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Supplemental Figure 3: compares the effects of two NOS inhibitors on SP-increased cGMP in MCF-7 and MDA-231 cells.

Supplemental Figures Collated: All four supplemental data figures combined with description

Supplemental Figure 4: shows the response of MDA-231 xenografts to >30 days treatment with SP in terms of tumor growth measured as tumor volumes and by a Kaplan Meier analysis of animal survival.

Supplemental Figure 2: shows a time course of changes in BH4:BH2 in MCF7 cells after addition of SP. This established the time course used in the in vitro experiments.

Supplemental Figure 1: shows an example of the HPLC technique used to measure BH4:BH2 throughout the manuscript.

Background: Drug-resistant tuberculosis (DR-TB) is the major cause of mortality worldwide. Our objectives were to determine the distribution of DR-TB by sex, age groups, occupation, province, division, district, type of disease, type of drug resistance, treatment regimen and outcome of treatment in DR-TB population in D.I.Khan Division, Pakistan. Materials & Methods: This cross-sectional study was conducted in Department of Community Medicine, Gomal Medical College, D.I.Khan, Pakistan. A sample of 286 DR-TB patients was selected consecutively from population at risk. Sex, age groups, occupation, province, division and district were demographic while type of disease, type of drug resistance, treatment regimen and outcome of treatment were research variables. All variables being nominal were described by count, percentage & cumulative percentage with 95% confidence interval for proportion. Distribution of DR-TB patients by all the ten variables were substantiated by chi-square goodness-of-fit test. Results: Out of 286 DR-TB patients, 123 (43%) were men and 163 (57%) women. DR-TB cases were most prevalent in age group 15-44 years 172 (60.14%), housewife 140 (48.95%), Khyber Pakhtunkhwa 175 (61.19%), D.I.Khan Division 178 (62.24%) and district 121 (42.31%). Most common type of disease, drug resistance and treatment regimen was pulmonary TB 282 (98.60%), MDR 273 (95.45%) and longer treatment (n=273 MDR-TB) 246 (90.11%) respectively. Treatment success rate was 161 (56.29%). The observed prevalence by occupation, province, division, district and type of disease in our sample was similar to expected prevalence in population (p>.05 for all), while it was different from population by sex, age groups, type of drug resistance, regimen and treatment outcome (p

ObjectivesIn traumatically injured patients, excessive blood loss necessitating the transfusion of red blood cell (RBC) units is common. Indicators of early RBC transfusion in the pre-hospital setting are needed. This study aims to evaluate the association between hypothermia (MethodsWe completed an audit of all traumatically injured patients who had emergent surgery at a single tertiary care center between 2010 and 2014. Using multivariable logistic regression analysis, we evaluated the association between pre-hospital hypothermia and transfusion of ≥1 unit of RBC within 24 hours of arrival to the trauma bay.ResultsOf the 703 patients included to evaluate the association between hypothermia and RBC transfusion, 203 patients (29%) required a transfusion within 24 hours. After controlling for important confounding variables, including age, sex, coagulopathy (platelets and INR), hemoglobin, and vital signs (blood pressure and heart rate), hypothermia was associated with a 68% increased odds of transfusion in multivariable analysis (OR: 1.68; 95% CI: 1.11-2.56).ConclusionsHypothermia is strongly associated with RBC transfusion in a cohort of trauma patients requiring emergent surgery. This finding highlights the importance of early measures of temperature after traumatic injury and the need for intervention trials to determine if strategies to mitigate the risk of hypothermia will decrease the risk of transfusion and other morbidities.

Despite studies showing improved safety, efficacy, and cost-effectiveness of endoscopic resection for nonmalignant colorectal polyps, colectomy rates for nonmalignant colorectal polyps have been increasing in the United States and Europe. Given this alarming trend, we aimed to investigate whether colectomy rates for nonmalignant colorectal polyps are increasing or declining in a large, integrated, community-based healthcare system with access to advanced endoscopic resection procedures.We identified all individuals aged 50-85 years who underwent a colonoscopy between 2008 and 2018 and were diagnosed with a nonmalignant colorectal polyp(s) at the Kaiser Permanente Northern California integrated healthcare system. Among these individuals, we identified those who underwent a colectomy for nonmalignant colorectal polyps within 12 months after the colonoscopy. We calculated annual colectomy rates for nonmalignant colorectal polyps and stratified rates by age, sex, and race and ethnicity. Changes in rates over time were tested by the Cochran-Armitage test for a linear trend.Among 229,730 patients who were diagnosed with nonmalignant colorectal polyps between 2008 and 2018, 1,611 patients underwent a colectomy. Colectomy rates for nonmalignant colorectal polyps decreased significantly from 125 per 10,000 patients with nonmalignant polyps in 2008 to 12 per 10,000 patients with nonmalignant polyps in 2018 (P0.001 for trend). When stratified by age, sex, and race and ethnicity, colectomy rates for nonmalignant colorectal polyps also significantly declined from 2008 to 2018.In a large, ethnically diverse, community-based population in the United States, we found that colectomy rates for nonmalignant colorectal polyps declined significantly over the past decade likely because of the establishment of advanced endoscopy centers, improved care coordination, and an organized colorectal cancer screening program.

Previously, we demonstrated that nitric oxide (NO) synthase (NOS) is uncoupled in a wide range of solid tumors and that restoring NOS coupling with the tetrahydrobiopterin precursor sepiapterin (SP) inhibits tumor progression. Endothelial dysfunction characterizes the poorly functional vasculature of solid tumors, and since NO is critical for regulation of endothelial function we asked whether SP, by recoupling NOS, improves tumor vasculature structure and function-enhancing chemotherapeutic delivery and response to radiotherapy. MMTV-neu mice with spontaneous breast tumors were treated with SP by oral gavage and evaluated by multispectral optoacoustic tomographic analysis of tumor HbO2 and by tissue staining for markers of hypoxia, blood perfusion, and markers of endothelial and smooth muscle proteins. Recoupling tumor NOS activity results in vascular normalization observed as reduced tumor hypoxia, improved tumor percentage of HbO2 and perfusion, as well as increased pericyte coverage of tumor blood vessels. The normalized vasculature and improved tumor oxygenation led to a greater than 2-fold increase in radiation-induced apoptosis compared with radiation or SP alone. High-performance liquid chromatography analysis of tumor doxorubicin levels showed a greater than 50% increase in doxorubicin uptake and a synergistic effect on tumor cell apoptosis. This study highlights for the first time the importance of NOS uncoupling and endothelial dysfunction in the development of tumor vasculature and presents a new approach for improving the tumoricidal efficacies of chemotherapy and radiotherapy.

Hypothermia (36°C) exacerbates trauma-induced coagulopathy and worsens morbidity and mortality among severely injured trauma patients; there is a paucity of published data describing how well trauma centres adhere to standards regarding measurement of temperature, and best practices for preventing and treating hypothermia.We completed a retrospective quality audit of all severely injured trauma patients (Injury Severity Score (ISS≥20)) who had urgent surgery at Sunnybrook Health Sciences Centre (SHSC) between 2010 and 2014. Information regarding temperature monitoring was evaluated over the course of the initial resuscitation and admission. Independent risk factors for in-hospital mortality were elucidated through a multivariable regression analysis.Out of a total of 4492 trauma patients, 495 were severely-injured and went to the operating room (OPR) after being treated in the trauma bay (TB) at SHSC between 2010 and 2014. The majority of the patients were male (n=384, 77.6%) and had a blunt mechanism of injury (n=391, 79.0%). The median ISS score was 29 (interquartile range (IQR) 26, 35). Eighty-nine (17.9%) patients died; 26 (5.2%) of these patients died intra-operatively. Less than one fifth of patients (n=82,16.6%) received a temperature measurement during pre-hospital transport phase. Upon arrival to the TB, almost two-thirds (n=301, 60.8%) of patients had their temperature recorded and a similar proportion (n=175, 58.1%) of those patients were hypothermic (36°C). In the OPR, close to 80% (n=389, 78.6%) of patients had their temperature measured on both arrival; almost 60% (n=223, 57.3%) were hypothermic on arrival. Almost all patients had their temperature measured upon arrival to the ICU or specialized ward (n=450, 98.3%). Warming initiatives were documented in only 36 (7.3%) patients in the TB, yet documented in almost all patients in OR (n=464, 93.7%). An increased risk of in-hospital mortality was correlated with not taking a temperature measurement in the TB (Odds Ratio (OR) 2.86 (95% Confidence Interval (CI) [1.64-4.99]) or OPR (OR 4.66 (95% CI [2.50-8.69]).A majority of severely injured trauma patients are hypothermic well into the perioperative period after initial admission. An absence of having temperature measurement during initial hospitalization is associated with increased in-hospital mortality amongst this patient group. Quality improvement initiatives should aim to strive for ongoing temperature measurement as a key performance indicator and early prevention and treatment of hypothermia during initial resuscitation.

PURPOSE This study evaluated the proportion and characteristics of international medical graduates (IMGs) who have been disciplined by professional regulatory colleges in Canada in comparison with disciplined North American medical graduates (NAMGs). METHOD The authors compiled a database of the nature of professional misconduct and penalties incurred by disciplined physicians from January 2000 to May 2015 using public records. They compared discipline data for IMGs versus those for NAMGs, and calculated risk ratios (RRs) and 95% confidence intervals (CIs) for select outcomes. RESULTS There were 794 physicians disciplined; 922 disciplinary cases during the 15-year study period. IMGs composed an average of 23.4% (standard deviation = 1.1%) of the total physician population and represented one-third of disciplined physicians and discipline cases. The overall disciplinary rate for all Canadian physicians was 8.52 cases per 10,000 physician years (95% CI [7.77, 9.31]). This rate per group was higher for IMGs than for NAMGs (12.91 [95% CI (11.50, 14.43)] vs. 8.16 [95% CI (7.53, 8.82)] cases per 10,000 physician years, P < .01, and RR 1.58 (95% CI [1.38, 1.82]). IMGs were disciplined at significantly higher rates than NAMGs if they were trained in South Africa (RR 1.73 [95% CI (1.14, 2.51), P < .01), Egypt (RR 3.59 [95% CI (2.18, 5.52)], P < .01), or India (RR 1.66 [95% CI (1.01, 2.55)], P = .03). CONCLUSIONS IMGs are disciplined at a higher rate than NAMGs. Future initiatives should be focused to delineate the exact cause of this observation.

Background Decreased plasma fibrinogen concentration shortly after injury is associated with higher blood transfusion needs and mortality. In North America and the UK, cryoprecipitate transfusion is the standard-of-care for fibrinogen supplementation during acute haemorrhage, which often occurs late during trauma resuscitation. Alternatively, fibrinogen concentrate (FC) can be beneficial in trauma resuscitation. However, the feasibility of its early infusion, efficacy and safety remain undetermined. The objective of this trial was to evaluate the feasibility, effect on clinical and laboratory outcomes and complications of early infusion of FC in trauma. Methods Fifty hypotensive (systolic arterial pressure ≤100 mm Hg) adult patients requiring blood transfusion were randomly assigned to either 6 g of FC or placebo, between Oct 2014 and Nov 2015 at a tertiary trauma centre. The primary outcome, feasibility, was assessed by the proportion of patients receiving the intervention (FC or placebo) within one h of hospital arrival. Plasma fibrinogen concentration was measured, and 28-day mortality and incidence of thromboembolic events were assessed. Results Overall, 96% (43/45) [95% CI 86–99%] of patients received the intervention within one h; 95% and 96% in the FC and placebo groups, respectively (P=1.00). Plasma fibrinogen concentrations remained higher in the FC group up to 12 h after admission with the largest difference at three h (2.9 mg dL − 1 vs. 1.8 mg dL − 1; P Conclusions Early infusion of FC is feasible and increases plasma fibrinogen concentration during trauma resuscitation. Larger trials are justified.

BACKGROUND Physician rating websites are commonly used by the public, yet the relationship between web-based physician ratings and health care quality is not well understood. OBJECTIVE The objective of our study was to use physician disciplinary convictions as an extreme marker for poor physician quality and to investigate whether disciplined physicians have lower ratings than nondisciplined matched controls. METHODS This was a retrospective national observational study of all disciplined physicians in Canada (751 physicians, 2000 to 2013). We searched ratings (2005-2015) from the country’s leading online physician rating website for this group, and for 751 matched controls according to gender, specialty, practice years, and location. We compared overall ratings (out of a score of 5) as well as mean ratings by the type of misconduct. We also compared ratings for each type of misconduct and punishment. RESULTS There were 62.7% (471/751) of convicted and disciplined physicians (cases) with web-based ratings and 64.6% (485/751) of nondisciplined physicians (controls) with ratings. Of 312 matched case-control pairs, disciplined physicians were rated lower than controls overall (3.62 vs 4.00; PP=.81). Sexual misconduct was the only category in which mean ratings for physicians were higher than those for other disciplined physicians (3.63 vs 3.35; P=.003) CONCLUSIONS Physicians convicted for disciplinary misconduct generally had lower web-based ratings. Physicians convicted of sexual misconduct did not have lower ratings and were rated higher than other disciplined physicians. These findings may have future implications for the identification of physicians providing poor-quality care.

Background A massive hemorrhage protocol (MHP) enables rapid delivery of blood components in a patient who is exsanguinating pending definitive hemorrhage control, but there is variability in MHP implementation rates, content and compliance owing to challenges presented by infrequent activation, variable team performance and patient acuity. The goal of this project was to identify the key evidence-based principles and quality indicators required to develop a standardized regional MHP. Methods A modified Delphi consensus technique was performed in the spring and summer of 2018. Panellists used survey links to independently review and rate (on a 7-point Likert scale) 43 statements and 8 quality indicators drafted by a steering committee composed of transfusion medicine specialists and technologists, and trauma physicians. External stakeholder input from all hospitals in Ontario was sought. Results Three rounds were held with 36 experts from diverse clinical backgrounds. Consensus was reached for 42 statements and 8 quality indicators. Additional modifications from external stakeholders were incorporated to form the foundation for the proposed MHP. Interpretation This MHP template will provide the basis for the design of an MHP toolkit, including specific recommendations for pediatric and obstetrical patients, and for hospitals with limited availability of blood components or means to achieve definitive hemorrhage control. We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient comfort and safety, and, ultimately, improve patient outcomes.

BACKGROUND The optimal method of providing transfusion medicine (TM) education has not been determined. Transfusion Camp was established in 2012 at the University of Toronto as a centrally delivered TM education program for postgraduate trainees. The impact of Transfusion Camp on knowledge, attitudes, and self-reported behavior was evaluated. METHODS Didactic lectures (delivered locally, by webinar, or recorded) and locally facilitated team-based learning seminars were delivered over 5 days during the academic year to 8 sites: 7 in Canada and 1 in the United Kingdom. Knowledge assessment using a validated 20-question multiple-choice exam was conducted before and after Transfusion Camp. Attitudes and self-reported behavior were collected through a survey. RESULTS Over 2 academic years (July 2016 to June 2018), 390 trainees from 16 different specialties (predominantly anesthesia, 41%; hematology, 14%; and critical care, 7%) attended at least 1 day of Transfusion Camp. The mean pretest score was 10.3 of 20 (±2.9; n = 286) compared with posttest score of 13.0 (±2.8; n = 194; p < 0.0001). Lower pretest score and greater attendance (4-5 days compared with 1-3 days) were associated with larger improvement in posttest score; delivery format, specialty, and postgraduate year were not. Trainees reported an improvement in self-rated abilities to manage TM scenarios; 95% rated TM knowledge as very or extremely important in providing patient care; and 81% indicated that they had applied learning from Transfusion Camp into clinical practice. CONCLUSIONS Transfusion Camp increased TM knowledge, fostered a positive attitude toward TM, and enabled a self-reported positive impact on transfusion practice in postgraduate trainees. It is a novel and scalable approach to delivering TM education.

Objectives To evaluate the current state of transfusion medicine (TM) knowledge among obstetricians using a valid assessment tool. Background Transfusion issues are common in obstetrical patients. Methods Knowledge topics were identified and rated by experts in obstetrics, anaesthesia, haematology and TM using a modified Delphi method. A knowledge assessment tool was developed and validated during pilot testing. The assessment tool, consisting of 15 multiple choice questions, was administered electronically to members of the Society of Obstetricians and Gynaecologists of Canada (SOGC). Results A total of 192 SOGC members completed the assessment tool: 121 faculty obstetricians and 71 trainees. The average score was 65·8% ± 15·5. Scores for faculty were higher than trainees (68·9% ± 13·5 vs 60·6% ± 17·2; P

Massive transfusion protocols became common practice between 2006 and 2010. The terminology of ‘massive transfusion protocol’ was improved to ‘massive haemorrhage protocol (MHP)’ with the astute recognition that at the start of such a protocol, it is unclear which patients will meet the definition of massive transfusion (10 U/24 h). Despite the majority of the literature being reported from the trauma population, hospitals have generally adopted a single MHP for all patients. It remains unclear whether the same protocol can be used for all patients. MHPs assist with the prevention and management of the acute coagulopathy of trauma/shock (ACOTS). The goals of a MHP are to improve haemostasis, communication and patient outcomes. The protocol must be specific for an individual hospital, depending on factors such as prehospital transport times, distance from laboratory to trauma and operating rooms, patient populations served and types of tests available. The key components of a MHP are the 6Ts: triggering of the protocol, laboratory testing, tranexamic acid, temperature maintenance, transfusion support and termination of the protocol when haemostasis is achieved. The evidence and importance of each of these steps will be discussed in detail. It is also critical that a quality assurance programme supports the MHP. Poor compliance with the institutional MHP is associated with inferior survival. Each MHP activation should be followed by a formal debrief by the team. Audits should be performed to determine compliance and to inform annual update of the MHP. Formal training and/or simulation should be a core part of the policy.

Background Physician rating websites are commonly used by the public, yet the relationship between web-based physician ratings and health care quality is not well understood. Objective The objective of our study was to use physician disciplinary convictions as an extreme marker for poor physician quality and to investigate whether disciplined physicians have lower ratings than nondisciplined matched controls. Methods This was a retrospective national observational study of all disciplined physicians in Canada (751 physicians, 2000 to 2013). We searched ratings (2005-2015) from the country’s leading online physician rating website for this group, and for 751 matched controls according to gender, specialty, practice years, and location. We compared overall ratings (out of a score of 5) as well as mean ratings by the type of misconduct. We also compared ratings for each type of misconduct and punishment. Results There were 62.7% (471/751) of convicted and disciplined physicians (cases) with web-based ratings and 64.6% (485/751) of nondisciplined physicians (controls) with ratings. Of 312 matched case-control pairs, disciplined physicians were rated lower than controls overall (3.62 vs 4.00; P Conclusions Physicians convicted for disciplinary misconduct generally had lower web-based ratings. Physicians convicted of sexual misconduct did not have lower ratings and were rated higher than other disciplined physicians. These findings may have future implications for the identification of physicians providing poor-quality care.

