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No adjuvant treatment has been established for patients who remain at high risk for hepatocellular carcinoma recurrence after curative-intent resection or ablation. We aimed to assess the efficacy of adjuvant atezolizumab plus bevacizumab versus active surveillance in patients with high-risk hepatocellular carcinoma.

Biliary tract cancers, which arise from the intrahepatic or extrahepatic bile ducts and the gallbladder, generally have a poor prognosis and are rising in incidence worldwide. The standard-of-care treatment for advanced biliary tract cancer is chemotherapy with gemcitabine and cisplatin. Because most biliary tract cancers have an immune-suppressed microenvironment, immune checkpoint inhibitor monotherapy is associated with a low objective response rate. We aimed to assess whether adding the immune checkpoint inhibitor pembrolizumab to gemcitabine and cisplatin would improve outcomes compared with gemcitabine and cisplatin alone in patients with advanced biliary tract cancer.

Tardigrades are microscopic organisms with exceptional resilience to environmental extremes. Most protocols to visualize the internal anatomy of tardigrades rely on fixation, hampering our understanding of dynamic changes to organelles and other subcellular components. Here, we provide protocols for staining live tardigrade adults and other postembryonic stages, facilitating real-time visualization of structures including lipid droplets, mitochondria, lysosomes, and DNA.

Objective: Risperidone has been found efficacious for decreasing severe tantrums, aggression, and self-injurious behavior in children and adolescents with autistic disorder (autism). The authors report on whether risperidone improves the core symptoms of autism, social and communication impairment and repetitive and stereotyped behavior. Method: The database from an 8-week double-blind, placebo-controlled trial (N = 101) and 16-week open-label continuation study (N = 63) of risperidone for children and adolescents with autism was used to test for drug effects on secondary outcome measures: scores on the Ritvo-Freeman Real Life Rating Scale, the Children's Yale-Brown Obsessive Compulsive Scale, and the maladaptive behavior domain of the Vineland Adaptive Behavior Scales. Results: Compared to placebo, risperidone led to a significantly greater reduction in the overall score on the Ritvo-Freeman Real Life Rating Scale, as well as the scores on the subscales for sensory motor behaviors (subscale I), affectual reactions (subscale III), and sensory responses (subscale IV). No statistically significant difference was observed, however, on the subscale for social relatedness (subscale II) or language (subscale V). Risperidone also resulted in significantly greater reductions in scores on the Children's Yale-Brown Obsessive Compulsive Scale and Vineland maladaptive behavior domain. This pattern of treatment response was maintained for 6 months. Conclusions: Risperidone led to significant improvements in the restricted, repetitive, and stereotyped patterns of behavior, interests, and activities of autistic children but did not significantly change their deficit in social interaction and communication. Further research is necessary to develop effective treatments for the core social and communicative impairments of autism.

Objective: The authors conducted a meta-analysis of published randomized, controlled medication trials in children and adolescents with obsessive-compulsive disorder (OCD) to assess evidence for differential efficacy based on type of drug, study design, and outcome measure. Method: A systematic literature search was performed for articles pertaining to the pharmacological treatment of pediatric and/or adolescent OCD. All baseline, posttreatment, and change scores with standard deviations reported in each study were included in the analyses. Effect sizes for dependent measures were expressed as standardized mean differences. The analysis included data on efficacy for four selective serotonin reuptake inhibitors (SSRIs) (paroxetine, fluoxetine, fluvoxamine, and sertraline) and clomipramine, four study designs, four dependent outcome measures, and two types of outcome scores (change and posttreatment scores). Multivariate regression was performed to assess the degree to which the effect sizes varied with the methodological features of each study. Results: Twelve studies with a total of 1,044 participants met all inclusion criteria for the analysis. The pooled standardized mean difference for the results of all studies was 0.46 and showed a highly significant difference between drug and placebo treatment. Only one of the four outcome measures evaluated was not sensitive to change with treatment. A multivariate regression analysis of drug effect with other variables controlled showed that clomipramine was significantly superior to each of the SSRIs but that the SSRIs were comparably effective. Conclusions: Although highly significant, the overall effect sizes for medication were modest. Similarities and differences between the variables studied that emerged in the meta-analysis may have implications for both clinical care and future research.

