Genetic Characterization of Novel Oral Polio Vaccine Type 2 Viruses During Initial Use Phase Under Emergency Use Listing - Worldwide, March-October 2021.

The emergence and international spread of neurovirulent circulating vaccine-derived polioviruses (cVDPVs) across multiple countries in Africa and Asia in recent years pose a major challenge to the goal of eradicating all forms of polioviruses. Approximately 90% of all cVDPV outbreaks are caused by the type 2 strain of the Sabin vaccine, an oral live, attenuated vaccine; cVDPV outbreaks typically occur in areas of persistently low immunization coverage (1). A novel type 2 oral poliovirus vaccine (nOPV2), produced by genetic modification of the type 2 Sabin vaccine virus genome (2), was developed and evaluated through phase I and phase II clinical trials during 2017-2019. nOPV2 was demonstrated to be safe and well-tolerated, have noninferior immunogenicity, and have superior genetic stability compared with Sabin monovalent type 2 (as measured by preservation of the primary attenuation site [domain V in the 5' noncoding region] and significantly lower neurovirulence of fecally shed vaccine virus in transgenic mice) (3-5). These findings indicate that nOPV2 could be an important tool in reducing the risk for generating vaccine-derived polioviruses (VDPVs) and the risk for vaccine-associated paralytic poliomyelitis cases. Based on the favorable preclinical and clinical data, and the public health emergency of international concern generated by ongoing endemic wild poliovirus transmission and cVDPV type 2 outbreaks, the World Health Organization authorized nOPV2 for use under the Emergency Use Listing (EUL) pathway in November 2020, allowing for its first use for outbreak response in March 2021 (6). As required by the EUL process, among other EUL obligations, an extensive plan was developed and deployed for obtaining and monitoring nOPV2 isolates detected during acute flaccid paralysis (AFP) surveillance, environmental surveillance, adverse events after immunization surveillance, and targeted surveillance for adverse events of special interest (i.e., prespecified events that have the potential to be causally associated with the vaccine product), during outbreak response, as well as through planned field studies. Under this monitoring framework, data generated from whole-genome sequencing of nOPV2 isolates, alongside other virologic data for isolates from AFP and environmental surveillance systems, are reviewed by the genetic characterization subgroup of an nOPV working group of the Global Polio Eradication Initiative. Global nOPV2 genomic surveillance during March-October 2021 confirmed genetic stability of the primary attenuating site. Sequence data generated through this unprecedented global effort confirm the genetic stability of nOPV2 relative to Sabin 2 and suggest that nOPV2 will be an important tool in the eradication of poliomyelitis. nOPV2 surveillance should continue for the duration of the EUL.

Sensitivity of the acute flaccid paralysis surveillance system for poliovirus in South Africa, 2016-2019.

Introduction. Global poliovirus eradication is a public health emergency of international concern. The acute flaccid paralysis (AFP) surveillance programme in South Africa has been instrumental in eliminating polioviruses and keeping the country poliovirus free.Gap statement. The sensitivity of surveillance for polioviruses by every African country is of global interest in the effort to ensure global health security from poliovirus re-emergence.Aim. To describe the epidemiology of polioviruses from AFP cases and environmental samples in South Africa and to report the performance of the AFP surveillance system for the years 2016-2019 against targets established by the World Health Organization (WHO).Methods. Stool specimens from AFP or suspected AFP cases were received and tested as per WHO guidelines. Environmental samples were gathered from sites across the Gauteng province using the grab collection method. Concentration was effected by the two-phase polyethylene glycol method approved by the WHO. Suspected polioviruses were isolated in RD and/or L20B cell cultures through identification of typical cytopathic effects. The presence of polioviruses was confirmed by intratypic differentiation PCR. All polioviruses were sequenced using the Sanger method, and their VP1 gene analysed for mutations.Results. Data from 4597 samples (2385 cases) were analysed from the years 2016-2019. Two cases of immunodeficiency-associated vaccine-derived poliovirus (iVDPV) type 3 were detected in 2017 and 2018. A further 24 Sabin type 1 or type 3 polioviruses were detected for the 4 years. The national surveillance programme detected an average of 3.1 cases of AFP/100 000 individuals under 15 years old (2.8/100 000-3.5/100 000). The stool adequacy of the samples received was 53.0 % (47.0-55.0%), well below the WHO target of 80 % adequacy. More than 90 % of results were released from the laboratory within the turnaround time (96.6 %) and non-polio enteroviruses were detected in 11.6 % of all samples. Environmental surveillance detected non-polio enterovirus in 87.5 % of sewage samples and Sabin polioviruses in 12.5 % of samples.Conclusion. The AFP surveillance programme in South Africa is sensitive to detect polioviruses in South Africa and provided no evidence of wild poliovirus or VDPV circulation in the country.