BACKGROUND Despite reducing mortality, the use of intravenous (IV) corticosteroids has not significantly reduced inpatient colectomy rates among hospitalized patients with ulcerative colitis (UC). Whether the occurrence of colectomy, estimated at 20–30% in this population in the prebiologic era, remains elevated is unknown. Methods A retrospective cohort study was conducted among health plan members of an integrated health care delivery organization that serves approximately 4.0 million members in urban, suburban, and semi-rural regions throughout Northern California. The study population consisted of 524 health plan members age >18 years of age with a 1) diagnosis of ulcerative colitis (ICD-9 code 556; ICD-10 code K51); 2) first hospitalization between 2009 and 2017 coded with ulcerative colitis as the primary cause for admission; 3) no prior hospitalizations for UC; 4) at least 1 year of continuous membership prior to the index hospitalization; 5) No dispensing of biologic therapy (infliximab, adalimumab, golimumab, vedolizumab) recorded prior to hospitalization; 6) No record of Clostridium difficile or cytomegalovirus infection during the hospitalization or 30 days prior. The primary outcome was the occurrence of colectomy during the index hospitalization and up to 12 months after hospitalization. Additional outcomes assessed were trends in colectomy over this time period and predictors for colectomy during the index hospitalization. Results A total of 5.3% of UC patients underwent colectomy during the index hospitalization (95%CI 3.3–7.3%) and 11.9% underwent colectomy within the first year after hospitalization (95% CI: 9.1–14.6%). Inpatient colectomy declined from 6.5% (95%CI: 2.5–10.6%) in 2009–2010 to 3.4% (95%CI: 3.3–7.3%) in 2015–2017. Colectomy in the first year after admission declined from 15.7% (95%CI 10.0–21.4%) in 2009–2011 to (10.1%; 95% CI: 5.4–14.7) in 2015–2017. A total of 16.3% of patients received infliximab in the hospital and 36.3% received within the first year of admission. In a multivariable model, the 2015–2017 cohort experienced a 64% reduction in inpatient colectomy compared to the 2009–2011 cohort (OR 0.36; 95%CI: 0.11–1.14, p=0.082) and a 54% reduction in colectomy in the first year (OR 0.46; 95%CI: 0.22–0.96, p=0.038). A prior study between 1998–2004 in this same population showed colectomy rates of 20% during the index hospitalization and 30% at 1 year. Conclusion Colectomy within the first year after hospital admission for UC has declined over time in the modern era of biologics with a magnitude of colectomy that is lower than the historical rate of 20–30%. Our data imply cause for optimism that the natural history of colectomy in acute severe UC may be different and modifiable in the modern biologic era compared to the past.

The objectives for preparing this article were to review the historical context and epidemiology surrounding the North American prescription opioid crisis, to summarize the evidence regarding the benefits and harms of long-term opioid therapy for non-cancer pain, and to outline ways in which anesthesiologists may help ameliorate the problem. We searched PubMed, Google Scholar, and EMBASE™ for relevant articles using various search terms, including pain, opioid epidemic, history of opioid use, perioperative care, and addiction. Related citations were further explored and searched depending on the specific subtopic of interest. In the 1980s and early 1990s, opioids were infrequently used for the treatment of chronic pain. Thereafter, however, physicians were gradually inculcated with the message that long-term opioid therapy was a safe and effective treatment option for patients with chronic non-cancer pain. Pharmaceutical companies supported this growing movement and employed aggressive and sometimes misleading marketing strategies for new opioid formulations. As a result, the practice of prescribing opioids flourished in the late 1990s. The surge in prescribing opioids was accompanied by a marked increase in opioid-related morbidity and mortality. This change in practice transpired despite the absence of randomized trials showing clinically significant benefit from the long-term use of opioids. Subsequently, however, a large and growing body of evidence has emerged quantifying the harms associated with long-term opioid therapy. Anesthesiologists widely prescribe opioids for acute and chronic pain; yet, as a group, they may be largely unaware of the current state of this growing epidemic and what role they can play to rectify this problem. Anesthesiologists are well positioned to take a leadership role in the management of postoperative discharge opioid therapy in an effort to curb the overutilization of opioids. Furthermore, anesthesiologists who regularly prescribe opioids for chronic pain patients should appreciate the limited evidence base for this practice and communicate the risks of opioid therapy to their patients.

Thoracic X-ray therapy (XRT), used in cancer treatment, is associated with increased risk of heart failure. XRT-mediated injury to the heart induces an inflammatory response leading to cardiomyopathy. The aim of this study was to determine the role of inter-leukin (IL)-1 in response to XRT injury to the heart and on the cardiomyopathy development in the mouse. Female mice with genetic deletion of the IL-1 receptor type I (IL-1R1 knockout mice [IL-1R1 KO]) and treatment with recombinant human IL-1 receptor antagonist anakinra, 10 mg/kg twice daily for 7 d, were used as independent approaches to determine the role of IL-1. Wild-type (wt) or IL-1R1 KO mice were treated with a single session of XRT (20 or 14 gray [Gy]). Echocardiography (before and after isoproterenol challenge) and left ventricular (LV) catheterization were performed to evaluate changes in LV dimensions and function. Masson’s trichrome was used to assess myocardial fibrosis and pericardial thickening. After 20 Gy, the contractile reserve was impaired in wt mice at d 3, and the LV ejection fraction (EF) was reduced after 4 months when compared with sham-XRT. IL-1R1 KO mice had preserved contractile reserve at 3 d and 4 months and LVEF at 4 months after XRT. Anakinra treatment for 1 d before and 7 d after XRT prevented the impairment in contractile reserve. A significant increase in LV end-diastolic pressure, associated with increased myocardial interstitial fibrosis and pericardial thickening, was observed in wt mice, as well as in IL-1R1 KO-or anakinra-treated mice. In conclusion, induction of IL-1 by XRT mediates the development of some, such as the contractile impairment, but not all aspects of the XRT-induced cardiomyopathy, such as myocardial fibrosis or pericardial thickening.

