Catastrophes and complicated intraoperative events during robotic lung resection.

Intraoperative complications and catastrophes are an accepted and perhaps inevitable aspect of all surgeries. Anatomic pulmonary resection puts in close proximity the tracheal-bronchial tree, pulmonary vasculature, heart and great vessels within the small volume area of the chest. Fortunately, major complications and catastrophes are uncommon regardless of surgical approach. Pulmonary arterial injury is the most frequently reported. Most injuries necessitate a thoracotomy for definitive management though novel techniques are emerging for minimally invasive management. This section focuses on intraoperative pulmonary artery and vein injuries, major airway injuries and transections, injuries to major abdominal organs and effects of carbon dioxide insufflation during robotic pulmonary resection

The current state of per oral endoscopic myotomy for achalasia.

Achalasia is an acquired neuromuscular disorder that has been treated using a variety of modalities throughout medical history. Recently, the technique of per oral endoscopic myotomy (POEM) was introduced to treat the disease using a truly minimally invasive, natural orifice technique that is rapidly being adopted across the world. This review outlines the development of POEM, the technique itself, and gives a comparison to other procedures, specifically laparoscopic Heller myotomy (LHM)

Interaction of nitrogen dioxide with human plasma Antioxidant depletion and oxidative damage

AbstractNitrogen dioxide (NO*2) is often present in inhaled air and may be generated in vivo from nitric oxide. Exposure of human blood plasma to NO*2 caused rapid losses of ascorbic acid, uric acid and protein thiol groups, as well as lipid peroxidation and depletions of α-tocopherol, bilirubin and ubiquinol-10. No increase in protein carbonyls was detected. Supplementation of plasma with ascorbate decreased the rates of lipid peroxidation. α-tocopherol depletion and loss of uric acid. Uric acid supplementation decreased rates of lipid peroxidation but not the loss of α-tecopherol. We conclude that ascorbic acid, protein -SH groups, uric acid and α-tocopherol may be important agents protecting against NO*2 in vivo. If these antioxidants are depleted, peroxidation of lipids occurs and might contribute to the toxicity of NO*2

Assessing Survival and Grading the Severity of Complications in Octogenarians Undergoing Pulmonary Lobectomy.

Introduction. Octogenarians are at increased risk for complications after lung resection. With alternatives such as radiation, understanding the risks of surgery and associated survival are valuable. Data grading the severity of complications and long-term survival in this population is lacking. We reviewed our experience with lobectomy in octogenarians, grading complications using a validated thoracic morbidity and mortality schema. Methods. We retrospectively reviewed consecutive patients aged ≥80 undergoing lobectomy between 2004 and 2012. Demographics, clinical/pathologic stage, complications, recurrence, and mortality were collected. Complications were graded by the Seely thoracic morbidity and mortality model. Results. 45 patients (mean age 82.2 years) were analyzed. The majority of patients (28/45, 62%) were clinical stage IA/IB. 62% (28/45) of patients experienced a complication. Only 15.6% (7/45) were considered significantly morbid (≥ grade IIIB) per the Seely model. Perioperative mortality was 2% and half of patients were living at a follow-up of 53 months. Overall five-year survival was 52%. Conclusions. In carefully selected octogenarians, lobectomy carries a 15.6% rate of significantly morbid complications with encouraging overall survival. These data provide the basis for a more complete discussion with patients regarding lobectomy for lung cancer

Electronic Medical Record Inaccuracies: Multicenter Analysis of Challenges with Modified Lung Cancer Screening Criteria.

The National Comprehensive Cancer Network expanded their lung cancer screening (LCS) criteria to comprise one additional clinical risk factor, including chronic obstructive pulmonary disease (COPD). The electronic medical record (EMR) is a source of clinical information that could identify high-risk populations for LCS, including a diagnosis of COPD; however, an unsubstantiated COPD diagnosis in the EMR may lead to inappropriate LCS referrals. We aimed to detect the prevalence of unsubstantiated COPD diagnosis in the EMR for LCS referrals, to determine the efficacy of utilizing the EMR as an accurate population-based eligibility screening trigger using modified clinical criteria. We performed a multicenter review of all individuals referred to three LCS programs from 2012 to 2015. Each individual\u27s EMR was searched for COPD diagnostic terms and the presence of a diagnostic pulmonary functionality test (PFT). An unsubstantiated COPD diagnosis was defined by an individual\u27s EMR containing a COPD term with no PFTs present, or the presence of PFTs without evidence of obstruction. A total of 2834 referred individuals were identified, of which 30% (840/2834) had a COPD term present in their EMR. Of these, 68% (571/840) were considered unsubstantiated diagnoses: 86% (489/571) due to absent PFTs and 14% (82/571) due to PFTs demonstrating no evidence of postbronchodilation obstruction. A large proportion of individuals referred for LCS may have an unsubstantiated COPD diagnosis within their EMR. Thus, utilizing the EMR as a population-based eligibility screening tool, employing expanded criteria, may lead to individuals being referred, potentially, inappropriately for LCS

Associations of variants In the hexokinase 1 and interleukin 18 receptor regions with oxyhemoglobin saturation during sleep

Sleep disordered breathing (SDB)-related overnight hypoxemia is associated with cardiometabolic disease and other comorbidities. Understanding the genetic bases for variations in nocturnal hypoxemia may help understand mechanisms influencing oxygenation and SDB-related mortality. We conducted genome-wide association tests across 10 cohorts and 4 populations to identify genetic variants associated with three correlated measures of overnight oxyhemoglobin saturation: average and minimum oxyhemoglobin saturation during sleep and the percent of sleep with oxyhemoglobin saturation under 90%. The discovery sample consisted of 8,326 individuals. Variants with p −6 were analyzed in a replication group of 14,410 individuals. We identified 3 significantly associated regions, including 2 regions in multi-ethnic analyses (2q12, 10q22). SNPs in the 2q12 region associated with minimum SpO2 (rs78136548 p = 2.70 × 10−10). SNPs at 10q22 were associated with all three traits including average SpO2 (rs72805692 p = 4.58 × 10−8). SNPs in both regions were associated in over 20,000 individuals and are supported by prior associations or functional evidence. Four additional significant regions were detected in secondary sex-stratified and combined discovery and replication analyses, including a region overlapping Reelin, a known marker of respiratory complex neurons.These are the first genome-wide significant findings reported for oxyhemoglobin saturation during sleep, a phenotype of high clinical interest. Our replicated associations with HK1 and IL18R1 suggest that variants in inflammatory pathways, such as the biologically-plausible NLRP3 inflammasome, may contribute to nocturnal hypoxemia

Performance of Risk-Based Criteria for Targeting Acute HIV Screening in San Francisco

Federal guidelines now recommend supplemental HIV RNA testing for persons at high risk for acute HIV infection. However, many rapid HIV testing sites do not include HIV RNA or p24 antigen testing due to concerns about cost, the need for results follow-up, and the impact of expanded venipuncture on clinic flow. We developed criteria to identify patients in a municipal STD clinic in San Francisco who are asymptomatic but may still be likely to have acute infection.Data were from patients tested with serial HIV antibody and HIV RNA tests to identify acute HIV infection. BED-CEIA results were used to classify non-acute cases as recent or longstanding. Demographics and self-reported risk behaviors were collected at time of testing. Multivariate models were developed and preliminarily evaluated using predictors associated with recent infection in bivariate analyses as a proxy for acute HIV infection. Multivariate models demonstrating ≥70% sensitivity for recent infection while testing ≤60% of patients in this development dataset were then validated by determining their performance in identifying acute infections.From 2004-2007, 137 of 12,622 testers had recent and 36 had acute infections. A model limiting acute HIV screening to MSM plus any one of a series of other predictors resulted in a sensitivity of 83.3% and only 47.6% of patients requiring testing. A single-factor model testing only patients reporting any receptive anal intercourse resulted in 88.9% sensitivity with only 55.2% of patients requiring testing.In similar high risk HIV testing sites, acute screening using "supplemental" HIV p24 antigen or RNA tests can be rationally targeted to testers who report particular HIV risk behaviors. By improving the efficiency of acute HIV testing, such criteria could facilitate expanded acute case identification

Pharmacodynamic Modeling of Anti-Cancer Activity of Tetraiodothyroacetic Acid in a Perfused Cell Culture System

