Completeness and readability of GPT-4-generated multilingual discharge instructions in the pediatric emergency department.

Objectives: The aim of this study was to assess the completeness and readability of generative pre-trained transformer-4 (GPT-4)-generated discharge instructions at prespecified reading levels for common pediatric emergency room complaints. Materials and Methods: The outputs for 6 discharge scenarios stratified by reading level (fifth or eighth grade) and language (English, Spanish) were generated fivefold using GPT-4. Specifically, 120 discharge instructions were produced and analyzed (6 scenarios: 60 in English, 60 in Spanish; 60 at a fifth-grade reading level, 60 at an eighth-grade reading level) and compared for completeness and readability (between language, between reading level, and stratified by group and reading level). Completeness was defined as the proportion of literature-derived key points included in discharge instructions. Readability was quantified using Flesch-Kincaid (English) and Fernandez-Huerta (Spanish) readability scores. Results: English-language GPT-generated discharge instructions contained a significantly higher proportion of must-include discharge instructions than those in Spanish (English: mean (standard error of the mean) = 62% (3%), Spanish: 53% (3%), P = .02). In the fifth-grade and eighth-grade level conditions, there was no significant difference between English and Spanish outputs in completeness. Readability did not differ across languages. Discussion: GPT-4 produced readable discharge instructions in English and Spanish while modulating document reading level. Discharge instructions in English tended to have higher completeness than those in Spanish. Conclusion: Future research in prompt engineering and GPT-4 performance, both generally and in multiple languages, is needed to reduce potential for health disparities by language and reading level.

An investigation of composition, morphology, mechanical properties, and microdamage accumulation of human type 2 diabetic bone.

This study investigates the biomechanics of type 2 diabetic bone fragility through a multiscale experimental strategy that considers structural, mechanical, and compositional components of ex vivo human trabecular and cortical bone. Human tissue samples were obtained from the femoral heads of patients undergoing total hip replacement. Mechanical testing was carried out on isolated trabecular cores using monotonic and cyclic compression loading and nanoindentation experiments, with bone microdamage analysed using micro-computed tomography (CT) imaging. Bone composition was evaluated using Raman spectroscopy, high-performance liquid chromatography, and fluorometric spectroscopy. It was found that human type 2 diabetic bone had altered mechanical, compositional, and morphological properties compared to non-type 2 diabetic bone. High-resolution micro-CT imaging showed that cores taken from the central trabecular region of the femoral head had higher bone mineral density (BMD), bone volume, trabecular thickness, and reduced trabecular separation. Type 2 diabetic bone also had enhanced macro-mechanical compressive properties under mechanical loading compared to non-diabetic controls, with significantly higher apparent modulus, yield stress, and pre-yield toughness evident, even when properties were normalised against the bone volume. Using nanoindentation, there were no significant differences in the tissue-level mechanical properties of cortical or trabecular bone in type 2 diabetic samples compared to controls. Through compositional analysis, higher levels of furosine were found in type 2 diabetic trabecular bone, and an increase in both furosine and carboxymethyl-lysine (an advanced glycation end-product) was found in cortical bone. Raman spectroscopy showed that type 2 diabetic bone had a higher mineral-to-matrix ratio, carbonate substitution, and reduced crystallinity compared to the controls. Together, this study shows that type 2 diabetes leads to distinct changes in both organic and mineral phases of the bone tissue matrix, but these changes did not coincide with any reduction in the micro- or macro-mechanical properties of the tissue under monotonic or cyclic loading.

Electrophysiology of human iPSC-derived vascular smooth muscle cells and cell autonomous consequences of Cantu Syndrome mutations.

