Angiotensin II enhances bacterial clearance via myeloid signaling in a murine sepsis model.

Sepsis, defined as organ dysfunction caused by a dysregulated host-response to infection, is characterized by immunosuppression. The vasopressor norepinephrine is widely used to treat low blood pressure in sepsis but exacerbates immunosuppression. An alternative vasopressor is angiotensin-II, a peptide hormone of the renin-angiotensin system (RAS), which displays complex immunomodulatory properties that remain unexplored in severe infection. In a murine cecal ligation and puncture (CLP) model of sepsis, we found alterations in the surface levels of RAS proteins on innate leukocytes in peritoneum and spleen. Angiotensin-II treatment induced biphasic, angiotensin-II type 1 receptor (AT1R)-dependent modulation of the systemic inflammatory response and decreased bacterial counts in both the blood and peritoneal compartments, which did not occur with norepinephrine treatment. The effect of angiotensin-II was preserved when treatment was delivered remote from the primary site of infection. At an independent laboratory, angiotensin-II treatment was compared in LysM-Cre AT1aR-/- (Myeloid-AT1a-) mice, which selectively do not express AT1R on myeloid-derived leukocytes, and littermate controls (Myeloid-AT1a+). Angiotensin-II treatment significantly reduced post-CLP bacteremia in Myeloid-AT1a+ mice but not in Myeloid-AT1a- mice, indicating that the AT1R-dependent effect of angiotensin-II on bacterial clearance was mediated through myeloid-lineage cells. Ex vivo, angiotensin-II increased post-CLP monocyte phagocytosis and ROS production after lipopolysaccharide stimulation. These data identify a mechanism by which angiotensin-II enhances the myeloid innate immune response during severe systemic infection and highlight a potential role for angiotensin-II to augment immune responses in sepsis.

Safe Use of Erythromycin For Refractory Gastroparesis After Small Bowel Transplantation.

Current therapeutic options with prokinetic agents for posttransplant gastroparesis are limited. Erythromycin is associated with adverse reactions, including corrected QT interval prolongation and cytochrome P450 3A4 isoenzyme inhibition. The use of erythromycin has been avoided in patients undergoing treatment with cyclosporine or tacrolimus because of significant fluctuations in therapeutic immunosuppression levels. We report herein the successful use of erythromycin after visceral transplant to treat delayed gastric emptying. Two patients were managed with oral erythromycin (initial dose of 750 mg/d divided into 3 doses) for gastroparesis after visceral transplant. Patient 1 was a woman aged 42 years with a history of chronic intestinal pseudo-obstruction syndrome who underwent isolated small bowel transplant with dual (gastric and duodenal) proximal allograft anastomosis. Posttransplant gastroparesis was initially managed with oral metoclopramide. The patient also required high doses of tacrolimus (36 mg/d) to maintain adequate immunosuppression levels. The decision was made to change metoclopramide to erythromycin, which significantly decreased the daily tacrolimus dose requirement (from 36 to 9 mg/d), with resolution of nausea and intermittent bloating symptoms. Patient 2 was a woman aged 35 years with ultra-short gut syndrome after extensive enterectomy due to intestinal volvulus who underwent uneventful combined intestinal and colon transplant. Conventional pharmacologic therapy for gastroparesis was initiated after surgery without success. Erythromycin was started 15 days posttransplant, with significant improvement in her symptoms, and discontinued 47 days post-transplant. To maintain therapeutic levels (8-10 mg/dL), daily tacrolimus dose was decreased 75.8% and 36.5% for patients 1 and 2, respectively. No significant side effects associated with erythromycin use were observed in either patient. Our findings here suggest that erythromycin may be safely used for gastroparesis after small bowel transplant. Close monitoring of immunosuppressive drug levels and dose adjustments of other medications affected by inhibition of cytochrome P450 3A4 are advised.

Mid-Devonian Archaeopteris Roots Signal Revolutionary Change in Earliest Fossil Forests.

