Endoluminal Sigmoid Sinus Occlusion During Jugular Foramen Tumor Surgery: Novel Technique, Operative Nuances, and Clinical Experience With 33 Patients.

BACKGROUND AND IMPORTANCE: Surgery of jugular foramen tumors (JFTs) often requires vascular control by means of ligating the internal jugular vein and sigmoid sinus (SS) to allow intrabulbar access. Occlusion of the SS traditionally involves presigmoid and retrosigmoid durotomies allowing introduction of ligature devices, predisposing to cerebrospinal fluid (CSF) leakage and pseudomeningoceles. We describe a simple and novel endoluminal sigmoid sinus occlusion (ESSO) technique with Gelfoam that is entirely extradural. CLINICAL PRESENTATION: An extended anterolateral infralabyrinthine approach with ESSO was performed in 33 patients with JFTs. After ligating the internal jugular vein, the SS is opened and Gelfoam is placed endoluminally into the proximal SS. Care is taken to avoid occlusion of the venous outflow of the vein of Labbe to avoid temporal lobe venous infarction. Hemostatic gelatin matrix is injected distally to stop venous backflow from the inferior petrosal sinus. The jugular venous system is isolated, and the outer jugular wall can be opened to expose the JFT for resection. There were no complications of temporal lobe venous infarction or postoperative hematoma observed. Four patients with intradural tumor extension developed pseudomeningoceles. For patients with purely extradural JFTs, none developed postoperative incisional CSF leaks and one had pseudomeningocele. CONCLUSION: This ESSO technique is fast and effective, permitting occlusion of the SS during JFT surgery. It has the advantage of being entirely extradural, avoiding durotomy which can result in postoperative CSF leak. It is important to keep the Gelfoam distal to the transverse-sigmoid junction to avoid occlusion of the vein of Labbe inlet and temporal lobe venous infarction.

Economic assessment of using Bermudagrass stockpiling and annual cereal pasture to extend grazing in cow-calf operations.

Bermudagrass (Cynodon dactylon L.) stockpiling and cool-season annual pastures can extend grazing seasons in cow-calf operations and reduce winter feeding costs, but less is known about how these practices interact and their effect on producer profitability. Data from a completely randomized-design experiment in South-Central Oklahoma were collected on three grazing systems for cows and calves: bermudagrass pasture (CONTROL), stockpiled bermudagrass and interseeded cool-season pasture (SPINT), and stockpiled bermudagrass plus cropland no-till seeded with a summer cover-crop followed by cool-season annuals (SPCROP). A mixed model was used to estimate the effects of grazing system on weaning weights, total hay, and total range cubes (crude protein [CP] = 30%) fed in each system. Enterprise budgeting was used to calculate the expected net return of each system. Weaning weight did not vary between systems (P = 0.6940), resulting in similar revenues. Relative to other treatments, the quantity of cubes fed in the CONTROL system were significantly higher (P < 0.0001) while hay fed was significantly higher in the SPCROP system (P = 0.0036). Increased machinery costs, seed costs, and fertilization requirements in bermudagrass stockpiling, interseeding, and cropland production outweighed the cost savings associated with less feeding. Total costs were $446 ha-1 ($722 hd-1), $451 ha-1 ($732 hd-1), and $553 ha-1 ($895 ha-1) for the CONTROL, SPINT, and SPCROP systems, respectively. Overall, the CONTROL system was $3.13 ha-1 ($5.08 hd-1) and $98.91 ha-1 ($160.10 hd-1) more profitable than the SPINT and SPCROP systems.

Analysis of neurosurgery resident research activity in the United States.

