ATP8B1 Deficiency Results in Elevated Mitochondrial Phosphatidylethanolamine Levels and Increased Mitochondrial Oxidative Phosphorylation in Human Hepatoma Cells.

ATP8B1 is a phospholipid flippase that is deficient in patients with progressive familial intrahepatic cholestasis type 1 (PFIC1). PFIC1 patients suffer from severe liver disease but also present with dyslipidemia, including low plasma cholesterol, of yet unknown etiology. Here we show that ATP8B1 knockdown in HepG2 cells leads to a strong increase in the mitochondrial oxidative phosphorylation (OXPHOS) without a change in glycolysis. The enhanced OXPHOS coincides with elevated low-density lipoprotein receptor protein and increased mitochondrial fragmentation and phosphatidylethanolamine levels. Furthermore, expression of phosphatidylethanolamine N-methyltransferase, an enzyme that catalyzes the conversion of mitochondrial-derived phosphatidylethanolamine to phosphatidylcholine, was reduced in ATP8B1 knockdown cells. We conclude that ATP8B1 deficiency results in elevated mitochondrial PE levels that stimulate mitochondrial OXPHOS. The increased OXPHOS leads to elevated LDLR levels, which provides a possible explanation for the reduced plasma cholesterol levels in PFIC1 disease.

Among classic myeloproliferative neoplasms, essential thrombocythemia is associated with the greatest risk of venous thromboembolism during COVID-19.

In a multicenter European retrospective study including 162 patients with COVID-19 occurring in essential thrombocythemia (ET, n = 48), polycythemia vera (PV, n = 42), myelofibrosis (MF, n = 56), and prefibrotic myelofibrosis (pre-PMF, n = 16), 15 major thromboses (3 arterial and 12 venous) were registered in 14 patients, of whom all, but one, were receiving LMW-heparin prophylaxis. After adjustment for the competing risk of death, the cumulative incidence of arterial and venous thromboembolic events (VTE) reached 8.5% after 60 days follow-up. Of note, 8 of 12 VTE were seen in ET. Interestingly, at COVID-19 diagnosis, MPN patients had significantly lower platelet count (p < 0.0001) than in the pre-COVID last follow-up.This decline was remarkably higher in ET (-23.3%, p < 0.0001) than in PV (-16.4%, p = 0.1730) and was associated with higher mortality rate (p = 0.0010) for pneumonia. The effects of possible predictors of thrombosis, selected from those clinically relevant and statistically significant in univariate analysis, were examined in a multivariate model. Independent risk factors were transfer to ICU (SHR = 3.73, p = 0.029), neutrophil/lymphocyte ratio (SHR = 1.1, p = 0.001) and ET phenotype (SHR = 4.37, p = 0.006). The enhanced susceptibility to ET-associated VTE and the associated higher mortality for pneumonia may recognize a common biological plausibility and deserve to be delved to tailor new antithrombotic regimens including antiplatelet drugs.

High mortality rate in COVID-19 patients with myeloproliferative neoplasms after abrupt withdrawal of ruxolitinib.

We report the clinical presentation and risk factors for survival in 175 patients with myeloproliferative neoplasms (MPN) and COVID-19, diagnosed between February and June 2020. After a median follow-up of 50 days, mortality was higher than in the general population and reached 48% in myelofibrosis (MF). Univariate analysis, showed a significant relationship between death and age, male gender, decreased lymphocyte counts, need for respiratory support, comorbidities and diagnosis of MF, while no association with essential thrombocythemia (ET), polycythemia vera (PV), and prefibrotic-PMF (pre-PMF) was found. Regarding MPN-directed therapy ongoing at the time of COVID-19 diagnosis, Ruxolitinib (Ruxo) was significantly more frequent in patients who died in comparison with survivors (p = 0.006). Conversely, multivariable analysis found no effect of Ruxo alone on mortality, but highlighted an increased risk of death in the 11 out of 45 patients who discontinued treatment. These findings were also confirmed in a propensity score matching analysis. In conclusion, we found a high risk of mortality during COVID-19 infection among MPN patients, especially in MF patients and/or discontinuing Ruxo at COVID-19 diagnosis. These findings call for deeper investigation on the role of Ruxo treatment and its interruption, in affecting mortality in MPN patients with COVID-19.

Socio-Cultural Context and Bulling Others in Childhood.

