Dual blockade of IL-4 and IL-13 with dupilumab ameliorates sensorineural olfactory dysfunction in mice with eosinophilic sinonasal inflammation.

BACKGROUND: Dupilumab, an antibody that binds IL-4Rα and inhibits IL-4 and IL-13 signals, has demonstrated efficacy in chronic rhinosinusitis with nasal polyps (CRSwNP) primarily characterized by type 2 inflammation. Current evidence suggests that the rate of improvement in olfactory dysfunction with dupilumab exceeds that of nasal polyp reduction, yet the underlying mechanism remains undisclosed. We hypothesize that dupilumab may initially ameliorate sensorineural olfactory dysfunction. METHODOLOGY: Male BALB/c mice were intranasally administered ovalbumin and Aspergillus protease for 12 weeks to induce eosinophilic sinonasal inflammation. Dupilumab treatment was also administered. The mice underwent histological assessment, olfactory behavioural test, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb. RESULTS: Dupilumab treatment resulted in a reduction in the number of mucosal protruding lesions, as well as decreased infiltration of eosinophils and neutrophils, along with a decrease in olfactory sensory neuron injury. Furthermore, there was a downregulation in the mRNA expression related to microglia activation and neuroinflammation in the olfactory bulb. CONCLUSIONS: Dupilumab improves the sensorineural pattern of olfactory dysfunction in mice, potentially explaining why olfaction improves more rapidly than polyp reduction in patients with CRSwNP.

Development of a reliable surgical quality assurance tool for gastrectomy in oncological trials.

BACKGROUND: Despite its recognized importance, there is currently no reliable tool for surgical quality assurance (SQA) of gastrectomy in surgical oncology. The aim of this study was to develop an SQA tool for gastrectomy and to apply this tool within the ADDICT Trial in order to assess the extent and completeness of lymphadenectomy. METHODS: The operative steps for D1+ and D2 gastrectomy have been previously described in the literature and ADDICT trial manual. Two researchers also performed fieldwork in the UK and Japan to document key operative steps through photographs and semi-structured interviews with expert surgeons. This provided the steps that were used as the framework for the SQA tool. Sixty-two photographic cases from the ADDICT Trial were rated by three independent surgeons. Generalizability (G) theory determined inter-rater reliability. D-studies examined the effect of varying the number of assessors and photographic series they rated. Chi-square assessed intra-rater reliability, comparing how the individual assessor's responses corresponded to their global rating for extent of lymphadenectomy. RESULTS: The tool comprised 20 items, including 19 anatomical landmarks and a global rating score. Overall reliability had G-coefficient of 0.557. Internal consistency was measured with a Cronbach's alpha score of 0.869 and Chi-square confirmed intra-rater reliability for each assessor as < 0.05. CONCLUSIONS: A photographic surgical quality assurance tool is presented for gastrectomy. Using this tool, the assessor can reliably determine not only the quality but also the extent of the lymphadenectomy performed based on remaining anatomy rather than the excised specimen.

Differences of bioelectrical impedance in the development and healing phase of pressure ulcers and erythema in mouse model.

Pressure ulcers (PUs) are economically burdensome medical conditions. Early changes in pressure ulcers are associated with erythema. In this study, bioelectrical impedance was used to measure the differences between PUs and blanchable erythema. We divided 21 ICR mice into three groups: control, 1000 mmHg-1h, and 1000 mmHg-6h. Healthy skin, blanchable erythema, and PUs were induced on the dorsal skin. The results indicated an immediate increase in impedance, resistance, and reactance values in the pressure group after release, followed by a subsequent decrease until two days after release. Compared with the control group, impedance and reactance significantly increased by 30.9% (p < 0.05) and 30.1% (p < 0.01), respectively, in the 6 h-loading group immediately after release. One and two days after release, the 1 h-loading and 6 h-loading groups exhibited significantly different degrees of decline. One day after release, impedance and resistance decreased by 30.2% (p < 0.05) and 19.8% (p < 0.05), respectively, in the 1 h-loading group; while impedance, resistance, and reactance decreased by 39.2% (p < 0.01), 26.8% (p < 0.01), and 45.7% (p < 0.05), respectively, in the 6 h-loading group. Two days after release, in the 1 h-loading group, impedance and resistance decreased by 28.3% (p < 0.05) and 21.7% (p < 0.05), respectively; while in the 6 h-loading group, impedance, resistance, and reactance decreased by 49.8% (p < 0.001), 34.2% (p < 0.001), and 59.8% (p < 0.01), respectively. One and two days after release the pressure group reductions were significantly greater than those in the control group. Additionally, we monitored changes during wound healing. Distinguishing early PUs from blanchable erythema by noninvasive bioelectrical impedance technology may have applications value in early assessment of PUs.