OBJECTIVE: Evaluation of the demographic and academic characteristics of current neurosurgery residents may provide prospective students with insight into factors that affect research output. Therefore, this study aimed to evaluate the research output among neurosurgery residents. METHODS: US neurosurgery residency programs were abstracted from the American Association of Neurological Surgeons website. Demographic data on 1690 current residents across 119 programs were collected using publicly available institutional websites, Doximity, and LinkedIn. The h-index of each resident was recorded using Scopus and exported into the NIH iCite tool to determine the weighted relative citation ratio (w-RCR) and mean relative citation ratio (m-RCR). The total number of publications, h-index, and w-RCR were used as a proxy for research output, while m-RCR was used to measure research impact. One-way ANOVA and Kruskal-Wallis H-tests were used to assess the statistical significance of relationships between demographic data and measures of research activity. RESULTS: A total of 1690 residents (25.4% female), representing 119 programs, were evaluated. Neurosurgery residents had an average of 17 publications, h-index of 5.5, m-RCR of 1.4, and w-RCR of 16.9, with an upward trend of research activity by postgraduate year (PGY) class. Male residents on average had a greater total number of publications (p < 0.001), higher h-index (p < 0.001), and higher w-RCR (p = 0.002) compared with their female peers. Significant differences in research activity were also observed by degree (Doctor of Medicine [MD], Doctor of Osteopathy [DO], or other), where those with MD and other degrees had higher metrics than those with DO degrees. International medical graduates (IMGs) also had higher research output than American medical graduates (AMGs) (p < 0.001). Differences in all measures of research activity except impact were also observed in research activity when pre-residency medical school ranks were compared. CONCLUSIONS: The authors observed overall high research activity among neurosurgery residents. Factors such as gender, degree, PGY, IMG/AMG status, and medical school rank may therefore be related to the success of matching within neurological surgery. Although large disparities in gender representation have been identified in neurosurgery, newer classes are trending toward shrinking the gap. These data may be used by prospective residents to gauge changes and progress occurring in the neurosurgery match.

Education and non-communicable diseases in India: an exploration of gendered heterogeneous relationships.

BACKGROUND: While the association between education and non-communicable diseases (NCDs) is well established, it remains unclear whether this association varies by gender. The aim of this study was to examine two critical research questions: whether the association of education and NCDs is conditioned by gender and, if so, what are the factors contributing to this? METHODS: Data from the Longitudinal Aging Study in India Wave 1 (2017-2018) was used for the empirical analysis. The study employs bivariate, binary logistic regression and Oaxaca decomposition analyses. RESULTS: The results reveal that the net likelihood of having at least one chronic NCD increases with an increase in education level for men (<5 y of schooling: odds ratio [OR] 1.18 [95% confidence interval {CI} 1.09 to 1.28]; ≥10 y of schooling: OR 1.43 [95% CI 1.33 to 1.53]). However, for women, the result showed a contrasting pattern. The decomposition analysis revealed that the distinctive roles of marital status and working status in the diagnosis of morbidity for men and women are the key factors behind the gendered heterogeneous relationship of education and NCDs in India. CONCLUSIONS: The study found that it is important to acknowledge the potential impact of self-reporting bias in morbidity data while examining the relationship between education and NCDs.

Glucose-driven histone lactylation promotes the immunosuppressive activity of monocyte-derived macrophages in glioblastoma.

Immunosuppressive macrophages restrict anti-cancer immunity in glioblastoma (GBM). Here, we studied the contribution of microglia (MGs) and monocyte-derived macrophages (MDMs) to immunosuppression and mechanisms underlying their regulatory function. MDMs outnumbered MGs at late tumor stages and suppressed T cell activity. Molecular and functional analysis identified a population of glycolytic MDM expressing GLUT1 with potent immunosuppressive activity. GBM-derived factors promoted high glycolysis, lactate, and interleukin-10 (IL-10) production in MDMs. Inhibition of glycolysis or lactate production in MDMs impaired IL-10 expression and T cell suppression. Mechanistically, intracellular lactate-driven histone lactylation promoted IL-10 expression, which was required to suppress T cell activity. GLUT1 expression on MDMs was induced downstream of tumor-derived factors that activated the PERK-ATF4 axis. PERK deletion in MDM abrogated histone lactylation, led to the accumulation of intratumoral T cells and tumor growth delay, and, in combination with immunotherapy, blocked GBM progression. Thus, PERK-driven glucose metabolism promotes MDM immunosuppressive activity via histone lactylation.

Japanese Encephalitis Virus and Schizophyllum commune Co-Infection in a Harbor Seal in Japan.

The Japanese encephalitis virus (JEV), a mosquito-borne flavivirus, has a wide host range, extending from pigs and ardeid birds to opportunistic dead-end hosts, such as humans and horses. However, JEV encephalitis infections in aquatic mammals are rare, with only two cases in seals reported to date. Here, we report a lethal case of JEV and Schizophyllum commune co-infection in an aquarium-housed harbor seal in Japan. We isolated JEV from the brain of the dead seal and characterized its phylogeny and pathogenicity in mice. The virus isolate from the seal was classified as genotype GIb, which aligns with recent Japanese human and mosquito isolates as well as other seal viruses detected in China and Korea, and does not exhibit a unique sequence trait distinct from that of human and mosquito strains. We demonstrated that the seal isolate is pathogenic to mice and causes neuronal symptoms. These data suggest that seals should be considered a susceptible dead-end host for circulating JEV in natural settings.

Efficient measurement of multiple ventricular assist device patient-reported outcomes: Creation of a 20-item profile from the MCS A-QOL study.

BACKGROUND: Patient-reported outcome (PRO) measures of distinct concepts are often put together into patient profile assessments. When brief, profile assessments can decrease respondent burden and increase measure completion rates. In this report, we describe the creation of 5 self-reported 4-item short forms and the Mechanical Circulatory Support: Measures of Adjustment and Quality of Life (MCS A-QOL) 20-item profile to assess PROs specific to adjustment and health-related quality of life (HRQOL) among patients who undergo left ventricular assist device (LVAD) implantation. METHODS: Using a cross-sectional sample of patients (n = 620) who underwent LVAD implantation at 12 U.S. sites or participated in the MyLVAD.com support group, we created 5 4-item short forms: Satisfaction with Treatment, ventricular assist device (VAD) Team Communication, Being Bothered by VAD Self-care and Limitations, Self-efficacy Regarding VAD self-care, and Stigma, which we combined into a 20-item profile. Analyses included intercorrelations among measures, Cronbach's alpha (i.e., internal consistency reliability)/score-level-specific reliability, and construct validity. RESULTS: The 620 patients were mean age = 57 years, 78% male, 70% White, and 56% on destination therapy LVADs. Intercorrelations among the 5 4-item measures were low to moderate (≤0.50), indicating they are associated yet largely distinct, and correlations with calibrated measures and 6-item short forms were ≥0.76, indicating their ability to reflect full-item bank scores. Internal consistency reliability for the 5 4-item short forms ranged from acceptable (≥0.70) to good (≥0.80). Construct validity was demonstrated for these measures. CONCLUSIONS: Our 5 4-item short forms are reliable and valid and may be used individually or together as a 20-item profile to assess adjustment and HRQOL in patients who undergo LVAD implantation.

Corrigendum: Lithium-ion battery second life: pathways, challenges and outlook.

[This corrects the article DOI: 10.3389/fchem.2024.1358417.].

Assessment of the Antinociceptive, Respiratory-Depressant, and Reinforcing Effects of the Low pKa Fluorinated Fentanyl Analogs, FF3 and NFEPP.

RATIONALE: Recent studies report that fentanyl analogs with relatively low pKa values produce antinociception in rodents without other mu opioid-typical side effects due to the restriction of their activity to injured tissue with relatively low pH values. However, it is unclear if and to what degree these compounds may produce mu opioid-typical side effects (respiratory depression, reinforcing effects) at doses higher than those required to produce antinociception. OBJECTIVES: The present study compared the inflammatory antinociceptive, respiratory-depressant, and reinforcing effects of fentanyl and two analogs of intermediate (FF3) and low (NFEPP) pKa values in terms of potency and efficacy in male and female Sprague-Dawley rats. METHODS: Nociception was produced by administration of Complete Freund's Adjuvant into the hind paw of subjects, and antinociception was measured using an electronic Von Frey test. Respiratory depression was measured using whole-body plethysmography. Reinforcing effects were measured in self-administration using a progressive-ratio schedule of reinforcement. The dose ranges tested for each drug encompassed no effect to maximal effects. RESULTS: All compounds produced full effects in all measures but varied in potency. FF3 and fentanyl were equipotent in antinociception and self-administration, but FF3 was less potent than fentanyl in respiratory depression. NFEPP was less potent than fentanyl in every measure. The magnitude of potency difference between antinociception and other effects was greater for FF3 than for NFEPP or fentanyl, indicating that FF3 had the widest margin of safety when relating antinociception to respiratory-depressant and reinforcing effects. CONCLUSIONS: Low pKa fentanyl analogs possess potential as safer analgesics, but determining the optimal degree of difference for pKa relative to fentanyl will require further study due to some differences between the current results and findings from prior work with these analogs.