Post-Transcriptional Regulation in Skeletal Muscle Development, Repair, and Disease.

Skeletal muscle formation is a complex process that requires tight spatiotemporal control of key myogenic factors. Emerging evidence suggests that RNA processing is crucial for the regulation of these factors, and that multiple post-transcriptional regulatory pathways work dependently and independently of one another to enable precise control of transcripts throughout muscle development and repair. Moreover, disruption of these pathways is implicated in neuromuscular disease, and the recent development of RNA-mediated therapies shows enormous promise in the treatment of these disorders. We discuss the overlapping post-transcriptional regulatory pathways that mediate muscle development, how these pathways are disrupted in neuromuscular disorders, and advances in RNA-mediated therapies that present a novel approach to the treatment of these diseases.

The Impact of Next-Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorders.

The impact of high-throughput sequencing in genetic neuromuscular disorders cannot be overstated. The ability to rapidly and affordably sequence multiple genes simultaneously has enabled a second golden age of Mendelian disease gene discovery, with flow-on impacts for rapid genetic diagnosis, evidence-based treatment, tailored therapy development, carrier-screening, and prevention of disease recurrence in families. However, there are likely many more neuromuscular disease genes and mechanisms to be discovered. Many patients and families remain without a molecular diagnosis following targeted panel sequencing, clinical exome sequencing, or even genome sequencing. Here we review how massively parallel, or next-generation, sequencing has changed the field of genetic neuromuscular disorders, and anticipate future benefits of recent technological innovations such as RNA-seq implementation and detection of tandem repeat expansions from short-read sequencing.

Human antibodies neutralize enterovirus D68 and protect against infection and paralytic disease.

Enterovirus D68 (EV-D68) causes outbreaks of respiratory illness, and there is increasing evidence that it causes outbreaks of acute flaccid myelitis (AFM). There are no licensed therapies to prevent or treat EV-D68 infection or AFM disease. We isolated a panel of EV-D68-reactive human monoclonal antibodies that recognize diverse antigenic variants from participants with prior infection. One potently neutralizing cross-reactive antibody, EV68-228, protected mice from respiratory and neurologic disease when given either before or after infection. Cryo-electron microscopy studies revealed that EV68-228 and another potently neutralizing antibody (EV68-159) bound around the fivefold or threefold axes of symmetry on virion particles, respectively. The structures suggest diverse mechanisms of action by these antibodies. The high potency and effectiveness observed in vivo suggest that antibodies are a mechanistic correlate of protection against AFM disease and are candidates for clinical use in humans with EV-D68 infection.

Reorganization of Active Surveillance of Acute Flaccid Paralysis (AFP) in Emilia-Romagna, Italy: a two-step Public Health intervention.

BACKGROUND AND AIM OF THE WORK: The International Health Regulations Emergency Committee declared in 2014 that poliovirus circulation is a public health emergency of international concern. In 2017 and 2018 Italy was classified at intermediate risk of poliovirus reintroduction based on suboptimal poliovirus surveillance. Acute flaccid paralysis active surveillance is the gold standard in the polio eradication process. The aims of this study were to investigate the causes of reduced acute flaccid paralysis case reporting in Emilia-Romagna in the last few years (step 1) and to study a public health intervention to restore an adequate level of acute flaccid paralysis surveillance in that region (step 2). METHODS: In the first step a context analysis was performed by analysing the 2015-2017 Hospital Discharge Registers in Emilia-Romagna with the ICD-9-CM differential diagnosis codes for acute flaccid paralysis. Data from context analysis was then used to plan a new regional collaborative network of acute flaccid paralysis active surveillance. RESULTS: The active surveillance network was, at the end of the study, composed by 49 doctors from both hospital administrations and clinical wards from 4 University Hospitals and 7 Local Health Authorities throughout the Region. In 15 months, 7 acute flaccid paralysis cases have been reported; 85,7% received a full clinical and virological investigation and 83,3% completed the 60 day's follow-up. The mean response to each e-mail was 48,5% (SD 7,5%). CONCLUSIONS: In 2019, the Emilia-Romagna's active surveillance system reached the sensitivity, completeness of case investigation and follow-up required to achieve the minimum levels for certification standard surveillance.

