A Suite of Tutorials for the WESTPA 2.0 Rare-Events Sampling Software [Article v2.0].

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present two sets of tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. The first set of more basic tutorials describes a range of simulation types, from a molecular association process in explicit solvent to more complex processes such as host-guest association, peptide conformational sampling, and protein folding. The second set ecompasses six advanced tutorials instructing users in the best practices of using key new features and plugins/extensions of the WESTPA 2.0 software package, which consists of major upgrades for larger systems and/or slower processes. The advanced tutorials demonstrate the use of the following key features: (i) a generalized resampler module for the creation of "binless" schemes, (ii) a minimal adaptive binning scheme for more efficient surmounting of free energy barriers, (iii) streamlined handling of large simulation datasets using an HDF5 framework, (iv) two different schemes for more efficient rate-constant estimation, (v) a Python API for simplified analysis of WE simulations, and (vi) plugins/extensions for Markovian Weighted Ensemble Milestoning and WE rule-based modeling for systems biology models. Applications of the advanced tutorials include atomistic and non-spatial models, and consist of complex processes such as protein folding and the membrane permeability of a drug-like molecule. Users are expected to already have significant experience with running conventional molecular dynamics or systems biology simulations.

Impact of routine completion angiography on the results of primary carotid endarterectomy: a prospective study in a teaching hospital.

OBJECTIVE: To assess the usefulness of completion angiography in the prevention of stroke, carotid occlusion and residual stenosis after primary carotid endarterectomy (CEA) in the setting of a teaching hospital. MATERIAL AND METHODS: From January 1995 to August 2009, 1055 consecutive patients having 1179 CEAs were entered in a prospective study excluding patients with severe renal insufficiency, allergy to contrast media and patients with repeat CEA or carotid bypass. In this cohort, 552 patients (52.3%) were asymptomatic, 318 (30.2%) had a transient ischaemic attack (TIA) and 185 (17.5%) had a stroke. Routine completion angiography was obtained in all 1055 patients. The decision to perform a surgical revision was decided for any of the following defects: (1) a residual stenosis of more than 50% of the internal carotid artery (ICA) or common carotid artery (CCA) and of more than 70% of the external carotid artery (ECA), (2) any flap and (3) any intraluminal-filling defect. A postoperative duplex scan was obtained within a week after surgery and thereafter on a yearly basis. Median follow-up was 7 years. RESULTS: CEA was performed by a senior surgeon as first operator in 812 cases (69%) and by a trainee, with a scrubbed senior surgeon, in 367 cases (31%). Completion angiography revealed significant defects in 72 cases (6.1%) warranting revision for ECA flap (n = 30), thrombus in contact with the patch (n = 7), distal ICA flap or stenosis (n = 20) and CCA flap or residual plaque (n = 15). Logistic regression analysis showed that total length of the carotid plaque >6 cm (p = 0.02, Odds ratio: 2.31; 95% confidence interval (CI) (1.21-3.72)), eversion endarterectomy of the ECA (p = 0.01, Odds ratio 3.41; 95%CI (2.10-5.94)) and trainee as first operator (p = 0.02, Odds ratio 2.42; 95%CI (1.81-4.23)) were independent predictors of operative defects seen on completion angiography. No complication in relation to carotid catheterisation or injection of contrast media occurred in this series. The 30-day combined stroke and death rate was 1.5%, comparable between senior surgeons and trainees (p = 0.60). There was no significant difference in the combined stroke and death rate observed in patients with normal completion angiography (1.4%) compared with that of the patients with a defect corrected (2.8%) (p = 0.28, Odds ratio: 0.67; 95%CI (0.22-2.09)). But there was an increased incidence of postoperative TIA in the group with revision (p = 0.001, odds ratio: 5.8, 95%CI: 1.8-18.9). At 7 years, the freedom rate from >50% carotid restenosis or occlusion was 87.5 ± 6.7% in patients with normal completion angiography and 92 ± 5.4% in patients, who undergo a surgical revision. CONCLUSION: In a single centre, CEA with routine completion angiography resulted in good perioperative outcome. Plaque length, technique for external carotid artery (ECA) endarterectomy and trainee as first operator were independent predictors of operative defects seen on completion angiography.

A Suite of Tutorials for the WESTPA Rare-Events Sampling Software [Article v1.0].

