Potential Access to Emergency General Surgical Care in Ontario.

Limited access to timely emergency general surgery (EGS) care is a probable driver of increased mortality and morbidity. Our objective was to estimate the portion of the Ontario population with potential access to 24/7 EGS care. Geographic information system-based network-analysis was used to model 15-, 30-, 45-, 60-, and 90-min land transport catchment areas for hospitals providing EGS care, 24/7 emergency department (ED) access, and/or 24/7 operating room (OR) access. The capabilities of hospitals to provide each service were derived from a prior survey. Population counts were based on 2016 census blocks, and the 2019 road network for Ontario was used to determine speed limits and driving restrictions. Ninety-six percent of the Ontario population (n = 12,933,892) lived within 30-min's driving time to a hospital that provides any EGS care. The availability of 24/7 EDs was somewhat more limited, with 95% (n = 12,821,747) having potential access at 30-min. Potential access to all factors, including 24/7 ORs, was only possible for 93% (n = 12,471,908) of people at 30-min. Populations with potential access were tightly clustered around metropolitan centers. Supplementation of 24/7 OR capabilities, particularly in centers with existing 24/7 ED infrastructure, is most likely to improve access without the need for new hospitals.

A Standardized Minimal Opioid Prescription Post-Thoracic Surgery Provides Adequate Pain Control.

BACKGROUND: Given the national opioid crisis, postoperative analgesia at discharge must be thoughtfully prescribed. Data specifically related to thoracic procedures remain scarce. This study assessed adequacy of pain control with standardized and limited opioids after thoracic procedures. METHODS: A standardized prescription comprised 15 hydromorphone tabs, 7 days of acetaminophen, and 3 days of ibuprofen was provided on discharge to elective thoracic surgery patients. On the first postoperative visit, patients completed a questionnaire regarding the number of hydromorphones used, use of additional opioids, pain-related limitation to function, and adequacy of pain control. RESULTS: A total of 122 patients undergoing thoracic surgery procedures were surveyed. Twelve underwent open procedures and were excluded. An additional 6 patients who used opioids chronically preoperatively were also excluded. The remaining 104 patients were included in the study. Median age was 66 years (age range, 17-90 years) and median length of stay was 2 days (range, 1-15 days). Seventeen (16%) patients used all prescribed hydromorphone and 56 (54%) used none, 18 (17%) asked for additional or other opioid, and 14 (13%) felt that their pain significantly limited their function. Nine (9%) felt that that their pain was inadequately controlled. CONCLUSIONS: Pain after thoracic procedures, especially video-assisted thoracoscopic surgery, is adequately controlled with minimal opioid doses (combined with adjuncts), with less than 1 in 5 patients requiring additional prescriptions and very few patients complaining of pain that significantly limited their function. This study shows that a standardized limited opioid prescription is safe, is adequate, and can easily be implemented for the majority of thoracic surgery patients.

Structures, processes and models of care for emergency general surgery in Ontario: a cross-sectional survey.

