Heterozygous RTEL1 variants in bone marrow failure and myeloid neoplasms.

Biallelic germline mutations in RTEL1 (regulator of telomere elongation helicase 1) result in pathologic telomere erosion and cause dyskeratosis congenita. However, the role of RTEL1 mutations in other bone marrow failure (BMF) syndromes and myeloid neoplasms, and the contribution of monoallelic RTEL1 mutations to disease development are not well defined. We screened 516 patients for germline mutations in telomere-associated genes by next-generation sequencing in 2 independent cohorts; one constituting unselected patients with idiopathic BMF, unexplained cytopenia, or myeloid neoplasms (n = 457) and a second cohort comprising selected patients on the basis of the suspicion of constitutional/familial BMF (n = 59). Twenty-three RTEL1 variants were identified in 27 unrelated patients from both cohorts: 7 variants were likely pathogenic, 13 were of uncertain significance, and 3 were likely benign. Likely pathogenic RTEL1 variants were identified in 9 unrelated patients (7 heterozygous and 2 biallelic). Most patients were suspected to have constitutional BMF, which included aplastic anemia (AA), unexplained cytopenia, hypoplastic myelodysplastic syndrome, and macrocytosis with hypocellular bone marrow. In the other 18 patients, RTEL1 variants were likely benign or of uncertain significance. Telomeres were short in 21 patients (78%), and 3' telomeric overhangs were significantly eroded in 4. In summary, heterozygous RTEL1 variants were associated with marrow failure, and telomere length measurement alone may not identify patients with telomere dysfunction carrying RTEL1 variants. Pathogenicity assessment of heterozygous RTEL1 variants relied on a combination of clinical, computational, and functional data required to avoid misinterpretation of common variants.

Transmural Healing Is Associated with Improved Long-term Outcomes of Patients with Crohn's Disease.

BACKGROUND: Mucosal healing (MH) is currently accepted as one of the best treatment targets in Crohn's disease. However, even in patients with sustained MH, residual bowel wall inflammation can still be detected by cross-sectional imaging. The long-term benefits of obtaining transmural healing (TH) have not been previously assessed. METHODS: We performed an observational study including 214 patients with Crohn's disease with a magnetic resonance enterography (MRE) and colonoscopy performed within a 6-month interval. Patients were classified as having TH (inactive MRE and colonoscopy), MH (active MRE with inactive colonoscopy), or no healing (active colonoscopy). Need for surgery, hospital admission, and therapy escalation were evaluated at 12 months of follow-up. RESULTS: Patients with TH presented lower rates of hospital admission, therapy escalation, and surgery than patients with MH or no healing. In logistic regression analysis, endoscopic remission (odds ratio 0.331 95% confidence interval [0.178-0.614], P < 0.001) and MRE remission (odds ratio 0.270 95% confidence interval [0.130-0.564], P < 0.001) were independently associated with a lower likelihood of reaching any unfavorable outcome. CONCLUSIONS: TH is associated with improved long-term outcomes in Crohn's disease and may be a more suitable target than MH.

Repetitive transcranial magnetic stimulation to treat substance use disorders and compulsive behavior.

Compulsions, like pathological gambling, binge-eating disorder, alcohol, tobacco or cocaine abuse and compulsive shopping have similar neurophysiological processing. This study aimed to examine the efficacy of repetitive transcranial magnetic stimulation (rTMS) in improving patient control over compulsive behavior. The rTMS modulatory role in cortical mesolimbic pathways possibly implies improvement of the inhibitory control system and compulsive consumption drive. Thus, craving reduction would be a component for control achievement. Within this context, 17 studies were found. Most studies applied rTMS over the left dorsolateral prefrontal cortex. Craving reduction was observed in 10 studies and was associated with improved control of compulsion in two of them. In one study reduction in consumption was found without reduction in craving. In addition, improvement in decision making was found in one study.