Suppression of Richtmyer-Meshkov Instability via Special Pairs of Shocks and Phase Transitions.

The classical Richtmyer-Meshkov instability (RMI) is a hydrodynamic instability characterizing the evolution of an interface following shock loading. In contrast to other hydrodynamic instabilities such as Rayleigh-Taylor, it is known for being unconditionally unstable: regardless of the direction of shock passage, any deviations from a flat interface will be amplified. In this article, we show that for negative Atwood numbers, there exist special sequences of shocks which result in a nearly perfectly suppressed instability growth. We demonstrate this principle computationally and experimentally with stepped fliers and phase transition materials. A fascinating immediate corollary is that in specific instances, a phase-transitioning material may self-suppress RMI.

A multi-centre retrospective study of Nocardia speciation and antimicrobial susceptibility in Queensland, Australia.

The study aims to characterise the species identification and antimicrobial susceptibility testing (AST) results of Nocardial isolates from adult patients across major public hospitals in Queensland, Australia, over a 15-year period. A multi-centre retrospective observational study of Nocardia sp. isolates was conducted from 7 major public hospitals in Queensland, Australia, over a 15-year period. Clinical samples from patients aged ≥ 18 years that isolated Nocardia sp. were included. Demographic and clinical data were collected, along with species identification and AST results. Overall, 484 Nocardia sp. were isolated. Most patients were male (297, 61%) with a mean (IQR) age of 60 (51-75) and a median (IQR) Charlson Comorbidity Index of 4 (2-6). Of these, 239 (49%) patients were immunosuppressed. Organisms were most frequently isolated from sputum (174, 36%), and superficial swabs (102, 21%). Patients presented with pulmonary infections (165, 35%) and superficial skin and soft tissue infections (87, 18%) most commonly. One hundred (21%) isolates were deemed pulmonary colonisation and were not treated. Of the speciated organisms, N. nova complex was the most common (93, 19%), followed by N. farcinica complex (79, 16%). Organisms were reliably susceptible to linezolid (240/245, 98%), amikacin (455/470, 97%), and trimethoprim/sulfamethoxazole (459/476, 96%), but less so to imipenem (243/472, 51%) and ceftriaxone (261/448, 58%). This is the largest Australian description of Nocardia sp. to date. Given antimicrobials are often commenced prior to AST results and sometimes even speciation, characterisation of local species and antibiogram data is important to guide empiric choices and local guidelines.

MIF is a common genetic determinant of COVID-19 symptomatic infection and severity.

BACKGROUND: Genetic predisposition to coronavirus disease 2019 (COVID-19) may contribute to its morbidity and mortality. Because cytokines play an important role in multiple phases of infection, we examined whether commonly occurring, functional polymorphisms in macrophage migration inhibitory factor (MIF) are associated with COVID-19 infection or disease severity. AIM: To determine associations of common functional polymorphisms in MIF with symptomatic COVID-19 or its severity. METHODS: This retrospective case-control study utilized 1171 patients with COVID-19 from three tertiary medical centers in the USA, Hungary and Spain, together with a group of 637 pre-pandemic, healthy control subjects. Functional MIF promoter alleles (-794 CATT5-8,rs5844572), serum MIF and soluble MIF receptor levels, and available clinical characteristics were measured and correlated with COVID-19 diagnosis and hospitalization. Experimental mice genetically engineered to express human high- or low-expression MIF alleles were studied for response to coronavirus infection. RESULTS: In patients with COVID-19, there was a lower frequency of the high-expression MIF CATT7 allele when compared to healthy controls [11% vs. 19%, odds ratio (OR) 0.54 [0.41-0.72], P < 0.0001]. Among inpatients with COVID-19 (n = 805), there was a higher frequency of the MIF CATT7 allele compared to outpatients (n = 187) (12% vs. 5%, OR 2.87 [1.42-5.78], P = 0.002). Inpatients presented with higher serum MIF levels when compared to outpatients or uninfected healthy controls (87 ng/ml vs. 35 ng/ml vs. 29 ng/ml, P < 0.001, respectively). Among inpatients, circulating MIF concentrations correlated with admission ferritin (r = 0.19, P = 0.01) and maximum CRP (r = 0.16, P = 0.03) levels. Mice with a human high-expression MIF allele showed more severe disease than those with a low-expression MIF allele. CONCLUSIONS: In this multinational retrospective study of 1171 subjects with COVID-19, the commonly occurring -794 CATT7MIF allele is associated with reduced susceptibility to symptomatic SARS-CoV-2 infection but increased disease progression as assessed by hospitalization. These findings affirm the importance of the high-expression CATT7MIF allele, which occurs in 19% of the population, in different stages of COVID-19 infection.

