Genetic modeling of GNAO1 disorder delineates mechanisms of Gαo dysfunction.

GNAO1 encephalopathy is a neurodevelopmental disorder with a spectrum of symptoms that include dystonic movements, seizures and developmental delay. While numerous GNAO1 mutations are associated with this disorder, the functional consequences of pathological variants are not completely understood. Here, we deployed the invertebrate C. elegans as a whole-animal behavioral model to study the functional effects of GNAO1 disorder-associated mutations. We tested several pathological GNAO1 mutations for effects on locomotor behaviors using a combination of CRISPR/Cas9 gene editing and transgenic overexpression in vivo. We report that all three mutations tested (G42R, G203R and R209C) result in strong loss of function defects when evaluated as homozygous CRISPR alleles. In addition, mutations produced dominant negative effects assessed using both heterozygous CRISPR alleles and transgenic overexpression. Experiments in mice confirmed dominant negative effects of GNAO1 G42R, which impaired numerous motor behaviors. Thus, GNAO1 pathological mutations result in conserved functional outcomes across animal models. Our study further establishes the molecular genetic basis of GNAO1 encephalopathy, and develops a CRISPR-based pipeline for functionally evaluating mutations associated with neurodevelopmental disorders.

Loss-of-function variants in MYCBP2 cause neurobehavioural phenotypes and corpus callosum defects.

The corpus callosum is a bundle of axon fibres that connects the two hemispheres of the brain. Neurodevelopmental disorders that feature dysgenesis of the corpus callosum as a core phenotype offer a valuable window into pathology derived from abnormal axon development. Here, we describe a cohort of eight patients with a neurodevelopmental disorder characterized by a range of deficits including corpus callosum abnormalities, developmental delay, intellectual disability, epilepsy and autistic features. Each patient harboured a distinct de novo variant in MYCBP2, a gene encoding an atypical really interesting new gene (RING) ubiquitin ligase and signalling hub with evolutionarily conserved functions in axon development. We used CRISPR/Cas9 gene editing to introduce disease-associated variants into conserved residues in the Caenorhabditis elegans MYCBP2 orthologue, RPM-1, and evaluated functional outcomes in vivo. Consistent with variable phenotypes in patients with MYCBP2 variants, C. elegans carrying the corresponding human mutations in rpm-1 displayed axonal and behavioural abnormalities including altered habituation. Furthermore, abnormal axonal accumulation of the autophagy marker LGG-1/LC3 occurred in variants that affect RPM-1 ubiquitin ligase activity. Functional genetic outcomes from anatomical, cell biological and behavioural readouts indicate that MYCBP2 variants are likely to result in loss of function. Collectively, our results from multiple human patients and CRISPR gene editing with an in vivo animal model support a direct link between MYCBP2 and a human neurodevelopmental spectrum disorder that we term, MYCBP2-related developmental delay with corpus callosum defects (MDCD).

Context-dependent operation of neural circuits underlies a navigation behavior in Caenorhabditis elegans.

The nervous system evaluates environmental cues and adjusts motor output to ensure navigation toward a preferred environment. The nematode Caenorhabditis elegans navigates in the thermal environment and migrates toward its cultivation temperature by moving up or down thermal gradients depending not only on absolute temperature but on relative difference between current and previously experienced cultivation temperature. Although previous studies showed that such thermal context-dependent opposing migration is mediated by bias in frequency and direction of reorientation behavior, the complete neural pathways-from sensory to motor neurons-and their circuit logics underlying the opposing behavioral bias remain elusive. By conducting comprehensive cell ablation, high-resolution behavioral analyses, and computational modeling, we identified multiple neural pathways regulating behavioral components important for thermotaxis, and demonstrate that distinct sets of neurons are required for opposing bias of even single behavioral components. Furthermore, our imaging analyses show that the context-dependent operation is evident in sensory neurons, very early in the neural pathway, and manifested by bidirectional responses of a first-layer interneuron AIB under different thermal contexts. Our results suggest that the contextual differences are encoded among sensory neurons and a first-layer interneuron, processed among different downstream neurons, and lead to the flexible execution of context-dependent behavior.

Ingested removable partial denture causing esophageal perforation in a patient with autism: Management and prevention.

