Northeast Health

Intraoperative cholangiography (IOC) is frequently performed during laparoscopic cholecystectomy to delineate biliary anatomy and detect choledocholithiasis. While generally safe, postoperative pancreatitis following IOC is an uncommon and under-recognized complication. We report the case of a 41-year-old male patient who presented with postprandial pain on a background of symptomatic gallstones. Preoperative blood tests, including liver function tests, were unremarkable, and ultrasound demonstrated gallstones with a non-dilated common bile duct (CBD). He underwent an uncomplicated laparoscopic cholecystectomy with IOC, which revealed contrast reflux into the pancreatic duct. The following day, he developed severe epigastric pain radiating to the back, nausea, vomiting, tachycardia, and low-grade fever. Blood tests showed elevated lipase (2000 U/L) and deranged liver function. Computed tomography (CT) cholangiogram confirmed acute interstitial pancreatitis without evidence of bile leak, choledocholithiasis, or pancreaticobiliary maljunction. He was managed with intravenous fluids, patient-controlled analgesia, and supportive care, and discharged home on day 4. This case highlights the importance of recognising contrast reflux as a possible precipitant of pancreatitis and the need for close postoperative monitoring.

We previously theorized that Attention-Deficit Hyperactivity Disorder (ADHD) may increase susceptibility to narcolepsy and hypersomnia, potentially sharing genomic and pathophysiological features with addictive behaviours linked to Reward Deficiency Syndrome (RDS). We further suggested that the emergence of narcolepsy in individuals with underlying ADHD or RDS may place additional stress on the dopaminergic reward system. To explore this, we conducted comprehensive data mining using GWAS catalog databases focused on ADHD and narcolepsy, identifying three relevant datasets. These were individually analyzed in GWAS meta-analyses, followed by a combined GWAS meta-meta-analysis. From this, we derived a Primary Gene List (PGL) of 512 genes and a Secondary Gene List (SGL) of 42 genes, which were further examined through in-depth silico, systems biology, and pharmacogenomic (PGx) approaches. Our findings revealed a fully connected protein–protein interaction (PPI) network between ADHD and narcolepsy, with FOXP2 and RBFOX1 emerging as shared genes. We also identified schizophrenia as a potential endophenotype linking ADHD and narcolepsy. PGx analysis revealed pharmacogenomic relevance for seven genes from the SGL. To further investigate PGx–PPI relationships, we incorporated ten GARS family genes along with eight identified pharmacogenes in PGx-PPIs, and included FOXP2, RBFOX1, and GRIN2A, despite the absence of PGx data for the latter three. This analysis highlighted DRD2 and NRXN1 as central components of the dopaminergic [Genetic Addiction Risk Severity (GARS)] pathway, forming critical connections in the ADHD–schizophrenia–narcolepsy axis. These results support our initial hypothesis of a shared genetic basis between ADHD and narcolepsy. Additionally, we identified potentially overlapping genes with schizophrenia and highlighted dopaminergic regulatory variants of FOXP2, RBFOX1, and GRIN2A as promising diagnostic markers and therapeutic targets for future research.

Pseudomonas aeruginosa is a major gram-negative pathogen responsible for a variety of infections and possessing an array of both intrinsic and acquired resistance mechanisms, including β-lactamases, like the chromosomal Pseudomonas-derived cephalosporinase (PDC). β-Lactams are the most widely prescribed class of antibiotics in the United States, and antipseudomonal cephalosporins (including cefepime) are important therapies (alone or combined with β-lactamase inhibitors) for P. aeruginosa infections. Taniborbactam is a novel, bicyclic boronate β-lactamase inhibitor with activity against all β-lactamase classes and is being developed in combination with cefepime. PDC-88 is an R2-loop deletion variant conferring resistance to cefepime and ceftazidime and elevating ceftolozane/tazobactam minimum inhibitory concentration (MIC). Herein, we elucidated PDC-88 resistance mechanisms and compared inhibition by taniborbactam and avibactam. In an isogenic background, PDC-88 increased cefepime MICs by 16-fold compared to PDC-3. In vitro, compared to PDC-3, PDC-88 had 8.3-fold higher catalytic efficiency for cefepime achieved by decreasing KM 12.8-fold and decreasing kcat 1.6-fold. This is supported by our crystallographic observation that the PDC-88 deletion enlarged the active site in the vicinity of the R2-loop, likely better accommodating cefepime. Taniborbactam and avibactam restored cefepime activity by inhibiting PDC-88. Compared to avibactam, taniborbactam had 4.1- and 9-fold lower Ki app values for PDC-3 and PDC-88, respectively, with higher kon (k2/K) and similar koff for both enzymes. Structurally, taniborbactam positioned very similarly in the PDC-3 and PDC-88 active sites, interacting with many nearby residues. Based upon these data, cefepime-taniborbactam may represent an important alternative to ceftazidime-avibactam and ceftolozane-tazobactam for P. aeruginosa infections.

Artificially increasing dopamine transmission is the common mechanism by which substances with addictive potential lead to addiction. A key area of research in neurobiology is the role of dopamine. Significant advancements have been made in uncovering the intracellular signaling pathways that mediate both dopamine's immediate effects and its long-term influence on brain function. Recent discoveries have also highlighted specific molecules that could serve as potential therapeutic targets for neurological and psychiatric disorders. While understanding several important caveats, we believe dopamine acts as a master regulator of brain circuitry across major chromosomes mapping the mental health genome. This view may have important clinical relevance, emphasizing the critical role of dopaminergic activity across the genome. Importantly, we are cognizant that dopamine does not work in insolation, and its finite actions are due to a highly interactive network (known as the brain reward cascade), involving at least seven other major neurotransmitters.

Overdose involving opioids is the black heart of the addiction crisis. "Pre-addiction," as an encouraging concept by NIDA and NIAAA, seems best captured with the construct of dopamine dysregulation. Referring to the abundant publications on "Reward Deficiency Syndrome" (RDS), Genetic Addiction Risk Score (GARS) test, RDSQ29, and KB220, Pre-addiction can be referred to as "reward dysregulation" as a suitable suggestion. The hypothesis is that the true phenotype is RDS, and other behavioral disorders are endophenotypes where the genetic variants play important roles, specifically in the Brain Reward Cascade (BRC). This study tested the pharmacogenomics of the GARS panel by a multi-model in silico investigation in four layers: 1) Protein-Protein Interactions (PPIs); 2) Gene Regulatory Networks (GRNs); 3) Disease, drugs and chemicals (DDCs); and 4) Gene Coexpression Networks (GCNs). All in silico findings were combined in an Enrichment Analysis for 59 refined genes, which represented highly significant associations of dopamine pathways in the BRC and supported our hypothesis. This paper provides scientific evidence for the importance of incorporating GARS as a predictive test to identify Pre-addiction, introduce unique therapeutic targets assisting in the treatment of pain, drug dosing of prescription pharmaceuticals, and identify the risk for subsequent addiction early in -life.

Abstract Introduction: Midline catheters have been reported to be an effective and safe means of providing patients with intravenous access within the hospital and community setting. With minimal experience in the introduction of a midline service across the local health network, a regional hospital pursued this task. This observational study assesses the provision of a safe clinical framework for midline insertion, and the improvement of patient care and experiences by avoiding treatment interruptions and unnecessary cannulation attempts from failed traditional peripheral vascular access devices. Methods: From the introduction of the midline service in June 2018, outcome measures of all patients who received a midline over the following two-year period were documented including rate of line success, complication rates, dwell time, and the number of insertion attempts. Results: The midline service provided 207 lines over a two-year period with a total dwell time of 1,585 days. Project goals were achieved with 85% (Aim ≥ 85%) of all lines completing treatment prior to removal. First attempt insertion was 86% (Aim ≥ 80%) with a maximum insertion attempt of two. Rates of line-related complications were less than 8%, with five documented cases of phlebitis (2.5%) and one deep vein thrombosis with no infections documented. Conclusion: Despite limited resources, a successful midline service was introduced. Future expansion will see an increase in insertor numbers providing improved access to the service.

Alcohol use disorder (AUD) is a significant risk factor, accounting for approximately 13% of all deaths in the US. AUD not only destroys families but also causes economic losses due to reduced productivity, absenteeism, and healthcare expenses. Statistics revealing the sustained number of individuals affected by AUD over the years underscore the need for further understanding of the underlying pathophysiology to advance novel therapeutic strategies. Previous research has implicated the limbic brain regions N-methyl-D-aspartate glutamate receptors (NMDAR) in the emotional and behavioral effects of AUD. Given that aerobic exercise can modulate NMDAR activity and sensitivity to alcohol, this review presents a summary of clinical and basic science studies on NMDAR levels induced by alcohol consumption, as well as acute and protracted withdrawal, highlighting the potential role of aerobic exercise as an adjunctive therapy for AUD. Based on our findings, the utility of exercise in the modulation of reward-linked receptors and AUD may be mediated by its effects on NMDA signaling. These data support further consideration of the potential of aerobic exercise as a promising adjunctive therapy for AUD.

This study examined the relationship between trauma, ego functioning, and internet addiction. We recruited 323 participants via Amazon Mechanical Turk, a crowdsourcing platform that can be used for survey research. We gave participants the Internet Addiction Test, the Life Events Checklist, the Ego Function Assessment questionnaire, and a demographic questionnaire. Our results indicate that 41.5% reported no internet addiction, with the majority of our sample reporting behaviors that were consistent with internet addiction: mild internet addiction = 37.8%, moderate internet addiction = 19.8%, and severe internet addiction = 0.9%. The constrictive factor of ego functioning was significantly worse in those with internet addiction. Path analysis showed that the constrictive factor of ego functioning partially mediated the relationship between a self-reported history of trauma and the presence of self-reported internet addiction.