Effect of bivalirudin on coagulation in neonatal (cord) and adult human blood in vitro.

INTRODUCTION: Bivalirudin is recommended as an alternative to heparin in cardiac surgery with cardiopulmonary bypass. Although it has been used in infants and children for this indication, there is a paucity of data on the pharmacologic effects of bivalirudin in neonates. Given the immaturity of the hemostatic system in neonates, we hypothesized that coagulation responses to bivalirudin in this population would be different than in adults. METHODS: Blood samples were drawn from placenta-cord units and from healthy adult donors. The study was carried out in two steps. First, bivalirudin was added to cord and adult blood samples at concentrations of 0, 5, 10, 15, and 20 µg/mL. Activated clotting time and thromboelastographic variables were recorded. Next, we used a Chandler loop system to assess the efficacy of bivalirudin in a simple model of cardiopulmonary bypass. The loops were primed with cord or adult blood and were run until thrombus was detected. Plasma bivalirudin concentrations were measured at 1, 15, 30, 45, 60, and 75 min after initiating rotation of the loops using liquid chromatography/mass spectrometry. RESULTS: Bivalirudin elicited a dose-dependent prolongation inhibition of coagulation in both cord and adult blood samples with greater potency in cord blood in comparison to adult blood (activated clotting time: 627 ± 50 vs. 452 ± 22 s at 15 µg/mL bivalirudin, p < .0001). This relative potency was also demonstrated in the Chandler loop system, but interestingly, cord blood appeared to inactivate bivalirudin more rapidly than adult blood with earlier clotting in loops containing cord blood. CONCLUSIONS: This study demonstrates that bivalirudin has greater potency in cord blood in vitro than in adult blood. Plasma degradation appears to proceed more rapidly in cord blood than in adults. Both of these findings should be considered when planning dosing regimens in neonatal patients.

Tumor Treating Fields therapy with standard systemic therapy versus standard systemic therapy alone in metastatic non-small-cell lung cancer following progression on or after platinum-based therapy (LUNAR): a randomised, open-label, pivotal phase 3 study.

BACKGROUND: Tumor Treating Fields (TTFields) are electric fields that disrupt processes critical for cancer cell survival, leading to immunogenic cell death and enhanced antitumour immune response. In preclinical models of non-small-cell lung cancer, TTFields amplified the effects of chemotherapy and immune checkpoint inhibitors. We report primary results from a pivotal study of TTFields therapy in metastatic non-small-cell lung cancer. METHODS: This randomised, open-label, pivotal phase 3 study recruited patients at 130 sites in 19 countries. Participants were aged 22 years or older with metastatic non-small-cell lung cancer progressing on or after platinum-based therapy, with squamous or non-squamous histology and ECOG performance status of 2 or less. Previous platinum-based therapy was required, but no restriction was placed on the number or type of previous lines of systemic therapy. Participants were randomly assigned (1:1) to TTFields therapy and standard systemic therapy (investigator's choice of immune checkpoint inhibitor [nivolumab, pembrolizumab, or atezolizumab] or docetaxel) or standard therapy alone. Randomisation was performed centrally using variable blocked randomisation and an interactive voice-web response system, and was stratified by tumour histology, treatment, and region. Systemic therapies were dosed according to local practice guidelines. TTFields therapy (150 kHz) was delivered continuously to the thoracic region with the recommendation to achieve an average of at least 18 h/day device usage. The primary endpoint was overall survival in the intention-to-treat population. The safety population included all patients who received any study therapy and were analysed according to the actual treatment received. The study is registered with ClinicalTrials.gov, NCT02973789. FINDINGS: Between Feb 13, 2017, and Nov 19, 2021, 276 patients were enrolled and randomly assigned to receive TTFields therapy with standard therapy (n=137) or standard therapy alone (n=139). The median age was 64 years (IQR 59-70), 178 (64%) were male and 98 (36%) were female, 156 (57%) had non-squamous non-small-cell lung cancer, and 87 (32%) had received a previous immune checkpoint inhibitor. Median follow-up was 10·6 months (IQR 6·1-33·7) for patients receiving TTFields therapy with standard therapy, and 9·5 months (0·1-32·1) for patients receiving standard therapy. Overall survival was significantly longer with TTFields therapy and standard therapy than with standard therapy alone (median 13·2 months [95% CI 10·3-15·5] vs 9·9 months [8·1-11·5]; hazard ratio [HR] 0·74 [95% CI 0·56-0·98]; p=0·035). In the safety population (n=267), serious adverse events of any cause were reported in 70 (53%) of 133 patients receiving TTFields therapy plus standard therapy and 51 (38%) of 134 patients receiving standard therapy alone. The most frequent grade 3-4 adverse events were leukopenia (37 [14%] of 267), pneumonia (28 [10%]), and anaemia (21 [8%]). TTFields therapy-related adverse events were reported in 95 (71%) of 133 patients; these were mostly (81 [85%]) grade 1-2 skin and subcutaneous tissue disorders. There were three deaths related to standard therapy (two due to infections and one due to pulmonary haemorrhage) and no deaths related to TTFields therapy. INTERPRETATION: TTFields therapy added to standard therapy significantly improved overall survival compared with standard therapy alone in metastatic non-small-cell lung cancer after progression on platinum-based therapy without exacerbating systemic toxicities. These data suggest that TTFields therapy is efficacious in metastatic non-small-cell lung cancer and should be considered as a treatment option to manage the disease in this setting. FUNDING: Novocure.

