Genome-wide association analysis identifies six new loci associated with forced vital capacity

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR129-2–HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease

RA-MAP, molecular immunological landscapes in early rheumatoid arthritis and healthy vaccine recipients

Rheumatoid arthritis (RA) is a chronic inflammatory disorder with poorly defined aetiology characterised by synovial inflammation with variable disease severity and drug responsiveness. To investigate the peripheral blood immune cell landscape of early, drug naive RA, we performed comprehensive clinical and molecular profiling of 267 RA patients and 52 healthy vaccine recipients for up to 18 months to establish a high quality sample biobank including plasma, serum, peripheral blood cells, urine, genomic DNA, RNA from whole blood, lymphocyte and monocyte subsets. We have performed extensive multi-omic immune phenotyping, including genomic, metabolomic, proteomic, transcriptomic and autoantibody profiling. We anticipate that these detailed clinical and molecular data will serve as a fundamental resource offering insights into immune-mediated disease pathogenesis, progression and therapeutic response, ultimately contributing to the development and application of targeted therapies for RA.</p

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Multi-messenger Observations of a Binary Neutron Star Merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ∼ 1.7 {{s}} with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of {40}-8+8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 {M}ȯ . An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ∼ 40 {{Mpc}}) less than 11 hours after the merger by the One-Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ∼10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ∼ 9 and ∼ 16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC 4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta.</p

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

A Technique for Autologous Priming of the Veno-Venous Bypass Circuit during Liver Transplantation

Orthotopic liver transplantations (OLT) have been associated with significant blood loss and hemodilution, necessitating significant homologous blood component replacement. Increasing administration of homologous blood products has been found to be inversely related to patient and graft survival. Various methods to reduce the amount of blood products patients receive during OLT, such as antifibrinolytic therapy, thromboelastography-guided transfusion, phlebotomy, reduced central venous pressures intraoperatively, and the use of the veno-venous bypass (VVB) circuit, have been explored. The asanguineous priming volume of the VVB circuit increases the likelihood of the patient receiving homologous blood products due to hemodilution. It was reasoned that autologous priming of the VVB circuit in OLT surgery was a plausible adjunctive blood conservation technique given its application to the extracorporeal circuit during cardiac surgery. We describe our technique of modifying the VVB circuit for autologous priming. This technique adds minimal risk and a small amount of cost to the procedure, requires slightly more communication among members of the surgical team, and with proper sequencing, adds no additional length to the surgical procedure. It is recommended that this technique be considered for addition to the arsenal of blood conservation techniques when VVB is used during OLT

In Vitro Drug Adsorption and Plasma Free Hemoglobin Levels Associated With Hollow Fiber Oxygenators in the Extracorporeal Life Support (ECLS) Circuit

The purpose of this study was to identify the percentage of fentanyl or morphine sulfate lost from adhesion to either the polyvinylchloride (PVC) tubing or the surface of two different hollow fiber oxygenators used in current extracorporeal life support circuits and to identify any difference in the plasma free hemoglobin (PFH) levels generated when using these oxygenator and/or drug combinations. For each drug examined, six simple circuits were assembled; for each drug, two circuits contained tubing without an oxygenator (control), two circuits contained the Jostra Quadrox D (Maquet Cardiopulmonary, AG Hirrlingen, Germany), and two circuits contained the Terumo Baby Rx (Terumo Cardiovascular Systems Corp., Ann Arbor, MI). Fentanyl or morphine sulfate was added to yield initial circuit concentrations equal to 1430 ng/mL, respectively. Throughout the 6-hour in vitro testing, samples to evaluate the drug and PFH levels were drawn at various time intervals. Significance in this study is defined as p < .05. Fentanyl’s initial adsorption seems to be 80% in circuits without oxygenators, 86% in the circuits containing the Quadrox D oxygenator, and 83% in the circuits with the Baby Rx oxygenator. Morphine sulfate seems to be initially adsorbed at a rate of 40% in all circuits and does not seem to be adsorbed by either of the tested oxygenators. The PFH levels were significantly (p < .05) elevated in the fentanyl circuits. The type of oxygenator does not seem to play a significant role in drug adsorption. During this in vitro study, the majority of both drugs were lost to the PVC tubing. The type of oxygenator did not seem to significantly affect PFH. However, fentanyl in any combination or alone was associated with increased PFH levels

