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Pulmonary hypertension (PH) is a broad term describing the mean pulmonary artery pressure, as measured by right heart catheterization, exceeds 20mmHg. Pulmonary arterial hypertension (PAH) exists when PH is accompanied by a normal wedge pressure and elevated pulmonary vascular resistance. PAH is typified by dysmorphic and dysfunctional pulmonary arterial vasculature. Attempting to restore the functionality of the pulmonary artery is a hallmark of care to the PAH patient. Riociguat is a powerful stimulator of soluble guanylate cyclase and increases blood flow through the pulmonary arteries by dilating vascular smooth muscle cells. This review examines the pharmacology of riociguat, the fundamental clinical trials applying it to PAH patients, practical aspects when selecting its use, and future directions for its utilization.

Robotic thoracic surgery has demonstrated benefits. We aimed to evaluate implementation of a robotic thoracic surgery program on postoperative outcomes at our Veteran's Administration Medical Center (VAMC). We retrospectively reviewed our VAMC database from 2015 to 2021. Patients who underwent surgery with intention to treat lung nodules were included. Primary outcome was patient length of stay (LOS). Patients were grouped by surgical approach and stratified to before and after adoption of robotic surgery. Univariate comparison of postoperative outcomes was performed using Wilcoxon rank sums and chi-squared tests. Multivariate regression was performed to control for ASA class. P values 0.05 were considered significant. Outcomes of 108 patients were assessed. 63 operations (58%) occurred before and 45 (42%) after robotic surgery implementation. There were no differences in patient preoperative characteristics. More patients underwent minimally invasive surgery (MIS) in the post-implementation era than pre-implementation (85% vs. 42%, p 0.001). Robotic operations comprised 53% of operations post-implementation. On univariate analysis, patients in the post-implementation era had a shorter LOS vs. pre-implementation, regardless of surgical approach (mean 4.7 vs. 6.0 days, p = 0.04). On multivariate analysis, patients who underwent MIS had a shorter LOS [median 4 days (IQR 2-6 days) vs. 7 days (6-9 days), p 0.001] and were more likely to be discharged home than to inpatient facilities [OR (95% CI) 13.00 (1.61-104.70), p = 0.02]. Robotic thoracic surgery program implementation at a VAMC decreased patient LOS and increased the likelihood of discharging home. Implementation at other VAMCs may be associated with improvement in some patient outcomes.

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Purpose: Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γc) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified.Experimental Design: To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (TCM), effector memory (TEM), and stem cell memory (TSCM) subsets on the strength of tumor regression as well as the dose and type of clinically available γc cytokines, including IL-2, IL-7, IL-15, and IL-21.Results: We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γc cytokine only moderately correlated with response.Conclusion: Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γc cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. Clin Cancer Res; 17(16); 5343–52. ©2011 AACR.

The objective of this study was to evaluate the educational impact following the implementation of a robotic thoracic surgery program on cardiothoracic (CT) surgery trainees. We hypothesized that the introduction of a robotic thoracic surgery program would adversely affect the CT surgery resident experience, decreasing operative involvement and subsequent competency of surgical procedures. CT surgery residents and thoracic surgery attendings from a single academic institution were administered a recurring, electronic survey from September 2019 to September 2020 following each robotic thoracic surgery case. Surveys evaluated resident involvement and operative performance. This study was exempt from review by our Institutional Review Board. Attendings and residents completed surveys for 86 and 75 cases, respectively. Residents performed > 50% of the operation independently at the surgeon console in 66.2 and 73.3% of cases according to attending and resident responses, respectively. The proportion of trainees able to perform > 75% of the operation increased with each increasing year in training (p = 0.002). Based on the Global Evaluative Assessment of Robotic Skills grading tool, third-year residents averaged higher scores compared to first-year residents (22.9 versus 17.4 out of 30 possible points, p

Summary Stenosis at either the pulmonary artery (PA) or pulmonary vein (PV) anastomosis during lung transplantation (LTx) is a serious complication that requires an accurate and timely diagnosis for optimal clinical management. Transesophageal echocardiography (TEE) can play an essential role in making these diagnoses, both intraoperatively and postoperatively. However, it is important to recognize the limitations of TEE in this setting, including the lack of official guidelines to diagnose PA or PV stenosis. In this series, we describe four cases of vascular complications associated with LTx. We highlight the utility of TEE in the perioperative management of these patients, and discuss the diagnostic considerations when using this tool to assess the PA and PV anastomoses. As experts in perioperative echocardiography, anesthesiologists can employ TEE to enhance surgical success and improve patient outcomes after LTx. We therefore advocate the use of TEE during all cases of LTx, and encourage further efforts into the development of official echocardiographic guidelines specific to this patient population.

The objectives were to determine factors associated with conversion to open surgery in patients with esophageal cancer who underwent minimally invasive esophagectomy (MIE, including laparo-thoracoscopic and robotic) and the impact of conversion to open surgery on patient outcomes. We included patients from the National Cancer Database with esophageal and gastroesophageal junction cancer who underwent MIE from 2010 to 2015. Patient-, tumor-, and facility-related characteristics as well as short-term and oncologic outcomes were compared between patients who were converted to open surgery and those who underwent successful MIE without conversion to open surgery. Multivariable logistic regression models were used to analyze risk factors for conversion to open surgery from attempted MIE. 7306 patients underwent attempted MIE. Of these patients, 82 of 1487 (5.2%) robotic-assisted esophagectomies were converted to open, compared to 691 of 5737 (12.0%) laparo-thoracoscopic esophagectomies (p

Background Our objective was to evaluate the association of bridge to transplant (BTT) extracorporeal membrane oxygenation (ECMO) on survival after lung transplantation (LTx) and determine the degree to which transplant center volume affects this relationship. Methods Using the United Network for Organ Sharing database, we performed a retrospective cohort study evaluating the survival of patients undergoing LTx between 2005 and 2017. On the basis of previous literature, LTx centers were classified into 3 groups using their average annual LTx volume over the preceding 5 years: less than 25, 25 to 49, and more than 50. Survival of BTT ECMO and non-ECMO patients was analyzed using a log-rank test. Propensity scores for BTT ECMO were calculated, and a weighted proportional hazards model was used to compare BTT ECMO and non-ECMO patients by center volume. Results There were 20,976 patients who met inclusion criteria, with 611 (2.9%) undergoing BTT ECMO. Overall, BTT ECMO was associated with increased posttransplantation hazard of mortality (hazard ratio, 1.37; 95% confidence interval, 1.14 to 1.64). Kaplan-Meier plots by center volume suggest that BTT ECMO–associated mortality may be mitigated at high-volume LTx centers. In the propensity score–weighted proportional hazards model, we determined that when centers perform more than 35 LTxs per year, the increased hazard of BTT ECMO on mortality is no longer observed. Conclusions BTT ECMO can be performed as a bridge to LTx without significantly increasing patient mortality in high-volume centers. Patients undergoing BTT ECMO at LTx centers that perform more than 35 LTxs annually have equivalent mortality to those who do not require ECMO before transplantation.

The objective of this study was to evaluate the educational impact following the implementation of a robotic thoracic surgery program on cardiothoracic (CT) surgery trainees. We hypothesized that the introduction of a robotic thoracic surgery program would adversely affect the CT surgery resident experience, decreasing operative involvement and subsequent competency of surgical procedures. CT surgery residents and thoracic surgery attendings from a single academic institution were administered a recurring, electronic survey from September 2019 to September 2020 following each robotic thoracic surgery case. Surveys evaluated resident involvement and operative performance. This study was exempt from review by our Institutional Review Board. Attendings and residents completed surveys for 86 and 75 cases, respectively. Residents performed 50% of the operation independently at the surgeon console in 66.2 and 73.3% of cases according to attending and resident responses, respectively. The proportion of trainees able to perform 75% of the operation increased with each increasing year in training (p = 0.002). Based on the Global Evaluative Assessment of Robotic Skills grading tool, third-year residents averaged higher scores compared to first-year residents (22.9 versus 17.4 out of 30 possible points, p 0.001), indicating that more extensive prior operative experience could shorten the learning curve of robotic thoracic surgery. CT surgery residents remain actively involved in an operative role during the establishment of a robotic thoracic surgery program. The transition to a robotic thoracic surgery platform appears feasible in a large academic setting without jeopardizing the educational experience of resident trainees.

Introduction: The impact of radiation prescription dose on postoperative complications during standard of care trimodality therapy for operable stage II-III esophageal and gastroesophageal junction cancers has not been established.Methods: We retrospectively reviewed 82 patients with esophageal or gastroesophageal junction cancers treated between 2004 and 2016 with neoadjuvant chemoradiation followed by resection at a single institution. Post-operative complications within 30 days were reviewed and scored using the Comprehensive Complication Index (CCI). Results were compared between patients treated with Results: Twenty-nine patients were treated with Conclusions: In selected esophageal and gastroesophageal junction cancer patients, radiation doses ≥ 50 Gy do not appear to increase 30 day post-operative complication rates. These findings suggest that the use of definitive doses of radiotherapy (50–50.4 Gy) in the neoadjuvant setting may not increase post-operative complications.

Background Pulmonary segmentectomy provides an anatomic lung resection while avoiding removal of excess normal lung tissue. This may be beneficial in patients with minimal pulmonary reserve who present with early-stage non-small cell lung cancer (NSCLC). However, the operative performance of a segmentectomy using a video-assisted thoracoscopic approach can be technically challenging. We hypothesized that introduction of the robotic surgical system would facilitate the performance of a segmentectomy as measured by an increase in the proportion of segmentectomies being pursued. Methods We completed a retrospective analysis of thoracoscopic and robotic anatomic lung resections, including lobectomies and segmentectomies, performed in patients with primary lung cancer from the time of initiation of the robotic thoracic surgery program in November 2017 to November 2019. We compared the proportion of thoracoscopic and robotic segmentectomies performed during the first year compared to the second year of the data collection period. Results A total of 138 thoracoscopic and robotic anatomic lung resections were performed for primary lung cancer. Types of lung cancer resected (adenocarcinoma, squamous cell carcinoma, or other), tumor size based on clinical T staging (T1-T4), and tumor location were not significantly different between years (P=0.44, P=0.98, and P=0.26, respectively). The proportion of segmentectomies increased from 8.6% during the first year to 25.0% during the second year (P=0.01). One out of 6 (16.7%) segmentectomies were performed using the robot during the first year versus 15 out of 17 (88.2%) during the second year (P=0.003). Conclusions Use of the robot led to a significant increase in the number of segmentectomies performed in patients undergoing anatomic lung resection. With increasing lung cancer awareness and widely available screening, a greater number of small, early-stage tumors suitable for segmentectomy will likely be detected. We conclude that robotic-assisted surgery may facilitate the challenges of performing a minimally invasive segmentectomy.

Small cell lung cancer (SCLC) is an aggressive tumor type characterized by rapid growth and overall poor prognosis. For the past several decades, chemotherapy and radiotherapy have served as the cornerstone of treatment. Recently, however, the role of surgery for early stage disease has gained considerable interest. Multiple retrospective and observational studies have shown excellent survival for early stage SCLC treated with surgical resection. We herein review the past and present evidence regarding surgical options for limited stage SCLC.

Background The objective of this study was to evaluate the impact of unplanned conversion to open esophagectomy during minimally invasive esophagectomy (MIE) on postoperative morbidity and mortality for patients with esophageal cancer, as well as to evaluate the variables that influence the need for conversion. Methods This study was a retrospective analysis of patients with esophageal cancer who underwent open esophagectomy or MIE by either a laparothoracoscopic approach or a robotic approach from 2016 to 2018 by using the esophagectomy-specific American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database. Poisson regression models were used to analyze 30-day outcomes and risk factors for conversion to open esophagectomy during attempted MIE. Results A total of 2616 patients were identified. The overall conversion rate for MIE was 6.3%. Compared with completed MIE, patients requiring conversion to open esophagectomy had a significantly increased risk of 30-day mortality (risk ratio, 2.63; 95% confidence interval, 1.03 to 6.69) and experienced a variety of other postoperative complications. Patients requiring conversion to open esophagectomy during MIE also experienced worse perioperative outcomes when compared to patients who underwent planned open esophagectomy. Estimated surgical risk on the basis of the ACS NSQIP Surgical Risk Calculator was the only variable found to be independently associated with conversion from minimally invasive to open esophagectomy (risk ratio, 1.03; 95% confidence interval, 1.01 to 1.04, for each 10% increase in risk score). Conclusions Unplanned conversion to open esophagectomy during MIE is associated with significantly greater morbidity and a 2.6-fold increased risk of death when compared with both completed MIE and planned open esophagectomy. The ACS NSQIP Surgical Risk Calculator may help identify patients preoperatively who are at higher risk for conversion to open esophagectomy during MIE.

BACKGROUND: Neoadjuvant chemotherapy with concurrent radiotherapy (nCRT) is an accepted treatment regimen for patients with potentially curable esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The purpose of this study was to evaluate if induction chemotherapy (IC) before nCRT is associated with improved pathologic complete response (pCR) and overall survival (OS) when compared with patients who received nCRT alone for esophageal and GEJ adenocarcinoma. METHODS: Using the National Cancer Database (NCDB), patients who received nCRT and curative intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006–2015 were included. Chemotherapy and radiation therapy start dates were used to define cohorts who received IC before nCRT (IC + nCRT) versus those who only received concurrent nCRT before surgery. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. RESULTS: 12,460 patients met inclusion criteria. 11,880 (95%) patients received nCRT and 580 (5%) patients received IC + nCRT. Following propensity weighting, OS was significantly improved among patients who received IC + nCRT versus nCRT (HR 0.82; 95% CI 0.74–0.92; p

In August 2016, a group including sport medicine clinicians, researchers, and a bioethicist met in Vail, Colorado to discuss regenerative medicine and its potential role in youth sports injuries. There was consensus that a call to action is urgently needed to understand the current evidence base, the risks and rewards, and future directions of research and clinical practice for regenerative medicine therapies in youth sports. We present here a summary of our meeting, which was supported by the National Youth Sports Health and Safety Institute (NYSHSI), a partnership between the American College of Sports Medicine (ACSM) and Sanford Health. The group's goal is to educate practitioners and the public, and to pioneer a means of accumulating meaningful clinical data on regenerative medicine therapies in pediatric and adolescent athletes.

Patients express strong opinion regarding discharge destination, preferring discharge home vs elsewhere. As focus on patient satisfaction increases, we sought to understand differences in postoperative discharge destination after minimally invasive vs open anatomic lung resection for lung cancer to guide patient education and management and better understand the postoperative patient experience.Procedures were identified by Current Procedural Terminology and International Classification of Diseases codes using the 2012-2017 American College of Surgeons National Surgical Quality Improvement Program dataset. Propensity score analysis was used to assess the relationship between the surgical approach and nonhome discharge destination (primary outcome) and postoperative complications; related, unplanned readmission; and mortality (secondary outcomes).A total of 17,303 patients underwent anatomic lung resection for lung cancer, including 10,121 (58.5%) minimally invasive and 7182 (41.5%) open resections. Patients undergoing open resection had 60% greater odds of nonhome discharge (P.001), 58% greater odds of postoperative mortality (P = .003), 36% greater odds of postoperative complication (P.001), and 17% greater odds of readmission (P = .04) compared with patients undergoing minimally invasive resection.The minimally invasive approach to lung resection for lung cancer offers patients a more desirable patient-centered postoperative experience, as well as more favorable clinical outcomes, and should be favored when feasible.

The process of metastasis relies on a series of stochastic and sequential steps, with selective pressure exerted on a large number of genetically volatile cancer cells to produce a very small fraction of tumor cells with the ability to navigate the transition from primary tumor cell to end-organ metastasis. This process is intricately determined by cell-microenvironment interactions, the mechanistic understanding of which is steadily increasing. The continued elucidation of pathways that govern these interactions offers potential therapeutic options to patients with advanced disease.