Enamel Remineralisation with a Novel Sodium Fluoride-Infused Bristle Toothbrush.

This study aims to investigate whether toothbrushes with fluoride-infused bristles have any (re)mineralisation effects on bovine enamel. Bovine incisors (N = 160) were extracted, and the buccal side of the crown was cut into dimensions of ~5 mm × 5 mm with a low-speed saw. These specimens were randomly allocated into four groups: half (80 teeth) were stored in demineralising solution (DM), and the other half were stored in deionised water (DW) for 96 h. Then, they were brushed with a force of 2.0 ± 0.1 N for five min with a manual toothbrush with either fluoride-infused (TF) or regular (TR) bristles. Microhardness (Vickers), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), and scanning electron microscopy (SEM) were used to investigate the surfaces of the bovine enamel specimens before and after brushing. Two-way ANOVA was used to analyse the hardness data, and the pairwise comparison method was used to analyse the Ca/P ratio, for each group at α = 0.05. The results show that brushing with either of these toothbrushes increased the Vickers microhardness on DM and DW enamel (p < 0.001), whereas hydroxyapatite was revealed in all groups by XRD. The DM samples showed a significant increase (p < 0.05) in the Ca/P ratios after brushing with TR and TF. Conversely, under DW conditions, these ratios decreased significantly after brushing. In terms of the F atomic%, TF increased significantly. SEM revealed mineral deposition in the DM groups after toothbrushing. To conclude, toothbrushing effectively induces the microhardness of sound and demineralised enamel, while fluoride-infused bristles might be able to retain fluoride on the enamel surface.

Design of Multi-Functional Bio-Safe Dental Resin Composites with Mineralization and Anti-Biofilm Properties.

This study aims to develop multi-functional bio-safe dental resin composites with capabilities for mineralization, high in vitro biocompatibility, and anti-biofilm properties. To address this issue, experimental resin composites consisting of UDMA/TEGDMA-based dental resins and low quantities (1.9, 3.8, and 7.7 vol%) of 45S5 bioactive glass (BAG) particles were developed. To evaluate cellular responses of resin composites, MC3T3-E1 cells were (1) exposed to the original composites extracts, (2) cultured directly on the freshly cured resin composites, or (3) cultured on preconditioned composites that have been soaked in deionized water (DI water), a cell culture medium (MEM), or a simple HEPES-containing artificial remineralization promotion (SHARP) solution for 14 days. Cell adhesion, cell viability, and cell differentiation were, respectively, assessed. In addition, the anti-biofilm properties of BAG-loaded resin composites regarding bacterial viability, biofilm thickness, and biofilm morphology, were assessed for the first time. In vitro biological results demonstrated that cell metabolic activity and ALP expression were significantly diminished when subjected to composite extracts or direct contact with the resin composites containing BAG fillers. However, after the preconditioning treatments in MEM and SHARP solutions, the biomimetic calcium phosphate minerals on 7.7 vol% BAG-loaded composites revealed unimpaired or even better cellular processes, including cell adhesion, cell proliferation, and early cell differentiation. Furthermore, resin composites with 1.9, 3.8, and 7.7 vol% BAG could not only reduce cell viability in S. mutans biofilm on the composite surface but also reduce the biofilm thickness and bacterial aggregations. This phenomenon was more evident in BAG7.7 due to the high ionic osmotic pressure and alkaline microenvironment caused by BAG dissolution. This study concludes that multi-functional bio-safe resin composites with mineralization and anti-biofilm properties can be achieved by adding low quantities of BAG into the resin system, which offers promising abilities to mineralize as well as prevent caries without sacrificing biological activity.

Compositional and surface changes of retrieved stainless-steel hardware and its effects on surrounding soft tissues: A prospective study.