A 60-year-old woman with autism and a repetitive swallowing behavior ingested a removable partial denture that impacted in the proximal esophagus. Attempts at endoscopic removal were unsuccessful. Esophageal perforation was recognized, necessitating emergency transcervical surgical exploration, esophagotomy with foreign body removal, and repair of the esophageal perforation. She had a prolonged postoperative stay involving mechanical ventilatory support and gastric tube feeds. This situation was predictable and preventable, and application of key principles may help avoid such catastrophic incidents in similar patients.

Impact of the acute care surgery model on resident operative experience in emergency general surgery.

Background: The acute care surgery (ACS) model has been shown to improve patient, hospital and surgeon-specific outcomes. To date, however, little has been published on its impact on residency training. Our study compared the emergency general surgery (EGS) operative experiences of residents assigned to ACS versus elective surgical rotations. Methods: Resident-reported EGS case logs were prospectively collected over a 9-month period across 3 teaching hospitals. Descriptive statistics were tabulated and group comparisons were made using χ2 statistics for categorical data and t tests for continuous data. Results: Overall, 1061 cases were reported. Resident participation exceeded 90%). Appendiceal and biliary disease accounted for 49.7% of EGS cases. Residents on ACS rotations reported participating in twice as many EGS cases per block as residents on elective rotations (12.64 v. 6.30 cases, p < 0.01). Most cases occurred after hours while residents were on call rather than during daytime ACS hours (78.8% v. 21.1%, p < 0.01). Senior residents were more likely than junior residents to report having a primary operator role (71.3% v. 32.0%, p < 0.01). Although the timing of cases made no difference in the operative role of senior residents, junior residents assumed the primary operator role more often during the daytime than after hours (50.0% v. 33.1%, p = 0.01). Conclusion: Despite implementation of the ACS model, residents in our program obtained most of their EGS operative experience after hours while on call. Although further research is needed, our study suggests that improved daytime access to the operating room may represent an opportunity to improve the quantity and quality of the EGS operative experience at our academic network.

Contexte: Il a été prouvé que le modèle de chirurgie en soins actifs (CSA) améliore les résultats pour le patient, l'hôpital et le chirurgien. Pour le moment, peu de publications s'intéressent aux effets de ce modèle sur les résidents. Notre étude compare l'expérience des chirurgies générales d'urgence (CGU) chez les résidents effectuant un stage en CSA et chez les résidents effectuant un stage optionnel en chirurgie. Méthodes: Les cas de CGU rapportés par les résidents ont été recueillis de manière prospective pendant 9 mois dans 3 hôpitaux universitaires. Les statistiques descriptives ont été compilées, et les 2 groupes ont été comparés à l'aide du test du χ2 pour les variables catégorielles et du test t pour les variables continues. Résultats: En tout, 1061 cas ont été rapportés (la participation des résidents était de plus de 90 %). Les atteintes de l'appendice et de la vésicule biliaire représentaient 49,7 % des CGU. Les résidents en CSA ont indiqué participer à 2 fois plus de CGU que les résidents en stage optionnel (12,64 c. 6,30 cas, p < 0,01). La plupart des CGU se sont produites en dehors des heures normales, alors que les résidents étaient de garde, plutôt que pendant les heures de CSA (78,8 % c. 21,1 %, p < 0,01). Les médecins résidents finissants étaient plus susceptibles d'indiquer avoir tenu le rôle de chirurgien principal que les résidents en début de parcours (71,3 % c. 32,0 %, p < 0,01). Le moment des chirurgies ne faisait aucune différence pour ce qui est du rôle des résidents finissants, mais les résidents en début de parcours ont davantage assumé le rôle de chirurgien principal pendant les heures de CSA que pendant les périodes de garde (50,0 % c. 33,1 %, p < 0,01). Conclusion: Malgré l'adoption du modèle de CSA, les résidents de notre programme ont acquis la majorité de leur expérience en CGU en dehors des heures normales, alors qu'ils étaient de garde. Bien que d'autres études soient nécessaires, notre étude laisse croire qu'un meilleur accès aux salles d'opération pendant le jour pourrait augmenter la quantité et la qualité de l'expérience en CGU dans le réseau universitaire.

A complex containing the O-GlcNAc transferase OGT-1 and the ubiquitin ligase EEL-1 regulates GABA neuron function.

