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Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.

INTRODUCTION: Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking. METHODS: This was a retrospective study describing our centers' experiences in treating SMA1 patients with combination therapy. RESULTS: Five children received nusinersen and onasemnogene abeparvovec-xioi (onasemnogene). Four were receiving nusinersen prior to onasemnogene. Nusinersen was continued in three. Marked liver enzyme elevations resulted in prolonged corticosteroid treatment in two patients with hospitalization and liver biopsy in one; milder liver enzyme elevations were noted in the other two. One patient received onasemnogene first, and then nusinersen. No adverse effects were noted. All patients improved. DISCUSSION: Combination molecular therapy is tolerated in SMA1 patients. Further studies are needed to determine whether there are circumstances in which combination therapy would be more efficacious than either monotherapy. Prolonged corticosteroid use and liver toxicity monitoring may be necessary with onasemnogene therapy. This article is protected by copyright. All rights reserved.

Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.

Reflex seizure provoked by light or pattern stimulation are an interesting and, at times, difficult to treat entity. Such seizures occur in patients with a variety of well-described epileptic syndromes, although in most spontaneous seizures are also described. This paper attempts to describe epileptic syndromes with primarily light or pattern provoked seizures.

Sneddon syndrome (SS) is an episodic or chronic, slowly progressive disorder and characterized by generalized livedo racemosa (patchy, violaceous, skin discoloration) and recurrent cerebrovascular events. The histopathology of skin and brain is remarkable for a noninflammatory thrombotic vasculopathy involving medium- and small-sized dermal and cerebral arteries, respectively. Approximately 80% of the SS patients are women with a median age of diagnosis at 40 years. However, the onset of the disease during childhood have been reported. Etiopathogenesis of SS is unknown with 2 primary mechanisms proposed - autoimmune/inflammatory versus thrombophilia. SS is primarily classified as antiphospholipid positive or negative type. Neurological manifestations usually occur in 3 phases: (1) prodromal symptoms such as headaches, dizziness, and vertigo, (2) recurrent strokes, and (3) early onset dementia. Livedo racemosa precedes the onset of recurrent strokes by more than 10 years, but in many instances, the significance of the skin lesion is recognized only after the appearance of the stroke. The involvement of the heart valves, systolic labile hypertension, and retinal changes are also commonly associated with this syndrome. Treatment of SS is primarily based on anecdotal reports. Antiplatelet and antithrombotic agents are used for secondary stroke prophylaxis, and a recent study showed a relatively lower stroke recurrence rate with the universal use of antiplatelet/antithrombotic agents. Routine use of anti-inflammatory or immunosuppressive therapies is controversial. Neuropsychiatric prognosis of SS is relatively poor with predominant deficits in the concentration, attention, visual perception, and visuospatial skills.

We can increase the efficiency of public cloud datacenters by harvesting allocated but temporarily idling CPU cores from customer virtual machines (VMs) to run batch or analytics workloads. Even small efficiency gains translate into substantial savings, since provisioning and operating a datacenter costs hundreds of millions of dollars per year. The main challenge is to harvest idle cores with little or no impact on customer VMs, which could be running latency-sensitive services and are essentially black-boxes to the cloud provider. We introduce ElasticVM, a new VM type that can run batch workloads cheaply using mainly harvested cores. We also propose SmartHarvest, a system that dynamically manages the number of cores available to ElasticVMs in each fine-grained time window. SmartHarvest uses online learning to predict the core demand of primary, customer VMs and compute the number of cores that can be safely harvested. Our results show that SmartHarvest can harvest a significant amount of CPU resources without increasing the 99th-percentile tail latency of latency-critical primary workloads by more than 10%. Unlike static harvesting techniques that rely on offline profiling, SmartHarvest is robust to different primary workloads, batch workloads, and load changes. Finally, we show that the online learning in SmartHarvest is complementary to systems optimizations for VM management.

The coronavirus disease 2019 (COVID‐19) pandemic has resulted in reorganization of healthcare settings affecting the delivery of clinical care to patients with spinal muscular atrophy (SMA). There is a concern that patients with SMA may be at increased risk of manifesting severe symptoms of COVID‐19. Currently approved therapies for SMA improve survival and motor function; however, their delivery requires an increased exposure to the health system and a dedicated healthcare team. In this study, we discuss consensus recommendations pertaining to care of SMA patients during the pandemic. We highlight that SMA treatments should not be perceived as elective. Decisions regarding the delay of treatments should be made with consideration of the potential risks of COVID‐19 exposure and the risk of that delay. We emphasize the importance of collaborative treatment decisions between the patient, family, and healthcare provider, considering any geographic‐ or institution‐specific policies and precautions for COVID‐19.

There is increasing recognition of the role played by neuroinflammation both as a factor in the development of epilepsy as well as a consequence of seizures. Autoimmune encephalitis and epilepsies have emerged as an important etiology of drug-refractory epilepsies. The recognition of these entities is vital for immunomodulation and is the cornerstone in its management. Immunotherapy treatment regimens in these conditions continue to be refined, and there is an increasing knowledge in their use. This article attempts to review the experience with the use of different immunotherapies in specific autoimmune and neuroinflammation-related encephalitis and epilepsies including their mechanisms of action and potential side effects.

Asymmetry in frontal alpha activation (FAA) has been associated with specific behavior patterns. Greater activation in the left frontal cortex is related to "approach" motivation, while greater activation in the right cortex is associated with "withdrawal" motivation. Moreover, resting FAA is stable over time among adults. This stability has not been demonstrated among adolescents, and the correspondence between resting FAA and personality has been inconsistently observed. The present study examined stability of FAA and the association between resting FAA and behavioral activation among adolescents. At baseline and 4 months, 99 adolescents completed a resting electroencephalogram (EEG) and a pencil-and-paper measure of personality (BIS/BAS). FAA showed good stability over time (Intra-class correlation coefficient=0.65, p

The following article has been retracted on the request of the Authors Dr. Kapil Arya and Dr. Dhanraj T. Masram entitled “Conversion of Sugar to Aldonic Acids: An Important Industrial Precursor”; published in Mini-Reviews in Organic Chemistry, vol.13, no. 3; Pp. 198-205”. The above article contains a graphical abstract which was used by the authors without soliciting per-mission from the License Compliance UAE, which represents a copyright violation. Bentham Science apologizes to the readers of the journal for not detecting this omission during the publishing process. We thank Mr. Ameer Alian for bringing this breach of conduct to our attention. BENTHAM SCIENCE DISCLAIMER It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication.

Double-paging is an often-cited, if unsubstantiated, problem in multi-level scheduling of memory between virtual machines (VMs) and the hypervisor. This problem occurs when both a virtualized guest and the hypervisor overcommit their respective physical address-spaces. When the guest pages out memory previously swapped out by the hypervisor, it initiates an expensive sequence of steps causing the contents to be read in from the hypervisor swapfile only to be written out again, significantly lengthening the time to complete the guest I/O request. As a result, performance rapidly drops. We present Tesseract, a system that directly and transparently addresses the double-paging problem. Tesseract tracks when guest and hypervisor I/O operations are redundant and modifies these I/Os to create indirections to existing disk blocks containing the page contents. Although our focus is on reconciling I/Os between the guest disks and hypervisor swap, our technique is general and can reconcile, or deduplicate, I/Os for guest pages read or written by the VM. Deduplication of disk blocks for file contents accessed in a common manner is well-understood. One challenge that our approach faces is that the locality of guest I/Os (reflecting the guest's notion of disk layout) often differs from that of the blocks in the hypervisor swap. This loss of locality through indirection results in significant performance loss on subsequent guest reads. We propose two alternatives to recovering this lost locality, each based on the idea of asynchronously reorganizing the indirected blocks in persistent storage. We evaluate our system and show that it can significantly reduce the costs of double-paging. We focus our experiments on a synthetic benchmark designed to highlight its effects. In our experiments we observe Tesseract can improve our benchmark's throughput by as much as 200% when using traditional disks and by as much as 30% when using SSD. At the same time worst case application responsiveness can be improved by a factor of 5.

A zeolite supported Bronsted-acid catalyst system has been developed for the synthesis of novel N-substituted spiro[indole-pyridothiazine] analogs under ultrasonication in shorter reaction times with higher yields. The antiproliferative effects of the synthesized compounds were also tested against a wide range of tumor cell lines.

Microporous zeolite, having well-defined pore sizes, was found to be most efficient catalyst for regioselective synthesis of pyrimidobenzimidazoles. Different kinds of zeolites were studied as supported microporous material and showed quite different catalytic activities due to high acidity, excellent textural parametersm and cage-type 3D porous structure under microwaves, and hold great promise due to excellent reusability properties. The structure of the products was confirmed by spectral and X-ray studies. Furthermore, the reaction was performed over a considerably shorter reaction time and generated significantly higher yields under microwaves than by traditional methods. Ordered microporous materials with well-defined pore sizes are proven as active green catalysts for regioselective synthesis of pyrimidobenzimidazoles. Five kinds of zeolites were studied and showed quite different catalytic activities due to their wide acid sites distributions and various pore structures. The structure of the product was confirmed by NOE and X-ray studies.

1-Butyl-3-methylimidazolium and inorganic anions such as BF4 −, PF6 − and PTSA− are used as green catalyst and reaction medium for synthesis of fluorinated benzothiazolo[2,3-b]quinazoline-2H-ones analogues via one-pot reaction of 2-amino-6-chlorobenzothiazole (1), fluorinated aldehydes (2) dimedone and (3) using microwave irradiation. The whole procedure is simple and straightforward, and no aqueous work-up is needed. Synthesized compounds are screened for photo-antiproliferative activity against human keratinocytes cell line and carcinoma cell lines like promyelocytic leukemia (HL-60) cells and adenocarcinoma (LoVo) cells. Structure activity relationship studies revealed that the substitution on aryl ring played a dominant role and was responsible for the antiproliferative activity.