Outcomes of DCIS treated with breast conserving surgery without radiotherapy on recurrence, survival, and health-related quality of life.

BACKGROUND: Sector resection for Ductal Carcinoma in Situ (DCIS) allows wide excision without compromising breast shape. There are concerns that radiotherapy for some DCIS after sector resection is unnecessary and reduces patient satisfaction and quality of life without affecting survival. This study aimed to investigate whether women with DCIS managed with sector resection without radiotherapy had acceptable rates of recurrence and health-related quality of life outcomes. METHODS: Retrospective study of patients who underwent sector resection for DCIS without adjuvant radiotherapy from 1992 to 2021. Tumour size, grade, necrosis, margins, follow up and time to ipsilateral recurrence was recorded. Patients were posted a BREAST-Q to assess health-related quality of life. RESULTS: One hundred and thirty-eight patients were treated for pure DCIS by two surgeons from 1992 to 2018. One hundred and sixteen patients underwent sector resection, 22 had mastectomy. Average age 61 years. Mean follow up 9.14 years. Recurrence rate after sector resection was 18.97%. 55% were DCIS. Annualized recurrence rate was 2.07%. There were no cancer-related deaths. BREAST-Q completion rate was 44%. Satisfaction with breasts, physical, psychosocial, and sexual well-being scores were significantly higher than normative Australian values and a mixed cohort of women who underwent breast conserving surgery with radiotherapy. CONCLUSION: DCIS can be safely managed with sector resection without radiotherapy and regular long-term follow up. This approach results in low annualized recurrence rates, high levels patient satisfaction and health-related quality of life and should be considered a safe alternative for patients with DCIS to minimize morbidity without affecting cancer survival.

Racial and Ethnic Disparities in Access to Minimally Invasive Mitral Valve Surgery.

Importance: Whether people from racial and ethnic minority groups experience disparities in access to minimally invasive mitral valve surgery (MIMVS) is not known. Objective: To investigate racial and ethnic disparities in the utilization of MIMVS. Design, Setting, and Participants: This cross-sectional study used data from the Society of Thoracic Surgeons Database for patients who underwent mitral valve surgery between 2014 and 2019. Statistical analysis was performed from January 24 to August 11, 2022. Exposures: Patients were categorized as non-Hispanic White, non-Hispanic Black, and Hispanic individuals. Main Outcomes and Measures: The association between MIMVS (vs full sternotomy) and race and ethnicity were evaluated using logistic regression. Results: Among the 103 753 patients undergoing mitral valve surgery (mean [SD] age, 62 [13] years; 47 886 female individuals [46.2%]), 10 404 (10.0%) were non-Hispanic Black individuals, 89 013 (85.8%) were non-Hispanic White individuals, and 4336 (4.2%) were Hispanic individuals. Non-Hispanic Black individuals were more likely to have Medicaid insurance (odds ratio [OR], 2.21; 95% CI, 1.64-2.98; P < .001) and to receive care from a low-volume surgeon (OR, 4.45; 95% CI, 4.01-4.93; P < .001) compared with non-Hispanic White individuals. Non-Hispanic Black individuals were less likely to undergo MIMVS (OR, 0.65; 95% CI, 0.58-0.73; P < .001), whereas Hispanic individuals were not less likely to undergo MIMVS compared with non-Hispanic White individuals (OR, 1.08; 95% CI, 0.67-1.75; P = .74). Patients with commercial insurance had 2.35-fold higher odds of undergoing MIMVS (OR, 2.35; 95% CI, 2.06-2.68; P < .001) than those with Medicaid insurance. Patients operated by very-high volume surgeons (300 or more cases) had 20.7-fold higher odds (OR, 20.70; 95% CI, 12.7-33.9; P < .001) of undergoing MIMVS compared with patients treated by low-volume surgeons (less than 20 cases). After adjusting for patient risk, non-Hispanic Black individuals were still less likely to undergo MIMVS (adjusted OR [aOR], 0.88; 95% CI, 0.78-0.99; P = .04) and were more likely to die or experience a major complication (aOR, 1.25; 95% CI, 1.16-1.35; P < .001) compared with non-Hispanic White individuals. Conclusions and Relevance: In this cross-sectional study, non-Hispanic Black patients were less likely to undergo MIMVS and more likely to die or experience a major complication than non-Hispanic White patients. These findings suggest that efforts to reduce inequity in cardiovascular medicine may need to include increasing access to private insurance and high-volume surgeons.

