Fate of chronic myeloid leukemia patients treated with allogeneic bone marrow transplantation or chemotherapy and/or interferon at a single center: long-term results

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Natural history, phenotypic spectrum, and discriminative features of multisystemic RFC1 disease

Objective To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of replication factor complex subunit 1 (RFC1) repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). Methods Multimodal RFC1 repeat screening (PCR, Southern blot, whole-exome/genome sequencing?based approaches) combined with cross-sectional and longitudinal deep phenotyping in (1) cross-European cohort A (70 families) with ?2 features of CANVAS or ataxia with chronic cough (ACC) and (2) Turkish cohort B (105 families) with unselected late-onset ataxia. Results Prevalence of RFC1 disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1 disease was also identified in Western and Eastern Asian individuals and even by whole-exome sequencing. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea or dystonia (11%). Ataxia progression was ?1.3 Scale for the Assessment and Rating of Ataxia points per year (32 cross-sectional, 17 longitudinal assessments, follow-up ?9 years [mean 3.1 years]) but also included early falls, variable nonlinear phases of MSA-C?like progression (SARA points 2.5?5.5 per year), and premature death. Treatment trials require 330 (1-year trial) and 132 (2-year trial) patients in total to detect 50% reduced progression. Conclusions RFC1 disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1 treatment trials. Classification of Evidence This study provides Class II evidence that RFC1 repeat expansions are associated with CANVAS and ACC.FUNDING: Study Funding This work was supported via the European Union’s Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607; to M. Synofzik,M.A., H.P., B.P.v.d.W.), by the DFG under the frame of EJP-RD network PROSPAX (No. 441409627; M. Synofzik, B.P.v.d.W., A.N.B.), and grant 779257 “Solve-RD” (toM. Synofzik, B.P.v.d.W.). B.P.v.d.W. receives additional research support from ZonMW, Hersenstichting, Gossweiler Foundation, uniQure, and Radboud University Medical Centre. T.B.H. was supported by the DFG (No 418081722). A.T. receives funding from the University of T¨ubingen, medical faculty, for the Clinician Scientist Program grant 439-0-0. A.C. thanks Medical Research Council, MR/T001712/1) and Fondazione CARIPLO (2019-1836) for grant support. L.S., T.K., B.P.v.d.W., and M. Synofzik are members of the European Reference Network for Rare Neurological Diseases, project 739510. A.N.B. is supported by the Suna and Inan Kirac Foundation and Koç University School of Medicine

Natural History, Phenotypic Spectrum, and Discriminative Features of Multisystemic RFC1-disease

OBJECTIVE: To delineate the full phenotypic spectrum, discriminative features, piloting longitudinal progression data, and sample size calculations of RFC1-repeat expansions, recently identified as causing cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS). METHODS: Multimodal RFC1 repeat screening (PCR, southern blot, whole-exome/genome (WES/WGS)-based approaches) combined with cross-sectional and longitudinal deep-phenotyping in (i) cross-European cohort A (70 families) with ≥2 features of CANVAS and/or ataxia-with-chronic-cough (ACC); and (ii) Turkish cohort B (105 families) with unselected late-onset ataxia. RESULTS: Prevalence of RFC1-disease was 67% in cohort A, 14% in unselected cohort B, 68% in clinical CANVAS, and 100% in ACC. RFC1-disease was also identified in Western and Eastern Asians, and even by WES. Visual compensation, sensory symptoms, and cough were strong positive discriminative predictors (>90%) against RFC1-negative patients. The phenotype across 70 RFC1-positive patients was mostly multisystemic (69%), including dysautonomia (62%) and bradykinesia (28%) (=overlap with cerebellar-type multiple system atrophy [MSA-C]), postural instability (49%), slow vertical saccades (17%), and chorea and/or dystonia (11%). Ataxia progression was ∼1.3 SARA points/year (32 cross-sectional, 17 longitudinal assessments, follow-up ≤9 years [mean 3.1]), but also included early falls, variable non-linear phases of MSA-C-like progression (SARA 2.5-5.5/year), and premature death. Treatment trials require 330 (1-year-trial) and 132 (2-year-trial) patients in total to detect 50% reduced progression. CONCLUSIONS: RFC1-disease is frequent and occurs across continents, with CANVAS and ACC as highly diagnostic phenotypes, yet as variable, overlapping clusters along a continuous multisystemic disease spectrum, including MSA-C-overlap. Our natural history data help to inform future RFC1-treatment trials. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that RFC1-repeat expansions are associated with CANVAS and ACC

Evaluation of the ICT Tuberculosis test for the routine diagnosis of tuberculosis

BACKGROUND: Rapid and accurate diagnosis of tuberculosis (TB) is crucial to facilitate early treatment of infectious cases and thus to reduce its spread. To improve the diagnosis of TB, more rapid diagnostic techniques such as antibody detection methods including enzyme-linked immunosorbent assay (ELISA)-based serological tests and immunochromatographic methods were developed. This study was designed to evaluate the validity of an immunochromatographic assay, ICT Tuberculosis test for the serologic diagnosis of TB in Antalya, Turkey. METHODS: Sera from 72 patients with active pulmonary (53 smear-positive and 19 smear-negative cases) and eight extrapulmonary (6 smear-positive and 2 smear-negative cases) TB, and 54 controls from different outpatient clinics with similar demographic characteristics as patients were tested by ICT Tuberculosis test. RESULTS: The sensitivity, specificity, and negative predictive value of the ICT Tuberculosis test for pulmonary TB were 33.3%, 100%, and 52.9%, respectively. Smear-positive pulmonary TB patients showed a higher positivity rate for antibodies than smear-negative patients, but the difference was not statistically significant. Of the eight patients with extrapulmonary TB, antibody was detected in four patients. CONCLUSION: Our results suggest that ICT Tuberculosis test can be used to aid TB diagnosis in smear-positive patients until the culture results are available

Guidance for the Management of Patients with Vascular Disease or Cardiovascular Risk Factors and COVID-19: Position Paper from VAS-European Independent Foundation in Angiology/Vascular Medicine .

COVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH

Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behcet's disease

Behcet's disease is a genetically complex disease of unknown etiology characterized by recurrent inflammatory attacks affecting the orogenital mucosa, eyes and skin. We performed a genome-wide association study with 311,459 SNPs in 1,215 individuals with Behcet's disease (cases) and 1,278 healthy controls from Turkey. We confirmed the known association of Behcet's disease with HLA-B*51 and identified a second, independent association within the MHC Class I region. We also identified an association at IL10 (rs1518111, P = 1.88 x 10(-8)). Using a meta-analysis with an additional five cohorts from Turkey, the Middle East, Europe and Asia, comprising a total of 2,430 cases and 2,660 controls, we identified associations at IL10 (rs1518111, P = 3.54 x 10(-18), odds ratio = 1.45, 95% CI 1.34-1.58) and the IL23R-IL12RB2 locus (rs924080, P = 6.69 x 10(-9), OR = 1.28, 95% CI 1.18-1.39). The disease-associated IL10 variant (the rs1518111 A allele) was associated with diminished mRNA expression and low protein production

Perspectives on care and communication involving incurably ill Turkish and Moroccan patients, relatives and professionals: a systematic literature review

<p>Abstract</p> <p>Background</p> <p>Our aim was to obtain a clearer picture of the relevant care experiences and care perceptions of incurably ill Turkish and Moroccan patients, their relatives and professional care providers, as well as of communication and decision-making patterns at the end of life. The ultimate objective is to improve palliative care for Turkish and Moroccan immigrants in the Netherlands, by taking account of socio-cultural factors in the guidelines for palliative care.</p> <p>Methods</p> <p>A systematic literature review was undertaken. The data sources were seventeen national and international literature databases, four Dutch journals dedicated to palliative care and 37 websites of relevant national and international organizations. All the references found were checked to see whether they met the structured inclusion criteria. Inclusion was limited to publications dealing with primary empirical research on the relationship between socio-cultural factors and the health or care situation of Turkish or Moroccan patients with an oncological or incurable disease. The selection was made by first reading the titles and abstracts and subsequently the full texts. The process of deciding which studies to include was carried out by two reviewers independently. A generic appraisal instrument was applied to assess the methodological quality.</p> <p>Results</p> <p>Fifty-seven studies were found that reported findings for the countries of origin (mainly Turkey) and the immigrant host countries (mainly the Netherlands). The central themes were experiences and perceptions of family care, professional care, end-of-life care and communication. Family care is considered a duty, even when such care becomes a severe burden for the main female family caregiver in particular. Professional hospital care is preferred by many of the patients and relatives because they are looking for a cure and security. End-of-life care is strongly influenced by the continuing hope for recovery. Relatives are often quite influential in end-of-life decisions, such as the decision to withdraw or withhold treatments. The diagnosis, prognosis and end-of-life decisions are seldom discussed with the patient, and communication about pain and mental problems is often limited. Language barriers and the dominance of the family may exacerbate communication problems.</p> <p>Conclusions</p> <p>This review confirms the view that family members of patients with a Turkish or Moroccan background have a central role in care, communication and decision making at the end of life. This, in combination with their continuing hope for the patient’s recovery may inhibit open communication between patients, relatives and professionals as partners in palliative care. This implies that organizations and professionals involved in palliative care should take patients’ socio-cultural characteristics into account and incorporate cultural sensitivity into care standards and care practices<it>.</it></p