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Background: In the midst of the North American opioid crisis, identifying and intervening on drivers of high-risk opioid prescriptions is an important step towards reducing iatrogenic harm. Objectives: We aimed to identify factors associated with variations in high-risk opioid discharge prescriptions, following select surgical procedures, to guide future quality improvement initiatives. Methods: This retrospective cohort study analyzed 1322 patients who underwent select open pelvic and open abdominal surgeries between January 1 and December 31, 2017, in a tertiary health care centre in Montreal. Results: Patients who underwent open abdominal surgeries were prescribed significantly higher daily doses of morphine milligram equivalents (MME) (45 mg; interquartile range, 30-60), than patients who underwent either a caesarean delivery (20 mg, 20-20) or a hysterectomy (30 mg, 22-30). After adjustment for multiple potential confounders, abdominal surgery was associated with 4 times the odds of receiving more than 50 MME at hospital discharge compared with pelvic surgeries (odds ratio, 3.96; 95% confidence interval, 1.31-11.97). The availability of postoperative preprinted order sets with fixed high doses of opioids was also highly associated with the outcome. Conclusion: In our institution, some surgeries were more likely to receive high-risk opioid prescriptions at discharge. Efforts to optimize safer prescribing practices should address the creation and/or updating of preprinted order sets to reflect current best practice guidelines. This initiative could be overseen by hospital pharmacy and therapeutics committees.

Background Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection causes high morbidity and mortality in older adults with chronic illnesses. Several trials are currently underway evaluating the antimalarial drug hydroxychloroquine as a potential treatment for acute infection. However, polypharmacy predisposes patients to increased risk of drug–drug interactions with hydroxychloroquine and may render many in this population ineligible to participate in trials. Objectives We aimed to quantify the degree of polypharmacy and burden of potentially inappropriate medications (PIMs) that older hospitalized adults are taking which would interact with hydroxychloroquine. Methods We reanalyzed data from the cohort of patients 65 years and older enrolled in the MedSafer pilot study. We first identified patients taking medications with potentially harmful drug–drug interactions with hydroxychloroquine that might exclude them from participation in a typical coronavirus disease 2019 (COVID‐19) therapeutic trial. Next, we identified medications that were flagged by MedSafer as being potentially inappropriate and crafted guidance around medication management if contemplating the use of hydroxychloroquine. Results The cohort contained a total of 1,001 unique patients with complete data on their home medications at admission. Of these 1,001 patients, 590 (58.9%) were receiving one or more home medications that could potentially interact with hydroxychloroquine, and of these 255 (43.2%) were flagged as potentially inappropriate by the MedSafer tool. Common classes of PIMs observed were antipsychotics, cardiac medications, and anti‐diabetic agents. Conclusion The COVID‐19 pandemic highlights the importance of medication optimization and deprescribing PIMs in older adults. By acting now to reduce polypharmacy and use of PIMs, we can better prepare this vulnerable population for inclusion in trials and, if substantiated, pharmacologic treatment or prevention of COVID‐19. This article is protected by copyright. All rights reserved.

ImportanceOlder adults, at high-risk of developing complications from COVID-19, could benefit from nirmatrelvir-ritonavir, an oral antiviral treatment for outpatients at high risk of complications from COVID-19; however, due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).ObjectivesIdentify how common DDIs are between nirmatrelvir-ritonavir, common medications, and PIMs in older adults with polypharmacy. Craft anticipatory deprescribing guidance for PIMs that interact with nirmatrelvir-ritonavir to help prioritize deprescribing resources, and increase the proportion of older adults potentially benefitting from treatment.DesignIn this secondary analysis, we retrospectively analyzed all patients in the MedSafer cluster randomized deprescribing trial (N=5698 participants) to investigate the proportion of older adults (age >65) with polypharmacy (≥5 usual home medications) who would be ineligible for treatment with nirmatrelvir-ritonavir due to pre-existing DDIs.SettingThe setting of the primary study was in medical inpatient units at 11 Canadian acute care hospitals.ParticipantsHospitalized persons, age 65 years and older, on 5 or more daily home medications, with an expected survival of 3 months or longer were included in this secondary analysis.Main outcomes and measuresWe identified the prevalence of (PIMs), as defined by the MedSafer software. We then developed deprescribing guidance, so clinicians could proactively deprescribe in an effort to increase the proportion of older adults eligible for safe treatment with nirmatrelvir-ritonavir in the event of a SARS-CoV-2 infection.ResultsOf 5698 participants, a total of 3869 (68%) were taking a medication with a known nirmatrelvir-ritonavir DDI, and of these 823 (21%) had at least one PIM. Of 823 PIMs, 627 (76%) were medications with a known high risk DDI and 213 (26%) were considered moderate risk DDIs with nirmatrelvir-ritonavir. Many of the PIMs required “advanced deprescribing” and could not simply be stopped, held, or adjusted at the time of nirmatrelvir-ritonavir receipt.Conclusions and relevanceOlder adults are at high risk of developing severe complications from COVID-19. Deprescribing PIMs in advance of a COVID-19 infection could increase the proportion of older adults who can safely receive nirmatrelvir-ritonavir, in addition to the usual benefits observed with medication management.Impact StatementWe certify that this work is novel. This timely clinical investigation explores the unforeseen consequences of polypharmacy and the use of potentially inappropriate medication in older adults during the COVID-19 pandemic. This manuscript addresses the many drug-drug interactions between nirmatrelvir-ritonavir, an antiviral treatment for COVID-19, and potentially inappropriate medications in older adults with polypharmacy from the MedSafer cluster randomized trial. Our work highlights that the pandemic has created an even greater urgency to examine the medication lists of older adults and proactively deprescribe to improve the safety and tolerability of different COVID-19 treatments.Key PointsQuestion: How does polypharmacy affect the eligibility of older adults to receive Nirmatrelvir-ritonavir?Findings: 68% of older adults in the MedSafer cluster randomized trial had a DDI with nirmatrelvir-ritonavir, and 21% were taking at least 1 potentially inappropriate medication.Meaning: Due to its potent CYP3A4 inhibition, nirmatrelvir-ritonavir is associated with many drug-drug interactions (DDI).

Coronavirus disease 2019 (COVID-19) has altered the availability of face-to-face care in family practice. The negative effect on routine care for chronic disease management is an ongoing challenge. The purpose of this article is to describe some of those challenges and to suggest solutions. High

Objectives Proton pump inhibitor (PPI) therapy is a potentially modifiable risk factor for recurrent Clostridioides difficile infection (CDI). Citing an absence of clinical trials, many guidelines do not provide recommendations for addressing PPI management. Our aim was to perform an updated systematic review and meta-analysis evaluating the association between PPI use and recurrent CDI addressing prior methodological limitations. Methods Data sources were MEDLINE and EMBASE. Eligible studies were cohort and case–control studies; there were no restrictions on study setting or duration of follow-up. Participants were adults with prior CDI who did or did not receive PPI therapy and were assessed for recurrent CDI. Summary (unadjusted) odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using a random effects model. Prespecified subgroup analyses were performed to explore heterogeneity including study design, study quality, duration of follow-up, adjustment for confounders, and outcome definition. Results Sixteen studies were included in the meta-analysis, comprising 57 477 patients with CDI, of whom 6870 (12%) received PPIs. The rate of recurrent CDI was 24% in patients treated with PPIs versus 18% in those who were not. A meta-analysis that pooled unadjusted odds ratios demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.69, 95%CI 1.46–1.96) versus those who did not. There was moderate heterogeneity between studies (I2 56%); however, a sensitivity analysis restricted to studies with 56 days of follow-up substantially reduced the heterogeneity (OR 1.59, 95%CI 1.36–1.85; I2 12%). An analysis restricted to multivariate studies that combined adjusted ORs also demonstrated higher odds of recurrent CDI in patients who received PPIs (OR 1.49, 95%CI 1.12–2.00). No publication bias was identified. Conclusions We found significantly higher odds of recurrent CDI among users of PPIs that persisted across multiple sensitivity analyses. These results support stronger recommendations for PPI stewardship at CDI diagnosis.

Objectives To distribute the EMPOWER patient education brochure and use hospitalization as an opportunity to reduce inappropriate sedatives. Design Participants were sequentially recruited until we achieved 30-day follow-up telephone and pharmacy records for 50 individuals. The proportion meeting the primary outcome was compared with that of a control cohort and with rates of cessation achieved in the community. Setting Fifty-two-bed medical clinical teaching unit in Montreal, Canada. Participants Inpatients aged 65 and older who were chronic, regular sedative users. Measurements The primary outcome was short-term sustained cessation 30-days after discharge. As a secondary outcome, we compared self-reported sleep disturbance before and after the intervention. Results Sedatives were deprescribed in 32 of 50 (64%) participants who received the EMPOWER brochure, which was significantly higher than our historical rate of 21% (p

