Quantitative estimation of nerve fiber engagement by vagus nerve stimulation using physiological markers

© 2020 The Author(s) Background: Cervical vagus nerve stimulation (VNS) is an emerging bioelectronic treatment for brain, metabolic, cardiovascular and immune disorders. Its desired and off-target effects are mediated by different nerve fiber populations and knowledge of their engagement could guide calibration and monitoring of VNS therapies. Objective: Stimulus-evoked compound action potentials (eCAPs) directly provide fiber engagement information but are currently not feasible in humans. A method to estimate fiber engagement through common, noninvasive physiological readouts could be used in place of eCAP measurements. Methods: In anesthetized rats, we recorded eCAPs while registering acute physiological response markers to VNS: cervical electromyography (EMG), changes in heart rate (ΔHR) and breathing interval (ΔBI). Quantitative models were established to capture the relationship between A-, B- and C-fiber type activation and those markers, and to quantitatively estimate fiber activation from physiological markers and stimulation parameters. Results: In bivariate analyses, we found that EMG correlates with A-fiber, ΔHR with B-fiber and ΔBI with C-fiber activation, in agreement with known physiological functions of the vagus. We compiled multivariate models for quantitative estimation of fiber engagement from these markers and stimulation parameters. Finally, we compiled frequency gain models that allow estimation of fiber engagement at a wide range of VNS frequencies. Our models, after calibration in humans, could provide noninvasive estimation of fiber engagement in current and future therapeutic applications of VNS

Has VZV epidemiology changed in Italy? Results of a seroprevalence study

The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013–2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996–1997 and 2003–2004 showed significant differences in age groups 1–19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1–4 years, expression of vaccine interventions already adopted in some regions

Isolated talonavicular arthrodesis in patients with rheumatoid arthritis of the foot and tibialis posterior tendon dysfunction

<p>Abstract</p> <p>Background</p> <p>The foot is often affected in patients with rheumatoid arthritis. Subtalar joints are involved more frequently than ankle joints. Deformities of subtalar joints often lead to painful flatfoot and valgus deformity of the heel. Major contributors to the early development of foot deformities include talonavicular joint destruction and tibialis posterior tendon dysfunction, mainly due to its rupture.</p> <p>Methods</p> <p>Between 2002 and 2005 we performed isolated talonavicular arthrodesis in 26 patients; twenty women and six men. Tibialis posterior tendon dysfunction was diagnosed preoperatively by physical examination and by MRI. Talonavicular fusion was achieved via screws in eight patients, memory staples in twelve patients and a combination of screws and memory staples in six cases. The average duration of immobilization after the surgery was four weeks, followed by rehabilitation. Full weight bearing was allowed two to three months after surgery.</p> <p>Results</p> <p>The mean age of the group at the time of the surgery was 43.6 years. MRI examination revealed a torn tendon in nine cases with no significant destruction of the talonavicular joint seen on X-rays. Mean of postoperative followup was 4.5 years (3 to 7 years). The mean of AOFAS Hindfoot score improved from 48.2 preoperatively to 88.6 points at the last postoperative followup. Eighteen patients had excellent results (none, mild occasional pain), six patients had moderate pain of the foot and two patients had severe pain in evaluation with the score. Complications included superficial wound infections in two patients and a nonunion developed in one case.</p> <p>Conclusions</p> <p>Early isolated talonavicular arthrodesis provides excellent pain relief and prevents further progression of the foot deformities in patients with rheumatoid arthritis and tibialis posterior tendon dysfunction.</p

Hiding in plain sight: observing planet-starspot crossings with the James Webb Space Telescope

Transiting exoplanets orbiting active stars frequently occult starspots and faculae on the visible stellar disc. Such occultations are often rejected from spectrophotometric transits, as it is assumed they do not contain relevant information for the study of exoplanet atmopsheres. However, they can provide useful constraints to retrieve the temperature of active features and their effect on transmission spectra. We analyse the capabilities of the James Webb Space Telescope in the determination of the spectra of occulted starspots, despite its lack of optical wavelength instruments on board. Focusing on K and M spectral types, we simulate starspots with different temperatures and in different locations of the stellar disc, and find that starspot temperatures can be determined to within a few hundred kelvins using NIRSpec/Prism and the proposed NIRCam/F150W2$+$F322W2's broad wavelength capabilities. Our results are particularly promising in the case of K and M dwarfs of mag$_K \leq 12.5$ with large temperature contrasts

The impact of rheumatoid foot on disability in Colombian patients with rheumatoid arthritis

<p>Abstract</p> <p>Background</p> <p>Alterations in the feet of patients with rheumatoid arthritis (RA) are a cause of disability in this population. The purpose of this research was to evaluate the impact that foot impairment has on the patients' global quality of life (QOL) based on validated scales and its relationship to disease activity.</p> <p>Methods</p> <p>This was a cross-sectional study in which 95 patients with RA were enrolled. A complete physical examination, including a full foot assessment, was done. The Spanish versions of the Health Assessment Questionnaire (HAQ) Disability Index and of the Disease Activity Score (DAS 28) were administered. A logistic regression model was used to analyze data and obtain adjusted odds ratios (AORs).</p> <p>Results</p> <p>Foot deformities were observed in 78 (82%) of the patients; hallux valgus (65%), medial longitudinal arch flattening (42%), claw toe (lesser toes) (39%), dorsiflexion restriction (tibiotalar) (34%), cock-up toe (lesser toes) (25%), and transverse arch flattening (25%) were the most frequent. In the logistic regression analysis (adjusted for age, gender and duration of disease), forefoot movement pain, subtalar movement pain, tibiotalar movement pain and plantarflexion restriction (tibiotalar) were strongly associated with disease activity and disability. The positive squeeze test was significantly associated with disability risk (AOR = 6,3; 95% CI, 1.28–30.96; P = 0,02); hallux valgus, and dorsiflexion restriction (tibiotalar) were associated with disease activity.</p> <p>Conclusion</p> <p>Foot abnormalities are associated with active joint disease and disability in RA. Foot examinations provide complementary information related to the disability as an indirect measurement of quality of life and activity of disease in daily practice.</p

Co-inhibition of SMAD and MAPK signaling enhances 124I uptake in BRAF-mutant thyroid cancers.

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid-differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFB1 also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of BRAFV600E-PTC with thyroid-specific knockout of the Tgfbr1 gene to investigate the role of TGFB1 on thyroid-differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of Tgfbr1, pSMAD levels remained high, indicating that ligands other than TGFB1 were engaging in this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BRAFV600E-mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFBR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BRAFV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BRAFV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting TGFβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells

Total ankle prostheses in rheumatoid arthropathy: Outcome in 52 patients followed for 1–9 years

Background and purpose The first generations of total ankle replacements (TARs) showed a high rate of early failure. In the last decades, much progress has been made in the development of TARs, with the newer generation showing better results. We evaluated TARs implanted with rheumatoid arthritis (RA) or juvenile inflammatory arthritis (JIA) as indication

Geoeconomic variations in epidemiology, ventilation management, and outcomes in invasively ventilated intensive care unit patients without acute respiratory distress syndrome: a pooled analysis of four observational studies

Background: Geoeconomic variations in epidemiology, the practice of ventilation, and outcome in invasively ventilated intensive care unit (ICU) patients without acute respiratory distress syndrome (ARDS) remain unexplored. In this analysis we aim to address these gaps using individual patient data of four large observational studies. Methods: In this pooled analysis we harmonised individual patient data from the ERICC, LUNG SAFE, PRoVENT, and PRoVENT-iMiC prospective observational studies, which were conducted from June, 2011, to December, 2018, in 534 ICUs in 54 countries. We used the 2016 World Bank classification to define two geoeconomic regions: middle-income countries (MICs) and high-income countries (HICs). ARDS was defined according to the Berlin criteria. Descriptive statistics were used to compare patients in MICs versus HICs. The primary outcome was the use of low tidal volume ventilation (LTVV) for the first 3 days of mechanical ventilation. Secondary outcomes were key ventilation parameters (tidal volume size, positive end-expiratory pressure, fraction of inspired oxygen, peak pressure, plateau pressure, driving pressure, and respiratory rate), patient characteristics, the risk for and actual development of acute respiratory distress syndrome after the first day of ventilation, duration of ventilation, ICU length of stay, and ICU mortality. Findings: Of the 7608 patients included in the original studies, this analysis included 3852 patients without ARDS, of whom 2345 were from MICs and 1507 were from HICs. Patients in MICs were younger, shorter and with a slightly lower body-mass index, more often had diabetes and active cancer, but less often chronic obstructive pulmonary disease and heart failure than patients from HICs. Sequential organ failure assessment scores were similar in MICs and HICs. Use of LTVV in MICs and HICs was comparable (42\ub74% vs 44\ub72%; absolute difference \u20131\ub769 [\u20139\ub758 to 6\ub711] p=0\ub767; data available in 3174 [82%] of 3852 patients). The median applied positive end expiratory pressure was lower in MICs than in HICs (5 [IQR 5\u20138] vs 6 [5\u20138] cm H2O; p=0\ub70011). ICU mortality was higher in MICs than in HICs (30\ub75% vs 19\ub79%; p=0\ub70004; adjusted effect 16\ub741% [95% CI 9\ub752\u201323\ub752]; p&lt;0\ub70001) and was inversely associated with gross domestic product (adjusted odds ratio for a US$10 000 increase per capita 0\ub780 [95% CI 0\ub775\u20130\ub786]; p&lt;0\ub70001). Interpretation: Despite similar disease severity and ventilation management, ICU mortality in patients without ARDS is higher in MICs than in HICs, with a strong association with country-level economic status. Funding: No funding