The Role of Botulinum Toxin Type-A in Spasticity: Research Trends from a Bibliometric Analysis.

Botulinum toxin type-A (BoNT-A) has emerged as a key therapeutic agent for the management of spasticity. This paper presents a comprehensive bibliometric and visual analysis of research concerning BoNT-A treatment of spasticity to elucidate current trends and future directions in this research area. A search was conducted in the Web of Science database for articles focused on the use of BoNT-A in spasticity published between 2000 and 2022. We extracted various metrics, including counts of publications and contributions from different countries, institutions, authors, and journals. Analytical methods in CiteSpace were employed for the examination of co-citations, collaborations, and the co-occurrence of keywords. Our search yielded 1489 publications. Analysis revealed a consistent annual increase in research output. The United States, United Kingdom, and Italy were the leading contributors. The top institution in this research was Assistance Publique Hopitaux, Paris. The journal containing the highest number of relevant publications was Toxins. Key frequently occurring keywords were 'stroke', 'cerebral palsy', 'adult spasticity', and 'upper extremity'. This study identified 12 clusters of keywords and 15 clusters of co-cited references, indicating the main focus areas and emerging themes in this field. This study comprehensively analyzed and summarized trends in BoNT-A research in the field of spasticity over the past 22 years.

Estimating measures to reduce the transmission of SARS-CoV-2 in Australia to guide a 'National Plan' to reopening.

The availability of COVID-19 vaccines promised a reduction in the severity of disease and relief from the strict public health and social measures (PHSMs) imposed in many countries to limit spread and burden of COVID-19. We were asked to define vaccine coverage thresholds for Australia's transition to easing restrictions and reopening international borders. Using evidence of vaccine effectiveness against the then-circulating Delta variant, we used a mathematical model to determine coverage targets. The absence of any COVID-19 infections in many sub-national jurisdictions in Australia posed particular methodological challenges. We used a novel metric called Transmission Potential (TP) as a proxy measure of the population-level effective reproduction number. We estimated TP of the Delta variant under a range of PHSMs, test-trace-isolate-quarantine (TTIQ) efficiencies, vaccination coverage thresholds, and age-based vaccine allocation strategies. We found that high coverage across all ages (≥70%) combined with ongoing TTIQ and minimal PHSMs was sufficient to avoid lockdowns. At lesser coverage (≤60%) rapid case escalation risked overwhelming of the health sector or the need to reimpose stricter restrictions. Maintaining low case numbers was most beneficial for health and the economy, and at higher coverage levels (≥80%) further easing of restrictions was deemed possible. These results directly informed easing of COVID-19 restrictions in Australia.

Estimating the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission in Australia.

BACKGROUND: Australian states and territories used test-trace-isolate-quarantine (TTIQ) systems extensively in their response to the COVID-19 pandemic in 2020-2021. We report on an analysis of Australian case data to estimate the impact of test-trace-isolate-quarantine systems on SARS-CoV-2 transmission. METHODS: Our analysis uses a novel mathematical modelling framework and detailed surveillance data on COVID-19 cases including dates of infection and dates of isolation. First, we directly translate an empirical distribution of times from infection to isolation into reductions in potential for onward transmission during periods of relatively low caseloads (tens to hundreds of reported cases per day). We then apply a simulation approach, validated against case data, to assess the impact of case-initiated contact tracing on transmission during a period of relatively higher caseloads and system stress (up to thousands of cases per day). RESULTS: We estimate that under relatively low caseloads in the state of New South Wales (tens of cases per day), TTIQ contributed to a 54% reduction in transmission. Under higher caseloads in the state of Victoria (hundreds of cases per day), TTIQ contributed to a 42% reduction in transmission. Our results also suggest that case-initiated contact tracing can support timely quarantine in times of system stress (thousands of cases per day). CONCLUSION: Contact tracing systems for COVID-19 in Australia were highly effective and adaptable in supporting the national suppression strategy from 2020-21, prior to the emergence of the Omicron variant in November 2021. TTIQ systems were critical to the maintenance of the strong suppression strategy and were more effective when caseloads were (relatively) low.

