FAMIN Is a Multifunctional Purine Enzyme Enabling the Purine Nucleotide Cycle.

Mutations in FAMIN cause arthritis and inflammatory bowel disease in early childhood, and a common genetic variant increases the risk for Crohn's disease and leprosy. We developed an unbiased liquid chromatography-mass spectrometry screen for enzymatic activity of this orphan protein. We report that FAMIN phosphorolytically cleaves adenosine into adenine and ribose-1-phosphate. Such activity was considered absent from eukaryotic metabolism. FAMIN and its prokaryotic orthologs additionally have adenosine deaminase, purine nucleoside phosphorylase, and S-methyl-5'-thioadenosine phosphorylase activity, hence, combine activities of the namesake enzymes of central purine metabolism. FAMIN enables in macrophages a purine nucleotide cycle (PNC) between adenosine and inosine monophosphate and adenylosuccinate, which consumes aspartate and releases fumarate in a manner involving fatty acid oxidation and ATP-citrate lyase activity. This macrophage PNC synchronizes mitochondrial activity with glycolysis by balancing electron transfer to mitochondria, thereby supporting glycolytic activity and promoting oxidative phosphorylation and mitochondrial H+ and phosphate recycling.

Quantitative temporal viromics: an approach to investigate host-pathogen interaction.

A systematic quantitative analysis of temporal changes in host and viral proteins throughout the course of a productive infection could provide dynamic insights into virus-host interaction. We developed a proteomic technique called "quantitative temporal viromics" (QTV), which employs multiplexed tandem-mass-tag-based mass spectrometry. Human cytomegalovirus (HCMV) is not only an important pathogen but a paradigm of viral immune evasion. QTV detailed how HCMV orchestrates the expression of >8,000 cellular proteins, including 1,200 cell-surface proteins to manipulate signaling pathways and counterintrinsic, innate, and adaptive immune defenses. QTV predicted natural killer and T cell ligands, as well as 29 viral proteins present at the cell surface, potential therapeutic targets. Temporal profiles of >80% of HCMV canonical genes and 14 noncanonical HCMV open reading frames were defined. QTV is a powerful method that can yield important insights into viral infection and is applicable to any virus with a robust in vitro model.

C13orf31 (FAMIN) is a central regulator of immunometabolic function.

Single-nucleotide variations in C13orf31 (LACC1) that encode p.C284R and p.I254V in a protein of unknown function (called 'FAMIN' here) are associated with increased risk for systemic juvenile idiopathic arthritis, leprosy and Crohn's disease. Here we set out to identify the biological mechanism affected by these coding variations. FAMIN formed a complex with fatty acid synthase (FASN) on peroxisomes and promoted flux through de novo lipogenesis to concomitantly drive high levels of fatty-acid oxidation (FAO) and glycolysis and, consequently, ATP regeneration. FAMIN-dependent FAO controlled inflammasome activation, mitochondrial and NADPH-oxidase-dependent production of reactive oxygen species (ROS), and the bactericidal activity of macrophages. As p.I254V and p.C284R resulted in diminished function and loss of function, respectively, FAMIN determined resilience to endotoxin shock. Thus, we have identified a central regulator of the metabolic function and bioenergetic state of macrophages that is under evolutionary selection and determines the risk of inflammatory and infectious disease.

HCMV-secreted glycoprotein gpUL4 inhibits TRAIL-mediated apoptosis and NK cell activation.