Agility Training to Integratively Promote Neuromuscular, Cognitive, Cardiovascular and Psychosocial Function in Healthy Older Adults: A Study Protocol of a One-Year Randomized-Controlled Trial.

Exercise training effectively mitigates aging-induced health and fitness impairments. Traditional training recommendations for the elderly focus separately on relevant physiological fitness domains, such as balance, flexibility, strength and endurance. Thus, a more holistic and functional training framework is needed. The proposed agility training concept integratively tackles spatial orientation, stop and go, balance and strength. The presented protocol aims at introducing a two-armed, one-year randomized controlled trial, evaluating the effects of this concept on neuromuscular, cardiovascular, cognitive and psychosocial health outcomes in healthy older adults. Eighty-five participants were enrolled in this ongoing trial. Seventy-nine participants completed baseline testing and were block-randomized to the agility training group or the inactive control group. All participants undergo pre- and post-testing with interim assessment after six months. The intervention group currently receives supervised, group-based agility training twice a week over one year, with progressively demanding perceptual, cognitive and physical exercises. Knee extension strength, reactive balance, dual task gait speed and the Agility Challenge for the Elderly (ACE) serve as primary endpoints and neuromuscular, cognitive, cardiovascular, and psychosocial meassures serve as surrogate secondary outcomes. Our protocol promotes a comprehensive exercise training concept for older adults, that might facilitate stakeholders in health and exercise to stimulate relevant health outcomes without relying on excessively time-consuming physical activity recommendations.

Exercise Countermeasures to Neuromuscular Deconditioning in Spaceflight.

The mechanical unloading of spaceflight elicits a host of physiological adaptations including reductions in muscle mass, muscle strength, and muscle function and alterations in central interpretation of visual, vestibular, and proprioceptive information. Upon return to a terrestrial, gravitational environment, these result in reduced function and performance, the potential consequences of which will be exacerbated during exploration missions to austere and distant destinations such as the moon and Mars. Exercise is a potent countermeasure to unloading-induced physiological maladaptations and has been employed since the early days of spaceflight. In-flight exercise hardware has evolved from rudimentary and largely ineffective devices to the current suite onboard the International Space Station (ISS) comprised of a cycle ergometer, treadmill, and resistance exercise device; these contemporary devices have either fully protected or significantly attenuated neuromuscular degradation in spaceflight. However, unlike current microgravity operations on the ISS, future exploration missions will include surface operations in partial gravity environments, which will require greater physiological capacity and work output of their crews. For these flights, it is critical to identify physiological thresholds below which task performance will be impaired and to develop exercise countermeasures-both pre- and in-flight-to ensure that crewmembers are able to safely and effectively complete physically demanding mission objectives. © 2020 American Physiological Society. Compr Physiol 10:171-196, 2020.

Proteasome inhibition preserves longitudinal growth of denervated muscle and prevents neonatal neuromuscular contractures.

Muscle contractures are a prominent and disabling feature of many neuromuscular disorders, including the 2 most common forms of childhood neurologic dysfunction: neonatal brachial plexus injury (NBPI) and cerebral palsy. There are currently no treatment strategies to directly alter the contracture pathology, as the pathogenesis of these contractures is unknown. We previously showed in a mouse model of NBPI that contractures result from impaired longitudinal muscle growth. Current presumed explanations for growth impairment in contractures focus on the dysregulation of muscle stem cells, which differentiate and fuse to existing myofibers during growth, as this process has classically been thought to control muscle growth during the neonatal period. Here, we demonstrate in a mouse model of NBPI that denervation does not prevent myonuclear accretion and that reduction in myonuclear number has no effect on functional muscle length or contracture development, providing definitive evidence that altered myonuclear accretion is not a driver of neuromuscular contractures. In contrast, we observed elevated levels of protein degradation in NBPI muscle, and we demonstrate that contractures can be pharmacologically prevented with the proteasome inhibitor bortezomib. These studies provide what we believe is the first strategy to prevent neuromuscular contractures by correcting the underlying deficit in longitudinal muscle growth.

