Homozygous SOD1 Variation L144S Produces a Severe Form of Amyotrophic Lateral Sclerosis in an Iranian Family

ObjectivesAmyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by degeneration of motor neurons determining progressive muscular atrophy, weakness, and death from respiratory failure.MethodsHere, we report clinical and molecular findings of a novel Iranian family affected with a severe form of early-onset familial ALS.ResultsThree siblings born to consanguineous parents developed a form of ALS characterized by early-onset lower limb involvement and a fast progression, proving fatal at age 16 years for 1 of them. Molecular analysis of the SOD1 gene revealed the homozygous substitution c.434T>C in exon 5 resulting in the amino acid change p.Leu144Ser (L144S), previously reported as a dominant variant. Both parents were heterozygous carriers. The probands' mother recently developed a late-onset ALS with predominant upper motor neuron involvement.DiscussionThis report adds p.L144S to the short list of homozygous SOD1 variants and suggests that the development of an earlier-onset and/or faster disease progression can occur when 2 mutated alleles are present.

Distinguishing Between Multisystem Inflammatory Syndrome, Associated With COVID-19 in Children and the Kawasaki Disease: Development of Preliminary Criteria Based on the Data of the Retrospective Multicenter Cohort Study

Objectives: Diagnostic between multisystem inflammatory syndrome associated with COVID-19 in children (MIS-C) and Kawasaki disease (KD) can make difficulties due to many similarities. Our study aimed to create a Kawasaki/MIS-C differentiation score (KMDscore) allowing discrimination of MIS-C and KD.Study design: The retrospective multicenter cohort study included clinical, laboratory, and instrumental information about MIS-C (n = 72) and KD (n = 147). The variables allowed to discriminate both conditions used to construct and validate the diagnostic score called the KMDscore.Results: Patients with MIS-C were older, had earlier admission to the hospital, had a shorter time before fever resolution, two times frequently had signs of GI and CNS involvement observed, and had more impressive thrombocytopenia, higher level of CRP, ferritin, ALT, AST, LDH, creatinine, triglycerides, troponin, and D-dimer compared to KD patients. Respiratory signs in MIS-C were presented with pleuritis, acute respiratory distress syndrome, oxygen dependency, lung infiltration, and ground-glass opacities in CT. The heart involvement with fast progression of myocarditis provided the severity of MIS-C and ICU admission due to 12 times higher arterial hypotension or shock and required cardiotonic. No differences in the frequency of CA lesions were seen in the majority of cases. Five criteria, CRP >11 mg/dl (18 points), D-dimer >607 ng/ml (27 points), age >5 years (30 points), thrombocytopenia (25 points), and GI involvement (28 points), were included in the KMDscore. The summa >55 points allowed to discriminate MIS-C from KD with a sensitivity of 87.5% and specificity of 89.1%.Conclusion: The KMDscore can be used to differentiate the diagnostic of MIS-C from KD.

Built Environment Characteristics, Daily Travel, and Biometric Readings: Creation of an Experimental Tool Based on a Smartwatch Platform

Travel surveys can uncover information regarding travel behaviour, needs, and more. Collected information is utilised to make choices when reorganising or planning built environments. Over the years, methods for conducting travel surveys have changed from interviews and forms to automated travel diaries in order to monitor trips made by travellers. With the fast progression of technological advancements, new possibilities for operationalising such travel diaries can be implemented, changing from utilising mobile to wearable devices. Wearable devices are often equipped with sensors which collect continuous biometric data from sources that are not reachable from standard mobile devices. Data collected through wearable devices range from heart rate and blood pressure to temperature and perspiration. This advancement opens new possible layers of information in the collection of travel data. Such biometric data can be used to derive psychophysiological conditions related to cognitive load, which can uncover in-depth knowledge regarding stress and emotions. This paper aims to explore the possibilities of data analysis on the data collected through a software combining travel survey data, such as position and time, with heartrate, to gain knowledge of the implications of such data. The knowledge about the implications of spatial configurations can be used to create more accessible environments.