395 Background: Neoadjuvant therapy is the standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma, with most patients receiving neoadjuvant chemoradiation (CRT). CRT can be delivered concurrently or sequentially after induction chemotherapy. The purpose of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) among patients who received concurrent versus sequential CRT in the National Cancer Database (NCDB). Methods: Patients who received neoadjuvant CRT and underwent curative intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006-2015 were included. Patients with clinical T4 or metastatic disease were excluded. Concurrent CRT was defined as radiation treatment starting within 6 weeks of chemotherapy start. Sequential CRT was defined as radiation treatment starting greater than 6 weeks after chemotherapy start. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. Results: 12,460 patients met inclusion criteria. 11,880 (95%) patients received concurrent CRT and 580 (5%) patients received sequential CRT. Patients who received sequential CRT were significantly younger (mean age: 60.7 vs 62.2 years), had higher clinical nodal stage (N2-3: 14.7% vs 10.1%), and were more often treated at academic/research hospitals (67.1 vs 55.5) (all p≤0.001). pCR was achieved in 16.2% of patients who received sequential CRT and in 14.0% of patients who received concurrent CRT (p = 0.131). Following propensity weighting, OS was significantly improved among patients who received sequential versus concurrent CRT (HR 0.82; 95% CI 0.74-0.92; p < 0.001) with a median OS for the sequential cohort of 41.4 months versus 29.4 months for those who received concurrent CRT. Conclusions: In this retrospective study from a large national database of patients who received neoadjuvant CRT for esophageal and GEJ adenocarcinoma, sequential CRT is associated with a significant OS benefit. These results merit consideration of a well powered prospective multi-institutional randomized clinical trial to further evaluate this observed difference.

119 Background: Neoadjuvant chemoradiation (nCRT) followed by resection is standard of care for operable stage II-III EC and GEJC; however, it can be associated with significant risk of postoperative complications (POC). The CROSS study group reported no increase in POC severity with nCRT using 41.4 Gy compared to surgery alone as defined by the Comprehensive Complication Index (CCI). We applied the CCI metric to evaluate the impact of nCRT radiation dose of < 50 Gy vs. ≥ 50 Gy on POC rates and compared to the CROSS rates. Methods: We retrospectively reviewed 82 pts (2004-2016) with EC or GEJC treated with nCRT followed by resection at our institution. 29 (35%) pts were treated with < 50 Gy (range 39.6-46.8 Gy) and 53 (65%) were treated with ≥ 50 Gy (range 50.0-52.5 Gy) delivered using IMRT/VMAT (41%), 3D-CRT (46%), or tomotherapy IMRT (12%). Concurrent chemotherapy were carboplatin/paclitaxel (59%), cisplatin/5-FU (17%), or other (24%). Resection was performed by Ivor Lewis esophagectomy (67%), esophagogastrectomy (14%), or trans-hiatal approach (11%). POC within 30 days were graded using the Clavien-Dindo scale and CCI scores were computed and compared between the two dose groups and with the CROSS nCRT group. Results: CCI scores and complication rates between our < 50 Gy and ≥ 50 Gy groups were not significantly different. Assuming a normal distribution of the CROSS CCI scores, there was no significant difference in CCI scores between the CROSS study nCRT, < 50 Gy, or ≥ 50 Gy groups. Rates of pulmonary complications were greater in the CROSS study. Conclusions: In highly selected EC and GEJC pts, definitive nCRT radiation doses do not appear to increase POC rates. Thus, 50 Gy can likely be delivered without increasing toxicity while also achieving a definitive dose for pts not able or willing to undergo subsequent surgery. [Table: see text]

Retinoic acid is required to maintain pre-DC–derived CD11b+CD8α−Esamhigh dendritic cells (DCs) in the spleen and CD11b+CD103+ DCs in the gut., Dendritic cells (DCs) comprise distinct populations with specialized immune-regulatory functions. However, the environmental factors that determine the differentiation of these subsets remain poorly defined. Here, we report that retinoic acid (RA), a vitamin A derivative, controls the homeostasis of pre-DC (precursor of DC)–derived splenic CD11b+CD8α−Esamhigh DCs and the developmentally related CD11b+CD103+ subset within the gut. Whereas mice deprived of RA signaling significantly lost both of these populations, neither pre-DC–derived CD11b−CD8α+ and CD11b−CD103+ nor monocyte-derived CD11b+CD8α−Esamlow or CD11b+CD103− DC populations were deficient. In fate-tracking experiments, transfer of pre-DCs into RA-supplemented hosts resulted in near complete conversion of these cells into the CD11b+CD8α− subset, whereas transfer into vitamin A–deficient (VAD) hosts caused diversion to the CD11b−CD8α+ lineage. As vitamin A is an essential nutrient, we evaluated retinoid levels in mice and humans after radiation-induced mucosal injury and found this conditioning led to an acute VAD state. Consequently, radiation led to a selective loss of both RA-dependent DC subsets and impaired class II–restricted auto and antitumor immunity that could be rescued by supplemental RA. These findings establish a critical role for RA in regulating the homeostasis of pre-DC–derived DC subsets and have implications for the management of patients with immune deficiencies resulting from malnutrition and irradiation.

Purpose: Adoptive cell transfer (ACT) of tumor infiltrating or genetically engineered T cells can cause durable responses in patients with metastatic cancer. Multiple clinically modifiable parameters can comprise this therapy, including cell dose and phenotype, in vivo antigen restimulation, and common gamma-chain (γc) cytokine support. However, the relative contributions of each these individual components to the magnitude of the antitumor response have yet to be quantified. Experimental Design: To systematically and quantitatively appraise each of these variables, we employed the Pmel-1 mouse model treating large, established B16 melanoma tumors. In addition to cell dose and magnitude of in vivo antigen restimulation, we also evaluated the relative efficacy of central memory (TCM), effector memory (TEM), and stem cell memory (TSCM) subsets on the strength of tumor regression as well as the dose and type of clinically available γc cytokines, including IL-2, IL-7, IL-15, and IL-21. Results: We found that cell dose, T-cell differentiation status, and viral vaccine titer each were correlated strongly and significantly with the magnitude of tumor regression. Surprisingly, although the total number of IL-2 doses was correlated with tumor regression, no significant benefit to prolonged (≥6 doses) administration was observed. Moreover, the specific type and dose of γc cytokine only moderately correlated with response. Conclusion: Collectively, these findings elucidate some of the key determinants of successful ACT immunotherapy for the treatment of cancer in mice and further show that γc cytokines offer a similar ability to effectively drive antitumor T-cell function in vivo. Clin Cancer Res; 17(16); 5343–52. ©2011 AACR.

Stroke is an important complication of cardiopulmonary bypass (CPB). This study determined if the timing of stroke events after CPB predicted stroke-related mortality or rehabilitation needs at hospital discharge.We performed a retrospective review of 7201 consecutive cardiac surgical patients during a 10-year period and identified 202 strokes. Postoperative stroke after CPB was classified as early (or = 24 hours) or late (24 hours). Data were collected on patient characteristics, intraoperative variables and outcomes, postoperative course, stroke severity, and discharge status, including death from stroke. Logistic regression analysis was used to assess the relationship between the timing of stroke and discharge status after adjusting for clinically relevant factors.The stroke incidence was 2.8%. Postoperative strokes occurred within 24 hours in 22.8% (46 of 202) and after 24 hours in 77.2% (156 of 202). Factors found in logistic regression analysis to be independently associated with stroke-related death included stroke within 24 hours postoperatively (odds ratio [OR], 9.16; p0.0001), preoperative chronic renal insufficiency (OR, 4.46; p = 0.01), and National Institute of Health Stroke Scale (NIHSS) score (OR, 1.16 per NIHSS point increase; p0.0001). Among survivors, early stroke was associated with greater rehabilitation needs (p0.001).Early stroke after CPB is independently associated with higher stroke-related death and is associated with increased need for skilled rehabilitation at discharge. Neuroprotective strategies aimed at reducing early postoperative stroke may positively impact death and neurologic disability after CPB.

This study is based on a panel sample of small farm households drawn from eight rural communities in Chile interviewed in 1968 and 1986. The incidence and intensity of poverty based on primary income increased over this period. However, after including earnings from the minimum employment programmes and public transfers, both the headcount ratio and squared poverty gap fell markedly between the two surveys. Mobility analysis showed more households moving out of than into poverty. Of those households who became impoverished, around half may have suffered a transitory decline in income in 1986. The other half experienced pauperisation as a result of investing in projects with negative rates of return, investing in the accumulation of human capital by their children, sustaining a large rise in the household's dependency ratio or suffering political discrimination in the labour market. Per capita income was positively related to schooling of the household head (in 1968), land ownership (in 1986) and living in...

A patient simulator thermometer was designed to meet the demands of training students in a simulated clinical environment. This is achieved through the use of an instructor interface, Bluetooth signal generation, and a student interface which simulates a clinical temporal thermometer.

OBJECTIVE: To determine the effects of delaying permanent pacemaker implantation in cardiac transplant recipients from less than tree weeks to three weeks or more post transplantation-a change prompted by an earlier audit. DESIGN: Retrospective review of resting 12 lead electrocardiograms and prospective 24 hour ambulatory electrocardiograms. Comparison of pacemaker usage before (period 1) and after (period 2) the policy change in November 1990. SETTING: Outpatient department, supra-regional cardiopulmonary transplant unit. PATIENTS: All 30 consecutive orthotopic cardiac transplant recipients who received a permanent pacemaker within one month of transplantation between May 1985 and August 1995. MAIN OUTCOME MEASURES: Presence of pacing on the 12 lead electrocardiogram and during 24 hour ambulatory electro-cardiogram monitoring (pacemaker programmed to 50 beats per minute). RESULTS: 16/152 (10.5%) cardiac transplant recipients received permanent pacemakers in period 1 compared with 14/180 (7.8%) in period 2 (P = NS). Evidence of pacing was seen on 12 lead electrocardiograms at three months in 37.5% recipients in period 1 compared with 78.6% in period 2 (P = 0.03). At six months pacemaker usage had declined to 18.8% in period 1 and 35.7% in period 2 and at three years to 13.3% in period 1 and 40% in period 2 (P = NS for both). 21% patients in period 1 paced on ambulatory 24 hour monitoring compared with 38.5% in period 2 (P = NS). CONCLUSIONS: Delaying permanent pacemaker implantation to three weeks or more after cardiac transplantation reduced the proportion of permanent pacemaker implantations, slightly but not significantly. There was a significant increase in permanent pacemaker usage at three months post transplantation with trends towards increased usage at later times, suggesting more appropriate selection of patients for permanent pacing.

The clinical usefulness of certain electrophysiological measurements, particularly those of sinus node function, is limited by variation in autonomic tone resulting in poor reproducibility. The denervated transplanted heart is not susceptible to direct autonomic control and, therefore, electrophysiological measurements may be more reproducible in this group. To our knowledge, this hypothesis has not previously been systematically evaluated. Ten adult recipients underwent serial electrophysiological studies between 10-18 days after cardiac transplantation. Five studies were performed at 2-hour intervals during a single day, between 9:00 a.m. and 5:00 p.m. Spontaneous cycle length (SCL) was recorded. Sinus node recovery time (SNRT), sinoatrial conduction time (SACT), and atrioventricular (AV) Wenckebach cycle length were measured using standard techniques. The effective refractory periods of the complete AV conducting system (AVERP), atrium (AERP), and ventricle (VERP) were measured. Corrected maximal SNRT was normal in all subjects. Mean coefficients of variation (Cv) for SCL, corrected maximal SNRT, and SACT were 2.8%, 7.4%, and 3.5%, respectively. AVERP was less than AERP in seven subjects, limiting further analysis. The mean Cv for AV Wenckebach cycle length was 2.1%. The mean coefficients of variation for AERP were 3.6% and 3.7%, and for VERP 3% and 3.3%, at 600- and 400-ms drive cycle lengths, respectively. Previous studies report much greater variation in innervated subjects particularly of indices of sinus node function. Thus, the reproducibility of electrophysiological measurements of sinus and AV node function in the transplanted heart is better than in normal subjects. This may have important implications for the reliability of electrophysiological testing in transplant recipients.

T-cell receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for preclinical immunotherapy studies. Here, we describe the superiority of γ-retroviral vectors compared with lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naive/memory-stem cell like (TN/TSCM; CD62L(hi)/CD44(low)) and central memory (TCM; CD62L(hi)/CD44(hi)) CD8+ T cells using murine stem cell-based γ-retroviral vectors (MSGV1). We created MSGV1 vectors for a major histocompatibility complex-class I-restricted TCR specific for the melanocyte-differentiation antigen, glycoprotein 100 (MSGV1-pmel-1), and a major histocompatibility complex-class II-restricted TCR specific for tyrosinase-related protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1 TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4 T cells. We simultaneously created lentiviral vectors encoding the pmel-1 TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using γ-retroviral rather than lentiviral vectors.

Cluster of differentiation (CD)8+ T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8+ T cells for patient treatments is controversial and understudied. We investigated human CD8+ T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or “exhaustion,” maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.

OBJECTIVE--To determine the need for long-term pacing and optimum mode of pacing in cardiac transplant recipients. DESIGN--(a) A retrospective review of patient records. (b) A prospective study of pacemaker use by 24 hour ambulatory electrocardiography before and after reprogramming to minimise use of pacemakers. SETTING--Outpatient clinic, supra-regional cardiopulmonary transplant unit. PATIENTS--All 21 patients at this centre who had received permanent pacemakers after cardiac transplantation. 18 of 19 survivors completed the prospective part of the study. MAIN OUTCOME MEASURE--The presence of pacing during a 24 hour ambulatory electrocardiographic recording (programming: 50 beats/min, rate sensor inactivated). RESULTS--21 of 191 (11%) recipients surviving one month or more received permanent pacemakers. The indication was sinus node dysfunction in 13 (62%) and atrioventricular (AV) block in eight (38%). Patients who paced on follow up 12 lead electrocardiograms declined from 38% at three months to 10% at three years after transplantation. After programming to 50 beats/min only five of 18 (28%) patients paced during a 24 hour ambulatory recording. Four of 11 (36%) recipients who received pacemakers for sinus node dysfunction paced compared with one of seven patients (14%) paced for AV block. No patient who had a pacemaker before the 16th day after operation continued to pace whereas five of nine implanted later were used long-term. CONCLUSION--Only five of 18 (28%) patients with pacemakers continued to pace long-term. Continued pacing was more common in those with persistent sinus node dysfunction after the second week after operation but the need for long-term pacing was not predictable.

Cecal volvulus is an uncommon cause of intestinal obstruction, accounting for less than 1% of cases in Western countries. In the literature, it has been described as a complication following numerous common surgeries as well as a number of minimally invasive procedures. Presumably, it is more likely to occur following any surgical procedure which might require some degree of medial visceral rotation or disruption of the fusion plane between the cecum or ascending colon with the lateral peritoneum, providing sufficient mobility to allow for cecal volvulization to occur. In addition, cadaver and autopsy studies have also suggested that 10-20% of the population may have sufficient mobility of the colon to allow for volvulization. We present a review of the literature pertaining to the diagnosis and management of cecal volvulus as well as the case of J.R., a 78-year-old male with cecal volvulus six days following a right radical nephrectomy for renal cell carcinoma.

Angiotensin II type 2 receptor (AT2-R) overexpression in the mouse heart preserves left ventricular (LV) size and global LV function during post-MI remodeling. We hypothesized that CMR tagging would localize regional improvements in myocardial function during post-MI remodeling in AT2-R cardiac overexpressed transgenic mice (TG), which could explain the preservation of global LV function post-MI. Six male wild-type (WT) C57BL/6 mice and 10 TG mice were studied by CMR at baseline (day 0) and days 1, 7, and 28 post-MI. MI was induced by 1 hour occlusion of the LAD followed by reperfusion. On day 1 post-MI, gadolinium-DTPA was injected to assess infarct size. LV size and function was assessed by cine CMR. Mean % circumferential shortening (%CS) was calculated within infarcted, adjacent, and remote regions at each time point in WT and TG mice. Quantitative interstitial collagen and mean myocyte cross-sectional area was measured postmortem at day 28 post-MI. LV end-systolic volume was lower and ejection fraction higher at baseline in the TG group and these differences were maintained post-MI. Within infarcted and remote zones, although %CS was higher in TG mice at day 0, there was no difference by day 28 between groups. Within adjacent regions, while there was no difference at day 0 or 1 in TG vs. WT, %CS was significantly higher in TG mice by day 7, and these changes persisted out to day 28 post-MI. Regional interstitial collagen and myocyte size were similar between groups. Thus, myocardial tagging can detect regional differences in contractile function post-MI in TG mice, and AT2-R overexpression is associated with improved contractile function in adjacent noninfarcted myocardium.

