A novel lung explant model for the ex vivo study of efficacy and mechanisms of anti-influenza drugs.

Influenza A virus causes considerable morbidity and mortality largely because of a lack of effective antiviral drugs. Viral neuraminidase inhibitors, which inhibit viral release from the infected cell, are currently the only approved drugs for influenza, but have recently been shown to be less effective than previously thought. Growing resistance to therapies that target viral proteins has led to increased urgency in the search for novel anti-influenza compounds. However, discovery and development of new drugs have been restricted because of differences in susceptibility to influenza between animal models and humans and a lack of translation between cell culture and in vivo measures of efficacy. To circumvent these limitations, we developed an experimental approach based on ex vivo infection of human bronchial tissue explants and optimized a method of flow cytometric analysis to directly quantify infection rates in bronchial epithelial tissues. This allowed testing of the effectiveness of TVB024, a vATPase inhibitor that inhibits viral replication rather than virus release, and to compare efficacy with the current frontline neuraminidase inhibitor, oseltamivir. The study showed that the vATPase inhibitor completely abrogated epithelial cell infection, virus shedding, and the associated induction of proinflammatory mediators, whereas oseltamivir was only partially effective at reducing these mediators and ineffective against innate responses. We propose, therefore, that this explant model could be used to predict the efficacy of novel anti-influenza compounds targeting diverse stages of the viral replication cycle, thereby complementing animal models and facilitating progression of new drugs into clinical trials.

Ambulatory chest drainage with advanced nurse practitioner-led follow-up facilitates early discharge after thoracic surgery.

OBJECTIVES: To demonstrate the safety and feasibility of advanced nurse practitioner-led (ANP-led) outpatient follow-up after discharge with ambulatory chest drains for prolonged air leak and excessive fluid drainage. METHODS: Patients discharged with ambulatory chest drains between January 2017 and December 2019 were retrospectively reviewed. Discharge criteria included air leak < 200 ml/min or fluid drainage > 100 ml/24 h on a digital drain. Patients were reviewed weekly in the clinic by ANPs, a highly skilled cohort of nurses with physician support available. Outcomes included length of stay, duration of air or fluid leak and complications. RESULTS: Two-hundred patients were included, amounting to 368 clinic episodes. The median age was 68 ± 13 years and 119 (60%) were male. 112 (56%) patients underwent anatomical lung resection (total anatomical lung resections during the study period = 917) equating to a discharge with ambulatory chest drain rate of 12.2% in this group. The median length of stay was 6 ± 3 days and 176 (88%) patients were discharged with air leak versus 24 (12%) with excessive fluid drainage. The median time to drain removal was 12 ± 11 days. Complications occurred in 16 patients (8%) and 12 (6%) required readmission. An estimated 2075 inpatient days were saved over the study period equating to an annual cost saving of £123,167 (US$149,032) per annum. CONCLUSIONS: Patients with air leak or excessive fluid drainage can safely be discharged with ambulatory chest drains, allowing them to return to their familiar home environment safely and quickly. ANP-led clinics are a robust and cost-effective follow-up strategy and are associated with a low complication rate.

Combined minimally invasive resection of thoracic neurogenic dumbbell tumors: A European case series.

BACKGROUND: Paraspinal tumors are rare neoplasms arising from neurogenic elements of the posterior mediastinum and surgical resection can be challenging. Here, we demonstrate feasibility and outcomes from the first European case series of combined laminectomy and video-assisted thoracoscopic surgery (VATS) resection of thoracic neurogenic dumbbell tumors. METHODS: A retrospective review of all combined thoracic dumbbell tumor resections performed at our institution between March 2015 to February 2019 was undertaken. Outcomes included operative time, blood loss, length of stay and recurrence rate. Statistical analysis was performed with SPSS statistics (v26). Values are given as mean ± standard deviation and median ± interquartile range. RESULTS: Seven patients were included in the case series and there were no major complications or mortality. Mean tumor size and operative time were 66 (± 35) mm and 171 (± 63) min, respectively. Median blood loss and length of stay were 40 (± 70) ml and four (± 3) days, respectively. One patient required conversion to thoracotomy to remove a tumor of 135 mm in maximal dimension. Histology in all seven cases confirmed schwannoma. There was no disease recurrence at a maximum follow-up of 54 months. CONCLUSIONS: Our experience demonstrates favorable operative times, minimal blood loss and short length of stay when dealing with relatively large tumors compared to previous reports. Thoracotomy may be required for tumors exceeding 90 mm and chest drain removal on the operative day can facilitate early mobility and discharge. We advocate a combined, minimally invasive laminectomy and VATS resection as the gold-standard approach for thoracic neurogenic dumbbell tumors.

Recurrent Pneumothorax in a Critically Ill Ventilated COVID-19 Patient.

We present this case of a young woman with SARS-CoV-2 viral infection resulting in coronavirus 2019 (COVID-19) lung disease complicated by a complex hydropneumothorax, recurrent pneumothorax, and pneumatoceles. A 33-year-old woman presented to the hospital with a one-week history of cough, shortness of breath, and myalgia, with no other significant past medical history. She tested positive for COVID-19 and subsequently, her respiratory function rapidly deteriorated, necessitating endotracheal intubation and mechanical ventilation. She had severe hypoxic respiratory failure requiring a protracted period on the mechanical ventilator with different ventilation strategies and multiple cycles of prone positioning. During her proning, after two weeks on the intensive care unit, she developed tension pneumothorax that required bilateral intercostal chest drains (ICD) to stabilise her. After 24 days, she had a percutaneous tracheostomy and began her respiratory wean; however, this was limited due to the ongoing infection. Thorax CT demonstrated a left-sided pneumothorax, with bilateral pneumatoceles and a sizeable, complex hydropneumothorax. Despite the insertion of ICDs, the hydropneumothorax persisted over months and initially progressed in size on serial scans needing multiple ICDs. She was too ill for surgical interventions initially, opting for conservative management. After 60 days, she successfully underwent a video-assisted thoracoscopic surgery (VATS) for a washout and placement of further ICDs. She was successfully decannulated after 109 days on the intensive care unit and was discharged to a rehabilitation unit after 116 days of being an inpatient, with her last thorax CT showing some residual pneumatoceles but significant improvement. Late changes may mean patients recovering from the COVID-19 infection are at increased risk of pneumothoracies. Clinicians need to be alert to this, especially as bullous rupture may not present as a classical pneumothorax.

Video-assisted cervical thoracoscopy: a novel approach for diagnosis, staging and pleurodesis of malignant pleural mesothelioma.

OBJECTIVES: In the preoperative workup for radical surgery for malignant pleural mesothelioma (MPM), mediastinal lymph node staging, diagnostic pleural biopsies and effusion control with talc pleurodesis are required. We present a new technique combining these objectives via a single cervical incision using the videomediastinoscope and demonstrate its clinical benefits. METHODS: Video-assisted cervical thoracoscopy (VACT) was attempted in 15 patients (13 male, mean age 57 years), who were potential candidates for radical surgery. Following conventional cervical videomediastinoscopy, a 5 mm thoracoscope was advanced into the relevant pleural cavity through the mediastinoscope via a mediastinal pleurotomy. Pleural biopsies were taken followed by talc insufflation and cervical tube drainage. The clinical outcome was compared with 26 patients undergoing a staged preoperative workup during the same period. RESULTS: VACT was successful in 10 patients (66.6%). In five patients (three right and two left), thoracoscopy was abandoned due to excessive mediastinal fat (1), thick pleura (2) and inability to enter the left hemithorax (2). Mean operative time was 71 (65-90) min and hospital stay 4 (3-7) days. One patient suffered recurrent laryngeal nerve palsy and one had persistent air leak. Ten patients subsequently underwent radical surgery. Time to radical surgery was significantly reduced by nearly 2 months in VACT patients (28+/-17 days vs 87+/-56 days, p<0.001). CONCLUSIONS: The benefits of this approach include reduction in postoperative pain, risk of biopsy site tumour seeding, and preoperative delay to radical surgery. VACT is feasible in right-sided mesothelioma but has not yet been validated on the left.

Short- and long-term effects of cytochalasin D, paclitaxel and rapamycin on wall thickening in experimental porcine vein grafts.

OBJECTIVES: Neointima formation and wall thickening caused by smooth muscle cell proliferation compromise long-term patency of human aorto-coronary vein-grafts. We investigated short- and long-term effects of anti-proliferative pharmacological agents on experimental pig vein-grafts with similar dimensions and kinetics to human coronary grafts. METHODS AND RESULTS: Saphenous veins were treated for 1 h ex vivo with vehicle or concentrations of cytochalasin D, paclitaxel or rapamycin found to be anti-proliferative in preliminary studies. Vehicle and treated veins were implanted contralaterally, end-to-end into the carotid arteries of pigs. Cytochalasin D 2.5 mug/ml non-significantly reduced neointima formation in 4-week vein-grafts (mean+/-standard error, 2.5+/-0.6 vs. 3.3+/-0.6 mm2, n = 10, p = NS), whilst paclitaxel 10 microM produced significant inhibition (1.7+/-0.2 vs. 3.0+/-0.3 mm2, n = 8, p < 0.01) as did rapamycin 0.1 mg/ml (0.6+/-0.3 vs. 1.7+/-0.5 mm(2), n = 8, p < 0.02). Similar effects were found on total wall cross-sectional area but medial area was unaffected. PCNA staining of 1-week vein grafts confirmed in vivo anti-proliferative effects of paclitaxel (21+/-2 vs. 36+/-3%, n = 5, p < 0.01) and rapamycin (32+/-1 vs. 57+/-6%, n = 6, p < 0.005); neither agent stimulated loss of endothelium at these concentrations. Neointima and total wall area increased significantly between 4- and 12-weeks in all vein-grafts such that there was no longer a significant effect on neointima formation of either paclitaxel (7.5+/-1.3 vs. 8.9+/-1.9 mm2 in control, n = 5, p = NS) or rapamycin (6.0+/-0.9 vs. 7.9+/-1.1 mm2 in control, n = 9, p = NS) or on total wall area in 12-week grafts. CONCLUSIONS: Pre-treatment of saphenous vein with anti-proliferative agents paclitaxel or rapamycin reduced neointima and total wall area after 4 weeks but continued growth abolished differences by 12 weeks. These results may help to understand the failure of clinical studies using anti-proliferative treatments in vein-grafts.

VATS Plication of the Diaphragm: A Descriptive Observational 10-Year Southampton Experience.

OBJECTIVE: The aim of the study was to report the safety and efficacy of video-assisted thoracoscopic (VATS) plication of the diaphragm at our institution between 2006 and 2016. METHODS: Adult patients selected on etiology and combination of investigations including plain chest x-ray, computed tomography of chest and abdomen, lung functions in supine and sitting positions, radiological/ultrasonic screening for diaphragmatic movement, and phrenic nerve conduction studies. We incorporated a triportal VATS and Endostitch device for plication, using CO2 insufflation to maximum 12 mm Hg. Bilateral simultaneous plication and high-risk patients were electively admitted to intensive therapy unit postoperatively. RESULTS: Thirty-five patients (24 males) had their diaphragm plicated. The mean age was 56.6 years (range = 23-76 years). The mean body mass index was 32.1 (range = 22.2-45.4). Twenty one were right, 13 left, 2 patients had VATS simultaneous bilateral plication, and 1 had sequential VATS bilateral plication. Paralysis was idiopathic in 17, posttraumatic in 5, postremoval of mediastinal tumor in 4, and postcardiac surgery in 3. All patients presented with lifestyle-limiting dyspnea and orthopnea, three were on nocturnal noninvasive ventilation. Five were diabetic and 16 were smokers. The mean supine forced expiratory volume in the first second was 62.5% of predicted. Twenty two were performed by VATS (63%), three converted to thoracotomy, and 13 were open limited thoracotomy (historic). The mean hospital stay was 4.5 days (range = 1-18, mode 2 days). Intensive therapy unit admission was required in six patients for mechanical ventilation 0 to 3 days. Five patients (14%) had no improvement in symptoms. There were no deaths, no 30-day readmissions, and no long-term neuralgia in this series. CONCLUSIONS: We found minimal access VATS plication of the diaphragm to be feasible and safe, but no firm conclusions should be drawn from our limited resources. We report the feasibility of concomitant bilateral VATS plication of the diaphragm in two adults, and this was not previously reported in the adult population. There is a need for further good quality, prospective studies, and randomized controlled studies evaluating efficacy of VATS diaphragmatic plication.

Effect of body mass index on early outcomes in patients undergoing coronary artery bypass surgery.

OBJECTIVES: This study sought to quantify the effect of body mass index (BMI) on early clinical outcomes following coronary artery bypass grafting (CABG). BACKGROUND: Obesity is considered a risk factor for postoperative morbidity and mortality after cardiac surgery, although existing evidence is contradictory. METHODS: A concurrent cohort study of consecutive patients undergoing CABG from April 1996 to September 2001 was carried out. Main outcomes were early death; perioperative myocardial infarction; infective, respiratory, renal, and neurological complications; transfusion; duration of ventilation, intensive care unit, and hospital stay. Multivariable analyses compared the risk of outcomes between five different BMI groups after adjusting for case-mix. RESULTS: Out of 4,372 patients, 3.0% were underweight (BMI <20 kg/m(2)), 26.7% had a normal weight (BMI >or=20 and <25 kg/m(2)), 49.7% were overweight (BMI >or=25 and <30 kg/m(2)), 17.1% obese (BMI >or=30 and <35 kg/m(2)) and 3.6% severely obese (BMI >or=35 kg/m(2)). Compared with the normal weight group, the overweight and obese groups included more women, diabetics, and hypertensives, but fewer patients with severe ischemic heart disease and poor ventricular function. Underweight patients were more likely than normal weight patients to die in hospital (odds ratio [OR] = 4.0, 95% CI 1.4 to 11.1), have a renal complication (OR = 1.9, 95% confidence interval [CI] 1.0 to 3.7), or stay in hospital longer (>7 days) (OR = 1.7, 95% CI 1.1 to 2.5). Overweight, obese, and severely obese patients were not at higher risk of adverse outcomes than normal weight patients, and were less likely than normal weight patients to require transfusion (ORs from 0.42 to 0.86). CONCLUSIONS: Underweight patients undergoing CABG have a higher risk of death or complications than normal weight patients. Obesity does not affect the risk of perioperative death and other adverse outcomes compared to normal weight, yet obese patients appear less likely to be selected for surgery than normal weight patients.

Evaluation of the effectiveness of off-pump coronary artery bypass grafting in high-risk patients: an observational study.

BACKGROUND: Coronary artery bypass grafting in high-risk patients carries substantial morbidity. We compared the effectiveness of off-pump revascularization with that of conventional coronary artery bypass grafting using cardiopulmonary bypass and cardioplegic arrest in consecutive high-risk patients. METHODS: From April 1996 to December 2000, clinical data for consecutive patients undergoing coronary artery revascularization were prospectively entered into a database. Data were extracted for all patients considered to be high risk, defined as the presence of one or more of ten adverse prognostic factors. Hospital mortality and early morbidity were compared between two groups of patients, the on-pump and off-pump groups. RESULTS: The study group comprised 1,570 consecutive high-risk patients, 332 (21.1%) of whom underwent an off-pump operation. Patients in the on-pump group had fewer high-risk factors and lower Parsonnet scores and were less likely to be 75 years of age or older, to have peripheral vascular disease or hypercholesterolemia, or to have sustained a previous transient ischemic attack. However, they were more likely to be assigned to a higher Canadian Cardiovascular Society class and had more extensive coronary artery disease and were more likely to have unstable angina, to require urgent or emergency operations, and to receive more grafts than those undergoing off-pump procedures. Unadjusted odds ratios for intensive care unit or high-dependency unit stay, total length of stay, blood loss of more than 1,000 mL, postoperative hemoglobin and transfusion requirement all showed a highly significant benefit for the off-pump group (p < or = 0.005; odds ratios, 0.33 to 0.65). After adjustment for prognostic variables, odds ratios remained essentially unaltered (adjusted odds ratio estimates 0.36 to p < 0.05) except for blood loss of more than 1,000 mL (adjusted odds ratio estimate, 0.82; p = 0.22). Sensitivity analyses confirmed the robustness of these findings. CONCLUSIONS: Off-pump coronary artery bypass grafting is safe, effective, and associated with reduced morbidity in high-risk patients compared with conventional coronary artery revascularization.

Predictors of stroke in the modern era of coronary artery bypass grafting: a case control study.

BACKGROUND: Stroke is a rare but devastating complication after coronary artery bypass grafting (CABG) and its prevention remains elusive. We used a case control design to investigate the extent to which preoperative and perioperative factors were associated with occurrence of stroke in a cohort of consecutive patients undergoing myocardial revascularization. METHODS: From April 1996 to March 2001, data from 4,077 patients undergoing CABG were prospectively entered into a database. The association of preoperative and perioperative factors with stroke was investigated by univariate analyses. Factors observed to be significantly associated with stroke in these analyses were further investigated using multiple logistic regression to estimate the strength of the associations with the occurrence of stroke, after taking account of the other factors. RESULTS: During the study period, 4,077 patients underwent CABG and of these 923 (22.6%) had off-pump surgery. Forty-five patients suffered a perioperative stroke (1.1%). Overall there were 46 in-hospital deaths (1.1%), of whom 6 also suffered a stroke. Brain imaging of the stroke patients showed embolic lesions in 58%, watershed in 28%, and mixed in 14%. Multivariate regression analysis identified several preoperative factors as independent predictors of stroke, ie, age, unstable angina, serum creatinine greater than 150 mcg/ml, previous cerebrovascular accident (CVA), peripheral vascular disease (PVD), and salvage operation. When operative risk factors were added to the adjusted model, off-pump surgery was associated with a substantial, but not significant, protective effect against stroke (odds ratio = 0.56, 95% confidence interval 0.20 to 1.55). Survival for stroke patients was 93% and 78% at 1 and 5 years, respectively. CONCLUSIONS: Overall incidence of stroke is relatively low in our series. Age, unstable angina, previous CVA, PVD, serum creatinine greater than 150 mcg/ml, and salvage operation are independent predictors of stroke. These factors should be taken into account when informing each individual patient on the possible risk of stroke and in the decision-making process on the surgical strategy.

Early and late results of partial left ventriculectomy: single center experience and review of the literature.

AIM: To evaluate early and late outcome of partial left ventriculectomy (PLV) in a single center and to conduct a review of the literature. METHODS: From February 1996 to August 2001, 24 patients with dilated cardiomyopathy (DCM) (12 idiopathic, 12 ischemic) underwent PLV. Perioperative and follow-up data were prospectively entered into a database and analyzed. An observational analysis of the literature was carried out of all the published series of PLV reporting on > or =15 patients. RESULTS: In our series there were 22 males with amean age of 65 years (range 49 to73). Of the 22, there were 3 (12.5%) in-hospital deaths. Mean duration of follow-up was 26 months (range 3 to 71) with 9 late deaths (38%), 6 in the idiopathic group. The five-year actuarial survival was 74% in the ischemic group and 33% in the idiopathic group. The observational analysis of literature included a total of 506 patients (425 males, age 50.2 +/- 5.2 years)]. The etiology was idiopathic in 255 (50.4%), and ischemic in 89 (17.6%) patients. Baseline characteristics of the whole population include: ejection fraction 18.9 +/- 3.9%, NYHA functional class 3.7 +/- 0.2, and LVEDD of 7.7 +/- 0.4 cm. Severe mitral regurgitation was present in 368 (72.7%) patients. There were 88 (17.4%) in-hospital deaths. Cause of death included 55 due to (62.5%) low cardiac output, 10 (11.3%) due to severe bleeding, 7 (7.95%) caused by malignant arrhythmias, 8 (9%) due to sepsis, and 5 (5.7%) as a result of stroke. Ten of the selected series (overall 386 patients) reported late outcome. There were 89 (22.9%) late deaths, 12 (13.5%) were not cardiac-related, 50 (56.2%) were due to recurrence of congestive heart failure (CHF), 20 (22.5%) caused by sudden arrhythmias, 5 (5.6%) due to infections, and 2 (2.2%) from strokes. Overall, there were 248 (64.2%) survivors, of whom 179 (72.17%) were reported to be in NYHA functional class I or II. All 10 papers reported one-year survival ranging from 50% to 85%. Seven reported a two-year survival of 45% to 72%, and 4 reported a three-year survival of 33% to 64%. CONCLUSIONS: Our results and the review of the literature seem to suggest a relatively high early mortality with satisfactory late results of PLV in patients with dilated cardiomyopathy.