One versus two biological parents with mental disorders: Relationship to educational attainment in the next generation.

BACKGROUND: Both maternal and, separately, paternal mental illness are associated with diminished academic attainment among children. However, the differential impacts of diagnostic type and degree of parental burden (e.g. one v. both parents affected) on these functional outcomes are unknown. METHODS: Using the Swedish national patient (NPR) and multi-generation (MGR) registers, 2 226 451 children (1 290 157 parental pairs), born 1 January 1973-31 December 1997, were followed through 31 December 2013. Diagnostic status of all cohort members was defined for eleven psychiatric disorders, and families classed by exposure: (1) parents affected with any disorder, (2) parents affected with a disorder group (e.g. neuropsychiatric disorders), and (3) parents affected with a specific disorder (e.g. ADHD). Pairs were further defined as 'unaffected,' 'single-affected,', or 'dual-affected.' Among offspring, the study evaluated fulfillment of four academic milestones, from compulsory (primary) school through University (college). Sensitivity analyses considered the impact of child's own mental health, as well as parental education, on main effects. RESULTS: Marked reductions in the odds of achievement were observed, emerging at the earliest levels of schooling for both single-affected [adjusted odds ratio (aOR), 0.50; 95% CI 0.49-0.51] and dual-affected (aOR 0.29, 95% CI 0.28-0.30) pairs and persisting thereafter [aOR range (single), 0.52-0.65; aOR range (dual), 0.30-0.40]. This pattern was repeated for analyses within diagnosis/diagnostic group. Main results were robust to adjustment for offspring mental health and parent education level. CONCLUSIONS: Parental mental illness is associated with profound reductions in educational attainment in the subsequent generation, with children from dual-affected families at uniquely high risk.

Innovative Therapeutic Approaches in Non-Alcoholic Fatty Liver Disease: When Knowing Your Patient Is Key.

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disorders ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Hepatic steatosis may result from the dysfunction of multiple pathways and thus multiple molecular triggers involved in the disease have been described. The development of NASH entails the activation of inflammatory and fibrotic processes. Furthermore, NAFLD is also strongly associated with several extra-hepatic comorbidities, i.e., metabolic syndrome, type 2 diabetes mellitus, obesity, hypertension, cardiovascular disease and chronic kidney disease. Due to the heterogeneity of NAFLD presentations and the multifactorial etiology of the disease, clinical trials for NAFLD treatment are testing a wide range of interventions and drugs, with little success. Here, we propose a narrative review of the different phenotypic characteristics of NAFLD patients, whose disease may be triggered by different agents and driven along different pathophysiological pathways. Thus, correct phenotyping of NAFLD patients and personalized treatment is an innovative therapeutic approach that may lead to better therapeutic outcomes.

Do borderline personality disorder and attention-deficit/hyperactivity disorder co-aggregate in families? A population-based study of 2 million Swedes.

Large-scale family studies on the co-occurrence of attention-deficit/hyperactivity disorder (ADHD) and borderline personality disorder (BPD) are lacking. Thus, we aimed to estimate the co-occurrence and familial co-aggregation of clinically ascertained ADHD and BPD diagnoses using the entire Swedish population. In a register-based cohort design we included individuals born in Sweden 1979-2001, and identified their diagnoses during 1997-2013; in total, 2,113,902 individuals were included in the analyses. We obtained clinical diagnoses of ADHD and BPD from inpatient and outpatient care. Individuals with an ADHD diagnosis had an adjusted (for birth year, sex, and birth order) odds ratio (aOR) of 19.4 (95% confidence interval [95% CI] = 18.6-20.4) of also having a BPD diagnosis, compared to individuals not diagnosed with ADHD. Having a sibling with ADHD also increased the risk for BPD (monozygotic twins, aOR = 11.2, 95% CI = 3.0-42.2; full siblings, aOR = 2.8, 95% CI = 2.6-3.1; maternal half-siblings, aOR = 1.4, 95% CI = 1.2-1.7; paternal half-siblings, aOR = 1.5, 95% CI = 1.3-1.7). Cousins also had an increased risk. The strength of the association between ADHD and BPD was similar in females and males, and full siblings showed similar increased risks regardless of sex. Among both males and females, ADHD and BPD co-occur within individuals and co-aggregate in relatives; the pattern suggests shared genetic factors and no robust evidence for etiologic sex differences was found. Clinicians should be aware of increased risks for BPD in individuals with ADHD and their relatives, and vice versa.

