Germline genetic variants that predispose to myeloproliferative neoplasms and hereditary myeloproliferative phenotypes.

Epidemiological evidence of familial predispositions to myeloid malignancies and myeloproliferative neoplasms (MPN) has long been recognised, but recent studies have added to knowledge of specific germline variants in multiple genes that contribute to the familial risk. These variants may be common risk alleles in the general population but have low penetrance and cause sporadic MPN, such as the JAK2 46/1 haplotype, the variant most strongly associated with MPN. Association studies are increasingly identifying other MPN susceptibility genes such as TERT, MECOM, and SH2B3, while some common variants in DDX41 and RUNX1 appear to lead to a spectrum of myeloid malignancies. RBBP6 and ATM variants have been identified in familial MPN clusters and very rare germline variants such as chromosome 14q duplication cause hereditary MPN with high penetrance. Rarely, there are hereditary non-malignant diseases with an MPN-like phenotype. Knowledge of those genes and germline genetic changes which lead to MPN or diseases that mimic MPN helps to improve accuracy of diagnosis, aids with counselling regarding familial risk, and may contribute to clinical decision-making. Large scale population exome and genome sequencing studies will improve our knowledge of both common and rare germline genetic contributions to MPN.

Long-Term Follow-Up of Non-Paraneoplastic Autoimmune Encephalitis: A Canadian Single-Center Experience.

BACKGROUND: Autoimmune encephalidities (AIE) are becoming an increasingly recognized cause of encephalitis. While diagnosis and acute management are well described, information on long-term management and outcomes is limited. Given this, we reviewed 5 years of AIE patients, reporting on chronic management, relapse incidence and possible relapse predictors. METHODS: We performed a chart review of all patients with non-paraneoplastic AIE presenting to Calgary Neuro-Immunology Clinic and Tom Baker Cancer Centre between 2015 and 2020. Severity of relapse was determined using the Clinical Assessment Scale in Autoimmune Encephalitis (CASE). Variables were assessed with descriptive analysis and/or t-test. RESULTS: Patients were followed for a mean of 38.2 months. Outcome data were assessable in 37/38 patients. Relapse rate ranged from 0% (GFAP) to 67% (NMDA), with a mean of 46%. Most relapses (76%) occurred within 3 years. Time to treatment initiation at relapse was significantly shorter than initial presentation (p = 0.0015), and patients had less severe relapses compared to initial presentation (CASE score 5.18 vs 6.53; p = 0.040).Use of chronic immunotherapy did not appear to impact overall relapse risk, although patients on any immunotherapy at relapse had milder relapses based on ΔCASE (p = 0.0035). CONCLUSION: Relapse was not uncommon (46%) for various AIE subtypes in our cohort, particularly within the first 3 years. Our data enforce the importance of long-term follow-up, which in our study allowed for earlier treatment and less severe relapses compared to initial presentation, as well as the need to further explore which patients would benefit from chronic immunotherapy.

Corrosion and Enhanced Hydrogen Evolution in Electrochemical Reduction of Ammonium Carbamate on Transition Metal Surfaces.

Experiments and theory are combined to search for catalyst activity and stability descriptors for the direct reactive capture and conversion (RCC) of CO2 in ammonia capture solutions using Cu, Ag, Au, Sn, and Ti electrodes. Two major phenomena emerge in RCC that are not predominant in the electrochemical CO2 reduction (CO2R) reaction, namely, the rapid corrosion and restructuring of the catalyst in the presence of the CO2-ammonia adducts and the promotion of the competing hydrogen evolution reaction (HER). The prevalence of HER in RCC is correlated to the electrostatic attraction of the protonated amine to the electrode and the repulsion of the captured CO2, using the potential of zero charge (PZC). The stability of catalysts under RCC conditions is a function of the applied potential and cannot be readily predicted using binding energy descriptors commonly used in the prediction of CO2R activity. A direct correlation between calculated binding energies of CO2R intermediates, atomic oxygen, hydrogen, and ammonia and the activity and stability of transition metals for RCC cannot be found, highlighting the need for descriptors beyond those known for CO2R.

Reactive capture and electrochemical conversion of CO2 with ionic liquids and deep eutectic solvents.