The origin of trees and forests in the Mid Devonian (393-383 Ma) was a turning point in Earth history, marking permanent changes to terrestrial ecology, geochemical cycles, atmospheric CO2 levels, and climate. However, how all these factors interrelate remains largely unknown. From a fossil soil (palaeosol) in the Catskill region near Cairo NY, USA, we report evidence of the oldest forest (mid Givetian) yet identified worldwide. Similar to the famous site at Gilboa, NY, we find treefern-like Eospermatopteris (Cladoxylopsida). However, the environment at Cairo appears to have been periodically drier. Along with a single enigmatic root system potentially belonging to a very early rhizomorphic lycopsid, we see spectacularly extensive root systems here assigned to the lignophyte group containing the genus Archaeopteris. This group appears pivotal to the subsequent evolutionary history of forests due to possession of multiple advanced features and likely relationship to subsequently dominant seed plants. Here we show that Archaeopteris had a highly advanced root system essentially comparable to modern seed plants. This suggests a unique ecological role for the group involving greatly expanded energy and resource utilization, with consequent influence on global processes much greater than expected from tree size or rooting depth alone.

Unique growth strategy in the Earth's first trees revealed in silicified fossil trunks from China.

Cladoxylopsida included the earliest large trees that formed critical components of globally transformative pioneering forest ecosystems in the Mid- and early Late Devonian (ca. 393-372 Ma). Well-known cladoxylopsid fossils include the up to ∼1-m-diameter sandstone casts known as Eospermatopteris from Middle Devonian strata of New York State. Cladoxylopsid trunk structure comprised a more-or-less distinct cylinder of numerous separate cauline xylem strands connected internally with a network of medullary xylem strands and, near the base, externally with downward-growing roots, all embedded within parenchyma. However, the means by which this complex vascular system was able to grow to a large diameter is unknown. We demonstrate-based on exceptional, up to ∼70-cm-diameter silicified fossil trunks with extensive preservation of cellular anatomy from the early Late Devonian (Frasnian, ca. 374 Ma) of Xinjiang, China-that trunk expansion is associated with a cylindrical zone of diffuse secondary growth within ground and cortical parenchyma and with production of a large amount of wood containing both rays and growth increments concentrically around individual xylem strands by normal cambia. The xylem system accommodates expansion by tearing of individual strand interconnections during secondary development. This mode of growth seems indeterminate, capable of producing trees of large size and, despite some unique features, invites comparison with secondary development in some living monocots. Understanding the structure and growth of cladoxylopsids informs analysis of canopy competition within early forests with the potential to drive global processes.

Surgical and medical approach to patients requiring total small bowel resection: Managing the "no gut syndrome".

BACKGROUND: Total resection of the jejunum and ileum, a rarely performed procedure, is indicated after mesenteric vascular events, trauma, or resection of abdominal neoplasms. We describe our recent experience with the operative and medical management of patients with "no gut syndrome." METHODS: We retrospectively reviewed 341 adult patients who were referred to our center between January 2013 and December 2016. RESULTS: Thirteen patients with a mean age of 42.5 years (range 17 to 66 years) underwent near total enterectomy. Indications for small bowel resection were vascular event (n = 5), intraabdominal fibroid/desmoid (n = 4), and trauma (n = 4). Foregut secretions were managed with duodenocolostomy (n = 5), tube decompression (n = 5), and end duodenostomy (n = 2). Duodenal stump was stapled off in 4 cases. One patient underwent a spleen-preserving duodenopancreatectomy combined with total enterectomy. Biliary secretions were managed with choledochocolostomy. All patients were discharged on full total parenteral nutrition infused over a 10- to 16-hour period. Average total parenteral nutrition volume and caloric requirement were 2,800 mL/day (range 2,000 to 4,000) and 1,774 Kcal/day (range 1,443 to 2,290), respectively. Patients who underwent duodenocolonic anastomosis received smaller TPN volume (33.8 vs 49.8 mL/kg). Ten patients (77%) required supplemental intravenous fluid. There were no intraoperative or perioperative deaths. One patient was lost to follow-up 2 months after operation. After a 20-month median follow-up (range 4 to 48 months), 9 patients are still alive (75%). All patients with duodenocolostomy remain alive (median follow-up 36.4 months). Three patients underwent uneventful isolated small bowel transplantation, and another 4 are being evaluated or are already listed for visceral transplantation. CONCLUSION: In summary, resection of the entire small bowel is feasible and can be a lifesaving procedure for a select group of patients. Long-term survival can be achieved in specialized centers. In addition, reestablishment of gastrointestinal tract continuity after total enterectomy appears to be the best option for postoperative fluid and electrolyte management.

