations other than the oral cavity. RESULTS: We included a total of 13 papers of which 1 was a randomized clinical trial, 9 narrative literature reviews, 1 case series, 2 clinical cases and 1 expert opinion. Because we did not obtain any properly designed clinical trials, we were unable to conduct a meta-analysis. CONCLUSIONS: Currently, there is no consensus on the procedure to be followed in patients taking dabigatran. However, all authors agree to treat each case individually in accordance to the risk of embolism, postoperative bleeding and renal function. Also, it is necessary to perform minimally invasive interventions, and take the appropriate local anti-hemolytic measures.

The role of hyperthermic intraperitoneal chemotherapy using paclitaxel in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction.

BACKGROUND: We analyzed the role of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) on the microscopic component of the disease in patients with a first recurrence of platinum-sensitive ovarian cancer after complete cytoreduction (CCR). PATIENTS AND METHODS: We analyzed the data of 54 patients who were operated on between January 2001 and July 2012 with the diagnosis of platinum-sensitive recurrent ovarian cancer. In all patients, it was possible to achieve a CCR. Patients were divided into two groups: group I (cytoreduction alone) consisted of 22 surgical patients and group II (cytoreduction and HIPEC) consisted of 32 patients. RESULTS: There were no significant differences in any of the preoperative variables studied. After a multivariate analysis of factors identified in the univariate analysis, only the presence of tumors with undifferentiated histology (hazard ratio 2.57; 95% CI 1.21-5.46; p < 0.05) was an independent factor associated with a reduced disease-free survival. The 1- and 3-year disease-free survival was 77 and 23% in patients from group I and 77 and 45% in patients from group II, respectively, with a tendency, but no significant differences (p = 0.078). There was no significant difference in postoperative morbidity between the two groups. CONCLUSIONS: The administration of HIPEC in patients in whom it is possible to achieve a CCR of the disease has not increased postoperative morbidity and mortality rates in our center. HIPEC with paclitaxel is effective in the treatment of microscopic disease in platinum-sensitive recurrent epithelial ovarian cancer patients with microscopic residual disease after cytoreduction, although with no statistically significant difference.

Intake of water and beverages of children and adolescents in 13 countries.

PURPOSE: To describe the intake of water and all other beverages in children and adolescents in 13 countries of three continents. METHODS: Data of 3611 children (4-9 years) and 8109 adolescents (10-17 years) were retrieved from 13 cross-sectional surveys (47 % males). In three countries, stratified cluster sampling design was applied to randomly recruit schools classes. A quota method was applied in the other countries to randomly recruit participants. Details on the intake of all fluid types were obtained with a fluid-specific record over 7 consecutive days. RESULTS: In the total sample, the highest mean intakes were observed for water (738 ± 567 mL/day), followed by milk (212 ± 209 mL/day), regular soft beverages (RSB) (168 ± 290 mL/day) and juices (128 ± 228 mL/day). Patterns characterized by a high contribution of water, RSB or hot beverages to total fluid intake were identified among the countries with close geographical location. Adolescents had a significantly lower milk intake and higher intake of RSB and hot beverages than children in most countries. The most consistent gender difference observed was that in both age groups males reported a significantly higher RSB consumption than females. CONCLUSION: On average, water was the fluid consumed in the largest volume by children and adolescents, but the intake of the different fluid types varied substantially between countries. Since the RSB intake was as large, or even larger, than water intake in some countries, undertaking actions to improve fluid intake habits of children and adolescents are warranted.

The Usefulness of International Cooperation in the Repair of Inguinal Hernias in Sub-Saharan Africa.

INTRODUCTION: The burden of disease and mortality associated with inguinal hernia in Africa, especially in sub-Saharan Africa, is very high. The purpose of this study is to show that International Cooperation work in the field of hernia repair is effective; it minimizes the delay in hernia repairs in the targeted population, and can prevent a large number of disability-adjusted life years (DALYs). MATERIALS AND METHODS: As a part of an International Cooperation program, a total of 990 black patients with inguinal hernias were studied, in whom hernioplasty was performed using polypropylene mesh. The type of hernia and surgical technique were studied. Indicators of scientific and technical quality, indicators of efficiency and of effectiveness were analyzed. The results on the usefulness of interventions were calculated as avoided DALYs. RESULTS: Surgery was performed on 926 patients with a total of 1033 hernia repairs. 87.2 % of the repairs were made with mesh. There was no mortality in the series, complications were minor, and 85.7 % of patients remained less than 24 h in the center. There was a 2.8 % of recurrence, with a follow-up 58.7 % of the patients in the first year. 5014 DALYs were avoided, and the average of the avoided DALYs per patient was of 5.41. CONCLUSIONS: Hernia repair with mesh in low development countries is a procedure with low morbidity and high effectiveness that can prevent a large number of DALYs.

C-reactive protein reference percentiles among pre-adolescent children in Europe based on the IDEFICS study population.

OBJECTIVES: C-reactive protein (CRP) is involved in a wide range of diseases. It is a powerful marker for inflammatory processes used for diagnostic and monitoring purposes. We aimed to establish reference values as data on the distribution of serum CRP levels in young European children are scarce. SUBJECTS: Reference values of high-sensitivity CRP concentrations were calculated for 9855 children aged 2.0-10.9 years, stratified by age and sex. The children were recruited during the population-based European IDEFICS study (Identification and prevention of Dietary- and lifestyle-induced health Effects in Children and infantS) with 18 745 participants recruited from 2007 to 2010. RESULTS: In 44.1% of the children, CRP values were below or equal the detection limit of 0.2 mg/l. Median CRP concentrations showed a slight negative age trend in boys and girls, whereas serum CRP values were slightly higher in girls than in boys across all age groups. CONCLUSIONS: Our population-based reference values of CRP may guide paediatric practice as elevated values may require further investigation or treatment. Therefore, the presented reference values represent a basis for clinical evaluation and for future research on risk assessment of diseases associated with increased CRP levels among children.

Treatment of microscopic disease with hyperthermic intraoperative intraperitoneal chemotherapy after complete cytoreduction improves disease-free survival in patients with stage IIIC/IV ovarian cancer.

BACKGROUND: We analyze the efficacy of hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) for microscopic residual disease in patients with stage IIIC/IV ovarian cancer after a complete cytoreduction of their disease. PATIENTS AND METHODS: We analyzed the data of 87 consecutive patients diagnosed with stage IIIC/IV ovarian cancer operated between December 1998 and July 2011. In every patient it was possible to achieve a complete cytoreduction of their disease. (Since January 2008, our center has incorporated the use of HIPEC in patients with peritoneal surface malignancies, including patients with peritoneal dissemination of primary ovarian cancer.) RESULTS: Of 87 patients, 52 were treated with HIPEC (paclitaxel 60 mg/m(2), 60 min, 42 °C). After a univariate analysis, factors associated with lower disease-free interval were: performing a gastrointestinal anastomosis, operative time greater than 270 min, poorly differentiated histology, and not being treated with HIPEC. After multivariate analysis, independent prognostic factors included not being treated with HIPEC [hazard ratio (HR) 8.77, 95 % CI 2.76-14.42, p < 0.01] and the presence of poorly differentiated tumors (HR 1.98, 95 % CI 1.45-8.56, p < 0.05). Disease-free survival at 1 and 3 years was 66 and 18 %, respectively, in patients without HIPEC and 81 and 63 %, respectively, in patients treated with HIPEC (p < 0.01). HIPEC administration did not alter the results obtained for disease-free survival in patients with undifferentiated tumors. CONCLUSIONS: The treatment of the microscopic disease following complete cytoreduction with HIPEC in patients with advanced ovarian cancer is effective and can prolong disease-free survival. This survival benefit was not seen in undifferentiated tumors.

Surgical treatment of endemic goiter in a nonhospital setting without general anesthesia in Africa.

BACKGROUND: Endemic goiter remains a serious public health problem and 75 % of people affected live in underdeveloped countries where treatment is difficult for various reasons. The aim of this article is to report our experience in African countries with the management and surgical treatment of endemic goiter, performed in a nonhospital setting and without general anesthesia in the context of a collaborative development project by experienced endocrine surgeons. METHODS: Fifty-six black African patients with a goiter were studied. Those in poor general health, the elderly, patients with either small goiters or clinical hyperthyroidism, and those presenting with an acute episode of malaria were excluded from the study. Cervical epidural anesthesia with spontaneous ventilation was used and a partial thyroidectomy was performed. The technique used, its immediate complications, and early and late follow-up were analyzed. RESULTS: Surgery was performed on 31 patients with grades 3 and 4 goiter without mortality and a morbidity rate of 11.9 %, with 97 % of all complications being minor. There were no instances of dysphonia or symptomatic hypocalcemia and the mean stay was 1.57 days (range 1.25-1.93). Follow-up in the first year was 71 % and no case of severe or recurrent hypothyroidism was detected. CONCLUSIONS: Surgery without general anesthesia performed in a nonhospital setting in underdeveloped countries in patients with goiter is a viable option with good results and low morbidity.