The purpose of this research is to synthesize better anti-inflammatory compounds derived from 5-mercapto-3-(4′-pyridyl)-4H-1,2,4-triazol-4-yl-thiosemicarbazide (5). 2-Substituted-N-[3-(pyridin-4-yl)-5-sulfanyl-4H-1,2,4-triazol-4-yl]hydrazine carbothioamide derivatives (6a–j)/(7a–e) are synthesized by the condensation of 5 with variously substituted aromatic aldehydes/1H-indole-2,3-diones, respectively, under conventional and microwave irradiation methods. The microwave method is found to be superior with higher chemical yields, tremendous reduction in time, and is environmentally benign as compared to conventional heating method. The chemical structures of the newly synthesized compounds (6/7) have been confirmed by IR, 1H NMR, and 13C NMR spectra and have been evaluated for anti-inflammatory activity by carrageenan-induced acute paw edema method in rats.

Fault tolerance for the upcoming exascale generation has long been an area of active research. One of the components of a fault tolerance strategy is checkpointing. Petascale-level checkpointing is demonstrated through a new mechanism for virtualization of the InfiniBand UD (unreliable datagram) mode, and for updating the remote address on each UD-based send, due to lack of a fixed peer. Note that InfiniBand UD is required to support modern MPI implementations. An extrapolation from the current results to future SSD-based storage systems provides evidence that the current approach will remain practical in the exascale generation. This transparent checkpointing approach is evaluated using a framework of the DMTCP checkpointing package. Results are shown for HPCG (linear algebra), NAMD (molecular dynamics), and the NAS NPB benchmarks. In tests up to 32,752 MPI processes on 32,752 CPU cores, checkpointing of a computation with a 38 TB memory footprint in 11 minutes is demonstrated. Runtime overhead is reduced to less than 1%. The approach is also evaluated across three widely used MPI implementations., 18 pages, 5 figures, to be published in ICPADS 2016

System-level checkpoint-restart is a critical technology for long-running jobs in high-performance computing. Yet, only two approaches to checkpointing MPI applications continue to survive in wide use today. One approach is to use the kernel module-based BLCR in combination with an MPI checkpoint-restart service particular to the MPI implementation in use. Unfortunately, this lacks support for some important Linux system services such as SysV IPC (e.g., shared memory objects). A second approach has been to use the original 2009 DMTCP implementation (herein referred to as DMTCP-09) for transparent, system-level checkpointing. Unfortunately, DMTCP-09 lacked support for checkpointing many of the necessary features found by MPI in a modern batch environment. These include: ssh, the InfiniBand network, process migration (restarting an MPI application on different cluster nodes), and modified file path prefixes on restart (typically due to a changing current directory, mount points, library paths, etc.). This work presents DMTCP-PV, a new user-space transparent checkpointing system based on the concept of process virtualization. This approach separately models the state of each local or distributed subsystem while decoupling it from the core checkpointing engine. By separating these concerns, a domain expert can extend checkpointing into a new domain without any knowledge of the core checkpointing engine. This allowed DMTCP-PV to address the deficiencies noted above and many others. It is shown that the runtime overhead of DMTCP-PV is generally less than 1%, and the checkpointing time is dominated by the time to write an image file to stable storage.

We sought to determine the prevalence of interictal epileptiform discharges (IEDs) in healthy 11- and 12-year-old children. Sixth grade students with no history of seizure, or neurologic or psychiatric disease, were enrolled in a longitudinal physical activity intervention study. Per study protocol, each student had two EEG recordings approximately 6months apart. Epileptiform discharges were present in 4 (2.9%) of 140 students: centrotemporal in three and generalized in one. In three children, the discharges were still present six months later. None of the children had developed seizures a minimum of one year after the second EEG. These results are consistent with those of two landmark European studies performed nearly a half century ago, before the modern era of digital EEG. Healthy 11- and 12-year-old children with no history of seizure may have centrotemporal or generalized epileptiform discharges on EEG, which can persist for at least 6months. Based on both our results and those of the two prior European studies, such discharges, if found incidentally in otherwise healthy children in this age group, should not prompt further evaluation or treatment.

One of the most versatile applications of Group Policy is to manage Microsoft Office, which you will explore in detail in this chapter. There are more than 2,000 Group Policy Settings (including both User and Machine configurations) for Office applications.

This chapter introduces Group Policy and explains how it can be used and configured via its editor, the Group Policy snap-in. With the help of Group Policy, you can save a huge amount of time deploying software on different machines, restricting access to a particular program or feature, enhancing the security and networking of your corporate environment, and making management easier and smoother.