Perioperative Outcomes of Patients with Bleeding Disorders Undergoing Major Surgery at an Academic Hemophilia Treatment Center.

Persons with bleeding disorders (PwBD) are at high risk for bleeding with invasive procedures. However, the risk of bleeding in PwBD undergoing major surgery and outcomes of patients managed perioperatively at a hemophilia treatment center (HTC) are not well described. We performed a retrospective review of surgical outcomes among PwBD undergoing major surgery between January 1st, 2017 and December 31st, 2019 at the Cardeza Foundation Hemophilia and Thrombosis Center in Philadelphia, PA. The primary outcome was postoperative bleeding, assessed according to the ISTH-SSC's 2010 definition. Secondary outcomes included use of unplanned postoperative hemostatic therapy, LOS, and 30-day readmission rate. Results were compared to non-PwBD population from a surgical database, matched for surgery, age, and sex. During the study period, 50 PwBD underwent 63 major surgeries. The most common diagnoses were VWD (64%) and hemophilia A (20.0%). The most common surgical procedure category was orthopedic (33.3%), predominantly arthroplasties. Postoperatively,4.8% of procedures were complicated by major bleeding and 1.6% by non-major bleeding. The mean LOS was 1.65 days, and 30-day readmission rate was 1.6%. In comparison to matched, non-PwBD patients in a national surgical database undergoing the same procedures, study patients had a similar rate of bleeding complications per procedure (5.0% vs 1.04% P = .071, Fisher's exact test). PwBD undergoing major surgeries have low rates of major bleeding when receiving comprehensive care at an HTC. Bleeding and hospital readmission rates were similar to non-PwBD baseline in a large database.

A universal bacteriophage T4 nanoparticle platform to design multiplex SARS-CoV-2 vaccine candidates by CRISPR engineering.

A "universal" platform that can rapidly generate multiplex vaccine candidates is critically needed to control pandemics. Using the severe acute respiratory syndrome coronavirus 2 as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates was engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers was found to be the most potent vaccine candidate in animal models. Without any adjuvant, this vaccine stimulated robust immune responses, both T helper cell 1 (TH1) and TH2 immunoglobulin G subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new nanovaccine design framework might allow the rapid deployment of effective adjuvant-free phage-based vaccines against any emerging pathogen in the future.

A Universal Bacteriophage T4 Nanoparticle Platform to Design Multiplex SARS-CoV-2 Vaccine Candidates by CRISPR Engineering.

A "universal" vaccine design platform that can rapidly generate multiplex vaccine candidates is critically needed to control future pandemics. Here, using SARS-CoV-2 pandemic virus as a model, we have developed such a platform by CRISPR engineering of bacteriophage T4. A pipeline of vaccine candidates were engineered by incorporating various viral components into appropriate compartments of phage nanoparticle structure. These include: expressible spike genes in genome, spike and envelope epitopes as surface decorations, and nucleocapsid proteins in packaged core. Phage decorated with spike trimers is found to be the most potent vaccine candidate in mouse and rabbit models. Without any adjuvant, this vaccine stimulated robust immune responses, both T H 1 and T H 2 IgG subclasses, blocked virus-receptor interactions, neutralized viral infection, and conferred complete protection against viral challenge. This new type of nanovaccine design framework might allow rapid deployment of effective phage-based vaccines against any emerging pathogen in the future.

Successful liver transplant from a hemophilia A donor with no development of hemophilia A in recipient.

BACKGROUND: Hemophilia A is an X-linked inherited bleeding disorder caused by deficiency of coagulation factor VIII. Factor VIII is activated as part of the intrinsic coagulation cascade. It plays a crucial role as the cofactor in the intrinsic "tenase" complex activating factor X to assist in clot formation. Absence or mutation of this coagulation factor leads to excessive bleeding. Clinical manifestations of hemophilia relate to bleeding from impaired hemostasis, sequelae from bleeding, or complications of coagulation factor infusion. Diagnostic criteria for Hemophilia A include factor VIII activity level below 40% of normal, presence of a mutated F8 gene, and the absence of von Willebrand disease (F8 gene - Genetics Home Reference - NIH. https://ghr.nlm.nih.gov/gene/F8). Patients who have this intrinsic defect in the coagulation cascade have a characteristically prolonged PTT. It is theorized that the majority of factor VIII is synthesized mainly in the liver, by way of liver sinusoidal endothelial cells (Arruda VR. Haematologica. 2015;100(7):849-850). Extrahepatic production also occurs in the endothelial cells, kidneys, and lymphatic tissue. In 1969, Marchioro et al showed that transplantation of normal liver to hemophilia dog could normalize plasma factor VIII levels (Marchioro T L, Science. 1969;163(3863):188-190). These results were subsequently proven in humans. Liver transplantation from hemophilia A donors without factor VIII inhibitor is not commonly performed due to the perceived risk of developing hemophilia A in the recipient. There is currently limited literature aimed at elucidating this risk. We present a case of liver transplantation in a hemophilia A donor to a recipient with no history of hemophilia A with literature reviewis a case report, objective and method do not apply. OBJECTIVE AND METHOD: We did a case report and literature review of a liver transplant receipient fro ma hemohpila A donor. RESULTS: The receipient of the liver from hemophilia A donor did not develop hemophilia post transplant and had normal factor VIII levels. CONCLUSION: To our knowledge, this is only the second case in humans of hemophilia A patient as a donor in liver transplantation. As the indications for liver transplantation have expanded, there is a need to expand the donor list, and possibly not exclude this population as viable donor option.

Transport of ice into the stratosphere and the humidification of the stratosphere over the 21st century.

Climate models predict that tropical lower-stratospheric humidity will increase as the climate warms. We examine this trend in two state-of-the-art chemistry-climate models. Under high greenhouse gas emissions scenarios, the stratospheric entry value of water vapor increases by ~1 part per million by volume (ppmv) over this century in both models. We show with trajectory runs driven by model meteorological fields that the warming tropical tropopause layer (TTL) explains 50-80% of this increase. The remainder is a consequence of trends in evaporation of ice convectively lofted into the TTL and lower stratosphere. Our results further show that, within the models we examined, ice lofting is primarily important on long time scales - on interannual time scales, TTL temperature variations explain most of the variations in lower stratospheric humidity. Assessing the ability of models to realistically represent ice-lofting processes should be a high priority in the modeling community.

Chemical and Dynamical Impacts of Stratospheric Sudden Warmings on Arctic Ozone Variability.

We use the Global Modeling Initiative (GMI) chemistry and transport model with Modern-Era Retrospective Analysis for Research and Applications (MERRA) meteorological fields to quantify heterogeneous chemical ozone loss in Arctic winters 2005-2015. Comparisons to Aura Microwave Limb Sounder N2O and O3 observations show the GMI simulation credibly represents the transport processes and net heterogeneous chemical loss necessary to simulate Arctic ozone. We find that the maximum seasonal ozone depletion varies linearly with the number of cold days and with wave driving (eddy heat flux) calculated from MERRA fields. We use this relationship and MERRA temperatures to estimate seasonal ozone loss from 1993-2004 when inorganic chlorine levels were in the same range as during the Aura period. Using these loss estimates and the observed March mean 63-90°N column O3, we quantify the sensitivity of the ozone dynamical resupply to wave driving, separating it from the sensitivity of ozone depletion to wave driving. The results show that about 2/3 of the deviation of the observed March Arctic O3 from an assumed climatological mean is due to variations in O3 resupply and 1/3 is due to depletion. Winters with a stratospheric sudden warming (SSW) before mid-February have about 1/3 the depletion of winters without one and export less depletion to the midlatitudes. However, a larger effect on the spring midlatitude ozone comes from dynamical differences between warm and cold Arctic winters, which can mask or add to the impact of exported depletion.

The status of sleep abnormalities as a diagnostic test for major depressive disorder.

BACKGROUND: Psychiatry lags other fields in development of diagnostic tests. METHODS: A literature review and meta-analysis was conducted to ascertain if polysomnographic abnormalities (REM density, REM latency, sleep efficiency, slow wave sleep, stage 1 and stage 2 sleep) warrant additional effort to develop them into a clinical diagnostic test for major depressive disorder (MDD). The 31 publications meeting inclusion criteria were then classified into one of three progressive steps using guidelines for evaluating the clinical usefulness of a diagnostic test. RESULTS: Most of the abnormalities found in MDD patients, when compared to healthy controls, occurred in the expected direction with moderate effect sizes but with substantial publication bias and heterogeneity. Eleven studies compared abnormalities in MDD to other psychiatric disorders (step 2a), and four studies provided data on the sensitivity or specificity of the findings in differentiating among the psychiatric disorders that frequently appear on the same differential diagnostic list as MDD (step 2b). No multicenter trial has been conducted prospectively to test the clinical utility of the diagnostic test (step 3). LIMITATIONS: Only published articles in the English language were used. CONCLUSIONS: Sleep studies for the detection of MDD appear replicable with a moderate effect size. However, additional step 1 studies are needed to define the sensitivity and specificity. The heterogeneity of sleep recording, scoring techniques, and MDD must also be addressed.

Malaria parasite liver stages render host hepatocytes susceptible to mitochondria-initiated apoptosis.

Intracellular eukaryotic parasites and their host cells constitute complex, coevolved cellular interaction systems that frequently cause disease. Among them, Plasmodium parasites cause a significant health burden in humans, killing up to one million people annually. To succeed in the mammalian host after transmission by mosquitoes, Plasmodium parasites must complete intracellular replication within hepatocytes and then release new infectious forms into the blood. Using Plasmodium yoelii rodent malaria parasites, we show that some liver stage (LS)-infected hepatocytes undergo apoptosis without external triggers, but the majority of infected cells do not, and can also resist Fas-mediated apoptosis. In contrast, apoptosis is dramatically increased in hepatocytes infected with attenuated parasites. Furthermore, we find that blocking total or mitochondria-initiated host cell apoptosis increases LS parasite burden in mice, suggesting that an anti-apoptotic host environment fosters parasite survival. Strikingly, although LS infection confers strong resistance to extrinsic host hepatocyte apoptosis, infected hepatocytes lose their ability to resist apoptosis when anti-apoptotic mitochondrial proteins are inhibited. This is demonstrated by our finding that B-cell lymphoma 2 family inhibitors preferentially induce apoptosis in LS-infected hepatocytes and significantly reduce LS parasite burden in mice. Thus, targeting critical points of susceptibility in the LS-infected host cell might provide new avenues for malaria prophylaxis.