Objective: The study examined trends in use of inpatient and outpatient mental health services, including pharmacotherapy, among privately insured children and adolescents from 1997 to 2000. Method: Data from a national database of more than 1.7 million privately insured individuals were used in an analysis of inpatient, outpatient, and pharmacy claims of users of mental health care age 17 years and younger (approximately 20,000 patients per year). Annual utilization rates and adjusted costs for services and dispensed psychotropic medications were calculated. Results from 1997 and 2000 were compared across diagnostic and age categories. Results: The proportion of youths with an inpatient psychiatric admission decreased by 23.7% from 1997 to 2000, and annual inpatient and outpatient costs decreased by $1,216 (18.4%) and $157 (14.4%), respectively. Decreases were driven by a reduction in inpatient days (20.0%) and by a combination of a reduction in outpatient visits (11.3%) and declining payments per outpatient visit (6.1%). Payment trends across diagnoses varied considerably, with the largest reductions seen in treatment of depression, hyperactivity, adjustment disorders, and anxiety disorders. Over the same period, the proportion of youths receiving medication increased by 4.9%, and mean annual medication-related costs per outpatient increased by $41 (12.1%). Conclusions: Reductions in inpatient and outpatient mental health service intensity and reimbursements documented in previous research continued through the late 1990s. Declines were accompanied by concurrent increases in the use of and costs associated with psychotropic medications, particularly for youths with mood and anxiety disorders. These results document a shift toward medication-based outpatient treatment modalities.

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Objective: The authors examined the developmental impact and temporal characteristics of risperidone-associated weight change. Method: Weight change was measured for 63 children and adolescents with autism treated with risperidone for 6 months. Change in serum leptin levels after 2 months was examined as a predictor of final weight gain in mixed regression models that controlled for site, gender, age, and risperidone dose. Results: Age- and gender-standardized weight increased after 6 months of treatment (gross: mean=5.6 kg [SD=3.9]; standardized: mean=0.6 z [SD=0.5]) and was positively correlated with weight gained after 1 month. Change in leptin levels after 2 months of treatment (mean=-0.3 ng/ml, SD=6.2) (N=48) did not predict final weight gain. Conclusions: Chronic risperidone exposure in children with autism causes weight gain in excess of developmentally expected norms that follows a curvilinear trajectory and decelerates over time. Serum leptin change does not reliably predict risperidone-associated weight gain.

Objective: This study investigated whether the functional abnormalities in prefrontal systems observed in adult bipolar disorder are manifested in adolescents with this illness. Method: Ten adolescents with bipolar disorder and 10 healthy comparison subjects participated in a color-naming Stroop task during event-related functional magnetic resonance imaging. Results: Signal increases in the left putamen and thalamus were significantly greater in the bipolar disorder group than in the healthy group. Age correlated positively with signal increases in the bilateral rostroventral prefrontal cortex and the striatum in the healthy group but not in the bipolar disorder group. In the bipolar disorder subjects, depressive symptoms correlated positively with signal increases in the ventral striatum. Conclusions: These findings suggest the presence of dysfunction in the subcortical portions of the frontostriatal circuits in adolescents with bipolar disorder. The absence of the prefrontal abnormalities that were observed previously in adults and the absence of the age-related increases in prefrontal activity observed in normal comparison subjects suggest that a developmental disturbance in prefrontal function may emerge in bipolar disorder over the course of adolescence.

The cellular basis of age-related tissue deterioration remains largely obscure. The ability to activate compensatory mechanisms in response to environmental stress is an important factor for survival and maintenance of cellular functions. Autophagy is activated both under short and prolonged stress and is required to clear the cell of dysfunctional organelles and altered proteins. We report that specific autophagy inhibition in muscle has a major impact on neuromuscular synaptic function and, consequently, on muscle strength, ultimately affecting the lifespan of animals. Inhibition of autophagy also exacerbates aging phenotypes in muscle, such as mitochondrial dysfunction, oxidative stress, and profound weakness. Mitochondrial dysfunction and oxidative stress directly affect acto-myosin interaction and force generation but show a limited effect on stability of neuromuscular synapses. These results demonstrate that age-related deterioration of synaptic structure and function is exacerbated by defective autophagy.

There is a critical shortage of child and adolescent psychiatrists in the United States. Increased exposure, through mentorship, clinical experiences, and research opportunities, may increase the number of medical students selecting child and adolescent psychiatry (CAP) as a career choice. Between 2008 and 2011, 241 first-year participants of a program to increase exposure to CAP, funded by the Klingenstein Third-Generation Foundation (KTGF) at 10 medical schools completed baseline surveys assessing their opinions of and experiences in CAP, and 115 second-year participants completed follow-up surveys to reflect 1 year of experience in the KTGF Program. Students reported significantly increased positive perception of mentorship for career and research guidance, along with perceived increased knowledge and understanding of CAP. Results suggest that the KTGF Program positively influenced participating medical students, although future studies are needed to determine whether these changes will translate into more medical students entering the field of CAP.