OBJECTIVE: Cantu Syndrome (CS), a multisystem disease with a complex cardiovascular phenotype, is caused by GoF variants in the Kir6.1/SUR2 subunits of ATP-sensitive potassium (KATP) channels, and is characterized by low systemic vascular resistance, as well as tortuous, dilated vessels, and decreased pulse-wave velocity. Thus, CS vascular dysfunction is multifactorial, with both hypomyotonic and hyperelastic components. To dissect whether such complexities arise cell-autonomously within vascular smooth muscle cells (VSMCs), or as secondary responses to the pathophysiological milieu, we assessed electrical properties and gene expression in human induced pluripotent stem cell-derived VSMCs (hiPSC-VSMCs), differentiated from control and CS patient-derived hiPSCs, and in native mouse control and CS VSMCs. APPROACH AND RESULTS: Whole-cell voltage-clamp of isolated aortic and mesenteric arterial VSMCs isolated from wild type (WT) and Kir6.1[V65M] (CS) mice revealed no clear differences in voltage-gated K+ (Kv) or Ca2+ currents. Kv and Ca2+ currents were also not different between validated hiPSC-VSMCs differentiated from control and CS patient-derived hiPSCs. While pinacidil-sensitive KATP currents in control hiPSC-VSMCs were consistent with those in WT mouse VSMCs, they were considerably larger in CS hiPSC-VSMCs. Under current-clamp conditions, CS hiPSC-VSMCs were also hyperpolarized, consistent with increased basal K conductance, and providing an explanation for decreased tone and decreased vascular resistance in CS. Increased compliance was observed in isolated CS mouse aortae, and was associated with increased elastin mRNA expression. This was consistent with higher levels of elastin mRNA in CS hiPSC-VSMCs, suggesting that the hyperelastic component of CS vasculopathy is a cell-autonomous consequence of vascular KATP GoF. CONCLUSIONS: The results show that hiPSC-VSMCs reiterate expression of the same major ion currents as primary VSMCs, validating the use of these cells to study vascular disease. Results in hiPSC-VSMCs derived from CS patient cells suggest that both the hypomyotonic and hyperelastic components of CS vasculopathy are cell-autonomous phenomena driven by KATP overactivity within VSMCs.

Do joint-preserving hip procedures compromise subsequent total hip arthroplasty? A meta-analysis of complications, functional outcome and survivorship.

BACKGROUND: Joint-preserving hip operations can help relieve pain and delay the need for long-term joint arthroplasty. Previous research has not identified procedures that can compromise outcomes following total hip arthroplasty (THA). This meta-analysis aims to evaluate the effect of joint-preserving hip operations on outcomes following subsequent THA. METHODS: MEDLINE, EMBASE and Scopus databases were searched from the date of inception until February 2024. All studies comparing outcomes following THA in individuals with (PS) and without prior surgery (NPS) of the femur or pelvis were included. Data on operative time, blood loss, intra- and post-operative complications, functional outcomes, and implant survivorship were extracted. RESULTS: 16 studies, comprising 2576 patients were included (PS = 939, NPS = 1637). The PS group was associated with significantly longer operative time [MD: 8.1, 95% CI: 4.6-11.6], significantly greater blood loss [MD: 167.8, 95% CI: 135.6-200.0], and a higher risk of intra-operative peri-prosthetic fracture [RR: 1.9, 95% CI: 1.2-3.0], specifically, with prior femoral osteotomy. There were no differences in terms of risks of dislocation [RR: 1.8, 95% CI: 1.0-3.2], implant loosening [RR: 1.0, 95% CI: 0.7-1.5], or revision surgery [RR: 1.3, 95% CI: 1.0-1.7] between the two groups. The PS group was associated with significantly poorer improvements in functional outcome [MD: -5.6, 95% CI: -7.6-(-3.5)], specifically, with prior acetabular osteotomy. Implant survivorship in the two groups was comparable after one year [HR: 1.9, 95% CI: 0.6-6.2] but significantly inferior in the PS group after five years [HR: 2.5, 95% CI: 1.4-4.7], specifically, with prior femoral osteotomy. CONCLUSION: Joint-preserving hip operations are associated with greater intra-operative challenges and complications. In subsequent joint arthroplasty, prior acetabular procedures affect functional outcomes while prior femoral procedures influence implant survivorship. Hip pain due to the morphological sequelae of pediatric hip pathology can be debilitating at a young age. Surgical decision-making at that time needs to consider the survivorship of a THA implanted at that young age against the consequences of hip preservation surgery on further THA.