Paralytic rabies: An acute flaccid myelitis after inadequate post exposure prophylaxis.

Rabies has two distinct clinical syndromes, encephalitic (or 'furious') and paralytic (or 'dumb'). The paralytic form presents as acute flaccid myelitis and is more common in patients who received post-exposure anti-rabies vaccination without rabies immunoglobulins. We have recently had the opportunity to manage a middle-aged man presenting as 'dumb' paralytic rabies.

Ergonomics in Surgery: A Review.

OBJECTIVE: Work-related musculoskeletal disorders (WMSDs) are prevalent among surgeons and may result in practice modification. We aimed to perform a comprehensive review of the English-language literature regarding ergonomic risk, prevalence of WMSDs, and unique ergonomic considerations by route of surgery. METHODS: Multiple searches were performed of PubMed and University library resources to access English-language publications related to surgeon ergonomics. Combinations of keywords were used for each mode of surgery, including the following: "ergonomics," "guidelines," "injury," "operating room," "safety," "surgeon," and "work-related musculoskeletal disorders." Each citation was read in detail, and references were reviewed. RESULTS: Surgeon WMSDs are prevalent, with rates ranging from 66% to 94% for open surgery, 73% to 100% for conventional laparoscopy, 54% to 87% for vaginal surgery, and 23% to 80% for robotic-assisted surgery. Risk factors for injury in open surgery include use of loupes, headlamps, and microscopes. Unique risks in laparoscopic surgery include table and monitor position, long-shafted instruments, and poor instrument handle design. In vaginal surgery, improper table height and twisted trunk position create injury risk. Although robotic surgery offers some advantages, it remains associated with trunk, wrist, and finger strain. Surgeon WMSDs often result in disability but are under-reported to institutions. Additionally, existing research tools face limitations in the operating room environment. CONCLUSIONS: Work-related musculoskeletal disorders are prevalent among surgeons but have received little attention owing to under-reporting of injury and logistical constraints of studying surgical ergonomics. Future research must aim to develop objective surgical ergonomics instruments and guidelines and to correlate ergonomics assessments with pain and tissue-level damage in surgeons with WMSDs. Ergonomics training should be developed to protect surgeons from preventable, potentially career-altering injuries.

Early mobilization: Why, what for and how?

Early mobilization strategies in the intensive care unit may result in the prevention and reduction of polyneuromyopathy in the critical patient, improved quality of life, shortened ICU and hospital stay, and lesser mortality during hospitalization. However, it is well known that factors such as the protocol used, the population included in the studies, the timing of the strategy, the severity of the patients and different barriers directly influence the outcomes. This study examines the main protocols described in the literature and their associated results. The main techniques used were kinesitherapy, transfer and locomotion training, as well as neuromuscular electrical stimulation and cycle ergometry. Although two trials and a meta-analysis found no positive results with mobilization, programs that focus on specific populations, such as patients with weakness due to immobility and with preserved neuromuscular excitability can derive more positive effects from such treatment.

Physiotherapy management of intensive care unit-acquired weakness.

[Hodgson CL, Tipping CJ (2016) Physiotherapy management of intensive care unit-acquired weakness.Journal of Physiotherapy63: 4-10].

Neutralization of the neuromuscular inhibition of venom and taipoxin from the taipan (Oxyuranus scutellatus) by F(ab')2 and whole IgG antivenoms.

The neuromuscular junction activity of Oxyuranus scutellatus venom and its presynaptic neurotoxin, taipoxin, and their neutralization by two antivenoms were examined in mouse phrenic nerve-diaphragm preparations. The action of taipoxin was also studied at 21°C. The efficacy of the antivenoms was also assessed in an in vivo mouse model. Both antivenoms were effective in neutralizing the neuromuscular blocking activity in preincubation-type experiments. In experiments involving independent addition of venom and antivenoms, neutralization depended on the time interval between venom addition and antivenom application. When taipoxin was incubated for 5, 10 or 20min at 21°C, and antivenom added and temperature increased to 37°C, neutralization was achieved only when the toxin was incubated for 5 or 10min. The neutralization by the two antivenoms in an in vivo model showed that both whole IgG and F(ab')2 antivenoms were effective in neutralizing lethality. Our findings highlight the very rapid action of taipan venom at the nerve terminal, and the poor capacity of antivenoms to revert neurotoxicity as the time interval between venom or taipoxin application and antivenom addition increased. Additionally the disparity between molecular masses of the active substances of the two antivenoms did not result in differences in neutralization.