Safety and real-world dosing of onabotulinumtoxinA for the treatment of adult spasticity: post hoc analysis of the Adult Spasticity International Registry study.

OBJECTIVE: To evaluate the safety of onabotulinumtoxinA treatment for spasticity across dose ranges in real-world practice. DESIGN: Adult Spasticity International Registry (ASPIRE) was a multicenter, prospective, observational study (NCT01930786) of onabotulinumtoxinA treatment for adult spasticity over 2 years. Adverse events (AEs), serious AEs (SAEs), treatment-related AEs (TRAEs), and TRSAEs were sorted into 5 categories (≤200 U, 201-400 U, 401-600 U, 601-800 U, ≥801 U) based on cumulative dose per session. RESULTS: In 3103 treatment sessions (T), 730 patients received ≥1 dose of onabotulinumtoxinA. Dose categories included: ≤200 U (n = 312; t = 811), 201-400 U (n = 446, t = 1366), 401-600 U (n = 244, t = 716), 601-800 U (n = 69, t = 149), ≥801 U (n = 29, t = 61). Of these patients, 261 reported 827 AEs, 94 reported 195 SAEs, 20 reported 23 TRAEs, and 2 patients treated with 201-400 U onabotulinumtoxinA reported 3 TRSAEs. TRAEs reported: ≤200 U (8 TRAEs/811, 0.9%); 201-400 U (7/1366, 0.5%); 401-600 U (6/716, 0.8%); 601-800 U (1/149, 0.7%); ≥801 U (1/61, 1.6%). CONCLUSIONS: In this post hoc analysis, most treatment sessions were performed with 201-400 U onabotulinumtoxinA. Patients treated with 201-400 U onabotulinumtoxinA had an AE profile consistent with onabotulinumtoxinA package inserts globally (eg, United States, European Union, United Kingdom, Canada). No new safety signals were identified.

The hypoxia-inducible factor EPAS1 is required for spermatogonial stem cell function in regenerative conditions.

In this study we explored the role of hypoxia and the hypoxia-inducible transcription factor EPAS1 in regulating spermatogonial stem cell (SSC) function in the mouse testis. We have demonstrated that SSCs reside in hypoxic microenvironments in the testis through utilization of the oxygen-sensing probe pimonidazole, and by confirming the stable presence of EPAS1, which is degraded at >5% O2. Through the generation of a germline-specific Epas1 knockout mouse line, and through modulation of EPAS1 levels in primary cultures of spermatogonia with the small drug molecule Daprodustat, we have demonstrated that EPAS1 is required for robust SSC function in regenerative conditions (post-transplantation and post-chemotherapy), via the regulation of key cellular processes such as metabolism. These findings shed light on the relationship between hypoxia and male fertility and will potentially facilitate optimization of in vitro culture conditions for infertility treatment pipelines using SSCs, such as those directed at pediatric cancer survivors.

Trends in the Utilization of Herbal and Dietary Supplements in Patients with Chronic Liver Disease During the SARS-CoV2 Pandemic.

Background: We studied the pattern of herbal and dietary supplement (HDS) use in patients with chronic liver disease (CLD) during the first year of the COVID-19 pandemic. Methods: A questionnaire/survey was sent to hepatology patients with CLD under the care of hepatologists at Johns Hopkins University School of Medicine. Results: The 5 most taken dietary supplements during the pandemic included vitamin B12 (27.7%), vitamin C (32.4%), vitamin D (54.6%), zinc (25.4%) and green tea extract (20.8%). Most participants (82.3%) did not discuss their HDS use with their hepatology providers. Conclusions: Healthcare providers should be mindful of potential HDS use in patients with CLD.

Current practice focus trends in physical medicine and rehabilitation.