Association of Time Elapsed Since Ischemic Stroke With Risk of Recurrent Stroke in Older Patients Undergoing Elective Nonneurologic, Noncardiac Surgery.

Importance: Perioperative strokes are a major cause of death and disability. There is limited information on which to base decisions for how long to delay elective nonneurologic, noncardiac surgery in patients with a history of stroke. Objective: To examine whether an association exists between the time elapsed since an ischemic stroke and the risk of recurrent stroke in older patients undergoing elective nonneurologic, noncardiac surgery. Design, Setting, and Participants: This cohort study used data from the 100% Medicare Provider Analysis and Review files, including the Master Beneficiary Summary File, between 2011 and 2018 and included elective nonneurologic, noncardiac surgeries in patients 66 years or older. Patients were excluded if they had more than 1 procedure during a 30-day period, were transferred from another hospital or facility, were missing information on race and ethnicity, were admitted in December 2018, or had tracheostomies or gastrostomies. Data were analyzed May 7 to October 23, 2021. Exposures: Time interval between a previous hospital admission for acute ischemic stroke and surgery. Main Outcomes and Measures: Acute ischemic stroke during the index surgical admission or rehospitalization for stroke within 30 days of surgery, 30-day all-cause mortality, composite of stroke and mortality, and discharge to a nursing home or skilled nursing facility. Multivariable logistic regression models were used to estimate adjusted odds ratios (AORs) to quantify the association between outcome and time since ischemic stroke. Results: The final cohort included 5 841 539 patients who underwent elective nonneurologic, noncardiac surgeries (mean [SD] age, 74.1 [6.1] years; 3 371 329 [57.7%] women), of which 54 033 (0.9%) had a previous stroke. Patients with a stroke within 30 days before surgery had higher adjusted odds of perioperative stroke (AOR, 8.02; 95% CI, 6.37-10.10; P < .001) compared with patients without a previous stroke. The adjusted odds of stroke were not significantly different at an interval of 61 to 90 days between previous stroke and surgery (AOR, 5.01; 95% CI, 4.00-6.29; P < .001) compared with 181 to 360 days (AOR, 4.76; 95% CI, 4.26-5.32; P < .001). The adjusted odds of 30-day all-cause mortality were higher in patients who underwent surgery within 30 days of a previous stroke (AOR, 2.51; 95% CI, 1.99-3.16; P < .001) compared with those without a history of stroke, and the AOR decreased to 1.49 (95% CI, 1.15-1.92; P < .001) at 61 to 90 days from previous stroke to surgery but did not decline significantly, even after an interval of 360 or more days. Conclusions and Relevance: The findings of this cohort study suggest that, among patients undergoing nonneurologic, noncardiac surgery, the risk of stroke and death leveled off when more than 90 days elapsed between a previous stroke and elective surgery. These findings suggest that the recent scientific statement by the American Heart Association to delay elective nonneurologic, noncardiac surgery for at least 6 months after a recent stroke may be too conservative.

Association Between the COVID-19 Pandemic and Disparities in Access to Major Surgery in the US.

Importance: Racial minority groups account for 70% of excess deaths not related to COVID-19. Understanding the association of the Centers for Medicare & Medicaid Services' (CMS's) moratorium delaying nonessential operations with racial disparities will help shape future pandemic responses. Objective: To evaluate the association of the CMS's moratorium on elective operations during the first wave of the COVID-19 pandemic among Black individuals, Asian individuals, and individuals of other races compared with White individuals. Design, Setting, and Participants: This cross-sectional study assessed a 719-hospital retrospective cohort of 3 470 905 adult inpatient hospitalizations for major surgery between January 1, 2018, and October 31, 2020. Exposure: The first wave of COVID-19 infections between March 1, 2020, and May 31, 2020. Main Outcomes and Measures: The main outcome was the association between changes in monthly elective surgical case volumes and the first wave of COVID-19 infections as a function of patient race, evaluated using negative binomial regression analysis. Results: Among 3 470 905 adults (1 823 816 female [52.5%]) with inpatient hospitalizations for major surgery, 70 752 (2.0%) were Asian, 453 428 (13.1%) were Black, 2 696 929 (77.7%) were White, and 249 796 (7.2%) were individuals of other races. The number of monthly elective cases during the first wave was 49% (incident rate ratio [IRR], 0.49; 95% CI, 0.486-0.492; P < .001) compared with the baseline period. The relative reduction in unadjusted elective surgery cases for Black (unadjusted IRR, 0.99; 95% CI, 0.97-1.01; P = .36), Asian (unadjusted IRR, 1.08; 95% CI, 1.03-1.14; P = .001), and other race individuals (unadjusted IRR, 0.97; 95% CI, 0.95-1.00; P = .05) during the surge period compared with the baseline period was very close to the change in cases for White individuals. After adjustment for age, sex, comorbidities, and surgical procedure, there was still no evidence that the first wave of the pandemic was associated with disparities in access to elective surgery. Conclusions and Relevance: In this cross-sectional study, the CMS's moratorium on nonessential operations was associated with a 51% reduction in elective operations. It was not associated with greater reductions in operations for racial minority individuals than for White individuals. This evidence suggests that the early response to the pandemic did not increase disparities in access to surgical care.

