Rate of prophylactic anti-Xa achievement and impact on venous thromboembolism following oncologic hepato-pancreatico-biliary surgery: A prospective cohort study.

BACKGROUND: Hepato-pancreatico-biliary (HPB) patients experience competing risk of venous thromboembolism (VTE) and bleeding. We sought to evaluate the effect of anti-Xa levels on VTE and bleeding, and to characterize factors associated with subprophylaxis. METHODS: This prospective cohort study evaluated adult HPB surgical patients; cohorts were described by anti-Xa levels as subprophylactic (<0.2 IU/mL), prophylactic (0.2-0.5 IU/mL), and supraprophylactic (>0.5 IU/mL). Primary outcome evaluated bleeding and VTE complications. Secondary outcomes evaluated factors associated with subprophylaxis. RESULTS: We included 157 patients: 68 (43.6%) attained prophylactic anti-Xa and 89 (56.7%) were subprophylactic. Subprophylactic patients experienced more VTE compared to prophylactic patients (6.9% vs 0%; p = 0.028) without differences in bleeding complications (14.6% vs 5.9%; p = 0.081). Factors associated with subprophylactic anti-Xa included female sex (OR 2.90, p = 0.008), and Caprini score (OR 1.30, p = 0.035). Enoxaparin was protective against subprophylaxis compared to tinzaparin (OR 0.43, p = 0.029). CONCLUSIONS: Many HPB patients have subprophylactic anti-Xa levels, placing them at risk of VTE. Enoxaparin may be preferential, however, studies evaluating optimized prophylaxis are needed.

Relationship between anti-Xa level achieved with prophylactic low-molecular weight heparin and venous thromboembolism in trauma patients: A systematic review and meta-analysis.

BACKGROUND: Trauma patients have simultaneously high venous thromboembolism (VTE) and bleeding risk. Optimal chemoprophylaxis regimens remain unclear. This study aims to answer three questions for trauma patients. Is there any association between anti-Xa and VTE? Does dose adjustment improve prophylactic anti-Xa rates? Does dose adjustment improve anti-Xa adequacy and VTE compared with standard dosing? METHODS: Systematic search of MEDLINE, Embase, Scopus, and Web of Science occurred in May 2021. Two author reviews included trauma studies that evaluated low molecular weight heparin chemoprophylaxis, reported anti-Xa level, and evaluated more than one outcome. Data were dually extracted and estimated effects were calculated using RevMan 5.4 applying the Mantel-Haenszel method. Analysis 1 compared patients with peak anti-Xa of 0.2 IU/mL or greater or trough 0.1 IU/mL or greater to those with lower anti-Xa using VTE as the primary outcome. Analysis 2 reported the effect of dose adjustment on anti-Xa. Analysis 3 compared standard dosing to dose adjustment with the primary outcome being anti-Xa adequacy; secondary outcomes were VTE, pulmonary embolism, and bleeding complications. RESULTS: There were 3,401 studies evaluated with 24 being included (19 retrospective studies, 5 prospective studies). In analysis 1, achieving adequate anti-Xa was associated with reduced odds of VTE (4.0% to 3.1%; odds ratio [OR], 0.52; p = 0.03). Analysis 2 demonstrated that 768 (75.3%) patients achieved prophylactic anti-Xa with adjustment protocols. Analysis 3 suggested that dose-adjusted chemoprophylaxis achieves prophylactic anti-Xa more frequently (OR, 4.05; p = 0.007) but without VTE (OR, 0.72; p = 0.15) or pulmonary embolism (OR, 0.48; p = 0.10) differences. In subgroup analysis, anti-Xa dose adjustment also suggested no VTE reduction (OR, 0.68; p = 0.08). CONCLUSION: Patients with higher anti-Xa levels are less likely to experience VTE, and anti-Xa guided chemoprophylaxis increases anti-Xa adequacy. However, dose adjustment, including anti-Xa guided dosing, may not reduce VTE. LEVEL OF EVIDENCE: Systematic Review Meta-Analysis, Level IV.

Drug Resistance in Metastatic Breast Cancer: Tumor Targeted Nanomedicine to the Rescue.

Breast cancer, specifically metastatic breast, is a leading cause of morbidity and mortality in women. This is mainly due to relapse and reoccurrence of tumor. The primary reason for cancer relapse is the development of multidrug resistance (MDR) hampering the treatment and prognosis. MDR can occur due to a multitude of molecular events, including increased expression of efflux transporters such as P-gp, BCRP, or MRP1; epithelial to mesenchymal transition; and resistance development in breast cancer stem cells. Excessive dose dumping in chemotherapy can cause intrinsic anti-cancer MDR to appear prior to chemotherapy and after the treatment. Hence, novel targeted nanomedicines encapsulating chemotherapeutics and gene therapy products may assist to overcome cancer drug resistance. Targeted nanomedicines offer innovative strategies to overcome the limitations of conventional chemotherapy while permitting enhanced selectivity to cancer cells. Targeted nanotheranostics permit targeted drug release, precise breast cancer diagnosis, and importantly, the ability to overcome MDR. The article discusses various nanomedicines designed to selectively target breast cancer, triple negative breast cancer, and breast cancer stem cells. In addition, the review discusses recent approaches, including combination nanoparticles (NPs), theranostic NPs, and stimuli sensitive or "smart" NPs. Recent innovations in microRNA NPs and personalized medicine NPs are also discussed. Future perspective research for complex targeted and multi-stage responsive nanomedicines for metastatic breast cancer is discussed.

A gap analysis of the potential use of resuscitative endovascular balloon occlusion of the aorta (REBOA) in trauma at two major Canadian trauma centers.

OBJECTIVE: Uncontrolled hemorrhage poses significant morbidity and mortality among injured patients. Resuscitative endovascular balloon occlusion of the aorta (REBOA) utilizes a rapidly-administered minimally invasive transfemoral balloon catheter that is inflated for aortic occlusion, allowing for time to arrange definitive surgical or angiographic intervention. As indications for its use continue to evolve, this study sought to evaluate whether there is a potential need for REBOA implementation in two high-volume trauma centers in Edmonton. METHODS: Patient data within our provincial trauma registry was reviewed between 2015 and 2017 to identify major trauma patients (Injury Severity Score ≥ 12). Patients eligible for REBOA included patients with blunt or penetrating trauma to the torso or pelvis, AND death prior to discharge; and patients taken to the operating room or interventional radiology suite within 4 h of arrival. Charts were reviewed to determine if patients met current conventional criteria for REBOA. RESULTS: Out of 3415 trauma patients during our study period, 237 patients met the registry screen as potentially eligible for REBOA. After primary researcher review, 67 patients underwent full chart review and then 2 trauma surgeons determined that 38 (1.1% of the study population) met criteria for deploying REBOA. CONCLUSION: A small but significant number of trauma patients at the two trauma centers were identified as potential candidates for REBOA use. Implementation of a REBOA program should be done in alignment with existing clinical practice guidelines and professional society recommendations.

RéSUMé: OBJECTIF: L'hémorragie incontrôlée entraîne une morbidité et une mortalité importantes chez les patients blessés. Le clampage aortique par sonde d'occlusion aortique endovasculaire (resuscitative endovascular balloon occlusion of the aorta [REBOA]) utilise un cathéter à ballonnet transfémoral mini-invasif à administration rapide qui est gonflé pour l'occlusion aortique, ce qui laisse le temps d'organiser une intervention chirurgicale ou angiographique définitive. Alors que les indications de son utilisation continuent d'évoluer, cette étude a cherché à évaluer s'il y avait un besoin potentiel de mise en œuvre de REBOA dans deux centres de traumatologie à haut volume à Edmonton. MéTHODES: Les données sur les patients dans notre registre provincial des traumatismes ont été examinées entre 2015 et 2017 afin d'identifier les patients traumatisés majeurs (Score de gravité des blessures ≥ 12). Les patients éligibles au REBOA comprenaient des patients présentant un traumatisme contondant ou pénétrant au torse ou au bassin, ET le décès avant la sortie; et les patients conduits à la salle d'opération ou à la salle de radiologie interventionnelle dans les 4 heures suivant leur arrivée. Les graphiques ont été examinés pour déterminer si les patients répondaient aux critères conventionnels actuels de REBOA. RéSULTATS: Sur les 3 415 patients traumatisés pendant notre période d'étude, 237 patients ont répondu à l'examen du registre comme étant potentiellement éligibles pour le REBOA. Après examen par le chercheur principal, soixante-sept patients ont été soumis à un examen complet de leur dossier, puis deux chirurgiens traumatologues ont déterminé que 38 (1,1 % de la population étudiée) répondaient aux critères de déploiement de la REBOA. CONCLUSION: Un nombre restreint mais significatif de patients traumatisés dans les deux centres de traumatologie a été identifié comme des candidats potentiels à l'utilisation de REBOA. La mise en œuvre d'un programme REBOA doit se faire en conformité avec les directives de pratique clinique existantes et les recommandations de la société professionnelle.

Undertriage Despite Use of Geriatric-Specific Trauma Team Activation Guidelines : Who Are We Missing?

BACKGROUND: Elderly trauma patients are at risk for undertriage, resulting in substantial morbidity and mortality. The objective of this study was to determine whether implementation of geriatric-specific trauma team activation (TTA) protocols appropriately identified severely-injured elderly patients. METHODS: This single-center retrospective study evaluated all severely injured (injury severity score [ISS] >15), geriatric (≥65 years) patients admitted to our Level 1 tertiary-care hospital between January 2014 and September 2017. Undertriage was defined as the lack of TTA despite presence of severe injuries. The primary outcome was all-cause in-hospital mortality; secondary outcomes were mortality within 48 hours of admission and urgent hemorrhage control. A multivariable logistic regression analysis was performed to identify predictors of appropriate triage in this study. RESULTS: Out of 1039 severely injured geriatric patients, 628 (61%) did not undergo TTA. Undertriaged patients were significantly older and had more comorbidities. In-hospital mortality was 5% and 31% in the undertriaged and appropriately triaged groups, respectively (P < .0001). One percent of undertriaged patients needed urgent hemorrhage control, compared to 6% of the appropriately triaged group (P < .0001). One percent of undertriaged patients died within 48 hours compared to 19% in the appropriately triaged group (P < .0001). Predictors of appropriate triage include GCS, heart rate, systolic blood pressure, lactic acid, ISS, shock, and absence of dementia, stroke, or alcoholism. DISCUSSION: Geriatric-specific TTA guidelines continue to undertriage elderly trauma patients when using ISS as a metric to measure undertriage. However, undertriaged patients have much lower morbidity and mortality, suggesting the geriatric-specific TTA guidelines identify those patients at highest risk for poor outcomes.

Evaluation of trauma resources in rural northern Alberta identifies opportunities for improvement.

Background: The care of rural trauma patients in northern Alberta can be extremely challenging because of the vast geographic area, the limited access to health care facilities and the lack of adequate resources to manage severe injuries. Identifying gaps in equipment and personnel in rural centres can provide opportunities for improving the care of injured patients in these environments. We conducted a survey based on Canadian Accreditation Council quality indicators to evaluate trauma infrastructure and human resources in rural centres across northern Alberta. Methods: A standardized survey was developed to assess the availability of trauma-specific equipment and personnel across the prehospital and emergency department (ED) settings. The survey was distributed to 50 peripheral hospitals biannually from January 2017 to September 2018. Two-tailed paired t tests were used to evaluate changes in survey responses; a p value of less than 0.05 was considered statistically significant. Results: The survey response rate was 100%. By the end of the study period, there were significant improvements in the number of providers (p = 0.04), nurses (p = 0.01) and dedicated trauma resuscitation bays (p = 0.04) in the ED for managing injured patients. There were also significant increases in the availability of equipment, including advanced airway management tools (p = 0.02), rapid infusion devices (p = 0.02) and warmers (p = 0.04). Access to x-ray equipment (p = 0.03) and computed tomography (CT) scanners (p = 0.04) as well as equipment to support telehealth and teleconferencing (p = 0.04) increased during the study period. Access to, and supply of, blood products also increased significantly (p = 0.02) during the study period. Conclusion: Our study demonstrates that the trauma resources of rural health care centres may be evaluated in a standardized fashion centres, and the results point to opportunities to remedy gaps in equipment and personnel. Our methods may be applied to any trauma network that serves geographically large areas with a sparse distribution of health care facilities, to provide critical information for the optimization of resources in rural trauma.

Contexte: Les soins aux patients victimes de traumatismes en région rurale dans le nord de l'Alberta peuvent être très difficiles en raison de la superficie de la région, de l'accès limité aux établissements de santé et du manque de ressources pour soigner adéquatement les blessures graves. En repérant les lacunes en équipement et en personnel dans les établissements en région rurale, on peut créer des occasions d'améliorer les soins aux patients blessés dans ces milieux. Nous avons mené un sondage fondé sur les indicateurs de qualité du Conseil d'accréditation canadien pour évaluer les infrastructures et les ressources humaines en traumatologie dans les établissements des régions rurales du nord de l'Alberta. Méthodes: Un sondage standardisé a été créé pour évaluer la disponibilité des équipements et des ressources humaines en traumatologie en contexte préhospitalier et aux services d'urgence. Le sondage a été distribué 2 fois par année à 50 hôpitaux entre janvier 2017 et septembre 2018. Des tests t appariés ayant une hypothèse non nulle ont été utilisés pour évaluer les changements dans les réponses au sondage; les résultats ayant une valeur p < 0,05 étaient considérés comme statistiquement significatifs. Résultats: Le taux de participation au sondage était de 100 %. À la fin de la période étudiée, il y avait une amélioration significative du nombre de fournisseurs (p = 0,04), de personnel infirmier (p = 0,01) et d'espaces de réanimation réservés à la traumatologie (p = 0,04) dans les services d'urgence. Il y avait aussi une augmentation significative de la disponibilité de l'équipement, notamment des outils de prise en charge avancée des voies respiratoires (p = 0,02), des appareils de perfusion rapide (p = 0,02) et d'armoires chauffantes (p = 0,04). Les équipements de radiographie (p = 0,03) et de tomographie par ordinateur (p = 0,04) ainsi que les équipements facilitant la télémédecine et les téléconférences (p = 0,04) sont devenus plus accessibles pendant la période étudiée. Les réserves de produits sanguins et l'accès à ces produits a aussi augmenté de manière significative (p = 0,02). Conclusion: Notre étude montre que les ressources en traumatologie dans les établissements de santé en région rurale peuvent être évaluées de manière standardisée, et les résultats indiquent qu'il y a des occasions de combler les lacunes en équipement et en personnel. Notres méthodes peuvent être reproduites dans tout réseau de traumatologie couvrant un grand territoire où les établissements de santé sont dispersés, pour fournir des données critiques sur l'organisation des ressources de traumatologie en région rurale.

Methamphetamine augment HIV-1 Tat mediated memory deficits by altering the expression of synaptic proteins and neurotrophic factors.

Methamphetamine (METH) abuse is common among individuals infected with HIV-1 and has been shown to affect HIV replication and pathogenesis. These HIV-1 infected individuals also exhibit greater neuronal injury and higher cognitive decline. HIV-1 proteins, specifically gp120 and HIV-1 Tat, have been earlier shown to affect neurocognition. HIV-1 Tat, a viral protein released early during HIV-1 replication, contributes to HIV-associated neurotoxicity through various mechanisms including production of pro-inflammatory cytokines, reactive oxygen species and dysregulation of neuroplasticity. However, the combined effect of METH and HIV-1 Tat on neurocognition and its potential effect on neuroplasticity mechanisms remains largely unknown. Therefore, the present study was undertaken to investigate the combined effect of METH and HIV-1 Tat on behavior and on the expression of neuroplasticity markers by utilizing Doxycycline (DOX)-inducible HIV-1 Tat (1-86) transgenic mice. Expression of Tat in various brain regions of these mice was confirmed by RT-PCR. The mice were administered with an escalating dose of METH (0.1 mg/kg to 6 mg/kg, i.p) over a 7-day period, followed by 6 mg/kg, i.p METH twice a day for four weeks. After three weeks of METH administration, Y maze and Morris water maze assays were performed to determine the effect of Tat and METH on working and spatial memory, respectively. Compared with controls, working memory was significantly decreased in Tat mice that were administered METH. Moreover, significant deficits in spatial memory were also observed in Tat-Tg mice that were administered METH. A significant reduction in the protein expressions of synapsin 1, synaptophysin, Arg3.1, PSD-95, and BDNF in different brain regions were also observed. Expression levels of Calmodulin kinase II (CaMKII), a marker of synaptodendritic integrity, were also significantly decreased in HIV-1 Tat mice that were treated with METH. Together, this data suggests that METH enhances HIV-1 Tat-induced memory deficits by reducing the expression of pre- and postsynaptic proteins and neuroplasticity markers, thus providing novel insights into the molecular mechanisms behind neurocognitive impairments in HIV-infected amphetamine users.

Surgical intervention in pediatric trauma at a level 1 trauma hospital: a retrospective cohort study and report of cost data.

BACKGROUND: Given that the management of severely injured children requires coordinated care provided by multiple pediatric surgical subspecialties, we sought to describe the frequency and associated costs of surgical intervention among pediatric trauma patients admitted to a level 1 trauma centre in southwestern Ontario. METHODS: All pediatric (age < 18 yr) trauma patients treated at the Children's Hospital - London Health Sciences Centre (CH-LHSC) between 2002 and 2013 were included in this study. We compared patients undergoing surgical intervention with a nonsurgical group with respect to demographic characteristics and outcomes. Hospital-associated costs were calculated only for the surgical group. RESULTS: Of 784 injured children, 258 (33%) required surgery, 40% of whom underwent orthopedic interventions. These patients were older and more severely injured, and they had longer lengths of stay than their nonsurgical counterparts. There was no difference in mortality between the groups. Seventy-four surgical patients required intervention within 4 hours of admission; 45% of them required neurosurgical intervention. The median cost of hospitalization was $27 571 for the surgical group. CONCLUSION: One-third of pediatric trauma patients required surgical intervention, of whom one-third required intervention within 4 hours of arrival. Despite the associated costs, the surgical treatment of children was associated with comparable mortality to nonsurgical treatment of less severely injured patients. This study represents the most recent update to the per patient cost for surgically treated pediatric trauma patients in Ontario, Canada, and helps to highlight the multispecialty care needed for the management of injured children.

CONTEXTE: La prise en charge des enfants grièvement blessés nécessite la coordination des soins fournis dans le contexte de plusieurs surspécialités chirurgicales pédiatriques. Dans ce contexte, nous avons cherché à décrire la fréquence et les coûts des interventions chirurgicales chez les patients pédiatriques victimes de trauma admis dans un centre de traumatologie de niveau 1 dans le sud-ouest de l'Ontario. MÉTHODES: Tous les patients pédiatriques (moins de 18 ans) ayant subi un trauma traités à l'Hôpital pour enfants du Centre des sciences de la santé de London entre 2002 et 2013 ont été retenus pour l'étude. Nous avons comparé les caractéristiques démographiques et les résultats cliniques des patients ayant subi une intervention chirurgicale et de ceux n'en ayant pas subi. Les coûts d'hospitalisation n'ont été calculés que pour le premier groupe. RÉSULTATS: Parmi les 784 enfants à l'étude, 258 (33 %) avaient eu besoin d'une intervention chirurgicale; 40 % de ceux-ci avaient subi des interventions orthopédiques. Ces patients étaient plus âgés et plus grièvement blessés que les enfants n'ayant pas subi d'intervention chirurgicale, et leur séjour à l'hôpital était généralement plus long. Nous n'avons relevé aucune différence entre les 2 groupes quant à la mortalité. En outre, 74 des patients ayant subi une intervention chirurgicale ont dû être opérés dans les 4 heures suivant l'admission; 45 % d'entre eux ont eu besoin d'une intervention neurochirurgicale. Le coût médian d'une hospitalisation était de 27 571 $. CONCLUSION: Le tiers des patients pédiatriques victimes de trauma ont eu besoin d'une intervention chirurgicale, et le tiers de ceux-ci ont dû être opérés dans les 4 heures suivant leur arrivée. Malgré les coûts, le traitement chirurgical des enfants était associé à un taux de mortalité comparable à celui du traitement non chirurgical des patients blessés moins grièvement. Cette étude est la source d'information la plus récente sur le coût par patient associé au traitement chirurgical des enfants victimes de trauma en Ontario, et elle met en évidence le besoin de soins de multiples spécialités.

An Overview of Human Immunodeficiency Virus Type 1-Associated Common Neurological Complications: Does Aging Pose a Challenge?

With increasing survival of patients infected with human immunodeficiency virus type 1 (HIV-1), the manifestation of heterogeneous neurological complications is also increasing alarmingly in these patients. Currently, more than 30% of about 40 million HIV-1 infected people worldwide develop central nervous system (CNS)-associated dysfunction, including dementia, sensory, and motor neuropathy. Furthermore, the highly effective antiretroviral therapy has been shown to increase the prevalence of mild cognitive functions while reducing other HIV-1-associated neurological complications. On the contrary, the presence of neurological disorder frequently affects the outcome of conventional HIV-1 therapy. Although, both the children and adults suffer from the post-HIV treatment-associated cognitive impairment, adults, especially depending on the age of disease onset, are more prone to CNS dysfunction. Thus, addressing neurological complications in an HIV-1-infected patient is a delicate balance of several factors and requires characterization of the molecular signature of associated CNS disorders involving intricate cross-talk with HIV-1-derived neurotoxins and other cellular factors. In this review, we summarize some of the current data supporting both the direct and indirect mechanisms, including neuro-inflammation and genome instability in association with aging, leading to CNS dysfunction after HIV-1 infection, and discuss the potential strategies addressing the treatment or prevention of HIV-1-mediated neurotoxicity.

The Future Liver Remnant in Patients Undergoing the Associating Liver Partition with Portal Vein Ligation for Staged Hepatectomy (ALPPS) Maintains the Immunological Components of a Healthy Organ.

BACKGROUND AND AIMS: A short-interval, two-stage approach termed associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) increases the number of patients with extensive malignant disease of the liver and a small future liver remnant (FLR) that can undergo liver resection. While this approach results in accelerated liver hypertrophy of the FLR, it remains unknown whether this phenomenon is restricted to liver parenchymal cells. In the current study, we evaluated whether ALPPS alters the immunological composition of the deportalized lobe (DL) and the FLR. METHODS: In this prospective, single-center study, liver tissue from the DL and the FLR were collected intra-operatively from adult patients undergoing ALPPS for their liver metastases. The extent of hypertrophy of the FLR was determined by volumetric helical computed tomography. Flow cytometry and histological analyses were conducted on liver tissues to compare the frequency of several immune cell subsets, and the architecture of the liver parenchyma between both stages of ALPPS. RESULTS: A total of 12 patients completed the study. Histologically, we observed a patchy peri-portal infiltration of lymphocytes within the DL, and a significant widening of the liver cords within the FLR. Within the DL, there was a significantly higher proportion of B cells and CD4(+) T cells as well innate-like lymphocytes, namely mucosa-associated invariant T (MAIT) cells and natural killer T (NKT) cells following ALPPS. In contrast, the frequency of all evaluated immune cell types remained relatively constant in the FLR. CONCLUSION: Our results provide the first description of the immunological composition of the human liver following ALPPS. We show that following the ALPPS procedure, while the immune composition of the FLR remains relatively unchanged, there is a moderate increase in several immune cell populations in DL. Overall, our results support the continued utilization of the ALPPS procedure.

CD1d- and MR1-Restricted T Cells in Sepsis.

Dysregulated immune responses to infection, such as those encountered in sepsis, can be catastrophic. Sepsis is typically triggered by an overwhelming systemic response to an infectious agent(s) and is associated with high morbidity and mortality even under optimal critical care. Recent studies have implicated unconventional, innate-like T lymphocytes, including CD1d- and MR1-restricted T cells as effectors and/or regulators of inflammatory responses during sepsis. These cell types are typified by invariant natural killer T (iNKT) cells, variant NKT (vNKT) cells, and mucosa-associated invariant T (MAIT) cells. iNKT and vNKT cells are CD1d-restricted, lipid-reactive cells with remarkable immunoregulatory properties. MAIT cells participate in antimicrobial defense, and are restricted by major histocompatibility complex-related protein 1 (MR1), which displays microbe-derived vitamin B metabolites. Importantly, NKT and MAIT cells are rapid and potent producers of immunomodulatory cytokines. Therefore, they may be considered attractive targets during the early hyperinflammatory phase of sepsis when immediate interventions are urgently needed, and also in later phases when adjuvant immunotherapies could potentially reverse the dangerous state of immunosuppression. We will highlight recent findings that point to the significance or the therapeutic potentials of NKT and MAIT cells in sepsis and will also discuss what lies ahead in research in this area.

Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals.

Mild-to-moderate tobacco smoking is highly prevalent in HIV-infected individuals, and is known to exacerbate HIV pathogenesis. The objective of this study was to determine the specific effects of mild-to-moderate smoking on viral load, cytokine production, and oxidative stress and cytochrome P450 (CYP) pathways in HIV-infected individuals who have not yet received antiretroviral therapy (ART). Thirty-two human subjects were recruited and assigned to four different cohorts as follows: a) HIV negative non-smokers, b) HIV positive non-smokers, c) HIV negative mild-to-moderate smokers, and d) HIV positive mild-to-moderate smokers. Patients were recruited in Cameroon, Africa using strict selection criteria to exclude patients not yet eligible for ART and not receiving conventional or traditional medications. Those with active tuberculosis, hepatitis B or with a history of substance abuse were also excluded. Our results showed an increase in the viral load in the plasma of HIV positive patients who were mild-to-moderate smokers compared to individuals who did not smoke. Furthermore, although we did not observe significant changes in the levels of most pro-inflammatory cytokines, the cytokine IL-8 and MCP-1 showed a significant decrease in the plasma of HIV-infected patients and smokers compared with HIV negative non-smokers. Importantly, HIV-infected individuals and smokers showed a significant increase in oxidative stress compared with HIV negative non-smoker subjects in both plasma and monocytes. To examine the possible pathways involved in increased oxidative stress and viral load, we determined the mRNA levels of several antioxidant and cytochrome P450 enzymes in monocytes. The results showed that the levels of most antioxidants are unaltered, suggesting their inability to counter oxidative stress. While CYP2A6 was induced in smokers, CYP3A4 was induced in HIV and HIV positive smokers compared with HIV negative non-smokers. Overall, the findings suggest a possible association of oxidative stress and perhaps CYP pathway with smoking-mediated increased viral load in HIV positive individuals.

Molecular mechanisms involved in HIV-1 Tat-mediated induction of IL-6 and IL-8 in astrocytes.

BACKGROUND: HIV-associated neurocognitive disorders (HAND) exist in approximately 50% of infected individuals even after the introduction of highly active antiretroviral therapy. HIV-1 Tat has been implicated in HIV-associated neurotoxicity mediated through production of pro-inflammatory cytokines like IL-6 and IL-8 by astrocytes among others as well as oxidative stress. However, the underlying mechanism(s) in the up-regulation of IL-6 and IL-8 are not clearly understood. The present study was designed to determine the mechanism(s) responsible for IL-6 and IL-8 up-regulation by HIV-1 Tat. METHODS: SVG astrocytes were transiently transfected with a plasmid encoding HIV-1 Tat. The HIV-1 Tat-mediated mRNA and protein expression levels of both IL-6 and IL-8 in SVG astrocytes were quantified using real time RT-PCR and multiplex cytokine assay respectively. We also employed immunocytochemistry for staining of IL-6 and IL-8. The underlying signaling mechanism(s) were identified using pharmacological inhibitors and siRNA for different intermediate steps involved in PI3K/Akt, p38 MAPK and JNK MAPK pathways. Appropriate controls were used in the experiments and the effect of pharmacological antagonists and siRNA were observed on both mRNA expression and protein levels. RESULTS: Both IL-6/IL-8 mRNA and protein showed peak expressions at 6 hours and 96 hours post-transfection, respectively. Elevated levels of IL-6/IL-8 were also confirmed by immunocytochemistry. Our studies indicated that both NF-kB and AP-1 transcription factors were involved in IL-6 and IL-8 expression mediated by HIV-1 Tat; however, AP-1 was differentially activated for either cytokine. In the case of IL-6, p38δ activated AP-1 whereas JNK but not p38 MAPK was involved in AP-1 activation for IL-8 production. On the other hand both PI3K/Akt and p38 MAPK (ß subunit) were found to be involved in activation of NF-κB that led to IL-6 and IL-8 production. CONCLUSION: Our results demonstrate HIV-1 Tat-mediated induction of both IL-6 and IL-8 in a time-dependent manner in SVG astrocytes. Furthermore, we also showed the involvement of NF-κB and AP-1 transcription factors regulated by PI3/Akt, p38 MAPK and JNK MAPK upstream signaling molecules. These results present new therapeutic targets that could be used in management of HAND.

Recalcitrant prosthetic valve endocarditis requiring repeated reconstruction: running out of options.

In this report we describe a previously healthy 36-year-old man who presented with septic shock secondary to bacterial endocarditis with multiple cerebral, mesenteric, and peripheral embolic phenomena. He underwent emergent porcine prosthetic valve replacement with aortic annular reconstruction. Subsequently, he developed recalcitrant Candida parapsilosis endocarditis requiring treatment with multiple antifungal agents and 4 repeated complex reconstructions of the aortic root and fibrous trigones over 3 years, before the infection was successfully controlled. This case underscores the significant morbidity associated with fungal endocarditis and importance of an early combined medical and surgical approach.

A robust scoring system to evaluate sepsis severity in an animal model.

BACKGROUND: The lack of a reliable scoring system that predicts the development of septic shock and death precludes comparison of disease and/or treatment outcomes in animal models of sepsis. We developed a murine sepsis score (MSS) that evaluates seven clinical variables, and sought to assess its validity and reliability in an experimental mouse model of polymicrobial sepsis. METHODS: Stool collected from the cecum of C57BL/6 (B6) mice was dissolved in 0.9% normal saline (NS) and filtered, resulting in a fecal solution (FS) which was injected intraperitoneally into B6 mice. Disease severity was monitored by MSS during the experimental timeline. Blood and tissue samples were harvested for the evaluation of inflammatory changes after sepsis induction. The correlation between pro-inflammatory markers and MSS was assessed by the Spearman rank correlation coefficient. RESULTS: Mice injected with FS at a concentration of 90 mg/mL developed polymicrobial sepsis with a 75% mortality rate at 24 hours. The MSS was highly predictive of sepsis progression and mortality, with excellent discriminatory power, high internal consistency (Cronbach alpha coefficient = 0.92), and excellent inter-rater reliability (intra-class coefficient = 0.96). An MSS of 3 had a specificity of 100% for predicting onset of septic shock and death within 24 hours. Hepatic dysfunction and systemic pro-inflammatory responses were confirmed by biochemical and cytokine analyses where the latter correlated well with the MSS. Significant bacterial dissemination was noted in multiple organs. Furthermore, the liver, spleen, and intestine demonstrated histopathological evidence of injury. CONCLUSIONS: The MSS reliably predicts disease progression and mortality in an animal model of polymicrobial sepsis. More importantly, it may be used to assess and compare outcomes among various experimental models of sepsis, and serve as an ethically acceptable alternative to death as an endpoint.

An acute care surgery service expedites the treatment of emergency colorectal cancer: a retrospective case-control study.

INTRODUCTION: Emergency colorectal cancer (CRC) is a complex disease that requires multidisciplinary approaches for management. However, it is unclear whether acute care surgery (ACS) services can expedite the workup and treatment of complex surgical diseases such as emergency CRC. We sought to assess the impact of an Acute Care and Emergency Surgery Service (ACCESS) on wait-times for inpatient colonoscopy and surgical resection among emergency CRC patients. METHODS: This retrospective case-control study was conducted at a tertiary-care, university-affiliated, cancer centre in London, Ontario, Canada. All patients aged 18 or older who presented to the emergency department with a recent (within 48 hours) diagnosis of CRC, or were diagnosed with CRC after admission, were included in the study. Patients were either in the pre-ACCESS (July 1, 2007-June 31, 2010) or post-ACCESS (July 1, 2010-June 30, 2012) groups. A third group of emergency CRC patients treated at an adjacent cancer centre that lacked ACCESS (non-ACCESS) was evaluated separately. The primary outcome was time from admission to colonoscopy and surgery. RESULTS: A total of 149 patients (47 pre-ACCESS, 37 post-ACCESS, and 65 non-ACCESS) were identified. Only 19% (n = 9) of pre-ACCESS patients underwent inpatient colonoscopy, compared to 38% (n = 14) in the post-ACCESS group (p = 0.023). Additionally, 100% of patients in the post-ACCESS era underwent inpatient colonoscopy and surgery during the same admission, compared to only 44% of pre-ACCESS patients (p = 0.006). Median wait-times for inpatient colonoscopy (2.0 and 1.8 days for pre- and post-ACCESS groups respectively, p = 0.08) and surgical resection (1.6 and 2.3 days for pre- and post-ACCESS groups respectively, p = 0.40) were similar. CONCLUSIONS: Patients admitted to ACCESS underwent more inpatient colonoscopies and were more likely to have definitive surgery on that admission. ACS services can facilitate the workup and management of complex surgical diseases such as emergency CRC without delaying treatment.

Allocating operating room resources to an acute care surgery service does not affect wait-times for elective cancer surgeries: a retrospective cohort study.

INTRODUCTION: Acute care surgical services provide timely comprehensive emergency general surgical care while optimizing the use of limited resources. At our institution, 50% of the daily dedicated operating room (OR) time allocated to the Acute Care Emergency Surgery Service (ACCESS) came from previous elective general surgery OR time. We assessed the impact of this change in resource allocation on wait-times for elective general surgery cancer cases. METHODS: We retrospectively reviewed adult patients who underwent elective cancer surgeries in the pre-ACCESS (September 2009 to June 2010) and post-ACCESS (September 2010 to June 2011) eras. Wait-times, calculated as the time between booking and actual dates of surgery, were compared within assigned priority classifications. Categorical and continuous variables were compared using chi-square and Mann-Whitney U tests respectively. RESULTS: A total of 732 cases (367 pre-ACCESS and 365 post-ACCESS) were identified, with no difference in median wait-times (25 versus 23 days) between the eras. However, significantly fewer cases exceeded wait-time targets in the post-ACCESS era (p <0.0001). There was a significant change (p = 0.027) in the composition of cancer cases, with fewer breast cancer operations (22% versus 28%), and more colorectal (41% versus 32%) and hepatobiliary cancer cases (5% versus 2%) in the post-ACCESS era. CONCLUSION: These results suggest that shifting OR resources towards emergency surgery does not affect the timeliness of surgical cancer care. This study may encourage more centres to adopt acute care surgical services alongside their elective or subspecialty practices.

Implementation of an acute care emergency surgical service: a cost analysis from the surgeon's perspective.

BACKGROUND: Acute care surgical services provide comprehensive emergency general surgical care while potentially using health care resources more efficiently. We assessed the volume and distribution of emergency general surgery (EGS) procedures before and after the implementation of the Acute Care and Emergency Surgery Service (ACCESS) at a Canadian tertiary care hospital and its effect on surgeon billings. METHODS: This single-centre retrospective case-control study compared adult patients who underwent EGS procedures between July and December 2009 (pre-ACCESS), to those who had surgery between July and December 2010 (post-ACCESS). Case distribution was compared between day (7 am to 3 pm), evening (3 pm to 11 pm) and night (11 pm to 7 am). Frequencies were compared using the χ(2) test. RESULTS: Pre-ACCESS, 366 EGS procedures were performed: 24% during the day, 55% in the evening and 21% at night. Post-ACCESS, 463 operations were performed: 55% during the day, 36% in the evening and 9% at night. Reductions in night-time and evening EGS were 57% and 36% respectively (p < 0.001). Total surgeon billings for operations pre- and post-ACCESS were $281 066 and $287 075, respectively: remuneration was $6008 higher post-ACCESS for an additional 97 cases (p = 0.003). Using cost-modelling analysis, post-ACCESS surgeon billing for appendectomies, segmental colectomies, laparotomies and cholecystectomies all declined by $67 190, $125 215, $66 362, and $84 913, respectively (p < 0.001). CONCLUSION: Acute care surgical services have dramatically shifted EGS from nighttime to daytime. Cost-modelling analysis demonstrates that these services have cost-savings potential for the health care system without reducing overall surgeon billing.

CONTEXTE: La mise sur pied d'un service d'urgences chirurgicales permet d'offrir des soins de chirurgie générale d'urgence complets, tout en assurant une utilisation potentiellement plus efficiente des ressources en soins de santé. Nous avons évalué le volume et la distribution des interventions de chirurgie générale d'urgence (CGU) avant et après la mise sur pied d'un service de soins chirurgicaux d'urgence (SSCU) dans un hôpital de soins tertiaires canadien et mesuré son effet sur la facturation émise par les chirurgiens. MÉTHODES: Cette étude rétrospective cas­témoins réalisée dans un seul centre a comparé des patients adultes soumis à des interventions de CGU entre juillet et décembre 2009 (pré-SSCU) à ceux qui avaient subi une intervention chirurgicale entre juillet et décembre 2010 (post-SSCU). Nous avons comparé la distribution des cas entre les quarts de jour (de 7 heures à 15 heures), de soir (de 15 heures à 23 heures) et de nuit (de 23 heures à 7 heures). Nous avons utilisé le test χ2 pour comparer les fréquences. RÉSULTATS: Pendant la période pré-SSCU, 366 interventions de CGU ont été effectuées : 24 % durant le jour, 55 % durant la soirée et 21 % durant la nuit. Après la mise en place du SSCU, 463 opérations ont été effectuées : 55 % durant le jour, 36 % durant la soirée et 9 % durant la nuit. Les réductions observées au plan des CGU réalisées durant la nuit et la soirée ont été de 57 % et 36 %, respectivement (p < 0,001). La facturation totale soumise par les chirurgiens pour les interventions réalisées avant et après la mise en place du SSCU a été respectivement de 281 066 $ et de 287 075 $ : la rémunération a été de 6008 $ supérieure après la mise en place du SSCU, pour 97 cas additionnels (p = 0,003). L'analyse de modélisation des coûts a révélé qu'après la mise en place du SSCU, la facturation soumise par les chirurgiens pour les appendicectomies, les colectomies segmentaires, les laparotomies et les cholécystectomies a diminué de 67 190 $, 125 215 $, 66 362 $ et 84 913 $, respectivement (p < 0,001). CONCLUSION: Les services de soins chirurgicaux d'urgence ont considérablement modifié les interventions de CGU, les faisant passer des quarts de travail de nuit à ceux du jour. L'analyse de modélisation des coûts démontre que le SSCU recèle un potentiel d'économies pour le système de soins de santé sans réduire la facturation totale émise par les chirurgiens.