Modulation of TMEM16B channel activity by the calcium-activated chloride channel regulator 4 (CLCA4) in human cells.

The Ca2+-activated Cl- channel regulator CLCA1 potentiates the activity of the Ca2+-activated Cl- channel (CaCC) TMEM16A by directly engaging the channel at the cell surface, inhibiting its reinternalization and increasing Ca2+-dependent Cl- current (ICaCC) density. We now present evidence of functional pairing between two other CLCA and TMEM16 protein family members, namely CLCA4 and the CaCC TMEM16B. Similar to CLCA1, (i) CLCA4 is a self-cleaving metalloprotease, and the N-terminal portion (N-CLCA4) is secreted; (ii) the von Willebrand factor type A (VWA) domain in N-CLCA4 is sufficient to potentiate ICaCC in HEK293T cells; and (iii) this is mediated by the metal ion-dependent adhesion site motif within VWA. The results indicate that, despite the conserved regulatory mechanism and homology between CLCA1 and CLCA4, CLCA4-dependent ICaCC are carried by TMEM16B, rather than TMEM16A. Our findings show specificity in CLCA/TMEM16 interactions and suggest broad physiological and pathophysiological links between these two protein families.

Simultaneous bilateral total hip arthroplasty-a survey of Irish orthopaedic surgeons' practice.

BACKGROUND: Bilateral total hip arthroplasty may be performed simultaneously (SIMTHA) or in two staged operations. AIM: To assess attitudes towards and utilization of SIMTHA in Irish orthopaedic practice, and to assess patient and surgeon factors which are associated with the management of bilateral hip arthritis. METHODS: A 16-question electronic survey (Google Forms) was distributed via email to consultant Irish orthopaedic surgeons who perform total hip arthroplasty, followed by a reminder 1 month later. A p value < 0.05 was considered significant. RESULTS: There were 53 responses from arthroplasty surgeons, with 28% reporting they never perform SIMTHA, 26% have performed ≤ 5 SIMTHA, and 46% do ≥ 1 SIMTHA per year. Amongst the 15 surgeons who do not do SIMTHA, 60% reported a preference for staged arthroplasty, 20% felt it was not feasible in their institution, and a third reported a lack of experience with SIMTHA. There was a significant association between not performing SIMTHA and years of consultant experience (p = 0.002). There were no institutional guidelines on eligibility criteria for SIMTHA. The most common time interval for staged bilateral arthroplasty was 6-12 weeks (60%). Overall, 56% of surgeons felt SIMTHA is underutilised in the Irish healthcare system; this was associated with greater SIMTHA volume (p = 0.023). CONCLUSION: Half of the Irish arthroplasty surgeons report SIMTHA is a regular aspect of their practice. Performing SIMTHA is associated with greater arthroplasty volume, more recent consultant appointments, and a perception that the operation is underutilised.

The antimicrobial effectiveness of chlorhexidine and chlorhexidine-silver sulfadiazine-impregnated central venous catheters against the emerging fungal pathogen Candida auris.

