Functional intermuscular reduction in spasticity for people with multiple sclerosis

Background Eighty-five percent of people with multiple sclerosis (MS) incur gait impairments debilitating enough to significantly impact their function. Objectives The aim of this study was to determine if a novel combination of intermuscular electrical stimulation, followed by functional electrical stimulation combined with supported bodyweight treadmill training, would improve gait, decrease spasticity and fatigue, and improve muscle strength. Methods Using a pre-post experimental design, we implemented this combination six-week protocol in 16 individuals with MS. We completed summary statistics and longitudinal pre-post results using Wilcoxon sign rank tests with Bonferroni adjustment. Results Participants responded with median increases of 29.4 feet ( p < 0.0001) during the Six Minute Walk Test, median decreases of 0.7 s ( p = 0.0011) in the 25-Foot Walk Test, median increases of 3.8 toe taps to fatigue ( p = 0.0306) and median increases of 5.0 heel raises ( p = 0.0093). Significant changes were noted in the Modified Ashworth Scale, both after intermuscular electrical stimulation (median change = −0.5 p = 0.0039) and after treadmill walking (median change = −0.5, p < 0.0005). Conclusions Results of this novel protocol suggest this intervention combination has the potential to decrease spasticity, and improve gait speed and endurance in individuals with MS. Observed changes in mobility occurred without accompanying increases in fatigue.

The Continuing Effect of COVID-19 Pandemic on Physical Well-Being and Mental Health of ICU Healthcare Workers in Turkey: A Single-Centre Cross-Sectional Later-Phase Study

Background This study aimed to evaluate the effect of COVID-19 pandemic on physical well-being and mental health of ICU healthcare workers (HCWs). Methods A total of 51 ICU HCWs working at a tertiary care hospital were included in this cross-sectional study conducted before (January 2019-January 2020) and during (January 2021-April 2021) COVID-19 pandemic. Data on sociodemographic and work-related characteristics, COVID 19 history and current mental health issues via Hospital Anxiety-Depression Scale (HADS), Pittsburgh Sleep Quality Index (PSQI), Eating Attitudes Test (EAT-40), Suicidal Ideation Scale (SIS) and Maslach Burnout Inventory (MBI) were recorded. Results Overall, 62.7% of participants were nurses, heavy workload (working ≥200 h/month) was reported by 76.5% of participants and previous history of COVID-19 was confirmed by 62.7%. Current mental health issues involved poor sleep quality in majority (96.1%) of participants, anxiety (51.0%), depression (51.0%) in at least half of them and a moderate degree of emotional exhaustion Heavy workload was associated with more remarkable decrease in sleep duration (median change: −0.5 vs. −1.0 h/day, P = .020), Vit B12 (median change: 60[−48-293] vs. −65[−371-262] pg/mL, P < .001) and Vit D (median change: −1.6[−13.1-20] vs. −9.7[−39.7-21.8] ng/mL, P = .004) during pandemic, while working hours per month were also significantly higher in those with versus without anxiety (264[150-390] vs. 240[150-264] h, P = .003) and with versus without depression (264[150-390] vs. 240[150-264] h, P = .037). Conclusion Our findings indicate high prevalence of mental health issues including anxiety and depression as well as poor sleep quality and emotional burnout among ICU HCWs, particularly those with heavy workload.

Nonmyeloablative HLA-Identical Sibling Donor Transplantation for Children and Young Adults with Sickle Cell Disease: Interim Results of the SUN Multicenter Phase II Trial

Background: HLA-identical sibling hematopoietic stem cell transplant (HSCT) using myeloablative chemotherapy conditioning is a proven cure for sickle cell disease (SCD), but is associated with serious short and long-term toxicities. Additionally graft versus host disease (GVHD) can complicate care post-HSCT and contribute to mortality. Given these concerns many pediatric hematologists and families are reluctant to pursue HSCT for SCD. Nonmyeloablative HSCT resulting in stable mixed chimerism has been demonstrated to abrogate the SCD phenotype in adults. Data on outcomes of this approach to decrease toxicities and achieve cure in children remains scarce. Objective: To evaluate event-free survival (EFS), toxicity, health-related quality of life (HRQL), and transfusion burden among pediatric patients with SCD using a chemotherapy-free nonmyeloablative regimen. Methods/design: Children and young adults with SCD were prospectively enrolled in the Sickle transplant Using a Nonmyeloablative approach (SUN) multicenter clinical trial (NCT03587272). Six Sickle Cell Transplant Advocacy and Research Alliance (STAR) sites in the United States and Canada enrolled patients. The conditioning regimen consisted of alemtuzumab IV (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on Days -5 to -3), low-dose total body irradiation with gonadal shielding (300 cGY on day -2), peripheral blood stem cells from an HLA-identical sibling, and sirolimus for at least one year. Baseline HRQL was compared with scores at day +30 and day +100 post-HSCT using the PedsQL and PROMIS measures. EFS was defined by any of the following events: death, graft failure (myeloid donor chimerism &lt;10%), or GVHD. Results: All 30 of the patients planned for the primary endpoint of EFS have been enrolled. As of 7/20/2021, 24 patients are greater than 100 days post-HSCT with a median follow-up of 365 days (range 189-1105). The median age of this group at time of transplant was 13.5 years (range 2-22). All patients had neutrophil recovery (ANC &gt;500/ul x 3 days) at a median of 21.5 days (range 0-29). Eleven patients (46%) did not require any platelet transfusions. Median transplant hospitalization was 16.5 days (range 14-43). Seven patients (29%) were again hospitalized (median 4 days, range 1-26). Three patients had secondary graft rejection at Day +71, +91, and +92 with no major complications and autologous recovery resulting in an EFS of 87.5% (Figure 1). Three additional patients have stable low donor chimerism (myeloid chimerism 11%, 38%, and 47%). The remaining 18 patients (75%) are disease-free and have robust donor engraftment (72-100% myeloid chimerism). Nine of these patients are &gt;1 year post-HSCT and off sirolimus. Overall survival is 100% with no acute or chronic GVHD. Figure 2 shows total PedsQL scores during the peri-transplant time period. The median change in day +30 scores compared to baseline was 0 (IQR -7, +10), p=0.66. The median change in day +100 scores compared to baseline was +5 (IQR 0, +10), p=0.02. Conclusions: Outcomes of pediatric nonmyeloablative HLA-identical sibling HSCT for SCD appear similar to the larger adult experience with a GVHD-free, rejection-free survival of &gt;80%. Importantly, patients have no worsening of their quality of life in the first month post-HSCT and already an improvement at day +100, suggesting that the short-term toxicities experienced by patients transplanted with this regimen are minimal. The majority of patients achieve disease resolution with no GVHD, but graft failure incidence appears higher than with myeloablative HSCT. Given the low intensity of this approach, a reasonable strategy may be to reserve myeloablation for a second transplant in the minority of patients who experience graft failure. Figure 1 Figure 1. Disclosures Rangarajan: Medexus (Treosulfan): Consultancy, Honoraria. Guilcher: BlueBirdBio: Research Funding; Project Sickle Cure Study: Other: Principal Investigator, Research Funding. OffLabel Disclosure: alemtuzumab and sirolimus were used off-label as part of the studied transplant regimen

A Randomized Placebo-Controlled Trial of Primary Prophylaxis with Weekly Alendronate Against Glucocorticoid-Induced Osteoporosis in Lymphoma Patients Treated with Steroid-Containing Chemotherapy.

Introduction: Many lymphoma patients receive high doses of glucocorticoids as part of standard therapy, and several recent observational studies have highlighted a possible risk of glucocorticoid-induced osteoporosis (GIO) and excess bone fracture risk. As a substantial fraction of lymphoma patients become long-term survivors, studies that focus on mitigating the negative effects of treatment toxicities on survivorship are important. The objective of the SIESTA trial was to determine if primary prophylaxis with oral alendronate (ALN) is safe and effective against (GIO) in lymphoma patients. Methods: SIESTA was a single-center randomized and double-blinded phase 2 study performed at the Department of Hematology, Aalborg University Hospital, Denmark, enrolling lymphoma patients that were planned for glucocorticoid-containing chemotherapy regimens such as (R-)CVP and all variants of (R)-CHOP. Patients were randomized to weekly oral ALN 70mg or placebo with a treatment duration of 52 weeks. Study assessments included bone mineral density (BMD) measurements at baseline, after completion of chemotherapy at 4-6 months (EOT), and after 12 months, as well as vertebral fracture assessment (VFA) at baseline and at 12 months. The primary study endpoint was change in lumbar spine T-score from baseline to 12 months. Key secondary endpoints were change in T-score from baseline to 12 months at total hip and femoral neck levels, vertebral compression fractures and early T-score changes. Biomarker analyses were exploratory. The target recruitment was 60 patients in a three-year period. Results: A total of 59 patients (36 Diffuse large B-cell lymphoma, 15 follicular lymphoma, 8 other) were enrolled with 22 of 30 patients in the ALN arm and 23 of 29 patients in the placebo arm completing the study (efficacy group). Patient characteristics in the two arms were balanced with exception of more advanced stage diseases (Ann Arbor stage III-IV) in the ALN arm (70·0% vs 41·4%), and a lower median baseline T-score at the lumbar spine in the ALN arm (median T-score -0·6 vs 1·0). Patients in the ALN group received a median of 3,291 mg prednisone versus 3,398 mg for the placebo group. Median change in T-score from baseline to 12 months at the lumbar spine level (primary endpoint) was +0·2 for the ALN arm and -0·2 for the placebo arm (P=0·013) (figure 1), with stronger effect for female patients (median change; ALN +0·25; placebo -0·25) (figure 2). ALN had no effect on BMD for total hip (P=0·30) and femoral neck (P=0·58) at 12 months (figure 1). ALN had no significant early effects on BMD for any measured sites (4-6 months). No new fractures were observed. Nine patients experienced AEs related to the upper gastro-intestinal (GI) system (7 grade 1-2, 2 grade 3-4) with 5 AEs being assessed as related to the study treatment (3 in the ALN group and 2 in the placebo group). One patient (placebo group) discontinued study treatment due to upper GI AE (bleeding ulcer). Biomarker analyses (C-terminal telopeptide cross links (CTX) as marker of bone resorption and N-terminal propeptides of collagen type 1 (P1NP) as marker for bone formation) showed reduced bone resorption for ALN treated patients opposed to the placebo treated patients. From baseline to EOT the mean change in CTX was -0.17 in the ALN group and 0.10 in the placebo group respectively (P&lt;0.001). From baseline to 12 months the mean change in CTX was -0.19 in the ALN group and 0.00 in the placebo group respectively (P=0.002). Interpretation: ALN was a safe and effective primary prophylaxis against GIO in lymphoma patients planned for glucocorticoid-containing chemotherapy regimens. The treatment effects were clinically meaningful across all patient subgroups, but the largest effect size was observed in females. Biomarker analyses supported reduced bone resorption for ALN treated patients. Figure 1 Figure 1. Disclosures Vestergaard: Novo Nordisk Foundation: Other: Head of Research at Steno Diabetes Center North Jutland funded by the Novo Nordisk Foundation, Research Funding. El-Galaly: Abbvie: Other: Speakers fee; ROCHE Ltd: Ended employment in the past 24 months.

Abstract 1122‐000128: Imaging Follow‐Up in Carotid Webs: Is There Vascular Remodeling?

Introduction : Carotid web (CaW) is a shelf‐like fibrotic projection at the carotid bulb and constitutes an underrecognized cause of ischemic stroke. Atherosclerotic lesions are known to have dynamic remodeling with time however, little is known regarding the evolution of CaW over time. We aimed to better understand if CaW is a static or dynamic entity on delayed vascular imaging. Methods : This was a retrospective analysis of the CaW database at our comprehensive stroke center, including patients diagnosed with CaW between September 2014 through June 2021. Patients who had at least two good quality CT angiograms (CTAs) that were at least 6 months apart were included (CTAs with CaW and superimposed thrombus were excluded). CaW were quantified with 3‐D measurements using Horos software. This was done via volumetric analysis of free‐hand delineated CaW borders on thin cuts of axial CTA (Figure 1 Panel A). NASCET criteria was used to evaluate the degree of stenosis. Results : Sixteen CaW in 13 patients were identified and included. The median imaging follow‐up window was 16 months (IQR 12–22, range 6–29). Median patient age was 45.5 years‐old, 69% were women, 25% had hypertension, 38% hyperlipidemia, 25% diabetes mellitus, 0% atrial fibrillation, and 13% active smokers. 75% of the included CaW were symptomatic while 25% were asymptomatic. Median volume of CaW on initial CTA (8.52 mm3 [IQR 3.7‐13], range 2.2‐30.4) was comparable to median volume of CaW on most recent CTA (8.47 mm3 [IQR 4.0‐12.8], range 2.3‐29.4; p = <0.001 (Figure 1 Panel B). The CaW volumetric measurement correlation between the initial and most recent CTA was near perfect (rs = ‐0.99, p = <0.001). The median change in measured volume of CaW between first and last CTA was ‐0.19 mm3 [IQR ‐0.6‐0.4], range ‐1‐0.8. Median degree of stenosis was 8.1% [IQR 4.5‐17.1], range 0.4‐31.2. The duration of follow‐up imaging was not correlated with the change in CaW volume (Kendall tau‐b[τb] = ‐0.17, p = 0.93). The initial CaW volume was not found to be correlated to the degree of stenosis (τb = ‐0.08, p = 0.65). Conclusions : The volume of the CaW was not found to change over time, reinforcing the idea that this is a relatively static lesion. The CaW volume was not found to correlate with the degree of stenosis caused by it. Further longitudinal studies with longer follow‐up intervals are warranted.

P.213 Long-Term Improvement Of Gait And Cognition After Primary Endoscopic Third Ventriculostomy (ETV) In Adult Obstructive Hydrocephalus

Background: Adults with obstructive hydrocephalus often present with cognitive and/or gait dysfunction in addition to symptoms of raised ICP. We previously reported improvement of cognitive and gait function 3 months following primary adult ETV. This abstract presents long-term results in this group. Methods: Obstructive hydrocephalus was identified based on tri-ventriculomegaly on CT and/or MRI. Gait velocity (10 m timed gait) and cognitive function (Montreal Cognitive Assessment [MoCA]) were measured at two timepoints: pre-ETV and ≥9 months post-ETV. Results: Sixteen adults underwent primary ETV and completed a long-term assessment. Mean age was 60 years and 10 (63%) were male. Etiology: 10 (62.5%) congenital and 6 (37.5%) acquired. Mean long-term follow-up time for cognitive and gait assessments was 14.4 and 13.7 months, respectively. The long-term MoCA within patient median change was +2 points (n= 15; p = 0.007). Group medians were 23/30 (pre-ETV) and 26/30 (post-ETV). The long-term gait velocity within patient median change was +0.4 m/s (n= 12; p < 0.001). Group medians were 0.7 m/s (pre-ETV) and 1.3 m/s (post-ETV). Conclusions: ETV in adults with obstructive hydrocephalus results in long-term improvement of cognition and gait velocity when assessed ≥9 months post-ETV. Larger cohorts will determine the generalizability of these results. Hydrocephalus Association supported project.

Associations between plasma concentrations of lenvatinib and angiopoietin and clinical responses to lenvatinib therapy in Japanese patients with thyroid cancer

The purpose of this study was to investigate the relationships among plasma concentrations (C0) of lenvatinib, angiopoietin (Ang)-1 and Ang-2, and clinical responses to lenvatinib therapy in thyroid cancer patients. The median change rates of Ang-1 and Ang-2 at 1 month after treatment from baseline in all patients were − 15.3% and − 48.4%, respectively. However, the change of Ang-1 and Ang-2 at 1 month from baseline did not correlate with lenvatinib C0. In patients with partial response (PR) and stable disease to lenvatinib, Ang-2 at 1 month were significantly lower than Ang-2 at baseline (P < 0.001 and P < 0.05, respectively), but were not significantly lower in patients with progressive disease. The area under the ROC for PR prediction was 0.667, giving the best sensitivity (69.2%) and specificity (73.9%) at a threshold of the change rate of Ang-2 of -49.83%. In patients who continued treatment with lenvatinib for 1 year, Ang-2 at 1 month and 1 year were significantly lower than those at baseline (each P < 0.001). The change of Ang-2 at 1 month after treatment from baseline rather than simply the Ang-2 level at baseline may be important as a biomarker of the inhibitory effect of angiogenesis by lenvatinib.

Severe Fatigue in Long COVID: Web-Based Quantitative Follow-up Study in Members of Online Long COVID Support Groups

Background Fatigue is the most commonly reported symptom in patients with persistent complaints following COVID-19 (ie, long COVID). Longitudinal studies examining the intensity of fatigue and differentiating between physical and mental fatigue are lacking. Objective The objectives of this study were to (1) assess the severity of fatigue over time in members of online long COVID peer support groups, and (2) assess whether members of these groups experienced mental fatigue, physical fatigue, or both. Methods A 2-wave web-based follow-up study was conducted in members of online long COVID peer support groups with a confirmed diagnosis approximately 3 and 6 months after the onset of infectious symptoms. Demographics, COVID-19 diagnosis, received health care (from medical professionals or allied health care professionals), fatigue (Checklist Individual Strength–subscale subjective fatigue [CIS-Fatigue]; 8-56 points), and physical and mental fatigue (self-constructed questions; 3-21 points) were assessed. Higher scores indicated more severe fatigue. A CIS-Fatigue score ≥36 points was used to qualify patients as having severe fatigue. Results A total of 239 patients with polymerase chain reaction/computed tomography–confirmed COVID-19 completed the survey 10 weeks (SD 2) and 23 weeks (SD 2) after onset of infectious symptoms, respectively (T1 and T2). Of these 239 patients, 198 (82.8%) were women; 142 (59.4%) had no self-reported pre-existing comorbidities; 208 (87%) self-reported being in good health before contracting COVID-19; and 62 (25.9%) were hospitalized during acute infection. The median age was 50 years (IQR 39-56). The vast majority of patients had severe fatigue at T1 and T2 (n=204, 85.4%, and n=188, 78.7%, respectively). No significant differences were found in the prevalence of normal, mild, and severe fatigue between T1 and T2 (P=.12). The median CIS-Fatigue score was 48 points (IQR 42-53) at T1, and it decreased from T1 to T2 (median change: –2 points, IQR –7 to 3; P<.001). At T1, a median physical fatigue score of 19 points (IQR 16-20) and a median mental fatigue score of 15 points (IQR 10-17) were reported; these scores were lower at T2 for physical but not for mental fatigue (median change for physical fatigue –1 point, IQR –3 to 0, P<.001; median change for mental fatigue 0 points, IQR –3 to 3, P=.52). At the time of completing the follow-up survey, 194/239 (81.2%) and 164/239 (68.6%) of all patients had received care from at least one medical professional and one allied health care professional, respectively. Conclusions Fatigue in members of online long COVID support groups with a confirmed COVID-19 diagnosis decreases from 10 to 23 weeks after onset of symptoms. Despite this, severe fatigue remains highly prevalent. Both physical and mental fatigue are present. It remains unclear whether and to what extent fatigue will resolve spontaneously in the longer term. Trial Registration Netherlands Trial Register NTR8705; https://www.trialregister.nl/trial/8705.

1404 NELA Risk Mortality Scores from Admission to Theatre in Emergency Gastrointestinal Perforation – A Retrospective Cohort Study

Background Patients with acute abdominal pathology requiring emergency laparotomy who experience a delay to theatre have an increased risk of morbidity, mortality and complications. The aim of this study was to assess delay, from symptom onset to theatre in patients with gastrointestinal perforation and its effect on perioperative risk. Method A single-centre retrospective study was performed in the Leeds Trust Hospitals, UK investigating the NELA database for patients requiring emergency laparotomy for perforated gastrointestinal viscus who presented to the acute surgical unit or emergency department between 1st February 2018 and 31st January 2020. Results 101 patients met the inclusion criteria (47% F and 53% M), mean age 59 [21-91]. 37% of patients’ NELA scores worsened from admission to pre-op (median change of + 5.9% IQR 1.3-11.5]), 14% stayed the same and 49% improved (median change of -4.4%[IQR 0.4-9.1]) 3% had their NELA score documented at the time of consent. 18% did not wait for a CT report or went straight to theatre. Mean time from admission to scan report was 9.3 hours (0.9-22.0). Median time from symptom onset to presentation (2 days [IQR 1-13]) was greater in patients with an Index of Multiple Deprivation Decile of 1-5, (n = 64, median 2 days [IQR 1-6]) compared to those in deciles 6-10, (n = 37, median 1 day[IQR 1-3]), p = 0.097. Conclusions NELA mortality risk score changes from presentation to surgery in patients with acute gastrointestinal perforation requiring emergency laparotomy. There is suggestion that delay in symptom onset to presentation may correlate with Index of Multiple Deprivation Decile.

Evaluation of potential tissue heating during percutaneous drill-assisted bone sampling in an in vivo porcine study

Background Minimally invasive, battery-powered drilling systems have become the preferred tool for obtaining representative samples from bone lesions. However, the heat generated during battery-powered bone drilling for bone biopsies has not yet been sufficiently investigated. Thermal necrosis can occur if the bone temperature exceeds a critical threshold for a certain period of time. Purpose To investigate heat production as a function of femur temperature during and after battery-powered percutaneous bone drilling in a porcine in vivo model. Methods We performed 16 femur drillings in 13 domestic pigs with an average age of 22 weeks and an average body temperature of 39.7 °C, using a battery-powered drilling system and an intraosseous temperature monitoring device. The standardized duration of the drilling procedure was 20 s. The bone core specimens obtained were embedded in 4% formalin, stained with haematoxylin and eosin (H&E) and sent for pathological analysis of tissue quality and signs of thermal damage. Results No significant changes in the pigs’ local temperature were observed after bone drilling with a battery-powered drill device. Across all measurements, the median change in temperature between the initial measurement and the temperature measured after drilling (at 20 s) was 0.1 °C. Histological examination of the bone core specimens revealed no signs of mechanical or thermal damage. Conclusion Overall, this preliminary study shows that battery-powered, drill-assisted harvesting of bone core specimens does not appear to cause mechanical or thermal damage.