BACKGROUND: Emergency general surgery (EGS) patients require urgent surgical evaluation and intervention for various conditions, such as infectious or obstructive diseases of the gastrointestinal tract. We aimed to characterize the structures and processes that are relevant to the delivery of EGS care across Ontario hospitals and to evaluate the availability of critical resources at hospitals with formal EGS models. METHODS: Between August 2019 and July 2020, we conducted a cross-sectional survey of Ontario hospitals that offered urgent general surgery (defined as the ability to provide nonelective surgical intervention within 24 to 48 hours of presentation) to adults. People with intimate knowledge of their hospital's EGS program completed a Web-based or telephone survey characterizing the program's organizational structure and staffing, operating room availability, interventional radiology and interventional endoscopy availability, intensive care unit availability and staffing, and regional participation. Their responses were compiled and comparisons were made between hospitals with and without formal EGS models of care, as well as between hospitals based on size and academic status. RESULTS: Of the 114 Ontario hospitals identified, 109 responded (95.6% response rate). A third (34.6%; n = 37/107) of hospitals had EGS models of care. Thirty-four of these (91.9%) were large (> 100-bed) institutions that would be likely to have increased resources. However, even for hospitals of similar size, those with EGS models had increased staffing levels compared to those without (clinical associates 17.6% [n = 3/17] v. 10.0% [n = 2/20]; nurse practitioners or physician assistants 27.8% [n = 5/18] v. 14.3% [n = 3/21]). They also had better access to diagnostic and interventional equipment (24/7 access to computed tomography 94.1% [n = 16/17] v. 69.2% [n = 18/26]), interventional radiology (88.9% [n = 16/18] v. 42.3% [n = 11/26]), endoscopy (100% [n = 18/18] v. 69.2% [n = 18/26]) and endoscopic retrograde cholangiopancreatography (77.8% [n = 14/18] v. 42.3% [n = 11/26]), as well as dedicated operating room time (72.2% [n = 13/18] v. 0% [n = 0/25]). INTERPRETATION: The structures and processes available to care for patients requiring EGS in Ontario were highly variable between hospitals. Hospitals with formal EGS models were more likely to have access to key resources.

Massive traumatic abdominal wall hernia with significant tissue loss: challenges in management.

A 41-year-old woman presented to our trauma centre following a high-speed motor vehicle collision with a seatbelt pattern of injury resulting in extensive rupture of her abdominal wall musculature and associated hollow viscus injuries. The abdominal wall had vertical separation between transected rectus, bilateral transverse abdominis and oblique muscles allowing evisceration of small and large bowel into the flanks without skin rupture. Intraoperatively, extensive liquefaction and tissue loss of the abdominal wall was found with significant retraction of the remaining musculature. Initial operative management focused on repair of concomitant intra-abdominal injuries with definitive repair performed in delayed, preplanned stages including bridging with absorbable mesh and placement of an overlying split-thickness skin graft. The patient was discharged from hospital and underwent extensive rehabilitation. One year later, the abdominal wall was definitively repaired with components separation and biological mesh underlay. This stepwise repair process provided her with a robust and enduring abdominal wall reconstruction.

Perforated appendicitis in the setting of a massive ventral hernia, morbid obesity, and multiple severe comorbidities: challenges in acute management.

Case summary: A 57-year-old woman with morbid obesity (body mass index [BMI] of 43), systemic lupus on steroids, type 2 insulin-dependent diabetes, peripheral vascular disease, unprovoked pulmonary embolism on rivaroxaban, and hypertension presented with 3 days of worsening abdominal pain and nausea. She had an extensive surgical history including a cesarean section, multiple laparotomies for small bowel obstructions (one complicated by bowel perforation requiring resection), and a double-barrelled ileostomy, which had been since reversed. As a result, she had a massive incisional hernia (figure 1). On presentation she was afebrile but tachycardic at 110 beats per minute. Physical examination revealed tenderness to deep palpation in the right upper and lower quadrants. CT demonstrated an 11 mm appendix with an appendicolith outside the hernia sac abutting the right kidney, discontinuity of the appendix tip, free fluid, and associated stranding in the subhepatic region (figure 2A). She was admitted to the surgical floor for a trial of conservative management with ancef and flagyl. On day 3, her pain worsened, her white cell count remained stable at 12 x109/L, her temperature was 37.8°C, she was not tachycardic, and a repeat CT showed a 15 mm perforated appendix with increased periappendiceal stranding and an associated small volume of free fluid. There was no phlegmon or organized abscess (figure 2B).Figure 1Patient's abdomen demonstrating midline laparotomy incisional scar, previous ileostomy scar, and massive ventral hernia.Figure 2Abdominal CT showing increased stranding centered around the appendix, with discontinuity of the wall of the appendix tip and free fluid within the abdomen and pelvis. (A) Admission CT. White arrow: appendix. (B) CT on postadmit day 3 as patient worsened clinically. Black arrow: fecalith. WHAT WOULD YOU DO?: Continue non-operative management with broadened intravenous antibiotic coverage and bowel rest.Laparoscopic ± open appendectomy without concomitant hernia repair.Laparoscopic ± open appendectomy with abdominal wall reconstruction.

Endothelial Cell-Targeted Deletion of PPARγ Blocks Rosiglitazone-Induced Plasma Volume Expansion and Vascular Remodeling in Adipose Tissue.

Thiazolidinediones (TZDs) are peroxisome proliferator-activated receptor γ (PPARγ) agonists that represent an effective class of insulin-sensitizing agents; however, clinical use is associated with weight gain and peripheral edema. To elucidate the role of PPARγ expression in endothelial cells (ECs) in these side effects, EC-targeted PPARγ knockout (Pparg ΔEC) mice were placed on a high-fat diet to promote PPARγ agonist-induced plasma volume expansion, and then treated with the TZD rosiglitazone. Compared with Pparg-floxed wild-type control (Pparg f/f) mice, Pparg ΔEC treated with rosiglitazone are resistant to an increase in extracellular fluid, water content in epididymal and inguinal white adipose tissue, and plasma volume expansion. Interestingly, histologic assessment confirmed significant rosiglitazone-mediated capillary dilation within white adipose tissue of Pparg f/f mice, but not Pparg ΔEC mice. Analysis of ECs isolated from untreated mice in both strains suggested the involvement of changes in endothelial junction formation. Specifically, compared with cells from Pparg f/f mice, Pparg ΔEC cells had a 15-fold increase in focal adhesion kinase, critically important in EC focal adhesions, and >3-fold significant increase in vascular endothelial cadherin, the main component of focal adhesions. Together, these results indicate that rosiglitazone has direct effects on the endothelium via PPARγ activation and point toward a critical role for PPARγ in ECs during rosiglitazone-mediated plasma volume expansion.

Toll-like receptor 4 mutant and null mice retain morphine-induced tolerance, hyperalgesia, and physical dependence.

The innate immune system modulates opioid-induced effects within the central nervous system and one target that has received considerable attention is the toll-like receptor 4 (TLR4). Here, we examined the contribution of TLR4 in the development of morphine tolerance, hyperalgesia, and physical dependence in two inbred mouse strains: C3H/HeJ mice which have a dominant negative point mutation in the Tlr4 gene rendering the receptor non-functional, and B10ScNJ mice which are TLR4 null mutants. We found that neither acute antinociceptive response to a single dose of morphine, nor the development of analgesic tolerance to repeated morphine treatment, was affected by TLR4 genotype. Likewise, opioid induced hyperalgesia and opioid physical dependence (assessed by naloxone precipitated withdrawal) were not altered in TLR4 mutant or null mice. We also examined the behavioural consequence of two stereoisomers of naloxone: (-) naloxone, an opioid receptor antagonist, and (+) naloxone, a purported antagonist of TLR4. Both stereoisomers of naloxone suppressed opioid induced hyperalgesia in wild-type control, TLR4 mutant, and TLR4 null mice. Collectively, our data suggest that TLR4 is not required for opioid-induced analgesic tolerance, hyperalgesia, or physical dependence.

Loss of PPARγ expression in mammary secretory epithelial cells creates a pro-breast tumorigenic environment.