BACKGROUND: Candida auris is an emerging multidrug-resistant fungus associated with catheter-related bloodstream infections. In vitro efficacy of chlorhexidine (CHX) and CHX-silver sulfadiazine-impregnated (CHX-S) antimicrobial central venous catheters (CVCs) against C auris was investigated. METHODS: Minimum inhibitory and bactericidal CHX concentrations were determined against 19 C auris isolates. To assess extraluminal efficacy, segments from CVCs impregnated externally (CHX-S1) and both externally and internally (CHX-S2) were plasma-conditioned for 1- and 6-day, and to assess intraluminal efficacy, CHX-S2 CVCs were preconditioned with saline-lock for 6days, followed by 24-hour C auris inoculation and microbial adherence determination on impregnated and nonimpregnated CVCs. RESULTS: CHX inhibited all C auris isolates with minimum inhibitory and bactericidal concentrations range of 8 to 128 µg/mL. C auris adherence was reduced on CHX-S1 and CHX-S2 extraluminally by 100% on day 1, 86.96% to 100% on day 7, and intraluminally on CHX-S2 by 56.86% to 90.52% on day 7. DISCUSSION: CHX and CHX-S CVC performance against C auris observed in this study is consistent with antimicrobial benefits observed in prior preclinical and randomized controlled clinical studies. CONCLUSIONS: CHX showed strong inhibitory and cidal effects on C auris. CHX-S CVCs proved highly efficacious against this pathogen under in vitro conditions. Additional studies, however, are required to confirm clinical benefit.

Increasing the Dye Payload of Cetuximab-IRDye800CW Enables Photodynamic Therapy.

Cetuximab (Cet)-IRDye800CW, among other antibody-IRDye800CW conjugates, is a potentially effective tool for delineating tumor margins during fluorescence image-guided surgery (IGS). However, residual disease often leads to recurrence. Photodynamic therapy (PDT) following IGS is proposed as an approach to eliminate residual disease but suffers from a lack of molecular specificity for cancer cells. Antibody-targeted PDT offers a potential solution for this specificity problem. In this study, we show, for the first time, that Cet-IRDye800CW is capable of antibody-targeted PDT in vitro when the payload of dye molecules is increased from 2 (clinical version) to 11 per antibody. Cet-IRDye800CW (1:11) produces singlet oxygen, hydroxyl radicals, and peroxynitrite upon activation with 810 nm light. In vitro assays on FaDu head and neck cancer cells confirm that Cet-IRDye800CW (1:11) maintains cancer cell binding specificity and is capable of inducing up to ∼90% phototoxicity in FaDu cancer cells. The phototoxicity of Cet-IRDye800CW conjugates using 810 nm light follows a dye payload-dependent trend. Cet-IRDye800CW (1:11) is also found to be more phototoxic to FaDu cancer cells and less toxic in the dark than the approved chromophore indocyanine green, which can also act as a PDT agent. We propose that antibody-targeted PDT using high-payload Cet-IRDye800CW (1:11) could hold potential for eliminating residual disease postoperatively when using sustained illumination devices, such as fiber optic patches and implantable surgical bed balloon applicators. This approach could also potentially be applicable to a wide variety of resectable cancers that are amenable to IGS-PDT, using their respective approved full-length antibodies as a template for high-payload IRDye800CW conjugation.

The experiences of people living with obesity and chronic pain: A Qualitative Evidence Synthesis (QES) protocol.

INTRODUCTION: There is a substantial and progressive association between chronic pain (CP) and living with overweight or obesity. The relationship between obesity and CP is intricate and complex, with obesity being associated with increased pain-related disability, pain intensity, reduction in physical functioning and poorer psychological well-being. A Qualitative Evidence Synthesis (QES) provides an opportunity to better understand and reveal key areas within the patient experience of these complex interactions to inform best practice and future intervention design. AIMS: The aim of this QES is to methodically and systematically review and synthesise the qualitative literature reporting on the personal experiences of people who are both living with obesity (PwO) and chronic pain. METHODS: The phenomenon of interest of this QES is the lived experiences of PwO and CP. The following research question was developed using a modified Population, Intervention, Comparison, Outcome and Study type (PICOS) framework: "What are the lived experiences of people living with obesity and chronic pain?". One review author will conduct a systematic search based on keywords and Medical Subject Headings (MeSH) terms for finding relevant articles in five peer-review databases, from inception to the date of searching. Two review authors will independently apply inclusion and exclusion criteria and screen articles in a two-stage process. The methodological quality of included studies will be assessed using the Critical Appraisal Skills Programme (CASP) tool and data will be extracted using a customised template. We will undertake a thematic synthesis of qualitative data from included studies and report our findings narratively. Confidence in the findings will be assessed based on the Grading of Recommendations Assessment, Development and Evaluation Confidence in Evidence from Reviews of Qualitative Research (GRADE-CER-Qual) approach. FINDINGS AND DISSEMINATION: This study will follow the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA) and Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ) guidelines. It is anticipated that the findings of the review will facilitate a deep and broad understanding of the complex interactions between CP and obesity and will help inform best practice and future intervention design. Findings will be disseminated through journals that undergo peer review, presentations at conferences, engagement with public and patient advocacy groups, and social media. ETHICS AND DISSEMINATION: Ethical approval is not required to conduct this review. TRAIL REGISTRATION: PROSPERO registration number: CRD42023361391.

SAGES guidelines for the use of laparoscopy during pregnancy.

BACKGROUND: When pregnant patients present with nonobstetric pathology, the physicians caring for them may be uncertain about the optimal management strategy. The aim of this guideline is to develop evidence-based recommendations for pregnant patients presenting with common surgical pathologies including appendicitis, biliary disease, and inflammatory bowel disease (IBD). METHODS: The Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) Guidelines Committee convened a working group to address these issues. The group generated five key questions and completed a systematic review and meta-analysis of the literature. An expert panel then met to form evidence-based recommendations according to the Grading of Recommendations Assessment, Development, and Evaluation approach. Expert opinion was utilized when the available evidence was deemed insufficient. RESULTS: The expert panel agreed on ten recommendations addressing the management of appendicitis, biliary disease, and IBD during pregnancy. CONCLUSIONS: Conditional recommendations were made in favor of appendectomy over nonoperative treatment of appendicitis, laparoscopic appendectomy over open appendectomy, and laparoscopic cholecystectomy over nonoperative treatment of biliary disease and acute cholecystitis specifically. Based on expert opinion, the panel also suggested either operative or nonoperative treatment of biliary diseases other than acute cholecystitis in the third trimester, endoscopic retrograde cholangiopancreatography rather than common bile duct exploration for symptomatic choledocholithiasis, applying the same criteria for emergent surgical intervention in pregnant and non-pregnant IBD patients, utilizing an open rather than minimally invasive approach for pregnant patients requiring emergent surgical treatment of IBD, and managing pregnant patients with active IBD flares in a multidisciplinary fashion at centers with IBD expertise.

Ru(II) Oligothienyl Complexes with Fluorinated Ligands: Photophysical, Electrochemical, and Photobiological Properties.

A series of Ru(II) complexes incorporating two 4,4'-bis(trifluoromethyl)-2,2'-bipyridine (4,4'-btfmb) coligands and thienyl-appended imidazo[4,5-f][1,10]phenanthroline (IP-nT) ligands was characterized and assessed for phototherapy effects toward cancer cells. The [Ru(4,4'-btfmb)2(IP-nT)]2+ scaffold has greater overall redox activity compared to Ru(II) polypyridyl complexes such as [Ru(bpy)3]2+. Ru-1T-Ru-4T have additional oxidations due to the nT group and additional reductions due to the 4,4'-btfmb ligands. Ru-2T-Ru-4T also exhibit nT-based reductions. Ru-4T exhibits two oxidations and eight reductions within the potential window of -3 to +1.5 V. The lowest-lying triplets (T1) for Ru-0T-2T are metal-to-ligand charge-transfer (3MLCT) excited states with lifetimes around 1 µs, whereas T1 for Ru-3T-4T is longer-lived (∼20-24 µs) and of significant intraligand charge-transfer (3ILCT) character. Phototoxicity toward melanoma cells (SK-MEL-28) increases with n, with Ru-4T having a visible EC50 value as low as 9 nM and PI as large as 12,000. Ru-3T and Ru-4T retain some of this activity in hypoxia, where Ru-4T has a visible EC50 as low as 35 nM and PI as high as 2900. Activity over six biological replicates is consistent and within an order of magnitude. These results demonstrate the importance of lowest-lying 3ILCT states for phototoxicity and maintaining activity in hypoxia.