Human cytomegalovirus (HCMV) is a paradigm of pathogen immune evasion and sustains lifelong persistent infection in the face of exceptionally powerful host immune responses through the concerted action of multiple immune-evasins. These reduce NK cell activation by inhibiting ligands for activating receptors, expressing ligands for inhibitory receptors, or inhibiting synapse formation. However, these functions only inhibit direct interactions with the infected cell. To determine whether the virus also expresses soluble factors that could modulate NK function at a distance, we systematically screened all 170 HCMV canonical protein-coding genes. This revealed that UL4 encodes a secreted and heavily glycosylated protein (gpUL4) that is expressed with late-phase kinetics and is capable of inhibiting NK cell degranulation. Analyses of gpUL4 binding partners by mass spectrometry identified an interaction with TRAIL. gpUL4 bound TRAIL with picomolar affinity and prevented TRAIL from binding its receptor, thus acting as a TRAIL decoy receptor. TRAIL is found in both soluble and membrane-bound forms, with expression of the membrane-bound form strongly up-regulated on NK cells in response to interferon. gpUL4 inhibited apoptosis induced by soluble TRAIL, while also binding to the NK cell surface in a TRAIL-dependent manner, where it blocked NK cell degranulation and cytokine secretion. gpUL4 therefore acts as an immune-evasin by inhibiting both soluble and membrane-bound TRAIL and is a viral-encoded TRAIL decoy receptor. Interestingly, gpUL4 could also suppress NK responses to heterologous viruses, suggesting that it may act as a systemic virally encoded immunosuppressive agent.

ADAM17 targeting by human cytomegalovirus remodels the cell surface proteome to simultaneously regulate multiple immune pathways.

Human cytomegalovirus (HCMV) is a major human pathogen whose life-long persistence is enabled by its remarkable capacity to systematically subvert host immune defenses. In exploring the finding that HCMV infection up-regulates tumor necrosis factor receptor 2 (TNFR2), a ligand for the pro-inflammatory antiviral cytokine TNFα, we found that the underlying mechanism was due to targeting of the protease, A Disintegrin And Metalloproteinase 17 (ADAM17). ADAM17 is the prototype 'sheddase', a family of proteases that cleaves other membrane-bound proteins to release biologically active ectodomains into the supernatant. HCMV impaired ADAM17 surface expression through the action of two virally-encoded proteins in its UL/b' region, UL148 and UL148D. Proteomic plasma membrane profiling of cells infected with an HCMV double-deletion mutant for UL148 and UL148D with restored ADAM17 expression, combined with ADAM17 functional blockade, showed that HCMV stabilized the surface expression of 114 proteins (P < 0.05) in an ADAM17-dependent fashion. These included reported substrates of ADAM17 with established immunological functions such as TNFR2 and jagged1, but also numerous unreported host and viral targets, such as nectin1, UL8, and UL144. Regulation of TNFα-induced cytokine responses and NK inhibition during HCMV infection were dependent on this impairment of ADAM17. We therefore identify a viral immunoregulatory mechanism in which targeting a single sheddase enables broad regulation of multiple critical surface receptors, revealing a paradigm for viral-encoded immunomodulation.

Association of Hemometabolic Trajectory and Mortality: Insights From the Cardiogenic Shock Working Group Registry.

Cardiogenic shock (CS) is a hemodynamic syndrome that can progress to systemic metabolic derangements and end-organ dysfunction. Prior studies have reported hemodynamic parameters at the time of admission to be associated with mortality but hemodynamic trajectories in CS have not been well described. We studied the association between hemodynamic profiles and their trajectories and in-hospital mortality in patients with CS due to heart failure (HF-CS) and acute myocardial infarction (MI-CS). Using data from the large multicenter Cardiogenic Shock Working Group (CSWG) registry, we analyzed hemodynamic data obtained at the time of pulmonary artery catheter (PAC) insertion (dataset at baseline) and at PAC removal or death (dataset at final time point). Univariable regression analyses for prediction of in-hospital mortality were conducted for baseline and final hemodynamic values, as well as the interval change (delta-P). Data was further analyzed based on CS etiology and survival status. A total of 2260 patients with PAC data were included (70% male, age 61 ± 14 years, 61% HF-CS, 27% MI-CS). In-hospital mortality was higher in the MI-CS group (40.1%) compared with HF-CS (22.4%, P < .01). In the HF-CS cohort, survivors exhibited lower right atrial pressure (RAP), pulmonary artery pressure (PAP), cardiac output/index (CO/CI), lactate, and higher blood pressure (BP) than nonsurvivors at baseline. In this cohort, during hospitalization, improvement in metabolic (aspartate transaminase, lactate), BP, hemodynamic (RAP, pulmonary artery pulsatility index [PAPi], pulmonary artery compliance for right-sided profile and CO/CI for left-sided profile), had association with survival. In the MI-CS cohort, a lower systolic BP and higher PAP at baseline were associated with odds of death. Improvement in metabolic (lactate), BP, hemodynamic (RAP, PAPi for right-sided profile and CO/CI for left-sided profile) were associated with survival. In a large contemporary CS registry, hemodynamic trajectories had a strong association with short-term outcomes in both cohorts. These findings suggest the clinical importance of timing and monitoring hemodynamic trajectories to tailor management in patients with CS.