Inhibitory GABAergic transmission is required for proper circuit function in the nervous system. However, our understanding of molecular mechanisms that preferentially influence GABAergic transmission, particularly presynaptic mechanisms, remains limited. We previously reported that the ubiquitin ligase EEL-1 preferentially regulates GABAergic presynaptic transmission. To further explore how EEL-1 functions, here we performed affinity purification proteomics using Caenorhabditis elegans and identified the O-GlcNAc transferase OGT-1 as an EEL-1 binding protein. This observation was intriguing, as we know little about how OGT-1 affects neuron function. Using C. elegans biochemistry, we confirmed that the OGT-1/EEL-1 complex forms in neurons in vivo and showed that the human orthologs, OGT and HUWE1, also bind in cell culture. We observed that, like EEL-1, OGT-1 is expressed in GABAergic motor neurons, localizes to GABAergic presynaptic terminals, and functions cell-autonomously to regulate GABA neuron function. Results with catalytically inactive point mutants indicated that OGT-1 glycosyltransferase activity is dispensable for GABA neuron function. Consistent with OGT-1 and EEL-1 forming a complex, genetic results using automated, behavioral pharmacology assays showed that ogt-1 and eel-1 act in parallel to regulate GABA neuron function. These findings demonstrate that OGT-1 and EEL-1 form a conserved signaling complex and function together to affect GABA neuron function.

A MIG-15/JNK-1 MAP kinase cascade opposes RPM-1 signaling in synapse formation and learning.

The Pam/Highwire/RPM-1 (PHR) proteins are conserved intracellular signaling hubs that regulate synapse formation and axon termination. The C. elegans PHR protein, called RPM-1, acts as a ubiquitin ligase to inhibit the DLK-1 and MLK-1 MAP kinase pathways. We have identified several kinases that are likely to form a new MAP kinase pathway that suppresses synapse formation defects, but not axon termination defects, in the mechanosensory neurons of rpm-1 mutants. This pathway includes: MIG-15 (MAP4K), NSY-1 (MAP3K), JKK-1 (MAP2K) and JNK-1 (MAPK). Transgenic overexpression of kinases in the MIG-15/JNK-1 pathway is sufficient to impair synapse formation in wild-type animals. The MIG-15/JNK-1 pathway functions cell autonomously in the mechanosensory neurons, and these kinases localize to presynaptic terminals providing further evidence of a role in synapse development. Loss of MIG-15/JNK-1 signaling also suppresses defects in habituation to repeated mechanical stimuli in rpm-1 mutants, a behavioral deficit that is likely to arise from impaired glutamatergic synapse formation. Interestingly, habituation results are consistent with the MIG-15/JNK-1 pathway functioning as a parallel opposing pathway to RPM-1. These findings indicate the MIG-15/JNK-1 pathway can restrict both glutamatergic synapse formation and short-term learning.

Diagnosis and management of acute cholecystitis: a single-centre audit of guideline adherence and patient outcomes.

Background: The Tokyo Guidelines were published in 2007 and updated in 2013 and 2018, with recommendations for the diagnosis and management of acute cholecystitis. We assessed guideline adherence at our academic centre and its impact on patient outcomes. Methods: This is a retrospective chart review of patients with acute calculous cholecystitis who underwent cholecystectomy at our institution between November 2013 and March 2015. Severity of cholecystitis was graded retrospectively if it had not been documented preoperatively. Compliance with the Tokyo Guidelines' recommendations on antibiotic use and time to operation was recorded. Cholecystitis severity groups were compared statistically, and logistic regression was used to determine predictors of complications. Results: One hundred and fifty patients were included in the study. Of these, 104 patients were graded as having mild cholecystitis, 45 as having moderate cholecystitis, and 1 as having severe cholecystitis. Severity was not documented preoperatively for any patient. Compliance with antibiotic recommendations was poor (18.0%) and did not differ by cholecystitis severity (p = 0.90). Compliance with the recommendation on time to operation was 86.0%, with no between-group differences (p = 0.63); it improved when an acute care surgery team was involved (91.0% v. 76.0%, p = 0.025). On multivariable analysis, comorbidities (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.19-1.85, p < 0.001) and conversion to laparotomy (OR 13.45, 95% CI 2.16-125.49, p = 0.01) predicted postoperative complications, while severity of cholecystitis, antibiotic compliance and time to operation had no effect. Conclusion: In this study, compliance with the Tokyo Guidelines was acceptable only for time to operation. Although the poor compliance with recommendations relating to documentation of severity grading and antibiotic use did not have a negative affect on patient outcomes, these recommendations are important because they facilitate appropriate antibiotic use and patient risk stratification.