Breast cancer is the leading cause of new cancer diagnoses among women. Using peroxisome proliferator-activated receptor (PPAR)γ((+/-)) mice, we showed normal expression of PPARγ was critical to stop 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast tumorigenesis. PPARγ is expressed in many breast cell types including mammary secretory epithelial (MSE) cells. MSEs proliferate as required during pregnancy, and undergo apoptosis or reversible transdifferentiation during involution once lactation is complete. Thus, MSE-specific loss of PPARγ was hypothesized to enhance DMBA-mediated breast tumorigenesis. To test this, MSE cell-specific PPARγ knockout (PPARγ-MSE KO) and control (PPARγ-WT) mice were generated, mated and allowed to nurse for three days. One week after involution, dams were treated with DMBA to initiate breast tumors, and randomized on week 7 to continue receiving a normal chow diet (DMBA Only: PPARγ-WT, n = 15; PPARγ-MSE KO, n = 25) or one supplemented with a PPARγ activating drug (DMBA + ROSI: PPARγ-WT, n = 17; PPARγ-MSE KO, n = 24), and monitored for changes in breast tumor outcomes. PPARγ-MSE KOs had significantly lower overall survival and decreased mammary tumor latency as compared to PPARγ-WT controls. PPARγ activation significantly reduced DMBA-mediated malignant mammary tumor volumes irrespective of genotype. MSE-specific PPARγ loss resulted in decreased mammary gland expression of PTEN and Bax, increased superoxide anion production, and elevated serum eotaxin and RANTES, creating a protumorigenic environment. Moreover, PPARγ activation in MSEs delayed mammary tumor growth in part by down-regulating Cox-1, Cox-2 and cyclin D1. Collectively, these studies highlight a protective role of MSE-specific PPARγ during breast tumorigenesis, and support a novel chemotherapeutic role of PPARγ activation in breast cancer.

The Key to Unlocking the Chemotherapeutic Potential of PPARγ Ligands: Having the Right Combination.

Despite extensive preclinical evidence that peroxisome proliferator-activated receptor (PPAR)γ activation protects against tumourigenesis, results from a few clinical trials using PPARγ ligands as monotherapy show modest success. In spite of this, several groups reported exciting results with therapeutic regimens that combine PPARγ ligands with other compounds: chemotherapeutic agents, retinoid x receptor (RXR)α agonists, statins, or cell-to-cell signaling molecules in preclinical cancer models and human trials. Here we have compiled an extensive review, consolidating the existing literature, which overwhelmingly supports a beneficial effect of treating with PPARγ ligands in combination with existing chemotherapies versus their monotherapy in cancer. There are many examples in which combination therapy resulted in synergistic/additive effects on apoptosis, differentiation, and the ability to reduce cell growth and tumour burden. There are also studies that indicate that PPARγ ligand pretreatment overcomes resistance and reduces toxicities. Several mechanisms are explored to explain these protective effects. This paper highlights each of these studies that, collectively, make a very strong case for the use of PPARγ ligands in combination with other agents in the treatment and management of several cancers.

Stromal adipocyte PPARγ protects against breast tumorigenesis.

Peroxisome proliferator-activated receptor (PPAR)γ regulates the expression of genes essential for fat storage, primarily through its activity in adipocytes. It also has a role in carcinogenesis. PPARγ normally stops the in vivo progression of 7,12-dimethylbenz[a]anthracene (DMBA)-mediated breast tumours as revealed with PPARγ haploinsufficient mice. Since many cell types associated with the mammary gland express PPARγ, each with unique signal patterns, this study aimed to define which tissues are required for PPARγ-dependent antitumour effects. Accordingly, adipocyte-specific PPARγ knockout (PPARγ-A KO) mice and their wild-type (PPARγ-WT) controls were generated, and treated with DMBA for 6 weeks to initiate breast tumorigenesis. On week 7, mice were randomized to continue on normal chow diet or one supplemented with rosiglitazone (ROSI), and followed for 25 weeks for tumour outcomes. In PPARγ-A KO versus PPARγ-WT mice, malignant mammary tumour incidence was significantly higher and mammary tumour latency was decreased. DMBA + ROSI treatment reduced average mammary tumour volumes by 50%. Gene expression analyses of mammary glands by quantitative real-time polymerase chain reaction and immunofluorescence indicated that untreated PPARγ-A KOs had significantly decreased BRCA1 expression in mammary stromal adipocytes. Compared with PPARγ-WT mice, serum leptin levels in PPARγ-A KOs were also significantly higher throughout the study. Together, these data are the first to suggest that in vivo PPARγ expression in mammary stromal adipocytes attenuates breast tumorigenesis through BRCA1 upregulation and decreased leptin secretion. This study supports a protective effect of activating PPARγ as a novel chemopreventive therapy for breast cancer.