The weighted ensemble (WE) strategy has been demonstrated to be highly efficient in generating pathways and rate constants for rare events such as protein folding and protein binding using atomistic molecular dynamics simulations. Here we present five tutorials instructing users in the best practices for preparing, carrying out, and analyzing WE simulations for various applications using the WESTPA software. Users are expected to already have significant experience with running standard molecular dynamics simulations using the underlying dynamics engine of interest (e.g. Amber, Gromacs, OpenMM). The tutorials range from a molecular association process in explicit solvent to more complex processes such as host-guest association, peptide conformational sampling, and protein folding.

Diabetes mellitus and optic atrophy in two siblings: a report on a new association and a review of the literature.

Two siblings with diabetes mellitus and optic atrophy (Wolfram syndrome) are described. As often noted, they also had atonic urinary bladders. Only one of the siblings had some impairment of hearing. Other findings not previously reported that appeared in each subject were esophageal dysphagia and vertigo. An autopsy in one revealed brain stem hypoplasia and thinning and flattening of the optic nerves with atrophy of the lateral geniculate bodies.

Postinfarction ventricular septal rupture: early repair through the right atrial approach.

OBJECTIVE: Early repair of posterior ventricular septal rupture associated with myocardial infarction by means of transinfarct ventriculotomy is technically challenging and can be associated with significant mortality and morbidity. An alternative route of exposing the septum is through the right atrium. This technique, which avoids direct incision of the ventricle in select patients, reduces postrepair bleeding and impairment of ventricular contractile function. METHODS: The results of 12 patients operated on over a 20-year period were reviewed and analyzed. Late follow-up was obtained in all patients who survived the operation. There were 9 men and 3 women, with a mean age of 69.9 years. The mean time between acute myocardial infarction and surgery was 7.3 days (range, 2-16 days). Six patients were in New York Heart Association class IV, and 3 patients presented for surgery in cardiogenic shock. One patient had previously undergone a coronary artery bypass. The surgical technique included a standard sternotomy approach with a transatrial approach to the septal rupture. In all patients the septal rupture was repaired with a Dacron patch. RESULTS: There were 3 early deaths and 1 late death; one patient was reoperated on for a residual shunt. Postoperative complications included low cardiac output, acute renal tubular necrosis, and supraventricular arrhythmia. Eight patients are alive and undergoing echocardiographic investigation, and only 1 patient had a small residual shunt. CONCLUSION: Our experience shows that a posterior ventricular septal rupture can be safely repaired through a transatrial approach. Avoiding additional damage to the ventricle, it reduces the risks of the postoperative bleeding and enhances survival.

Corticosteroids as adjunctive treatment in Austrian's syndrome (pneumococcal endocarditis, meningitis, and pneumonia): report of two cases and review of the literature.

This report describes two cases of Osler's triad of pneumonia, meningitis, and endocarditis, as a result of Streptococcus pneumoniae infection, also called Austrian's syndrome. In the first patient, a 51 year old non-alcoholic man, the aortic valve was affected and needed to be replaced in an emergency operation. The mitral valve was affected in a 70 year old woman without underlying disease, who only benefited from medical treatment. Both patients received corticosteroids, either dexamethasone followed by low doses of hydrocortisone and fludrocortisone, or only hydrocortisone and fludrocortisone, at the onset of the illness, and their outcome was favourable. These case reports focus on the presentation, prognosis, and therapeutic options for this severe syndrome.

Modified biatrial approach for the extensive resection of left atrial myxomas.

Surgical excision of left atrial myxomas is usually curative. When the root of the pedicle and the full thickness of the adjacent interatrial septum are excised, the repair of the created atrial septal defect requires a pericardial or Dacron patch. The biatrial approach generally has been accepted as the technique having the advantages of well identifying the site of attachment and inspection of the four cardiac chambers. We proposed a modification of this technique that allows the reconstruction of the created septal defect without any foreign patch.

A special adapted retractor for the mini-sternotomy approach.

Minimally invasive cardiac operations are now possible through different approaches. To provide the best exposure and sufficient space to manipulate the heart, a special adapted thoracic retractor has been developed for the ministernotomy approach. It is universally adjustable and provides excellent and consistent exposure especially below the incision edges. The retractor has the further advantage of a very low profile on the surgeon's side and at the cephalic and caudal extremes of the operative field, which permits the greatest possible access through a limited access. We have successfully used this retractor in more than 180 patients. A less invasive median sternotomy through a 6-9-cm incision has been our original approach.