The Impact of Three Different Wash Solutions on Autotransfusion Products

Many blood conservation techniques and strategies have been implemented to aid in decreasing the use of allogenic blood utilization during pediatric cardiothoracic surgery. Use of techniques, such as acute normovolemic hemodilution, retrograde autologous prime, venous autologous prime, and autotransfuion, may lead to a decrease in the need for allogenic blood products. Autotransfusion has become a standard of care for all cardiothoracic surgical procedures requiring cardiopulmonary bypass (CPB). Although widely used, there is still debate over which wash solution will produce the most physiologically normal autotransfusion product. Pediatric patients can be at a higher risk for electrolyte imbalance intraoperatively and postoperatively. In an attempt to minimize this, we sought out to evaluate three different wash solutions and how they would affect the final autotransfusion product. This comparison consisted of three wash solutions; .9% sodium chloride, Normosol-R™, and Plasma-Lyte A. Based on the evaluation of all wash solutions, Plasma-Lyte A produced the most physiological normal final autotransfusion product in regards to electrolytes

Bloodless Pediatric Cardiopulmonary Bypass for a 3.2-kg Patient Whose Parents are of Jehovah’s Witness Faith

Patients and parents of Jehovah’s Witness (JW) faith present multiple challenges to a medical team, especially in the neonatal and pediatric population. The medical team must balance honoring the parents’ request of not receiving blood products and fulfilling our commitment as advocates for the child’s wellbeing. A multidisciplinary approach to cardiac surgery must be embraced for bloodless cardiopulmonary bypass (CPB) to be successful. At our institution, we have developed strategies and techniques for blood conservation that are used preoperatively, intraoperatively, and postoperatively for every CPB case with the goal of a bloodless procedure. These protocols include: preoperative erythropoietin, preoperative iron administration, selection of a CPB circuit specific to the patient’s height and weight, acute normovolemic hemodilution, retrograde autologous prime and venous autologous prime, tranexamic acid administration, zerobalance ultrafiltration, flushing of the pump suckers post-CPB, modified ultrafiltration, and cell salvage. We present an 8-day-old, 3.2-kg patient of JW faith with aortic valve stenosis and regurgitation and a patent foramen ovale who underwent a bloodless left ventricle-to-aorta tunnel repair and aortic valve repair on CPB

Bloodless Repair for a 3.6 Kilogram Transposition of the Great Arteries with Jehovah’s Witness Faith

Achieving pediatric cardiac surgery using cardiopulmonary bypass (CPB) without allogeneic blood transfusion is challenging. There are many clinical and economic factors that point to the importance of avoiding blood transfusions. In some instances, honoring patients or parents beliefs may be the reason for avoiding blood transfusions. For example, patients or parents of the Jehovah’s Witness faith refuse blood transfusion based on their religious beliefs. Over the last decade, our institution has seen a steady increase in our pediatric Jehovah’s Witness patient population. Caring for these patients have allowed us to develop specific protocols that enable us to safely provide bloodless CPB in all of our patient populations. The success of such an approach to minimize the need for blood transfusions should not start in the operating room; it must include the preoperative period and the postoperative care by the critical care team in the cardiac intensive care unit (CICU). A multidisciplinary team approach has to be in place with clear communication between the cardiologist, anesthesiologist, cardiac surgeon, perfusionist, and the cardiac intensivist. We present a case of a 7 day old male (3.6 kg) with a preoperative diagnosis of Transposition of the Great Arteries and intact ventricular septum who underwent an arterial switch procedure without the transfusion of any blood products throughout his entire hospital stay