Neuromuscular dysfunction in type 2 diabetes: underlying mechanisms and effect of resistance training.

Diabetic patients are at higher risk of developing physical disabilities than non-diabetic subjects. Physical disability appears to be related, at least in part, to muscle dysfunction. Several studies have reported reduced muscle strength and power under dynamic and static conditions in both the upper and lower limbs of patients with type 2 diabetes. Additional effects of diabetes include a reduction in muscle mass, quality, endurance and an alteration in muscle fibre composition, though the available data on these parameters are conflicting. The impact of diabetes on neuromuscular function has been related to the co-existence of long-term complications. Peripheral neuropathy has been shown to affect muscle by impairing motor nerve conduction. Also, vascular complications may contribute to the decline in muscle strength. However, muscle dysfunction occurs early in the course of diabetes and affects also the upper limbs, thus suggesting that it may develop independently of micro and macrovascular disease. A growing body of evidence indicates that hyperglycaemia may cause an alteration of the intrinsic properties of the muscle to generate force, via several mechanisms. Recently, resistance exercise has been shown to be an effective strategy to counteract the deterioration of muscular performance. High-intensity exercise seems to provide greater benefits than moderate-intensity training, whereas the effect of a power training is yet unknown. This article reviews the available literature on the impairment of muscle function induced by diabetes, the underlying mechanisms, and the effect of resistance training on this defect. Copyright © 2015 John Wiley & Sons, Ltd.

Detecting within- and between-day manifestations of neuromuscular fatigue at work: an exploratory study.

Cumulative neuromuscular fatigue may result from exposure to physically demanding work, such as repetitive and/or sustained work with insufficient recovery. The aims of this exploratory study were to develop a battery of field usable fatigue measures and to document hand/arm fatigue in physically demanding work over multiple workdays and after a weekend break. Sixteen plumbers were observed for five days and measures of handgrip force, variability, tremor and discomfort were obtained pre-, mid- and post-shift. This exploratory study demonstrated increasing fatigue of the hand/arm over the day and persistent fatigue from Tuesday to Friday, and that a number of the measures did not return to baseline values following a weekend break. The findings provide preliminary evidence of cumulative fatigue in residential plumbing and insight into neuromuscular fatigue measurement. However, further work is needed to develop and refine a set of fatigue measures to detect neuromuscular fatigue at the workplace. PRACTITIONER SUMMARY: Cumulative fatigue has been linked to long-term health outcomes, including work-related musculoskeletal disorders. This paper presents findings from a physically demanding job (i.e. plumbing) revealing persistent fatigue over the work shift(s) and insufficient recovery after a weekend break, and provides insight into fatigue measurement at the workplace.

[Magnesium: a supercation misunderstood? Overview and survey of GPs in "Ille-et-Vilaine"]. / Le magnésium: un super cation méconnu? Revue générale et enquête auprès des généralistes d'Ille-et-Vilaine.

Since the introduction of the first magnesium pharmaceutical specialty in 1928, multiple medical indications were attributed to magnesium supplementation, despite rigorous scientific researches, leading to a very confuse therapeutic chapter. Real hypomagnesemia, acute or chronic, is rare, however oral magnesium drugs are numerous and widely prescribed. Moreover, in France, only proven magnesium deficiency, isolated or combined, are accepted by the HAS for magnesium supplementation. The purpose of this article is to review current knowledges on magnesium and analyze the prescribing practices of GPs. After telephone agreement, 100 doctors of Ille-et-Vilaine received an e-questionnaire that included 27 questions (38 items). These questions concerned the prescribing practices of magnesium, magnesium knowledge, and demographic data: 70% of responders say that prescribing magnesium shows an interest in their daily practice and 96% of responders that they often prescribe magnesium leading to 26% who prescribe magnesium even if they do not see the point! In only 7% of cases, prescription is the renewal of a specialist, and in 7% of cases, the request comes from the patient. GPs report that their knowledge on magnesium and its treatment indications come from the pharmaceutical industry. There is also a significant number of requirements driven by the patient himself, probably under the influence of the media especially Internet forums.