Evolving Trends and Impact of Waitlist Transfusion on Recipient Outcomes Following Heart Transplantation.

BACKGROUND: This study evaluates the clinical trends, risk factors, and impact of waitlist blood transfusion on outcomes following isolated heart transplantation. METHODS: The UNOS registry was queried to identify adult recipients from January 1, 2014, to June 30, 2022. The recipients were stratified into two groups depending on whether they received a blood transfusion while on the waitlist. The incidence of waitlist transfusion was compared before and after the 2018 allocation policy change. The primary outcome was survival. Propensity score-matching was performed. Multivariable logistic regression was performed to identify predictors of waitlist transfusion. A sub-analysis was performed to evaluate the impact of waitlist time on waitlist transfusion. RESULTS: From the 21 926 recipients analyzed in this study, 4201 (19.2%) received waitlist transfusion. The incidence of waitlist transfusion was lower following the allocation policy change (14.3% vs. 23.7%, p < 0.001). The recipients with waitlist transfusion had significantly reduced 1-year posttransplant survival (88.8% vs. 91.9%, p < 0.001) compared to the recipients without waitlist transfusion in an unmatched comparison. However, in a propensity score-matched comparison, the two groups had similar 1-year survival (90.0% vs. 90.4%, p = 0.656). Multivariable analysis identified ECMO, Impella, and pretransplant dialysis as strong predictors of waitlist transfusion. In a sub-analysis, the odds of waitlist transfusion increased nonlinearly with longer waitlist time. CONCLUSION: There is a lower incidence of waitlist transfusion among transplant recipients under the 2018 allocation system. Waitlist transfusion is not an independent predictor of adverse posttransplant outcomes but rather a marker of the patient's clinical condition. ECMO, Impella, and pretransplant dialysis are strong predictors of waitlist transfusion.

Oligourea helix bundle binds detergents with diverse polar head groups.

Here we report a series of crystal structures (and accompanying biophysical data) of an array of diverse detergent guests bound to an oligourea foldamer helix bundle. These results significantly increase our structural and chemical understanding of aqueous guest recognition by oligourea foldamers and will aid the design of further functionalised oligourea-based self-assemblies.

Clinical Outcomes Associated With Diltiazem Use in Heart Failure With Reduced Ejection Fraction After Implementation of a Clinical Support System.

BACKGROUND: Despite atrial fibrillation guideline recommendations, many patients with heart failure with reduced ejection fraction (EF) continue to receive IV diltiazem for acute rate control. OBJECTIVE: Our institution recently implemented a clinical decision support system (CDSS)-based tool that recommends against the use of diltiazem in patients with an EF ≤ 40%. The objective of this study was to evaluate outcomes of adherence to the aforementioned CDSS-based tool. METHODS: This multi-hospital, retrospective study assessed patients who triggered the CDSS alert and compared those who did and did not discontinue diltiazem. The primary outcome was the occurrence of clinical deterioration. The primary endpoint was compared utilizing a Fisher's Exact Test, and a multivariate logistic regression model was developed to confirm the results of the primary analysis. RESULTS: A total of 246 patients were included in this study with 146 patients in the nonadherent group (received diltiazem) and 100 patients in the adherent group (did not receive diltiazem). There was a higher proportion of patients experiencing clinical deterioration in the alert nonadherence group (33% vs 21%, P = 0.044), including increased utilization of inotropes and vasopressors, and higher rate of transfer to ICU. CONCLUSION AND RELEVANCE: In patients with heart failure with reduced EF, diltiazem use after nonadherence to a CDSS alert resulted in an increased risk of clinical deterioration. This study highlights the need for improved provider adherence to diltiazem clinical decision support systems.