Introduction Surgery is essential for cure of early-stage non-small cell lung cancer (NSCLC). Rates of postoperative bacterial pneumonias, however, remain high, and clinical data suggests that post-operative infectious complications confer an increased risk for metastasis. Toll-like receptors (TLRs) mediate the inflammatory response to infection by recognizing evolutionarily conserved bacterial structures at the surface of numerous pulmonary cell types; yet, little is known about how host TLR activation influences NSCLC metastasis. TLR4 recognizes gram-negative bacterium lipopolysaccharide activating the innate immune system. Methods C57BL/6 and TLR4 knockout murine airways were inoculated with Escherichia coli or lipopolysaccharide. Hepatic metastasis assays and intravital microscopy were performed. Bronchoepithelial conditioned media was generated through coincubation of bronchoepithelial cells with TLR4 activating Escherichia coli or lipopolysaccharide. Subsequently, H59 NSCLC were stimulated with conditioned media and subject to various adhesion assays. Results We demonstrate that gram-negative Escherichia coli pneumonia augments the formation of murine H59 NSCLC liver metastases in C57BL/6 mice through TLR4 activation. Additionally, infected C57BL/6 mice demonstrate increased H59 NSCLC in vivo hepatic sinusoidal adhesion compared with negative controls, a response that is significantly diminished in TLR4 knockout mice. Similarly, intratracheal injection of purified TLR4 activating lipopolysaccharide increases in vivo adhesion of H59 cells to murine hepatic sinusoids. Furthermore, H59 cells incubated with bronchoepithelial conditioned medium show increased cell adhesion to in vitro extracellular matrix proteins and in vivo hepatic sinusoids through a mechanism dependent on bronchoepithelial TLR4 activation and interleukin-6 secretion. Conclusion TLR4 is a viable therapeutic target for NSCLC metastasis augmented by gram-negative pneumonia.

Trauma remains a leading cause of death worldwide. The development of trauma systems in low-resource settings may be of benefit. The objective of this study was to describe operative procedures performed for trauma at a tertiary care facility in Kigali, Rwanda, and to evaluate geographical variations and referral patterns of trauma care.We retrospectively reviewed all prospectively collected operative cases performed at the largest referral hospital in Rwanda, the Centre Hospitalier Universitaire de Kigali (CHUK), between June 1 and Dec. 1, 2011, for injury-related diagnoses. We used the Pearson χ² and Fisher exact tests to compare cases arising from within Kigali to those transferred from other provinces. Geospatial analyses were also performed to further elucidate transfer patterns.Over the 6-month study period, 2758 surgical interventions were performed at the CHUK. Of these, 653 (23.7%) were for trauma. Most patients resided outside of Kigali city, with 337 (58.0%) patients transferred from other provinces and 244 (42.0%) from within Kigali. Most trauma procedures were orthopedic (489 [84.2%]), although general surgery procedures represented a higher proportion of trauma surgeries in patients from other provinces than in patients from within Kigali (28 of 337 [8.3%] v. 10 of 244 [4.1%]).To our knowledge, this is the first study to highlight geographical variations in access to trauma care in a low-income country and the first description of trauma procedures at a referral centre in Rwanda. Future efforts should focus on maturing prehospital and interfacility transport systems, strengthening district hospitals and further supporting referral institutions.Les traumatismes demeurent l’une des principales causes de décès dans le monde. La mise au point de systèmes de traumatologie dans des milieux défavorisés pourrait toutefois contribuer à améliorer la situation. Notre étude avait pour objectif de décrire les interventions chirurgicales pratiquées sur les victimes de traumatismes dans un établissement de soins tertiaires de Kigali, au Rwanda, et d’évaluer les variations géographiques et les habitudes d’orientation des patients dans le domaine de la traumatologie.Nous avons évalué rétroactivement les données recueillies de façon prospective sur l’ensemble des interventions réalisées au plus grand centre hospitalier régional du Rwanda, le Centre hospitalier universitaire de Kigali (CHUK), du 1er juin au 1er décembre 2011 pour les diagnostics liés à des blessures. Nous avons eu recours au test χ² de Pearson et au test exact de Fisher pour comparer les cas issus de la province de Kigali à ceux provenant d’autres provinces. Nous avons en outre effectué des analyses géospatiales afin de mieux comprendre les habitudes d’orientation des patients.Au cours des 6 mois de l’étude, 2758 interventions chirurgicales ont été pratiquées au CHUK, dont 653 (23,7 %) pour des traumatismes. La majorité des patients résidaient à l’extérieur de la capitale : 337 (58,0 %) d’entre eux avaient été transférés d’autres provinces, et 244 (42,0 %), d’ailleurs dans la province. Si la plupart des interventions chirurgicales étaient orthopédiques (489, soit 84,2 %), les patients d’autres provinces ont plus souvent subi des interventions générales que leurs compatriotes de la province de Kigali (28 sur 337, soit 8,3 %, par rapport à 10 sur 244, soit 4,1 %).À notre connaissance, il s’agit de la première étude mettant en lumière les variations géographiques de l’accès aux soins en traumatologie dans un pays à faible revenu et de la première description des interventions chirurgicales pratiquées sur des victimes de traumatismes dans un centre régional du Rwanda. Les travaux à venir devraient être axés sur le développement des systèmes de transport avant l’hospitalisation et entre les établissements, le renforcement des hôpitaux de district et l’augmentation du soutien aux centres régionaux.

To distribute the EMPOWER patient education brochure and use hospitalization as an opportunity to reduce inappropriate sedatives.Participants were sequentially recruited until we achieved 30-day follow-up telephone and pharmacy records for 50 individuals. The proportion meeting the primary outcome was compared with that of a control cohort and with rates of cessation achieved in the community.Fifty-two-bed medical clinical teaching unit in Montréal, Canada.Inpatients aged 65 and older who were chronic, regular sedative users.The primary outcome was short-term sustained cessation 30-days after discharge. As a secondary outcome, we compared self-reported sleep disturbance before and after the intervention.Sedatives were deprescribed in 32 of 50 (64%) participants who received the EMPOWER brochure, which was significantly higher than our historical rate of 21% (p.001). Participants did not report significant worsening in their quality of sleep after sedative cessation.Hospitalized individuals are willing to deprescribe, and contact with the healthcare system provides the opportunity to initiate the process with educational brochures. This type of intervention requires few resources and is feasible and inexpensive.

Purpose The incidence of sensorineural hearing loss (SNHL;>20dB loss) in CDH survivors is debated. We evaluated long-term audiological outcomes at a single tertiary care center with ECMO capability and an established neonatal follow-up program. Methods With REB approval, records of CDH survivors from 2000 to 2010 were retrospectively analyzed. Demographic, postnatal, and audiometric information was gathered. All underwent auditory brainstem response (ABR) or otoacoustic emissions screening before discharge and complete audiological surveillance. Thirty-three patients were evaluated to age 4+ years with others continuing follow-up. Results Forty-three patient records were reviewed with 1 excluded (transferred to another institution). Median GA and BW were 39weeks (35–41) and 3.1kg (2–4), respectively. Median ventilation days were 10 (2–189) with 34 infants ventilated 5+ days. Sixteen (36%) received HFOV, 21 (49%) iNO, and 5 (12%) ECMO. The median time to CDH repair was 3days (1–23), and 11 (26%) required patch repair. Nine infants (21%) received diuretics and oxygen after discharge. Audiological surveillance identified only one patient with SNHL (received HFO, iNO, and patch repair). Conclusion Neonatal screening identifies CDH survivors at risk for hearing difficulties but must be followed with comprehensive testing until school age. The incidence of SNHL may be less than previously reported in this population.

Purpose Little is known about liveborn CDH patients who die without surgery. We audited a national CDH cohort to determine whether these patients were different from patients who received CDH repair. Methods A national CDH database was analyzed (2005–2009). After excluding infants with severe physiologic instability and genetic/congenital malformations, a potential surgical candidate (PSC) subgroup was identified. PSCs were compared to the operative group (OG) and the operative non-survivor (ONS) subgroup. Standard statistical analyses were performed. Results Of 275 liveborns, 35 (13%) died without surgery. The PSC subgroup ( n =11) had a median survival of 10days (range: 3–18). Ten of 11 PSC infants were treated in ECMO centers, with 4 receiving ECMO. No differences in BW, GA, and rates of minor malformation were observed between PSC and OG patients. While neonatal illness severity (SNAP-II) predicted overall mortality, SNAP-II scores were similar between PSC and ONS groups (34 vs. 29; p =0.431). Furthermore, greater than 80% of infants with SNAP-II scores between 30 and 39 survived in the OG cohort. Conclusion Our analysis demonstrated that PSCs were similar to infants offered surgery based on illness severity and the presence of congenital malformations. We suggest that criteria for surgical ineligibility be developed to standardize the selection of surgical candidates.