The etiology and clinical significance of sustained arrhythmias, and atrial and ventricular premature complexes (APCs and VPCs, respectively) after heart transplantation are controversial. Fifty adult recipients surviving > 2 weeks were studied by continuous telemetry while in the hospital and by ambulatory electrocardiographic monitoring at 2, 4, 6, 12 and 24 weeks after transplantation. The median APC frequency was greater among subjects who experienced allograft rejection in the early postoperative period (0.7/hour, range 0 to 23) than among those who did not (0.2/hour, range 0 to 10.4) (p = 0.04). The APC frequency in all subjects decreased from 0.25/hour (range 0 to 23) early to 0/hour (0 to 14) later (p = 0.04). Atrial flutter was the most frequent sustained arrhythmia; it was recorded in 5 of 21 rejectors and in 1 of 29 nonrejectors (p = 0.04), and 11 of 16 episodes (69%) were related to acute rejection temporally. VPCs were recorded in all patients early after transplantation, but the median frequency subsequently decreased from 4.6/hour (range 0.5 to 470) early to 1.25/hour (range 0 to 225) later (p < 0.001). VPC frequency was unrelated to rejection. Sustained ventricular tachycardia was recorded once and was caused by the proarrhythmic effect of flecainide. Thus, APCs and VPCs occur frequently after transplantation. Frequent APCs are associated with rejection, whereas the main determinant of VPC frequency is time after transplantation. Atrial flutter is closely associated with rejection and should be regarded as an indication for endomyocardial biopsy. Ventricular tachycardia occurs seldom, and in this study was due to proarrhythmic drug effects.

The chronotropic response to exercise is abnormal in cardiac transplant recipients as a result of autonomic denervation. Differences in the response between recent transplant recipients and longer-term survivors have been described in previous cross-sectional studies. These changes have not been assessed directly using serial studies. The effect of sinus node dysfunction on the chronotropic response has not previously been determined. Thirty-one transplant recipients underwent serial treadmill exercise tests using the chronotropic exercise assessment protocol 3 and 6 weeks and 3 and 6 months after transplantation. Sinus node function was assessed using standard electrophysiologic techniques. The chronotropic response increased between 3 and 6 weeks after transplantation in all subjects. Six months after transplantation, there was a further marked increase in the response in a subgroup of 5 subjects. These subjects also had a dramatic decrease in heart rate on cessation of exercise. Three subjects had abnormal sinus node function. Although heart rates and chronotropic response were below average in these subjects, 2 other subjects with normal sinus node function on electrophysiologic testing had lower heart rates and worse chronotropic responses. Thus, the chronotropic response to exercise evolves over the first 6 weeks after cardiac transplantation in all subjects. In a number of recipients (16%), there is a marked increase in chronotropic response between 3 and 6 months, which suggests efferent sympathetic reinnervation. There was no clear difference in chronotropic response between subjects with and without evidence of sinus node dysfunction.

Objectives. This study aimed to examine changes over time in sinus node function after cardiac transplantation; to determine the incidence, natural history and etiology of sinus node dysfunction in transplant recipients; and to identify any early predictors of long-term sinus node function. Background. Bradyarrhythmias caused by sinus node dysfunction are common immediately after cardiac transplantation. Existing electrophysiologic studies have been limited by small numbers and have reported an unexpectedly high incidence of sinus node dysfunction (~50%) compared with the incidence of bradyarrhythmias in other studies, There have been no previous studies reporting serial electrophysiologic data. Thus, the natural history of sinus node dysfunction after transplantation has not been adequately described. Methods. Serial electrophysiologic studies of sinus node function and 24-h ambulatory electrocardiographic recordings were performed at 1, 2, 3 and 6 weeks and 3 and 6 months after transplantation in 40 adult recipients. Results. The overall incidence of sinus node dysfunction was 17.5% (7 of 40). Six patients (15%) had sinus node dysfunction from week 1; one developed sinus node dysfunction at 3 months. Sinus node recovery time returned to normal by 6 week in all six patients with early sinus node dysfunction, but abnormalities of sinoatrial conduction persisted in two. Two patients who required pacing during ambulatory monitoring at 2 weeks after transplantation (temporary pacemaker 50 beats/min, demand) received a permanent pacemaker. One patient required pacing at 3 weeks and continued to require pacing 6 months after transplantation. Conclusions. The incidence of sinus node dysfunction after cardiac transplantation is lower than has been previously reported in electrophysiologic studies. Sinus node automaticity improves with time, although abnormalities of sinoatrial conduction may persist. The best predictor of permanent pacing requirements is the temporary pacing requirements during 24-h Holter monitoring 2 and 3 weeks after transplantation, with temporary pacing set at 50 beats/min on demand.