Detection of hypermethylated BCAT1 and IKZF1 DNA in blood and tissues of colorectal, breast and prostate cancer patients.

BACKGROUND: Detection of circulating cell-free DNA (ccfDNA) methylated in BCAT1 and IKZF1 is sensitive for detection of colorectal cancer (CRC), but it is not known if these biomarkers are present in other common adenocarcinomas. OBJECTIVE: Compare methylation levels of BCAT1 and IKZF1 in tissue and plasma from breast, prostate, and colorectal cancer patients. METHODS: Blood was collected from 290 CRC, 32 breast and 101 prostate cancer patients, and 606 cancer-free controls. Tumor and matched normal tissues were collected at surgery: 26 breast, 9 prostate and 15 CRC. DNA methylation in BCAT1 and IKZF1 was measured in blood and tissues. RESULTS: Either biomarker was detected in blood from 175/290 (60.3%) of CRC patients. The detection rate was higher than that measured in controls (48/606 (8.1%), OR = 18.2, 95%CI: 11.1-29.0). The test positivity rates in breast and prostate cancer patients were 9.4% (3/32) and 6.9% (7/101), respectively, and not significantly different to that measured in gender-matched controls (8.0% (33/382) females (OR = 0.84, 95%CI: 0.23-3.1) and 7.6% (26/318) males (OR = 0.86, 95%CI: 0.65-2.1). In tumor and non-neoplastic tissues, 93.5% (14/15) of CRC tumors were methylated in BCAT1 and/or IKZF1 (p< 0.004). Only 11.5% (3/26) and 44.4% (4/9) (p= 0.083) of breast and prostate tumors were hypermethylated in these two genes. CONCLUSIONS: Detection of circulating DNA methylated in BCAT1 and IKZF1 is sensitive and specific for CRC but not breast or prostate cancer.

Survey of Practice Pattern in Patients With Heparin-Induced Thrombocytopenia Requiring Cardiopulmonary Bypass.

BACKGROUND: Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are routinely anticoagulated with heparin before the initiation of bypass. Heparin is contraindicated, however, in patients with acute HIT, and alternatives to routine practice are often used. While guidelines have recently been published addressing this topic 10, there remains variance between institutions in how these cases are treated. Our goal was to better delineate practice trends in the diagnosis and management of HIT patients requiring CPB. METHODS: We surveyed members of the Society of Cardiovascular Anesthesiologists (SCA) and the American Society for Extracorporeal Technology (AmSECT) using an online survey tool. RESULTS: We received 304 completed surveys (5.8% response rate), 75% completed by an anesthesiologist, and 24% by a perfusionist. The majority of respondents used clinical history and/or antibody testing (71% and 63%, respectively) to diagnose HIT. Seventy-five percent of respondents reported using an institutional protocol for HIT-CPB cases. Most respondents (89%) reported having at least 1 case in the last 3 years, with a total case experience of at least 785 cases (785 = the minimum number of cases in each case volume category × the number of respondents choosing that category). The strategy recommended in published guidelines, bivalirudin, was the most commonly reported alternative anticoagulation strategy (75%) used by respondents in HIT cases, with most (83%) using the activated clotting time (ACT) to monitor anticoagulation. CONCLUSIONS: Most responding SCA and AmSECT members reported that their institution used a protocol or guideline for HIT/CPB cases, and most guidelines directed the use of bivalirudin as an alternative anticoagulant. Various other methods such as plasmapheresis are also being used with success in this patient population. Further research, including comparison studies of alternative anticoagulant strategies, is required to elucidate the best approach to these difficult cases.

Re-excision rate after sector resection for breast cancer: A 5-year retrospective cohort study.