Background Physician misconduct adversely affects patient safety and is therefore of societal importance. Little work has specifically examined re-disciplined physicians. A study was conducted to compare the characteristics of re-disciplined to first-time disciplined physicians. Methods A retrospective review of Canadian physicians disciplined by medical boards between 2000 and 2015 was conducted. Physicians were divided into those disciplined once and those disciplined more than once. Differences in demographics, transgressions, and penalties were evaluated. Results There were 938 disciplinary events for 810 disciplined physicians with 1 in 8 ( n = 101, 12.5%) being re-disciplined. Re-disciplined physicians had up to six disciplinary events in the study period and 4 (4.0%) had events in more than one jurisdiction. Among those re-disciplined, 94 (93.1%) were male, 34 (33.7%) were international medical graduates, and 88 (87.1%) practiced family medicine ( n = 59, 58.4%), psychiatry ( n = 11, 10.9%), surgery ( n = 9, 8.9%), or obstetrics/gynecology ( n = 9, 8.9%). The proportion of obstetrician/gynecologists was higher among re-disciplined physicians (8.9% vs. 4.2%, p = 0.048). Re-disciplined physicians had more mental illness (1.7% vs. 0.1%, p = 0.01), unlicensed activity (19.2% vs. 7.2%, p 0.01), and less sexual misconduct (20.1% vs. 27.9%, p = 0.02). License suspension occurred more frequently among those re-disciplined (56.8% vs. 48.0%, p = 0.02) as did license restriction (38.4% vs. 26.7%, p 0.01). License revocation was not different between cohorts (10.9% vs. 13.5%, p = 0.36). Conclusion Re-discipline is not uncommon and underscores the need for better identification of at-risk individuals and optimization of remediation and penalties. The distribution of transgression argues for a national disciplinary database that could improve communication between jurisdictional medical boards.

Considerable progress has been made in recent years in understanding platelet biology and in strengthening the clinical evidence base around platelet transfusion thresholds and appropriate platelet dosing. Platelet alloimmunization rates have also declined. Nevertheless, controversies and uncertainties remain that are relevant to how these products can best be used for the benefit of platelet transfusion recipients. Platelets are unique among the blood products directly derived from whole blood or apheresis donations in requiring storage, with shaking, at ambient temperature. Storage is accordingly constrained between the need to limit the growth of any microbes in the product and the need to minimize losses in platelet function associated with storage. Proteomic and genomic approaches are being applied to the platelet storage lesion. Platelet inventory management is made challenging by these constraints. Although bacterial screening has enhanced the safety of platelet transfusions, pathogen reduction technology may offer further benefits. Continuing clinical investigations are warranted to understand the value of transfusing platelets prophylactically or only in response to bleeding in different patient groups and how best to manage the most grievously injured trauma patients. Patients refractory to platelet transfusions also require expert clinical management. The engineering of platelet substitute products is an active area of research, but considerable hurdles remain before any clinical uses may be contemplated. Roles for platelets in biological areas distinct from hemostasis are also emerging. Platelet utilization is variably affected by all of the above factors, by demographic changes, by new medications, and by new patient care approaches.

Background: The cornerstone of a massive hemorrhage protocol (MHP) is the rapid delivery of blood components to mitigate the consequences of hemorrhagic shock, coagulopathy, and hypothermia in the exsanguinating patient pending definitive hemorrhage control. MHPs are used to facilitate protocol activation/termination, mobilize an interdisciplinary team, provide immediate access to blood, prioritize rapid blood testing, and commence hypothermia-prevention strategies. Non-randomized, before-after implementation studies have found an association between MHPs and improved patient outcomes, including mortality. There is variability in MHP implementation rates, content, and protocol compliance due to challenges presented by infrequent activation, variable team performance, and patient acuity. Methods: We used a modified Delphi technique to establish the framework for a standardized Provincial MHP toolkit and develop quality indicators. We assembled a panel of 36 content experts to represent relevant stakeholders at 150 Ontario hospitals. Panelists included physicians, nurses, and technologists from anesthesia, trauma, obstetrics, hematology, transfusion, emergency, transport, critical care, as well as representation by blood suppliers and patients. The group represented the diverse geographic healthcare program including academic, pediatric, suburban, and small rural hospitals. Panelists were required to attend a two-day MHP forum and complete all rounds of the Delphi. Panelists used digital surveys (LimeSurvey, Hamburg, Germany) to independently review 43 statements and 8 quality indicators drafted by a steering committee. Each statement was rated on a 7-point Likert scale from "definitely should not" to "definitely should include". Disposition of items was based on critieria determined a priori on the median Likert score. Round 1: (1) score at least >5.5 incorporated as written, (2) 2.6-5.4, discussed at the forum with all panelists, with a 2nd round revision, (3) 5.5, accepted, (2) 2.4-5.4, rewritten and sent for round 3, (3) Results: After 3 rounds, consensus was reached for 42 statements and 8 quality indicators. A 100% response rate was achieved from panelists in all three rounds. There were four main areas that required additional rounds and major modifications: (1) selection of the name of the protocol; (2) selection of the laboratory resuscitation targets; (3) determination of the pack configurations; and, (4) clarification of the role of rVIIa. The obstacle to selecting a unified name for the protocol was that many of the hospitals already had longstanding MHPs with specific names. Consensus on the laboratory targets and pack configuration was achieved by splitting statements into sub-sections. The rVIIa statement required three rounds of review to ensure the phrasing satisfied all the panelists for this controversial therapy. Interpretation: We believe that harmonization of MHPs in our region will simplify training, increase uptake of evidence-based interventions, enhance communication, improve patient safety, and ultimately improve outcomes. We highlight areas that need additional study: (1) RCTs are needed to determine if MHPs improve patient outcomes. (2) A "streamlined" version for community hospitals for stabilization before transfer to a tertiary care centre must be tested. (3) Activation and termination criteria have not been validated. (4) The frequency and type of laboratory testing has not been investigated. (5) Laboratory targets for resuscitation must be tested. (6) Does maintaining normothermia decrease transfusion? (7) Can fibrinogen concentrates and PCCs can be considered equivalent to cryoprecipitate and plasma, respectively? (8) Does compliance with the selected quality indicators result in improved outcome? These MHP recommendations will provide the basis for the design of local MHPs including specific recommendations for pediatric patients and for hospitals where definitive hemorrhage control may not be available. Disclosures Arnold: Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Rigel: Consultancy, Research Funding; Principia: Consultancy. Pai:Novartis: Honoraria. Sholzberg:Takeda: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Baxter: Honoraria, Research Funding. Zeller:Canadian Blood Services: Consultancy; Pfizer: Other: Advisory Board; Ontario Ministry of Health and Long Term Care: Consultancy. Pavenski:Ablynx: Honoraria, Research Funding; Bioverativ: Research Funding; Shire: Honoraria; Alexion: Honoraria, Research Funding; Octapharma: Research Funding.