Myofibromas are benign congenital tumors of soft tissue that can present at birth or during infancy in solitary or multicentric forms. Visceral myofibromas are rarely reported, but are typically symptomatic due to involvement of vital structures. We present two cases of congenital myofibromas, one obstructing the proximal esophagus and the other obstructing the distal rectum. Lessons learned from the treatment of these two patients are shared and the pertinent literature is reviewed.

Oncolytic viruses (OVs) have shown promise as cancer therapeutics in pre-clinical and clinical testing; however, it is unlikely that OVs will constitute a stand-alone treatment. Histone deacetylase inhibitors (HDIs) represent a class of anticancer agents known to influence epigenetic modifications of chromatin, alter gene expression and manipulate a variety of signaling pathways, in some cases blunting the cellular antiviral response. Recent studies have shown that combining OV therapy with HDI treatment enhances viral replication and synergistically induces the killing of cancer cells in vitro and in vivo, an effect that has now been demonstrated in variety of virus/HDI combinations. This review discusses the results obtained with the different OV/HDI combinations, the rationale supporting these combinations and the advantages for oncolytic virus therapy.

Introduction: Vesicular stomatitis Virus (VsV) is an oncolytic virus that preferentially replicates in and kills cancerous cells. however, many cancer cell lines are resistant to VsV treatment alone. previous work has shown that treating cancerous cells with histone deacetylase inhibitors makes them more susceptible to VsV infection and oncolysis. We hypothesize that treatment with a histone deacetylase inhibitor, suberoylanilide hydroxamic acid (saha or Voronistat), and a methyltransferase inhibitor, 5-aza-2'-deoxycytidine (5-aza or Decitabine), will result in an increase in VsV replication and virus-induced oncolysis in vitro. Methods: pC3 prostate cancer cells were treated with 1 μm saha, 1 μm 5-aza or both. of these samples, half were infected with oncolytic Vesicular stomatitis Virus expressing green fluorescent protein VsV aV1 – gFp at a multiplicity of infection of 1 × 10-2, 24 hours after treatment. Cells were then collected and subjected to either FaCs analysis or protein extraction at 12, 24, 48 and 72 hours post-infection. We confirmed increases in cell death by western blotting for cleavage of poly a Riboprotein, an important downstream effector of the Caspase pathway, as well as Caspases 8 and 9, hallmarks for the extrinsic and intrinsic apoptotic pathways respectively. results: Treatment with saha, 5-aza or a combination of both resulted in increases in VsV replication and cell death. These observations were consistent over four time points spanning 72 hours. discussion: Treatment with histone deacetylase inhibitor/methyltransferase inhibitor combination increases VsV replication and cell death in tumour cell lines resistant to VsV infection. In combination with previous work, this data suggests that modulation of the antiviral response and apoptotic pathways increases susceptibility to VsV.

Background Surgical management of emergent, life-threatening diseases is an important public health priority. The objectives of this study were to (1) describe acute care general surgery procedures performed at the largest referral hospital in Rwanda and (2) understand the geographic distribution of disease presentations and referral patterns. Methods We performed a retrospective review of prospectively collected acute care surgery cases performed at the Centre Hospitalier Universitaire de Kigali (CHUK) in Rwanda between June 1 and December 1, 2011. Using Pearson's χ2 test and the Fisher exact test, we compared cases originating from within Kigali and transfers from other provinces. Geospatial analyses also were used to further describe transfer patterns. Results During the study period, 2,758 surgical interventions were performed, of which 25.6% (707/2,758) were general surgery operations. Of these, 45.4% (321/707) met the definition of acute care surgery. Only about one-third—32.3% (92/285)—of patients resided within Kigali, whereas about two-thirds—67.7% (193/285)—were transferred from other provinces. Most patients transferred from other provinces were younger than 18 years of age (40.4%; 78/193), and 83.0% (39/47) of patients older than 50 years of age originated from outside of Kigali. Specific operative indications and surgical procedures varied substantially between patients from Kigali and patients transferred from other provinces. Conclusion Emergency surgical conditions remain important contributors to the global burden of disease, particularly in low- and middle-income countries. Geographic variations exist in terms of operative diagnoses and procedures, which implies a need for improved access to surgical care at the district level with defined transfer mechanisms to greater-level care facilities when needed.