BACKGROUND: Positive margins after Breast conserving surgery (BCS) for breast cancer can result in local recurrence (LR) requiring further surgery. This can lead to unnecessary patient anxiety, poor prognosis and impose additional economic burden to our health system. The aim of this study is to assess the rate of re-excision for positive margins after BCS using the sector resection technique. METHODS: This single centre retrospective cohort study included all women who underwent BCS using sector resection between the years of 2012 and 2016. A total of 456 patients underwent sector resection. We evaluated the margin status, re-excision rates and their predictive risk factors. RESULTS: 415 (91%) patients had clear margins. 41 (9%) patients underwent further re-excision for positive or close margin. 75.6% of those patients had DCIS and 51% had invasive carcinoma involving the margins. Patient and tumour characteristics associated with an increased risk of positive margin were women under the age of 50 (p = 0.19), tumours >50 mm (p = 0.001), grade-2 (p = 0.48) and grade-3 (p = 0.63), HER-2 positivity (p = 0.02), sentinel lymph node positivity (p = 0.03), and patients undergoing axillary lymph node dissection (p = 0.01). CONCLUSION: BCS using the sector resection technique has a low re-excision rate for positive margins. Younger patients and aggressive tumour biology are important predictive risk factors for positive margins.

Role of radiotherapy in women over the age of 65 after breast conserving surgery for breast cancer: A 5-year retrospective study.

BACKGROUND/OBJECTIVE: This study aimed to analyse the local recurrence (LR) and breast cancer related mortality (BCRM) in older women who underwent breast-conserving surgery (BCS) with and without adjuvant radiotherapy (XRT). METHODS: This retrospective study included a total of 299 women who underwent BCS for early breast carcinoma, between the years of 2007 and 2011. Predictive risk factors, local recurrence (LR) and breast cancer related mortality (BCRM) were assessed with a mean follow-up period of 84 months. RESULTS: Women over the age of 65 in the XRT and No-XRT groups showed similar incidence of LR (5.8% vs 5%, p = 0.838). Women over 65 years old with XRT had a higher rate of BCRM (5.8% vs 0%, p = 0.05). Resection margins >5 mm had a lower rate of BCRM (HR 0.395, p = 0.05). Women under the age of 65, invasive ductal carcinoma, grade-3 tumours, HER-2 positive, triple negative, lympho-vascular invasion, axillary lymph node positivity, high breast density on mammography were associated with increased risk of LR and BCRM. CONCLUSIONS: XRT in women over the age of 65 did not decrease the risk of LR. Adjuvant XRT in older women should be offered to selective patients with high risk patient and tumour factors.

Impact of the Choice of Risk Model for Identifying Low-risk Patients Using the 2014 American College of Cardiology/American Heart Association Perioperative Guidelines.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: The 2014 American College of Cardiology Perioperative Guideline recommends risk stratifying patients scheduled to undergo noncardiac surgery using either: (1) the Revised Cardiac Index; (2) the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator; or (3) the Myocardial Infarction or Cardiac Arrest calculator. The aim of this study is to determine how often these three risk-prediction tools agree on the classification of patients as low risk (less than 1%) of major adverse cardiac event. METHODS: This is a retrospective observational study using a sample of 10,000 patient records. The risk of cardiac complications was calculated for the Revised Cardiac Index and the Myocardial Infarction or Cardiac Arrest models using published coefficients, and for the American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator using the publicly available website. The authors used the intraclass correlation coefficient and kappa analysis to quantify the degree of agreement between these three risk-prediction tools. RESULTS: There is good agreement between the American College of Surgeons National Surgical Quality Improvement Program and Myocardial Infarction or Cardiac Arrest estimates of major adverse cardiac events (intraclass correlation coefficient = 0.68, 95% CI: 0.66 to 0.70), while only poor agreement between (1) American College of Surgeons National Surgical Quality Improvement Program Surgical Risk Calculator and the Revised Cardiac Index (intraclass correlation coefficient = 0.37; 95% CI: 0.34 to 0.40), and (2) Myocardial Infarction or Cardiac Arrest and Revised Cardiac Index (intraclass correlation coefficient = 0.26; 95% CI: 0.23 to 0.30). The three prediction models disagreed 29% of the time on which patients were low risk. CONCLUSIONS: There is wide variability in the predicted risk of cardiac complications using different risk-prediction tools. Including more than one prediction tool in clinical guidelines could lead to differences in decision-making for some patients depending on which risk calculator is used.

Elevated free hemoglobin and decreased haptoglobin levels are associated with adverse clinical outcomes, unfavorable physiologic measures, and altered inflammatory markers in pediatric cardiac surgery patients.

BACKGROUND: There are data suggesting that free hemoglobin (Hb), heme, and iron contribute to infection, thrombosis, multiorgan failure, and death in critically ill patients. These outcomes may be mitigated by haptoglobin. STUDY DESIGN AND METHODS: 164 consecutively treated children undergoing surgery for congenital heart disease were evaluated for associations between free Hb and haptoglobin and clinical outcomes, physiologic metrics, and biomarkers of inflammation RESULTS: Higher perioperative free Hb levels (and lower haptoglobin levels) were associated with mortality, nosocomial infection, thrombosis, hours of intubation and inotropes, increased interleukin-6, peak serum lactate levels, and lower nadir mean arterial pressures. The median free Hb in patients without infection (30 mg/dL; 29 interquartile range [IQR], 24-52 mg/dL) was lower than in those who became infected (39 mg/dL; IQR, 33-88 mg/ 31 dL; p = 0.0046). The median mechanical ventilation requirements were 19 (IQR, 7-72) hours in patients with higher levels of haptoglobin versus 48 (IQR, 18-144) hours in patients with lower levels (p = 0.0047). Transfusion dose, bypass duration, and complexity of surgery were all significantly correlated with Hb levels and haptoglobin levels. Multivariate analyses demonstrated that these variables were independently and significantly associated with outcomes. CONCLUSIONS: Elevated pre- and postoperative levels of free Hb and decreased levels of haptoglobin were associated with adverse clinical outcomes, inflammation, and unfavorable physiologic metrics. Transfusion, RACHS score, and duration of bypass were associated with increased free Hb and decreased haptoglobin. Further investigation of the role of hemolysis and haptoglobin as potential mediators or markers of outcomes is warranted.

Loss of the nutrient sensor TAS1R3 leads to reduced bone resorption.

The taste receptor type 1 (TAS1R) family of heterotrimeric G protein-coupled receptors participates in monitoring energy and nutrient status. TAS1R member 3 (TAS1R3) is a bi-functional protein that recognizes amino acids such as L-glycine and L-glutamate or sweet molecules such as sucrose and fructose when dimerized with TAS1R member 1 (TAS1R1) or TAS1R member 2 (TAS1R2), respectively. It was recently reported that deletion of TAS1R3 expression in Tas1R3 mutant mice leads to increased cortical bone mass but the underlying cellular mechanism leading to this phenotype remains unclear. Here, we independently corroborate the increased thickness of cortical bone in femurs of 20-week-old male Tas1R3 mutant mice and confirm that Tas1R3 is expressed in the bone environment. Tas1R3 is expressed in undifferentiated bone marrow stromal cells (BMSCs) in vitro and its expression is maintained during BMP2-induced osteogenic differentiation. However, levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) are unchanged in the serum of 20-week-old Tas1R3 mutant mice as compared to controls. In contrast, levels of the bone resorption marker collagen type I C-telopeptide are reduced greater than 60% in Tas1R3 mutant mice. Consistent with this, Tas1R3 and its putative signaling partner Tas1R2 are expressed in primary osteoclasts and their expression levels positively correlate with differentiation status. Collectively, these findings suggest that high bone mass in Tas1R3 mutant mice is due to uncoupled bone remodeling with reduced osteoclast function and provide rationale for future experiments examining the cell-type-dependent role for TAS1R family members in nutrient sensing in postnatal bone remodeling.

Supplemental Antithrombin Is Effective in Achieving Adequate Anticoagulation in Infants and Children With an Inadequate Response to Heparin.

OBJECTIVE: To demonstrate that supplemental antithrombin (AT) is effective in establishing adequate anticoagulation in infants and children with initially inadequate responses to heparin. DESIGN: Following institutional review board approval, a retrospective chart review was conducted on pediatric patients receiving AT during cardiac surgery requiring cardiopulmonary bypass. SETTING: A single institutional review in a hospital setting. PARTICIPANTS: Thirty-one pediatric patients with age ranging from 1 day to 36 months (median 12 weeks) receiving AT during the study period. INTERVENTIONS: As this was a retrospective chart review, no active interventions on patients were performed. MEASUREMENTS AND MAIN RESULTS: Data collected included: patient age, sex, weight, activated clotting time (ACT) values, as well as heparin and AT doses. Primary outcomes were the increase in the ACT from pre- to post-AT and the number of patients who achieved an ACT>480 seconds. The paired t-test was used to compare pre- and post-AT ACT. Mean dose of AT was 50 U/kg (standard deviation 6). Following administration of AT, 30 pediatric patients achieved an ACT of>480 seconds. The post-AT ACT was significantly higher than the pre-AT by a mean of 327 seconds (p<0.0001); 96% of patients achieved an adequate ACT to initiate cardiopulmonary bypass. No adverse events attributable to AT were recorded. CONCLUSION: AT was effective in achieving adequate anticoagulation in a small cohort of infants and children undergoing cardiac surgery who initially were poorly responsive to heparin. Further research to examine the utility of AT in improving clinical outcomes is warranted.

Toxoplasma gondii Cyclic AMP-Dependent Protein Kinase Subunit 3 Is Involved in the Switch from Tachyzoite to Bradyzoite Development.

