Initial Time Point Research Articles

Paper 11: Utility of Objective Testing for Initiation of a Throwing Program Following Shoulder and Elbow Surgery in Competitive Baseball Players

Paper 11: Utility of Objective Testing for Initiation of a Throwing Program Following Shoulder and Elbow Surgery in Competitive Baseball Players

Nasopharyngeal Carcinoma Radiomic Evaluation with Serial PET/CT: Exploring Features Predictive of Survival in Patients with Long-Term Follow-Up.

Simple SummaryNasopharyngeal carcinoma (NPC) is a frequent head and neck cancer, especially in Asian countries. Our studies investigated the value of minable data derived from standard of care PET/CT imaging in patients with NPC. The here presented evaluation found that certain specific imaging features in this patient population can be potentially used to predict overall survival and progression free survival at different time points in those patients. Purpose: We aim determine the value of PET and CT radiomic parameters on survival with serial follow-up PET/CT in patients with nasopharyngeal carcinoma (NPC) for which curative intent therapy is undertaken. Methods: Patients with NPC and available pre-treatment as well as follow up PET/CT were included from 2005 to 2006 and were followed to 2021. Baseline demographic, radiological and outcome data were collected. Univariable Cox proportional hazard models were used to evaluate features from baseline and follow-up time points, and landmark analyses were performed for each time point. Results: Sixty patients were enrolled, and two-hundred and seventy-eight (278) PET/CT were at baseline and during follow-up. Thirty-eight percent (38%) were female, and sixty-two patients were male. All patients underwent curative radiation or chemoradiation therapy. The median follow-up was 11.72 years (1.26–14.86). Five-year and ten-year overall survivals (OSs) were 80.0% and 66.2%, and progression-free survival (PFS) was 90.0% and 74.4%. Time-dependent modelling suggested that, among others, PET gray-level zone length matrix (GLZLM) gray-level non-uniformity (GLNU) (HR 2.74 95% CI 1.06, 7.05) was significantly associated with OS. Landmark analyses suggested that CT parameters were most predictive at 15 month, whereas PET parameters were most predictive at time points 3, 6, 9 and 15 month. Conclusions: This study with long-term follow up data on NPC suggests that mainly PET-derived radiomic features are predictive for OS but not PFS in a time-dependent evaluation. Furthermore, CT radiomic measures may predict OS and PFS best at initial and long-term follow-up time points and PET measures may be more predictive in the interval. These modalities are commonly used in NPC surveillance, and prospective validation should be considered.

Height restoration and sustainability using bilateral vertebral augmentation systems for vertebral compression fractures: a cadaveric study

BACKGROUND CONTEXTThe treatment of vertebral compression fractures using percutaneous augmentation is an effective method to reduce pain and decrease mortality rates. Surgical methods include vertebroplasty, kyphoplasty, and vertebral augmentation with implants. A previous study suggested that a titanium implantable vertebral augmentation device (TIVAD) produced superior height restoration compared to balloon kyphoplasty (BKP) but was based on a less clinically relevant biomechanical model. Moreover, the introduction of high pressure balloons and directional instruments may further aid in restoring height. PURPOSEThe objective was to evaluate three procedures (BKP, BKP w/ Kyphon Assist (KA; directional instruments), and TIVAD) used for percutaneous augmentation of vertebral fractures with respect to height restoration and sustainability post-operatively. STUDY DESIGN/SETTINGThis is an in vitro cadaver study performed in a laboratory setting. METHODSFive osteoporotic female human cadaver thoracolumbar spines (age: 63–77 years, T-score: -2.5 to -3.5, levels: T7–S1) were scanned using computed tomography and dissected into 30 two-functional spine units (2FSUs). Vertebral wedge compression fractures were created by reducing the anterior height of the vertebrae by 25% and holding the maximum displacement for 15 minutes. Post-fracture, surgery was performed on each 2FSU with a constant 100 N load. Surgeries included BKP, BKP w/ KA, or TIVAD (n=10 per treatment group). Post-surgery, cyclic loading was performed on each 2FSU for 10,000 cycles at 600 N (walking), followed by 5,000 cycles at 850 N (standing up/sitting down), and 5,000 cycles at 1250 N (lifting a 5-10kg weight from the floor). Fluoroscopic images were taken and analyzed at the initial, post-fracture, post-surgery, and post-loading timepoints. Anterior, central, and posterior heights, Beck Index, and angle between endplates were assessed. RESULTSNo difference in height restoration was observed among treatment groups (p=.72). Compared to the initial height, post-surgery anterior height was 96.3±8.7% for BKP, 94.0±10.0% for BKP w/ KA, and 95.3±5.8% for TIVAD. No difference in height sustainability in response to 600 N (p=.76) and 850 N (p=.20) load levels was observed among treatment groups. However, after 1250 N loading, anterior height decreased to 93.8±6.8% of the post-surgery height for BKP, 95.9±6.4% for BKP w/ KA, and 86.0±6.6% for TIVAD (p=.02). Specifically, the mean anterior height reduction between post-surgery and post-1250 N loading timepoints was lower for BKP w/ KA compared to TIVAD (p=.02), but not when comparing BKP to TIVAD (p=.07). No difference in Beck Index or angle between endplates was observed at any timepoint among the treatment groups. CONCLUSIONSThe present study, utilizing a clinically relevant biomechanical model, demonstrated equivalent height restoration post-surgery and at relatively lower-level cyclic loading using BKP, BKP w/ KA, and TIVAD, contrary to results from a previous study. Less anterior height reduction in response to high-level cyclic loading was observed in the BKP w/ KA group compared to TIVAD. CLINICAL SIGNIFICANCEAll three treatments can restore height similarly after a vertebral compression fracture, which may lead to pain reduction and decreased mortality. BKP w/ KA may exhibit less height loss in higher-demand patients who engage in physical activities that involve increased weight resistance.

Utility of Whole Blood Real-Time PCR Testing for the Diagnosis of Early Lyme Disease.

Whole blood real-time polymerase chain reaction (WB-RTPCR) detection of Borrelia burgdorferi is not currently recommended for diagnosing Lyme disease. This study aims to elucidate the utility of WB-RTPCR as a diagnostic aid for early Lyme disease (ELD), defined as either positive PCR or positive immunoglobulin M with negative immunoglobulin G immunoblot. A retrospective analysis was performed on 33,199 blood specimens evaluated concurrently by WB-RTPCR and antibody-capture serology (ACEIA) methods (group A). Fifty-six pairs of specimens from a separate data set were retrospectively identified and analyzed at initial and follow-up time points to monitor for seroconversion (group B). Also, a separate data set of 2,526 specimens concurrently assessed by molecular and modified two-tiered enzyme-linked immunosorbent assay serology methods was analyzed (group C). Group A yielded 1,379 specimens consistent with ELD when tested by ACEIA and WB-RTPCR. In total, 131 (9.5% of positive results) were identified by WB-RTPCR, with negative serology. Group C identified 358 samples compatible with ELD, with 31 (8.7% of positive results) identified by RTPCR alone. When used concurrently with serologic testing, WB-RTPCR testing increases diagnostic sensitivity in cases of ELD.

Effect of Stone Crusher Dust Pollution on Biomass of Pigeon Pea

Stone crusher dust produces deleterious effects on growth and development of plants. This study was done on pigeon pea plants grown on different agro-climatic conditions of Nawada district of Bihar to evaluate the effect of stone crush pollution on its biomass. This study was done on samples collected at an interval of 30 days for up to 240 days. Five plants from each group were collected at each time point. The stem and root of the collected samples were evaluated for biomass. At the initial time point, we did not observe any significant difference in biomass in both stem and root among the study groups. However, we observed significantly decreased biomass in both stem and root in plants in the affected area compared with the unaffected area at later time points (90 days onward). Stone crusher dust may affect the plants through encrustation of leaves, plugging of stomata, changes in the quantum of light absorbed by leaves, changes in pH both outside and inside the leaf as well as through modification in soil condition. Further, the significantly reduced biomass may be due to inhibition of the metabolic activity of plants in affected areas. The present study gives the evidence to the fact that stone crusher dust pollution is harmful to pigeon pea plants off all ages, irrespective of the stage of growth and development.

Abstract 422: Novel approach to destabilization of oncogenic mutant p53 and therapeutic implications

Abstract Introduction: Mutant p53 drives several hallmarks of cancer through a gain-of-function oncogenic program. The oncogenicity of mutant p53 includes sustained proliferation, increased survival and resistance to therapy, increased invasion and metastasis, and genomic instability. The oncogenicity of mutant p53 is related to its stability and accumulation in cells by evading degradation by the proteasome. Therefore, destabilization of mutant p53 has been sought as a therapeutic strategy, but so far without clinical success. We and others observe that proteasome inhibitors cause paradoxical depletion of mutant p53 in lung cancer cell lines. Objectives: In this project, we sought to determine the mechanism(s) of mutant p53 depletion by proteasome inhibition and its therapeutic implications in lung cancer. Methods: Human lung cancer cell lines bearing mutant p53 and wildtype p53 (WTp53) were used in this study. An isogenic panel of cell lines with mutant p53, WTp53 and a vector control was also used to determine mutant p53 dependency of the observed effects. Western blotting, immunoprecipitation, siRNA technology, DNA transfection were used for protein detection, protein-protein interactions, gene knock-down and overexpression respectively. Cycloheximide chase assay was used to determine protein degradation. The cancer genome atlas (TCGA) analysis was performed using the cBioPortal platform. Results: Proteasome inhibitors resulted in depletion of mutant p53 in the lung cancer cell line H1975. This effect was also confirmed using the isogenic model described above. Depletion of mutant p53 occurred through a degradation mechanism and was time dependent. While WTp53 accumulated at initial timepoints of proteasome inhibition, mutant p53 did not accumulate but instead depleted with time. This suggested that the proteasome is not the primary mechanism for mutant p53, in contrast to WTp53. Since autophagy is an alternative mechanism of protein degradation in eukaryotes, we evaluated for, and found evidence of autophagy upon proteasome inhibition. We further showed that autophagic degradation of mutant p53 could involve the heat shock protein 70. Our TCGA data analysis showed proteasome genes amplification in mutant p53 lung cancers, suggesting a possible functional dependency. Furthermore, RNA sequencing analysis showed upregulation of most proteasome genes upon stable expression of the R273H mutant in p53-null lung cancer cell line. Finally, in vitro cell viability assays using two different proteasome inhibitors showed increased sensitivity of the lung cancer cell line with mutant p53 compared to WTp53. Conclusion: The cumulative evidence of proteasome hyperactivity, degradation of mutant p53 and in vitro evidence of increased susceptibility of mutant p53 lung cancer cell lines suggests that proteasome inhibitors warrant a closer attention for therapeutic targeting of mutant p53 in lung cancer. Citation Format: Eziafa I. Oduah, Larisa Litovchick, Steven R. Grossman. Novel approach to destabilization of oncogenic mutant p53 and therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 422.

Biodegradable open-porous scaffolds made of sintered magnesium W4 and WZ21 short fibres show biocompatibility in vitro and in long-term in vivo evaluation

Open-porous scaffolds made of W4 and WZ21 fibres were evaluated to analyse their potential as an implant material. WZ21 scaffolds without any surface modification or coating, showed promising mechanical properties which were comparable to the W4 scaffolds tested in previous studies. Eudiometric testing results were dependent on the experimental setup, with corrosion rates differing by a factor of 3. Cytotoxicity testing of WZ21 showed sufficient cytocompatibility. The corrosion behavior of the WZ21 scaffolds in different cell culture media are indicating a selective dealloying of elements from the magnesium scaffold by different solutions. Long term in-vivo studies were using 24 W4 scaffolds and 12 WZ21 scaffolds, both implanted in rabbit femoral condyles. The condyles and important inner organs were explanted after 6, 12 and 24 weeks and analyzed. The in-vivo corrosion rate of the WZ21 scaffolds calculated by microCT-based volume loss was up to 49 times slower than the in-vitro corrosion rate based on weight loss. Intramembranous bone formation within the scaffolds of both alloys was revealed, however a low corrosion rate and formation of gas cavities at initial time points were also detected. No systemic or local toxicity could be observed. Investigations by μ-XRF did not reveal accumulation of yttrium in the neighboring tissue. In summary, the magnesium scaffold´s performance is biocompatible, but would benefit from a surface modification, such as a coating to obtain lower the initial corrosion rates, and hereby establish a promising open-porous implant material for load-bearing applications. Statement of significanceMagnesium is an ideal temporary implant material for non-load bearing applications like bigger bone defects, since it degrades in the body over time. Here we developed and tested in vitro and in a rabbit model in vivo degradable open porous scaffolds made of sintered magnesium W4 and WZ21 short fibres. These scaffolds allow the ingrowth of cells and blood vessels to promote bone healing and regeneration. Both fibre types showed in vitro sufficient cytocompatibility and proliferation rates and in vivo, no systemic toxicity could be detected. At the implantation site, intramembranous bone formation accompanied by ingrowth of supplying blood vessels within the scaffolds of both alloys could be detected.

Modulating the Carrier Relaxation Dynamics in Heterovalently (Bi3+) Doped CsPbBr3 Nanocrystals.

Manipulation of intrinsic carrier relaxation is crucial for designing efficient lead halide perovskite nanocrystal (NC) based optoelectronic devices. The influence of heterovalent Bi3+ doping on the ultrafast carrier dynamics and hot carrier (HC) cooling relaxation of CsPbBr3 NCs has been studied using femtosecond transient absorption spectroscopy and first-principles calculations. The initial HC temperature and LO phonon decay time point to a faster HC relaxation rate in the Bi3+-doped CsPbBr3 NCs. The first-principles calculations disclose the acceleration of carrier relaxation in Bi3+-doped CsPbBr3 NCs due to the appearance of localized bands (antitrap states) within the conduction band. The higher Born effective charges (Z*) and higher soft energetic optical phonon density of states cause higher electron-phonon scattering rates in the Bi-doped CsPbBr3 system, which is responsible for the faster HC cooling rate in doped systems.

Physicochemical Stability Study of Oral Suspension Containing Ruxolitinib in Children with Steroid-Refractory Acute Graft-Versus-Host Disease.

Ruxolitinib, used in children with steroid-refractory acute graft-versus-host (GVH) disease, is currently commercially available only as a tablet adult dosage. For the paediatric population, an oral liquid would be an adapted dosage formulation. The aim of this study was to develop ruxolitinib compounded oral suspensions at 2 mg/mL by using commercial tablets in available aqueous vehicle (Inorpha) and to measure its stability at both room temperature and under refrigeration. Chemical stability of suspensions containing ruxolitinib was evaluated for 60 days based on pH, degradation, and drug content. Physical stability of the drug suspension was evaluated by visual aspect and odour. The remaining ruxolitinib concentration of the suspension was at least 95% of the initial concentration after 60 days at both temperatures. The pH, colour, and odour of the suspensions throughout the study remained unchanged with respect to the initial time point.

A dual process model of affective and instrumental implicit attitude, self-monitoring, and sedentary behavior

IntroductionA dual process model based upon the affect and health behavior framework was used to explain sedentary behavior, where affective and instrumental components of implicit attitude were measured. Extending dual process theory, we assessed the moderating role of self-monitoring on the effects of implicit attitude on behavior. MethodIn Study 1, 148 office workers completed measures of affective and instrumental implicit attitude and self-monitoring at baseline, followed by a measure of sedentary behavior one week later. We then replicated this study in 241 undergraduates, with the addition of measures of the theory of planned behavior at the initial time point to represent conscious pathways to behavior. ResultsIn both studies there was no direct effect of either form of implicit attitude on behavior. However, self-monitoring moderated the effect of affective implicit attitude such that affective implicit attitude was a significant correlate of sedentary behavior only in those low in self-monitoring. In Study 2, sedentary behavior was also associate with intention, and intention was in turn associated with explicit affective attitude, subjective norm, and perceived behavioral control. Self-monitoring was not associated with sedentary behavior, nor did it moderate the intention-behavior relationship. DiscussionFindings suggest sedentary behavior is a largely affect driven behavior. Further, both reasoned and automatic processes contribute to sedentary behavior, but automatic processes only make a significant contribution when individuals are not consistently monitoring their behavior.

Effects of room temperature and cold storage on the metabolic and haemostatic properties of whole blood for acute normovolaemic haemodilution.

BackgroundAcute normovolaemic haemodilution (ANH), as a blood-conservation technique, avoids the need for allogeneic blood transfusions. The historic practice of cold-storing type-O whole blood (WB) in military fields popularised the transfusion of refrigerated WB to treat acute bleeding. In this study, we compared the effects of room temperature (RT) and refrigeration up to 24 hours on the coagulation properties of WB for ANH.Materials and methodsEach WB sample, collected from 12 male volunteers, was divided into two parts, one stored at RT and the other refrigerated for 24 hours. Complete blood counts (CBC), blood gas levels, and coagulation profiles were measured, and rotational thromboelastometry (ROTEM) measurements were performed at the initial collection time point (baseline) and at 6, 12, and 24 hours after initial collection.ResultsThe preservation of platelet aggregation response induced by arachidonic acid and adenosine diphosphate was better in cold-stored WB compared to that in RT-stored WB. The platelet aggregation response induced by thrombin receptor-activating peptide 6 was significantly decreased in all samples after 24 hours of storage when compared with that at baseline. The lactate levels in WB stored at RT increased significantly after 6 hours of storage compared to that of cold-stored samples. There were no significant differences in CBC, coagulation parameters, and ROTEM variables between the cold-stored and RT-stored WB samples.ConclusionWB for ANH stored in the refrigerator showed better metabolic characteristics after 6 hours of storage and better aggregation response after 12 hours of storage than WB stored at RT.

Smartphone Measured Single- and Dual-Task Gait Evaluation in Adolescents Post-Concussion: A Longitudinal Comparison to Healthy Controls

Background: Impairments in postural stability are common following concussion. However, subjectively-scored assessments of postural control, such as the Balance Error Scoring System, may not accurately reflect postural instability. Objective measures, such as gait performance, can more accurately identify ongoing impairments in postural control throughout concussion recovery. Recent technological advances make gait evaluations more feasible across different clinical settings. Purpose: To compare performance on smartphone measured single- and dual-task gait evaluations among adolescent concussion participants and healthy controls across two timepoints. Methods: We evaluated concussed participants at initial (n=13; 14.6±1.3 years; 54% female; 5.5±1.6 days post-concussion) and follow-up visits (33.2±3.3 days post-concussion), and healthy control participants (n=21; 15.5±1.6 years; 48% female) at two timepoints 27.3±0.7 days apart on single- and dual-task gait performance. Single-task gait trials consisted of walking at a self-selected pace for 20 meters. Single-task cognitive trials involved responding to a cognitive task while standing in place. For dual-task trials, participants completed gait and cognitive tasks simultaneously. During each trial a smartphone affixed to the lumbar spine measured gait velocity and cognitive response accuracy and response time. We conducted a 2x2 mixed effects ANOVA to examine changes between groups across the testing timeline. Results: Concussion participants reported significantly greater symptom severity than control participants at the initial timepoint (23.1±13.5 vs 7.4±8.5; p=0.001); however, this difference did not persist to the second timepoint (p=0.99). The concussion group demonstrated significant improvements in single-task gait velocity between timepoints; although, between-group differences in gait velocity were not observed at either timepoint (Figure 1). No differences in cognitive accuracy between groups were identified. However, concussed participants performed worse than healthy controls on cognitive response time at both time points in single- and dual-task testing (Figure 2). Further, response time improved between testing periods for single-task, but not dual-task, conditions. Conclusion: Smartphone gait evaluations indicate improvement in single-task gait velocity during concussion recovery. However, no significant differences in gait velocity were found between concussed and control participants at either time point in single- or dual-task gait conditions. Interestingly, concussion patients had slower cognitive responses than healthy controls at both time points, despite no differences in cognitive accuracy or symptom severity at time 2. Our preliminary findings suggest that smartphone gait evaluations are effective in measuring changes in gait velocity and cognitive performance following adolescent concussion, as well as detecting subtle differences in gait and cognitive performance between concussed and control patients throughout recovery. [Figure: see text][Figure: see text]

Precision medicine in the era of potent antiviral therapy for chronic hepatitis B

With the wide use of potent and safe nucloes(t-)ide analogues (NAs) treatment, patient-centered care is getting important. Intensive care for comorbidity has gain utmost importance in care of aging chronic hepatitis B (CHB) patients with life-long antiviral treatment. Linkage to care of patients with CHB is essential for the goal of hepatitis B virus (HBV) eradication. As long-term suppression of HBV DNA replication does not prevent hepatocellular carcinoma (HCC), prevention of HCC is another challenge for NAs treatment. There is a possibility of hepatocarcinogenesis in the immune-tolerant phase and risk of loss of patients during active monitoring seeking the time point for antiviral treatment initiation. Initiation of NAs treatment from the immune-tolerant phase would improve the linkage to care. However, universal recommendation is premature and evidence for cost-effectiveness needs to be accumulated. Early initiation of NAs in the evidence of significant disease progression, either HBV associated or comorbidity associated, would be a better strategy to reduce the risk of HCC in patients located in the gray zone.

18F-FDG PET/CT During Neoadjuvant Targeted Therapy in Prior Unresectable Stage III Melanoma Patients: Can (Early) Metabolic Imaging Predict Histopathologic Response or Recurrence?

The aim of this study was to investigate whether 18F-FDG PET/CT can predict histopathological response or recurrence in BRAF-mutated unresectable locally advanced stage III melanoma treated with neoadjuvant BRAF/MEK inhibition followed by resection and the value of PET in detecting early recurrence after resection. Twenty BRAF-mutated, unresectable stage III melanoma patients received BRAF/MEK inhibitors before surgery. 18F-FDG PET/CT was performed at baseline and 2 and 8 weeks after initiation of therapy. After resection, PET/CT was performed at specific time points during 5 years of follow-up. Pathological response was assessed on the dissection specimen. Response monitoring was measured with SUVmax, SUVpeak, MATV, and TLG and according to EORTC and PERCIST criteria. Pathological response was assessed in 18 patients. Nine patients (50%) had a pathologic complete or near-complete response, and 9 (50%) had a pathologic partial or no response. EORTC or PERCIST response measurements did not correspond with pathologic outcome. SUVmax, SUVpeak, MATV, and TLG at all time points and absolute or percentage change among the 3 initial time points did not differ between the groups.During follow-up, 8 of 17 patients with R0 resection developed a recurrence, 6 recurrences were detected with imaging only, 4 of which with PET/CT in less than 6 months after surgery. PET parameters before surgery did not predict recurrence. Baseline 18F-FDG PET or PET response in previous unresectable stage III melanoma patients seems not useful to predict pathologic response after neoadjuvant BRAF/MEK inhibitors treatment. However, PET/CT seems valuable in detecting recurrence early after R0 resection.

High Melanin Content in Melanoma Cells Contributes to Enhanced DNA Damage after Rose Bengal Photosensitization.

Melanoma is a type of tumor that originates from melanocytes. Irradiation of melanin with UVA and visible light can produce reactive oxygen species (ROS) such as singlet molecular oxygen (1 O2 ). The objective of this study was to examine DNA damage in melanoma cells (B16-F10) with different melanin contents, subjected to 1 O2 generation. To this end, we used the photosensitizer Rose Bengal acetate (RBAc) and irradiation with visible light (526 nm) (RBAc-PDT). We used the modified comet assay with the repair enzymes hOGG1 and T4 endonuclease V to detect the DNA damage associated with 8-oxo-7,8-dihydro-2'-deoxyguanosine and cyclobutane pyrimidine dimers lesions, respectively. We observed increased formation of hOGG1- and T4endoV-sensitive DNA lesions after light exposure (with or without RBAc). Furthermore, 18 h after irradiation, hOGG1-sensitive DNA lesions increased compared to that at the initial time point (0 h), which shows that a high melanin content contributes to post-irradiation formation of them, mainly via sustained oxidative stress, as confirmed by the measurement of ROS levels and activity of antioxidant enzymes. Contrastingly, the number of T4endoV-sensitive DNA lesions decreased over time (18 h). Our data indicate that in melanoma cells, a higher amount of melanin may affect DNA damage levels when subjected to RBAc-PDT.

Fungal dynamics and potential functions during anaerobic digestion of food waste

Fungi could play an important role during anaerobic digestion (AD), but have received less attention than prokaryotes. Here, AD bioreactors of food waste were performed to explore fungal succession and their potential ecological and engineering value. We found that similar patterns in fungal biomass and diversity, decreasing from the initial time point (Day 0) to the lowest value within 3–6 days and then started to rise and stabilized between 9 and 42 days. Throughout the entire AD process, variations in fungal community composition were observed and dominant fungal taxa have the potential ability to degrade complex organic matter and alleviate fatty acid and ammonia accumulation. Furthermore, we found that deterministic processes gradually dominated fungal assembly succession (up to 84.85% at the final stage), suggesting changing environmental status responsible for fungal community dynamics and specifically, fungal community structure, diversity and biomass were regulated by different environmental variables or the same variables with opposite effects. AD bioreactors could directionally select specific fungal taxa over time, but some highly abundant fungi could not be mapped to any fungal species with defined function in the reference database, so function prediction relying on PICRUSt2 may underestimate fungal function in AD systems. Collectively, our study confirmed fungi have important ecological and engineering values in AD systems.

Relatively Early and Late-Onset Neuromyelitis Optica Spectrum Disorder in Central China: Clinical Characteristics and Prognostic Features.

BackgroundWe aimed to analyze the clinical characteristics and prognostic features of Chinese patients with relatively late-onset neuromyelitis optica spectrum disorder (RLO-NMOSD>40 years of age at disease onset), compared with patients with relatively early onset NMOSD (REO-NMOSD, ≤ 40 years of age at disease onset).MethodsWe retrospectively reviewed the medical records of patients with NMOSD in central China (with disease courses longer than 3 years) between January 2012 and January 2021. We further analyzed the clinical and prognostic differences between patients with REO-NMOSD and RLO-NMOSD.ResultsA total of 71 patients were included in this study. The results showed that 39 (54.9%) of the patients had RLO-NMOSD. The patients with RLO-NMOSD had higher expanded disability status scale (EDSS) scores than patients with REO-NMOSD at the initial (5.0 vs. 3.0, p = 0.01), 3-month (4.0 vs. 2.5, p = 0.001), 1-year (4.0 vs. 2.5, p = 0.003), 3rd-year (3.5 vs. 3.0, p = 0.0017), and final follow-up (4.0 vs. 2.5, P = 0.002) time points. The EDSS scores of visual function were 2.0 (1.0–3.0) in REO-NMOSD and 3.0 (2.0–3.0) in RLO-NMOSD (p = 0.038) at the final follow-up time point. The locations of spinal cord lesions at transverse myelitis (TM) onset were prone to cervical cord in patients with REO-NMOSD. There were no between-group treatment differences. The risk of requiring a cane to walk (EDSS score of 6.0) increased as the age of disease onset increased: for every 10-year increase in the age of disease onset, the risk of needing a cane to walk increased by 65% [hazard ratio (HR) = 1.65, 95% CI 1.15–2.38, p = 0.007]. Another significant predictor identified in the multivariate analysis was annualized relapse rate (ARR) (HR = 2.01, 95% CI 1.09–3.71, p = 0.025). In addition, we observed a positive correlation between age at onset and EDSS scores at the final follow-up (Spearman's r = 0.426, p < 0.0001) time point. EDSS scores at different periods were significantly different between patients with RLO-NMOSD and REO-NMOSD with anti-aquaporin-4 (AQP4) IgG positive.ConclusionThe patients with RLO-NMOSD developed more severe disabilities than patients with REO-NMOSD at a variety of time periods. All of the patients may experience recurrent aggravated symptoms after their first year, with only patients with REO-NMOSD partly recovering from the 3rd year. The age at onset and ARR were the main predictors of outcomes.

Recovery from aphasia in the first year after stroke.

Most individuals who experience aphasia after a stroke recover to some extent, with the majority of gains taking place in the first year. The nature and time course of this recovery process is only partially understood, especially its dependence on lesion location and extent, which are the most important determinants of outcome. The aim of this study was to provide a comprehensive description of patterns of recovery from aphasia in the first year after stroke. We recruited 334 patients with acute left hemisphere supratentorial ischaemic or haemorrhagic stroke and evaluated their speech and language function within 5 days using the Quick Aphasia Battery (QAB). At this initial time point, 218 patients presented with aphasia. Individuals with aphasia were followed longitudinally, with follow-up evaluations of speech and language at 1 month, 3 months, and 1 year post-stroke, wherever possible. Lesions were manually delineated based on acute clinical MRI or CT imaging. Patients with and without aphasia were divided into 13 groups of individuals with similar, commonly occurring patterns of brain damage. Trajectories of recovery were then investigated as a function of group (i.e. lesion location and extent) and speech/language domain (overall language function, word comprehension, sentence comprehension, word finding, grammatical construction, phonological encoding, speech motor programming, speech motor execution, and reading). We found that aphasia is dynamic, multidimensional, and gradated, with little explanatory role for aphasia subtypes or binary concepts such as fluency. Patients with circumscribed frontal lesions recovered well, consistent with some previous observations. More surprisingly, most patients with larger frontal lesions extending into the parietal or temporal lobes also recovered well, as did patients with relatively circumscribed temporal, temporoparietal, or parietal lesions. Persistent moderate or severe deficits were common only in patients with extensive damage throughout the middle cerebral artery distribution or extensive temporoparietal damage. There were striking differences between speech/language domains in their rates of recovery and relationships to overall language function, suggesting that specific domains differ in the extent to which they are redundantly represented throughout the language network, as opposed to depending on specialized cortical substrates. Our findings have an immediate clinical application in that they will enable clinicians to estimate the likely course of recovery for individual patients, as well as the uncertainty of these predictions, based on acutely observable neurological factors.

A Novel Faster-Acting, Dry Powder-Based, Naloxone Intranasal Formulation for Opioid Overdose

ObjectiveTo examine the pharmacokinetics and safety of FMXIN001, a new intranasal powder-based naloxone formulation, in comparison to Narcan® nasal liquid spray.MethodsFMXIN001, was developed by blending drug microspheres with larger lactose monohydrate particles, that serve as diluent and carrier, as well as a disaggregating agent. Scanning electron microscopy and X-ray were used to characterize the formulation and in vitro deposition was investigated using a nasal cast.We compared the pharmacokinetics and safety of FMXIN001 versus Narcan® in two clinical trials: a pilot study with 14 healthy adults and a pivotal trial in 42 healthy adults (NCT04713709). The studies were open-label, single-dose, randomized, two-period, two-treatment, two-sequence crossover studies to assess the pharmacokinetics and safety of FMXIN001 versus Narcan® nasal spray.ResultsFMXIN001 comprises naloxone microspheres (5-30 μM) and lactose particles (40–240 μM). Upon in vitro testing, naloxone deposits mainly to the middle turbinates region and the upper part of the nasal cavity of a nasal cast. In human subjects, FMXIN001 produced significantly higher exposure at the initial time points of 4, 10, and 30 min, post-administration, compared to Narcan®. Both treatments were safe and well tolerated. FMXIN001, powder-based spray, results in similar overall exposure to Narcan®, but with more rapid absorption in the first 30 min.ConclusionsFMXIN001 is expected to have a shorter onset of action for a more effective therapeutic intervention to manage opioid overdose. Rapid administration of naloxone in cases of opioid overdose is imperative, given the alarming increase in mortality rates.

The Pain Control Efficacy of Zolpidem versus Melatonin after Intervertebral Disc Herniation Surgery under General Anaesthesia: A Randomised Clinical Trial.

Background:Postoperative pain management has been linked with multiple clinically relevant complications such as thromboembolism, myocardial ischaemia, and cardiac arrhythmias.Objectives:The present study moves towards an evidence-based approach to the therapeutic efficacy of zolpidem and melatonin in a better clinically meaningful pain relief following intervertebral disc herniation surgery under general anaesthesia.Materials and Methods:Undertaking a randomised, parallel-group, double-blind, clinical trial, 60 patients meeting eligibility (mean age ≈ 39, 50% female and 50% men) were offered intervertebral disc surgery at the Arak-based Valiasr Hospital and stratified into two interventional arms by block randomisation. Data including (i) pain (visual analog scale) and sedation (Ramsay sedation scale) scores during recovery and at all five initial 24-h time points (two, four, six, 12, 24); (ii) adverse events inclusive of mild nausea and dizziness, pethidine consumption; and (iii) ongoing haemodynamic parameters, including heart rate, blood pressure, and oxygen saturation were collected. Data were analysed at a significance level of P = 0.05 (SPSS 20.0, IBM Corp).Results:Our results showed no perceived statistically significant between-arm difference in three functional haemodynamic parameters, duration of surgery, and adverse events, as well as in sedation and pain scores (P < 0.05). Our results showed no between-arm difference in analgesia and sedation, haemodynamic changes, and postoperative adverse events.Conclusion:The findings taken together lent a strong support for the highly encouraging efficacy of both drugs in affording adequate analgesia at 24 postoperative hours without any adverse events needing to be thought of. Therefore, both zolpidem and melatonin were promising postoperative pain relievers, while no drug is demonstrably superior to the other.