Genome-Wide Association Study of Treatment-Resistant Depression: Shared Biology With Metabolic Traits.

OBJECTIVE: Treatment-resistant depression (TRD) occurs in roughly one-third of all individuals with major depressive disorder (MDD). Although research has suggested a significant common variant genetic component of liability to TRD, with heritability estimated at 8% when compared with non-treatment-resistant MDD, no replicated genetic loci have been identified, and the genetic architecture of TRD remains unclear. A key barrier to this work has been the paucity of adequately powered cohorts for investigation, largely because of the challenge in prospectively investigating this phenotype. The objective of this study was to perform a well-powered genetic study of TRD. METHODS: Using receipt of electroconvulsive therapy (ECT) as a surrogate for TRD, the authors applied standard machine learning methods to electronic health record data to derive predicted probabilities of receiving ECT. These probabilities were then applied as a quantitative trait in a genome-wide association study of 154,433 genotyped patients across four large biobanks. RESULTS: Heritability estimates ranged from 2% to 4.2%, and significant genetic overlap was observed with cognition, attention deficit hyperactivity disorder, schizophrenia, alcohol and smoking traits, and body mass index. Two genome-wide significant loci were identified, both previously implicated in metabolic traits, suggesting shared biology and potential pharmacological implications. CONCLUSIONS: This work provides support for the utility of estimation of disease probability for genomic investigation and provides insights into the genetic architecture and biology of TRD.

Randomized Controlled Comparative Effectiveness Trial of Risk Model-Guided Clinical Decision Support for Suicide Screening.

Suicide prevention requires risk identification, appropriate intervention, and follow-up. Traditional risk identification relies on patient self-reporting, support network reporting, or face-to-face screening with validated instruments or history and physical exam. In the last decade, statistical risk models have been studied and more recently deployed to augment clinical judgment. Models have generally been found to be low precision or problematic at scale due to low incidence. Few have been tested in clinical practice, and none have been tested in clinical trials to our knowledge. Methods: We report the results of a pragmatic randomized controlled trial (RCT) in three outpatient adult Neurology clinic settings. This two-arm trial compared the effectiveness of Interruptive and Non-Interruptive Clinical Decision Support (CDS) to prompt further screening of suicidal ideation for those predicted to be high risk using a real-time, validated statistical risk model of suicide attempt risk, with the decision to screen as the primary end point. Secondary outcomes included rates of suicidal ideation and attempts in both arms. Manual chart review of every trial encounter was used to determine if suicide risk assessment was subsequently documented. Results: From August 16, 2022, through February 16, 2023, our study randomized 596 patient encounters across 561 patients for providers to receive either Interruptive or Non-Interruptive CDS in a 1:1 ratio. Adjusting for provider cluster effects, Interruptive CDS led to significantly higher numbers of decisions to screen (42%=121/289 encounters) compared to Non-Interruptive CDS (4%=12/307) (odds ratio=17.7, p-value <0.001). Secondarily, no documented episodes of suicidal ideation or attempts occurred in either arm. While the proportion of documented assessments among those noting the decision to screen was higher for providers in the Non-Interruptive arm (92%=11/12) than in the Interruptive arm (52%=63/121), the interruptive CDS was associated with more frequent documentation of suicide risk assessment (63/289 encounters compared to 11/307, p-value<0.001). Conclusions: In this pragmatic RCT of real-time predictive CDS to guide suicide risk assessment, Interruptive CDS led to higher numbers of decisions to screen and documented suicide risk assessments. Well-powered large-scale trials randomizing this type of CDS compared to standard of care are indicated to measure effectiveness in reducing suicidal self-harm. ClinicalTrials.gov Identifier: NCT05312437.

