Graph Regularized Probabilistic Matrix Factorization for Drug-Drug Interactions Prediction.

Co-administration of two or more drugs simultaneously can result in adverse drug reactions. Identifying drug-drug interactions (DDIs) is necessary, especially for drug development and for repurposing old drugs. DDI prediction can be viewed as a matrix completion task, for which matrix factorization (MF) appears as a suitable solution. This paper presents a novel Graph Regularized Probabilistic Matrix Factorization (GRPMF) method, which incorporates expert knowledge through a novel graph-based regularization strategy within an MF framework. An efficient and sounded optimization algorithm is proposed to solve the resulting non-convex problem in an alternating fashion. The performance of the proposed method is evaluated through the DrugBank dataset, and comparisons are provided against state-of-the-art techniques. The results demonstrate the superior performance of GRPMF when compared to its counterparts.

Anxiolysis for laceration repair in children: a survey of pediatric emergency providers in Canada.

OBJECTIVES: Intranasal dexmedetomidine is a potentially effective anxiolytic but its role in pediatric laceration repair is only emerging. Future trials and clinical adoption of intranasal dexmedetomidine depend on understanding pediatric emergency providers' practice patterns surrounding anxiolysis and perceived barriers to intranasal dexmedetomidine for anxiolysis during suture repair in children. Our objectives were to characterize these parameters to inform future research and facilitate clinical adoption. METHODS: We conducted an online survey of pediatric emergency physician members of Pediatric Emergency Research Canada from September to December 2020. Questions pertained to perceptions of anxiolysis for suture repair, with a focus on intranasal dexmedetomidine. The primary outcome was anxiolysis for suture repair. Data were reported using descriptive statistics. RESULTS: The response rate was 155/225 (68.9%). During suture repair, 127/148 (86%) believed that > 25% of young children experience distress requiring physical restraint. 116/148 (78%) would provide anxiolysis, mainly intranasal benzodiazepines (100/148, 68%). Only 6/148 (4%) would provide intranasal dexmedetomidine but 95/148 (64%) would consider it if there was evidence of benefit. The most common perceived barriers to intranasal dexmedetomidine included inadequate personal experience (114/145, 79%) and lack of access (60/145, 41%). CONCLUSIONS: Most Canadian pediatric emergency providers believe that laceration repair in a young child is distressing. Despite questionable efficacy, most would provide intranasal benzodiazepines, but would consider intranasal dexmedetomidine if there was evidence of benefit.

RéSUMé: OBJECTIFS: La dexmédétomidine intranasale est un anxiolytique potentiellement efficace mais son rôle dans la réparation des lacérations en pédiatrie n'est qu'émergent. Les futurs essais et l'adoption clinique de la dexmédétomidine intranasale dépendent de la compréhension des habitudes de pratique des urgentistes pédiatriques en matière d'anxiolyse et des obstacles perçus à la dexmédétomidine intranasale pour l'anxiolyse pendant la réparation des sutures chez les enfants. Nos objectifs étaient de caractériser ces paramètres pour éclairer les recherches futures et faciliter l'adoption clinique. MéTHODES: Nous avons mené un sondage en ligne auprès des médecins urgentistes pédiatriques membres de Recherche en urgence pédiatrique Canada (Pediatric Emergency Research Canada) de septembre à décembre 2020. Les questions portaient sur les perceptions de l'anxiolyse pour la réparation des sutures, en mettant l'accent sur la dexmédétomidine intranasale. Le résultat principal était l'anxiolyse pour la réparation des sutures. Les données ont été rapportées à l'aide de statistiques descriptives. RéSULTATS: Le taux de réponse était de 155/225 (68,9 %). Pendant la suture, 127/148 (86 %) ont estimé que > 25 % des jeunes enfants éprouvent une détresse nécessitant une contention physique. 116/148 (78 %) fourniraient une anxiolyse, principalement des benzodiazépines intranasales (100/148, 68 %). Seulement 6/148 (4 %) fourniraient de la dexmédétomidine intranasale, mais 95/148 (64 %) l'envisageraient s'il y avait une preuve de bénéfice. Les obstacles les plus fréquemment perçus à la dexmédétomidine intranasale étaient une expérience personnelle insuffisante (114/145, 79 %) et un manque d'accès (60/145, 41 %). CONCLUSIONS: La plupart des fournisseurs canadiens de services d'urgence pédiatriques croient que la réparation des lacérations chez un jeune enfant est pénible. En dépit d'une efficacité douteuse, la plupart d'entre eux fourniraient des benzodiazépines intranasales, mais envisageraient la dexmédétomidine intranasale s'il était prouvé qu'elle était bénéfique.

Hyoscine butylbromide versus acetaminophen for nonspecific colicky abdominal pain in children: a randomized controlled trial.