Outcomes of normothermic machine perfusion of liver grafts in repeat liver transplantation (NAPLES initiative).

BACKGROUND: Retransplantation candidates are disadvantaged owing to lack of good-quality liver grafts. Strategies that can facilitate transplantation of suboptimal grafts into retransplant candidates require investigation. The aim was to determine whether late liver retransplantation can be performed safely with suboptimal grafts, following normothermic machine perfusion. METHODS: A prospectively enrolled group of patients who required liver retransplantation received a suboptimal graft preserved via normothermic machine perfusion. This group was compared with both historical and contemporaneous cohorts of patient who received grafts preserved by cold storage. The primary outcome was 6-month graft and patient survival. RESULTS: The normothermic machine perfusion group comprised 26 patients. The historical (cold storage 1) and contemporaneous (cold storage 2) groups comprised 31 and 25 patients respectively. The 6-month graft survival rate did not differ between groups (cold storage 1, 27 of 31, cold storage 2, 22 of 25; normothermic machine perfusion, 22 of 26; P = 0.934). This was despite the normothermic machine perfusion group having significantly more steatotic grafts (8 of 31, 7 of 25, and 14 of 26 respectively; P = 0.006) and grafts previously declined by at least one other transplant centre (5 of 31, 9 of 25, and 21 of 26; P < 0.001). CONCLUSION: In liver retransplantation, normothermic machine perfusion can safely expand graft options without compromising short-term outcomes.

Liver transplantation is a life-saving procedure for many different diseases. In the UK, one in 10 patients awaiting transplant have had a previous liver transplant. These retransplant operations are complex, and the general belief is that a good-quality donor liver graft is required for best outcomes. However, there is a significant shortage of good-quality organs for liver transplantation, so many patients awaiting retransplantation spend longer on the waiting list. This study investigated whether a new technology, called normothermic machine perfusion, could be used to preserve lower-quality donor livers and have successful outcomes for patients undergoing retransplantation. Traditionally, good-quality livers are preserved in an ice box and the study compared the outcomes of these two different approaches. The aim was to prove that normothermic machine perfusion improves access to transplantation for this group of patients, without compromising outcomes. A group of patients who underwent retransplantation and received a lesser-quality liver preserved with normothermic machine perfusion was compared with two groups of patients who had received a transplant with traditional ice-box preservation. The complications, graft, and patient survival of the former group was compared with those in the latter two groups who underwent liver retransplantation with better-quality liver grafts. The rate of survival and adverse surgical outcomes were comparable between the groups of patients who received a liver preserved via traditional ice-box preservation, and those who received a lesser-quality liver preserved via normothermic machine perfusion. Normothermic machine perfusion can potentially expand the number of suitable donor livers available for retransplant candidates.

The inconsistency and instability of Parkinson's disease motor subtypes.

INTRODUCTION: Tremor-dominant (TD), indeterminate/mixed (ID/M) and postural instability gait difficulty/akinetic-rigid (PIGD/AR) are commonly used subtypes to categorize Parkinson's disease (PD) patients based on their most prominent motor signs. Three different algorithms to determine these motor subtypes are used. Here, we examined if PD subtypes are consistent among algorithms and if subtype stability over time depends on the applied algorithm. METHODS: Using a large longitudinal PD database, we applied 3 published algorithms of PD motor subtype classification in two sets of analyses: 1) cross-sectional analysis in 1185 patients, determining the prevalence of subtypes in 5-year intervals of disease duration; 2) longitudinal analysis of 178 patients, comparing subtypes of individual patients at baseline (within 5 years of diagnosis) and at follow-up ≥ 5 years after baseline. RESULTS: Cross-sectionally, prevalence of subtypes varied widely among the 3 algorithms: 5-32% TD, 9-31% ID/M, and 59-75% PIGD/AR. For all 3 algorithms, cross-sectional analysis showed a marked decline of TD prevalence with disease duration and a corresponding increase in PIGD/AR prevalence, driven by increasing gait/balance scores over time. Longitudinally, only 15-36% of baseline TD patients were still categorized as TD at 6.2 ± 1.0 years of follow-up. In 15-39% of baseline TD patients, the subtype changed to ID/M, and 46-50% changed to PIGD/AR. This shift was observed using all 3 algorithms. CONCLUSION: PD motor subtypes determined by different established algorithms are inconsistent and unstable over time. Lack of subtype fidelity should be considered when interpreting biomarker-subtype correlation and highlights the need for better definition of PD subtypes.

Novel Mechanisms of Ozone-Induced Pulmonary Inflammation and Resolution, and the Potential Protective Role of Scavenger Receptor BI.

INTRODUCTION: Increases in ambient levels of ozone (O3), a criteria air pollutant, have been associated with increased susceptibility and exacerbations of chronic pulmonary diseases through lung injury and inflammation. O3 induces pulmonary inflammation, in part by generating damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and scavenger receptors (SRs). This inflammatory response is mediated in part by alveolar macrophages (AMs), which highly express PRRs, including scavenger receptor BI (SR-BI). Once pulmonary inflammation has been induced, an active process of resolution occurs in order to prevent secondary necrosis and to restore tissue homeostasis. The processes known to promote the resolution of inflammation include the clearance by macrophages of apoptotic cells, known as efferocytosis, and the production of specialized pro-resolving mediators (SPMs). Impaired efferocytosis and production of SPMs have been associated with the pathogenesis of chronic lung diseases; however, these impairments have yet to be linked with exposure to air pollutants. SPECIFIC AIMS: The primary goals of this study were: Aim 1 - to define the role of SR-BI in O3-derived pulmonary inflammation and resolution of injury; and Aim 2 - to determine if O3 exposure alters pulmonary production of SPMs and processes known to promote the resolution of pulmonary inflammation and injury. METHODS: To address Aim 1, female wild-type (WT) and SR-BI-deficient, or knock-out (SR-BI KO), mice were exposed to either O3 or filtered air. In one set of experiments mice were instilled with an oxidized phospholipid (oxPL). Bronchoalveolar lavage fluid (BALF) and lung tissue were collected for the analyses of inflammatory and injury markers and oxPL. To estimate efferocytosis, mice were administered apoptotic cells (derived from the Jurkat T cell line) after O3 or filtered air exposure.To address Aim 2, male WT mice were exposed to either O3 or filtered air, and levels of SPMs were assessed in the lung, as well as markers of inflammation and injury in BALF. In some experiments SPMs were administered before exposure to O3or filtered air, to determine whether SPMs could mitigate inflammatory or resolution responses. Efferocytosis was measured as in Aim 1. RESULTS: For Aim 1, SR-BI protein levels increased in the lung tissue of mice exposed to O3, compared with mice exposed to filtered air. Compared with WT controls, SR-BI KO mice had a significant increase in the number of neutrophils in their airspace 24 hours post O3 exposure. The oxPL levels increased in the airspace of both WT and SR-BI KO mice after O3 exposure, compared with filtered air controls. Four hours after instillation of an oxPL, SR-BI KO mice had an increase in BALF neutrophils and total protein, and a nonsignificant increase in macrophages compared with WT controls. O3 exposure decreased efferocytosis in both WT and SR-BI KO female mice.For Aim 2, mice given SPM supplementation before O3 exposure showed significantly increased AM efferocytosis when compared with the O3exposure control mice and also showed some mitigation of the effects of O3 on inflammation and injury. Several SPMs and their precursors were measured in lung tissue using reverse-phase high performance liquid chromatography (HPLC) with tandem mass spectrometry (MS/MS). At 24 hours after O3 exposure 14R-hydroxydocosahexaenoic acid (HDHA) and 10,17-dihydroxydocosahexaenoic acid (diHDoHE) were significantly decreased in lung tissue, but at 6 hours after exposure, levels of these SPMs increased. CONCLUSIONS: Our findings identify novel mechanisms by which O3 may induce pulmonary inflammation and also increase susceptibility to and exacerbations of chronic lung diseases.

Severe Sepsis Mimicking Primary Nonfunction Following Liver Transplantation: Normothermic Machine Perfusion Is a Potential Environment for Bacterial Overgrowth and Transmission From Donor to Recipient. A Case Report.