Ionic liquids (ILs) and deep eutectic solvents (DESs) have tremendous potential for reactive capture and conversion (RCC) of CO2 due to their wide electrochemical stability window, low volatility, and high CO2 solubility. There is environmental and economic interest in the direct utilization of the captured CO2 using electrified and modular processes that forgo the thermal- or pressure-swing regeneration steps to concentrate CO2, eliminating the need to compress, transport, or store the gas. The conventional electrochemical conversion of CO2 with aqueous electrolytes presents limited CO2 solubility and high energy requirement to achieve industrially relevant products. Additionally, aqueous systems have competitive hydrogen evolution. In the past decade, there has been significant progress toward the design of ILs and DESs, and their composites to separate CO2 from dilute streams. In parallel, but not necessarily in synergy, there have been studies focused on a few select ILs and DESs for electrochemical reduction of CO2, often diluting them with aqueous or non-aqueous solvents. The resulting electrode-electrolyte interfaces present a complex speciation for RCC. In this review, we describe how the ILs and DESs are tuned for RCC and specifically address the CO2 chemisorption and electroreduction mechanisms. Critical bulk and interfacial properties of ILs and DESs are discussed in the context of RCC, and the potential of these electrolytes are presented through a techno-economic evaluation.

IDH-mutant myeloid neoplasms are associated with seronegative rheumatoid arthritis and innate immune activation.

ABSTRACT: High prevalence of IDH mutations in seronegative rheumatoid arthritis (RA) with myeloid neoplasm, elevated 2-hydroxyglutarate, dysregulated innate immunity, and proinflammatory microenvironment suggests causative association between IDH mutations and seronegative RA. Our findings merit investigation of IDH inhibitors as therapeutics for seronegative IDH-mutated RA.

Importance of Site Diversity and Connectivity in Electrochemical CO Reduction on Cu.

Electrochemical CO2 reduction on Cu is a promising approach to produce value-added chemicals using renewable feedstocks, yet various Cu preparations have led to differences in activity and selectivity toward single and multicarbon products. Here, we find, surprisingly, that the effective catalytic activity toward ethylene improves when there is a larger fraction of less active sites acting as reservoirs of *CO on the surface of Cu nanoparticle electrocatalysts. In an adaptation of chemical transient kinetics to electrocatalysis, we measure the dynamic response of a gas diffusion electrode (GDE) cell when the feed gas is abruptly switched between Ar (inert) and CO. When switching from Ar to CO, CO reduction (COR) begins promptly, but when switching from CO to Ar, COR can be maintained for several seconds (delay time) despite the absence of the CO reactant in the gas phase. A three-site microkinetic model captures the observed dynamic behavior and shows that Cu catalysts exhibiting delay times have a less active *CO reservoir that exhibits fast diffusion to active sites. The observed delay times and the estimated *CO reservoir sizes are affected by catalyst preparation, applied potential, and microenvironment (electrolyte cation identity, electrolyte pH, and CO partial pressure). Notably, we estimate that the *CO reservoir surface coverage can be as high as 88 ± 7% on oxide-derived Cu (OD-Cu) at high overpotentials (-1.52 V vs SHE) and this increases in reservoir coverage coincide with increased turnover frequencies to ethylene. We also estimate that *CO can travel substantial distances (up to 10s of nm) prior to desorption or reaction. It appears that active C-C coupling sites by themselves do not control selectivity to C2+ products in electrochemical COR; the supply of CO to those sites is also a crucial factor. More generally, the overall activity of Cu electrocatalysts cannot be approximated from linear combinations of individual site activities. Future designs must consider the diversity of the catalyst network and account for intersite transportation pathways.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

Atomic Layer Deposition of Cu Electrocatalysts on Gas Diffusion Electrodes for CO2 Reduction.

Electrochemical reduction of CO2 using Cu catalysts enables the synthesis of C2+ products including C2H4 and C2H5OH. In this study, Cu catalysts were fabricated using plasma-enhanced atomic layer deposition (PEALD), achieving conformal deposition of catalysts throughout 3-D gas diffusion electrode (GDE) substrates while maintaining tunable control of Cu nanoparticle size and areal loading. The electrochemical CO2 reduction at the Cu surface yielded a total Faradaic efficiency (FE) > 75% for C2+ products. Parasitic hydrogen evolution was minimized to a FE of ∼10%, and a selectivity of 42.2% FE for C2H4 was demonstrated. Compared to a line-of-sight physical vapor deposition method, PEALD Cu catalysts show significant suppression of C1 products compared to C2+, which is associated with improved control of catalyst morphology and conformality within the porous GDE substrate. Finally, PEALD Cu catalysts demonstrated a stable performance for 15 h with minimal reduction in the C2H4 production rate.

Characteristics of Carpal Tunnel Syndrome in Wild-Type Transthyretin Amyloidosis.