Bilateral tibial fractures associated with powered exoskeleton use in complete spinal cord injury - a case report & literature review.

INTRODUCTION: Powered robotic exoskeleton (PRE) physiotherapy programmes are a relatively novel frontier which allow patients with reduced mobility to engage in supported walking. Research is ongoing regarding their utility, risks, and benefits. This article describes the case of two fractures occurring in one patient using a PRE. CASE: We report the case of a 54 year old man who sustained bilateral tibial fractures while using a PRE, on a background of T10 AIS A SCI. The initial session was discontinued due to acute severe bilateral knee swelling after approximately 15 min. The patient attended their local hospital the following day, where radiographs demonstrated bilateral proximal tibial fractures. The patient was treated with manipulation under anaesthetic and long-leg casting for five weeks, at which point he was stepped down to hinged knee braces which were weaned gradually while he remained non-weight bearing for 12 weeks. The patient was investigated with DEXA scan and was diagnosed with osteoporosis. He was liaised with rheumatology services and bone protection was initiated. Fracture healing was achieved and weight-bearing precautions were discontinued, however this period of immobilisation led to significant spasticity. The patient was discharged from orthopaedic services, with ongoing rehabilitation and physiotherapy follow-up. CONCLUSION: PRE assisted physiotherapy programmes are a promising concept in terms of rehabilitation and independence, however they are not without risk and it is important that both providers and patients are aware of this. Furthermore, SCI patients are at increased risk for osteoporosis and should be monitored and considered for bone protection.

Research Note: Morphine influences circulating and tissue concentrations of met-enkephalin and proenkephalin (PENK) expression and plasma concentrations of corticosterone in chickens.

The effects of the administration of the opioid agonist, morphine, on plasma and tissue concentrations of Met-enkephalin were determined in 14 wk old female chickens. In addition, effects of morphine on proenkephalin (PENK) expression were examined. Plasma concentrations of Met-enkephalin were reduced 10 minutes after morphine administration. Plasma concentrations of peptides that contain Met-enkephalin motifs were decreased 30 minutes after morphine administration. Tissue concentrations of Met-enkephalin tended to be depressed following morphine administration. Adrenal concentrations of PENK peptides containing Met-enkephalin motifs were decreased in chickens challenged with morphine. Expression of PENK in the anterior pituitary gland and adrenal glands were decreased in morphine treated compared to control pullets. In contrast, plasma concentrations of corticosterone were elevated 10 min after morphine treatment. Morphine also induced changes in mu (µ) opioid receptors and delta (δ) opioid receptors in both anterior pituitary tissue and adrenal tissues.

Surgeon-Performed Percutaneous Endoscopic Biliary Lithectomy: Description of a Novel Technique and Initial Results.

Introduction: Percutaneous endoscopic biliary lithectomy (PEBL) can be performed through preexisting drain tracts, offering ductal clearance and definitive management for patients with complicated gallstone disease unable to undergo conventional therapy. The technique has not been widely adopted by general surgeons. Herein, we describe our technique with surgeon-performed PEBL and present initial results. Materials and Methods: A single institutional retrospective review of the electronic medical record was performed for patients who underwent percutaneous choledochoscopy between February 2019 and November 2020. All operations were performed by 1 of 2 board-certified general surgeons with fellowship training in surgical endoscopy. Preoperative, operative, and postoperative variables were analyzed using descriptive statistics. Results: Thirteen patients underwent PEBL. Seventeen total procedures were performed; 4 patients underwent repeat intervention. The diagnoses leading to PEBL were: cholelithiasis (8), choledocholithiasis (4), and recurrent pancreatitis (1). Complete ductal clearance was achieved in 9 patients (69.2%) during the initial procedure. The remaining 4 patients (30.8%) underwent repeat PEBL, at which point complete ductal clearance was then achieved. The percutaneous drain was removed at the time of final procedure in 5 patients (38.5%) or within 5 weeks in the remaining 8 (61.5%). No intraoperative complications occurred, and no pancreatic or biliary postoperative complications or recurrences were noted with a mean follow-up of 279 ± 240 days. Conclusion: Surgeon-performed PEBL is a safe and effective method of achieving biliary ductal clearance. The technique is readily achieved following basic endoscopic and fluoroscopic principles and should be understood by all physicians managing gallstone disease.

Effects of Restraint Stress on Circulating Corticosterone and Met Enkephalin in Chickens: Induction of Shifts in Insulin Secretion and Carbohydrate Metabolism.

This study examined the effects of acute restraint stress in the presence or absence of naltrexone on the circulating concentrations of insulin, glucose, Met-enkephalin and corticosterone in 14-week-old chickens [design: 2 sex × 2 stress/non-stress × 2 +/- naltrexone]. In chickens (five male and five females per treatment) subjected to restraint for 30 min, there were increases in the plasma concentrations of corticosterone and Met-enkephalin. The plasma concentrations of insulin and glucose were also increased in the chickens during restraint. Moreover, there were increases in the plasma concentrations of insulin and glucose in the chickens. The patterns of expression of the proenkephalin gene (PENK) in both the anterior pituitary gland and the adrenal gland were very similar to that of plasma Met-enkephalin. There were relationships between the plasma concentrations of corticosterone, Met-enkephalin, insulin and glucose after 30 min of restraint. The effects of naltrexone treatment on both untreated and stressed chickens were also examined, with naltrexone attenuating the stress-induced increases in the plasma concentrations of corticosterone, Met-enkephalin and glucose but not in those of insulin. The present study demonstrates that stress increases insulin secretion in chickens but also induces insulin resistance.

Advancing the study of protein-G4 interactions in DNA repair: Insights from biolayer interferometry.

Biolayer interferometry (BLI) is a powerful tool that enables direct observations of protein-G4 interactions in real-time. In this article, we discuss the crucial aspects in conducting a BLI experiment by using the TAR DNA-binding protein (TDP43) and a G4 DNA formed by (GGGGCC)4 as a sample application. We also describe the necessary precautions in designing the DNA substrate and evaluating the signal contributions arising from nonspecific binding interactions. A comprehensive guide is included that details the necessary materials and reagents, experimental procedures, and data analysis methods for researchers who are interested in using BLI for similar studies. The insights provided in this article will allow researchers to harness the potential of BLI and unravel the complexities of protein-G4 interactions with precision and confidence.

Novel loss-of-function variants expand ABCC9-related intellectual disability and myopathy syndrome.

Loss-of-function mutation of ABCC9, the gene encoding the SUR2 subunit of ATP sensitive-potassium (KATP) channels, was recently associated with autosomal recessive ABCC9-related intellectual disability and myopathy syndrome (AIMS). Here we identify nine additional subjects, from seven unrelated families, harbouring different homozygous loss-of-function variants in ABCC9 and presenting with a conserved range of clinical features. All variants are predicted to result in severe truncations or in-frame deletions within SUR2, leading to the generation of non-functional SUR2-dependent KATP channels. Affected individuals show psychomotor delay and intellectual disability of variable severity, microcephaly, corpus callosum and white matter abnormalities, seizures, spasticity, short stature, muscle fatigability and weakness. Heterozygous parents do not show any conserved clinical pathology but report multiple incidences of intra-uterine fetal death, which were also observed in an eighth family included in this study. In vivo studies of abcc9 loss-of-function in zebrafish revealed an exacerbated motor response to pentylenetetrazole, a pro-convulsive drug, consistent with impaired neurodevelopment associated with an increased seizure susceptibility. Our findings define an ABCC9 loss-of-function-related phenotype, expanding the genotypic and phenotypic spectrum of AIMS and reveal novel human pathologies arising from KATP channel dysfunction.