Are There Gaps in Current Thoracic Surgery Residency Training Programs?

BACKGROUND: Cardiothoracic surgery is rapidly evolving to adapt to a changing health care environment and a wider application of innovative techniques. The Society of Thoracic Surgeons Workforce on Thoracic Surgery Resident Issues Transition to Practice Task Force sought to identify new or existing gaps of training in contemporary thoracic surgery residency training programs. METHODS: A voluntary survey consisting of 24 questions was distributed to recent graduates of thoracic surgery residency programs in the United States during the 2014 American Board of Thoracic Surgery oral examination application process. Fifty-five of 132 applicants anonymously participated. RESULTS: The majority of respondents admitted that they needed more instruction or lacked confidence with the following specific cardiothoracic procedures: minimally invasive cardiac operations (25/52, 48%), robotic cardiac operations (29/52, 55.8%), endovascular operations (28/52, 53.8%), robotic pulmonary operations (29/52, 55.8%), minimally invasive esophageal operations (24/52, 46.2%), robotic esophageal operations (32/52, 61.5%), and operations on congenital cardiac conditions (31/52, 59.6%). The respondents further declared either a need for more instruction or lack of confidence in employment contracting (17/21, 81.0%), negotiating terms of employment (17/21, 81.0%), and professional service agreements (16/21, 76.2%). CONCLUSIONS: Further exposure to minimally invasive robotic procedures, operations on congenital conditions, and issues of practice management appear to be needed in contemporary cardiothoracic training in the United States. These identified gaps may assist cardiothoracic surgery residency programs to optimally prepare future graduates for our evolving specialty.

Repetitive patterns in rapid optical variations in the nearby black-hole binary V404 Cygni.

How black holes accrete surrounding matter is a fundamental yet unsolved question in astrophysics. It is generally believed that matter is absorbed into black holes via accretion disks, the state of which depends primarily on the mass-accretion rate. When this rate approaches the critical rate (the Eddington limit), thermal instability is supposed to occur in the inner disk, causing repetitive patterns of large-amplitude X-ray variability (oscillations) on timescales of minutes to hours. In fact, such oscillations have been observed only in sources with a high mass-accretion rate, such as GRS 1915+105 (refs 2, 3). These large-amplitude, relatively slow timescale, phenomena are thought to have physical origins distinct from those of X-ray or optical variations with small amplitudes and fast timescales (less than about 10 seconds) often observed in other black-hole binaries-for example, XTE J1118+480 (ref. 4) and GX 339-4 (ref. 5). Here we report an extensive multi-colour optical photometric data set of V404 Cygni, an X-ray transient source containing a black hole of nine solar masses (and a companion star) at a distance of 2.4 kiloparsecs (ref. 8). Our data show that optical oscillations on timescales of 100 seconds to 2.5 hours can occur at mass-accretion rates more than ten times lower than previously thought. This suggests that the accretion rate is not the critical parameter for inducing inner-disk instabilities. Instead, we propose that a long orbital period is a key condition for these large-amplitude oscillations, because the outer part of the large disk in binaries with long orbital periods will have surface densities too low to maintain sustained mass accretion to the inner part of the disk. The lack of sustained accretion--not the actual rate--would then be the critical factor causing large-amplitude oscillations in long-period systems.

Understanding Why Residents May Inaccurately Log Their Role in Operations: A Look at the 2013 In-Training Examination Survey.