Contexte: Les Tokyo Guidelines, publiées en 2007, puis mises à jour en 2013 et en 2018, contiennent des recommandations sur le diagnostic et la prise en charge de la cholécystite aiguë. Nous avons évalué le respect de ces lignes directrices dans notre centre universitaire et son incidence sur les issues pour les patients. Méthodes: Ce document est une revue rétrospective de dossiers des patients atteints de cholécystite aiguë calculeuse qui ont subi une cholécystectomie dans notre établissement entre novembre 2013 et mars 2015. La gravité de la cholécystite a été établie de manière rétrospective si elle n'avait pas été documentée avant l'opération. Le respect des recommandations des Tokyo Guidelines concernant le recours à des antibiotiques et la durée de l'opération a été étudié. Nous avons comparé statistiquement les groupes de gravité de la cholécystite, et avons utilisé une régression logistique pour déterminer les prédicteurs de complications. Résultats: Au total, 150 patients ont été inclus dans l'étude. Parmi eux, 104 avaient une cholécystite légère, 45, une cholécystite modérée et 1, une cholécystite grave. La gravité de la maladie n'avait été documentée avant l'opération pour aucun patient. Le respect des recommandations sur les antibiotiques était faible (18,0 %) et ne variait pas selon la gravité de la cholécystite (p = 0,90). Le respect des recommandations sur la durée de l'opération était de 86,0 %, sans différence entre les groupes (p = 0,63); il était toutefois plus élevé lorsqu'une équipe de soins chirurgicaux aigus participait aux soins (91,0 % c. 76,0 %, p = 0,025). L'analyse multivariée a permis de déterminer que les comorbidités (rapport des cotes [RC] 1,47, intervalle de confiance [IC] de 95 % 1,19­1,85, p < 0,001) et la conversion en laparotomie (RC 13,45, IC de 95 % 2,16­125,49, p = 0,01) étaient des prédicteurs de complications postopératoires, alors que la gravité de la cholécystite et le respect des recommandations sur les antibiotiques et la durée de l'opération n'avaient pas d'effet. Conclusion: Dans cette étude, le respect des Tokyo Guidelines était acceptable seulement pour la durée de l'opération. Bien qu'un faible respect des recommandations quant à la documentation de la gravité et à l'utilisation d'antibiotiques n'ait pas eu d'effets négatifs sur les issues pour les patients, ces recommandations sont importantes parce qu'elles favorisent l'utilisation appropriée des antibiotiques et une bonne stratification du risque pour le patient.

Operative timing is associated with increased morbidity and mortality in patients undergoing emergency general surgery: a multisite study of emergency general services in a single academic network.

Background: Despite the widespread implementation of the acute care surgery (ACS) model, limited access to operating room time represents a barrier to the optimal delivery of emergency general surgery (EGS) care. The objective of this study was to describe the effect of operative timing on outcomes in EGS in a network of teaching hospitals. Methods: We conducted a retrospective review of EGS operations performed at 3 teaching hospitals in a single academic network. Time of operation was categorized as daytime (8 am to 5 pm), after hours (5 pm to 11 pm) or overnight (11 pm to 8 am). Time to operation was calculated as the interval from admission to operative start time and categorized as less than 24 hours, 24-72 hours and greater than 72 hours. Results: After we excluded nonindex cases, trauma cases and cases occurring more than 5 days after admission, 1505 EGS cases were included. We found that 39.0% of operations were performed in the daytime, 46.3% after hours and 14.8% overnight. In terms of time to operation, 52.3% of operations were performed within 24 hours of admission, 33.4% in 24-72 hours and 14.3% in more than 72 hours. The overall complication rate was 20.6% (310 patients) and the overall mortality rate was 3.8% (57 patients). After multivariable analysis, time to operation more than 72 hours after admission was independently associated with increased odds of morbidity (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.09-2.47), while overnight operating was associated with increased odds of death (OR 3.15, 95% CI 1.29-7.70). Conclusion: Increasing time from admission to operation and overnight operating were associated with greater morbidity and mortality, respectively, for EGS patients. Strategies to provide timely access to the operating room should be considered to optimize care in an ACS model.