Neuroanatomical and morphometric study of S100ß positive astrocytes in the entorhinal cortex during ageing in the 3xTg-Alzehimer's disease mouse model.

Astrocytes contribute to the progression of neurodegenerative diseases, including Alzheimer's disease (AD). Here, we report the neuroanatomical and morphometric analysis of astrocytes in the entorhinal cortex (EC) of the aged wild type (WT) and triple transgenic (3xTg-AD) mouse model of AD. Using 3D confocal microscopy, we determined the surface area and volume of positive astrocytic profiles in male mice (WT and 3xTg-AD) from 1 to 18 months of age. We showed that S100ß-positive astrocytes were equally distributed throughout the entire EC in both animal types and showed no changes in Nv (number of cells/mm3) nor in their distribution at the different ages studied. These positive astrocytes, demonstrated an age-dependent gradual increase in their surface area and in their volume starting at 3 months of age, in both WT and 3xTg-AD mice. This last group demonstrated a large increase in both surface area and volume at 18 months of age when the burden of pathological hallmarks of AD is present (69.74% to 76.73% in the surface area and the volume, for WT and 3xTg-AD mice respectively). We observed that these changes were due to the enlargement of the cell processes and to less extend the somata. In fact, the volume of the cell body was increased by 35.82% in 18-month-old 3xTg-AD compared to WT. On the other hand, the increase on the astrocytic processes were detected as soon as 9 months of age where we found an increase of surface area and volume (36.56% and 43.73%, respectively) sustained till 18 month of age (93.6% and 113.78%, respectively) when compared age-matched non-Tg mice. Moreover, we demonstrated that these hypertrophic S100ß-positive astrocytes were mainly associated with Aß plaques. Our results show a severe atrophy in GFAP cytoskeleton in all cognitive areas; whilst within the EC astrocytes independent to this atrophy show no changes in GS and S100ß; which can play a key role in the memory impairment.

Erratum: Coherent Excitation of the Highly Forbidden Electric Octupole Transition in

This corrects the article DOI: 10.1103/PhysRevLett.125.163001.

A molecular interpretation of the toughness of multiple network elastomers at high temperature.

SignificanceSoft materials can be toughened by creating dissipative mechanisms in stretchy matrixes. Yet using them over a wide range of temperatures requires dissipative mechanisms independent of stretch rate or temperature. We show that sacrificial covalent bonds in multiple network elastomers are most useful in toughening elastomers at high temperature and act synergistically with viscoelasticity at lower temperature. We do not attribute this toughening mechanism only to the scission of bonds during crack propagation but propose that the highly stretched network diluted in a stretchy matrix acts by simultaneously stiffening the elastomer and delaying the localization of bond scission and the propagation of a crack. Such a toughening mechanism has never been proposed for elastomers and should guide network design.

The timing of auditory sensory deficits in Norrie disease has implications for therapeutic intervention.

Norrie disease is caused by mutation of the NDP gene, presenting as congenital blindness followed by later onset of hearing loss. Protecting patients from hearing loss is critical for maintaining their quality of life. This study aimed to understand the onset of pathology in cochlear structure and function. By investigating patients and juvenile Ndp-mutant mice, we elucidated the sequence of onset of physiological changes (in auditory brainstem responses, distortion product otoacoustic emissions, endocochlear potential, blood-labyrinth barrier integrity) and determined the cellular, histological, and ultrastructural events leading to hearing loss. We found that cochlear vascular pathology occurs earlier than previously reported and precedes sensorineural hearing loss. The work defines a disease mechanism whereby early malformation of the cochlear microvasculature precedes loss of vessel integrity and decline of endocochlear potential, leading to hearing loss and hair cell death while sparing spiral ganglion cells. This provides essential information on events defining the optimal therapeutic window and indicates that early intervention is needed. In an era of advancing gene therapy and small-molecule technologies, this study establishes Ndp-mutant mice as a platform to test such interventions and has important implications for understanding the progression of hearing loss in Norrie disease.