Fast Progression in Amyotrophic Lateral Sclerosis Is Associated With Greater TDP-43 Burden in Spinal Cord

Upper and lower motor neuron pathologies are critical to the autopsy diagnosis of amyotrophic lateral sclerosis (ALS). Further investigation is needed to determine how the relative burden of these pathologies affects the disease course. We performed a blinded, retrospective study of 38 ALS patients, examining the association between pathologic measures in motor cortex, hypoglossal nucleus, and lumbar cord with clinical data, including progression rate and disease duration, site of symptom onset, and upper and lower motor neuron signs. The most critical finding in our study was that TAR DNA-binding protein 43 kDa (TDP-43) pathologic burden in lumbar cord and hypoglossal nucleus was significantly associated with a faster progression rate with reduced survival (p < 0.02). There was no correlation between TDP-43 burden and the severity of cell loss, and no significant clinical associations were identified for motor cortex TDP-43 burden or severity of cell loss in motor cortex. C9orf72 expansion was associated with shorter disease duration (p < 0.001) but was not significantly associated with pathologic measures in these regions. The association between lower motor neuron TDP-43 burden and fast progression with reduced survival in ALS provides further support for the study of TDP-43 as a disease biomarker.

A Review: Computational approaches to design sgRNA of CRISPR-Cas9

: Clustered regularly interspaced short palindromic repeats along with CRISPR-associated protein mechanisms preserve the memory of previous experiences with DNA invaders, in particular spacers that are embedded in CRISPR arrays between coordinate repeats. There has been a fast progression in the comprehension of this immune system and its implementations; however, there are numerous points of view that anticipate explanations to make the field an energetic research zone. The efficiency of CRISPR-Cas depends on well considered single guide RNA. For this purpose, many bioinformatics methods and tools were created to support the design of greatly active and precise single guide RNA. In-silico single guide RNA architecture is a crucial point for effective gene editing by means of the CRISPR technique. Persistent attempts are prepared to improve in-silico single guide RNA formulation by great on-target effectiveness and decreased off-target effects. This review offers a summary of the CRISPR computational tools to help different researchers to pick a specific tool for their work according to their pros and cons, along with new thoughts to make new computational tools to overcome all existing limitations.

Fast Progression of Diabetic Retinopathy with SARS-CoV-2 Infection

COVID-19 is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has been shown to affect a multitude of organ systems. It is often associated with vasculitis or thromboembolic disease with resultant tissue hypoxia. This report presents a case of fast progression diabetic retinopathy in the case of a SARS-CoV-2 infection. The findings conclude that patients with diabetes should be more frequently monitored for emergence or progression of diabetic retinopathy if they present with COVID-19.

Testing the Eligibility of Glaucoma Patients for Potential Gene Therapy Among a Clinic Population

Purpose Glaucoma patients who deteriorate despite standard treatment may benefit from novel gene therapies. Key inclusion criteria for a glaucoma gene therapy trial were devised. A retrospective chart review in a glaucoma clinic population was conducted. Feasibility of gene therapy inclusion criteria and factors associated with progression and fast progression < -1 decibels/year (dB/y) were evaluated. Methods 374 Primary Open Angle Glaucoma patients all of whom had performed at least 5 Swedish Interactive Threshold Algorithm Standard visual fields within a 58 months period. Two definitions were applied to characterise visual field progression rate using Guided Progression Analysis for an individual patient based on A, the eye with the greatest visual field loss, or B, the eye with the most rapid progression rate. Results Mean rate of visual field progression was − 0.50 dB/y (Definition A) and − 0.64 dB/y (Definition B). 19.0% (A) and 21.9% (B) of eyes, 71 (A) and 82 (B) eyes, were ‘fast progressors’ (< -1 dB/y). 37 (A) and 43 (B) eyes met the putative gene therapy inclusion criteria (≥ 50 years; mean deviation ≤ -4 to ≥ -12; ≤ -20 dB, progression rate between − 1 to -4 dB/y). Beta blockers (Odds ratio (OR) with 95% Confidence Intervals (CI): 2.84 (1.39–5.80); p = 0.004) (A), (OR (95%CI): 2.48 (1.30–4.75); p = 0.006) (B) and alpha agonists (OR (95%CI): 2.18 (1.14–4.17); p = 0.02) (A), (OR (95%CI) 2.00 (1.08–3.73); p = 0.028) (B) were significantly associated with fast progression. Conclusion A substantial proportion (10%) of patients in this clinic population would meet recommended gene therapy inclusion criteria.