Ventricular vagal nerve endings are thought to trigger vasodepressor syncope. Reports of vasodepressor reactions associated with donor bradycardia after cardiac transplantation have led to speculation that vagal reinnervation occurs. We assessed reinnervation status in seven patients 23-36 months (median 24 months) post-transplantation. Heart rate responses to vagal manoeuvres (respiration, Valsalva) and sympathetic stimuli (exercise and injection of tyramine into the coronary artery supplying the sinus node) were measured. All patients underwent 60 min of 60 degrees head-up tilt with foot plate support. During tilt four of the seven had vasodepressor reactions with a fall in mean arterial pressure of 20-90 mmHg. During vasodepression two patients had falls in donor heart rate of 13 and 40% relative to peak heart rate during tilt. These two patients had evidence of functional sympathetic reinnervation. By contrast the two patients without donor bradycardia during vasodepression had only limited or no evidence of sympathetic reinnervation. No patient had consistent evidence of parasympathetic reinnervation as judged by the heart rate response to vagal manoeuvres. Head-up tilt can thus produce vasodepressor reactions with donor bradycardia after cardiac transplantation in the absence of consistent evidence of vagal reinnervation. Left ventricular nerve endings may not be the only mediators of tilt-induced vasodepressor reactions in man. Donor bradycardia during vasodepression may reflect sympathetic withdrawal and not vagal reinnervation.

There are currently 104 patients at this centre who have survived at least 3 months after orthotopic cardiac transplantation. Seven of these long-term survivors have subsequently died and in three cases death was sudden and unexpected. All three of these patients had been noted to have inappropriately high resting heart rates (> 130 b.min-1). The rhythm was sinus tachycardia, supraventricular tachycardia or both intermittently. The heart rates of all 104 long-term survivors were recorded from ECGs taken at routine follow-up visits every 3 months for one year and annually thereafter. The overall mean heart rate was 100 +/- 13.2 b.min-1. Four patients, including the three identified above, had mean heart rates greater than the 95th centile. The mortality rate in this group is 75%. Four deaths have occurred in the remaining 100 patients (P < 0.001). In our series, an inappropriately high resting heart rate due to sinus tachycardia or supraventricular tachycardia in long-term survivors of cardiac transplantation, is an adverse prognostic sign.

After 17 years of military dictatorship characterised by a preoccupation with microeconomic efficiency and macroeconomic stabilisation, the alleviation of poverty has once again become a political priority in Chile. This chapter attempts to contribute to the current debate on anti-poverty strategies by reviewing the experience of selected policies targeted at small farmers from the 1960s to the 1980s.

By the 1960s, the largest agro-industrial sugar complexes on the Peruvian coast had established systems of free health care, primary education, housing, electricity, drinking water and leisure facilities for their permanent labour force, as well as providing subsidized rations of food and clothing. The value of these benefits when added to a relatively high cash wage placed this group of workers in the top quartile of the country’s income earners (Figueroa, 1973).

Recipient pneumonectomy and the necessity for meticulous hemostasis in heart-lung transplantation can result in injury to the vagus nerves as they course through the posterior mediastinum, with consequent delay in gastric emptying. This has been reported to lead to chronic aspiration and associated pulmonary sequelae. To study the association between delayed gastric emptying, bronchiectasis, and bronchiolitis obliterans after heart-lung transplantation, we performed esophageal manometry, 24-hour pH monitoring, and radioisotopic gastric emptying in 10 patients who underwent heart-lung transplantation. Three patients had grossly delayed liquid and solid emptying that was compatible with complete vagotomy. Six other patients had delayed liquid but normal solid emptying--an unexplained finding that is the reverse of what one would expect from vagal injury. Two of these 9 patients had esophageal dysmotility, but none demonstrated gastroesophageal reflux. One remaining patient had faster than normal gastric emptying for both solids and liquids. Of the 10, 2 patients have radiologic changes of bronchiectasis and 3 have biopsy evidence of obliterative bronchiolitis. There is no relationship between these sequelae and the occurrence of esophageal dysmotility, gastroesophageal reflux, or vagotomy. We conclude that gastric emptying abnormalities can occur after heart-lung transplantation, but such abnormalities are not associated with gastroesophageal reflux and the development of pulmonary sequelae, as previously reported.

The indications for and timing of permanent pacing were reviewed in all 17 of 154 adult heart transplant recipients at this center who have had permanent pacemakers implanted. Resting 12-lead ECGs recorded during routine follow-up were examined. A prospective study of pacing requirement was then undertaken. Holter monitoring was performed before and after reprogramming the pacemakers to VVI mode at 50 beats/min. Exercise responses in various pacing modes were then assessed in seven patients with rate responsive pacemakers using a standard Bruce protocol treadmill test. The indication for pacing was sinus node dysfunction in 59% (10/17) and atrioventricular (AV) block in 41% (7/17). The majority of pacemakers were implanted between seven and 21 days after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. There was a progressive reduction in the frequency of pacing on 12-lead ECGs with time after transplantation. Eight of 14 patients with empirically selected programming paced during Holter monitoring. After reprogramming to 50 beats/min VVI mode only three of 14 patients, all with sinus node dysfunction, paced. Rate responsive pacing made no difference to exercise time. The requirement for long-term pacing in cardiac transplant recipients is small (3/154) and is limited to patients with sinus node dysfunction. Rate responsive pacing did not increase exercise tolerance.

For more than 20 years the literature on Latin American agriculture has argued that land reform, defined as the expropriation and redistribution of land on large estates, is the rural property rights issue par excellence in the region. While sharing the efficiency and equity concerns of those favouring agrarian reform, it can nevertheless be argued that many poor peasants living in countries which have recently experienced significant programmes of land reform and/or counter-reform, such as Chile and Peru, confront a set of property rights problems which the transfer of land from large owners to certain of their workers has done little to resolve.