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Background Gene regulatory network (GRN) models that are formulated as ordinary differential equations (ODEs) can accurately explain temporal gene expression patterns and promise to yield new insights into important cellular processes, disease progression, and intervention design. Learning such gene regulatory ODEs is challenging, since we want to predict the evolution of gene expression in a way that accurately encodes the underlying GRN governing the dynamics and the nonlinear functional relationships between genes. Most widely used ODE estimation methods either impose too many parametric restrictions or are not guided by meaningful biological insights, both of which impede either scalability, explainability, or both. Results We developed PHOENIX, a modeling framework based on neural ordinary differential equations (NeuralODEs) and Hill-Langmuir kinetics, that overcomes limitations of other methods by flexibly incorporating prior domain knowledge and biological constraints to promote sparse, biologically interpretable representations of GRN ODEs. We tested the accuracy of PHOENIX in a series of in silico experiments, benchmarking it against several currently used tools. We demonstrated PHOENIX’s flexibility by modeling regulation of oscillating expression profiles obtained from synchronized yeast cells. We also assessed the scalability of PHOENIX by modeling genome-scale GRNs for breast cancer samples ordered in pseudotime and for B cells treated with Rituximab. Conclusions PHOENIX uses a combination of user-defined prior knowledge and functional forms from systems biology to encode biological “first principles” as soft constraints on the GRN allowing us to predict subsequent gene expression patterns in a biologically explainable manner.

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R.sup.2 : 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R.sup.2 :8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.

Concurrent malignant biliary and gastric outlet obstruction requires urgent palliative intervention to improve patient quality of life and permit systemic therapy. Traditional management has been surgical gastrojejunostomy and hepaticojejunostomy, two morbid procedures. Comparatively, endoscopic stenting can relieve both sites of obstruction with less complications and quicker recovery. In patients with previous plastic biliary stents in situ, it is crucial for subsequent bilioduodenal obstructions to be managed with proper sequencing and precise stent placement to achieve successful bilioduodenal patency. We report a case of a 53-year-old male patient who presented with simultaneous jaundice secondary to blocked biliary stent and vomiting due to gastric outlet obstruction at the first part of the duodenum on background of unresectable pancreatic adenocarcinoma. Fourteen months prior, he had a plastic endobiliary stent placed for biliary obstruction secondary to choledocholithiasis, but intraprocedural cholangiogram also revealed a distal common bile stricture with subsequent investigations revealing unresectable pancreatic adenocarcinoma for which he underwent palliative chemotherapy. Duodenal stricture dilation with subsequent duodenal self-expanding metal stent was placed under direct endoscopic vision precisely proximal to the blocked biliary stent. After 48 hours, endoscopic retrograde cholangiopancreatography was then performed through the duodenal stent to exchange the blocked plastic biliary stent for a metal biliary stent. The patient had prompt relief of jaundice and tolerated oral intake by date of discharge post-procedure day two and was initiated on chemotherapy on post-procedure day 12. Endoscopic stenting of concomitant biliary and gastric outlet obstruction can be successful in patients with occluded indwelling plastic biliary stents.

Background Colonoscopy exposes endoscopists to awkward postures and prolonged forces, which increases their risk of musculoskeletal injury. Patient positioning has a significant impact on the ergonomics of colonoscopy. Recent trials have found the right lateral decubitus position is associated with quicker insertion, higher adenoma detection rates, and greater patient comfort compared to the left lateral decubitus position. However, this patient position is perceived as more strenuous by endoscopists. Methods Nineteen endoscopists were observed performing colonoscopies during a series of four-hour endoscopy clinics. Durations of each patient position (right lateral decubitus, left lateral decubitus, prone, and supine) were recorded for all observed procedures ( n  = 64). Endoscopist injury risk was estimated by a trained researcher for the first and last colonoscopies of the shifts ( n  = 34) using Rapid Upper Limb Assessment (RULA), an observational ergonomic tool that estimates risk of musculoskeletal injury by scoring postures of the upper body and factors such as muscle use, force, and load. The total RULA scores were compared with a Wilcoxon Signed-Rank test for patient position (right and left lateral decubitus) and time (first and last procedures) with significance taken at p  < 0.05. Endoscopist preferences were also surveyed. Results The right lateral decubitus position was associated with significantly higher RULA scores than the left lateral decubitus position (median 5 vs. 3, p  < 0.001). RULA scores were not significantly different between the first and last procedures of the shifts (median 5 vs. 5, p  = 0.816). 89% of endoscopists preferred the left lateral decubitus position, primarily due to superior ergonomics and comfort. Conclusion RULA scores indicate an increased risk of musculoskeletal injury in both patient positions, with greater risk in the right lateral decubitus position.

Lysophosphatidic acid (LPA) receptor signaling has been implicated in cardiovascular and obesity-related metabolic disease. However, the distribution and regulation of LPA receptors in the myocardium and adipose tissue remain unclear. This study aimed to characterize the mRNA expression of LPA receptors (LPA1-6) in the murine and human myocardium and adipose tissue, and its regulation in response to obesity. LPA receptor mRNA levels were determined by qPCR in i) heart ventricles, isolated cardiomyocytes, and perigonadal adipose tissue from chow or high fat-high sucrose (HFHS)-fed male C57BL/6 mice, ii) 3T3-L1 adipocytes and HL-1 cardiomyocytes under conditions mimicking gluco/lipotoxicity, and iii) human atrial and subcutaneous adipose tissue from non-obese, pre-obese, and obese cardiac surgery patients. LPA1-6 were expressed in myocardium and white adipose tissue from mice and humans, except for LPA3, which was undetectable in murine adipocytes and human adipose tissue. Obesity was associated with increased LPA4, LPA5 and/or LPA6 levels in mice ventricles and cardiomyocytes, HL-1 cells exposed to high palmitate, and human atrial tissue. LPA4 and LPA5 mRNA levels in human atrial tissue correlated with measures of obesity. LPA5 mRNA levels were increased in HFHS-fed mice and insulin resistant adipocytes, yet were reduced in adipose tissue from obese patients. LPA4, LPA5, and LPA6 mRNA levels in human adipose tissue were negatively associated with measures of obesity and cardiac surgery outcomes. This study suggests that obesity leads to marked changes in LPA receptor expression in the murine and human heart and white adipose tissue that may alter LPA receptor signaling during obesity.

Models that are formulated as ordinary differential equations (ODEs) can accurately explain temporal gene expression patterns and promise to yield new insights into important cellular processes, disease progression, and intervention design. Learning such ODEs is challenging, since we want to predict the evolution of gene expression in a way that accurately encodes the causal gene-regulatory network (GRN) governing the dynamics and the nonlinear functional relationships between genes. Most widely used ODE estimation methods either impose too many parametric restrictions or are not guided by meaningful biological insights, both of which impedes scalability and/or explainability. To overcome these limitations, we developed PHOENIX, a modeling framework based on neural ordinary differential equations (NeuralODEs) and Hill-Langmuir kinetics, that can flexibly incorporate prior domain knowledge and biological constraints to promote sparse, biologically interpretable representations of ODEs. We test accuracy of PHOENIX in a series of in silico experiments benchmarking it against several currently used tools for ODE estimation. We also demonstrate PHOENIX’s flexibility by studying oscillating expression data from synchronized yeast cells and assess its scalability by modelling genome-scale breast cancer expression for samples ordered in pseudotime. Finally, we show how the combination of user-defined prior knowledge and functional forms from systems biology allows PHOENIX to encode key properties of the underlying GRN, and subsequently predict expression patterns in a biologically explainable way. Having developed and validated PHOENIX, we next attempt to obtain very sparse representations of the PHOENIX model in order to aid interpretability. To this end, we explore the field of neural network sparsification and the Lottery Ticket Hypothesis (LTH). We argue how the goal of sparsity needs to be conceptualized conjunctively with the goal of biological meaning, and how traditional approaches of sparsification, such as iterative magnitude pruning, fail to bridge these two objectives. We conjecture that biologically meaningful representations can be obtained by leveraging domain knowledge in the sparsification process. This motivates the formulation of DASH, a domain-aware neural network pruning strategy. We use DASH to engineer an algorithm for pruning PHOENIX and demonstrate how this leads to biologically anchored sparsification in silico. We benchmark DASH against other sparsification strategies on both simulated and real world data. Finally, we apply PHOENIX and DASH to three different case studies in order to demonstrate how our tools can be used to understand gene regulation in the context of lung adenocarcinoma, hematopoietic stem cell differentiation, and Rituximab-treated in B cells.

Background There are limited prospective data, and conflicting retrospective data, providing guidance on how to optimally manage patients with morbid obesity and severe knee osteoarthritis. This study sought to review the effect of bariatric surgery on knee pain and knee surgery 30-day outcomes, as well as assess whether the sequence of bariatric and knee surgery has any effect on 30-day complications. Methods A retrospective chart review of all patients undergoing laparoscopic sleeve gastrectomy (LSG) from July 2006 to July 2016 at a university hospital was performed. Patients with knee pain or knee surgery (pre- or post-LSG) were identified using bariatric and orthopedic clinic notes. Those who had improvement in knee pain following LSG resulting in removal from orthopedic surgery waitlist were identified. We also assessed surgical outcomes in patients undergoing knee arthroscopy or total knee arthroplasty (TKA) followed by LSG compared to patients undergoing LSG followed by knee arthroscopy or TKA. Results During our study timeframe, 355 patients underwent LSG. Knee pain was documented in 150 (42.2%) patients, and orthopedic surgery consultation was completed for 57 (38.0%) patients with knee pain. Orthopedic intervention was performed prior to LSG for 24 patients and after LSG for 27 patients. Procedures were a combination of arthroscopy (18) and TKA (33). Six patients were removed from the waitlist for TKA following LSG due to resolution of symptoms. Order of interventions did not affect 30-day complications for patients undergoing LSG and arthroscopy (16% arthroscopy first, 0% LSG first, p  = 0.43). A higher rate of LSG complications was noted in patients who underwent TKA prior to LSG (25% vs 0%, p  = 0.04). There were no differences in TKA complications (8.3% TKA first, 4.8% LSG first, p  = 1.00). Conclusion In a small number of patients with morbid obesity and severe knee osteoarthritis, orthopedic intervention can be delayed and potentially avoided by undergoing LSG. In our study, 6/57 (10.5%) of patients with orthopedic consultation prior to LSG saw resolution of symptoms of knee pain. Referral to bariatric surgery should be considered for patients with morbid obesity and severe knee osteoarthritis.

Indigenous Peoples in Canada have higher obesity rates (30%–51%) than non-Indigenous populations (12%–31%), and the Truth and Reconciliation Commission of Canada (TRC) has called for expanded health research to address disparities between Indigenous and non-Indigenous communities. We sought to compare bariatric surgery outcomes and patient experiences in Newfoundland and Labrador’s bariatric surgery program among Indigenous versus non-Indigenous patients. We conducted a mixed-methods retrospective cohort study, including patients who underwent bariatric surgery in the province’s bariatric surgery program between 2011 and 2022. We assessed metabolic outcomes through chart review and captured patient experiences with phone survey questionnaires. Among the 30 included patients (8 Indigenous, 22 non-Indigenous), there were no significant differences in excess weight loss (45% v. 48%, p = 0.4), reduction in body mass index (9.5 v. 11.3, p = 0.2), comorbidity improvement (63% v. 73%, p = 0.6), or postoperative complications (25% v. 18%, p = 0.6) at 1 year. However, on a 1–10 Likert scale, Indigenous patients reported lower satisfaction with weight loss (6.3 v. 8.2, p = 0.03) and were less likely to recommend the program (5.6 v. 8.8, p = 0.04). Both groups cited similar challenges with program referral, transportation, and postoperative supports, and recommended a longer follow-up period and increased mental health counselling services. As a response to TRC’s Calls to Action, our study shows bariatric surgery outcomes in Newfoundland and Labrador were similar for Indigenous and non-Indigenous patients. Given their lower satisfaction with postoperative decrease in weight, Indigenous patients may benefit from being offered metabolic procedures with greater expected weight loss, such as Roux-en-Y gastric bypass and duodenal switch. Au Canada, les peuples autochtones ont un taux d’obésité plus élevé (30 %–51 %) que les populations non autochtones (12 %–31 %), et la Commission de vérité et réconciliation (CVR) du Canada a réclamé que soit menée une recherche élargie sur les disparités en matière de santé entre les communautés autochtones et non autochtones. Nous avons voulu comparer les résultats de la chirurgie bariatrique et l’expérience des patientes et patients suivis par le Programme de chirurgie bariatrique de Terre-Neuve-et-Labrador (TNL) selon leur appartenance ou non à un peuple autochtone. Nous avons procédé à une étude de cohorte rétrospective à méthodes mixtes regroupant des personnes soumises à une chirurgie bariatrique dans le cadre du programme de chirurgie bariatrique de TNL entre 2011 et 2022. Nous avons évalué les résultats métaboliques en analysant les dossiers et recueilli l’expérience des patientes et patients lors d’entrevues téléphoniques. Parmi les 30 personnes incluses (8 Autochtones, 22 non-Autochtones), on n’a noté aucune différence significative aux plans de la perte de poids (45 % c. 48 %, p = 0,4), de la réduction de l’indice de masse corporelle (9,5 c. 11,3, p = 0,2), de l’amélioration des comorbidités (63 % c. 73 %, p = 0.6), ou des complications postopératoires (25 % c. 18 %, p = 0,6) au bout de 1 an. Par contre sur une échelle de Likert allant de 1 à 10, les personnes autochtones se sont déclarées moins satisfaites de leur perte de poids, (6,3 c. 8,2, p = 0,03) et étaient moins susceptibles de recommander le programme (5,6 c. 8,8, p = 0,04). Les 2 groupes ont mentionné des difficultés similaires relativement au programme (demande de consultation, transport et soutien postopératoire) et ont suggéré de prolonger la période de suivi et d’ajouter des services en santé mentale. En réponse à la demande adressée par la CVR, notre étude montre que les résultats de la chirurgie bariatrique à TNL sont similaires selon que les patientes et patients sont ou non d’origine autochtone. Compte tenu du degré moindre de satisfaction des personnes autochtones à l’égard de la perte de poids après l’intervention, elles gagneraient peut-être à se voir offrir des modalités métaboliques permettant une plus grande perte de poids, comme la dérivation gastrique Roux-en-Y et la dérivation biliopancréatique avec commutation duodénale.

BackgroundProphylactic ursodeoxycholic acid (UDCA) may be beneficial in reducing gallstone disease after bariatric surgery. The American Society for Metabolic and Bariatric Surgery (ASMBS) 2019 guidelines recommend a 6-month course of UDCA for patients undergoing laparoscopic sleeve gastrectomy (LSG). This has not been adopted broadly. This study intends to assess the effect of routine UDCA administration following LSG on symptomatic gallstone disease.MethodsWe performed a retrospective chart review of patients who underwent LSG, between 2009 and 2019, at two tertiary care centers in Atlantic Canada. At one center, UDCA 250 mg oral twice daily was routinely prescribed following LSG for 6 months to patients with an intact gallbladder. At the other center, UDCA was not prescribed. Primary and secondary outcomes were cholecystectomy and endoscopic retrograde cholangiopancreatography (ERCP) rates. Compliance with and side effects of UDCA therapy were analyzed.ResultsA total of 751 patients were included in the study. Patients who had prior cholecystectomy or were lost to follow up were excluded. After exclusion criteria were applied, 461 patients were included for analysis: 303 in the UDCA group and 158 in the group who did not receive UDCA. Cholecystectomy rate was not significantly associated with UDCA administration, however there was a trend towards less cholecystectomy in patients who received UDCA (8.3% vs. 13.9%, p = 0.056). ERCP rate was significantly lower in patients who received UDCA (0.3% vs 2.5%, p = 0.031). Rate of gallstone disease requiring intervention, either cholecystectomy or ERCP, was significantly decreased in patients who received UDCA (8.9% vs 15.8%, p = 0.022). The most common barriers to compliance with UDCA were cost (45.4%) and nausea (18.1%).ConclusionThis is the first study to demonstrate lower rates of ERCP in patients receiving routine UDCA following LSG. Our findings support the ASMBS 2019 guidelines for administering UDCA after LSG for preventing gallstone disease.