UNLABELLED: Toxoplasma gondii is an obligate intracellular apicomplexan parasite that infects warm-blooded vertebrates, including humans. Asexual reproduction in T. gondii allows it to switch between the rapidly replicating tachyzoite and quiescent bradyzoite life cycle stages. A transient cyclic AMP (cAMP) pulse promotes bradyzoite differentiation, whereas a prolonged elevation of cAMP inhibits this process. We investigated the mechanism(s) by which differential modulation of cAMP exerts a bidirectional effect on parasite differentiation. There are three protein kinase A (PKA) catalytic subunits (TgPKAc1 to -3) expressed in T. gondii Unlike TgPKAc1 and TgPKAc2, which are conserved in the phylum Apicomplexa, TgPKAc3 appears evolutionarily divergent and specific to coccidian parasites. TgPKAc1 and TgPKAc2 are distributed in the cytomembranes, whereas TgPKAc3 resides in the cytosol. TgPKAc3 was genetically ablated in a type II cyst-forming strain of T. gondii (PruΔku80Δhxgprt) and in a type I strain (RHΔku80Δhxgprt), which typically does not form cysts. The Δpkac3 mutant exhibited slower growth than the parental and complemented strains, which correlated with a higher basal rate of tachyzoite-to-bradyzoite differentiation. 3-Isobutyl-1-methylxanthine (IBMX) treatment, which elevates cAMP levels, maintained wild-type parasites as tachyzoites under bradyzoite induction culture conditions (pH 8.2/low CO2), whereas the Δpkac3 mutant failed to respond to the treatment. This suggests that TgPKAc3 is the factor responsible for the cAMP-dependent tachyzoite maintenance. In addition, the Δpkac3 mutant had a defect in the production of brain cysts in vivo, suggesting that a substrate of TgPKAc3 is probably involved in the persistence of this parasite in the intermediate host animals. IMPORTANCE: Toxoplasma gondii is one of the most prevalent eukaryotic parasites in mammals, including humans. Parasites can switch from rapidly replicating tachyzoites responsible for acute infection to slowly replicating bradyzoites that persist as a latent infection. Previous studies have demonstrated that T. gondii cAMP signaling can induce or suppress bradyzoite differentiation, depending on the strength and duration of cAMP signal. Here, we report that TgPKAc3 is responsible for cAMP-dependent tachyzoite maintenance while suppressing differentiation into bradyzoites, revealing one mechanism underlying how this parasite transduces cAMP signals during differentiation.

Outcomes are Worse in US Patients Undergoing Surgery on Weekends Compared With Weekdays.

BACKGROUND: Increasing surgical access to previously underserved populations in the United States may require a major expansion of the use of operating rooms on weekends to take advantage of unused capacity. Although the so-called weekend effect for surgery has been described in other countries, it is unknown whether US patients undergoing moderate-to-high risk surgery on weekends are more likely to experience worse outcomes than patients undergoing surgery on weekdays. OBJECTIVE: The aim of this study was to determine whether patients undergoing surgery on weekends are more likely to die or experience a major complication compared with patients undergoing surgery on a weekday. RESEARCH DESIGN: Using all-payer data, we conducted a retrospective cohort study of 305,853 patients undergoing isolated coronary artery bypass graft surgery, colorectal surgery, open repair of abdominal aortic aneurysm, endovascular repair of abdominal aortic aneurysm, and lower extremity revascularization. We compared in-hospital mortality and major complications for weekday versus weekend surgery using multivariable logistic regression analysis. RESULTS: After controlling for patient risk and surgery type, weekend elective surgery [adjusted odds ratio (AOR)=3.18; 95% confidence interval (CI), 2.26-4.49; P<0.001] and weekend urgent surgery (AOR=2.11; 95% CI, 1.68-2.66; P<0.001) were associated with a higher risk of death compared with weekday surgery. Weekend elective (AOR=1.58; 95% CI, 1.29-1.93; P<0.001) and weekend urgent surgery (AOR=1.61; 95% CI, 1.42-1.82; P<0.001) were also associated with a higher risk of major complications compared with weekday surgery. CONCLUSIONS: Patients undergoing nonemergent major cardiac and noncardiac surgery on the weekends have a clinically significantly increased risk of death and major complications compared with patients undergoing surgery on weekdays. These findings should prompt decision makers to seek to better understand factors, such physician and nurse staffing, which may contribute to the weekend effect.

Feasibility of Report Cards for Measuring Anesthesiologist Quality for Cardiac Surgery.