Previous studies discussing the risk of medical misconduct amongst anesthesiologists differ in their conclusions. In Canada, there is a paucity of data regarding demographic information, disciplinary findings, and penalties received by anesthesiologists. The aim of this study was to identify potential characteristics for discipline within the specialty of anesthesiology by ascertaining disciplinary findings and types of penalties received by anesthesiologists and comparing these with cases of disciplinary action against other Canadian physicians.Using a retrospective cohort design, we constructed a database of all Canadian physicians disciplined by their respective provincial and territorial regulatory colleges between 2000-2011. We collected and compared physician demographic information, types of disciplinary findings, and penalties received by anesthesiologists and other physicians during that time period.Between 2000-2011, various physicians were disciplined 721 times in Canada. Nine anesthesiologists were found guilty of 11 (1.5%) disciplinary findings. One anesthesiologist was disciplined three separate times. All anesthesiologists subject to discipline were males, ten (90.9%) were independent practitioners, and almost two-thirds (63.6%) were international medical graduates. The most common types of disciplinary findings were related to standard of care issues, inappropriate prescribing, and fraudulent behaviour. Anesthesiologists appeared less likely than other physicians to be disciplined for sexual misconduct and unprofessional behaviour.Anesthesiologists in Canada have been subject to low rates of disciplinary action. Specifically, there have been low rates of sexual misconduct and unprofessional behaviour. Interventions to reduce disciplinary findings in anesthesiology could be directed toward bolstering education relating to standard of care issues, prescribing practices, and fraudulent behaviour.

Postoperative epidural analgesia is effective and widely utilised after major abdominal surgery. Spinal haematoma is a rare and devastating complication after epidural analgesia. Well-established risk factors for the development of spinal haematoma after neuraxial procedures have been documented. We present the case of a patient with normal pre-operative coagulation parameters who developed a spinal haematoma more than 24 h after removal of an epidural catheter; she had been without oral intake for only 4 days during which time she developed vitamin K-deficient coagulopathy. Clinicians should consider pre-operative screening of coagulation (International Normalised Ratio), or giving vitamin K supplementation, before performing neuraxial procedures in patients who are at risk of developing vitamin K deficiency or coagulopathy in the peri-operative period.

Transfusion-associated circulatory overload (TACO) is an important and potentially injurious complication of transfusion that is underappreciated by clinicians. Risk factors for TACO include being at an extreme of age, having preexisting cardiac and/or (potentially) renal dysfunction, acute myocardial infarction, and individuals receiving plasma. Keys to preventing TACO, aside from identifying high-risk individuals, should be multifaceted. We advocate for the widespread use of pretransfusion checklists and implementation of nonemergent transfusion protocols. We suggest the regular use of pretransfusion diuretics in high-risk individuals. When a transfusion is required, we believe that "critical" nursing supervision and leadership are instrumental in the coordination of slow transfusion rates on computerized infusion pumps and ensuring patients are appropriately monitored. We believe that using these methodologies on a global scale will prevent many TACO events and minimize the severity when it does occur.

High levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) are hallmarks of solid tumors, promoting genomic instability as well as uncontrolled proliferation. In inflammatory diseases such as diabetes, hypertension, atherosclerosis and cancer, loss of nitric oxide (NO) production is a common feature. Recent experiments demonstrated that under these conditions the relative levels of the nitric oxide synthase (NOS) cofactor, tetrahydrobiopterin (BH4), are relatively low resulting in an “uncoupled NOS” and reduced NO bioavailability and increased ROS/RNS. Similar evidence suggest that NOS uncoupling is also a critical “switching mechanism” essential for tumor progression. Furthermore, uncoupling can be exploited therapeutically as both in vitro and in vivo treatment with the BH4 precursor, Sepiapterin (SP), restores NOS coupling and shifts the balance of signaling from ROS/RNS and pro-proliferative to NO dependent and anti-proliferative pathways.

To the Editor, The coagulopathic patient with right ventricular failure presents a conundrum to the perioperative clinician. Because these patients are preload dependent, hemorrhage may rapidly result in cardiogenic shock and end-organ ischemia. Acute coagulation factor replacement to correct factor deficiencies and reverse bleeding entails the transfusion of a large volume of plasma (10-15 mL kg), which will increase most coagulation factors by 20-30% so as to approach the 30-40% target levels considered adequate for hemostasis. In turn, however, such large transfusion volumes can potentially decrease left ventricular preload and cardiac output through ventricular interdependence. Furthermore, when the surgical setting is cardiothoracic, volume overload may promote catastrophic wound or graft dehiscence. When confronted with such complex coagulopathic patients, we have administered the combination of prothrombin complex concentrates (PCCs) with cryoprecipitate as a lower-volume alternative to plasma transfusion. The combination of 1,000 units of a four-factor prothrombin complex and 10 units of cryoprecipitate provides most coagulation factors in doses comparable with four units of plasma, but at less than 15% of the volume (Table). We acknowledge that neither Factor V nor Factor XI is present in significant quantities in either PCCs or cryoprecipitate but propose that these shortfalls are unlikely to be clinically meaningful. The platelet transfusions that many hemorrhaging patients require (particularly in the setting of the acquired thrombasthenia of cardiopulmonary bypass circuits) likely provide an alternative source of Factor V, as 20% of circulating Factor V is contained within platelet alpha granules. While Factor XI concentrates are available, they are not currently licensed in Canada and are therefore difficult to obtain. Furthermore, the significance of not replenishing Factor XI in a patient with global coagulopathy is unclear. In patients with congenital Factor XI deficiency, for example, there is a poor correlation between factor levels and bleeding tendency, possibly reflecting the ability of tissue-factor(TF)/Factor VII to activate Factor IX, Factor XI’s natural substrate. As one of the hemostatic mechanisms of Factor XI is the induction of thrombin activatable fibrinolysis inhibitor, the co-administration of antifibrinolytic medications, such as tranexamic acid (considered a standard of care in patients undergoing cardiopulmonary bypass surgery), may also provide some compensation for relative Factor XI deficiency in hemorrhaging patients. Given the above, with the long circulating half-life of Factor XI at 50 hr and its thrombogenicity when plasma levels exceed 70%, we do not endorse specific replacement in this setting. Our anecdotal experience regarding the hemostatic efficacy of PCCs when combined with cryoprecipitate suggests that the combination may be a useful alternative to plasma in patients with global coagulopathy who are unable to tolerate plasma transfusions, particularly if they are already being managed concurrently with platelet transfusions and A. Alam, MD (&) C. Cserti-Gazdewich, MD J. Pendergrast, MD Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, ON, Canada e-mail: asim.alam@sunnybrook.ca