The objective of this epidemiological study was to examine, using an ecological perspective, which individual and distal contextual factors (familial, social and cultural) are associated with bullying other children across two different sites. Our sample included 1,271 Puerto Rican children 10 and older years of age at baseline residing in the South Bronx in New York and in the Standard Metropolitan Area in San Juan and Caguas, Puerto Rico. Bullying others was assessed through parents' and children's response to one item in the conduct disorder section of the Diagnostic Interview Schedule for Children Version IV (DISC IV). Child, family, social and cultural factors were examined as independent variables with bullying others as dependent variable in hierarchical models adjusting for gender, maternal education, poverty, single parent household and site. Prevalence of bullying others was 15.2% in South Bronx versus 4.6% in Puerto Rico (p<0.0001). Poor social adjustment and academic achievement, parental harsh discipline, negative school environment, exposure to violence, peer delinquency and level of acculturation in the child were all risk factors for bullying others. Child acculturation accounted for site differences in rates of bullying others. We conclude that, besides the school context, specific aspects of the community, family, and culture influence the development of bullying perpetration and should be targets for interventions and prevention programs. Minority youth living in at-risk contexts may benefit from contextually sensitive preventive interventions that address how assimilation into a high-risk context may increase involvement in bullying perpetration.

Psychiatric morbidity, functioning and quality of life in young people at clinical high risk for psychosis.

OBJECTIVE: Recent studies suggest that psychotic-like experiences may also act as markers for non-psychotic psychiatric disorders, which may indicate that the focus of research in individuals at high risk (HR) for psychosis needs updating. In this study we thoroughly examined the clinical and functional characteristics of a consecutive cohort of young people at HR for psychosis and compared them to a matched sample of healthy volunteers. METHOD: Between February 2010 and September 2012 60 help-seeking HR individuals, aged 16-35, were recruited from CAMEO Early Intervention in Psychosis Service, Cambridgeshire, UK. Forty-five age- and gender-matched healthy volunteers were randomly recruited from the same geographical area. Sociodemographic, psychiatric morbidity, functioning and quality of life measures were compared between both groups. RESULTS: HR individuals suffered a wide range of DSM-IV psychiatric disorders, mainly within the affective and anxiety diagnostic spectra. In comparison to healthy volunteers, young people at HR reported more suicidal ideation/intention, depressive and anxiety symptoms and presented with remarkably poor functioning and quality of life. CONCLUSION: The presence of co-morbid moderate or severe depressive and anxiety symptoms was common in our sample of young people at enhanced risk for psychosis. A HR mental state may be associated not only with an increased risk for psychosis, but also other psychiatric disorders. Our findings may have implications for the future implementation of therapeutic interventions that this population could benefit from.

Prevalence and correlates of child sexual abuse: a national study.

BACKGROUND: This study examines the prevalence, correlates, and psychiatric disorders of adults with history of child sexual abuse (CSA). METHODS: Data were derived from a large national sample of the US population. More than 34000 adults 18 years and older residing in households were interviewed face-to-face in a survey conducted during the 2004-2005 period. Diagnoses were based on the Alcohol Use Disorder and Associated Disabilities Interview Schedule-Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, version. Weighted means, frequencies, and odds ratios of sociodemographic correlates and prevalence of psychiatric disorders were computed. Logistic regression models were used to examine the strength of associations between CSA and psychiatric disorders, adjusted for sociodemographic characteristics, risk factors, and other Axis I psychiatric disorders. RESULTS: The prevalence of CSA was 10.14% (24.8% in men and 75.2% in women). Child physical abuse, maltreatment, and neglect were more prevalent among individuals with CSA than among those without it. Adults with CSA history had significantly higher rates of any Axis I disorder and suicide attempts. The frequency, type, and number of CSA were significantly correlated with psychopathology. CONCLUSIONS: The high correlation rates of CSA with psychopathology and increased risk for suicide attempts in adulthood suggest the need for a systematic assessment of psychiatric disorders and suicide risk in these individuals. The risk factors for CSA emphasize the need for health care initiatives geared toward increasing recognition and development of treatment approaches for the emotional sequelae CSA as well as early preventive approaches.

Acculturation and drug use disorders among Hispanics in the U.S.

The authors' objective was to examine the relationship between degree of acculturation across five different dimensions of acculturation and risk of drug use disorders (DUD) among US Hispanics. Data were derived from a large national sample of the US adult population, the National Epidemiological Survey on Alcohol and Related Conditions, collected using face-to-face interviews. The sample included civilian non-institutionalized U.S. population aged 18 years and older, with oversampling of Hispanics, Blacks and those aged 18-24 years. Interviews of more than 34,000 adults were conducted during 2004-2005 using the Alcohol Use Disorder and Associated Disabilities Interview Schedule - DSM-IV Version. A total of 6359 subjects who identified themselves as Hispanics were included in this study. Acculturation measures used in this study assessed:, time spent in the U.S., age at immigration, language preference, social network composition, and ethnic identification. Among Hispanics, there was an inverse relationship between five complementary dimensions of acculturation and DUD. Moreover, this relationship showed a significant gradient across all acculturation dimensions and DUD. The prevalence of DUD increases with acculturation in Hispanics, across several measures of acculturation in a dose-response relationship. Hispanic cultural features and values exert a protective effect on risk of DUD. Preservation and promotion of Hispanic values may be an important component of preventive interventions for Hispanics.

Course of comorbid anxiety disorders among adults with bipolar disorder in the U.S. population.

