The Effect of High-Frequency Repetitive Transcranial Magnetic Stimulation on Advancing Parkinson's Disease With Dysphagia: Double Blind Randomized Clinical Trial

We investigate if rTMS has a therapeutic role in the treatment of dysphagia in patients with Parkinson's disease (PD). MATERIAL AND METHODS: Thirty-three patients with PD and dysphagia were randomly classified with ratio 1:2 to receive sham or real rTMS (2000 pulses; 20 Hz; 90% resting motor threshold; 10 trains of 10 seconds with 25 seconds between each train) over the hand area of each motor cortex (5 minutes between hemispheres) for 10 days (5 days per week) followed by 5 booster sessions every month for 3 months. Assessments included the Unified Parkinson's Disease Rating Scale part III (UPDRS), Instrumental Activities of Daily Living (IADL), and Arabic-Dysphagia Handicap Index (A-DHI) before, after the last session, and 3 months later. Video-fluoroscopy measures of pharyngeal transit time (PTT) and time to maximal hyoid elevation (H1-H2) were taken before and after the treatment sessions. RESULTS: There were no significant differences between groups. There was a significant improvement on all rating scales (analysis of variance) after real rTMS with a significant time × group interaction. In particular, there was a significant and long-lasting (3 months) effect of time on all subitems of the A-DHI (functional, P = .0001; physical, P = .0001; emotional, P = .02) but not in the sham group. This was associated with significant improvement in H1-H2 ( P = .03) and PTT ( P = .01) during solid swallows in the real rTMS but not the sham group. CONCLUSION: Real rTMS improves dysphagia in PD as documented by A-DHI scores and by video-fluoroscopy

Prevalence, predictors and prognostic implications of PR interval prolongation in patients with heart failure

Aims: To determine the prevalence, incidence, predictors and prognostic implications of PR interval prolongation in patients referred with suspected heart failure. Methods and Results: Consecutive patients referred with suspected heart failure were prospectively enrolled. After excluding patients with implantable cardiac devices and atrial fibrillation, 1420 patients with heart failure and reduced ejection fraction (HeFREF) [age: median 71 (interquartile range IQR: 63-78) years; men: 71%; NT-ProBNP: 1319 (583-3378) ng/L], 1094 with heart failure and normal ejection fraction (HeFNEF) [age: 76 (70-82) years; men: 47%; NT-ProBNP: 547 (321-1171) ng/L], and 1150 without heart failure [age: 68 (60-75) years; men: 51%; NT-ProBNP: 86 (46-140) ng/L] were included. The prevalence of first degree heart block [heart-rate corrected PR interval (PRc) >200 ms] was higher in patients with heart failure (21% HeFREF, 20% HeFNEF, 9% without heart failure). In patients with HeFREF or HeFNEF, longer baseline PRc was associated with greater age, male sex, and longer QRS duration and, in those with HeFREF, treatment with amiodarone or digoxin. Patients with heart failure in the longest PRc quartile had worse survival compared to shorter PRc quartiles but PRc was not independently associated with survival in multivariable analysis. For patients without heart failure, shorter baseline PRc was independently associated with worse survival. Conclusion: PRc prolongation is common in patients with HeFREF or HeFNEF and associated with worse survival, although not an independent predictor of outcome. The results of clinical trials investigating the therapeutic potential of shortening the PR interval by pacing are awaited

Osteopetrosis

Osteopetrosis ("marble bone disease") is a descriptive term that refers to a group of rare, heritable disorders of the skeleton characterized by increased bone density on radiographs. The overall incidence of these conditions is difficult to estimate but autosomal recessive osteopetrosis (ARO) has an incidence of 1 in 250,000 births, and autosomal dominant osteopetrosis (ADO) has an incidence of 1 in 20,000 births. Osteopetrotic conditions vary greatly in their presentation and severity, ranging from neonatal onset with life-threatening complications such as bone marrow failure (e.g. classic or "malignant" ARO), to the incidental finding of osteopetrosis on radiographs (e.g. osteopoikilosis). Classic ARO is characterised by fractures, short stature, compressive neuropathies, hypocalcaemia with attendant tetanic seizures, and life-threatening pancytopaenia. The presence of primary neurodegeneration, mental retardation, skin and immune system involvement, or renal tubular acidosis may point to rarer osteopetrosis variants, whereas onset of primarily skeletal manifestations such as fractures and osteomyelitis in late childhood or adolescence is typical of ADO. Osteopetrosis is caused by failure of osteoclast development or function and mutations in at least 10 genes have been identified as causative in humans, accounting for 70% of all cases. These conditions can be inherited as autosomal recessive, dominant or X-linked traits with the most severe forms being autosomal recessive. Diagnosis is largely based on clinical and radiographic evaluation, confirmed by gene testing where applicable, and paves the way to understanding natural history, specific treatment where available, counselling regarding recurrence risks, and prenatal diagnosis in severe forms. Treatment of osteopetrotic conditions is largely symptomatic, although haematopoietic stem cell transplantation is employed for the most severe forms associated with bone marrow failure and currently offers the best chance of longer-term survival in this group. The severe infantile forms of osteopetrosis are associated with diminished life expectancy, with most untreated children dying in the first decade as a complication of bone marrow suppression. Life expectancy in the adult onset forms is normal. It is anticipated that further understanding of the molecular pathogenesis of these conditions will reveal new targets for pharmacotherapy

A review on experimental and clinical genetic associations studies on fear conditioning, extinction and cognitive-behavioral treatment

Fear conditioning and extinction represent basic forms of associative learning with considerable clinical relevance and have been implicated in the pathogenesis of anxiety disorders. There is considerable inter-individual variation in the ability to acquire and extinguish conditioned fear reactions and the study of genetic variants has recently become a focus of research. In this review, we give an overview of the existing genetic association studies on human fear conditioning and extinction in healthy individuals and of related studies on cognitive-behavioral treatment (CBT) and exposure, as well as pathology development after trauma. Variation in the serotonin transporter (5HTT) and the catechol-o-methyltransferase (COMT) genes has consistently been associated with effects in pre-clinical and clinical studies. Interesting new findings, which however require further replication, have been reported for genetic variation in the dopamine transporter (DAT1) and the pituitary adenylate cyclase 1 receptor (ADCYAP1R1) genes, whereas the current picture is inconsistent for variation in the brain-derived neurotrophic factor (BDNF) gene. We end with a discussion of the findings and their limitations, as well as future directions that we hope will aid the field to develop further

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease