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1.
Can J Neurol Sci ; : 1-9, 2020 Dec 21.
Artigo em Inglês | MEDLINE | ID: mdl-33342448

RESUMO

BACKGROUND: Wild-type transthyretin amyloidosis (wtATTR) is an important cause of heart failure (HF); however, the prevalence and clinical significance of neurologic complications remains uncertain. METHODS: This analysis reports findings from a single-centre experience of routine neuropathy screening at the time of wtATTR diagnosis by nerve conduction studies and neurologist assessment, compared with age-matched controls. RESULTS: Forty-one wtATTR patients were included, 39 (95%) males, mean age 78.4 ± 7.7 years, 22 (54%) New York Heart Association (NYHA) class III-IV HF, along with 15 age-matched controls (mean age 77.1 ± 4.2 years, 80% male). Twenty-one (51%) wtATTR patients were diagnosed with polyneuropathy, 15 (37%) with spinal stenosis, 36 (88%) with carpal tunnel syndrome (CTS) and 14 (34%) with ulnar neuropathy. Comparison diagnoses among controls were 1 (7%), 0, 1 (7%) and 3 (20%), respectively. Among patients with NYHA class III-IV HF, 16 (73%) had polyneuropathy compared with 5 (26%) with class I-II (p < 0.01), odds ratio of 7.5 (95% confidence interval 1.9-29.9). After neuropathy screening, 19 (46%) patients were offered neurologic therapy and/or additional diagnostic evaluation. This included CTS release surgery (16, 39%), neuropathic pain medication (3, 7%), nerve block (1, 2%), wrist splinting (2, 5%) and foot care (1, 2%). Spine imaging was performed for 3 (7%) patients, and deltoid muscle and sural nerve biopsy for 1 (2%) patient. CONCLUSIONS: Screening of wtATTR patients for neurologic complications resulted in a management change for nearly half. CTS, polyneuropathy and ulnar neuropathy were common. This approach warrants consideration as part of routine assessment for newly diagnosed wtATTR patients.

2.
J Am Chem Soc ; 2020 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-33382947

RESUMO

The electrochemical CO2 reduction reaction (CO2RR) using Cu-based catalysts holds great potential for producing valuable multi-carbon products from renewable energy. However, the chemical and structural state of Cu catalyst surfaces during the CO2RR remains a matter of debate. Here, we show the structural evolution of the near-surface region of polycrystalline Cu electrodes under in situ conditions through a combination of grazing incidence X-ray absorption spectroscopy (GIXAS) and X-ray diffraction (GIXRD). The in situ GIXAS reveals that the surface oxide layer is fully reduced to metallic Cu before the onset potential for CO2RR, and the catalyst maintains the metallic state across the potentials relevant to the CO2RR. We also find a preferential surface reconstruction of the polycrystalline Cu surface toward (100) facets in the presence of CO2. Quantitative analysis of the reconstruction profiles reveals that the degree of reconstruction increases with increasingly negative applied potentials, and it persists when the applied potential returns to more positive values. These findings show that the surface of Cu electrocatalysts is dynamic during the CO2RR, and emphasize the importance of in situ characterization to understand the surface structure and its role in electrocatalysis.

3.
Cureus ; 12(9): e10219, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-33042664

RESUMO

Hepatic portal venous gas (HPVG) has long been associated with catastrophic intraabdominal conditions. Advancements in ultrasound (US) and computed tomography (CT) imaging have resulted in an increased number of incidental and clinically benign HPVG cases identified. Causes of clinically benign HPVG include viral gastroenteritis, gastritis, pancreatitis, appendicitis and diverticulitis. Our case demonstrates the first reported case of HPVG in an adolescent patient associated with enteropathogenic E. coli (EPEC). The patient's course was favorable, marked by a short stay in the pediatric intensive care unit (ICU) and did not require surgical intervention. With higher sensitivity of imaging modalities to diagnose both suspected and incidental cases of HPVG, clinicians will be required to consider the risks and benefits of conservative treatment or surgical intervention.

5.
J Neuroimmunol ; 346: 577326, 2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32683185

RESUMO

The mechanisms for neurological complications of COVID-19, the disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), are not yet well understood. We present a critically ill man with a COVID-19-associated hemorrhagic encephalopathy. SARS-CoV-2 RNA was not detected in cerebrospinal fluid (CSF) or blood. CSF analyses suggested dysregulation of pro-inflammatory cytokine pathways, particularly tumor necrosis factor-α and interleukin-6, consistent with a cytokine release syndrome. The patient gradually recovered with supportive care and neurological rehabilitation. Awareness of this clinical entity may facilitate the identification of patients with a potentially remediable cause of encephalopathy in COVID-19.