OBJECTIVE: To examine the prevalence and correlates of comorbid anxiety disorders among individuals with bipolar disorders (BP) and their association with prospectively ascertained comorbidities, treatment, and psychosocial functioning. METHOD: As part of the National Epidemiologic Survey on Alcohol and Related Conditions, 1600 adults who met lifetime DSM-IV criteria for BP-I (n = 1172) and BP-II (n = 428) were included. Individuals were evaluated using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DMS-IV Version and data was analyzed from Waves 1 and 2, approximately 3 years apart. RESULTS: Sixty percent of individuals with BP had at least one lifetime comorbid anxiety disorder. Individuals with BP and anxiety disorders shared lifetime risk factors for major depressive disorder and had prospectively more depressive and manic/hypomanic episodes, suicidal ideation, suicide attempts, and more treatment seeking than those without anxiety. During the follow-up, higher incidence of panic disorder, drug use disorders, and lower psychosocial functioning were found in individuals with BP with versus without anxiety disorders. CONCLUSIONS: Anxiety disorders are prospectively associated with elevated BP severity and BP-related mental health service use. Early identification and treatment of anxiety disorders are warranted to improve the course and outcome of individuals with BP.

Psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorders.

We conducted a comprehensive review of studies assessing the efficacy and tolerability of psychostimulants for ADHD-like symptoms in individuals with autism spectrum disorder (encompassing autism disorder, Asperger's syndrome and pervasive developmental disorders not otherwise specified). PubMed, Ovid, EMBASE, Web of Science, ERIC and CINHAL were searched through 3 January 2012. From a pool of 348 potentially relevant references, 12 citations (11 studies) were retained as pertinent. Four of the included studies had a randomized controlled design. Most of the studies assessed methylphenidate immediate release. Despite inter-study heterogeneity, taken together, the results of the selected reports suggest that psychostimulants may be effective for ADHD-like symptoms in autism spectrum disorder individuals. The most common adverse events reported in the included trials were appetite reduction, sleep-onset difficulties, irritability and emotional outbursts. We discuss future directions in the field, including the need for trials assessing more ecological outcomes and combined treatment strategies tailored to the specific individual features.

Conduct disorder and adult psychiatric diagnoses: associations and gender differences in the U.S. adult population.

The authors' objective was to examine the presence of Axis I and II psychiatric disorders among adult males and females with a history in childhood and/or adolescence of conduct disorder (CD). Data were derived from a large national sample of the U.S. population. Face-to-face interviews of more than 34,000 adults ages 18 years and older were conducted during 2004-2005 using the Alcohol Use Disorder and Associated Disabilities Interview Schedule-DSM-IV Version. After adjusting for sociodemographic characteristics and psychiatric comorbidity, CD was associated with all Axis I and II disorders, particularly substance use disorders (SUD), bipolar disorder, and histrionic personality disorders. After adjusting for gender differences in the general population, men had significantly greater odds of social anxiety disorder and paranoid personality disorder, whereas women were more likely to have SUD. Furthermore, there was dose-response relationship between number of CD symptoms and risk for most psychiatric disorders. From a clinical standpoint, knowledge of the gender differences in associations of CD with other psychiatric disorders in adulthood may be informative of developmental pathways of the disorder, and of possible gender-specific risk factors. Early recognition and treatment of CD may help prevent the development of adult-onset disorders.

Parental familism and antisocial behaviors: development, gender, and potential mechanisms.

OBJECTIVE: To examine the relation between parental familism (strong values of attachment to nuclear and extended family members) and youth antisocial behaviors over time. METHOD: Puerto Rican children 5 to 13 years of age at baseline residing in the South Bronx in New York (n = 1,138) and in the Standard Metropolitan Area in San Juan and Caguas, Puerto Rico (n = 1,353) were followed over two waves 1 year apart from 2000 to 2004. Parental familism was assessed using an adaptation of the Sabogal Familism Scale. Level of youth past-year antisocial behaviors was measured by the Antisocial Behavior Index. The association between familism and Antisocial Behavior Index over three waves was examined through mixed models stratified by age and gender, adjusted by site (South Bronx or San Juan), propensity scores reflecting site differences in family income, maternal age and education, plus environmental and child risk factors. Specific family processes were examined as potential mediators. RESULTS: Parental familism was protective against antisocial behaviors in girls (estimate = -0.11, standard error = 0.03, p < .001 for 5- to 9-year-olds; estimate = -0.15, standard error = 0.03, p < .0001 for those ≥ 10 years old). For boys, parental familism was only protective in 5- to 9-year-olds (estimate = -0.09, standard error = 0.03, p = .0008). The protective effect of parental familism on antisocial behaviors operated mostly through parent-child relationships for 5- to 9-year-old children and parental attitudes/behaviors toward youth high-risk behaviors for both age groups. CONCLUSIONS: Familism may protect youth against increasing levels of antisocial behaviors (except for boys who are ≥ 10 years old). Incorporating familism as part of therapeutic approaches addressing antisocial behaviors for youth may be helpful.