Case Report: Progressive Asymmetric Parkinsonism Secondary to CADASIL Without Dementia

Parkinsonism is a rare phenotype of cerebral autosomal dominant arteriopathy with subcortical infarction and leukoencephalopathy (CADASIL), all of which involve cognitive decline. Normal cognition has not been reported in previous disease studies. Here we report the case of a 60-year-old female patient with a 2-year history of progressive asymmetric parkinsonism. On examination, she showed severe parkinsonism featuring bradykinesia and axial and limb rigidity with preserved cognition. Magnetic resonance imaging (MRI) revealed white matter hyperintensity in the external capsule and periventricular region. Dopaminergic response was limited. A missense mutation c.1630C>T (p.R544C) on the NOTCH3 gene was identified on whole-exome sequencing, which confirmed the diagnosis of vascular parkinsonism secondary to CADASIL. A diagnosis of CADASIL should be considered in asymmetric parkinsonism without dementia. Characteristic MRI findings support the diagnosis.

Domestic abuse and mental health: the amplified risks created during the pandemic

SUMMARY No recent pandemic has had such a severe socioeconomic impact as COVID-19. Significant economic uncertainty and social restrictions have led to increased levels of stress for many. There has been increased social isolation, financial stress and alcohol intake, all of which can increase domestic abuse and other forms of household abuse. Increases in abuse in the home found in other public health emergencies and economic recessions can be seen now – reported UK domestic abuse rates have increased since the start of COVID-19. This article focuses on how COVID-19 and its anticipated aftermath exacerbate the risk factors for domestic abuse in the general population and discusses clinical implications for mental health practitioners in the UK. It aims to provide a point of learning based on previous disease outbreaks and recessions, with a focus on specific factors, such as unemployment and alcohol misuse, and how these contribute to increasing incidence and severity of abuse – and more importantly, how mental health professionals can mitigate these for patients, 1 in 3 of whom are estimated to have already experienced abuse before the COVID-19 pandemic.

Limitations of lymphoblastoid cell lines for establishing genetic reference datasets in the immunoglobulin loci

Lymphoblastoid cell lines (LCLs) have been critical to establishing genetic resources for biomedical science. They have been used extensively to study human genetic diversity, genome function, and inform the development of tools and methodologies for augmenting disease genetics research. While the validity of variant callsets from LCLs has been demonstrated for most of the genome, previous work has shown that DNA extracted from LCLs is modified by V(D)J recombination within the immunoglobulin (IG) loci, regions that harbor antibody genes critical to immune system function. However, the impacts of V(D)J on data generated from LCLs has not been extensively investigated. In this study, we used LCL-derived short read sequencing data from the 1000 Genomes Project (n=2,504) to identify signatures of V(D)J recombination. Our analyses revealed sample-level impacts of V(D)J recombination that varied depending on the degree of inferred monoclonality. We showed that V(D)J associated somatic deletions impacted genotyping accuracy, leading to adulterated population-level estimates of allele frequency and linkage disequilibrium. These findings illuminate limitations of using LCLs for building genetic resources in the IG loci, with implications for interpreting previous disease association studies in these regions.

Midwakh (pipe) and seizure: The overlooked link

Objective: Numerous drugs and medications from various pharmacological classes can lead to seizures as an unwanted side effect. Midwakh is a pipe commonly used to smoke tobacco blend in small quantities. Midwakh use is increasing, especially among young people. Case Presentation: A 17-year-old patient with a history of seizures was provoked by smoking midwakh, despite having no previous disease history. Conclusion: Although the patient had a negative workup for epilepsy, midwakh should be classified as an epileptogenic drug. More studies need to be conducted on the effects of midwakh on the neurological system.

Prevalence of redetectable positive SARS-CoV-2 nucleic acid in recovered COVID-19 patients: a systematic review and meta-analysis

Background: The prevalence of positive SARS-CoV-2 nucleic acid in recovered COVID-19 patients has attracted attention. We aimed to investigate the repositive rate of SARS-CoV-2 and the clinical features of discharged COVID-19 patients. Methods: In this systematic review and meta-analysis, we searched PubMed, Embase, Web of Science, China National Knowledge Internet, Wanfang Data, China BioMedical Literature, VIP, and Google Scholar. Fixed or random-effect models were used to determine effect estimates. Results: Eleven studies were included. The pooled positive rate of viral RNA in discharged patients was 11% (95% CI 7-15; I2=90.4%). The median days from discharge to repositivity were 7 to 8 days. Coughing was the most common clinical symptom, occurring in 16% (95% CI 11-20; I2=0%) of patients at readmission. Chest CT and laboratory indicators of positive retest (PR) patients showed significant recovery trends. The prevalence of comorbidities between the PR patients and the negative retest patients were not significant (OR 0.86 [95% CI 0.38–1.95]; p=0.002; I2=76.5%). No close contacts were positive for SARS-CoV-2 RNA. Conclusion: PR patients were uncommon. The repositive result was likely due to the incomplete clearance of virus from a previous disease course. PR patients were less likely to be contagious. However, close monitoring and quarantine after discharge from the hospital are necessary. Registration: The protocol has been registered on PROSPERO, registration ID: CRD42021239650 Keywords: COVID-19, SARS-CoV-2, discharged patients, positive retest rate

Impact of previous disease-modifying treatment on effectiveness and safety outcomes, among patients with multiple sclerosis treated with alemtuzumab

ObjectivesAlemtuzumab is effective in patients with active multiple sclerosis but has a complex safety profile, including the development of secondary autoimmunity. Most of patients enrolled in randomised clinical trials with alemtuzumab were either treatment naïve or pretreated with injectable substances. Other previous disease-modifying treatments (DMTs) were not used in the study cohorts, and therefore, associated risks might yet remain unidentified.MethodsWe retrospectively evaluated a prospective dual-centre alemtuzumab cohort of 170 patients. We examined the baseline characteristics as well as safety and effectiveness outcomes, including the time to first relapse, the time to 3 months confirmed disability worsening and the time to secondary autoimmunity.ResultsThe regression analysis showed that, among all previously used DMTs, the pretreatment with fingolimod (n=33 HRs for the time to first relapse (HR 5.420, 95% CI 2.520 to 11.660; p<0.001)) and for the time to worsening of disability (HR 7.676, 95% CI 2.870 to 20.534; p<0.001). Additionally, patients pretreated with fingolimod were more likely to experience spinal relapses (55% vs 10% among previously naïve patients; p<0.001) and had an increased risk of secondary autoimmunity (HR 5.875, 95% CI 2.126 to 16.27; p<0.001).ConclusionIn the real-world setting, we demonstrated suboptimal disease control and increased risk of secondary autoimmunity following alemtuzumab, among patients previously treated with fingolimod. These data can provide guidance for improving MS therapeutic management.

A Protein Assembly Hypothesis for Population-Specific Decrease in Dementia with Time

A recent report in the journal, Neurology, documents age-normalized, nation-specific (e.g., United States and Western Europe), progressive decrease of dementia, beginning about 25 years ago. This observation has, thus far, not had explanation. We begin our proposed explanation with the following previous disease construct. (1) Some dementia is caused by innate immune over-response to infections. (2) The innate immune over-response occurs via excessive conversion of amyloid protein to α-sheet conformation. (3) This conversion evolved to inhibit invading microbes by binding microbe-associated α-sheet, e.g., in hyper-expanded capsid intermediates of some viruses. The rarity of human α-sheet makes this inhibition specific for microbial invaders. As foundation, here we observe directly, for the first time, extreme, sheet-like outer shell thinness in a hyper-expanded capsid of phage T3. Based on phage/herpesvirus homology, we propose the following. The above decrease in dementia is caused by varicella-zoster virus (VZV) vaccination, USFDA-approved about 25 years ago; VZV is a herpesvirus and causes chickenpox and shingles. In China and Japan, a cotemporaneous non-decrease is explained by lower anti-VZV vaccination. Co-assembly extension of α-sheet is relatively independent of amino acid sequence. Thus, we project that additional dementia is suppressible by vaccination against other viruses, including other herpesviruses.

A deletion in CFL-2 gene associated with Severe Nemaline Myopathy with peculiar features

Context: Nemaline myopathy (NM) is the most common congenital myopathy characterized by muscle weakness and presence of nemaline bodies (rods) in muscle biopsy. Phenotype ranges from neonatal death to normal lifespan. 13 genes have been reported. We describe a new variant in cofilin 2 gene (CFL2;OMIM*601443). Case report: A 5-year-old boy born severely hypotonic and unable to breathe, in need of mechanic ventilation. Healthy non-consanguineous parents. Physical examination: severe hypotonia with only extraocular motricity preserved and multiple contractures. Dysmorphic features were observed as brachycephaly, hypertelorism, pseudohypertrophy, macroglossia, premature pubic hair. Deep reflexes were absent. CK: 1010U/l. DHEA-S elevated. Muscular biopsy: Rods, cores and dystrophic pattern. Exome: homozygous deletion in exons 1 to 4 of CFL2 and partial deletion of the next gene Sorting nexin-6 (SNX6) in Chr14:34.563.122-34.714.639. Conclusion: 9 cases were described previously: Age onset was before 31 months. 4 presented respiratory distress at birth, 1 presented macroglossia, 2 contractures, 2 spinal deformities and 3 delayed motor milestones. Our patient presents an extent deletion in homozygosis not described before. A second deletion was found in SNX6, which is involved in protein trafficking and is expressed in different cells, as endocrine and cardiac. The early puberty and dimorphisms could be due to SNX6, though there is no previous disease caused by this gene. Among differential diagnosis of macroglossia, congenital myopathy caused by CFL2 should be considered.

Association of Demographic Variables with COVID-19 Knowledge: A Study on Pakistani Adults

With the outbreak of Novel Coronavirus disease (COVID-19), researchers set out to explore different behavioral patterns. It is natural for researchers to seek the differences in relation to different demographic variables. Research from previous disease outbreaks shows the importance of demographic variables. This research study aims to explore the differences with regard to different demographic variables regarding the knowledge of COVID-19. It was found that the demographic variables; gender, marital status and education level showed no statistical significance but the demographic variables; age group and profession showed statistical significance. Another important finding was that 73% respondents had scored 3-4 on scale of 5 assessing COVID-19 knowledge. Moreover, 51% respondents considered themselves affected psychologically by COVID-19 pandemic.