Introduction: Radiation therapy (XRT) used for the treatment of cancer, can expose the heart to the radiation beam causing cardiac injury. However, fatigue and exercise intolerance are common symptoms in patients treated with XRT for different types of cancer, in which the XRT field does not involve the heart. Hypothesis: We hypothesize that impaired cardiac reserve may occur even when the XRT field is distant from the heart (‘out of target effect’). Methods: C57BL/6J female mice underwent two different radiation treatments (20 Gray, single dose) using a Small Animal Radiation Research Platform: a) the isocenter was pointed to the right lung sparing the heart (‘out of target’) and b) the heart was chosen as isocenter, as positive control. An additional group of mice were sham-irradiated, as negative control. Transthoracic echocardiography was used to assess the left ventricular ejection fraction (LVEF) at baseline and the contractile reserve expressed as percentage change in the LVEF measured at rest (LVEFr) and 3 minutes after intraperitoneal administration of the β-adrenergic agonist, isoproterenol (LVEFi)[(LVEFi-LVEFr)/LVEFr]*100]. Results: Three days after radiation treatment irradiated and sham mice showed normal LVEF at rest. However, the ‘out of target’ irradiation group showed a significant impairment in cardiac contractile reserve compared with sham, and similar to the ‘on target’ group (Figure). Conclusions: ‘Out of target’ radiation therapy leads to impaired cardiac contractile reserve in the mouse.

Physician misconduct is of serious concern to patient safety and quality of care. Currently, there are limited data on disciplinary proceedings involving internal medicine (IM) physicians. The aim of this study was to investigate the number and nature of disciplinary cases among IM physicians compared with those of other disciplined physicians. Our retrospective study reviewed information from all provincial Colleges of Physicians and Surgeons (CPS) and compiled a database of all disciplined physicians from 2000 to 2013 in Canada. Disciplinary rate differences (RDs) were calculated for IM physicians and compared with other physicians. From 2000 to 2013, overall disciplinary rates were low (9.6 cases per 10,000 physician years). There were 899 disciplinary cases, 49 of which involved 45 different IM physicians. IM physicians comprised 10.8% of all disciplined physicians and were disciplined at a lower rate than non-IM physicians, incurring 5.18 fewer cases per 10,000 physician years than other physicians (95% confidence interval [CI] 3.62–6.73; P

Despite multimodal approaches to treatment, postpartum hemorrhage (PPH) is a life-threatening condition whose incidence continues to rise. In developing areas, such as sub-Saharan Africa, PPH is the leading cause of maternal mortality. Tranexamic acid (TXA) is a possible prophylactic treatment for the prevention of PPH. We performed a systematic review and meta-analysis of randomized trials comparing prophylactic TXA vs placebo or no treatment in term parturients to quantify the effects of prophylactic TXA administration on peripartum bleeding outcomes. The meta-analysis was performed using a random-effects model. The outcomes assessed were (i) incidence of PPH, (ii) mean blood loss (in milliliters) within 24hours, (iii) incidence of red blood cell transfusion within 24hours, (iv) use of additional uterotonics, (v) minor side effects (ie, nausea, vomiting, headache, etc), (vi) major venous thromboembolism, (vii) length of hospital stay, and (viii) mortality. Eighteen trials (3846 subjects) were included in the quantitative analysis, with 1935 patients receiving TXA. The studies were of poor to moderate quality. Prophylactic TXA administration was associated with a decreased incidence of PPH after delivery (odds ratio [OR], 0.32; 95% confidence interval [CI], 0.17-0.59; P = .0006), a reduction in mean blood loss by 149.1mL (95% CI, 112.9-185.2; P < .00001), and a reduction in red blood cell transfusions (OR, 0.28; 95% CI, 0.15-0.49; P < .00001) while also being associated with a reduction in the use of additional uterotonics (OR, 0.45; 95% CI, 0.30-0.66; P < .00001). Minor side effects were more common in those who received TXA (OR, 2.51; 95% CI, 1.69-3.74; P < .00001). There appeared to be no increased risk of venous thromboembolism and no difference in length of hospital stay associated with TXA use. Although prophylactic TXA administration may be associated with improved peripartum bleeding, existing evidence is insufficient for any definitive recommendations secondary to the poor to moderate quality of the literature. A large well-designed, methodologically sound, randomized controlled trial is needed to better delineate the true effect size and address potential safety concerns.

Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-d-glucose–deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth–promoting and antiapoptotic signaling properties. Implications: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth. Mol Cancer Res; 13(6); 1034–43. ©2015 AACR . This article is featured in Highlights of This Issue, [p. 955][1] [1]: /lookup/volpage/13/955?iss=6

Objectives: Exosomes (Exos) are 30-150 nm wide nanovesicles originating from the endosomal network and are found in most body fluids. Production of Exos increases in cancer, making Exos potential biomarkers. Exos are a fundamental driver of intercellular communication by transferring proteins, lipids and miRNA. Analysis of Exos and their interaction with the microenvironment may uncover cellular pathways involved with disease progression. We hypothesized that Exos may serve as a liquid biopsy for tumor recurrence. Materials and Methods: Six lung cancer patients (LCPs) were prospectively enrolled on an IRB approved study. Exos were precipitated and purified with a Norgen kit from 0.7 ml of blood samples collected prior to, during and 6 months after radiation therapy (RT). Exos numbers were quantified by Exocet Exosome Quantitation Kit (System Biosciences). Total exosomal RNA was isolated by the Norgen RNA/DNA/Protein Purification kit. For the miRNAs expression profiling we used the miRCURY LNA™ Universal RT microRNA PCR assay (Exiqon) and ExiLENT SYBR® Green Maser Mix (Exiqon). Expressions of 10 different miRNAs (let-7a-5p, miR-20a-5p, miR-21-5p, miR-30b-5p, miR-106a-5p, miR-146a-5p, miR-155-5p, miR-200b-5p, miR-203a, miR-208a) for all samples were determined. Human lung fibroblasts (MRC-5s) in serum-free medium for 24 hrs were treated with Exos, TGF-β (positive control) or PBS (negative control) to determine their relative effects on MRC-5 proliferation. Results: Of the 6 LCPs, 2 had limited stage small cell and 4 had non-small cell at diagnosis. Three patients were diagnosed with recurrence at the time of their post-RT blood draw. Six miRNAs demonstrated significantly different expressions between recurrent and non-recurrent groups of LCPs: let-7a-5p, miR-20a-5p, miR-21-5p, miR-106a-5p, miR-155-5p, and miR-203a. MRC-5 proliferation increases 2-fold when treated with Exos from blood collected prior to RT compared to PBS (p = 0.01). There is Conclusions: Recurrent and non-recurrent groups of LCPs demonstrated significant differences in exosomal miR profile before and after RT. Exos from untreated LCPs, and recurrent LCPs after RT, stimulate MRC-5 proliferation and possible conversion to CAFs. Our results suggest that Exos could serve as a “liquid biopsy” to assess the potential for recurrence when imaging modalities are equivocal. Citation Format: Nicholas Serrano, John Blue, Asim Alam, Christopher S. Rabender, Elisabeth Weiss, Mitchell S. Anscher, Ross B. Mikkelsen, Vasily A. Yakovlev. Analysis of circulating tumor exosomes: their ability to serve as a biomarker for recurrence in lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3800. doi:10.1158/1538-7445.AM2017-3800

Purpose This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets. Methods and Materials This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation ( HMOX1, NFE2L2, NOS3, and TGFβ1 ). DNA from blood samples of 179 patients (∼80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed. Results Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity. Conclusions These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.

Transfusion-related acute lung injury (TRALI) is a devastating transfusion-associated adverse event. There is a paucity of data on the incidence and characteristics of TRALI cases that occur perioperatively. We classified suspected perioperative TRALI cases reported to Canadian Blood Services between 2001 and 2012, and compared them to non-perioperative cases to elucidate factors that may be associated with an increased risk of developing TRALI in the perioperative setting.All suspected TRALI cases reported to Canadian Blood Services (CBS) since 2001 were reviewed by two experts or, from 2006 to 2012, the CBS TRALI Medical Review Group (TMRG). These cases were classified based on the Canadian Consensus Conference (CCC) definitions and detailed in a database. Two additional reviewers further categorized them as occurring within 72 h from the onset of surgery (perioperative) or not in that period (non-perioperative). Various demographic and characteristic variables of each case were collected and compared between groups.Between 2001 and 2012, a total of 469 suspected TRALI cases were reported to Canadian Blood Services; 303 were determined to be within the TRALI diagnosis spectrum. Of those, 112 (38%) were identified as occurring during the perioperative period. Patients who underwent cardiac surgery requiring cardiopulmonary bypass (25.0%), general surgery (18.0%) and orthopedics patients (12.5%) represented the three largest surgical groups. Perioperative TRALI cases comprised more men (53.6% vs. 41.4%, p=0.04) than non-perioperative patients. Perioperative TRALI patients more often required supplemental O2 (14.3% vs. 3.1%, p=0.0003), mechanical ventilation (18.8% vs. 3.1%), or were in the ICU (14.3% vs. 3.7%, p=0.0043) prior to the onset of TRALI compared to non-perioperative TRALI patients. The surgical patients were transfused on average more components than non-perioperative patients (6.0 [SD=8.3] vs. 3.6 [5.2] products per patient, p=0.0002). Perioperative TRALI patients were transfused more plasma (152 vs. 105, p=0.013) and cryoprecipitate (51 vs. 23, p0.01) than non-perioperative TRALI patients. There was no difference between donor antibody test results between the groups.CBS data has provided insight into the nature of TRALI cases that occur perioperatively; this group represents a large proportion of TRALI cases.

When exposed in the perioperative period to blood components containing immunoglobulin (Ig)A IgA-sensitized IgA-deficient patients are at an increased risk of transfusion-associated anaphylaxis. We present the case of an IgA-deficient patient whose candidacy for double-lung transplantation was under review in the preoperative period.A 49-yr-old patient with end-stage chronic obstructive lung disease secondary to deficiencies in IgA and IgG subclasses was being assessed for double-lung transplantation. Early recognition of the ramifications of perioperative transfusion prompted consultation with the transfusion medicine service. This in turn facilitated specialized laboratory testing and the coordinated provision of appropriate blood products for the unpredictable date of transplantation. The theoretical systemic risks of a non-IgA-deficient graft on the sensitized IgA-deficient host were considered. To affirm the patient's candidacy for transplantation, he was ultimately challenged preoperatively with IgA-containing products in a controlled intensive-care setting.Through a multidisciplinary approach [corrected], a successful transplantation outcome was achieved in an IgA-deficient patient undergoing major surgery. Strategies to mitigate risk include the procurement and transfusion of IgA-deficient components, which may be challenging or untenable in emergent perioperative settings.

The effects of modulating tetrahydrobiopterin (BH4) levels with a metabolic precursor, sepiapterin (SP), on dextran sodium sulfate (DSS)-induced colitis and azoxymethane (AOM)-induced colorectal cancer were studied. SP in the drinking water blocks DSS-induced colitis measured as decreased disease activity index (DAI), morphologic criteria, and recovery of Ca(2+)-induced contractility responses lost as a consequence of DSS treatment. SP reduces inflammatory responses measured as the decreased number of infiltrating inflammatory macrophages and neutrophils and decreased expression of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and IL-17A. High-performance liquid chromatography analyses of colonic BH4 and its oxidized derivative 7,8-dihydrobiopterin (BH2) are inconclusive although there was a trend for lower BH4:BH2 with DSS treatment that was reversed with SP. Reduction of colonic cGMP levels by DSS was reversed with SP by a mechanism sensitive to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), a specific inhibitor of the NO-sensitive soluble guanylate cyclase (sGC). ODQ abrogates the protective effects of SP on colitis. This plus the finding that SP reduces DSS-enhanced protein Tyr nitration are consistent with DSS-induced uncoupling of NOS. The results agree with previous studies that demonstrated inactivation of sGC in DSS-treated animals as being important in recruitment of inflammatory cells and in altered cholinergic signaling and colon motility. SP also reduces the number of colon tumors in AOM/DSS-treated mice from 7 to 1 per unit colon length. Thus, pharmacologic modulation of BH4 with currently available drugs may provide a mechanism for alleviating some forms of colitis and potentially minimizing the potential for colorectal cancer in patients with colitis.