Outcomes of Impella 5.0 and 5.5 for cardiogenic shock: A single-center 137 patient experience.

BACKGROUND: This study evaluated the outcomes of patients with cardiogenic shock (CS) supported with Impella 5.0 or 5.5 and identified risk factors for in-hospital mortality. METHODS: Adults with CS who were supported with Impella 5.0 or 5.5 at a single institution were included. Patients were stratified into three groups according to their CS etiology: (1) acute myocardial infarction (AMI), (2) acute decompensated heart failure (ADHF), and (3) postcardiotomy (PC). The primary outcome was survival, and secondary outcomes included adverse events during Impella support and length of stay. Multivariable logistic regression was performed to identify risk factors for in-hospital mortality. RESULTS: One hundred and thirty-seven patients with CS secondary to AMI (n = 47), ADHF (n = 86), and PC (n = 4) were included. The ADHF group had the highest survival rates at all time points. Acute kidney injury (AKI) was the most common complication during Impella support in all 3 groups. Increased rates of AKI and de novo renal replacement therapy were observed in the PC group, and the AMI group experienced a higher incidence of bleeding requiring transfusion. Multivariable analysis demonstrated diabetes mellitus, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine were independent predictors of in-hospital mortality, but the etiology of CS did not impact mortality. CONCLUSIONS: This study demonstrates that Impella 5.0 and 5.5 provide effective mechanical support for patients with CS with favorable outcomes, with nearly two-thirds of patients alive at 180 days. Diabetes, elevated pre-insertion serum lactate, and elevated pre-insertion serum creatinine are strong risk factors for in-hospital mortality.

Library Screening, In Vivo Confirmation, and Structural and Bioinformatic Analysis of Pentapeptide Sequences as Substrates for Protein Farnesyltransferase.

Protein farnesylation is a post-translational modification where a 15-carbon farnesyl isoprenoid is appended to the C-terminal end of a protein by farnesyltransferase (FTase). This process often causes proteins to associate with the membrane and participate in signal transduction pathways. The most common substrates of FTase are proteins that have C-terminal tetrapeptide CaaX box sequences where the cysteine is the site of modification. However, recent work has shown that five amino acid sequences can also be recognized, including the pentapeptides CMIIM and CSLMQ. In this work, peptide libraries were initially used to systematically vary the residues in those two parental sequences using an assay based on Matrix Assisted Laser Desorption Ionization-Mass Spectrometry (MALDI-MS). In addition, 192 pentapeptide sequences from the human proteome were screened using that assay to discover additional extended CaaaX-box motifs. Selected hits from that screening effort were rescreened using an in vivo yeast reporter protein assay. The X-ray crystal structure of CMIIM bound to FTase was also solved, showing that the C-terminal tripeptide of that sequence interacted with the enzyme in a similar manner as the C-terminal tripeptide of CVVM, suggesting that the tripeptide comprises a common structural element for substrate recognition in both tetrapeptide and pentapeptide sequences. Molecular dynamics simulation of CMIIM bound to FTase further shed light on the molecular interactions involved, showing that a putative catalytically competent Zn(II)-thiolate species was able to form. Bioinformatic predictions of tetrapeptide (CaaX-box) reactivity correlated well with the reactivity of pentapeptides obtained from in vivo analysis, reinforcing the importance of the C-terminal tripeptide motif. This analysis provides a structural framework for understanding the reactivity of extended CaaaX-box motifs and a method that may be useful for predicting the reactivity of additional FTase substrates bearing CaaaX-box sequences.

Solvent Minimized Synthesis of Amides by Reactive Extrusion.

Herein, we report on the translation of a small scale ball-milled amidation protocol into a large scale continuous reactive extrusion process. Critical components to the successful translation were: a) understanding how the different operating parameters of a twin-screw extruder should be harnessed to control prolonged continuous operation, and b) consideration of the physical form of the input materials. The amidation reaction is applied to 36 amides spanning a variety of physical form combinations (liquid-liquid, solid-liquid and solid-solid). Following this learning process, we have developed an understanding for the translation of each physical form combination and demonstrated a 7-hour reactive extrusion process for the synthesis of an amide on 500 gram scale (1.3 mols of product).