6.
JAMA Psychiatry ; 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32697288

RESUMO

Importance: Childhood abuse significantly increases the risk of developing posttraumatic stress disorder (PTSD), often accompanied by symptoms of borderline personality disorder (BPD) and other co-occurring mental disorders. Despite the high prevalence, systematic evaluations of evidence-based treatments for PTSD after childhood abuse are sparse. Objective: To compare the efficacy of dialectical behavior therapy for PTSD (DBT-PTSD), a new, specifically designed, phase-based treatment program, against that of cognitive processing therapy (CPT), one of the best empirically supported treatments for PTSD. Design, Setting, and Participants: From January 2014 to October 2016, women who sought treatment were included in a multicenter randomized clinical trial with blinded outcome assessments at 3 German university outpatient clinics. The participants were prospectively observed for 15 months. Women with childhood abuse-associated PTSD who additionally met 3 or more DSM-5 criteria for BPD, including affective instability, were included. Data analysis took place from October 2018 to December 2019. Interventions: Participants received equal dosages and frequencies of DBT-PTSD or CPT, up to 45 individual sessions within 1 year and 3 additional sessions during the following 3 months. Main Outcomes and Measures: The predefined primary outcome was the course of the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) score from randomization to month 15. Intent-to-treat analyses based on dimensional CAPS-5 scores were complemented by categorical outcome measures assessing symptomatic remission, reliable improvement, and reliable recovery. Results: Of 955 consecutive individuals assessed for eligibility, 193 were randomized (DBT-PTSD, 98; CPT, 95; mean [SD] age, 36.3 [11.1] years) and included in the intent-to-treat analyses. Analysis revealed significantly improved CAPS-5 scores in both groups (effect sizes: DBT-PTSD: d, 1.35; CPT: d, 0.98) and a small but statistically significant superiority of DBT-PTSD (group difference: 4.82 [95% CI, 0.67-8.96]; P = .02; d, 0.33). Compared with the CPT group, participants in the DBT-PTSD group were less likely to drop out early (37 [39.0%] vs 25 [25.5%]; P = .046) and had higher rates of symptomatic remission (35 [40.7%] vs 52 [58.4%]; P = .02), reliable improvement (53 [55.8%] vs 73 [74.5%]; P = .006), and reliable recovery (34 [38.6%] vs 52 [57.1%]; P = .01). Conclusions and Relevance: These findings support the efficacy of DBT-PTSD and CPT in the treatment of women with childhood abuse-associated complex PTSD. Results pertaining to the primary outcomes favored DBT-PTSD. The study shows that even severe childhood abuse-associated PTSD with emotion dysregulation can be treated efficaciously. Trial Registration: German Clinical Trials Register: DRKS00005578.

9.
Blood ; 136(1): 24-35, 2020 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-32430494

RESUMO

Recognition that germline mutations can predispose individuals to blood cancers, often presenting as secondary leukemias, has largely been driven in the last 20 years by studies of families with inherited mutations in the myeloid transcription factors (TFs) RUNX1, GATA2, and CEBPA. As a result, in 2016, classification of myeloid neoplasms with germline predisposition for each of these and other genes was added to the World Health Organization guidelines. The incidence of germline mutation carriers in the general population or in various clinically presenting patient groups remains poorly defined for reasons including that somatic mutations in these genes are common in blood cancers, and our ability to distinguish germline (inherited or de novo) and somatic mutations is often limited by the laboratory analyses. Knowledge of the regulation of these TFs and their mutant alleles, their interaction with other genes and proteins and the environment, and how these alter the clinical presentation of patients and their leukemias is also incomplete. Outstanding questions that remain for patients with these germline mutations or their treating clinicians include: What is the natural course of the disease? What other symptoms may I develop and when? Can you predict them? Can I prevent them? and What is the best treatment? The resolution of many of the remaining clinical and biological questions and effective evidence-based treatment of patients with these inherited mutations will depend on worldwide partnerships among patients, clinicians, diagnosticians, and researchers to aggregate sufficient longitudinal clinical and laboratory data and integrate these data with model systems.

10.
Can J Neurol Sci ; 47(3): 382-388, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32228724

RESUMO

BACKGROUND: Flow cytometry of the cerebrospinal fluid (CSF) is used in isolation or as an adjunct to cytology to increase the sensitivity of detecting central nervous system (CNS) lymphoma. We aimed to evaluate the sensitivity of CSF flow cytometry as a diagnostic screening tool for primary CNS lymphoma in patients presenting with undifferentiated neurologic symptoms. METHODS: We retrospectively reviewed all CSF samples received by the Calgary Laboratory Services Flow Cytometry Laboratory from 2012 to 2015. Clinical data, laboratory investigations, radiologic imaging studies, and pathological data were analyzed. Clinical review extended to 2 years post-CSF flow cytometric testing. RESULTS: Only 43/763 (5.6%) samples of CSF flow cytometry in 28/573 (4.9%) patients were found to be positive for a hematological malignancy in patients with undifferentiated neurologic symptoms. The overall sensitivity of the test was 13.8% with 25 patients with negative CSF flow cytometry later having a positive biopsy for CNS lymphoma. CSF flow cytometry was negative in all cases when at the time of CSF examination the patient did not have a previous hematological malignancy or findings of abnormal enhancement on MRI (n = 249). CONCLUSION: CSF flow cytometry has low utility in screening for primary CNS lymphoma in the absence of a previous history of hematologic malignancy or findings of abnormal enhancement on MRI.

11.
Acta Inform ; 57(1): 137-163, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32189717

RESUMO

We study the reactive synthesis problem for hyperproperties given as formulas of the temporal logic HyperLTL. Hyperproperties generalize trace properties, i.e., sets of traces, to sets of sets of traces. Typical examples are information-flow policies like noninterference, which stipulate that no sensitive data must leak into the public domain. Such properties cannot be expressed in standard linear or branching-time temporal logics like LTL, CTL, or CTL ∗ . Furthermore, HyperLTL subsumes many classical extensions of the LTL realizability problem, including realizability under incomplete information, distributed synthesis, and fault-tolerant synthesis. We show that, while the synthesis problem is undecidable for full HyperLTL, it remains decidable for the ∃ ∗ , ∃ ∗ ∀ 1 , and the linear ∀ ∗ fragments. Beyond these fragments, the synthesis problem immediately becomes undecidable. For universal HyperLTL, we present a semi-decision procedure that constructs implementations and counterexamples up to a given bound. We report encouraging experimental results obtained with a prototype implementation on example specifications with hyperproperties like symmetric responses, secrecy, and information flow.

12.
Can J Cardiol ; 36(3): 322-334, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32145862

RESUMO

Cardiac amyloidosis is an under-recognized and potentially fatal cause of heart failure and other cardiovascular manifestations. It is caused by deposition of misfolded precursor proteins as fibrillary amyloid deposits in cardiac tissues. The two primary subtypes of systemic amyloidosis causing cardiac involvement are immunoglobulin light chain (AL), a plasma cell dyscrasia, and transthyretin (ATTR), itself subdivided into a hereditary subtype caused by a gene mutation of the ATTR protein, and an age-related wild type, which occurs in the absence of a gene mutation. Clinical recognition requires a high index of suspicion, inclusive of the extracardiac manifestations of both subtypes. Diagnostic workup includes screening for serum and/or urine monoclonal protein suggestive of immunoglobulin light chains, along with serum cardiac biomarker measurement and performance of cardiac imaging for findings consistent with amyloid infiltration. Modern cardiac imaging techniques, including the use of nuclear scintigraphy with bone-seeking radiotracer to noninvasively diagnose ATTR cardiac amyloidosis, have reduced reliance on the gold standard endomyocardial biopsy. Disease-modifying therapeutic approaches have evolved significantly, particularly for ATTR, and pharmacologic therapies that slow or halt disease progression are becoming available. This Canadian Cardiovascular Society/Canadian Heart Failure Society joint position statement provides evidence-based recommendations that support the early recognition and optimal diagnostic approach and management strategies for patients with cardiac amyloidosis. This includes recommendations for the symptomatic management of heart failure and other cardiovascular complications such as arrhythmia, risk stratification, follow-up surveillance, use of ATTR disease-modifying therapies, and optimal clinical care settings for patients with this complex multisystem disease.


Assuntos
Amiloidose/diagnóstico , Amiloidose/terapia , Cardiomiopatias/diagnóstico , Cardiomiopatias/terapia , Algoritmos , Humanos
13.
BMC Med Genet ; 21(1): 35, 2020 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066420

RESUMO

BACKGROUND: We report a large family with four successive generations, presenting with a complex phenotype of severe congenital neutropenia (SCN), partially penetrant monocytosis, and hearing loss of varying severity. METHODS: We performed whole exome sequencing to identify the causative variants. Sanger sequencing was used to perform segregation analyses on remaining family members. RESULTS: We identified and classified a pathogenic GFI1 variant and a likely pathogenic variant in MYO6 which together explain the complex phenotypes seen in this family. CONCLUSIONS: We present a case illustrating the benefits of a broad screening approach that allows identification of oligogenic determinants of complex human phenotypes which may have been missed if the screening was limited to a targeted gene panel with the assumption of a syndromic disorder. This is important for correct genetic diagnosis of families and disentangling the range and severity of phenotypes associated with high impact variants.


Assuntos
Síndrome Congênita de Insuficiência da Medula Óssea/genética , Proteínas de Ligação a DNA/genética , Perda Auditiva Neurossensorial/genética , Cadeias Pesadas de Miosina/genética , Neutropenia/congênito , Fatores de Transcrição/genética , Adulto , Idoso , Síndrome Congênita de Insuficiência da Medula Óssea/complicações , Síndrome Congênita de Insuficiência da Medula Óssea/diagnóstico , Síndrome Congênita de Insuficiência da Medula Óssea/fisiopatologia , Exoma/genética , Feminino , Doenças Genéticas Inatas/complicações , Doenças Genéticas Inatas/diagnóstico , Doenças Genéticas Inatas/genética , Doenças Genéticas Inatas/fisiopatologia , Perda Auditiva Neurossensorial/complicações , Perda Auditiva Neurossensorial/diagnóstico , Perda Auditiva Neurossensorial/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Neutropenia/complicações , Neutropenia/diagnóstico , Neutropenia/genética , Neutropenia/fisiopatologia , Linhagem , Fenótipo , Sequenciamento Completo do Exoma
14.
Angew Chem Int Ed Engl ; 59(10): 4043-4050, 2020 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-31919948

RESUMO

Ni,N-doped carbon catalysts have shown promising catalytic performance for CO2 electroreduction (CO2 R) to CO; this activity has often been attributed to the presence of nitrogen-coordinated, single Ni atom active sites. However, experimentally confirming Ni-N bonding and correlating CO2 reduction (CO2 R) activity to these species has remained a fundamental challenge. We synthesized polyacrylonitrile-derived Ni,N-doped carbon electrocatalysts (Ni-PACN) with a range of pyrolysis temperatures and Ni loadings and correlated their electrochemical activity with extensive physiochemical characterization to rigorously address the origin of activity in these materials. We found that the CO2 R to CO partial current density increased with increased Ni content before plateauing at 2 wt % which suggests a dispersed Ni active site. These dispersed active sites were investigated by hard and soft X-ray spectroscopy, which revealed that pyrrolic nitrogen ligands selectively bind Ni atoms in a distorted square-planar geometry that strongly resembles the active sites of molecular metal-porphyrin catalysts.

15.
Proc Natl Acad Sci U S A ; 117(23): 12572-12575, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-31980521

RESUMO

Electrochemical CO reduction can serve as a sequential step in the transformation of CO2 into multicarbon fuels and chemicals. In this study, we provide insights on how to steer selectivity for CO reduction almost exclusively toward a single multicarbon oxygenate by carefully controlling the catalyst composition and its surrounding reaction conditions. Under alkaline reaction conditions, we demonstrate that planar CuAg electrodes can reduce CO to acetaldehyde with over 50% Faradaic efficiency and over 90% selectivity on a carbon basis at a modest electrode potential of -0.536 V vs. the reversible hydrogen electrode. The Faradaic efficiency to acetaldehyde was further enhanced to 70% by increasing the roughness factor of the CuAg electrode. Density functional theory calculations indicate that Ag ad-atoms on Cu weaken the binding energy of the reduced acetaldehyde intermediate and inhibit its further reduction to ethanol, demonstrating that the improved selectivity to acetaldehyde is due to the electronic effect from Ag incorporation. These findings will aid in the design of catalysts that are able to guide complex reaction networks and achieve high selectivity for the desired product.

16.
Nat Commun ; 11(1): 33, 2020 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-31911585

RESUMO

Electrochemical CO[Formula: see text] reduction is a potential route to the sustainable production of valuable fuels and chemicals. Here, we perform CO[Formula: see text] reduction experiments on Gold at neutral to acidic pH values to elucidate the long-standing controversy surrounding the rate-limiting step. We find the CO production rate to be invariant with pH on a Standard Hydrogen Electrode scale and conclude that it is limited by the CO[Formula: see text] adsorption step. We present a new multi-scale modeling scheme that integrates ab initio reaction kinetics with mass transport simulations, explicitly considering the charged electric double layer. The model reproduces the experimental CO polarization curve and reveals the rate-limiting step to be *COOH to *CO at low overpotentials, CO[Formula: see text] adsorption at intermediate ones, and CO[Formula: see text] mass transport at high overpotentials. Finally, we show the Tafel slope to arise from the electrostatic interaction between the dipole of *CO[Formula: see text] and the interfacial field. This work highlights the importance of surface charging for electrochemical kinetics and mass transport.

18.
Form Methods Syst Des ; 54(3): 336-363, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31806925

RESUMO

Hyperproperties, such as non-interference and observational determinism, relate multiple system executions to each other. They are not expressible in standard temporal logics, like LTL, CTL, and CTL*, and thus cannot be monitored with standard runtime verification techniques. HyperLTL extends linear-time temporal logic (LTL) with explicit quantification over traces in order to express hyperproperties. We investigate the runtime verification problem of HyperLTL formulas for three different input models: (1) The parallel model, where a fixed number of system executions is processed in parallel. (2) The unbounded sequential model, where system executions are processed sequentially, one execution at a time. In this model, the number of incoming executions is a-priori unbounded and may in fact grow forever. (3) The bounded sequential model where the traces are processed sequentially and the number of incoming executions is bounded. We show that the existence of a bound in the parallel and bounded sequential models leads to a different notion of monitorability than in the unbounded sequential model. We show that deciding the monitoriability problem for alternation-free HyperLTL is PS P A C E -complete while the problem is undecidable in general. For every input model, we provide monitoring algorithms along with run-time and storage optimizations. By recognizing properties of specifications such as reflexivity, symmetry, and transitivity, we reduce the number of comparisons between traces. For the sequential models, we present a technique that minimizes the number of traces that need to be stored. We evaluate our optimizations, showing that this leads to a more scalable monitoring and, in particular, a significantly lower memory consumption.

19.
NPJ Genom Med ; 4: 28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754459

RESUMO

We describe a sibling pair displaying an early infantile-onset, progressive neurodegenerative phenotype, with symptoms of developmental delay and epileptic encephalopathy developing from 12 to 14 months of age. Using whole exome sequencing, compound heterozygous variants were identified in SLC5A6, which encodes the sodium-dependent multivitamin transporter (SMVT) protein. SMVT is an important transporter of the B-group vitamins biotin, pantothenate, and lipoate. The protein is ubiquitously expressed and has major roles in vitamin uptake in the digestive system, as well as transport of these vitamins across the blood-brain barrier. Pathogenicity of the identified variants was demonstrated by impaired biotin uptake of mutant SMVT. Identification of this vitamin transporter as the genetic basis of this disorder guided targeted therapeutic intervention, resulting clinically in improvement of the patient's neurocognitive and neuromotor function. This is the second report of biallelic mutations in SLC5A6 leading to a neurodegenerative disorder due to impaired biotin, pantothenate and lipoate uptake. The genetic and phenotypic overlap of these cases confirms mutations in SLC5A6 as the genetic cause of this disease phenotype. Recognition of the genetic disorder caused by SLC5A6 mutations is essential for early diagnosis and to facilitate timely intervention by triple vitamin (biotin, pantothenate, and lipoate) replacement therapy.

20.
Angew Chem Int Ed Engl ; 58(45): 16172-16176, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31496012

RESUMO

Conversion of CO2 into valuable molecules is a field of intensive investigation with the aim of developing scalable technologies for making fuels using renewable energy sources. While electrochemical reduction into CO and formate are approaching industrial maturity, a current challenge is obtaining more reduced products like methanol. However, literature on the matter is scarce, and even more for the use of molecular catalysts. Here, we demonstrate that cobalt phthalocyanine, a well-known catalyst for the electrochemical conversion of CO2 to CO, can also catalyze the reaction from CO2 or CO to methanol in aqueous electrolytes at ambient conditions of temperature and pressure. The studies identify formaldehyde as a key intermediate and an unexpected pH effect on selectivity. This paves the way for establishing a sequential process where CO2 is first converted to CO which is subsequently used as a reactant to produce methanol. Under ideal conditions, the reaction shows a global Faradaic efficiency of 19.5 % and chemical selectivity of 7.5 %.

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