Primary nonfunction (PNF) in the early postoperative period following liver transplantation is fatal if not managed appropriately with early retransplantation. Severe early allograft dysfunction can mimic PNF. The identification of treatable causative factors such as sepsis, hepatic artery, or portal vein thrombosis is essential to distinguish it from PNF, and their early management may avoid the need for retransplantation. In this article, we describe a case of sepsis-induced severe liver dysfunction from a contaminated graft perfused with normothermic machine perfusion (NMP), which presented in a manner similar to PNF. The implications of graft contamination are poorly described. To our knowledge, this is the first report of bacterial contamination of a graft that underwent NMP and subsequently caused severe sepsis in the recipient. The conditions created with NMP may be optimal for certain micro-organisms to thrive. The role of the liver in the immune system is complex as it provides an essential barrier to enterically derived portal venous pathogens and produces numerous acute phase proteins that augment the systemic immune response. Additionally, the liver is also known to restrain harmful and excessive systemic immune responses such as those that occur with the sepsis syndrome. The relationship between bacterial graft contamination, sepsis, and graft dysfunction may be multidirectional.

Burkholderia pseudomallei multi-centre study to establish EUCAST MIC and zone diameter distributions and epidemiological cut-off values.

OBJECTIVES: Melioidosis, caused by Burkholderia pseudomallei, requires intensive antimicrobial treatment. However, standardized antimicrobial susceptibility testing (AST) methodology based on modern principles for determining breakpoints and ascertaining performance of methods are lacking for B. pseudomallei. This study aimed to establish MIC and zone diameter distributions on which to set epidemiological cut-off (ECOFF) values for B. pseudomallei using standard EUCAST methodology for non-fastidious organisms. METHODS: Non-consecutive, non-duplicate clinical B. pseudomallei isolates (9-70 per centre) were tested at eight study centres against eight antimicrobials by broth microdilution (BMD) and the EUCAST disc diffusion method. Isolates without and with suspected resistance mechanisms were deliberately selected. The EUCAST Development Laboratory ensured the quality of study materials, and provided guidance on performance of the tests and interpretation of results. Aggregated results were analysed according to EUCAST recommendations to determine ECOFFs. RESULTS: MIC and zone diameter distributions were generated using BMD and disc diffusion results obtained for 361 B. pseudomallei isolates. MIC and zone diameter ECOFFs (mg/L; mm) were determined for amoxicillin-clavulanic acid (8; 22), ceftazidime (8; 22), imipenem (2; 29), meropenem (2; 26), doxycycline (2; none), tetracycline (8; 23), chloramphenicol (8; 22) and trimethoprim-sulfamethoxazole (4; 28). CONCLUSIONS: We have validated the use of standard BMD and disc diffusion methodology for AST of B. pseudomallei. The MIC and zone diameter distributions generated in this study allowed us to establish MIC and zone diameter ECOFFs for the antimicrobials studied. These ECOFFs served as background data for EUCAST to set clinical MIC and zone diameter breakpoints for B. pseudomallei.

Outcome analysis of patients with Peyronie's disease who elect for vacuum erection device therapy.

INTRODUCTION: Peyronie's disease (PD) affects approximately 0.7-11% of men and has numerous proposed treatments. Invasive management options include surgical or injectable therapy, while penile traction therapy with vacuum erection device (VED) represents a non-invasive approach. Our objective is to assess outcomes for patients with PD who opt for non-invasive management. METHODS: We performed a retrospective analysis for patients with PD who were followed for at least three months and opted for noninvasive therapy. All patients were instructed to initiate VED traction therapy for 10 minutes twice per day. Patients were assessed for degree of PD deformity and erectile function (Sexual Health Inventory for Men [SHIM] score) at initial and subsequent encounters. RESULTS: Fifty-three patients met the inclusion criteria. The mean (standard deviation [SD]) age was 57 (12) years, and the mean (SD) duration of PD prior to assessment was 25 (15) months. The mean (SD) duration of followup was 14 (11) months. Among untreated patients who did not use a VED, nine showed improvement, 20 remained stable, and four had worsening curvature. The untreated group had a significant change in curvature, with a mean improvement (SD) of 3.6 (12)° (p=0.048). All 20 men who initiated VED traction therapy had an improvement in curvature with a significant mean (SD) improvement of 23 (16)° (p=2.6×10-6). Changes in SHIM scores did vary significantly between groups. No complications were noted. CONCLUSIONS: In patients who opt for non-invasive management of PD, VED traction therapy provides improved curvature resolution compared to those who do not use such a device. The limitations of this study include the retrospective nature and a small sample size at a single treatment center.