Much more than just shyness: the impact of social anxiety disorder on educational performance across the lifespan.

BACKGROUND: Social anxiety disorder (SAD) has been linked to academic underachievement, but previous studies had methodological limitations. We investigated the association between SAD and objective indicators of educational performance, controlling for a number of covariates and unmeasured confounders shared between siblings. METHODS: This population-based birth cohort study included 2 238 837 individuals born in Sweden between 1973 and 1997, followed-up until 2013. Within the cohort, 15 755 individuals had a recorded ICD-10 diagnosis of SAD in the Swedish National Patient Register. Logistic regression models tested the association between SAD and educational performance. We also identified 6488 families with full siblings discordant for SAD. RESULTS: Compared to unexposed individuals, individuals diagnosed with SAD were less likely to pass all subjects in the last year of compulsory education [adjusted odds ratios (aOR) ranging from 0.19 to 0.44] and less likely to be eligible for a vocational or academic programme in upper secondary education [aOR = 0.31 (95% confidence interval [CI] 0.30-0.33) and aOR = 0.52 (95% CI 0.50-0.55), respectively], finish upper secondary education [aOR = 0.19 (95% CI 0.19-0.20)], start a university degree [aOR = 0.47 (95% CI 0.45-0.49)], obtain a university degree [aOR = 0.35 (95% CI 0.33-0.37)], and finish postgraduate education [aOR = 0.58 (95% CI 0.43-0.80)]. Results were attenuated but remained statistically significant in adjusted sibling comparison models. When psychiatric comorbidities were taken into account, the results were largely unchanged. CONCLUSIONS: Treatment-seeking individuals with SAD have substantially impaired academic performance throughout the formative years. Early detection and intervention are warranted to minimise the long-term socioeconomic impact of the disorder.

The Epidermal Growth Factor Receptor Ligand Amphiregulin Protects From Cholestatic Liver Injury and Regulates Bile Acids Synthesis.

Intrahepatic accumulation of bile acids (BAs) causes hepatocellular injury. Upon liver damage, a potent protective response is mounted to restore the organ's function. Epidermal growth factor receptor (EGFR) signaling is essential for regeneration after most types of liver damage, including cholestatic injury. However, EGFR can be activated by a family of growth factors induced during liver injury and regeneration. We evaluated the role of the EGFR ligand, amphiregulin (AREG), during cholestatic liver injury and regulation of AREG expression by BAs. First, we demonstrated increased AREG levels in livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). In two murine models of cholestatic liver injury, bile duct ligation (BDL) and alpha-naphthyl-isothiocyanate (ANIT) gavage, hepatic AREG expression was markedly up-regulated. Importantly, Areg-/- mice showed aggravated liver injury after BDL and ANIT administration compared to Areg+/+ mice. Recombinant AREG protected from ANIT and BDL-induced liver injury and reduced BA-triggered apoptosis in liver cells. Oral BA administration induced ileal and hepatic Areg expression, and, interestingly, cholestyramine feeding reduced postprandial Areg up-regulation in both tissues. Most interestingly, Areg-/- mice displayed high hepatic cholesterol 7 α-hydroxylase (CYP7A1) expression, reduced serum cholesterol, and high BA levels. Postprandial repression of Cyp7a1 was impaired in Areg-/- mice, and recombinant AREG down-regulated Cyp7a1 mRNA in hepatocytes. On the other hand, BAs promoted AREG gene expression and protein shedding in hepatocytes. This effect was mediated through the farnesoid X receptor (FXR), as demonstrated in Fxr-/- mice, and involved EGFR transactivation. Finally, we show that hepatic EGFR expression is indirectly induced by BA-FXR through activation of suppressor of cytokine signaling-3 (SOC3). Conclusion: AREG-EGFR signaling protects from cholestatic injury and participates in the physiological regulation of BA synthesis.

Risk and protective factors for anxiety and obsessive-compulsive disorders: an umbrella review of systematic reviews and meta-analyses.

BACKGROUND: A multitude of risk/protective factors for anxiety and obsessive-compulsive disorders have been proposed. We conducted an umbrella review to summarize the evidence of the associations between risk/protective factors and each of the following disorders: specific phobia, social anxiety disorder, generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder, and to assess the strength of this evidence whilst controlling for several biases. METHODS: Publication databases were searched for systematic reviews and meta-analyses examining associations between potential risk/protective factors and each of the disorders investigated. The evidence of the association between each factor and disorder was graded into convincing, highly suggestive, suggestive, weak, or non-significant according to a standardized classification based on: number of cases (>1000), random-effects p-values, 95% prediction intervals, confidence interval of the largest study, heterogeneity between studies, study effects, and excess of significance. RESULTS: Nineteen systematic reviews and meta-analyses were included, corresponding to 216 individual studies covering 427 potential risk/protective factors. Only one factor association (early physical trauma as a risk factor for social anxiety disorder, OR 2.59, 95% CI 2.17-3.1) met all the criteria for convincing evidence. When excluding the requirement for more than 1000 cases, five factor associations met the other criteria for convincing evidence and 22 met the remaining criteria for highly suggestive evidence. CONCLUSIONS: Although the amount and quality of the evidence for most risk/protective factors for anxiety and obsessive-compulsive disorders is limited, a number of factors significantly increase the risk for these disorders, may have potential prognostic ability and inform prevention.

Labour market marginalisation in obsessive-compulsive disorder: a nationwide register-based sibling control study.

BACKGROUND: The impact of obsessive-compulsive disorder (OCD) on objective indicators of labour market marginalisation has not been quantified. METHODS: Linking various Swedish national registers, we estimated the risk of three labour market marginalisation outcomes (receipt of newly granted disability pension, long-term sickness absence and long-term unemployment) in individuals diagnosed with OCD between 2001 and 2013 who were between 16 and 64 years old at the date of the first OCD diagnosis (n = 16 267), compared with matched general population controls (n = 157 176). Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox regression models, adjusting for a number of covariates (e.g. somatic disorders) and stratifying by sex. To adjust for potential familial confounders, we further analysed data from 7905 families that included full siblings discordant for OCD. RESULTS: Patients were more likely to receive at least one outcome of interest [adjusted HR = 3.63 (95% CI 3.53-3.74)], including disability pension [adjusted HR = 16.36 (95% CI 15.34-17.45)], being on long-term sickness absence [adjusted HR = 3.07 (95% CI 2.95-3.19)] and being on long-term unemployment [adjusted HR = 1.72 (95% CI 1.63-1.82)]. Results remained similar in the adjusted sibling comparison models. Exclusion of comorbid psychiatric disorders had a minimal impact on the results. CONCLUSIONS: Help-seeking individuals with OCD diagnosed in specialist care experience marked difficulties to participate in the labour market. The findings emphasise the need for cooperation between policy-makers, vocational rehabilitation and mental health services in order to design and implement specific strategies aimed at improving the patients' participation in the labour market.

Interaction of glucocorticoids with FXR/FGF19/FGF21-mediated ileum-liver crosstalk.

At high doses, glucocorticoids (GC) have been associated with enhanced serum bile acids and liver injury. We have evaluated the effect of GC, in the absence of hepatotoxicity, on FXR/FGF91(Fgf15)/FGF21-mediated ileum-liver crosstalk. Rats and mice (wild type and Fxr-/-, Fgf15-/- and int-Gr-/- strains; the latter with GC receptor (Gr) knockout selective for intestinal epithelial cells), were treated (i.p.) with dexamethasone, prednisolone or budesonide. In both species, high doses of GC caused hepatotoxicity. At a non-hepatotoxic dose, GC induced ileal Fgf15 down-regulation and liver Fgf21 up-regulation, without affecting Fxr expression. Fgf21 mRNA levels correlated with those of several genes involved in glucose and bile acid metabolism. Surprisingly, liver Cyp7a1 was not up-regulated. The expression of factors involved in transcriptional modulation by Fxr and Gr (p300, Drip205, CBP and Smrt) was not affected. Pxr target genes Cyp3a11 and Mrp2 were not up-regulated in liver or intestine. In contrast, the expression of some Pparα target genes in liver (Fgf21, Cyp4a14 and Vanin-1) and intestine (Vanin-1 and Cyp3a11) was altered. In mice with experimental colitis, liver Fgf21 was up-regulated (4.4-fold). HepG2 cells transfection with FGF21 inhibited CYP7A1 promoter (prCYP7A1-Luc2). This was mimicked by pure human FGF21 protein or culture in medium previously conditioned by cells over-expressing FGF21. This response was not abolished by deletion of a putative response element for phosphorylated FGF21 effectors present in prCYP7A1. In conclusion, GC interfere with FXR/FGF19-mediated intestinal control of CYP7A1 expression by the liver and stimulate hepatic secretion of FGF21, which inhibits CYP7A1 promoter through an autocrine mechanism.

Prevalence and heritability of body dysmorphic symptoms in adolescents and young adults: a population-based nationwide twin study.

BACKGROUND: Body dysmorphic disorder (BDD) usually begins during adolescence but little is known about the prevalence, etiology, and patterns of comorbidity in this age group. We investigated the prevalence of BDD symptoms in adolescents and young adults. We also report on the relative importance of genetic and environmental influences on BDD symptoms, and the risk for co-existing psychopathology. METHODS: Prevalence of BDD symptoms was determined by a validated cut-off on the Dysmorphic Concerns Questionnaire (DCQ) in three population-based twin cohorts at ages 15 (n = 6968), 18 (n = 3738), and 20-28 (n = 4671). Heritability analysis was performed using univariate model-fitting for the DCQ. The risk for co-existing psychopathology was expressed as odds ratios (OR). RESULTS: The prevalence of clinically significant BDD symptoms was estimated to be between 1 and 2% in the different cohorts, with a significantly higher prevalence in females (1.3-3.3%) than in males (0.2-0.6%). The heritability of body dysmorphic concerns was estimated to be 49% (95% CI 38-54%) at age 15, 39% (95% CI 30-46) at age 18, and 37% (95% CI 29-42) at ages 20-28, with the remaining variance being due to non-shared environment. ORs for co-existing neuropsychiatric and alcohol-related problems ranged from 2.3 to 13.2. CONCLUSIONS: Clinically significant BDD symptoms are relatively common in adolescence and young adulthood, particularly in females. The low occurrence of BDD symptoms in adolescent boys may indicate sex differences in age of onset and/or etiological mechanisms. BDD symptoms are moderately heritable in young people and associated with an increased risk for co-existing neuropsychiatric and alcohol-related problems.

Glomerulonephritis and cryoglobulinemia: first manifestation of visceral leishmaniasis.

Visceral leishmaniasis due to Leishmania Infantum is an endemic parasitic infection in the Mediterranean area. Since 2009, Europe's largest outbreak of Leishmaniasis has been reported in the region of Madrid (Spain). Renal involvement is an unusual complication. Different forms of renal disease have been described: interstitial, glomerular, and vascular damage. Direct invasion of renal parenchyma by the parasite has been described as a mechanism of kidney damage, especially in the immunocompromised. Immune complex deposition and T cells adhesion molecules activation have demonstrated that a pathogenic role in glomerulonephritis related to visceral leishmaniasis. The association between mixed cryoglobulinemia and visceral leishmaniasis has been previously reported in six patients. Renal involvement is only described in one of them. From July 2009 to October 2012, 4 patients with membranoproliferative glomerulonephritis and mixed cryoglobulinemia with negative serology for hepatitis B and C were diagnosed in our hospital. Serology of Leishmania in serum bank samples was performed; it was positive in 3 patients. Leishmania parasite was confirmed by other tests. We present 3 patients with mixed cryoglobulinemia and membranoproliferative glomerulonephritis as first clinical manifestation of visceral leishmaniasis.

Mycophenolate in refractory and relapsing lupus nephritis.

BACKGROUND: Mycophenolate (MF) is effective as induction and maintenance treatment in patients with lupus nephritis (LN). This study evaluates the efficacy and safety of MF in patients with refractory and relapsing LN. METHODS: Data were retrospectively obtained for 85 patients (35 refractory and 50 relapsing) from 11 nephrology departments in Spain. The primary endpoints were the incidence and cumulative number of renal responses and relapses and their relationship with baseline clinical and analytical data. The secondary endpoint was the appearance of side effects. RESULTS: The main clinical and analytical variables were similar both in refractory and relapsing LN. Most of the patients had received cyclophosphamide, and all of them switched to MF. 74 patients (87%) achieved a response (69% partial, 31% complete). Age at starting MF, gender, pathological classification, body mass index, blood pressure, baseline renal function, and proteinuria were not associated with achieving response. After stopping MF, 3 of 19 patients (15.7%) relapsed, all at 6 months of follow-up. No differences were found between clinical and analytical variables and number of relapses. Side effects were unremarkable, except for 1 patient, who died of thrombocytopenia and ovarian hemorrhage. CONCLUSIONS: Switching to MF from other immunosuppressive treatments is effective and safe in refractory and relapsing LN.

Geriatric assessment for therapeutic decision-making regarding renal replacement in elderly patients with advanced chronic kidney disease.

UNLABELLED: In patients older than 75 years with advanced chronic kidney disease (CKD), the decision between treatment with dialysis [intention to treat with dialysis (ITD)] or conservative care (CC) is a challenge. Geriatric assessment can be helpful. The aim was to identify which factors had had an influence on decision-making. METHODS: We recruited 56 patients. At baseline we analyzed age, frailty (defined following the criteria of Fried et al. [J Gerontol A Biol Sci Med Sci 2001;56:146-156]), dependence for activities of daily living (ADL), cognitive impairment, depression, comorbidity, cardiovascular disease, and diabetes. After full information about prognosis and treatment options, the preferences of the patients and families were taken into consideration as determinants in the decision-making process. During the follow-up, we evaluated clinical and laboratory parameters, hospitalization, mortality and reevaluated frailty. RESULTS: Twenty patients opted for CC, and 36 patients opted for ITD. On univariate analysis, the predictive factors of the election of CC were age, prefrailty, cognitive impairment, and dependence for ADL. In the multivariate analysis, age and prefrailty remained as predictors for the choice of CC. Hospitalizations were more frequent in CC. Survival was similar in both groups (p = 0.098). CONCLUSIONS: Frailty assessment could be useful for decision-making about the treatment in elderly patients with CKD. CC may be a good treatment option.

Lower plasma sodium is associated with a microinflammatory state among patients with advanced chronic kidney disease.

BACKGROUND/AIMS: Lower serum sodium levels have been associated with increased mortality among patients with chronic kidney disease (CKD). Our aim was to analyze the independent factors associated with lower sodium levels among nondialysis patients with advanced CKD and to evaluate the evolution of these patients in comparison to those with higher plasma sodium over a 1-year period. METHODS: We included 72 patients with CKD stages 4 and 5 without clinically evident cardiopathy or liver disease. Bioelectrical impedance and echocardiography were performed to analyze the possible relation between plasma sodium and volume status and subclinical left ventricular (LV) dysfunction. During follow-up, we compared the evolution of patients with lower baseline plasma sodium (low quartile: <138 mEq/l) with that of patients with higher levels over a 1-year period. RESULTS: At baseline, the independent predictors of lower plasma sodium were C-reactive protein (CRP; OR 0.96; 95% CI 0.91-0.99) and body mass index (OR 0.89; 95% CI 0.78-0.99). An inverse correlation between plasma sodium and CRP was observed (r = -0.32; p = 0.01). Plasma sodium did not correlate with extracellular water and was not different between patients with or without echocardiographic data of LV dysfunction (p = 0.7). During follow-up, patients with lower sodium at baseline showed persistently lower sodium values (p = 0.04), higher CRP (p = 0.05), lower serum albumin (p < 0.01) and higher erythropoietin-stimulating agent resistance index (p = 0.05). CONCLUSIONS: Our results suggest an association between lower plasma sodium and a microinflammatory state among patients with advanced CKD. Inflammation could be an underlying confounding factor explaining the increased mortality in these patients.

Sensitization of cholangiocarcinoma cells to chemotherapy through BCRP inhibition with ß-caryophyllene oxide.

Cholangiocarcinomas (CCAs) are cancers originated in the biliary tree, which are characterized by their high mortality and marked chemoresistance, partly due to the activity of ATP-binding cassette (ABC) export pumps, whose inhibition has been proposed as a strategy for enhancing the response to chemotherapy. We have previously shown that ß-caryophyllene oxide (CRYO) acts as a chemosensitizer in hepatocellular carcinoma by inhibiting ABCB1, MRP1, and MRP2. Here, we have evaluated the usefulness of CRYO in inhibiting BCRP and improving the response of CCA to antitumor drugs. The TCGA-CHOL cohort (n = 36) was used for in silico analysis. BCRP expression (mRNA and protein) was assayed in samples from intrahepatic (iCCA) and extrahepatic (eCCA) tumors (n = 50) and CCA-derived cells (EGI-1 and TFK-1). In these cells, BCRP-dependent mitoxantrone transport was determined by flow cytometry. At non-toxic concentrations, CRYO inhibited BCRP function, which enhanced the cytostatic effect of drugs used in the treatment of CCA. The BCRP ability to confer resistance to a panel of antitumor drugs was determined in Chinese hamster ovary (CHO) cells with stable BCRP expression. At non-toxic concentrations, CRYO markedly reduced BCRP-induced resistance to known substrate drugs (mitoxantrone and SN-38) and cisplatin, gemcitabine, sorafenib, and 5-FU but not oxaliplatin. Neither CRYO nor cisplatin alone significantly affected the growth of BCRP-expressing tumors subcutaneously implanted in immunodeficient mice. In contrast, intratumor drug content was enhanced when administered together, and tumor growth was inhibited. In sum, the combined treatment of drugs exported by BCRP with CRYO can improve the response to chemotherapy in CCA patients.

Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.

Spontaneous remission is a well known characteristic of idiopathic membranous nephropathy, but contemporary studies describing predictors of remission and long-term outcomes are lacking. We conducted a retrospective, multicenter cohort study of 328 patients with nephrotic syndrome resulting from idiopathic membranous nephropathy that initially received conservative therapy. Spontaneous remission occurred in 104 (32%) patients: proteinuria progressively declined after diagnosis until remission of disease at 14.7 +/- 11.4 months. Although spontaneous remission was more frequent with lower levels of baseline proteinuria, it also frequently occurred in patients with massive proteinuria: 26% among those with baseline proteinuria 8 to 12 g/24 h and 22% among those with proteinuria >12 g/24 h. Baseline serum creatinine and proteinuria, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists, and a >50% decline of proteinuria from baseline during the first year of follow-up were significant independent predictors for spontaneous remission. Only six patients (5.7%) experienced a relapse of nephrotic syndrome. The incidence of death and ESRD were significantly lower among patients with spontaneous remission. In conclusion, spontaneous remission is common among patients with nephrotic syndrome resulting from membranous nephropathy and carries a favorable long-term outcome with a low incidence of relapse. A decrease in proteinuria >50% from baseline during the first year predicts spontaneous remission.