Contexte: Même si le modèle de chirurgie en soins actifs (CSA) est largement répandu, l'accès limité aux blocs opératoires représente un obstacle à la chirurgie générale chez les patients des services d'urgence (CGSU). L'objectif de cette étude était de décrire l'effet du moment de l'intervention sur l'issue des CGSU dans un réseau d'hôpitaux universitaires. Méthodes: Nous avons procédé à une revue des CGSU effectuées dans 3 hôpitaux d'enseignement d'un réseau universitaire. Le moment opératoire était catégorisé selon que les interventions étaient effectuées le jour (8 h 00 à 17 h 00), le soir (17 h 00 à 23 h 00) ou la nuit (23 h 00 à 8 h 00). Le délai opératoire représentait l'intervalle entre l'admission et le début de l'intervention et était réparti selon les catégories suivantes : moins de 24 heures, de 24 à 72 heures et plus de 72 heures. Résultats: Après exclusion des cas non index, des cas de traumatologie et des cas survenus plus de 5 jours après l'admission, 1505 CGSU ont été incluses. Nous avons constaté que 39,0 % des interventions avaient été effectuées le jour, 46,3 % le soir et 14,8 % la nuit. Pour ce qui est du délai opératoire, 52,3 % des interventions ont été effectuées dans les 24 heures suivant l'admission, 33,4 % dans les 24 à 72 heures et 14,3 % plus de 72 heures après l'admission. Le taux global de complications a été de 20,6 % (310 patients) et le taux de mortalité global a été de 3,8 % (57 patients). Après analyse multivariée, le délai opératoire de plus de 72 heures suivant l'admission a été associé de manière indépendante à un risque accru de morbidité (rapport ces cotes [RC] 1,64, intervalle de confiance [IC]) de 95 % 1,09 à 2,47), tandis que les interventions effectuées la nuit ont été associées à un risque de décès plus élevé (RC 3,15, IC de 95 % 1,29 à 7,70). Conclusion: L'augmentation du délai entre l'admission et l'intervention et les interventions de nuit ont été associées à une morbidité et une mortalité plus élevées, respectivement, chez les patients soumis à des CGSU. Des stratégies visant à offrir un accès rapide aux blocs opératoires sont à envisager pour optimiser le modèle de CSA.

General Thoracic Surgery in Rwanda: An Assessment of Surgical Volume and of Workforce and Material Resource Deficits.

BACKGROUND: Benchmarking operative volume and resources is necessary to understand current efforts addressing thoracic surgical need. Our objective was to examine the impact on thoracic surgery volume and patient access in Rwanda following a comprehensive capacity building program, the Human Resources for Health (HRH) Program, and thoracic simulation training. METHODS: A retrospective cohort study was conducted of operating room registries between 2011 and 2016 at three Rwandan referral centers: University Teaching Hospital of Kigali, University Teaching Hospital of Butare, and King Faisal Hospital. A facility-based needs assessment of essential surgical and thoracic resources was performed concurrently using modified World Health Organization forms. Baseline patient characteristics at each site were compared using a Pearson Chi-squared test or Kruskal-Wallis test. Comparisons of operative volume were performed using paired parametric statistical methods. RESULTS: Of 14,130 observed general surgery procedures, 248 (1.76%) major thoracic cases were identified. The most common indications were infection (45.9%), anatomic abnormalities (34.4%), masses (13.7%), and trauma (6%). The proportion of thoracic cases did not increase during the HRH program (2.07 vs 1.78%, respectively, p = 0.22) or following thoracic simulation training (1.95 2013 vs 1.44% 2015; p = 0.15). Both university hospitals suffer from inadequate thoracic surgery supplies and essential anesthetic equipment. The private hospital performed the highest percentage of major thoracic procedures consistent with greater workforce and thoracic-specific material resources (0.89% CHUK, 0.67% CHUB, and 5.42% KFH; p < 0.01). CONCLUSIONS AND RELEVANCE: Lack of specialist providers and material resources limits thoracic surgical volume in Rwanda despite current interventions. A targeted approach addressing barriers described is necessary for sustainable progress in thoracic surgical care.