Purpose: To evaluate the surface, compositional, and histological changes in the overlying soft tissues of retrieved stainless-steel mini-plates and screws used for rigid internal fixation in the maxillofacial skeleton. Materials and Method: A prospective study was conducted comprising 60 patients who sustained maxillofacial trauma and underwent ORIF in our unit previously and who required hardware retrieval in the post-operative phase. The retrieved hardware was evaluated for surface and compositional changes with the help of a scanning electron microscope for surface roughness and corrosion changes. Energy-dispersive X-ray study was done to know the composition and metal release from the hardware. The data obtained from these results were compared with a control unused and a sterile stainless-steel mini-plate and screw. The effects of the corrosion changes of this hardware on the adjacent soft tissues were evaluated histologically to assess the cellular changes of the soft tissue cover overlying the stainless-steel mini-plates and screws. Results: A total of 96 stainless-steel mini-plates and 380 stainless-steel screws were retrieved from 60 patients. The control plate was smooth without any surface and corrosion defects, while the retrieved mini-plates irrespective of the reason for removal have shown surface roughness. Fe and Ni ions were found to be significantly reduced in the retrieved mini-plates. The presence of CrC in the retrieved plates indicates corrosion, which was seen only in hardware retrieved from symptomatic patients. The histological study revealed chronic inflammatory cell infiltrate with hyalinized connective tissue in all the samples irrespective of the reason for the removal of the plate. Conclusion: Stainless-steel mini-plates and screws act as a potent foreign body material and initiate a localized inflammatory reaction due to its corrosive products with longer duration of stay. Hence, the authors advocate the overall shift in the use of stainless-steel hardware to titanium hardware for ORIF.

Momentum-exchange interactions in a Bragg atom interferometer suppress Doppler dephasing.

Large ensembles of laser-cooled atoms interacting through infinite-range photon-mediated interactions are powerful platforms for quantum simulation and sensing. Here we realize momentum-exchange interactions in which pairs of atoms exchange their momentum states by collective emission and absorption of photons from a common cavity mode, a process equivalent to a spin-exchange or XX collective Heisenberg interaction. The momentum-exchange interaction leads to an observed all-to-all Ising-like interaction in a matter-wave interferometer. A many-body energy gap also emerges, effectively binding interferometer matter-wave packets together to suppress Doppler dephasing in analogy to Mössbauer spectroscopy. The tunable momentum-exchange interaction expands the capabilities of quantum interaction-enhanced matter-wave interferometry and may enable the realization of exotic behaviors, including simulations of superconductors and dynamical gauge fields.

Rasch analysis of the Unidimensional Self-Efficacy Scale in Neuromuscular Disorders and comparison between sex, age, and diagnoses.

INTRODUCTION/AIMS: Self-efficacy reflects a person's perceptions of their capabilities for specific tasks and influences motivation and performance. The Unidimensional Self-Efficacy in Neuromuscular Disorders (USE-NM) was modified from the Multiple Sclerosis (MS) USE-MS scale and administered to patients attending a specialist neuromuscular clinic. The aim was to investigate this measure in neuromuscular disorders and to compare between patient sex, age, and diagnosis. METHODS: The USE-NM was posted to patients recruited from a specialist neuromuscular clinic at the Walton Centre. Responses were subjected to Rasch analysis using RUMM2030 software and descriptive statistics were performed using SPSS version 28. RESULTS: One hundred and ninety-eight patients (56.1% male) grouped by age (<50; 50-59; 60-69; and >69 years) and with varied NM disorders returned the USE-NM. It did not meet the Rasch model expectations due to disordered thresholds of items 6 and 8 ("Sometimes I feel inadequate as a person because of my neuromuscular disorder" and "I feel that my social life would be better if I did not have a neuromuscular disorder"). Following item re-scoring, the modified USE-NM satisfied the Rasch model with a unidimensional scale free from differential item functioning and an overall chi-square probability of 0.146 with good reliability and validity. Post hoc nonparametric testing showed no significant difference in fatigue between sex, age, and neuromuscular diagnoses. DISCUSSION: The Rasch-modified USE-NM offers a measure of self-efficacy for neuromuscular disorders encountered in a typical specialist clinic. Future considerations could be given to assessing any benefits of multidisciplinary team input, across a specialist neuromuscular service.

Improving alcohol and substance use screening in school-age children: translation, adaptation and psychometric evaluation of the CRAFFT tool for Lumasaaba, Uganda.

BACKGROUND: Children at risk of substance use disorders (SUD) should be detected using brief structured tools for early intervention. This study sought to translate and adapt the Car, Relax, Alone, Forget, Family/Friends, Trouble (CRAFFT) tool to determine its diagnostic accuracy, and the optimum cut-point to identify substance use disorders (SUD) risk in Ugandan children aged 6 to 13 years. METHODS: This was a sequential mixed-methods study conducted in two phases. In the first qualitative phase, in Kampala and Mbale, the clinician-administered CRAFFT tool version 2.1 was translated into the local Lumasaaba dialect and culturally adapted through focus group discussions (FGDs) and in-depth interviews, in collaboration with the tool's authors. Expert reviews and translations by bilingual experts provided insights on linguistic comprehensibility and cultural appropriateness, while pilot testing with the target population evaluated the tool's preliminary effectiveness. In the second phase, the CRAFFT tool, adapted to Lumasaaba, was quantitatively validated against the Mini International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) for diagnosing SUD in Mbale district, through a survey. Participants, chosen randomly from schools stratified according to ownership, location, and school size, were assessed for the tool's reliability and validity, including comparisons to the MINI KID as the Gold Standard for diagnosing SUD. Data were analyzed using STATA-15. Receiver-operating-characteristic analysis was performed to determine the sensitivity, specificity, and criterion validity of the CRAFFT with the MINI-KID. RESULTS: Of the 470 children enrolled, 2.1% (n = 10) had missing data on key variables, leaving 460 for analysis. The median age and interquartile range (IQR) was 11 (9-12) years and 56.6% were girls. A total of 116 (25.2%) children had consumed alcohol in the last twelve-month period and 7 (1.5%) had used other substances. The mean CRAFFT score for all the children (n = 460) was 0.32 (SD 0.95). The prevalence of any alcohol use disorder (2 or more positive answers on the MINI KID) in the last 12 months was 7.2% (n = 32). The Lumasaaba version of the CRAFFT tool demonstrated good internal consistency (Cronbach's α = 0.86) and inter-item correlation (Spearman correlation coefficient of 0.84 (p < 0.001). At a cut-off score of 1.00, the CRAFFT had optimal sensitivity (91%) and specificity (92%) (Area Under the Curve (AUC) 0.91; 95% CI 0.86-0.97) to screen for SUD. A total of 62 (13.5%) had CRAFFT scores of > 1. CONCLUSION: The Lumasaaba version of the CRAFFT tool has sufficient sensitivity and specificity to identify school-age children at risk of SUD.

Bladder instillations versus onabotulinumtoxinA injection for interstitial cystitis/bladder pain syndrome: A randomized clinical trial.

BACKGROUND: Interstitial cystitis/bladder pain syndrome is an unpleasant sensation related to the bladder with lower urinary tract symptoms lasting more than six weeks, unrelated to an otherwise identifiable cause. The etiology is likely multifactorial including urothelial abnormalities, neurogenic pain upregulation, and potentially bladder and vaginal microbiome alterations. Despite treatment effectiveness of both bladder instillations and intradetrusor onabotulinumtoxinA injection for this condition, a head-to-head comparison has not been performed. OBJECTIVES: To compare the efficacy of bladder instillations and intradetrusor onabotulinumtoxinA injection for treatment of interstitial cystitis/bladder pain syndrome. STUDY DESIGN: Patients with O'Leary-Sant (OLS) questionnaire scores of ≥ 6, meeting clinical criteria for interstitial cystitis/bladder pain syndrome, and desiring procedural management were randomized to bladder instillations or intradetrusor onabotulinumtoxinA injection. The primary outcome was the difference in OLS scores at 2 months post-treatment between groups. Secondary outcomes included evaluation of sexual function, physical/mental health status, pain, patient satisfaction, treatment perception, retreatment, and adverse event rates. RESULTS: 47 patients were analyzed with 22 randomized to bladder instillations and 25 to onabotulinumtoxinA injection. There were no differences in demographic and clinical characteristics between groups. From baseline to 2 months post-treatment, there was a decrease in OLS subscales in all patients (Interstitial Cystitis Symptom Index (ICSI) -6.3 (CI -8.54, -3.95), p<.0001; Interstitial Cystitis Problem Index (ICPI) -5.9 (CI -8.18, -3.57), p<.0001). At 2 months post-treatment, patients in the onabotulinumtoxinA group had significantly lower OLS scores compared to those in the bladder instillation group (ICSI 6.3 ± 4.5 [onabotulinumtoxinA] versus 9.6 ± 4.2 [instillation], p=.008; ICPI 5.9 ± 5.1 [onabotulinumtoxinA] versus 8.3 ± 4.0 [instillation], p=.048). The difference in OLS scores between groups did not persist at 6-9 months post-treatment. There were no statistically significant differences between baseline and post-treatment time points for the remaining questionnaires. Eight percent of patients who received onabotulinumtoxinA injection experienced urinary retention requiring self-catheterization. Patients who underwent onabotulinumtoxinA injection were significantly less likely to receive retreatment within 6-9 months compared to patients who received bladder instillations (relative risk 13.6; 95% CI, 1.92-96.6; P=.0002). There were no differences between groups regarding patient satisfaction, perception of treatment convenience, or willingness to undergo retreatment. CONCLUSIONS: Both onabotulinumtoxinA injection and bladder instillations are safe, effective treatments for patients with interstitial cystitis/bladder pain syndrome, with significant clinical improvement demonstrated at 2 months post-treatment. Our findings suggest that intradetrusor onabotulinumtoxinA injection is a more effective procedural treatment for this condition than bladder instillation therapy and associated with decreased rates of retreatment.

Desmosomal Cadherin Tension Loss in Pemphigus Vulgaris Mediated by the Inhibition of Active RhoA at Cell-Cell Adhesions.

Binding of autoantibodies to keratinocyte surface antigens, primarily desmoglein 3 (Dsg3) of the desmosomal complex, leads to the dissociation of cell-cell adhesion in the blistering disorder pemphigus vulgaris (PV). After the initial disassembly of desmosomes, cell-cell adhesions actively remodel in association with the cytoskeleton and focal adhesions. Growing evidence highlights the role of adhesion mechanics and mechanotransduction at cell-cell adhesions in this remodeling process, as their active participation may direct autoimmune pathogenicity. However, a large part of the biophysical transformations after antibody binding remains underexplored. Specifically, it is unclear how tension in desmosomes and cell-cell adhesions changes in response to antibodies, and how the altered tensional states translate to cellular responses. Here, we showed a tension loss at Dsg3 using fluorescence resonance energy transfer (FRET)-based tension sensors, a tension loss at the entire cell-cell adhesion, and a potentially compensatory increase in junctional traction force at cell-extracellular matrix adhesions after PV antibody binding. Further, our data indicate that this tension loss is mediated by the inhibition of RhoA at cell-cell contacts, and the extent of RhoA inhibition may be crucial in determining the severity of pathogenicity among different PV antibodies. More importantly, this tension loss can be partially restored by altering actomyosin based cell contractility. Collectively, these findings provide previously unattainable details in our understanding of the mechanisms that govern cell-cell interactions under physiological and autoimmune conditions, which may open the window to entirely new therapeutics aimed at restoring physiological balance to tension dynamics that regulates the maintenance of cell-cell adhesion.

A Comparison of Quality-Adjusted Life Years in Older Adults after Heart Transplantation Versus Long-Term Mechanical Support: Findings From the SUSTAIN-IT study.

BACKGROUND: The quality-adjusted life year (QALY) measures disease burden and treatment, combining overall survival and health-related quality of life (HRQOL). We estimated QALYs in three groups of older patients (60-80 years) with heart failure (HF) who underwent heart transplantation (HT, with pre-transplant mechanical circulatory support [HT MCS] or HT without pre-transplant MCS [HT Non-MCS]) or long-term MCS (destination therapy). We also identified factors associated with gains in QALYs through 24 months follow-up. METHODS: Of 393 eligible patients enrolled (10/1/15-12/31/18) at 13 U.S. sites, 161 underwent HT (n=68 HT MCS, n=93 HT Non-MCS) and 144 underwent long-term MCS. Survival and HRQOL data were collected through 24 months. QALY health utilities were based on patient self-report of EQ-5D-3L dimensions. Mean-restricted QALYs were compared among groups using generalized linear models. RESULTS: For the entire cohort, mean age in years closest to surgery was 67 (standard deviation, SD: 4.7), 78% were male, and 83% were White. By 18 months post-surgery, sustained significant differences in adjusted average+SD QALYs emerged across groups, with the HT Non-MCS group having the highest average QALYs (24-month window: HT Non-MCS=22.58+1.1, HT MCS=19.53+1.33, Long-term MCS=19.49+1.3, p=0.003). At 24 months post-operatively, a lower gain in QALYs was associated with HT MCS, long-term MCS, a lower pre-operative LVEF, NYHA class III or IV before surgery, and an ischemic or other etiology of HF. CONCLUSIONS: Determination of QALYs may provide important information for policy makers and clinicians to consider regarding benefits of HT and long-term MCS as treatment options for older patients with HF.

Effects of methamphetamine on actigraphy-based sleep parameters in female rhesus monkeys: Orexin receptor mechanisms.

BACKGROUND: The orexin system has been implicated as a mechanism underlying insomnia and methamphetamine-induced sleep disruptions, with a potential role for OX2 receptors in the sleep-modulating effects of orexin. The aim of the present study was to investigate the extent to which orexin receptors mediate the effects of acute methamphetamine administration on actigraphy-based sleep in female rhesus monkeys. METHODS: Actigraphy-based sleep measures were obtained in female rhesus monkeys (n=5) under baseline and acute test conditions. First, morning (10h) i.m. injections of methamphetamine (0.03 - 0.56mg/kg) were administered to determine the effects of methamphetamine alone. Then, saline or methamphetamine (0.3mg/kg) were administered at 10h, and evening (17h30) oral treatments with vehicle, the non-selective orexin receptor antagonist suvorexant (1 - 10mg/kg, p.o.), or the OX2-selective orexin receptor antagonist MK-1064 (1 - 10mg/kg, p.o.) were given. The ability of suvorexant and MK-1064 (10mg/kg, p.o.) to improve actigraphy-based sleep was also assessed in a group of female monkeys quantitatively identified with "short-duration sleep" (n=4). RESULTS: Methamphetamine dose-dependently disrupted actigraphy-based sleep parameters. Treatment with either suvorexant or MK-1064 dose-dependently improved actigraphy-based sleep in monkeys treated with methamphetamine. Additionally, both suvorexant and MK-1064 promoted actigraphy-based sleep in a group of monkeys with baseline short actigraphy-based sleep. CONCLUSIONS: These findings suggest that orexin-mediated mechanisms play a role in the effects of methamphetamine on actigraphy-based sleep in female monkeys. Targeting the orexin system, in particular OX2 receptors, could be an effective option for treating sleep disruptions observed in individuals with methamphetamine use disorder.

PyOKR: A Semi-Automated Method for Quantifying Optokinetic Reflex Tracking Ability.

The study of behavioral responses to visual stimuli is a key component of understanding visual system function. One notable response is the optokinetic reflex (OKR), a highly conserved innate behavior necessary for image stabilization on the retina. The OKR provides a robust readout of image tracking ability and has been extensively studied to understand visual system circuitry and function in animals from different genetic backgrounds. The OKR consists of two phases: a slow tracking phase as the eye follows a stimulus to the edge of the visual plane and a compensatory fast phase saccade that resets the position of the eye in the orbit. Previous methods of tracking gain quantification, although reliable, are labor intensive and can be subjective or arbitrarily derived. To obtain more rapid and reproducible quantification of eye tracking ability, we have developed a novel semi-automated analysis program, PyOKR, that allows for quantification of two-dimensional eye tracking motion in response to any directional stimulus, in addition to being adaptable to any type of video-oculography equipment. This method provides automated filtering, selection of slow tracking phases, modeling of vertical and horizontal eye vectors, quantification of eye movement gains relative to stimulus speed, and organization of resultant data into a usable spreadsheet for statistical and graphical comparisons. This quantitative and streamlined analysis pipeline, readily accessible via PyPI import, provides a fast and direct measurement of OKR responses, thereby facilitating the study of visual behavioral responses.