BACKGROUND: Carpal tunnel syndrome (CTS) is one of the most common extra-cardiac manifestations of wild-type transthyretin amyloidosis (wtATTR); however, the characteristics of CTS in this population remain poorly understood. METHODS: This retrospective cohort study reports findings from a single-centre experience of comprehensive neurological screening at the time of wtATTR diagnosis by nerve conduction studies (NCS) and neurologist assessment. RESULTS: Seventy-nine patients underwent neurological screening, 73 (92%) males, mean age 79.2 ± 7.5 years. Seventy-four (94%) had electrodiagnostic findings of median neuropathy at the wrist (MNW), 37 (50%) of which had a prior diagnosis of CTS and 37 (50%) had a new diagnosis of MNW. Over half of wtATTR patients (42, 53%) had bilateral MNW on screening. Most with pre-existing CTS had bilateral disease (28, 76%) and underwent bilateral carpal tunnel release (CTR) (23, 62%) prior to screening. Twenty-one (19%) wrists had mild MNW, 43 (38%) moderate and 49 (43%) severe. Twenty-one (28%) wtATTR patients with MNW were asymptomatic, 10 of which (48%) had moderate disease. Nineteen (36%) wtATTR patients with symptomatic MNW had recurrent disease despite previous CTR. As a result of screening, 36 (68%) patients with symptomatic MNW were referred for CTR. CONCLUSIONS: MNW is exceptionally common at the time of wtATTR diagnosis, affecting 94% of our patients. Most had severe, bilateral MNW on NCS. Some were asymptomatic, despite having moderate disease. The rate of recurrence following CTR was observed to be higher in wtATTR patients than the general population.

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy.

Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

Prognosis of Cardiac Arrest-Peri-arrest and Post-arrest Considerations.

There has been only a small improvement in survival and neurologic outcomes in patients with cardiac arrest in recent decades. Type of arrest, length of total arrest time, and location of arrest alter the trajectory of survival and neurologic outcome. In the post-arrest phase, clinical markers such as blood markers, pupillary light response, corneal reflex, myoclonic jerking, somatosensory evoked potential, and electroencephalography testing can be used to help guide neurological prognostication. Most of the testing should be performed 72 hours post-arrest with special considerations for longer observation periods in patients who underwent TTM or who had prolonged sedation and/or neuromuscular blockade.

TP53 mutation variant allele frequency of ≥10% is associated with poor prognosis in therapy-related myeloid neoplasms.

Revised diagnostic criteria for myeloid neoplasms (MN) issued by the International Consensus Classification (ICC) and the World Health Organization (WHO) recommended major change pertaining to TP53-mutated (TP53mut) MN. However, these assertions have not been specifically examined in therapy-related myeloid neoplasm (t-MN), a subset enriched with TP53mut. We analyzed 488 t-MN patients for TP53mut. At least one TP53mut with variant allele frequency (VAF) ≥ 2% with or without loss of TP53 locus was noted in 182 (37.3%) patients and 88.2% of TP53mut t-MN had a VAF ≥10%. TP53mut t-MN with VAF ≥ 10% had a distinct clinical and biological profile compared to both TP53mut VAF < 10% and wild-type TP53 (TP53wt) cases. Notably, TP53mut VAF ≥ 10% had a significantly shorter survival compared to TP53wt (8.3 vs. 21.6 months; P < 0.001), while the survival of TP53mut VAF < 10% was comparable to TP53wt. Within TP53mut VAF ≥ 10% cohort, the inferior outcomes persisted irrespective of the single- or multi-hit status, co-mutation pattern, or treatments received. Finally, survival of TP53mut patients was poor across all the blast categories and MDS patients with >10% blasts had inferior survival compared to <5%. In summary, TP53mut VAF ≥10% signified a clinically and molecularly homogenous cohort regardless of the allelic status.

Monoclonal Gammopathy of Undetermined Significance in Patients With Transthyretin Amyloidosis (ATTR): Analysis Using the iStopMM Criteria.

INTRODUCTION: To identify the prevalence of monoclonal gammopathy of undetermined significance (MGUS) in patients with transthyretin amyloid (ATTR). We used the iStopMM study revised reference ranges for serum free light-chain (sFLC) corrected for eGFR to identify ATTR patients with light-chain MGUS (LC-MGUS). Characteristics and frequencies of the ATTR cohort with underlying MGUS was compared to a cohort of MGUS patients without ATTR. PATIENTS AND METHODS: A retrospective analysis of ATTR and MGUS patients evaluated at our center between January 2014 to December 2021. A total of 149, predominantly male (87.5%) ATTR patients with a median age of 82 were included. This cohort was compared to 228 MGUS patients. RESULTS: Of the 149 ATTR patients, 27 (18.1%) had coexisting MGUS. Among ATTR patients with MGUS, 12/27 (44%) had LC-MGUS based on sFLC abnormalities assessed using the iStopMM reference ranges. Of the MGUS only cohort, 44/228 (19.3%) met criteria for LC-MGUS. Utilizing the iStopMM reference ranges, 6 ATTR patients did not meet criteria for abnormal sFLCs, uncovering a 20% false-positive rate. CONCLUSION: We noted higher rates of MGUS, particularly LC-MGUS, among ATTR patients when compared to our MGUS only cohort. The high prevalence remained after utilizing the iStopMM sFLC corrected for eGFR reference ranges. Additionally, 6 ATTR patients with renal-dysfunction would have met MGUS criteria if not evaluated using the iStopMM revised measures. These findings emphasize careful interpretation of sFLC abnormalities and encourage providers to keep ATTR on the differential when work-up uncovers sFLC aberrations.

Amyloidosis and Carpal Tunnel Syndrome: Surgical Technique for Extended Carpal Tunnel Release with Tenosynovium and Transverse Carpal Ligament Biopsies.

Carpal tunnel syndrome (CTS) is common in patients with transthyretin amyloidosis (ATTR), and many experience residual symptoms and/or develop recurrent disease following routine carpal tunnel release (CTR). An extended CTR with median nerve neurolysis is recommended for thorough nerve decompression. Tissue confirmation of amyloidosis can be performed at the time of CTR with biopsies of the transverse carpal ligament and/or tenosynovium. Methods: We describe a retrospective, single-center experience performing an extended CTR technique including unilateral and bilateral cases for 13 consecutive patients (18 wrists) with ATTR and symptomatic median neuropathy at the wrist. Results: The mean patient age was 83 (range 67-90) years and 11 (85%) were men. Notable intraoperative findings in all cases included thickened tenosynovium and median nerve epineurium, and adherence of the median nerve to the deep surface of transverse carpal ligament. Pathology findings were positive for amyloidosis from both the transverse carpal ligament and the tenosynovium biopsies in all patients. Conclusions: Extended CTR with simultaneous wrist tissue biopsy can be safely performed for ATTR patients with CTS. Characteristic intraoperative findings should increase clinical suspicion for undiagnosed ATTR and prompt performance of biopsy for diagnostic confirmation. Volar wrist tenosynovial biopsy is our preferred tissue for confirmation of ATTR, for patients with and without CTS, given its safety profile and 100% pathological yield in our series.

Novel modes of MPL activation in triple-negative myeloproliferative neoplasms.

The identification of a somatic mutation associated with myeloid malignancy is of diagnostic importance in myeloproliferative neoplasms (MPNs). Individuals with no mutation detected in common screening tests for variants in JAK2, CALR, and MPL are described as 'triple-negative' and pose a diagnostic challenge if there is no other evidence of a clonal disorder. To identify potential drivers that might explain the clinical phenotype, we used an extended sequencing panel to characterise a cohort of 44 previously diagnosed triple-negative MPN patients for canonical mutations in JAK2, MPL and CALR at low variant allele frequency (found in 4/44 patients), less common variants in the JAK-STAT signalling pathway (12 patients), or other variants in recurrently mutated genes from myeloid malignancies (18 patients), including hotspot variants of potential clinical relevance in eight patients. In one patient with thrombocytosis we identified biallelic germline MPL variants. Neither MPL variant was activating in cell proliferation assays, and one of the variants was not expressed on the cell surface, yet co-expression of both variants led to thrombopoietin hypersensitivity. Our results highlight the clinical value of extended sequencing including germline variant analysis and illustrate the need for detailed functional assays to determine whether rare variants in JAK2 or MPL are pathogenic.

Allogeneic hematopoietic stem cell transplant outcomes in adults with inherited myeloid malignancies.

There is increasing recognition that pathogenic germ line variants drive the development of hematopoietic cancers in many individuals. Currently, patients with hereditary hematologic malignancies (HHMs) receive similar standard therapies and hematopoietic stem cell transplant (HSCT) approaches as those with sporadic disease. We hypothesize that patients with myeloid malignancies and deleterious germ line predisposition variants have different posttransplant outcomes than those without such alleles. We studied 472 patients with myeloid neoplasms, of whom 26% had deleterious germ line variants and 34% underwent HSCT. Deleterious germ line variants in CHEK2 and DDX41 were most commonly seen in American and Australian cohorts, respectively. Patients with deleterious germ line DDX41 variants had a higher incidence of severe (stage 3-4) acute graft-versus-host disease (GVHD) (38%) than recipients with deleterious CHEK2 variants (0%), other HHM variants (12%), or patients without such germ line variants (9%) (P = .002). Importantly, the use of posttransplant cyclophosphamide reduced the risk of severe acute GVHD in patients receiving HSCT for deleterious germ line DDX41-associated myeloid neoplasms (0% vs 53%, P = .03). Based on these results, we advocate the use of posttransplant cyclophosphamide when individuals with deleterious germ line DDX41 variants undergo allogeneic HSCT for myeloid malignancies, even when transplantation has been performed using wild-type donors.