Prosthesis-Patient Mismatch after Aortic Valve Replacement with the Mosaic Ultra Bioprosthesis.

BACKGROUND: Several studies have reported high rates of prosthesis-patient mismatch (PPM) after aortic valve replacement (AVR) with the Mosaic prosthesis. This work assesses the incidence of PPM after AVR with a modified version of the Mosaic prosthesis, the Mosaic Ultra. METHODS: We performed a retrospective analysis of the data of 532 patients who underwent AVR with implantation of the Mosaic Ultra prosthesis in the period 2007-2016 in our institution. Patients were classified according to their indexed effective orifice area (EOAi) to severe (EOAi < 0.65 cm2/m2), moderate (EOAi 0.65-0.85 cm2/m2), and absent/mild PPM (EOAi > 0.85 cm2/m2). In-hospital postoperative outcomes and the impact of PPM on mean transvalvular pressure gradient after stratification by prosthesis size were assessed. RESULTS: Overall, 3 (0.6%) patients had severe, 92 (17.3%) moderate, and 437 (82.1%) absent/mild PPM. There was a significant difference in PPM proportions (moderate/severe vs absent/mild PPM) across different prosthesis sizes overall (p < 0.0001), observing gradually increasing rates of PPM with decreasing prosthesis sizes. Patients with moderate/severe PPM had higher mean transvalvular pressure gradients (19 [13-25] vs 13 [10-17] mm Hg, p < 0.0001) than patients with absent/mild PPM. There was a significant difference in mean transvalvular pressure gradient between the different aortic valve prosthesis sizes overall (p < 0.0001), observing gradually increasing gradients with decreasing prosthesis sizes. CONCLUSION: Patients undergoing AVR with the smaller sized (19, 21, and 23 mm) Mosaic Ultra aortic valve prostheses exhibit a higher risk for moderate/severe PPM and higher mean aortic transvalvular pressure gradients than patients receiving the larger sized (25, 27, and 29 mm) prostheses.

Healthcare seeking outside healthcare facilities and antibiotic dispensing patterns in rural Burkina Faso: A mixed methods study.

OBJECTIVE: Optimising antibiotic use is important to limit increasing antibiotic resistance. In rural Burkina Faso, over-the-counter dispensing of antibiotics in community pharmacies and non-licensed medicine retail outlets facilitates self-medication. We investigated its extent, reasons and dispensing patterns. METHODS: In an exploratory mixed-method design conducted between October 2020 and December 2021, this study first explored illness perceptions, the range of healthcare providers in communities, antibiotics knowledge and reasons for seeking healthcare outside healthcare facilities. Second, frequencies of illness and healthcare utilisation in the last 3 months were quantitatively measured. RESULTS: Participants distinguished between natural and magico-religious illnesses, according to origins. For illnesses considered to be 'natural', healthcare was mainly sought at healthcare facilities, private pharmacies and informal drug outlets. For illnesses considered as magico-religious, traditional healers were mainly visited. Antibiotics were perceived in the community as medicines similar to painkillers. Healthcare-seeking outside healthcare facilities was reported by 660/1973 (33.5%) participants reporting symptoms, including 315 (47.7%) to informal vendors. Healthcare seeking outside facilities was less common for 0-4-year-olds (58/534, 10.9% vs. 379/850, 44.1% for ≥5-year-olds) and decreased with improving socio-economic status (108/237, 45.6% in the lowest quintile; 96/418, 23.0% in the highest). Reported reasons included financial limitation, and also proximity to informal drug vendors, long waiting times at healthcare facilities, and health professionals' non-empathetic attitudes towards their patients. CONCLUSION: This study highlights the need to facilitate and promote access to healthcare facilities through universal health insurance and patient-centred care including reducing patients' waiting time. Furthermore, community-level antibiotic stewardship programmes should include community pharmacies and informal vendors.

CD11c+ Dendritic Cells Accelerate the Rejection of Older Cardiac Transplants via Interleukin-17A.