Predictors of Obstetric Fistula Repair Outcomes in Lubango, Angola.

OBJECTIVE: Obstetric fistulas have a significant physical and social impact on many women in Angola. The majority of the population of this sub-Saharan African nation does not have access to high-quality obstetric care, and this is associated with a risk of prolonged labour and formation of obstetric fistulas. Fistulas are challenging to correct surgically and may require repeated operations. The objective of the study was to determine predictors of successful obstetric fistula repair. METHODS: In this retrospective study, data from all recorded cases of fistula repair performed between July 2011 and December 2016 at the Centro Evangélico de Medicina do Lubango (CEML) hospital located in Lubango, Angola, were reviewed. Analysis of the data was carried out to determine factors affecting the success of fistula repair; parametric and non-parametric tests were used for group comparisons and logistic regression for outcome prediction (Canadian Task Force classification II-2). RESULTS: A total of 407 operations were performed on 243 women. Of these, 224 women were diagnosed with a vesicovaginal fistula and 19 with a combined vesicovaginal and rectovaginal fistula. The success rate for the attempted repairs was 42%. On multivariate analysis, the success of first surgery was negatively affected by the difficulty of repair (odds ratio 0.28; P < 0.01). For patients requiring repeat surgery, the odds of success were increased with each subsequent operation (odds ratio 5.32; P < 0.01). CONCLUSION: Although fistulas rated as difficult to repair had a higher likelihood of initial failure, successive attempts at repair increased the likelihood of a successful outcome.

Dopamine receptor DOP-4 modulates habituation to repetitive photoactivation of a C. elegans polymodal nociceptor.

Habituation is a highly conserved phenomenon that remains poorly understood at the molecular level. Invertebrate model systems, like Caenorhabditis elegans, can be a powerful tool for investigating this fundamental process. Here we established a high-throughput learning assay that used real-time computer vision software for behavioral tracking and optogenetics for stimulation of the C. elegans polymodal nociceptor, ASH. Photoactivation of ASH with ChR2 elicited backward locomotion and repetitive stimulation altered aspects of the response in a manner consistent with habituation. Recording photocurrents in ASH, we observed no evidence for light adaptation of ChR2. Furthermore, we ruled out fatigue by demonstrating that sensory input from the touch cells could dishabituate the ASH avoidance circuit. Food and dopamine signaling slowed habituation downstream from ASH excitation via D1-like dopamine receptor, DOP-4. This assay allows for large-scale genetic and drug screens investigating mechanisms of nociception modulation.

High-throughput behavioral analysis in C. elegans.

We designed a real-time computer vision system, the Multi-Worm Tracker (MWT), which can simultaneously quantify the behavior of dozens of Caenorhabditis elegans on a Petri plate at video rates. We examined three traditional behavioral paradigms using this system: spontaneous movement on food, where the behavior changes over tens of minutes; chemotaxis, where turning events must be detected accurately to determine strategy; and habituation of response to tap, where the response is stochastic and changes over time. In each case, manual analysis or automated single-worm tracking would be tedious and time-consuming, but the MWT system allowed rapid quantification of behavior with minimal human effort. Thus, this system will enable large-scale forward and reverse genetic screens for complex behaviors.

The aspherical human hip: implication for early osteoarthritis.

One marker for early-onset hip arthritis is femoral acetabular impingement. The current standard way of quantifying impingement is manual calculation of anatomical measures on plain radiographs, including the α-angle. Such measurements are user-dependent and prone to error. We provided a robust computational alternative and proposed using numerical fitting of geometrical shapes. We applied least-squares fitting of an ellipse to the femoral head contour and used the difference between the ellipse axes as a quantification method. The results showed a good correlation between the new measure and previous definitions of the α-angle.

Optimized protocol for in vivo affinity purification proteomics and biochemistry using C. elegans.