Recently, it has been suggested that C2ORF40is a candidate tumor suppressor gene in breast cancer. However, the mechanism for reduced expression of C2ORF40and its functional role in breast cancers remain unclear. Here we show that C2ORF40is frequently silenced in human primary breast cancers and cell lines through promoter hypermethylation. C2ORF40mRNA level is significantly associated with patient disease-free survival and distant cancer metastasis. Overexpression of C2ORF40 inhibits breast cancer cell proliferation, migration and invasion. By contrast, silencing C2ORF40expression promotes these biological phenotypes. Bioinformatics and FACS analysis reveal C2ORF40functions at G2/M phase by downregulation of mitotic genes expression, including UBE2C. Our results suggest that C2ORF40acts as a tumor suppressor gene in breast cancer pathogenesis and progression and is a candidate prognostic marker for this disease.

The authors assess mentors’ perceptions of mentoring and experiences participating in an intensive, small-group mentorship program, with particular attention to potential challenges in their retention and the recruitment of new mentors to similar, future programs. Similar group mentorship programs were implemented at two child and adolescent psychiatry conferences, one national and the other international. The program included three daily small group meetings, one closing meeting for all participants, and administration of a web-based survey. Of the 43 mentors, 42 (98%) completed the survey, and results were comparable across both programs. Among respondents, 93% found the group experience personally fulfilling and an equally valuable teaching and learning opportunity. Mentors unanimously agreed that co-mentoring enhanced the group mentoring experience. Group diversity enhanced the mentorship process, although differences in trainees’ interests and levels of experience as posed concrete challenges. Sixty-two percent of the mentors thought that they would be able to adapt lessons and experiences from the mentorship program in their home institutions, and 95% agreed to participate if invited to mentor in future programs. Mentors found the intensive, brief group mentorship model to be a powerful, time-efficient, and enjoyable approach to mentoring, increasing trainees’ exposure to child and adolescent psychiatry. Although group composition, schedule coordination, and logistics warrant closer scrutiny, these positive perceptions bode well for mentor recruitment and retention and for using a similar program in other settings.

Treatment-emergent adverse events (AEs) were monitored during an 8-week, double-blind, placebo-controlled trial of risperidone (0.5–3.5 mg/day) in 101 children and adolescents with a lifetime diagnosis of autistic disorder. In addition, 37 placebo nonresponders received open-label risperidone for another 8 weeks. Of all the risperidone responders (n = 65), 63 entered an open extension of another 16 weeks (6 months total risperidone exposure), and 32 of them were rerandomized to either continued risperidone therapy (n = 16) or gradual replacement with placebo (n = 16) over 8 weeks. We collected the following measures of safety and tolerability: (1) laboratory blood assessments (CBC with differential, electrolytes, and liver function tests) and urinalyses, (2) vital signs, (3) Side Effects Review of AEs thought to be associated with risperidone, (4) sleep records, (5) Simpson Angus Neurological Rating Scale (SARS), (6) Abnormal Involuntary Movement Scale (AIMS), and (7) height and weight. No clinically significant changes were found on the lab tests. During the 8-week acute trial, the most common AEs on the Side Effects Review, scored as moderate or higher, were as follows (placebo and risperidone, respectively): Somnolence (12% and 37%), enuresis (29% and 33%), excessive appetite (10% and 33%), rhinitis (8% and 16%), difficulty waking (8% and 12%), and constipation (12% and 10%). "Difficulty falling asleep" and anxiety actually favored the risperidone condition at statistically significant levels. The same AEs tended to recur through 6 months of treatment, although often at reduced levels. Using Centers for Disease Control (CDC) standardized scores, both weight and body mass index (BMI) increased with risperidone during the acute trial (0.5 and 0.6 SDs, respectively, for risperidone; 0.0 and 0.1 SDs, respectively, for placebo) and into open-label extension (0.19 and 0.16 SDs, respectively), although the amount of gain decelerated with time. Extrapyramidal symptoms, as assessed by the SARS, were no more common for drug than placebo, although drooling was reported more often in the risperidone group. There were no differences between groups on the AIMS. Two subjects had seizures (one taking placebo), but these were considered unrelated to active drug. Most AEs were mild to moderate and failed to interfere with therapeutic changes; there were no unanticipated AEs. The side effects of most concern were somnolence and weight gain.

Objective: To describe the methodological challenges and decisions made in developing a multisite, controlled study of risperidone in children and adolescents with autism.Methods: Review the design considerations for clinical trials in children with autistic disorder accompanied by severe tantrums, aggressive and/or self-injurious behaviors. These design considerations include the definition of inclusion criteria that are relevant to clinical practice and matching study design to the goal of evaluating short- and long-term effects. Additional ethical and scientific issues concern the length of trial and sample size.Results: We undertook a short-term, placebo-controlled study to evaluate the efficacy and safety of risperidone in children and adolescents with autistic disorder.This trial design was followed by an extended open-label maintenance on risperidone to confirm durability of treatment effects and to monitor safety. Finally, a placebo-controlled discontinuation study tested the need for continuous treatment.Conclusions: In the absence of standard pharmacological treatment for children with autistic disorder, a placebo-controlled study remains the most appropriate method of testing efficacy and safety. The clinical relevance of this study is enhanced by the addition of an extended maintenance phase followed by a placebo discontinuation.

In this report the results of experimental and theoretical research of the aero- and thermodynamics into massage with an air jet inclined to the calf surface are discussed. A need for such an investigation is caused by the development of air massage devices. The main attention in the present research has been concentrated on mathematical modelling of aero- and thermodynamic processes in massage depression to get these processes under control. Experimental investigations have also been undertaken to determine massage depression profiles and air velocity patterns. A radical control of massage and cooling effects above the skin enables us to develop more perfect massage devices.

Adolescents occupy a difficult and seemingly elusive developmental space, which makes them enigmas to most adults, including psychotherapists. Building upon dynamic theory such as that formulated by Winnicott or Erikson, this paper explores the relationship between adolescents and material elements of popular culture within a psychodynamic and developmental framework. Theoretical perspectives are integrated with case material to illustrate some of the roles of popular music and fashion in the lives of teenagers as a means of expression and in potential therapeutic alliance formation, dynamic understanding, and working through developmental conflicts in displacement.

Although the genetic triggers for gonadal sex differentiation vary across species, the cell biology of gonadal development was long thought to be largely conserved. Here, we present a comprehensive analysis of gonadal sex differentiation, using single-cell sequencing in the embryonic chicken gonad during sexual differentiation. The data show that chicken embryonic-supporting cells do not derive from the coelomic epithelium, in contrast to other vertebrates studied. Instead, they derive from a DMRT1+/PAX2+/WNT4+/OSR1+mesenchymal cell population. We find a greater complexity of gonadal cell types than previously thought, including the identification of two distinct sub-populations of Sertoli cells in developing testes and derivation of embryonic steroidogenic cells from a differentiated supporting-cell lineage. Altogether, these results indicate that, just as the genetic trigger for sex differs across vertebrate groups, cell lineage specification in the gonad may also vary substantially.

Our aim in this study was to compare the efficiency of 25G versus22G needles in diagnosing solid pancreatic lesions by EUS-FNA. We performed a systematic review and meta-analysis. Studies were identified in five databases using an extensive search strategy. Only randomized trials comparing 22G and 25G needles were included. The results were analyzed by fixed and random effects. A total of 504 studies were found in the search, among which 4 randomized studies were selected for inclusion in the analysis. A total of 462 patients were evaluated (233: 25G needle/229: 22G needle). The diagnostic sensitivity was 93% for the 25G needle and 91% for the 22G needle. The specificity of the 25G needle was 87%, and that of the 22G needle was 83%. The positive likelihood ratio was 4.57 for the 25G needle and 4.26 for the 22G needle. The area under the sROC curve for the 25G needle was 0.9705, and it was 0.9795 for the 22G needle, with no statistically significant difference between them (p=0.497). Based on randomized studies, this meta-analysis did not demonstrate a significant difference between the 22G and 25G needles used during EUS-FNA in the diagnosis of solid pancreatic lesions.

Serum levels of testosterone, FSH, LH and prolactin were measured by RIA in patients with BPH (benign prostatic hypertrophy) and in control men. The testosterone concentrations in the BPH group were significantly lower than that of the control group. Serum concentrations of FSH, LH, prolactin and estradiol, did not differ significantly in the 2 groups.

Presents numerous letters to the editor of `Newsweek' relating to school violence in Littleton, Colorado.