Pulmonary Artery Catheter Use and Risk of In-hospital Death in Heart Failure Cardiogenic Shock.

BACKGROUND: Pulmonary artery catheters (PACs) are increasingly used to guide management decisions in cardiogenic shock (CS). The goal of this study was to determine if PAC use was associated with a lower risk of in-hospital mortality in CS owing to acute heart failure (HF-CS). METHODS AND RESULTS: This multicenter, retrospective, observational study included patients with CS hospitalized between 2019 and 2021 at 15 US hospitals participating in the Cardiogenic Shock Working Group registry. The primary end point was in-hospital mortality. Inverse probability of treatment-weighted logistic regression models were used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CI), accounting for multiple variables at admission. The association between the timing of PAC placement and in-hospital death was also analyzed. A total of 1055 patients with HF-CS were included, of whom 834 (79%) received a PAC during their hospitalization. In-hospital mortality risk for the cohort was 24.7% (n = 261). PAC use was associated with lower adjusted in-hospital mortality risk (22.2% vs 29.8%, OR 0.68, 95% CI 0.50-0.94). Similar associations were found across SCAI stages of shock, both at admission and at maximum SCAI stage during hospitalization. Early PAC use (≤6 hours of admission) was observed in 220 PAC recipients (26%) and associated with a lower adjusted risk of in-hospital mortality compared with delayed (≥48 hours) or no PAC use (17.3% vs 27.7%, OR 0.54, 95% CI 0.37-0.81). CONCLUSIONS: This observational study supports PAC use, because it was associated with decreased in-hospital mortality in HF-CS, especially if performed within 6 hours of hospital admission. CONDENSED ABSTRACT: An observational study from the Cardiogenic Shock Working Group registry of 1055 patients with HF-CS showed that pulmonary artery catheter (PAC) use was associated with a lower adjusted in-hospital mortality risk (22.2% vs 29.8%, odds ratio 0.68, 95% confidence interval 0.50-0.94) compared with outcomes in patients managed without PAC. Early PAC use (≤6 hours of admission) was associated with a lower adjusted risk of in-hospital mortality compared with delayed (≥48 hours) or no PAC use (17.3% vs 27.7%, odds ratio 0.54, 95% confidence interval 0.37-0.81).

Extracorporeal Membrane Oxygenation for Graft Dysfunction Early After Heart Transplantation: A Systematic Review and Meta-analysis.

INTRODUCTION: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a prevailing option for the management of severe early graft dysfunction. This systematic review and individual patient data (IPD) meta-analysis aims to evaluate (1) mortality, (2) rates of major complications, (3) prognostic factors, and (4) the effect of different VA-ECMO strategies on outcomes in adult heart transplant (HT) recipients supported with VA-ECMO. METHODS AND RESULTS: We conducted a systematic search and included studies of adults (≥18 years) who received VA-ECMO during their index hospitalization after HT and reported on mortality at any timepoint. We pooled data using random effects models. To identify prognostic factors, we analysed IPD using mixed effects logistic regression. We assessed the certainty in the evidence using the GRADE framework. We included 49 observational studies of 1477 patients who received VA-ECMO after HT, of which 15 studies provided IPD for 448 patients. There were no differences in mortality estimates between IPD and non-IPD studies. The short-term (30-day/in-hospital) mortality estimate was 33% (moderate certainty, 95% confidence interval [CI] 28%-39%) and 1-year mortality estimate 50% (moderate certainty, 95% CI 43%-57%). Recipient age (odds ratio 1.02, 95% CI 1.01-1.04) and prior sternotomy (OR 1.57, 95% CI 0.99-2.49) are associated with increased short-term mortality. There is low certainty evidence that early intraoperative cannulation and peripheral cannulation reduce the risk of short-term death. CONCLUSIONS: One-third of patients who receive VA-ECMO for early graft dysfunction do not survive 30 days or to hospital discharge, and one-half do not survive to 1 year after HT. Improving outcomes will require ongoing research focused on optimizing VA-ECMO strategies and care in the first year after HT.

Reduction of HLA donor specific antibodies in heart transplant patients treated with proteasome inhibitors for antibody mediated rejection.

In this project, we describe proteasome inhibitor (PI) treatment of antibody-mediated rejection (AMR) in heart transplantation (HTX). From January 2018 to September 2021, 10 patients were treated with PI for AMR: carfilzomib (CFZ) n = 8; bortezomib (BTZ) n = 2. Patients received 1-3 cycles of PI. All patients had ≥1 strong donor-specific antibody (DSA) (mean fluorescence intensity [MFI] > 8000) in undiluted serum. Most DSAs (20/21) had HLA class II specificity. The MFI of strong DSAs had a median reduction of 56% (IQR = 13%-89%) in undiluted serum and 92% (IQR = 53%-95%) at 1:16 dilution. Seventeen DSAs in seven patients were reduced > 50% at 1:16 dilution after treatment. Four DSAs from three patients did not respond. DSA with MFI > 8000 at 1:16 dilution was less responsive to treatment. 60% (6/10) patients presented with graft dysfunction; 4/6 recovered ejection fraction > 40% after treatment. Pathologic AMR was resolved in 5/7 (71.4%) of patients within 1 year after treatment. 9/10 (90%) patients survived to 1 year after AMR diagnosis. Using PI in AMR resulted in significant DSA reduction with some resolution of graft dysfunction. Larger studies are needed to evaluate PI for AMR.

Basiliximab induction versus no induction in adult heart transplantation.

BACKGROUND: Induction immunosuppression in heart transplant recipients varies greatly by center. Basiliximab (BAS) is the most commonly used induction immunosuppressant but has not been shown to reduce rejection or improve survival. The objective of this retrospective study was to compare rejection, infection, and mortality within the first 12 months following heart transplant in patients who received BAS or no induction. METHODS: This was a retrospective cohort study of adult heart transplant recipients given BAS or no induction from January 1, 2017 to May 31, 2021. The primary endpoint was incidence of treated acute cellular rejection (ACR) at 12-months post-transplant. Secondary endpoints included ACR at 90 days post-transplant, incidence of antibody-mediated rejection (AMR) at 90 days and 1 year, incidence of infection, and all-cause mortality at 1 year. RESULTS: A total of 108 patients received BAS, and 26 patients received no induction within the specified timeframe. There was a lower incidence of ACR within the first year in the BAS group compared to the no induction group (27.7 vs. 68.2%, p < .002). BAS was independently associated with a lower probability of having a rejection event during the first 12-months post-transplant (hazard ratio (HR) .285, 95% confidence interval [CI] .142-.571, p < .001). There was no difference in the rate of infection and in mortality after hospital discharge at 1-year post-transplant (6% vs. 0%, p = .20). CONCLUSION: BAS appears to be associated with greater freedom from rejection without an increase in infections. BAS may be a preferred to a no induction strategy in patients undergoing heart transplantation.

Cost-effectiveness of pharmacogenomic-guided treatment for major depression.

BACKGROUND: Pharmacogenomic testing to identify variations in genes that influence metabolism of antidepressant medications can enhance efficacy and reduce adverse effects of pharmacotherapy for major depressive disorder. We sought to establish the cost-effectiveness of implementing pharmacogenomic testing to guide prescription of antidepressants. METHODS: We developed a discrete-time microsimulation model of care pathways for major depressive disorder in British Columbia, Canada, to evaluate the effectiveness and cost-effectiveness of pharmacogenomic testing from the public payer's perspective over 20 years. The model included unique patient characteristics (e.g., metabolizer phenotypes) and used estimates derived from systematic reviews, analyses of administrative data (2015-2020) and expert judgment. We estimated incremental costs, life-years and quality-adjusted life-years (QALYs) for a representative cohort of patients with major depressive disorder in BC. RESULTS: Pharmacogenomic testing, if implemented in BC for adult patients with moderate-severe major depressive disorder, was predicted to save the health system $956 million ($4926 per patient) and bring health gains of 0.064 life-years and 0.381 QALYs per patient (12 436 life-years and 74 023 QALYs overall over 20 yr). These savings were mainly driven by slowing or avoiding the transition to refractory (treatment-resistant) depression. Pharmacogenomic-guided care was associated with 37% fewer patients with refractory depression over 20 years. Sensitivity analyses estimated that costs of pharmacogenomic testing would be offset within about 2 years of implementation. INTERPRETATION: Pharmacogenomic testing to guide antidepressant use was estimated to yield population health gains while substantially reducing health system costs. These findings suggest that pharmacogenomic testing offers health systems an opportunity for a major value-promoting investment.

Taxonomic contributions to Hapalidiales (Corallinophycidae, Rhodophyta): Boreolithothamnion gen. nov., Lithothamnion redefined and with three new species and Roseolithon with new combinations.

Phylogenetic analyses of rbcL gene sequences and of concatenated rbcL, psbA, and nuclear SSU rRNA gene sequences resolved the generitype of Lithothamnion, L. muelleri, in a clade with three other southern Australian species, L. kraftii sp. nov., L. saundersii sp. nov., and L. woelkerlingii sp. nov. Cold water boreal species currently classified in Lithothamnion and whose type specimens have been sequenced are transferred to Boreolithothamnion gen. nov., with B. glaciale comb. nov. as the generitype. The other species are B. giganteum comb. nov., B. phymatodeum comb. nov., and B. sonderi comb. nov., whose type specimens are newly sequenced, and B. lemoineae comb. nov., B. soriferum comb. nov., and B. tophiforme comb. nov., whose type specimens were already sequenced. Based on rbcL sequences from the type specimens of Lithothamnion crispatum, L. indicum, and L. superpositum, each is recognized as a distinct species and transferred to the recently described Roseolithon as R. crispatum comb. nov., R. indicum comb. nov., and R. superpositum com. nov., respectively. To correctly assign species to these three genera based only on morpho-anatomy, specimens must have multiporate conceptacles and some epithallial cells with flared walls. The discussion provides examples demonstrating that only with phylogenetic analyses of DNA sequences can the evolution of morpho-anatomical characters of non-geniculate corallines be understood and applied at the correct taxonomic rank. Finally, phylogenetic analyses of DNA sequences support recognition of the Hapalidiales as a distinct order characterized by having multiporate tetra/bisporangial conceptacles, and not as a suborder of Corallinales whose tetra/bisporangial conceptacles are uniporate.

Outcomes of systemic bivalirudin and sodium bicarbonate purge solution for Impella 5.5.

BACKGROUND: Impella 5.5 (Abiomed; Danvers, MA) (IMP5) is a commonly used, surgically implanted, tMCS device that requires systemic anticoagulation and purge solution to avoid pump failure. To avoid heparin-induced thrombocytopenia (HIT) from unfractionated heparin (UFH) use, our program has explored the utility of bivalirudin (BIV) for systemic anticoagulation and sodium bicarbonate-dextrose purge solution (SBPS) in IMP5.5. METHODS: This single center, retrospective study included 34 patients supported on IMP5.5 with BIV based AC and SBPS between December 1st 2020 to December 1st 2021.The efficacy and safety end points were incidence of development of HIT, Tissue Plasminogen Activator (tPA) use for suspected pump thrombosis, stroke, and device failure as well as clinically significant bleeding. RESULTS: The median duration of IMP5.5 support was 9.8 days (IQR: 6-15). Most patients were bridged to HTX (58%) followed by recovery (27%) and LVAD implantation (15%). Patients were therapeutic on bivalirudin for 64% of their IMP5.5 support. One patient (2.9%) suffered from ischemic stroke and 26.5% (9) patients developed clinically significant bleeding. tPA was administered to 7(21%) patients. One patient in the entire cohort developed HIT. CONCLUSIONS: Our experience supports the use of systemic BIV and SBPS as a method to avoid heparin exposure in a patient population predisposed to the development of HIT.