BACKGROUND: With increased time and quality pressures, it may be more difficult for residents in cardiothoracic surgery residency programs to get independent operative experience. That may lead residents to inaccurately report their role as "surgeon" to meet American Board of Thoracic Surgery (ABTS) case requirements. METHODS: The 2013 In-Training Examination surveyed 312 cardiothoracic surgery residents and was used to contrast residents in traditional 2-year and 3-year cardiothoracic surgery residencies (traditional, n = 216) with those in 6-year integrated or 3+4-year programs (integrated, n = 96). RESULTS: Traditional program residents reported a higher percentage of cases that met the ABTS criteria of surgeon than did integrated program residents (p = 0.05) but were less likely to meet requirements if all cases were logged accurately (p = 0.03). The majority of residents in each program believed that their case log accurately reflected their experience as "surgeon." Residents who tended to log cases incorrectly had lower self-reported 2012 In-Training Examination percentiles, were less likely to meet case requirements if logged properly, and felt less prepared for board examinations and eventual practice compared with residents who logged cases correctly (all p < 0.001). Residents who believed they would not meet case requirements if logged correctly cited limited surgical opportunities, poor case diversity, and a compromised training environment but not the 80-hour work week, excessive simulation, or disproportionate number of complex cases as causes. CONCLUSIONS: Overall cardiothoracic surgery residents appear to be satisfied with their training. There were specific subsets of trainees in both traditional and Integrated programs that are misrepresenting their role on cases because they otherwise may not meet the requirements.

Resident Perception of Technical Skills Education and Preparation for Independent Practice.

BACKGROUND: Surgical skills are traditionally taught and practiced in the operating room. However, changes in health care policy and outcome-based evaluation have decreased trainee operative autonomy. We examined cardiothoracic residents' perceptions of operative experience and the role of simulation. METHODS: The In-Training Examination (ITE) is taken each year by all residents. Completion of a 30-question preexamination survey is mandatory, ensuring a 100% response rate. Survey data related to operative experience, career preparedness, and surgical simulation were analyzed. Opinion questions were asked on a 5-point Likert scale. Respondents were grouped into three cohorts by training paradigm (2-year versus 3-year traditional programs and 6-year integrated programs). RESULTS: In all, 314 respondents (122 2-year, 96 3-year, and 96 6-year integrated) completed the survey. Of the three groups, residents in 3-year programs had the highest levels of satisfaction. Advanced training was most common among residents in 6-year integrated programs (66%, versus 49% for 2-year and 26% for 3-year programs; p = 0.63). Desire to specialize drove further training (97%), with 2% stating further training was needed owing to inadequacy and 1% owing to a poor job market. In all assessed categories, the majority of residents believed that simulation did not completely replicate the educational value of an operative case. CONCLUSIONS: Cardiothoracic residents largely feel well prepared for the transition to practice under the current educational paradigm. Although many residents seek advanced training, it seems driven by the desire for specialization. Residents view simulation as an adjunct to traditional intraoperative education, but not as a viable replacement. Further study is necessary to better understand how best to integrate simulation with operative experience.

Predictors of Career Choice Among Cardiothoracic Surgery Trainees.

BACKGROUND: The impact of factors influencing career choice by cardiothoracic surgery (CTS) trainees remains poorly defined in the modern era. We sought to examine the associations between CTS trainee characteristics and future career aspirations. METHODS: The 2012 Thoracic Surgery In-Training Examination survey results were used to categorize responders according to career interest: congenital, adult cardiac, mixed cardiac/thoracic, and general thoracic surgery. Univariate and multivariable analyses were used to identify and analyze characteristics associated with career interest categories. RESULTS: With a 100% response rate, 300 responses from trainees in programs accredited by the Accreditation Council for Graduate Medical Education were included in the analysis. Multinomial logistic regression identified three factors associated with career choice in CTS: level of training (p < 0.001), type of training pathway (p < 0.001), and primary motivating factor to pursue CTS (p = 0.002). Trainees interested in general thoracic surgery were more likely to commit to CTS during their senior years of general surgery training and were more likely to enroll in 2-year or 3-year traditional fellowships, whereas individuals pursuing adult or congenital cardiac surgery were more likely to commit earlier during training and were more commonly interested in 6-year integrated or joint training pathways. Moreover, trainees interested in general thoracic surgery were predominantly influenced by early mentorship (p = 0.025 vs adult cardiac), and trainees interested in adult cardiac surgery were more likely to be influenced by types of operations (p = 0.047 vs general thoracic). CONCLUSIONS: Career choice in CTS appears strongly associated with level of training, exposure to mentors, and training paradigm. These results demonstrate the importance of maintaining all four currently approved training pathways to retain balance and diversity in future CTS practices.