BACKGROUND: Organ transplantation has seen an increased use of organs from older donors over the past decades in an attempt to meet the globally growing shortage of donor organs. However, inferior transplantation outcomes when older donor organs are used represent a growing challenge. METHODS AND RESULTS: Here, we characterize the impact of donor age on solid-organ transplantation using a murine cardiac transplantation model. We found a compromised graft survival when older hearts were used. Shorter graft survival of older hearts was independent of organ age per se, because chimeric young or old organs repopulated with young passenger leukocytes showed comparable survival times. Transplantation of older organs triggered more potent alloimmune responses via intragraft CD11c+ dendritic cells augmenting CD4+ and CD8+ T-cell proliferation and proinflammatory cytokine production, particularly that of interleukin-17A. Of note, depletion of donor CD11c+ dendritic cells before engraftment, neutralization of interleukin-17A, or transplantation of older hearts into IL-17A(-/-) mice delayed rejection and reduced alloimmune responses to levels observed when young hearts were transplanted. CONCLUSIONS: These results demonstrate a critical role of old donor CD11c+ dendritic cells in mounting age-dependent alloimmune responses with an augmented interleukin-17A response in recipient animals. Targeting interleukin-17A may serve as a novel therapeutic approach when older organs are transplanted.

Experience with a "hotline" service for outpatients on a ventricular assist device.

OBJECTIVES: With the growing number of outpatients on ventricular assist devices (VADs), there is an increasing need for "home discharge programs." One important feature is a 24-hour telephone service. In our center, the perfusionists run a so-called "hotline" for all of our VAD patients. This study analyzes the hotline calls with regard to frequency, the reason for calling, and the type of action undertaken. PATIENTS AND METHODS: Over a period of 5 years, 16 (12 EXCOR and 4 INCOR; Berlin Heart, Berlin, Germany) of 33 VAD patients (48%) were discharged and instructed to use the "hotline" service. All the calls received by the perfusionists were reviewed. We classified the calls into three levels according to the severity of the problem: Level (L) 1 = assistance provided by the perfusionist alone; L2 = calls requiring discussion with the surgeon on duty and/or visit to the outpatient clinic ahead of time; and L3 = immediate action and/or admission to the hospital. RESULTS: Over a period of 2,890 outpatient days (7.9 years), a total of 26 calls were registered. There were 0.9 calls per 100 patient days and 1.6 calls per discharged patient. Out of the 26 calls, 14 calls (54%) were classified as L1, 8 (31%) as L2, and 4 (15%) as L3. The most frequent reasons for L1 or L2 calls were fibrin deposits in the EXCOR pump chamber (39%), followed by battery dysfunction (19%). L3 calls were related to dysfunction of the EXCOR driving units in three cases and to an EXCOR pump chamber disconnection, which the patient did not survive. CONCLUSIONS: The institution of a hotline is an essential component of a VAD outpatient program. It provides a certain level of safety for the patient, although a residual risk remains.

Less invasive replacement of aortic root, ascending aorta and hemiarch via partial upper sternotomy: a propensity-score-matched comparison with full sternotomy.

OBJECTIVES: Less invasive surgery has emerged as an option for aortic pathologies. The current study compared our experience on early postoperative results of patients with aortic surgery between partial upper sternotomy (PUS) and full sternotomy (FS). METHODS: We performed a retrospective analysis of the data of patients undergoing aortic root surgery with concomitant ascending aorta and hemiarch replacement. Exclusion criteria were type A aortic dissection and other concomitant major cardiac surgery. After propensity score matching, we compared the perioperative outcomes of patients undergoing surgery with PUS versus FS. RESULTS: A total of 161 patients operated on between January 2013 and September 2022 met the inclusion criteria (PUS: n = 22, FS: n = 139). Propensity score matching yielded 22 pairs with a balanced distribution of propensity scores and covariates between the compared groups. There was no evidence that PUS affects cardiopulmonary bypass [108 (67-119) vs 113 (87-148) min, P = 0.154; PUS vs FS] and circulatory arrest duration [9 (7-10) vs 9 (8-13) min, P = 0.264; PUS vs FS]. There was a reduced cross-clamp duration in the PUS group [88 (58-96) vs 92 (71-122) min, P = 0.032]. Cumulative sum charts have shown consistently low cross-clamp and circulatory arrest duration for 2 experienced surgeons who performed 20 of the procedures in the PUS group (10 each). Perioperative mortality and morbidity were low, with no in-hospital mortality in the PUS group [0 vs 1(4.5%), P > 0.999] and absence of strokes in both groups. CONCLUSIONS: In summary, our initial experience suggests that less invasive aortic root, ascending aorta and hemiarch replacement via PUS could be performed in our patient cohort as safely as via full sternotomy. Advantages for the patient are reduced surgical trauma, improved cosmetic results and-presumably-less pain.

Navigating the challenges of minimally invasive mitral valve surgery: a risk analysis and learning curve evaluation.

BACKGROUND: This study aimed to report the risk and learning curve analysis of a minimally invasive mitral valve surgery program performed through a right mini-thoracotomy at a single institution. METHODS: From January 2013 through December 2019, 266 consecutive patients underwent minimally invasive mitral valve surgery in our department and were included in the current study. Multiple logistic regression analysis was used for the adverse event outcome. Distribution over time of perioperative complications, defined as clinical endpoints in the Valve Academic Research Consortium-2 (VARC-2) consensus document, as well as CUSUM charts for assessment of cardiopulmonary bypass and aortic cross-clamping duration over time, has been performed for learning curve assessment. RESULTS: Overall incidences of postoperative stroke (1.1%), myocardial infarction (1.1%), and thirty-day mortality (1.5%) were low. The mitral valve reconstruction rate in our series was 95%. Multivariable analysis revealed that concomitant tricuspid valve surgery (OR 4.44; 95%CI 1.61-11.80; p = 0.003) was significantly associated with adverse event outcomes. Despite a trend towards adverse event outcomes in patients with preexisting active mitral valve endocarditis (OR 2.69; 95%CI 0.81-7.87; p = 0.082), mitral valve pathology did not significantly impact postoperative morbidity and mortality. Distribution over time of perioperative complications, defined as clinical endpoints in the VARC-2 consensus document, showed a trend towards an improved complication rate after the initial 65-100 procedures. CONCLUSIONS: Mitral valve surgery via right-sided mini-thoracotomy can be implemented safely with low perioperative morbidity and mortality rates. Careful patient selection regarding isolated mitral valve surgery in the presence of degenerative mitral valve disease may represent a significant safety issue during the learning curve. TRIAL REGISTRATION: The cantonal ethics commission of Zurich approved the study (registration ID 2020-00752, date of approval 24 April 2020).

NAD+ prevents septic shock-induced death by non-canonical inflammasome blockade and IL-10 cytokine production in macrophages.

Septic shock is characterized by an excessive inflammatory response depicted in a cytokine storm that results from invasive bacterial, fungi, protozoa, and viral infections. Non-canonical inflammasome activation is crucial in the development of septic shock promoting pyroptosis and proinflammatory cytokine production via caspase-11 and gasdermin D (GSDMD). Here, we show that NAD+ treatment protected mice toward bacterial and lipopolysaccharide (LPS)-induced endotoxic shock by blocking the non-canonical inflammasome specifically. NAD+ administration impeded systemic IL-1ß and IL-18 production and GSDMD-mediated pyroptosis of macrophages via the IFN-ß/STAT-1 signaling machinery. More importantly, NAD+ administration not only improved casp-11 KO (knockout) survival but rendered wild type (WT) mice completely resistant to septic shock via the IL-10 signaling pathway that was independent from the non-canonical inflammasome. Here, we delineated a two-sided effect of NAD+ blocking septic shock through a specific inhibition of the non-canonical inflammasome and promoting immune homeostasis via IL-10, underscoring its unique therapeutic potential.

Generator pocket adhesions of cardiac leads: classification and correlation with transvenous lead extraction results.

OBJECTIVES: Pacemaker (PM) and implantable cardioverter defibrillator (ICD) leads become encapsulated intravascularly and in the generator pocket by fibrotic adhesions that accumulate over time. These adhesions are responsible for the difficulty and risk of lead extraction procedures. We developed a classification scheme for pocket adhesions, classified all of the patients in the cohort, and examined the relationship between pocket adhesions and the outcome of the procedure. METHODS: The classification of adhesions with respect to the intraoperative adhesion coverage was as followed: class 0 = adhesion free; class 1 ≤ 30% of adhesion coverage; class 2 = 30-60% of adhesion coverage; and class 3 ≥ 60% coverage. Patient data between December 2010 and March 2012 were collected. A total of 100 leads were extracted from 58 patients (1.7 ± 0.8 leads/patient); the mean lead implant duration was 78.5 ± 66.7 months, and the percentage of PM/ICD leads was 68% (n = 68)/32% (n = 32). RESULTS: Distribution of the leads among classes: 0 = 10; 1 = 17; 2 = 25; and 3 = 48. Average implant times (months) according to the adhesion classes: 0 = 1.2 ± 0.4; 1 = 19.8 ± 19.2; 2 = 79.3 ± 46.6; and 3 = 115.1 ± 106.0 (correlation-coefficient 0.71; P ≤ 0.05). Average numbers of extraction tools used according to the adhesions: 0 = none; 1 = 0.4 ± 0.7; 2 = 1.6 ± 1.0; and 3 = 2.3 ± 1.2 (correlation coefficient = 0.67; P ≤ 0.05). Complete removal was achieved in 100% of the patients in classes 0 and 1; 96% in class 2 (n = 24); and 75% in class 3 (n = 36) (P ≤ 0.05). Mortality = 0. CONCLUSIONS: Extensive adhesions in the generator pocket predict the need for a higher number of extraction tools. High-grade pocket adhesions predict lower success rates with regard to complete lead extraction. Both findings suggest that the degree of pocket adhesions predicts the degree of intravascular adhesions.

Use of WATCH antibiotics prior to presentation to the hospital in rural Burkina Faso.

BACKGROUND: In low- and middle-income countries, the prevalence of antimicrobial resistance (AMR) is increasing. To control AMR, WHO recommends monitoring antibiotic use, in particular Watch antibiotics. These are critically important antibiotics, with restricted use because at risk of becoming ineffective due to increasing AMR. We investigated pre-hospital antibiotic use in rural Burkina Faso. METHODS: During 2016-2017, we collected data from patients aged > 3 months presenting with severe acute fever to the rural hospital of Nanoro Health District, Burkina Faso, including antibiotic use in the two weeks prior to consultation or hospitalization. We analysed reported antibiotic use by applying the WHO Access, Watch, Reserve classification. RESULTS: Of 920 febrile participants (63.0% ≤ 14 years), pre-hospital antibiotic use was reported by 363 (39.5%). Among these 363, microbiological diagnoses were available for 275 (75.8%) patients, of whom 162 (58.9%) were non-bacterial infections. Use of more than one antibiotic was reported by 58/363 (16.0%) participants. Of 491 self-referred patients who did not previously visit a primary health care center, 131 (26.7%) reported antibiotic use. Of 424 antibiotics reported, 265 (62.5%) were Access and 159 (37.5%) Watch antibiotics. Watch antibiotic use was more frequent among patients > 14 year olds (51.1%) compared to those 0-14 year old (30.7%, p < 0.001) and among referrals from the primary health care centers (42.2%) compared to self-referred patients (28.1%, p = 0.004). Most frequently reported Watch antibiotics were ceftriaxone (114, 71.7%) and ciprofloxacin (32, 20.1%). CONCLUSION: The reported frequent use of Watch group antibiotics among febrile patients prior to presentation to the hospital in rural Burkina Faso highlights the need to develop targeted interventions to improve antibiotic use in community settings as part of strengthening antibiotic stewardship in low- and middle-income countries. This should include facilitating referral, access to qualified prescribers and diagnostic tools in rural primary health care centers. Trial registration ClinicalTrials.gov identifier: NCT02669823. Registration date was February 1, 2016.

Restored TDCA and valine levels imitate the effects of bariatric surgery.

Background: Obesity is widespread and linked to various co-morbidities. Bariatric surgery has been identified as the only effective treatment, promoting sustained weight loss and the remission of co-morbidities. Methods: Metabolic profiling was performed on diet-induced obese (DIO) mice, lean mice, and DIO mice that underwent sleeve gastrectomies (SGx). In addition, mice were subjected to intraperitoneal (i.p.) injections with taurodeoxycholic acid (TDCA) and valine. Indirect calorimetry was performed to assess food intake and energy expenditure. Expression of appetite-regulating hormones was assessed through quantification of isolated RNA from dissected hypothalamus tissue. Subsequently, i.p. injections with a melanin-concentrating hormone (MCH) antagonist and intrathecal administration of MCH were performed and weight loss was monitored. Results: Mass spectrometric metabolomic profiling revealed significantly reduced systemic levels of TDCA and L-valine in DIO mice. TDCA and L-valine levels were restored after SGx in both human and mice to levels comparable with lean controls. Systemic treatment with TDCA and valine induced a profound weight loss analogous to effects observed after SGx. Utilizing indirect calorimetry, we confirmed reduced food intake as causal for TDCA/valine-mediated weight loss via a central inhibition of the MCH. Conclusions: In summary, we identified restored TDCA/valine levels as an underlying mechanism of SGx-derived effects on weight loss. Of translational relevance, TDCA and L-valine are presented as novel agents promoting weight loss while reversing obesity-associated metabolic disorders. Funding: This work has been supported in part by a grant from NIH (UO-1 A1 132898 to S.G.T., DP and MA). M.Q. was supported by the IFB Integrated Research and Treatment Centre Adiposity Diseases (Leipzig, Germany) and the German Research Foundation (QU 420/1-1). J.I. was supported by the Biomedical Education Program (BMEP) of the German Academic Exchange Service (DAAD). T.H. (HE 7457/1-1) and F.K. (KR 4362/1-1) were supported by the German Research Foundation (DFG). H.R.C.B. was supported the Swiss Society of Cardiac Surgery. Y.N. was supported by the Chinese Scholarship Council (201606370196) and Central South University. H.U., T.M. and R.M. were supported by the Osaka Medical Foundation. C.S.F. was supported by the German Research Foundation (DFG, SFB738, B3).

MicroRNA Mediated Cardioprotection - Is There a Path to Clinical Translation?

In the past 20 years, there have been several approaches to achieve cardioprotection or cardiac regeneration using a vast variety of cell therapies and remote ischemic pre-conditioning (RIPC). To date, substantial proof that either cell therapy or RIPC has the potential for clinically relevant cardiac repair or regeneration of cardiac tissue is still pending. Preclinical trials indicate that the secretome of cells in situ (during RIPC) as well as of transplanted cells may exhibit cardioprotective properties in the acute setting of cardiac injury. The secretome generally consists of cell-specific cytokines and extracellular vesicles (EVs) containing microRNAs (miRNAs). It is currently hypothesized that a subset of known miRNAs play a crucial part in the facilitation of cardioprotective effects. miRNAs are small non-coding RNA molecules that inhibit post-transcriptional translation of messenger RNAs (mRNAs) and play an important role in gene translation regulation. It is also known that one miRNAs usually targets multiple mRNAs. This makes predictability of pharmacokinetics and mechanism of action very difficult and could in part explain the inferior performance of various progenitor cells in clinical studies. Identification of miRNAs involved in cardioprotection and remodeling, the composition of miRNA profiles, and the exact mechanism of action are important to the design of future cell-based but also cell-free cardioprotective therapeutics. This review will give a description of miRNA with cardioprotective properties and a current overview on known mechanism of action and potential missing links. Additionally, we will give an outlook on the potential for clinical translation of miRNAs in the setting of myocardial infarction and heart failure.

Corrigendum to: Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies.

[This corrects the article DOI: 10.15420/icr.2017:3:2.].

In vitro activity of bedaquiline against slow-growing nontuberculous mycobacteria.

Bedaquiline (BDQ) is a recently approved antibiotic for the treatment of multidrug-resistant tuberculosis, but its potential against slow-growing mycobacteria (SGM) is still unknown. The objective of this study was to determine the in vitro activity of BDQ on SGM by assessing their MIC and minimal bactericidal concentration (MBC). The MIC of BDQ against 17 clinical isolates including Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium chimaera, Mycobacterium kansasii and Mycobacterium simiae species was determined by the resazurin microtitre assay and the MBC by the c.f.u. determination on 7H10 agar plates. BDQ has a bacteriostatic activity on all SGM tested with a MIC range from 0.03 to 0.007 µg ml-1 and surprisingly a good bactericidal activity on the majority of the isolates tested with an MBC of 1-2 µg ml-1 . Based on these preliminary results BDQ seems to be very promising for treatment of diseases caused by SGM.