We present an optimized protocol for in vivo affinity purification proteomics and biochemistry using the model organism C. elegans. We describe steps for target tagging, large-scale culture, affinity purification using a cryomill, mass spectrometry and validation of candidate binding proteins. Our approach has proven successful for identifying protein-protein interactions and signaling networks with verified functional relevance. Our protocol is also suitable for biochemical evaluation of protein-protein interactions in vivo. For complete details on the use and execution of this protocol, please refer to Crawley et al.,1 Giles et al.,2 and Desbois et al.3.

Influence of a patient navigation program on timeliness of care in patients with esophageal cancer.

BACKGROUND: Patient navigation (P.N.) is designed to eliminate barriers to care. The objective of this study was to evaluate the impact of a novel P.N. program on timeliness of care in patients with esophageal cancer. METHODS: This retrospective study compared the timeliness of care for esophageal cancer patients before (January 2014-March 2018) and after the implementation of a novel P.N. program (April 2018-March 2020), called EDAP, at a tertiary care center. The primary outcome was time from biopsy to first treatment; secondary outcomes included time from biopsy to complete staging, biopsy to complete preoperative workup, and referral to the first point of contact. The outcomes were evaluated in the entire cohort and then in a subgroup of patients undergoing curative multimodality therapy. RESULTS: There were 96 patients in the pre-EDAP group and 98 patients in the post-EDAP group. There was no significant difference between pre- and post-EDAP in the time from biopsy to first treatment and time from biopsy to staging in the overall cohort. In the subgroup of patients undergoing curative multimodality therapy, there was a significant decrease in time from biopsy to first treatment postnavigation (60-51 days, p = 0.02), in addition to a significant decrease in time from biopsy to preoperative workup and time from biopsy to staging. CONCLUSIONS: This is the first study demonstrating that a novel P.N. program for patients with esophageal cancer improved timeliness of care. The group of patients who benefited most were those undergoing curative multimodality therapy, likely given the extensive coordination of services required by this group.

Ptchd1 mediates opioid tolerance via cholesterol-dependent effects on µ-opioid receptor trafficking.

Repeated exposure to opioids causes tolerance, which limits their analgesic utility and contributes to overdose and abuse liability. However, the molecular mechanisms underpinning tolerance are not well understood. Here, we used a forward genetic screen in Caenorhabditis elegans for unbiased identification of genes regulating opioid tolerance which revealed a role for PTR-25/Ptchd1. We found that PTR-25/Ptchd1 controls µ-opioid receptor trafficking and that these effects were mediated by the ability of PTR-25/Ptchd1 to control membrane cholesterol content. Electrophysiological studies showed that loss of Ptchd1 in mice reduced opioid-induced desensitization of neurons in several brain regions and the peripheral nervous system. Mice and C. elegans lacking Ptchd1/PTR-25 display similarly augmented responses to opioids. Ptchd1 knockout mice fail to develop analgesic tolerance and have greatly diminished somatic withdrawal. Thus, we propose that Ptchd1 plays an evolutionarily conserved role in protecting the µ-opioid receptor against overstimulation.

Assessment and treatment of depression in people with multiple sclerosis: A qualitative analysis of specialist clinicians' experiences.

BACKGROUND: Depression is common in people with multiple sclerosis (MS), with lifetime prevalence estimates between 25 and 50%. Depression is commonly underdiagnosed and undertreated in people with MS. This qualitative study assessed current practices, as well as facilitators and required resources to improve detection and management of depression in people with MS. METHODS: MS clinicians living in Australia were recruited through MS healthcare provider clinics and networks for online interviews. Interviews were transcribed and coded in NVivo for framework analysis. RESULTS: Participants included 15 MS specialists: nine nurses and six neurologists. Participants appreciated that depression was a common symptom of MS, and that untreated depression impacted patients' wellbeing, medication adherence, capacity for self-care, employment, and interpersonal relationships. Participants did not routinely screen for depression and noted that they lack the time and skills to manage depression once identified, most often recommending patients see their general practitioner. Clinicians recognised that people with MS commonly experience barriers to identifying and managing depressive symptoms, however few clinics provide information or discussion about depression as a symptom of MS with patients. CONCLUSION: Participants indicated a need for evidence-based guidance, more education and training to improve practices including screening for depression, and an urgent need for local referral pathways to affordable and accessible mental health services for people with MS. Findings suggest a need for better collaborative management of depression and improvement of systematic practices related to depression information, screening and treatment support.