Less invasive cardiac operations through a median sternotomy: 100 consecutive cases.

BACKGROUND: In the beginning of 1997, we developed a routine approach to intracardiac operations through a less invasive median sternotomy. A limited (6 to 9 cm) median skin incision followed by a subcomplete (manubrium and body) median sternotomy makes opening and closing of the chest easier; conventional central cardiopulmonary bypass is instituted, and no modifications to the surgical techniques are necessary. METHODS: In 100 consecutive patients (mean age, 62.04 years; range, 9 to 92 years), 70 aortic, 13 mitral, and 17 other cardiac procedures were performed. Surgical technique required many self-made instruments; anesthetic "fast-tracking" management was performed. RESULTS: Four patients died. One conversion to a standard sternotomy and five reoperations for bleeding were necessary. Cross-clamp time ranged from 33 to 140 minutes (mean +/- standard deviation, 69.23 +/- 20.99 minutes) and total drainage loss ranged from 120 to 1,800 mL x m(-2) x 24 h(-1) (mean, 288 mL x m(-2) x 24 h(-1)). The postoperative course was shorter than usual, and one complication in the healing wound was observed. The scar was shorter than 9 cm in all patients. CONCLUSIONS: Our work shows that a less invasive approach to many cardiac operations is possible through a modified median sternotomy. This technique provides many potential and practical advantages: there is less trauma and pain reported by patients, and the small wound reduces the risk of infection and blood loss. Patients are extubated and discharged from the hospital earlier.

Minimally invasive internal thoracic artery harvest: the hybrid approach.

BACKGROUND: Safe harvesting of the left internal thoracic artery is a difficult problem during minimally invasive coronary artery bypass grafting without cardiopulmonary bypass. A complete internal thoracic artery dissection through a limited approach is technically demanding and time consuming and different techniques have been proposed. METHODS AND RESULTS: Based on our experience, the different surgical approaches and technical considerations are reviewed. CONCLUSIONS: A hybrid technique using dissection under direct vision and completed by thoracoscopy is discussed and proposed as our preferred technique of internal thoracic artery harvesting.

Aortic root remodeling with the "cuff" technique for stentless valve implantation.

Aortic root and sinotubular junction dilatation and aneurysm of ascending aorta are considered relative contra-indications to implantation of a stentless valve prosthesis, because the modified aortic geometry leads to aortic incompetence and early failure of the prosthesis. Aortic root reconstruction can be performed according to various techniques. We present a surgical technique in which a tubular graft, replacing an ascending aortic aneurysm, allows sinotubular remodeling and satisfactory implantation of a stentless prosthesis. The native aorta is inserted into the vascular prosthesis at the level of the sinotubular junction which is wrapped in order to prevent commissure spreading. Sizing of the vascular and valve prosthesis is made according to annular diameter. Since October 1999, 6 patients have been operated using this technique with good results.

Pulmonary artery bullet injury following thoracic gunshot wound.

Thoracic trauma occurs frequently but seldom requires surgery (10-20%, [1]). The mortality rate for gunshot wound of the chest varies from 14.3 to 36.8% [2]. We report, herein an example of bullet injury to the pulmonary artery (PA) following a thoracic gunshot wound. This patient had previous history of coronary surgery. Absolute and relative indications for exploratory thoracotomy in emergency will be reviewed.

Less-invasive heart surgery: the preservation of median approach.

OBJECTIVE: Cardiac surgery has been traditionally performed via a median sternotomy incision where a large exposure of the mediastinum assured most of the cardiac procedures. Recently, the concepts of less-invasive surgery, well affirmed in many surgical specialties, led cardiac surgeons to develop limited accesses in coronary, valves and congenital operations. METHODS: Between January and May 1997, 30 patients were operated on with a less-invasive approach. A short (6-9 cm) median incision followed by a subcomplete sternotomy permitted a limited opening of the chest without compromising the surgical exposure; a conventional central CPB was instituted and valve surgery and most of intracardiac procedures were performed without modification of the standard technique. RESULTS: No mortality was observed; morbidity was minimal. Cardiopulmonary bypass time and aortic cross-clamp time averaged 84+/-9 and 61+/-11 min, respectively. The majority of patients were extubated and discharged from the ICU early. Chest drainage lost on average 290+/-180 ml/m2. CONCLUSIONS: Despite our limited initial experience, this technique seems to provide several potential and practical advantages: there is less trauma and pain reported by patients; the small wound reduces the potential for wound infection and blood loss. Patients are extubated and discharged from the hospital earlier with lower overall costs.