Ultrastructural preservation of tissues and their reaction to the infection with trichinella in the El Plomo mummy: Muscle fiber ultrastructure and trichinosis/mummy of the Cerro El Plomo.

The El Plomo mummy was a pre-Columbian Incan child who was found mummified in the Andes Mountains above an altitude of 17,700 feet. In the environment, natural mummification occurred due to low temperatures and strong winds. Dating measurements (relative dating) by experts from the National Museum of Natural History of Chile established that the mummified body corresponds the Inca period (1,450 to 1,500 AD). In 2003, the body was transferred to the University of Chile Medical School for exhaustive medical examination. Tissue samples from the right quadriceps muscle were extracted and fixed in glutaraldehyde and postfixed in osmium tetroxide to obtain ultrathin sections to be observed by transmission electron microscope. Images were recorded on photographic paper, digitalized and analyzed by experts on morphology. Results showed a preservation of cell boundaries in striated muscle cells, but specific subcellular organelles or contractile sarcomeric units (actin and myosin) were unable to be recognized. However, the classical ultrastructural morphology of the polypeptide collagen type I was preserved intact both in primary and secondary organization. Therefore, we concluded that the process of natural mummification by freezing and strong winds is capable of damaging the ultrastructure of muscle cells and preserving collagen type I intact.

Management of Tricuspid Regurgitation: The Role of Transcatheter Therapies.

Surgical treatment is the gold standard treatment of functional tricuspid regurgitation (FTR) but this carries high risks of morbidity and mortality. Percutaneous procedures are an attractive alternative to surgery for selected patients deemed to be high-risk surgical candidates. A number of tricuspid transcatheter devices have been developed to treat FTR, but at present, evidence of their efficacy and safety is scarce. Preliminary data have shown promising results, but ongoing and future studies will provide a clearer picture of the benefits of these new techniques.

Ventriculostomy-related infections in critically ill patients: a 6-year experience.

OBJECT: The authors undertook a study to analyze the risk factors for ventriculostomy-related infections (VRIs) in critically ill patients and their relation with outcome. METHODS: Demographic, clinical, laboratory, and microbiological data were collected from all 638 consecutive adult patients in whom an external ventriculostomy catheter was placed for monitoring during a 6-year period; patients were treated in a 31-bed intensive care unit (ICU) of a teaching hospital. Of 3726 cerebrospinal fluid (CSF) culture samples analyzed, 1348 (217 patients) showed bacterial growth; of these 97 (obtained in 58 patients [9%]) were considered to represent an infection, 106 (in 68 patients [11%]) colonization, and 145 (in 91 patients [14%]) contamination. Hence, a VRI was diagnosed in 58 (9%) of 638 patients. There were no significant differences in Acute Physiology and Chronic Health Evaluation II score, Glasgow Coma Scale score, and mortality rate, but patients with a VRI stayed longer in the ICU than those without one (p = 0.02). The duration of ventriculostomy monitoring was longer in patients with VRI (median 15 and 9 days, respectively; p = 0.02). Although the daily drained volume of CSF was higher after onset of the infection than before infection in patients with VRI (124 +/- 36 and 85 +/- 14 ml/day, respectively), the need for ventriculoperitoneal shunt placement was no more common in those with VRI than in those without (12 and 15%, respectively; p = 0.2). Multivariate logistic regression revealed that subarachnoid hemorrhage (SAH), intraventricular hemorrhage (IVH), craniotomy, and coinfection were risk factors for VRIs. CONCLUSIONS: In this large series of patients, VRI was associated with a longer ICU stay, but its presence did not influence survival. A longer duration of ventriculostomy catheter monitoring in patients with VRI might be due to an increased volume of drained CSF during infection. Risk factors associated with VRIs are SAH, IVH, craniotomy, and coinfection.

NAD+ protects against EAE by regulating CD4+ T-cell differentiation.

CD4(+) T cells are involved in the development of autoimmunity, including multiple sclerosis (MS). Here we show that nicotinamide adenine dinucleotide (NAD(+)) blocks experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, by inducing immune homeostasis through CD4(+)IFNγ(+)IL-10(+) T cells and reverses disease progression by restoring tissue integrity via remyelination and neuroregeneration. We show that NAD(+) regulates CD4(+) T-cell differentiation through tryptophan hydroxylase-1 (Tph1), independently of well-established transcription factors. In the presence of NAD(+), the frequency of T-bet(-/-) CD4(+)IFNγ(+) T cells was twofold higher than wild-type CD4(+) T cells cultured in conventional T helper 1 polarizing conditions. Our findings unravel a new pathway orchestrating CD4(+) T-cell differentiation and demonstrate that NAD(+) may serve as a powerful therapeutic agent for the treatment of autoimmune and other diseases.

Total arterial off-pump surgery provides excellent outcomes and does not compromise complete revascularization.

OBJECTIVES: The combination of aortic 'no-touch' off-pump surgery (OPCAB) and total arterial revascularization (TAR) can reduce peri-procedural morbidity and yields excellent long-term outcomes albeit at a reported risk of incomplete revascularization. The feasibility of OPCAB-TAR with specific regards to the complete revascularization (CR) in patients with multi-vessel disease was evaluated. METHODS: From 2003 to 2010, 712 patients underwent TAR including 526 patients who had OPCAB-TAR and 186 patients who received on-pump TAR [(ONCAB grafting (ONCABG)-TAR)]. Of these, 52% (n = 272; OPCAB) vs. 83% (n = 155; ONCABG) had triple-vessel disease (TVD). To balance patient characteristics, a non-parsimonious, propensity score (PS) model was applied. Endpoints evaluated were mortality, stroke, major adverse cardiac and cerebrovascular events (MACCE). To evaluate CR, an 'Index of CR' (ICOR) was calculated, defined as the number of distal anastomoses divided by the number of the diseased coronary vessels. CR was assumed when the following requirements were fulfilled: the number of distal anastomoses was equal to or higher than that of diseased vessels (ICOR ≥ 1), and all affected coronary territories (left anterior descending, circumflex artery and/or right coronary artery) were grafted. RESULTS: Mortality was comparable between groups, whereas OPCAB patients suffered from significantly decreased rates of MACCE [3.0 vs. 7.0%; propensity-adjusted odd ratio (PAOR) = 0.24; confidence interval (CI) 95% 0.08-0.66; P = 0.006] including a clear trend towards reduced stroke and myocardial infarction. In the subgroup with TVD, OPCAB patients presented with significantly reduced rates for MACCE (1.8 vs. 5.8%; PAOR = 0.07; CI 95% 0.01-0.65; P = 0.02), including a significantly lower rate for stroke. For all-comers, the number of diseased vessels was lower after OPCAB (2.36 ± 0.73 vs. 2.87 ± 0.39; P < 0.001) and consequently, these patients received an overall lower number of distal anastomoses (2.42 ± 1.15 vs. 3.06 ± 0.98; P < 0.001). Although the ICOR was slightly lower (1.04 ± 0.37 vs. 1.07 ± 0.37; P = 0.02), CR was achieved more frequently in OPCAB patients (82.1 vs. 73.1%; P = 0.01). In the subgroup with TVD, the number of distal anastomoses (2.99 ± 1.14 vs. 3.10 ± 0.98; P = 0.19) and the ICOR (1.00 ± 0.38 vs. 1.03 ± 0.33; P = 0.19) was comparable between groups. The frequency of CR was slightly higher (75 vs. 67.7%; P = 0.11), and the proportion of complete in situ grafting was significantly higher after OPCAB (37.1 vs. 23.9%; P = 0.005). CONCLUSIONS: Aortic 'no-touch' OPCAB-TAR leads to a significant reduction of MACCE. It does not compromise CR in patients with TVD and thus can be safely applied to these patients.