Total knee replacement in osteoarthritis patients on reducing the risk of major adverse cardiac events: a 18-year retrospective cohort study.

OBJECTIVES: Osteoarthritis (OA) is a common degenerative joint disease, and total knee replacement (TKR) is a successful surgical intervention for knee OA treatment. However, the risks of mortality and major cardiovascular events (MACEs) in patients receiving TKR remain unclear. This study investigated the risks of mortality and MACEs in knee OA patients who received TKR. METHODS: For this population-based cohort study, the Longitudinal Health Insurance Database 2000 was used. Two million individuals with knee OA defined by ICD-9-CM codes who received physical therapy between 1999 and 2017 were selected. For propensity score matching (PSM), we considered the year of knee OA diagnosis, demographics, comorbidities, co-medications, and knee OA-related hyaluronic acid or physical therapy at baseline. After PSM, regression analyses were performed to assess the association of mortality or MACEs with TKR and non-TKR individuals. RESULTS: We identified patients (n = 189,708) with a new diagnosis of knee OA between 2000 and 2017. In total, 10,314 propensity-score-paired TKR and non-TKR individuals were selected. The PSM cohort algorithm revealed that the risk of mortality or MACEs was lower in the TKR group (adjusted hazard ratio: 0.791; 95% confidence interval: 0.755-0.830) than in the non-TKR group. CONCLUSIONS: Patients with knee OA who received TKR had decreased risks of mortality and MACEs than those who did not receive TKR. Moreover, the TKR group received a reduced dosage of nonsteroidal anti-inflammatory drugs at the 1-year follow-up.

Why is mechanical fatigue different from toughness in elastomers? The role of damage by polymer chain scission.

Although elastomers often experience 10 to 100 million cycles before failure, there is now a limited understanding of their resistance to fatigue crack propagation. We tagged soft and tough double-network elastomers with mechanofluorescent probes and quantified damage by sacrificial bond scission after crack propagation under cyclic and monotonic loading. Damage along fracture surfaces and its spatial localization depend on the elastomer design, as well as on the applied load (i.e., cyclic or monotonic). The key result is that reversible elasticity and strain hardening at low and intermediate strains dictates fatigue resistance, whereas energy dissipation at high strains controls toughness. This information serves to engineer fatigue-resistant elastomers, understand fracture mechanisms, and reduce the environmental footprint of the polymer industry.

Structure and Functional Differences of Cysteine and 3-Mercaptopropionate Dioxygenases: A Computational Study.

Thiol dioxygenases are important enzymes for human health; they are involved in the detoxification and catabolism of toxic thiol-containing natural products such as cysteine. As such, these enzymes have relevance to the development of Alzheimer's and Parkinson's diseases in the brain. Recent crystal structure coordinates of cysteine and 3-mercaptopropionate dioxygenase (CDO and MDO) showed major differences in the second-coordination spheres of the two enzymes. To understand the difference in activity between these two analogous enzymes, we created large, active-site cluster models. We show that CDO and MDO have different iron(III)-superoxo-bound structures due to differences in ligand coordination. Furthermore, our studies show that the differences in the second-coordination sphere and particularly the position of a positively charged Arg residue results in changes in substrate positioning, mobility and enzymatic turnover. Furthermore, the substrate scope of MDO is explored with cysteinate and 2-mercaptosuccinic acid and their reactivity is predicted.

Clinical benefits of routine examination and synchronous repair of occult inguinal hernia during laparoscopic peritoneal dialysis catheter insertion: a single-center experience.

PURPOSE: Occult inguinal hernias (IH) predispose peritoneal dialysis (PD) patients to the symptomatic IH formation after starting PD, which may cause complications. We conducted a retrospective study to assess the benefit/risk profile of routine laparoscopic examination for occult IH (RLEOH) with a synchronous repair in patients receiving PD catheter placement. METHODS: 432 patients were enrolled in this study. Patients with an internal hernia sac at all sizes were deemed to have occult IH. We retrospectively reviewed data including demographic characteristics and operative details. We also measured incidence rates of symptomatic IH, metachronous IH repair, and catheter survival over a follow-up period after starting PD. RESULTS: These patients were classified into the RLEOH group (n = 365) and the non-RLEOH group (n = 67). The RLEOH group was subdivided into occult IH with a synchronous repair (n = 17; the subgroup A), no occult IH (n = 339; the subgroup B), and occult IH without a synchronous repair (n = 9; the subgroup C). The incidence rates of symptomatic IH developed after staring PD in subgroups A, B, and C were 0, 5.6, and 22.2%, respectively, whereas that in the non-RLEOH group was 13.4%. The RLEOH group had a reduced hazard ratio for metachronous IH repair compared with the non-RLEOH group (HR = 0.426; 95% CI 0.195-0.930, p = 0.032). None of our patients suffered from herniorrhaphy-related complications. CONCLUSION: RLEOH with a synchronous repair during PD catheter insertion confers clinical benefits in reducing the risk of developing IH after starting PD and the need for a metachronous repair. This is a safe and reasonable approach.

Coherent Excitation of the Highly Forbidden Electric Octupole Transition in

We report on the first coherent excitation of the highly forbidden ^{2}S_{1/2}→^{2}F_{7/2} electric octupole (E3) transition in a single trapped ^{172}Yb^{+} ion, an isotope without nuclear spin. Using the transition in ^{171}Yb^{+} as a reference, we determine the transition frequency to be 642 116 784 950 887.6(2.4) Hz. We map out the magnetic field environment using the forbidden ^{2}S_{1/2}→^{2}D_{5/2} electric quadrupole (E2) transition and determine its frequency to be 729 476 867 027 206.8(4.4) Hz. Our results are a factor of 1×10^{5} (3×10^{5}) more accurate for the E2 (E3) transition compared to previous measurements. The results open up the way to search for new physics via precise isotope shift measurements and improved tests of local Lorentz invariance using the metastable ^{2}F_{7/2} state of Yb^{+}.

From force-responsive molecules to quantifying and mapping stresses in soft materials.

Directly quantifying a spatially varying stress in soft materials is currently a great challenge. We propose a method to do that by detecting a change in visible light absorption. We incorporate a spiropyran (SP) force-activated mechanophore cross-linker in multiple-network elastomers. The random nature of the network structure of the polymer causes a progressive activation of the SP force probe with load, detectable by the change in color of the material. We first calibrate precisely the chromatic change in uniaxial tension. We then demonstrate that the nominal stress around a loaded crack can be detected for each pixel and that the measured values match quantitatively finite element simulations. This direct method to quantify stresses in soft materials with an internal force probe is an innovative tool that holds great potential to compare quantitatively stresses in different materials with simple optical observations.

Fast reversible isomerization of merocyanine as a tool to quantify stress history in elastomers.

A mechanochemistry based approach is proposed to detect and map stress history during dynamic processes. Spiropyran (SP), a force sensitive molecular probe, was incorporated as a crosslinker into multiple network elastomers (MNE). When these mechanochromic MNEs are loaded, SP undergoes a well-known force-activated reaction to merocyanine (MC) changing its absorption in the visible range (visible blue color). This SP to MC transition is not reversible within the time frame of the experiment and the color change reports the concentration of activated molecules. During subsequent loading-unloading cycles the MC undergoes a fast and reversible isomerization resulting in a slight shift of absorption spectrum and results in a second color change (blue to purple color corresponding to the loading-unloading cycles). Quantification of the color changes by using chromaticity shows that the exact color observed upon unloading is characteristic not only of the current stress (reported by the shift in color due to MC isomerization), but of the maximum stress that the material has seen during the loading cycle (reported by the shift in color due to the change in MC concentration). We show that these two color changes can be separated unambiguously and we use them to map the stress history in the loading and unloading process occurring as a crack opens up and propagates, breaking the material. Color maps on fractured samples are compared with finite element simulations and the agreement is excellent.

Midlife Body Mass Index Trajectory and Risk of Frailty 8 Years Later in Taiwan.

OBJECTIVES: Few studies have focused on weight change and frailty, especially in Asia. This research aimed to evaluate midlife body mass index (BMI) trajectory and assess its relationship with frailty 8 years later in Taiwan. DESIGN: A prospective cohort study. SETTING AND PARTICIPANTS: Data were retrieved from the Taiwan Longitudinal Study on Aging conducted from 1999 to 2007. The analysis was restricted to respondents aged between 50 to 69 years old, who were not frail in 1999 and were alive in 2007 (n=1609). MEASUREMENTS: Frailty was defined using the Fried criteria. The group-based model of trajectory was used to estimate BMI trajectories among elderly participants. Logistic regression analysis was used to examine the association between BMI change and frailty. RESULTS: Four trajectory classes were identified and each remained stable during the 8-year follow-up. There were 316 participants (20.3%) in the low-normal weight group (baseline BMI=20.38 kg/m2), 737 participants (44.7%) in the high-normal weight group (baseline BMI=23.22 kg/m2), 449 participants (28.4%) in the overweight group (baseline BMI=26.24 kg/m2), and 107 participants (6.6%) in the obesity group (baseline BMI=30.65 kg/m2). After adjustment for confounding factors, the low-normal weight group and obesity group were associated with increased frailty compared with the high-normal weight group. CONCLUSION: Our results showed that the BMI trajectories of midlife individuals tended to be constant and those in both the low-normal weight group and obesity group had an increased risk of developing frailty in later life. Therefore, an optimal weight-targeting strategy should be considered for Asian elderly individuals.

Comparison of Magnetic Auriculotherapy, Laser Auriculotherapy and Their Combination for Treatment of Insomnia in the Elderly: A Double-Blinded Randomised Trial.

BACKGROUND: Insomnia is common amongst the elderly. With the adverse effects of prolonged use of hypnotics, the exploration of noninvasive and nonpharmacological complementary methods for insomnia is warranted. Auriculotherapy (AT) is a therapeutic approach where specific points on the auricle are stimulated to manage various physiological disorders. The purpose of this study is to determine the desirable treatment modality using AT to improve the sleep conditions of the elderly. METHODS: A three-arm double-blinded randomised trial was conducted on 145 eligible subjects. This study investigated three minimally invasive procedures, namely, laser auriculotherapy (LAT), magneto-auriculotherapy (MAT), and their combination. Seven auricular points were used. Treatment was performed three times a week, for six weeks. Subjects were assessed at baseline, six weeks, and follow-up after six weeks, three months, and six months. Generalised estimating equations were used to evaluate interactions amongst the groups over time based on the Pittsburgh Sleep Quality Index (PSQI), sleep parameters using actigraphic monitoring, health-related quality of life (HRQOL) using SF-12, and PHQ-9 for depression status. RESULTS: The treatment effects of the three procedures were comparable. Significant improvements were found in all of the subjective measures (PSQI, HRQOL, and PHQ-9) for individual groups over time. Improvements in the objective sleep parameters using actigraphic monitoring were detected in subjects who received MAT procedures but not in those who received LAT. The combined MAT and LAT approach did not show any advantage over MAT. CONCLUSIONS: The treatment effects of the three procedures were comparable in subjective parameters but not by objective measures using actigraphic monitoring. Longer therapeutic course and more frequent administration of LAT may be considered in future trials to achieve the optimal treatment effect. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov: NCT02970695, registered May 2016.

Reduced use of emergency care and hospitalization in patients with post-stroke cognitive impairment treated with traditional Chinese medicine.

BACKGROUND: The effect of traditional Chinese medicine (TCM) on the outcomes of dementia remains unclear. Our purpose is to compare the use of emergency care and hospitalization in patients with post-stroke cognitive impairment (PSCI) with or without treatment of TCM. METHODS: In a stroke cohort of 67 521 patients with PSCI aged over 40 years obtained from the 23 million people in Taiwan's national health insurance between 2000 and 2007, we identified 6661 newly diagnosed PSCI patients who were treated with TCM and 6661 propensity score-matched PSCI patients who were not treated with TCM. Under the control of immortal time bias, we calculated the adjusted rate ratios (RRs) and 95% CIs of the 1-year use of emergency care and hospitalization associated with TCM. RESULTS: The means of the emergency care medical visits (0.40 ± 0.98 vs. 0.47 ± 1.01, P = 0.0001) and hospitalization (0.72 ± 1.29 vs. 0.96 ± 1.49, P < 0.0001) were lower in the PSCI patients treated with TCM than in those without the TCM treatment. The RRs of emergency care and hospitalization associated with TCM were 0.87 (95% CI = 0.82-0.92) and 0.81 (95% CI = 0.78-0.84), respectively. The PSCI patients treated with a combination of acupuncture and herbal medicine had the lowest risk of emergency care visits and hospitalization. CONCLUSIONS: Our study raises the possibility that TCM use was associated with reduced use of emergency care and hospitalization after PSCI. However, further randomized clinical trials are needed to provide solid evidence of this benefit and identify the underlying mechanism.

Diverse immune responses to HBV surface epitope variants after vaccine booster in adolescents immunized in infancy.

OBJECTIVES: We aimed to investigate immunity against hepatitis B surface antigen (HBsAg) mutants before and after boosters in adolescents who had lost antibodies against HBsAg (anti-HBs) despite neonatal vaccination. METHODS: We recruited 142 participants from 15 to 21 years old who had received complete vaccination in infancy but became anti-HBs-negative. Cellular immunity to HBsAg and T-cell epitope variants was assessed before and after boosters. Antibody affinity to variants was assessed after boosters. RESULTS: After one dose of booster, 12 out of 140 (8.6%) participants remained anti-HBs-negative. Anti-HBs titres were higher in those participants <17 (geometric mean, 337.9 ± 10.9 vs. 157.4 ± 16.6 mIU/mL, p = 0.012). Before the booster, HBsAg-specific cell proliferation was present in 58 out of 64 (90.6%) participants. The proliferation response rates to T-cell epitopes were 37.8% and 72.6% (p < 0.001) before and after the booster, respectively. The stimulation index improved from 1.25 ± 1.70 to 2.53 ± 2.32 (p < 0.001) for various T-cell epitopes. HBsAg-specific interleukin (IL)-5- and interferon (IFN)-γ-secreting T-cells were enhanced (45 ± 10 and 50 ± 4 to 420 ± 328 and 355 ± 424 spot-forming cells/106 cells, respectively, p < 0.001). IFN-γ-secreting T cells to epitope 16-33 containing R24K and the antibody affinity to sG145R were still significantly lower than to the wild type. CONCLUSIONS: In immunized adolescents who lost anti-HBs, around 10% also lost immune memory. Cellular immunity to some T-cell epitope variants improved after the booster. Antibody affinity to sG145R and the IFN-γ-secreting cell response to some epitope 16-33 variants were still impaired even after booster administration.

Neuron-Specific Genome Modification in the Adult Rat Brain Using CRISPR-Cas9 Transgenic Rats.

Historically, the rat has been the preferred animal model for behavioral studies. Limitations in genome modification have, however, caused a lag in their use compared to the bevy of available transgenic mice. Here, we have developed several transgenic tools, including viral vectors and transgenic rats, for targeted genome modification in specific adult rat neurons using CRISPR-Cas9 technology. Starting from wild-type rats, knockout of tyrosine hydroxylase was achieved with adeno-associated viral (AAV) vectors expressing Cas9 or guide RNAs (gRNAs). We subsequently created an AAV vector for Cre-dependent gRNA expression as well as three new transgenic rat lines to specifically target CRISPR-Cas9 components to dopaminergic neurons. One rat represents the first knockin rat model made by germline gene targeting in spermatogonial stem cells. The rats described herein serve as a versatile platform for making cell-specific and sequence-specific genome modifications in the adult brain and potentially other Cre-expressing tissues of the rat.