BACKGROUND: Less than two-thirds of children with abdominal pain in the emergency department receive analgesia. We sought to determine whether hyoscine butylbromide was superior to acetaminophen for children with nonspecific colicky abdominal pain. METHODS: We randomly allocated children aged 8-17 years with nonspecific colicky abdominal pain who presented to the pediatric emergency department of London Health Sciences Centre, London, Ontario to receive hyoscine butylbromide, 10 mg given orally, or acetaminophen, 15 mg/kg given orally (maximum 975 mg). We considered the minimal clinically important difference for the primary outcome (self-reported pain at 80 min) to be 13 mm on a 100 mm visual analogue scale. Secondary outcomes included administration of rescue analgesia, adverse effects and pain score less than 30 mm at 80 minutes. RESULTS: A total of 236 participants (120 in the hyoscine butylbromide group and 116 in the acetaminophen group) were included in the trial. The mean visual analogue scale scores at 80 minutes were 29 mm (standard deviation [SD] 26 mm) and 30 mm (SD 29 mm) with hyoscine butylbromide and acetaminophen, respectively (adjusted difference 1, 95% confidence interval -7 to 7). Rescue analgesia was administered to 4 participants (3.3%) in the hyoscine butylbromide group and 1 participant (0.9%) in the acetaminophen groups (p = 0.2). We found no significant differences in rates of adverse effects between hyoscine butylbromide (32/116 [27.6%]) and acetaminophen (28/115 [24.3]) (p = 0.5); no serious adverse effects were observed. The proportion with a pain score less than 30 mm at 80 minutes was 66 (55.0%) with hyoscine butylbromide and 63 (54.3%) with acetaminophen (p = 0.9). INTERPRETATION: Hyoscine butylbromide was not superior to acetaminophen in this setting. Both agents were associated with clinically important pain reduction, and either can be considered for children presenting to the emergency department with nonspecific colicky abdominal pain. Trial registration: Clinicaltrials.gov, no. NCT02582307.

Video Discharge Instructions for Acute Otitis Media in Children: A Randomized Controlled Open-label Trial.

BACKGROUND: Thirty percent of children with acute otitis media (AOM) experience symptoms < 7 days after initiating treatment, highlighting the importance of comprehensive discharge instructions. METHODS: We randomized caregivers of children 6 months to 17 years presenting to the emergency department (ED) with AOM to discharge instructions using a video on management of pain and fever to a paper handout. The primary outcome was the AOM Severity of Symptom (AOM-SOS) score at 72 hours postdischarge. Secondary outcomes included caregiver knowledge (10-item survey), absenteeism, recidivism, and satisfaction (5-item Likert scale). RESULTS: A total of 219 caregivers were randomized and 149 completed the 72-hour follow-up (72 paper and 77 video). The median (IQR) AOM-SOS score for the video was significantly lower than paper, even after adjusting for preintervention AOM-SOS score and medication at home (8 [7-11] vs. 10 [7-13], respectively; p = 0.004). There were no significant differences between video and paper in mean (±SD) knowledge score (9.2 [±1.3] vs. 8.8 [±1.8], respectively; p = 0.07), mean (±SD) number of children that returned to a health care provider (8/77 vs. 10/72, respectively; p = 0.49), mean (±SD) number of daycare/school days missed by child (1.2 [±1.5] vs. 1.1 [±2.1], respectively; p = 0.62), mean (±SD) number of workdays missed by caregiver (0.5 [±1] vs. 0.8 [±2], respectively; p = 0.05), or median (IQR) satisfaction score (5 [4-5] vs. 5 [4-5], respectively; p = 0.3). CONCLUSIONS: Video discharge instructions in the ED are associated with less perceived AOM symptomatology compared to a paper handout.

Cathepsins limit macrophage necroptosis through cleavage of Rip1 kinase.

It has recently been shown that programmed necrosis, necroptosis, may play a key role in the development of inflammation. Deciphering the regulation of this pathway within immune cells may therefore have implications in pathology associated with inflammatory diseases. We show that treatment of macrophages with the pan caspase inhibitor (zVAD-FMK) results in both increased phosphorylation and decreased cleavage of receptor interacting protein kinase-1 (Rip1), leading to necroptosis that is dependent on autocrine TNF signaling. Stimulation of cells with TLR agonists such as LPS in the presence of zVAD-FMK also induced Rip1-phosphorylation via a TNFR-independent mechanism. Further examination of Rip1 expression under these stimulatory conditions revealed a regulatory cleavage of Rip1 in macrophages that is not apparently attributable to caspase-8. Instead, we provide novel evidence that cysteine family cathepsins, which are highly abundant in myeloid cells, can also cleave Rip1 kinase. Using small interfering RNA knockdown, specific cathepsin inhibitors, and cell-free cleavage assays, we demonstrate that cysteine cathepsins B and S can directly cleave Rip1. Finally, we demonstrate that only through combined inhibition of cathepsins and caspase-8 could a potent induction of macrophage necroptosis be achieved. These data reveal a novel mechanism of regulation of necroptosis by cathepsins within macrophage cells.