Human Melioidosis.

The causative agent of melioidosis, Burkholderia pseudomallei, a tier 1 select agent, is endemic in Southeast Asia and northern Australia, with increased incidence associated with high levels of rainfall. Increasing reports of this condition have occurred worldwide, with estimates of up to 165,000 cases and 89,000 deaths per year. The ecological niche of the organism has yet to be clearly defined, although the organism is associated with soil and water. The culture of appropriate clinical material remains the mainstay of laboratory diagnosis. Identification is best done by phenotypic methods, although mass spectrometric methods have been described. Serology has a limited diagnostic role. Direct molecular and antigen detection methods have limited availability and sensitivity. Clinical presentations of melioidosis range from acute bacteremic pneumonia to disseminated visceral abscesses and localized infections. Transmission is by direct inoculation, inhalation, or ingestion. Risk factors for melioidosis include male sex, diabetes mellitus, alcohol abuse, and immunosuppression. The organism is well adapted to intracellular survival, with numerous virulence mechanisms. Immunity likely requires innate and adaptive responses. The principles of management of this condition are drainage and debridement of infected material and appropriate antimicrobial therapy. Global mortality rates vary between 9% and 70%. Research into vaccine development is ongoing.

Assessment of C-DBP and N-DBP formation potential and its reduction by MIEX® DOC and MIEX® GOLD resins using fluorescence spectroscopy and parallel factor analysis.

This study investigated the applicability of parallel factor analysis (PARAFAC) of fluorescence excitation-emission matrices (EEM) spectra to assess the formation potentials (FP) of carbonaceous and nitrogenous disinfection byproducts (C-DBP and N-DBP) and the FP reduction by the magnetic ion exchange resins, MIEX® DOC and MIEX® GOLD. Two source waters of different nature - a surface water and a secondary treated wastewater effluent - were studied. The samples were analyzed for formation potentials of trihalomethanes (THM4), haloacetonitriles (HAN4), haloketones (HK2), and chloropicrin (CPN). A 4-component PARAFAC model was developed from 150 EEM samples generated from the raw source waters and their treatment with MIEX® resins. Components C1, C2, and C3 corresponded to humic-like dissolved organic matter (DOM) while C4 corresponded to protein-like DOM. Both MIEX® resins preferentially removed components C1, C2, and C3 over C4, indicating affinity with humic materials. MIEX® resins were shown to be more effective to treat surface water than secondary effluent, including effective removal of DBP precursors with extended bed volume treatment. Among all parameters investigated, THM4-FP strongly correlated with humic-like component C3, while HAN4-FP strongly correlated with protein-like component C4 (ρ > 0.89 and p < 0.01); CPN-FP and HK2-FP both correlated with anthropogenic DOM C2 (ρ > 0.89 and p < 0.01). Our results indicate that EEM-PARAFAC was valuable for assessing DBP formation potentials and removal of their precursors by MIEX® resins in different water sources.

Peculiarities of Cirrhosis due to Nonalcoholic Steatohepatitis (NASH).

The prevalence of cirrhosis due to nonalcoholic steatohepatitis (NASH) has increased 2.5-fold in the United States in the last decade. These patients pose new challenges to hepatologists given their older age and higher frequency of coexisting metabolic diseases such as obesity and diabetes compared with other etiologies of liver disease. Patients with NASH cirrhosis are at higher risk for renal and cardiovascular disease, and the presence of these extrahepatic comorbidities has a significant impact on outcomes and survival. This review outlines how NASH cirrhosis differs from other etiologies of cirrhosis including natural history, noninvasive assessment, and the challenges in the management of the complications of cirrhosis including hepatic encephalopathy and hepatocellular carcinoma. Nutritional assessment and the impact of sarcopenic obesity and frailty in this population, and strategies to address the latter, are discussed. This review also addresses liver transplantation in patients with NASH cirrhosis in relation to assessment and posttransplant care.

Fluorescence spectroscopy for assessing trihalomethane precursors removal by MIEX resin.

This study investigated the applicability of fluorescence excitation-emission matrix spectroscopy (EEMS) to assess total trihalomethane formation potentials (TTHMFPs) and the ability of magnetic ion exchange (MIEX®) resin to reduce TTHMFP. We treated a surface water and secondary wastewater effluent with MIEX mimicking full-scale operation by repeatedly exposing the same resin batch to additional feed water, with batches ranging from 500 to 5,000 resin bed volumes. Results showed that MIEX was more effective at removing or reducing ultraviolet absorbance (UVA254), dissolved organic carbon (DOC), and TTHMFP in surface water than in secondary effluent. The greater UVA254, DOC and TTHMFP removal for surface waters was explained by the stronger affinity of MIEX for terrestrial dissolved organic matter (DOM) compared to microbial DOM. Fluorescence EEMS results showed that the ratio between terrestrial and microbial fluorescent signals of DOM was significantly greater in surface water than in secondary effluent. Fluorescence surrogate parameters were strongly correlated with TTHMFP, namely, fluorescence intensity of humic-like peak C (R2 = 0.98, p < 0.01), protein-like peak T (R2 = 0.96, p < 0.01), and fulvic-like peak A (R2 = 0.87, p < 0.01). Correlations between fluorescence surrogate parameters and TTHMFP were substantially stronger than correlations between DOC and TTHMFP. Overall, the results indicate that fluorescent parameters extracted from EEMS data can be used as quick surrogate parameters to monitor TTHMFP for a diverse group of raw and MIEX-treated waters.

Identification of Burkholderia pseudomallei by Use of the Vitek Mass Spectrometer.

Burkholderia pseudomallei is the causative agent of melioidosis. This condition most often presents as pneumonia and bacteremia, with mortality rates of 9% to 70%. Therefore, early identification of this organism may aid in directing appropriate management. This study aimed to use the Vitek matrix-assisted laser desorption ionization-time of flight mass spectrometer to create a spectrum for the rapid identification of B. pseudomallei Spectra from 85 isolate cultures were acquired using the Vitek mass spectrometer research mode. A SuperSpectrum was created using peak matching and subsequently activated for analysis of organism identification. All 85 isolates were correctly identified as B. pseudomallei A total of 899 spectra were analyzed and demonstrated a specificity of 99.8%. Eighty-one clinical isolates were used, of which 10 were neuromelioidosis, and no discernible spectrum difference was appreciated. Spectrum acquisition from a single spot was only successful in 374/899 (41%) of isolates. This increased to 100% when 3 spots of the same extract were analyzed. The Vitek mass spectrometer can be used for the rapid identification of B. pseudomallei with a high level of specificity.

Effects of Percutaneous LVAD Support on Right Ventricular Load and Adaptation.

Both operative and hemodynamic mechanisms have been implicated in right heart failure (RHF) following surgical left ventricular assist device (LVAD) implantation. We investigated the effects of percutaneous LVAD (pLVAD; Impella®, Abiomed) support on right ventricular (RV) load and adaptation. We reviewed all patients receiving a pLVAD for cardiogenic shock at our institution between July 2014 and April 2017, including only those with pre- and post-pLVAD invasive hemodynamic measurements. Hemodynamic data was recorded immediately prior to pLVAD implantation and up to 96 h post-implantation. Twenty-five patients were included. Cardiac output increased progressively during pLVAD support. PAWP improved early post-pLVAD but did not further improve during continued support. Markers of RV adaptation (right ventricular stroke work index, right atrial pressure (RAP), and RAP to pulmonary artery wedge pressure ratio (RAP:PAWP)) were unchanged acutely implant but progressively improved during continued pLVAD support. Total RV load (pulmonary effective arterial elastance; EA) and resistive RV load (pulmonary vascular resistance; PVR) both declined progressively. The relationship between RV load and RV adaptation (EA/RAP and EA/RAP:PAWP) was constant throughout. Median vasoactive-inotrope score declined after pLVAD placement and continued to decline throughout support. Percutaneous LVAD support in patients with cardiogenic shock did not acutely worsen RV adaptation, in contrast to previously described hemodynamic effects of surgically implanted durable LVADs. Further, RV load progressively declined during support, and the noted RV adaptation improvement was load-dependent as depicted by constant EA/RA and EA/RAP:PAWP relationships. These findings further implicate the operative changes associated with surgical LVAD implantation in early RHF following durable LVAD.

Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis.

BACKGROUND/INTRODUCTION: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. AIM: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. DESIGN: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. METHODS: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. RESULTS: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-ß and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. DISCUSSION/CONCLUSION: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker.