Neuropsychology of chronic back pain managed with long-term opioid use.

Chronic pain is commonly treated with long-term opioids, but the neuropsychological outcomes associated with stable long-duration opioid use remain unclear. Here, we contrasted the psychological profiles, brain activity, and brain structure of 70 chronic back pain patients on opioids (CBP+O, average opioid exposure 6.2 years) with 70 patients managing their pain without opioids. CBP+O exhibited moderately worse psychological profiles and small differences in brain morphology. However, CBP+O had starkly different spontaneous brain activity, dominated by increased mesocorticolimbic and decreased dorsolateral-prefrontal activity, even after controlling for pain intensity and duration. These differences strongly reflected cortical opioid and serotonin receptor densities and mapped to two antagonistic resting-state circuits. The circuits' dynamics were explained by mesocorticolimbic activity and reflected negative affect. We reassessed a sub-group of CBP+O after they briefly abstained from taking opioids. Network dynamics, but not spontaneous activity, reflected exacerbated signs of withdrawal. Our results have implications for the management and tapering of opioids in chronic pain.

TRPC3 Regulates Islet Beta-Cell Insulin Secretion.

Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3's involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3-/- mice. TRPC3's involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is KATP -independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one's knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes.

Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations.

This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; Mage = 8.93 years, SDage = 4.75), 23 with PTEN mutation without ASD (PTEN-no ASD; Mage = 8.94 years; SDage = 4.85) and 25 with ASD and macrocephaly but with no PTEN mutation (Macro-ASD; Mage = 11.99 years; SDage = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD.

Psychiatric Characteristics Across Individuals With PTEN Mutations.

Germline heterozygous PTEN mutations have been associated with high prevalence of autism spectrum disorder (ASD) and elevated rates and severity of broadly defined behavioral problems. However, limited progress has been made toward understanding whether PTEN mutation is associated with specific psychiatric co-morbidity profiles when compared to idiopathic ASD. The current study aimed to utilize a cross-measure approach to compare concurrent psychiatric characteristics across children and adolescents with PTEN mutation with (PTEN-ASD; n = 38) and without ASD (PTEN-No ASD; n = 23), and ASD with macrocephaly but no PTEN mutation (macro-ASD; n = 25) using the Child Behavior Checklist (CBCL) and the Aberrant Behavior Checklist (ABC). There were significant group effects for the CBCL Internalizing and Externalizing broad symptom score, the majority of specific CBCL syndrome scores, and all ABC subscale scores. Post-hoc comparisons revealed greater behavioral symptoms in the ASD groups (PTEN-ASD and macro-ASD) compared to the PTEN-no ASD group on nearly all subtest scores examined. There were no statistically significant differences between the PTEN-ASD and macro-ASD groups; however, there was a trend for the macro-ASD group showing higher levels of aggressive behaviors. Our findings provide evidence of specific behavior profiles across PTEN-No ASD, PTEN-ASD, and macro-ASD groups and highlight the importance of early identification of behavioral vulnerabilities in individuals with PTEN mutations in order to provide access to appropriate evidence-based interventions.

Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.

This study aimed to further our understanding of restricted and repetitive behaviors (RRB) among individuals with germline pathogenic mutations in PTEN by providing multimethod characterization and comparison of key RRB subdomains across individuals with PTEN mutations with autism spectrum disorder (ASD) (PTEN-ASD), with PTEN mutations without ASD (PTEN-No ASD) and with ASD and macrocephaly but without PTEN mutations (Macro-ASD). Of 86 total research participants, 38 had PTEN-ASD (Mage  = 8.93 years, SDage  = 4.75), 25 Macro-ASD (Mage  = 11.99 years; SDage  = 5.15), and 23 PTEN-No ASD (Mage  = 8.94 years; SDage  = 4.85). The Repetitive Behavior Scale-Revised (RBS-R) and the Autism Diagnostic Interview-Revised (ADI-R) were used as measures of distinct RRB domains. There were significant group differences in the RBS-R repetitive motor behaviors (RMB; F = 4.52, p = 0.014, ω2  = 0.08), insistence on sameness (IS; F = 4.11, p = 0.02, ω2  = 0.05), and circumscribed interests (CI; F = 7.80, p = 0.001, ω2  = 0.14) scales. Post hoc comparisons showed that the PTEN-No ASD group had significantly lower RMB, IS, and CI scores compared to both PTEN-ASD and Macro-ASD groups. Importantly, PTEN-No ASD group still showed elevated RRB levels. Furthermore, there was a portion of individuals in PTEN-No ASD group whose Full-Scale Intelligence Quotient (FSIQ) was >70 that did not show floor level scores in the RMB domain. After adjusting for age and FSIQ scores, group differences were no longer statistically significant. RMB, IS, and CI domains showed distinct association patterns with sex, age, and FSIQ. This investigation provides the largest and most comprehensive characterization of distinct RRB domains in individuals with PTEN mutations to date. Despite the limitations, our findings have important assessment and treatment implications.

COVID-19 and Suicide: A Deadly Association.

ABSTRACT: COVID-19 hit the world amidst an unprecedented suicide epidemic in this century. As the world focuses on limiting the spread of the virus and prioritizing acutely medically ill patients, containment measures are not without mental health consequences. With rising anxiety and depression, risk of suicide-acutely and in the aftermath of the pandemic-also rises. This article aims to shed light on this major public health problem and better understand what factors may create or exacerbate psychiatric symptoms and suicide. We review suicide data predating the pandemic and examine impact of previous epidemics on suicide rates. We then focus on the current pandemic's impacts and the world's response to COVID-19. We examine how these may lead to increased suicide rates, focusing on the US population. Finally, we offer suggestions on mitigating interventions to curb the impending rise in suicide and the resultant increased burden on an already stretched health care system.

Whole-exome and whole-genome sequencing in chronic lymphocytic leukemia: new biomarkers to target.

Many biomarkers indicate prognosis in chronic lymphocytic leukemia; such as fluorescence in situ hybridization testing: 17p or 11q deletions have a worse prognosis than trisomy 12, 13q deletion or normal result, or the mutational status of the immunoglobulin heavy chain (IGHV): unmutated IGHV have a worse prognosis than mutated IGHV. Recently, many gene mutations (TP53, NOTCH1 etc.,) have been linked to a worse prognosis. With the new era of high-throughput sequencing, it has become easier to study gene mutations and their implication in predicting prognosis. In this review, we aim to review all the studies that performed whole-exome sequencing or whole-genome sequencing on chronic lymphocytic leukemia cells and explore the implication of various genes in disease prognosis.

Urging medical students to publish: Advantages, disadvantages and new challenges.

As soon as they get accepted into medical school, students find themselves facing numerous expectations: coping with tremendous study burden, competing with others for the best rank, completing internships and participating in the race for publishing are only to name a few. This big juggle makes it hard for the medical student to focus on research. It is often easier to postpone publication and involvement in research to "later". In fact there are many advantages to publishing in the current publication system but there are many disadvantages as well. With the widespread of social media and open access systems, new challenges have arisen. The aim of this paper is to discuss the advantages and disadvantages of publishing in the current system while highlighting the new challenges that the students might need to overcome. Its aim is to provide medical students with information to enhance their understanding of the current publication system and thus most importantly, probe their desire to publish.

ALK-rearranged adenocarcinoma transformed to small-cell lung cancer: a new entity with specific prognosis and treatment?

Driving molecular mutations such as rearrangement of ALK and EGFR mutation is present in 5-10% of non-small-cell lung cancer. Tyrosine kinase inhibitors have shown good efficacy and thus become the standard of care. However, tumors have developed several resistance mechanisms against tyrosine kinase inhibitors, including transformation to small-cell lung carcinoma (SCLC). Transformation to SCLC after administration of anti-EGFR in EGFR-mutated adenocarcinoma has been well documented. Similarly, it appears that the same transformation happens in ALK-rearranged adenocarcinoma after the use of anti-ALK. In fact, to date eight cases have been reported in the literature. We aimed in this paper to focus on the characteristics, prognosis and treatment of these transformed SCLC.