Unmodified or as a poly[lactide-co-glycolide] nanoparticle, tetraiodothyroacetic acid (tetrac) acts at the integrin αvβ3 receptor on human cancer cells to inhibit tumor cell proliferation and xenograft growth. To study in vitro the pharmacodynamics of tetrac formulations in the absence of and in conjunction with other chemotherapeutic agents, we developed a perfusion bellows cell culture system. Cells were grown on polymer flakes and exposed to various concentrations of tetrac, nano-tetrac, resveratrol, cetuximab, or a combination for up to 18 days. Cells were harvested and counted every one or two days. Both NONMEM VI and the exact Monte Carlo parametric expectation maximization algorithm in S-ADAPT were utilized for mathematical modeling. Unmodified tetrac inhibited the proliferation of cancer cells and did so with differing potency in different cell lines. The developed mechanism-based model included two effects of tetrac on different parts of the cell cycle which could be distinguished. For human breast cancer cells, modeling suggested a higher sensitivity (lower IC50) to the effect on success rate of replication than the effect on rate of growth, whereas the capacity (Imax) was larger for the effect on growth rate. Nanoparticulate tetrac (nano-tetrac), which does not enter into cells, had a higher potency and a larger anti-proliferative effect than unmodified tetrac. Fluorescence-activated cell sorting analysis of harvested cells revealed tetrac and nano-tetrac induced concentration-dependent apoptosis that was correlated with expression of pro-apoptotic proteins, such as p53, p21, PIG3 and BAD for nano-tetrac, while unmodified tetrac showed a different profile. Approximately additive anti-proliferative effects were found for the combinations of tetrac and resveratrol, tetrac and cetuximab (Erbitux), and nano-tetrac and cetuximab. Our in vitro perfusion cancer cell system together with mathematical modeling successfully described the anti-proliferative effects over time of tetrac and nano-tetrac and may be useful for dose-finding and studying the pharmacodynamics of other chemotherapeutic agents or their combinations

Humoral and Cell-Mediated Immunity to Pandemic H1N1 Influenza in a Canadian Cohort One Year Post-Pandemic: Implications for Vaccination

We evaluated a cohort of Canadian donors for T cell and antibody responses against influenza A/California/7/2009 (pH1N1) at 8-10 months after the 2nd pandemic wave by flow cytometry and microneutralization assays. Memory CD8 T cell responses to pH1N1 were detectable in 58% (61/105) of donors. These responses were largely due to cross-reactive CD8 T cell epitopes as, for those donors tested, similar recall responses were obtained to A/California 2009 and A/PR8 1934 H1N1 Hviruses. Longitudinal analysis of a single infected individual showed only a small and transient increase in neutralizing antibody levels, but a robust CD8 T cell response that rose rapidly post symptom onset, peaking at 3 weeks, followed by a gradual decline to the baseline levels seen in a seroprevalence cohort post-pandemic. The magnitude of the influenza-specific CD8 T cell memory response at one year post-pandemic was similar in cases and controls as well as in vaccinated and unvaccinated donors, suggesting that any T cell boosting from infection was transient. Pandemic H1-specific antibodies were only detectable in approximately half of vaccinated donors. However, those who were vaccinated within a few months following infection had the highest persisting antibody titers, suggesting that vaccination shortly after influenza infection can boost or sustain antibody levels. For the most part the circulating influenza-specific T cell and serum antibody levels in the population at one year post-pandemic were not different between cases and controls, suggesting that natural infection does not lead to higher long term T cell and antibody responses in donors with pre-existing immunity to influenza. However, based on the responses of one longitudinal donor, it is possible for a small population of pre-existing cross-reactive memory CD8 T cells to expand rapidly following infection and this response may aid in viral clearance and contribute to a lessening of disease severity

The ciliopathy gene cc2d2a controls zebrafish photoreceptor outer segment development through a role in Rab8-dependent vesicle trafficking

Ciliopathies are a genetically and phenotypically heterogeneous group of human developmental disorders whose root cause is the absence or dysfunction of primary cilia. Joubert syndrome is characterized by a distinctive hindbrain malformation variably associated with retinal dystrophy and cystic kidney disease. Mutations in CC2D2A are found in ∼10% of patients with Joubert syndrome. Here we describe the retinal phenotype of cc2d2a mutant zebrafish consisting of disorganized rod and cone photoreceptor outer segments resulting in abnormal visual function as measured by electroretinogram. Our analysis reveals trafficking defects in mutant photoreceptors affecting transmembrane outer segment proteins (opsins) and striking accumulation of vesicles, suggesting a role for Cc2d2a in vesicle trafficking and fusion. This is further supported by mislocalization of Rab8, a key regulator of opsin carrier vesicle trafficking, in cc2d2a mutant photoreceptors and by enhancement of the cc2d2a retinal and kidney phenotypes with partial knockdown of rab8. We demonstrate that Cc2d2a localizes to the connecting cilium in photoreceptors and to the transition zone in other ciliated cell types and that cilia are present in these cells in cc2d2a mutants, arguing against a primary function for Cc2d2a in ciliogenesis. Our data support a model where Cc2d2a, localized at the photoreceptor connecting cilium/transition zone, facilitates protein transport through a role in Rab8-dependent vesicle trafficking and fusion