BACKGROUND: Physical medicine and rehabilitation (PM&R) is a diverse specialty, growing and evolving over a variety of subspecialty and practice focus areas. Accurate data regarding practice patterns of physiatrists are essential for updating requirements in training and certification, particularly as the Accreditation Council for Graduate Medical Education begins its process to update of the PM&R core residency training requirements. This study analyzes practice trends for nearly 98% of physiatrists in active practice, the largest study to date. OBJECTIVE: To update current demographics of physicians specializing in PM&R, including current areas of practice focus, to analyze the alignment of practice focus with subspecialty certification, and to determine the extent that electromyography is a component of current physiatric practice. DESIGN: Retrospective analysis of deidentified responses from American Board of Physical Medicine and Rehabilitation (ABPMR) board-certified PM&R physicians (diplomates) on annual enrollment in the ABPMR Continuing Certification program. PARTICIPANTS: A total of 9543 ABPMR diplomates. MAIN OUTCOME MEASURES: Demographics - age, gender, years in practice, practice setting(s) and area(s). Practice focus, subspecialty certifications. RESULTS: The majority of practicing physiatrists are men (62%) although the percentage of women in the field is growing (38%). Nearly 80% of physiatrists report more than one practice focus area, with pain medicine and sports medicine/musculoskeletal practices most commonly reported. CONCLUSIONS: This study confirms the growth trends in PM&R in pain and sports medicine but also highlights the substantial number of physiatrists focusing their practices in areas related to neurorehabilitation and medical rehabilitation. The large majority of physiatrists incorporate multiple focus areas into their practices. Electromyography is a focus for a declining percentage of practicing physiatrists.

High levels of maternally derived antibodies do not significantly interfere with the development of humoral and cell-mediated responses to Porcine circovirus 2 after intradermal vaccination.

BACKGROUND: Vaccination of pigs against PCV2 is usually performed around weaning when animals still have maternally derived antibodies (MDA). The present study aimed to assess the possible interference of MDA in the development of the PCV2-specific immune response after vaccination of commercial weaners. For this purpose, a PRRS-negative 600-sow farrow-to-finish farm was selected. Half of the sows were vaccinated and revaccinated with Porcilis® PCV ID against PCV2 7 and 3 weeks before farrowing. After farrowing, piglets were tested by AlphaLisa to select 72 animals with high and low levels of MDA. Groups were further subdivided and vaccinated intradermally with Porcilis® PCV ID at 21 or 28 days of age. Unvaccinated controls were also included. Animals were followed afterward for 42 days to examine the development of PCV2-specific antibodies and interferon-γ secreting cells (IFN-γ SC). RESULTS: The average titres of antibodies of the groups vaccinated in the presence of low or high MDA levels were similar at 28 and 42 days post-vaccination while in the controls the titres declined throughout the observation period. Results of vaccinating at 21 or 28 days of age were equivalent with regard to antibody development. Regarding the IFN-γ SC, vaccinated animals produced significant frequencies of IFN-γ SC by day 28. Again, no differences were observed between the groups with high or low antibody levels. CONCLUSION: High levels of MDA did not interfere with the development of humoral and cell-mediated responses to Porcine circovirus 2 after intradermal vaccination at 21 or 28 days of age.

Antidepressant mechanisms of ketamine: a review of actions with relevance to treatment-resistance and neuroprogression.

Concurrent with recent insights into the neuroprogressive nature of depression, ketamine shows promise in interfering with several neuroprogressive factors, and has been suggested to reverse neuropathological patterns seen in depression. These insights come at a time of great need for novel approaches, as prevalence is rising and current treatment options remain inadequate for a large number of people. The rapidly growing literature on ketamine's antidepressant potential has yielded multiple proposed mechanisms of action, many of which have implications for recently elucidated aspects of depressive pathology. This review aims to provide the reader with an understanding of neuroprogressive aspects of depressive pathology and how ketamine is suggested to act on it. Literature was identified through PubMed and Google Scholar, and the reference lists of retrieved articles. When reviewing the evidence of depressive pathology, a picture emerges of four elements interacting with each other to facilitate progressive worsening, namely stress, inflammation, neurotoxicity and neurodegeneration. Ketamine acts on all of these levels of pathology, with rapid and potent reductions of depressive symptoms. Converging evidence suggests that ketamine works to increase stress resilience and reverse stress-induced dysfunction, modulate systemic inflammation and neuroinflammation, attenuate neurotoxic processes and glial dysfunction, and facilitate synaptogenesis rather than neurodegeneration. Still, much remains to be revealed about ketamine's antidepressant mechanisms of action, and research is lacking on the durability of effect. The findings discussed herein calls for more longitudinal approaches when determining efficacy and its relation to neuroprogressive factors, and could provide relevant considerations for clinical implementation.

COVID-19 vaccine coverage targets to inform reopening plans in a low incidence setting.

Since the emergence of SARS-CoV-2 in 2019 through to mid-2021, much of the Australian population lived in a COVID-19-free environment. This followed the broadly successful implementation of a strong suppression strategy, including international border closures. With the availability of COVID-19 vaccines in early 2021, the national government sought to transition from a state of minimal incidence and strong suppression activities to one of high vaccine coverage and reduced restrictions but with still-manageable transmission. This transition is articulated in the national 're-opening' plan released in July 2021. Here, we report on the dynamic modelling study that directly informed policies within the national re-opening plan including the identification of priority age groups for vaccination, target vaccine coverage thresholds and the anticipated requirements for continued public health measures-assuming circulation of the Delta SARS-CoV-2 variant. Our findings demonstrated that adult vaccine coverage needed to be at least 60% to minimize public health and clinical impacts following the establishment of community transmission. They also supported the need for continued application of test-trace-isolate-quarantine and social measures during the vaccine roll-out phase and beyond.

Design and Validation of a Low-Cost Mobile EEG-Based Brain-Computer Interface.

Objective: We designed and validated a wireless, low-cost, easy-to-use, mobile, dry-electrode headset for scalp electroencephalography (EEG) recordings for closed-loop brain-computer (BCI) interface and internet-of-things (IoT) applications. Approach: The EEG-based BCI headset was designed from commercial off-the-shelf (COTS) components using a multi-pronged approach that balanced interoperability, cost, portability, usability, form factor, reliability, and closed-loop operation. Main Results: The adjustable headset was designed to accommodate 90% of the population. A patent-pending self-positioning dry electrode bracket allowed for vertical self-positioning while parting the user's hair to ensure contact of the electrode with the scalp. In the current prototype, five EEG electrodes were incorporated in the electrode bracket spanning the sensorimotor cortices bilaterally, and three skin sensors were included to measure eye movement and blinks. An inertial measurement unit (IMU) provides monitoring of head movements. The EEG amplifier operates with 24-bit resolution up to 500 Hz sampling frequency and can communicate with other devices using 802.11 b/g/n WiFi. It has high signal-to-noise ratio (SNR) and common-mode rejection ratio (CMRR) (121 dB and 110 dB, respectively) and low input noise. In closed-loop BCI mode, the system can operate at 40 Hz, including real-time adaptive noise cancellation and 512 MB of processor memory. It supports LabVIEW as a backend coding language and JavaScript (JS), Cascading Style Sheets (CSS), and HyperText Markup Language (HTML) as front-end coding languages and includes training and optimization of support vector machine (SVM) neural classifiers. Extensive bench testing supports the technical specifications and human-subject pilot testing of a closed-loop BCI application to support upper-limb rehabilitation and provides proof-of-concept validation for the device's use at both the clinic and at home. Significance: The usability, interoperability, portability, reliability, and programmability of the proposed wireless closed-loop BCI system provides a low-cost solution for BCI and neurorehabilitation research and IoT applications.

[First French-speaking days of users of decision support system in clinical pharmacy: Feedback and perspectives]. / Premières journées francophones des utilisateurs de système d'aide à la décision en pharmacie clinique : retour d'expériences et perspectives.

Clinical decision support systems (CDSS) are tools that have been used for several years by clinical pharmacy teams to support pharmaceutical analysis, with a perspective of contributing to the quality of care in collaboration with the other health care team members. These tools require both technical, logistical and human resources. The growing use of these systems in different establishments in France and in Europe gave birth to the idea of meeting to share our experiences. The days organized in Lille in September 2021 aimed at proposing a time of exchange and reflection on the use of these CDSS in clinical pharmacy. A first session was devoted to feedback from each establishment. These tools are essentially used to optimize pharmaceutical analysis and to secure patient medication management. This session outlined the clear advantages and common limitations of these CDSS. Two research projects were also presented to put the use of these tools into perspective. The second session of these days, in the form of workshops, addressed 4 themes that surround the implementation of CDSS: their usability, the legal aspect, the creation of rules and their possible valorization. Common problems were raised, the resolution of which requires close collaboration. This is a first step proposing a beginning of harmonization and sharing that should be deepened in order not to lose the dynamics created between the different centers. This event ended with the proposal to set up two working groups around these systems: the creation and structuring of rules for the detection of risk situations and the common valorization of the work.

Maternal diet modulates the infant microbiome and intestinal Flt3L necessary for dendritic cell development and immunity to respiratory infection.

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs.

Does Spasticity Correlate With Motor Impairment in the Upper and Lower Limbs in Ambulatory Chronic Stroke Survivors?

OBJECTIVE: This study aimed to explore correlations between spasticity and motor impairments in the upper and lower limbs in ambulatory chronic stroke survivors. DESIGN: We performed clinical assessments in 28 ambulatory chronic stroke survivors with spastic hemiplegia (female: 12; male: 16; mean ages = 57.8 ± 11.8 yrs; 76 ± 45 mos after stroke). RESULTS: In the upper limb, spasticity index and Fugl-Meyer Motor Assessment showed a significant correlation. Spasticity index for the upper limb showed a significant negative correlation with handgrip strength of the affected side ( r = -0.4, P = 0.035) while Fugl-Meyer Motor Assessment for the upper limb had a significant positive correlation ( r = 0.77, P < 0.001). In the LL, no correlation was found between SI_LL and FMA_LL. There was a significant and high correlation between timed up and go test and gait speed ( r = 0.93, P < 0.001). Gait speed was positively correlated with Spasticity index for the lower limb ( r = 0.48, P = 0.01), and negatively correlated with Fugl-Meyer Motor Assessment for the lower limb ( r = -0.57, P = 0.002). Age and time since stroke showed no association in analyses for both upper limb and lower limb. CONCLUSIONS: Spasticity has a negative correlation on motor impairment in the upper limb but not in the lower limb. Motor impairment was significantly correlated with grip strength in the upper limb and gait performance in the lower limb of ambulatory stroke survivors.

Vagus Nerve Stimulation Paired With Upper-Limb Rehabilitation After Stroke: 2- and 3-Year Follow-up From the Pilot Study.

OBJECTIVE: To assess whether a long-term home-based intervention using Paired VNS therapy is feasible and whether the benefits of Paired VNS therapy are maintained beyond 1 year. DESIGN: A long-term follow-up study. SETTING: Three centers in the United States and 1 in the United Kingdom. PARTICIPANTS: Adults with chronic ischemic stroke (n=15) with moderate to severe arm and hand impairment. INTERVENTIONS: Participants were implanted with a VNS device followed by 6 weeks of in-clinic therapy with Paired (Active) or control VNS followed by home-based rehabilitation through day 90 (blinded phase). The control VNS group then crossed over to receive 6 weeks of in-clinic Active VNS. Participants in both groups then continued a long-term home exercise program with self-administered Active VNS. MAIN OUTCOME MEASURES: Fugl-Meyer Assessment for Upper Extremity (FMA-UE) and Wolf Motor Function Test (WMFT) Functional scores were evaluated at the end of in-clinic therapy and day 90. Since both groups were subsequently receiving home-based rehabilitation with Active VNS during the long term, follow-up outcome assessments were pooled for the analyses at 6, 9, and 12 months, as previously reported. Here, we report pooled analysis of outcomes beyond 1 year. RESULTS: One year after Paired VNS therapy, FMA-UE improved by an average of 9.2±8.2 points, as previously reported. Overall, the 2- and 3-year FMA-UE gain from baseline was 11.4±8.7 (P<.001) and 14.8±10.2 points (P<.001), respectively. At years 2 and 3, FMA-UE improved by an additional 2.9 (P=.03 for change vs year 1, n=14) and 4.7 (P=.02 for change vs year 1, n=14) points, respectively. At year 1, 73% (11/15) of participants were responders (FMA-UE change ≥6) and by year 3, 85.7% (12/14) were responders. At years 2 and 3, the WMFT score improved by an additional 0.21 points (P=.03 for change vs year 1, n=15) and 0.42 points (P=.01 for change vs year 1, n=13), respectively. Responder rate (WMFT change ≥0.4) was 46.6% (7/15), 73.3% (11/15), and 69.2% (9/13) at years 1, 2, and 3, respectively. Long-term significant improvements were also observed for Motor Activity Log (MAL) and Stroke Impact Scale, Hand section (SIS-Hand). There were no serious long-term adverse events from the stimulation. CONCLUSIONS: Significant effects of Paired VNS therapy at 1 year were maintained at years 2 and 3, and further improvements in both impairment and function were observed in years 2 and 3. These changes were associated with improvements in measures of activity and participation.

Introduction of a PRRSV-1 strain of increased virulence in a pig production structure in Spain: virus evolution and impact on production.

BACKGROUND: A strain of Porcine reproductive and respiratory syndrome virus (PRRSV), showing characteristics of enhanced virulence, affected a pyramidal production system from Spain with 7600 sows in 4 genetic nuclei and 13,000 sows in multipliers. Different PRRSV strains circulating in this production system from December 2020 to October 2021 were detected and sequenced. The spread of each isolate was examined and their impact on health and production in three of the affected farms was evaluated. RESULTS: The newly emerged PRRSV isolate with enhanced virulence entered the system before the onset of the study (January 2020) and afterwards four significantly different clades were detected during the study period in different farms, probably because of independent introduction events. The diversification of the enhanced virulence strain was higher for those clades (substitution rates up to 1.1% nucleotides/year) compared to other PRRSV strains present in the production system (up to 0.17%), suggesting a faster spread and adaptation. The impact of the infection in the first affected farm was dramatic, with an average abortion rate above 27% during 17 weeks before returning to the baseline production. Fertile sow mortality reached 6.5% for 39 weeks. In two farms infected later by other clades of this enhanced virulence strain, the impact was less acute; despite the fact that for parameters such as the proportion of stillbirths or mummies, more than 10 months were needed to recover pre-outbreak values. In the examined nurseries, mortalities reached peaks between 28 and 50% and several months were needed to return to normality. CONCLUSION: Introduction of a PRRSV strain of enhanced virulence in a production system where several farms were previously positive for other PRRSV strains, resulted in a fast spread such as would be observed in naïve farms. The productive and health impact was very high taking several months to return to normality.

Vagus Nerve Stimulation Paired With Rehabilitation for Upper Limb Motor Impairment and Function After Chronic Ischemic Stroke: Subgroup Analysis of the Randomized, Blinded, Pivotal, VNS-REHAB Device Trial.

BACKGROUND: Vagus Nerve Stimulation (VNS) paired with rehabilitation improved upper extremity impairment and function in a recent pivotal, randomized, triple-blind, sham-controlled trial in people with chronic arm weakness after stroke. OBJECTIVE: We aimed to determine whether treatment effects varied across candidate subgroups, such as younger age or less injury. METHODS: Participants were randomized to receive rehabilitation paired with active VNS or rehabilitation paired with sham stimulation (Control). The primary outcome was the change in impairment measured by the Fugl-Meyer Assessment Upper Extremity (FMA-UE) score on the first day after completion of 6-weeks in-clinic therapy. We explored the effect of VNS treatment by sex, age (≥62 years), time from stroke (>2 years), severity (baseline FMA-UE score >34), paretic side of body, country of enrollment (USA vs UK) and presence of cortical involvement of the index infarction. We assessed whether there was any interaction with treatment. FINDINGS: The primary outcome increased by 5.0 points (SD 4.4) in the VNS group and by 2.4 points (SD 3.8) in the Control group (P = .001, between group difference 2.6, 95% CI 1.03-4.2). The between group difference was similar across all subgroups and there were no significant treatment interactions. There was no important difference in rates of adverse events across subgroups. CONCLUSION: The response was similar across subgroups examined. The findings suggest that the effects of paired VNS observed in the VNS-REHAB trial are likely to be consistent in wide range of stroke survivors with moderate to severe upper extremity impairment.