Attention-deficit/hyperactivity disorder and occupational outcomes: The role of educational attainment, comorbid developmental disorders, and intellectual disability.

BACKGROUND: Individuals with ADHD are at increased risk for poor occupational outcomes. Educational attainment and psychiatric comorbidity may be important contributing factors for these outcomes, but the role of these factors is not well characterized. This study aimed to investigate the associations between ADHD and occupational outcomes, and to examine the influence of educational attainment, comorbid developmental disorders and intellectual disability on these associations. METHODS: We linked the Swedish population graduating from compulsory school 1998-2008 (N = 1.2 millions) to population-wide register-based data on clinical psychiatric diagnoses and medications, objective annual measures of educational, and occupational outcomes. Individuals were followed for between 6 to 16 years after graduation. RESULTS: Individuals with ADHD had annually on average 17 percent lower income, ratio = 0.83 (95% CI 0.83-0.84), 12.19 (11.89-12.49) more days of unemployment, and a higher likelihood of receiving disability pension, odds-ratio = 19.0 (18.4-19.6), compared to controls. Comorbid diagnoses of intellectual disability and developmental disorder explained most of the association between ADHD and disability pension, while lifetime educational attainment partially explained associations between ADHD and all occupational outcomes. Analyses of occupational trajectories found that income was lower and unemployment elevated relative to controls with the same educational attainment. Higher educational attainment correlated with higher income similarly among individuals with ADHD and controls after accounting for individual background factors. CONCLUSIONS: The occupational burden associated with ADHD is substantial. Comorbid developmental disorders, intellectual disability and educational difficulties (e.g., failing grades) from childhood to adulthood are important factors to consider when designing interventions to improve occupational outcomes in individuals with ADHD.

Vitamin D deficiency in dialysis patients: effect of dialysis modality and implications on outcome.

OBJECTIVE: Vitamin D deficiency has been linked to cardiovascular disease and mortality in hemodialysis (HD) patients. The purpose of the present cross-sectional study was to analyze the Vitamin D status of dialysis patients from a single center, study determinants of Vitamin D deficiency, and assess its implications on outcome. METHODS: A prospective observational study of 115 prevalent dialysis patients was carried out, in which clinical and dialysis-related characteristics including routine biochemistry were studied in relation to levels of 25-hydroxyvitamin-D (25[OH]D, chemiluminescence). Survival was assessed after a median follow-up period of 413 days. RESULTS: 25(OH)D deficiency and insufficiency was present in 51% and 42% of the patients, respectively. Only 7% of the patients showed normal 25(OH)D levels. Peritoneal dialysis patients presented the lowest 25(OH)D levels. Also, a significant difference was found between on-line hemodiafiltration (OL-HDF) and conventional HD (11 [6 to 16] versus 19 [13 to 27] ng/mL; P < 0.001; 25th to 75th percentiles, conventional HD versus OL-HDF respectively). In multinomial logistic regression analysis, patients on conventional HD had 8.35 greater odds (95% CI [2.04 to 34.20]) of 25(OH)D deficiency than OL-HDF even after adjustment for sex, parathyroid hormone, pH, and Charlson comorbidity index. During the follow-up period, 18 patients died. Both crude and adjusted (hazard ratio, 6.96; 95% CI [1.44 to 33.64]) Cox analysis identified 25(OH)D deficiency as a mortality risk factor. CONCLUSION: This observational study underlines the high prevalence of hypovitaminosis D in dialysis patients and its strong implications on outcome. Furthermore, our results suggest that OL-HDF was associated with a better preservation of the vitamin D status as compared with conventional HD.

Plasma Membrane Transporters as Biomarkers and Molecular Targets in Cholangiocarcinoma.

The dismal prognosis of patients with advanced cholangiocarcinoma (CCA) is due, in part, to the extreme resistance of this type of liver cancer to available chemotherapeutic agents. Among the complex mechanisms accounting for CCA chemoresistance are those involving the impairment of drug uptake, which mainly occurs through transporters of the superfamily of solute carrier (SLC) proteins, and the active export of drugs from cancer cells, mainly through members of families B, C and G of ATP-binding cassette (ABC) proteins. Both mechanisms result in decreased amounts of active drugs able to reach their intracellular targets. Therefore, the "cancer transportome", defined as the set of transporters expressed at a given moment in the tumor, is an essential element for defining the multidrug resistance (MDR) phenotype of cancer cells. For this reason, during the last two decades, plasma membrane transporters have been envisaged as targets for the development of strategies aimed at sensitizing cancer cells to chemotherapy, either by increasing the uptake or reducing the export of antitumor agents by modulating the expression/function of SLC and ABC proteins, respectively. Moreover, since some elements of the transportome are differentially expressed in CCA, their usefulness as biomarkers with diagnostic and prognostic purposes in CCA patients has been evaluated.

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment.

The unsatisfactory response of colorectal cancer (CRC) to pharmacological treatment contributes to the substantial global health burden caused by this disease. Over the last few decades, CRC has become the cause of more than 800,000 deaths per year. The reason is a combination of two factors: (i) the late cancer detection, which is being partially solved by the implementation of mass screening of adults over age 50, permitting earlier diagnosis and treatment; (ii) the inadequate response of advanced unresectable tumors (i.e., stages III and IV) to pharmacological therapy. The latter is due to the existence of complex mechanisms of chemoresistance (MOCs) that interact and synergize with each other, rendering CRC cells strongly refractory to the available pharmacological regimens based on conventional chemotherapy, such as pyrimidine analogs (5-fluorouracil, capecitabine, trifluridine, and tipiracil), oxaliplatin, and irinotecan, as well as drugs targeted toward tyrosine kinase receptors (regorafenib, aflibercept, bevacizumab, cetuximab, panitumumab, and ramucirumab), and, more recently, immune checkpoint inhibitors (nivolumab, ipilimumab, and pembrolizumab). In the present review, we have inventoried the genes involved in the lack of CRC response to pharmacological treatment, classifying them into seven groups (from MOC-1 to MOC-7) according to functional criteria to identify cancer cell weaknesses. This classification will be useful to pave the way for developing sensitizing tools consisting of (i) new agents to be co-administered with the active drug; (ii) pharmacological approaches, such as drug encapsulation (e.g., into labeled liposomes or exosomes); (iii) gene therapy interventions aimed at restoring the impaired function of some proteins (e.g., uptake transporters and tumor suppressors) or abolishing that of others (such as export pumps and oncogenes).

Molecular Bases of Mechanisms Accounting for Drug Resistance in Gastric Adenocarcinoma.

Gastric adenocarcinoma (GAC) is the most common histological type of gastric cancer, the fifth according to the frequency and the third among the deadliest cancers. GAC high mortality is due to a combination of factors, such as silent evolution, late clinical presentation, underlying genetic heterogeneity, and effective mechanisms of chemoresistance (MOCs) that make the available antitumor drugs scarcely useful. MOCs include reduced drug uptake (MOC-1a), enhanced drug efflux (MOC-1b), low proportion of active agents in tumor cells due to impaired pro-drug activation or active drug inactivation (MOC-2), changes in molecular targets sensitive to anticancer drugs (MOC-3), enhanced ability of cancer cells to repair drug-induced DNA damage (MOC-4), decreased function of pro-apoptotic factors versus up-regulation of anti-apoptotic genes (MOC-5), changes in tumor cell microenvironment altering the response to anticancer agents (MOC-6), and phenotypic transformations, including epithelial-mesenchymal transition (EMT) and the appearance of stemness characteristics (MOC-7). This review summarizes updated information regarding the molecular bases accounting for these mechanisms and their impact on the lack of clinical response to the pharmacological treatment currently used in GAC. This knowledge is required to identify novel biomarkers to predict treatment failure and druggable targets, and to develop sensitizing strategies to overcome drug refractoriness in GAC.