Aortic balloon entrapment complicating intra-aortic balloon counterpulsation.

Short-term balloon counterpulsation may be complicated by aortic balloon entrapment. We report a patient in whom video-coronary surgery was performed using beating heart anastomosis. This patient developed intra-aortic balloon (IAB) entrapment 4 days after initiation of the counterpulsation previously implanted for a preoperative low ejection fraction. No limb ischaemia was detected, but urgent removal of the balloon catheter is mandatory if blood is detected in the tubing connecting the balloon to the console, even in the presence of adequate function of the IAB assistance.

Less invasive radial artery harvest.

BACKGROUND: Recent studies have sparked a renewed interest in the use of autogenous radial arteries in coronary operations. Some concerns have been found about sequelae of conventional harvesting. A less invasive technique for radial artery harvesting has been proposed by others using endoscopic devices. This technique is time consuming, needs expensive instrumentation and an important learning curve. METHODS: A new less invasive approach for radial harvesting has been developed with a light assisted retractor under direct vision. A small skin incision, median in the forearm, is followed by dissection of the proper plane of the artery. A subcutaneous tunnel is created around the vessel and all the branches are ligated or clipped. The dissection of the pedicle under the skin is completed with the aid of a modified light assisted retractor, originally designed for the saphenous vein harvesting. The incision is closed after heparin reversal with a small redon as drainage. RESULTS: A preliminary serie of 15 patients have been operated with this technique. In all patients the radial artery was patent and functional at the postoperative angiography. Morbidity included only a light hematoma at the beginning of our experience. CONCLUSION: This less invasive technique for the radial artery harvesting appears to be an excellent surgical compromise between the open technique and the endoscopic procedure; it is easy to perform, the learning curve is acceptable and it offers an excellent aesthetic result.

[Severe intoxication with cardiotoxic drugs: value of emergency percutaneous cardiocirculatory assistance]. / Intoxication sévère par médicaments cardiotoxiques: intérêt de l'assistance cardiocirculatoire percutanée en urgence.

Acute severe self-administration of an overdose of betablockers, calcium antagonists or antiarrhythmic drugs is rare but carries a mortality of 10-15%. Between May 1997 and March 2000, 6 patients with an average age of 34 years (range 17-55 years) had a cardiac arrest on admission requiring emergency cardiac massage and emergency intubation with ventilatory assistance following massive ingestion of cardiotoxic drugs. Echocardiography confirmed complete biventricular akinesia. The surgical team implanted a cardiovascular assist device (ECMO: Extra Corporeal Membrane Oxygenation) by the femoral approach with pre-heparinated percutaneous cannula. The first two patients died of multi-organ failure due to a delay in the installation of the assistance. The 4 other patients survived without sequellae or recurrences. The average time on ECMO was 59.25 +/- 2 hours (range 48-71 hours). The early recognition of the indication for ECMO was one of the most important predictive factors for morbidity and mortality. The strategy of patient management should be determined in the emergency room: in cases of cardiocirculatory arrest resistant to symptomatic treatment (stomach washout, intravenous fluids, isoprenaline, inotropic agents) an echocardiogram should be obtained and the cardiac surgical team alerted to the problem. The introduction of pre-heparinated circuits, percutaneous cannula and peripheral shunts has widened the indications, efficacy (detoxification, restoration of peripheral tissue perfusion) and accessibility to this material, while limiting its duration. The collaboration of experienced multidisciplinary teams (emergency room staff, cardiologists, anaesthetists and surgeons) should optimise the timing of implantation and the monitoring of these systems and improve the results of resuscitation of these patients.

[Leiomyosarcoma of the heart and great vessels]. / Les léiomyosarcomes du coeur et des gros vaisseaux.