A Decade of Change: Training and Career Paths of Cardiothoracic Surgery Residents 2003 to 2014.

BACKGROUND: During the past decade, cardiothoracic surgery (CTS) education has undergone tremendous change with the advent of new technologies and the implementation of integrated programs, to name a few. The goal of this study was to assess how residents' career paths, training, and perceptions changed during this period. METHODS: The 2006 to 2014 surveys accompanying the Thoracic Surgery Residents Association/Thoracic Surgery Directors' Association in-training examination taken by CTS residents were analyzed, along with a 2003 survey of graduating CTS residents. Of 2,563 residents surveyed, 2,434 (95%) responded. RESULTS: During the decade, fewer residents were interested in mixed adult cardiac/thoracic practice (20% in 2014 vs 52% in 2003, p = 0.004), more planned on additional training (10% in 2003 vs 41% to 47% from 2011 to 2014), and the frequent use of simulation increased from 1% in 2009 to 24% in 2012 (p < 0.001). More residents recommended CTS to potential trainees (79% in 2014 vs 65% in 2010, p = 0.007). Job offers increased from a low of 12% in 2008 with three or more offers to 34% in 2014. Debt increased from 0% with more than $200,000 in 2003 to 40% in 2013 (p < 0.001). Compared with residents in traditional programs, more integrated residents in 2014 were interested in adult cardiac surgery (53% vs 31%) and congenital surgery (22% vs 7%), fewer were interested in general thoracic surgery (5% vs 31%, p < 0.001), and more planned on additional training (66% vs 36%, p < 0.001). CONCLUSIONS: With the evolution in CTS over the last decade, residents' training and career paths have changed substantially, with increased specialization and simulation accompanied by increased resident satisfaction and an improved job market.

Resident Perceptions of 2-Year Versus 3-Year Cardiothoracic Training Programs.

BACKGROUND: Resident perceptions of 2-year (2Y) vs 3-year (3Y) programs have never been characterized. The objective was to use the mandatory Thoracic Surgery Residents Association and Thoracic Surgery Directors Association In-Training Examination survey to compare perceptions of residents graduating from 2Y vs 3Y cardiothoracic programs. METHODS: Each year Accreditation Council for Graduate Medical Education cardiothoracic residents are required to take a 30-question survey designed by the Thoracic Surgery Residents Association and the Thoracic Surgery Directors Association accompanying the In-Training Examination with a 100% response rate. The 2013 and 2014 survey responses of residents graduating from 2Y vs 3Y training programs were compared. The Wilcoxon signed rank test was used to analyze ordinal and interval data. RESULTS: Graduating residents completed 167 surveys, including 96 from 2Y (56%) and 71 from 3Y (43%) programs. There was no difference in the perception of being prepared for the American Board of Thoracic Surgery examinations or amount of debt between 2Y and 3Y respondents. There was no difference in intended academic vs private practice. Graduating 3Y residents felt more prepared to meet case requirements and better trained, were more likely to pass their written American Board of Thoracic Surgery examinations, and were less likely to pursue additional training beyond their cardiothoracic residency. CONCLUSIONS: There was no difference in field of interest, practice type, and amount of debt between graduating 2Y vs 3Y residents. Respondents from 2Y programs expressed more difficulty in meeting case requirements, whereas residents from 3Y programs felt more prepared for independent practice and had higher American Board of Thoracic Surgery written pass rates.