BACKGROUND: In creating the Merit-Based Incentive Payment System, Congress has mandated pay-for-performance (P4P) for all physicians, including anesthesiologists. There are currently no National Quality Forum-endorsed risk-adjusted outcome metrics for anesthesiologists to use as the basis for P4P. METHODS: Using clinical data from the New York State Cardiac Surgery Reporting System, we conducted a retrospective observational study of 55,436 patients undergoing cardiac surgery between 2009 and 2012. Hierarchical logistic regression modeling was used to examine the variation in in-hospital mortality or major complications (Q-wave myocardial infarction, renal failure, stroke, and respiratory failure) among anesthesiologists, controlling for patient demographics, severity of disease, comorbidities, and hospital quality. RESULTS: Although the variation in performance among anesthesiologists was statistically significant (P = 0.025), none of the anesthesiologists in the sample was classified as a high- or low-performance outliers. The contribution of anesthesiologists to outcomes represented 0.51% of the overall variability in patient outcomes (intraclass correlation coefficient [ICC] = 0.0051; 95% confidence interval [CI], 0.002-0.014), whereas the contribution of hospitals to patient outcomes was 2.90% (ICC = 0.029; 95% CI, 0.017-0.050). The anesthesiologist median odds ratio (MOR) was 1.13 (95% CI, 1.08-1.24), suggesting that the variation between anesthesiologist was modest, whereas the hospital MOR was 1.35 (95% CI, 1.25-1.48). In a separate analysis, the contribution of surgeons to overall outcomes represented 1.76% of the overall variability in patient outcomes (ICC = 0.018, 95% CI, 0.010-0.031), and the surgeon MOR was 1.26 (95% CI, 1.19-1.37). Twelve of the surgeons were identified as performance outliers. CONCLUSIONS: The impact of anesthesiologists on the total variability in cardiac surgical outcomes was probably about one-fourth as large as the surgeons' contribution. None of the anesthesiologists caring for cardiac surgical patients in New York State over a 3+ year period were identified as performance outliers. The use of a performance metric based on death or major complications for P4P may not be feasible for cardiac anesthesiologists.

Long-term venous access insertion: 'the learning curve'.

BACKGROUND: The central venous access port device (CVAPD) provides reliable vascular access and is used for delivery of fluids and for obtaining blood samples. However, it can carry some intra- and post-operative complications such as thrombosis, pneumothorax, catheter fracture and port malposition. This article describes one surgeon's experience over a 16-year period and strategies to avoid complications. METHODS: The data were prospectively collected from 1996 to 2012 (16-year period). Collected data included age and gender of the patient, pathology, type of port used, anaesthetic type, side and site of insertion, and complications. RESULTS: A total of 958 devices were implanted. The average age of the patient was 57.8 years. Sixty-eight complications were recorded with an average complication rate of 7.1%. This rate decreased from 23% between 1996 and 1997 to 3.6% from 2010 to 2013. Venous thrombosis was the main source of complications with an incidence of 2.5%. This complication occurred in seven of the first 86 patients (8.1%, 1996-1998) and decreased to 1.9% between 2000 and 2013. Twenty infections (2%), five pneumothoraces secondary to insertion (0.5%), one port malposition (0.1%) and three fractures of the catheter (0.3%) occurred over the 16 years. CONCLUSION: The surgeon's complications of CVAPD insertion requiring removal or revision of the port were considerably reduced as the surgeon's experience increases. It is suggested that all surgeons whose practice includes CVAPD insertion will have an initial learning curve, and strategies described in this paper may help decrease the number of complications.

The impact of anesthesiologists on coronary artery bypass graft surgery outcomes.

BACKGROUND: One of every 150 hospitalized patients experiences a lethal adverse event; nearly half of these events involves surgical patients. Although variations in surgeon performance and quality have been reported in the literature, less is known about the influence of anesthesiologists on outcomes after major surgery. Our goal of this study was to determine whether there is significant variation in outcomes between anesthesiologists after controlling for patient case mix and hospital quality. METHODS: Using clinical data from the New York State Cardiac Surgery Reporting System, we conducted a retrospective observational study of 7920 patients undergoing isolated coronary artery bypass graft surgery. Multivariable logistic regression modeling was used to examine the variation in death or major complications (Q-wave myocardial infarction, renal failure, stroke) across anesthesiologists, controlling for patient demographics, severity of disease, comorbidities, and hospital quality. RESULTS: Anesthesiologist performance was quantified using fixed-effects modeling. The variability across anesthesiologists was highly significant (P < 0.001). Patients managed by low-performance anesthesiologists (corresponding to the 25th percentile of the distribution of anesthesiologist risk-adjusted outcomes) experienced nearly twice the rate of death or serious complications (adjusted rate 3.33%; 95% confidence interval [CI], 3.09%-3.58%) as patients managed by high-performance anesthesiologists (corresponding to the 75th percentile) (adjusted rate 1.82%; 95% CI, 1.58%-2.10%). This performance gap was observed across all patient risk groups. CONCLUSIONS: The rate of death or major complications among patients undergoing coronary artery bypass graft surgery varies markedly across anesthesiologists. These findings suggest that there may be opportunities to improve perioperative management to improve outcomes among high-risk surgical patients.