Leiomyosarcomas (LMS) of the heart are exceptional primary malignant tumours with a catastrophic prognosis and a mean survival measured in months. Extensive radical surgical resection clearly remains the most appropriate treatment. We report three cases observed over a 3-year period, consisting of an LMS of the inferior vena cava, an LMS of the pulmonary artery trunk and an LMS of the left atrium. The first case was treated by radical resection and reconstruction by autologous vein graft of the cavorenal junction, the second case was treated by extensive resection and prosthetic reconstruction of the pulmonary artery bifurcation and the third case was treated by a first radical resection of the left atrium, requiring total cardiectomy and orthotopic heart transplantation for local recurrence at the sixth month. The survical was significantly improved compared to other treatment options (chemotherapy, radiotherapy). The first patient is still alive without recurrence at two years; the second died 12.5 months after the surgical procedure and the medium-term follow-up of the transplanted patient revealed cerebral and hepatic metastases nine months after transplantation. The authors review the literature concerning these extremely rare malignant tumours. Recent progress of diagnostic investigations, such as spiral CT with reconstruction, MRI, positron emission tomography (PET), are now able to establish the diagnosis more rapidly and therefore allow more radical surgical resection. This resection, possibly combined with venous reconstruction, must be associated with adjuvant therapies. Heart transplantation should be considered among the treatment options for leiomyosarcomas of the heart, in order to improve the poor prognosis of these lesions affections a young population.

Purine metabolism and differential inhibition of spore germination in Phytophthora infestans.

An analysis of the effect of various purines and pyrimidines on the germination process in three different isolates of the late blight fungus, Phytophthora infestans, revealed increased rates of indirect germination in one isolate by adenine, hypoxanthine, and the riboside of dimethylaminopurine. This observation coupled with the capacity of sporangia of the race affected (1.2.3.4) for the uptake and interconversion of purines, as demonstrated by experiments with labelled purines under in vivo and in vitro conditions, pointed to hypoxanthine as a key intermediate in the purine metabolism directly associated with spore formation and development. This enhanced germination contrasted sharply with the almost complete arrest of indirect germination that occurred when sporangia were incubated with the purine analogue, benzimidazole, or with either of the respiratory inhibitors, sodium azide and 2,4-dinitrophenol. The pattern of differential inhibition exhibited by sporangia versus zoospores upon treatment with actinomycin D, 4-FLUOROURACIL, OR CYCLOHEXIMIDE INDICATED THat continued translation on preformed messenger RNA may be one essential requirement for the formation and release of zoospores, whereas their subsequent germination and development may depend upon renewed transcription as well.

Pre-operative balloon counterpulsation and off-pump coronary surgery for high-risk patients.

UNLABELLED: Coronary artery bypass surgery (CABG) can be performed less invasively without cardiopulmonary bypass (CPB). Multivessel off-pump CABG (OPCAB) is challenging in patients with critical left main stenosis (> 70%) and/or severe ventricular dysfunction (ejection fraction < 0.35) Our objective was the evaluation of efficiency of intra aortic balloon pump (IABP) preoperatively in this high-risk group in order to perform OPCABG safely. MATERIAL AND METHOD: In a consecutive 10-month period (out of 88 OPCABG patients) 23 high-risk patients were treated and were compared with 15 on-pump patients (out of 69) with the same criteria. RESULTS: Preoperative implantation of IABP was significantly higher in the OPCABG group (70% vs 46%, p < 0.05). No conversion to CPB was required in the OPCABG group. Post-operative angiography was systematically performed and demonstrated 97.5% patency of anastomosis. No device-related complications occurred. No difference was found concerning age, risk factors, emergency surgery, ejection fraction, mean number of grafts per patient (2.64 versus 2.75) and average operating time. In contrast, OPCABG demonstrated a trend toward reduced morbidity in terms of atrial fibrillation, reexploration for bleeding and prolonged ventilator requirement > 12 h. Mortality was less in the OPCABG group (p < 0.05). CONCLUSION: More randomized controlled trials are needed to evaluate the true efficacy of elective IABP in OPCABG high-risk patients. Until such studies are evaluated, and therefore because older and sicker patients now constitute a greater percentage of candidates for OPCABG, the timing of application of the IABP is warranted. These results may further justify preoperative use of the IABP in a large proportion of this group of patients.

Non-penetrating subclavian artery trauma: management by selective transluminally placed stent device.

Non-penetrating injury to the subclavian artery has not often been reported. The limited experience of surgeons with this type of trauma and the difficult vascular control required for its management make it a surgical challenge. We report on two cases, one after blunt trauma and the other with a subclavian artery aneurysm following anterior dislocation of the shoulder. Percutaneous stent implantation in the subclavian artery was successfully performed with, in the second case, coil embolization of the aneurysm. Follow-up Doppler sonography and angiogram demonstrated patency and luminal integrity of the involved artery. This less invasive procedure may be a significant advance and a new approach in the conservative management of traumatic subclavian injury for selected cases.