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Abstract More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomial, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat Candida albicans infections. Our data indicates that these synthetic polymers cause endoplasmic reticulum stress and affect protein glycosylation, a mode of action distinct from currently approved antifungal drugs. The most promising polymer composition damaged the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of tolerant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

Abstract Obesity impairs tissue insulin sensitivity and signaling, promoting type-2 diabetes. Although improving insulin signaling is key to reversing diabetes, the multi-organ mechanisms regulating this process are poorly defined. Here, we screen the secretome and receptome in Drosophila to identify the hormonal crosstalk affecting diet-induced insulin resistance and obesity. We discover a complex interplay between muscle, neuronal, and adipose tissues, mediated by Bone Morphogenetic Protein (BMP) signaling and the hormone Bursicon, that enhances insulin signaling and sugar tolerance. Muscle-derived BMP signaling, induced by sugar, governs neuronal Bursicon signaling. Bursicon, through its receptor Rickets, a Leucine-rich-repeat-containing G-protein coupled receptor (LGR), improves insulin secretion and insulin sensitivity in adipose tissue, mitigating hyperglycemia. In mouse adipocytes, loss of the Rickets ortholog LGR4 blunts insulin responses, showing an essential role of LGR4 in adipocyte insulin sensitivity. Our findings reveal a muscle-neuronal-fat-tissue axis driving metabolic adaptation to high-sugar conditions, identifying LGR4 as a critical mediator in this regulatory network.

Abstract Purpose Reaction databases are a key resource for a wide variety of applications in computational chemistry and biochemistry, including Computer-aided Synthesis Planning (CASP) and the large-scale analysis of metabolic networks. The full potential of these resources can only be realized if datasets are accurate and complete. Missing co-reactants and co-products, i.e., unbalanced reactions, however, are the rule rather than the exception. The curation and correction of such incomplete entries is thus an urgent need. Methods The SynRBL framework addresses this issue with a dual-strategy: a rule-based method for non-carbon compounds, using atomic symbols and counts for prediction, alongside a Maximum Common Subgraph (MCS)-based technique for carbon compounds, aimed at aligning reactants and products to infer missing entities. Results The rule-based method exceeded 99% accuracy, while MCS-based accuracy varied from 81.19 to 99.33%, depending on reaction properties. Furthermore, an applicability domain and a machine learning scoring function were devised to quantify prediction confidence. The overall efficacy of this framework was delineated through its success rate and accuracy metrics, which spanned from 89.83 to 99.75% and 90.85 to 99.05%, respectively. Conclusion The SynRBL framework offers a novel solution for recalibrating chemical reactions, significantly enhancing reaction completeness. With rigorous validation, it achieved groundbreaking accuracy in reaction rebalancing. This sets the stage for future improvement in particular of atom-atom mapping techniques as well as of downstream tasks such as automated synthesis planning. Scientific Contribution SynRBL features a novel computational approach to correcting unbalanced entries in chemical reaction databases. By combining heuristic rules for inferring non-carbon compounds and common subgraph searches to address carbon unbalance, SynRBL successfully addresses most instances of this problem, which affects the majority of data in most large-scale resources. Compared to alternative solutions, SynRBL achieves a dramatic increase in both success rate and accurary, and provides the first freely available open source solution for this problem.

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Summary: Background: Hypertension is a modifiable risk factor for dementia affecting over 70% of individuals older than 60. Lowering dementia risk through preferential treatment with antihypertensive medication (AHM) classes that are otherwise equivalent in indication could offer a cost-effective, safe, and accessible approach to reducing dementia incidence globally. Certain AHM-classes have been associated with lower dementia risk, potentially attributable to angiotensin-II-receptor (Ang-II) stimulating properties. Previous study results have been inconclusive, possibly due to heterogeneous methodology and limited power. We aimed to comprehensively investigate associations between AHM (sub-)classes and dementia risk using large-scale continuous, real-world prescription and outcome data from primary care. Methods: We used data from three Dutch General Practice Registration Networks. Primary endpoints were clinical diagnosis of incident all-cause dementia and mortality. Using Cox regression analysis with time-dependent covariates, we compared the use of angiotensin-converting enzyme inhibitors (ACEi) to angiotensin receptor blockers (ARBs), beta blockers, calcium channel blockers (CCBs), and diuretics; and Ang-II-stimulating- to Ang-II-inhibiting AHM. Findings: Of 133,355 AHM-using participants, 5877 (4.4%) developed dementia, and 14,079 (10.6%) died during a median follow-up of 7.6 [interquartile range = 4.1–11.0] years. Compared to ACEi, ARBs [HR = 0.86 (95% CI = 0.80–0.92)], beta blockers [HR = 0.81 (95% CI = 0.75–0.87)], CCBs [HR = 0.77 (95% CI = 0.71–0.84)], and diuretics [HR = 0.65 (95% CI = 0.61–0.70)] were associated with significantly lower dementia risks. Regarding competing risk of death, beta blockers [HR = 1.21 (95% CI = 1.15–1.27)] and diuretics [HR = 1.69 (95% CI = 1.60–1.78)] were associated with higher, CCBs with similar, and ARBs with lower [HR = 0.83 (95% CI = 0.80–0.87)] mortality risk. Dementia [HR = 0.88 (95% CI = 0.82–0.95)] and mortality risk [HR = 0.86 (95% CI = 0.82–0.91)] were lower for Ang-II-stimulating versus Ang-II-inhibiting AHM. There were no interactions with sex, diabetes, cardiovascular disease, and number of AHM used. Interpretation: Among patients receiving AHM, ARBs, CCBs, and Ang-II-stimulating AHM were associated with lower dementia risk, without excess mortality explaining these results. Extensive subgroup and sensitivity analyses suggested that confounding by indication did not importantly influence our findings. Dementia risk may be influenced by AHM-classes’ angiotensin-II-receptor stimulating properties. An RCT comparing BP treatment with different AHM classes with dementia as outcome is warranted. Funding: Netherlands Organisation for Health, Research and Development (ZonMw); Stoffels-Hornstra Foundation.

Mitral regurgitation (MR) resulting from myxomatous mitral valve disease (MMVD) is a prevalent condition in dogs, particularly smaller breeds like Cavalier King Charles Spaniels (CKCSs) and Chihuahuas (CHHs). An accurate assessment of MR severity is essential for effective treatment and disease monitoring, yet a standardized method has yet to be established. In this retrospective study, we evaluated 124 client-owned dogs diagnosed with MMVD, including 64 CKCSs and 60 CHHs. Dogs were categorized into three stages: asymptomatic (B1), remodeled (B2), and congestive heart failure (CHF, C). The MR severity was quantified using the proximal isovelocity surface area (PISA) method, specifically focusing on the PISA radius (PISA-r). The PISA-r measurements exhibited significant increases across disease stages and demonstrated strong correlations with echocardiographic parameters (ranging from 0.83 to 0.94), including the left atrial size and left ventricular internal diameter. The receiver operating characteristic (ROC) curve analysis revealed the high sensitivity and specificity of PISA-r in classifying disease stages, establishing optimal cut-off values. The method displayed excellent repeatability (interobserver variability: 0.95) and reproducibility (intraobserver variability: 0.97). In conclusion, the PISA method, specifically PISA-r, was reliable for assessing MR severity in dogs with MMVD. By simplifying the diagnosis and management of MR, this research can potentially improve the life and management of MMVD-affected dogs.

The opportunistic fungal pathogen Candida albicans thrives on human mucosal surfaces as a harmless commensal, but frequently causes infections under certain predisposing conditions. Translocation across the intestinal barrier into the bloodstream by intestine-colonizing C. albicans cells serves as the main source of disseminated candidiasis. However, the host and microbial mechanisms behind this process remain unclear. In this study we identified fungal and host factors specifically involved in infection of intestinal epithelial cells (IECs) using dual-RNA sequencing. Our data suggest that host-cell damage mediated by the peptide toxin candidalysin-encoding gene ECE1 facilitates fungal zinc acquisition. This in turn is crucial for the full virulence potential of C. albicans during infection. IECs in turn exhibit a filamentation- and damage-specific response to C. albicans infection, including NFκB, MAPK, and TNF signaling. NFκB activation by IECs limits candidalysin-mediated host-cell damage and mediates maintenance of the intestinal barrier and cell-cell junctions to further restrict fungal translocation. This is the first study to show that candidalysin-mediated damage is necessary for C. albicans nutrient acquisition during infection and to explain how IECs counteract damage and limit fungal translocation via NFκB-mediated maintenance of the intestinal barrier.

Abstract Objectives To evaluate the clinical and prognostic behaviors of sinonasal papillomas. Methods Patients diagnosed with sinonasal papilloma were reviewed between 2001 and 2016 at a tertiary rhinology practice. Using pathology‐specific electronic medical record software, patients diagnosed with sinonasal papilloma were identified. Four subcategories of this lesion were identified: inverting (IP), exophytic (EP) oncocytic (OP) and inverting + exophytic (IP + EP) papillomas. Results A total of 107 patients were identified with unique sinonasal papilloma diagnoses. Of these, the majority were diagnosed with IP (87, 81.3%). The subpopulation of patients co‐diagnosed with IP and EP (IP + EP) was unique with respect to clinical presentation and prognosis relative to both the IP and EP alone populations. IP + EP patients (5, 4.7%) were older with an average age of 75.25 years compared to 45 (EP) and 55.26 (IP), p

Exercise-induced muscle injury and the subsequent release of Damage-Associated Molecular Patterns (DAMP) result in soreness and inflammation. Dietary supplements may accelerate the rate of recovery by supporting resolution of inflammation. The purpose of this study was to determine if methylsulfonylmethane (MSM) supplementation (30 d prior to exercise and during recovery) altered mRNA expression in LPS-exposed blood leukocytes after a bout of downhill running. Exercise consisted of 60 min of downhill running (−15% grade). Blood (baseline, pre-exercise, 4, 24, 48, and 72 h post-exercise) was diluted (1:10) and combined with LPS (20 µg/mL) for 24 h. Total RNA was isolated from leukocytes and analyzed for 574 immune-associated mRNA (Nanostring nCounter; ROSALIND.BIO). Data were expressed as log2 fold change from baseline for each condition (MSM and placebo). Compared to placebo, MSM supplementation was associated with an improved inflammation response (15 mRNA) and viral immune response (2 mRNA). The largest number of changes were found at 4 and 24 h post-exercise. The key finding in the present study is that MSM supplementation can improve inflammation management and the innate immune response after exercise.

Abstract Background Abnormally high serum cardiac troponin I (cTnI) concentration, reflecting leakage from or necrosis of cardiomyocytes, is a negative prognosticator for death in dogs. Objectives To investigate in critically ill cats whether serum cTnI concentration is abnormally high, identify conditions associated with abnormally high cTnI concentrations, and evaluate cTnI as an independent prognosticator for death and a potential coprognosticator to the acute patient physiologic and laboratory evaluation (APPLE) score in cats. Animals One hundred nineteen cats admitted to intensive care units (ICU) and 13 healthy cats at 2 university teaching hospitals. Methods Prospective study. Clinical examinations were performed, APPLE scores calculated, and serum cTnI and serum amyloid A (SAA) measured within 24 hours after admission. Outcome was defined as death/euthanasia or survival to discharge, 28 and 90 days after ICU‐admission. Prognostic capacity of cTnI, APPLE scores and models combining cTnI and scores were evaluated by receiver‐operator‐characteristic analyses. Results Median (IQR) serum cTnI concentration was higher in ill (0.63 [0.18‐2.65] ng/mL) compared to healthy (0.015 [0.005‐0.041] ng/mL) cats (P 5 mg/L (0.84 [0.23‐2.81] ng/mL; P = .009) than in cats without these characteristics (0.45 [0.12‐1.70] and 0.35 [0.015‐0.96] ng/mL). The in‐hospital case fatality rate was 29%. Neither serum cTnI concentration for all critically ill cats (area‐under‐the‐curve 0.567 [95% CI 0.454‐0.680], n = 119) or subgroups (0.625 [0.387‐0.863], n = 27; 0.506 [0.360‐0.652], n = 86), nor APPLE scores (fast 0.568 [0.453‐0.682], full 0.585 [0.470‐0.699], n = 100), were significant prognosticators for death. Conclusions and Clinical Importance Abnormally high serum cTnI concentration was common in critically ill cats. Unlike in dogs, cTnI did not confer prognostic information regarding death.

Abstract Uncombable hair syndrome (UHS) is a rare disorder of hair shaft morphology. UHS presents in early childhood with blonde, dry and frizzy scalp hair. The rate of hair growth may be normal or slow. The UHS hair shaft is characterized by a triangular shape with longitudinal grooves along the hair shaft axis. At writing, no curative treatment is available for UHS. However, research suggests that oral biotin supplementation results in a clinical improvement in growth rate and texture in some cases. Here, we present the case of a girl with UHS who was successfully treated with oral biotin supplementation. Our case highlights the diagnostic pathway in UHS, and demonstrates that two cycles of treatment with biotin, each separated by a period of 3 years, led to a significant improvement in combability and growth rate in a patient with UHS. We propose that biotin is a safe treatment option for UHS when both the health care provider and the family are aware of the possible interference with laboratory test results.

State-of-the-art myoelectric hand prostheses provide multi-functional control but lack somatosensory feedback. To accommodate the full functionality of a dexterous prosthesis, the artificial sensory feedback needs to convey several degrees of freedom (DoF) simultaneously. However, this is a challenge with current methods as they are characterized by a low information bandwidth. In this study, we leverage the flexibility of a recently developed system for simultaneous electrotactile stimulation and electromyography (EMG) recording to present the first solution for closed-loop myoelectric control of a multifunctional prosthesis with full-state anatomically congruent electrotactile feedback. The novel feedback scheme (coupled encoding) conveyed proprioceptive (hand aperture, wrist rotation) and exteroceptive information (grasping force). The coupled encoding was compared to the conventional approach (sectorized encoding) and incidental feedback in 10 non-disabled and one amputee participant who used the system to perform a functional task. The results showed that both feedback approaches increased the accuracy of position control compared to incidental feedback. However, the feedback increased completion time, and it did not significantly improve grasping force control. Importantly, the performance of the coupled feedback was not significantly different compared to the conventional scheme, despite the latter being easier to learn during training. Overall, the results indicate that the developed feedback can improve prosthesis control across multiple DoFs but they also highlight the subjects’ ability to exploit minimal incidental information. Importantly, the current setup is the first to convey three feedback variables simultaneously using electrotactile stimulation while providing multi-DoF myoelectric control with all hardware components mounted on the same forearm.

Bracher et al. compare 15 forecasting models of COVID-19 cases and deaths in Germany and Poland between January and mid-April 2021. Many, though not all, models outperform a simple baseline model up to four weeks ahead, with ensemble methods showing very good relative performance.

We have detected solar-like oscillations in the mid-K-dwarf ϵ Indi A, making it the coolest dwarf to have measured oscillations. The star is noteworthy for harboring a pair of brown dwarf companions and a Jupiter-type planet. We observed ϵ Indi A during two radial velocity campaigns, using the high-resolution spectrographs HARPS (2011) and UVES (2021). Weighting the time series, we computed the power spectra and established the detection of solar-like oscillations with a power excess located at 5265 ± 110 μ Hz—the highest frequency solar-like oscillations so far measured in any star. The measurement of the center of the power excess allows us to compute a stellar mass of 0.782 ± 0.023 M _⊙ based on scaling relations and a known radius from interferometry. We also determine the amplitude of the peak power and note that there is a slight difference between the two observing campaigns, indicating a varying activity level. Overall, this work confirms that low-amplitude solar-like oscillations can be detected in mid-K-type stars in radial velocity measurements obtained with high-precision spectrographs.

Solar-like oscillations have been detected in thousands of stars thanks to modern space missions. These oscillations have been used to measure stellar masses and ages, which have been widely applied in Galactic archeology. One of the pillars of such applications is the ${\nu }_{\max }$ scaling relation: the frequency of maximum power ${\nu }_{\max }$ , assumed to be proportional to the acoustic cutoff frequency, ν _ac , scales with effective temperature and surface gravity. However, the theoretical basis of the ${\nu }_{\max }$ scaling relation is uncertain, and there is an ongoing debate about whether it can be applied to metal-poor stars. We investigate the metallicity dependence of the ${\nu }_{\max }$ scaling relation by carrying out 3D near-surface convection simulations for solar-type stars with [Fe/H] between −3 and 0.5 dex. First, we found a negative correlation between ν _ac and metallicity from the 3D models. This is in tension with the positive correlation identified by studies using 1D models. Second, we estimated theoretical ${\nu }_{\max }$ values using velocity amplitudes determined from first principles, by quantifying the mode excitation and damping rates with methods validated in our previous works. We found that ${\nu }_{\max }$ does not show correlation with metallicity at solar effective temperature and surface gravity. This study opens an exciting prospect of testing the asteroseismic scaling relations against realistic 3D hydrodynamical stellar models.

Commensal bacteria such as Lactobacillus rhamnosus can inhibit the pathogenicity of the fungus Candida albicans. Here, Alonso-Roman et al. investigate the interplay between C. albicans, L. rhamnosus and intestinal epithelial cells, showing that changes in the metabolic environment, induced by the bacteria, trigger adaptations in C. albicans that reduce fungal pathogenicity.

Abstract Objective To assess for differences of intended meaning in the description of reflux‐related symptoms among otolaryngology patients and clinicians. Study Design Cross‐sectional survey‐based study. Setting Five tertiary, academic otolaryngology practices. Methods Between June 2020 and July 2022, a questionnaire consisting of 20 common descriptors of reflux‐related symptoms within four domains (throat‐, chest‐, stomach‐, and sensory‐related symptoms) was completed by patients. Attending otolaryngologists at five academic medical centers then completed the same survey. The primary outcome was to assess differences in patient and clinician perceptions of reflux‐related symptoms. Differences based on geographic location was a secondary outcome. Results A total of 324 patients and 27 otolaryngologists participated. Patients selected a median of six terms compared with 10.5 for otolaryngologists (p

IntroductionResistance exercise can significantly increase serum steroid concentrations after an exercise bout. Steroid hormones are involved in the regulation of several important bodily functions (e.g., muscle growth) through both systemic delivery and local production. Thus, we aimed to determine whether resistance exercise-induced increases in serum steroid hormone concentrations are accompanied by enhanced skeletal muscle steroid concentrations, or whether muscle contractions per se induced by resistance exercise can increase intramuscular steroid concentrations.MethodsA counterbalanced, within-subject, crossover design was applied. Six resistance-trained men (26 ± 5 years; 79 ± 8 kg; 179 ± 10 cm) performed a single-arm lateral raise exercise (10 sets of 8 to 12 RM - 3 min rest between sets) targeting the deltoid muscle followed by either squat exercise (10 sets of 8 to 12 RM - 1 min rest) to induce a hormonal response (high hormone [HH] condition) or rest (low hormone [LH] condition). Blood samples were obtained pre-exercise and 15 min and 30 min post-exercise; muscle specimens were harvested pre-exercise and 45 min post-exercise. Immunoassays were used to measure serum and muscle steroids (total and free testosterone, dehydroepiandrosterone sulfate, dihydrotestosterone, and cortisol; free testosterone measured only in serum and dehydroepiandrosterone only in muscle) at these time points.ResultsIn the serum, only cortisol significantly increased after the HH protocol. There were no significant changes in muscle steroid concentrations after the protocols.DiscussionOur study provides evidence that serum steroid concentration increases (cortisol only) seem not to be aligned with muscle steroid concentrations. The lack of change in muscle steroid after protocols suggests that resistance-trained individuals were desensitized to the exercise stimuli. It is also possible that the single postexercise timepoint investigated in this study might be too early or too late to observe changes. Thus, additional timepoints should be examined to determine if RE can indeed change muscle steroid concentrations either by skeletal muscle uptake of these hormones or the intramuscular steroidogenesis process.

Abstract The Draf Ⅲ procedure involves the creation of a common frontal sinus cavity. The most common indication for the Draf Ⅲ procedure is chronic rhinosinusitis of the frontal sinuses despite the failure of more conservative interventions such as bilateral Draf Ⅱa procedures. Primary Draf Ⅲ may be indicated in patients with a high risk of failures such as those with severe polyposis and those with a frontal sinus opening less than 4 mm on computed tomography imaging. Other indications for the Draf Ⅲ include access for tumor removal and repair of traumatic fractures of the frontal sinus. The “inside‐out” Draf Ⅲ procedure is the standard approach when the frontal recess anterior–posterior diameter is wide enough for instrument access, usually larger than 4–5 mm. The “outside‐in” Draf Ⅲ procedure can be done when the frontal recess is too narrow to safely accommodate instruments. Regular follow‐up with debridement should be done to prevent neo‐ostium stenosis.

GJ 367 is a bright ( V ≈ 10.2) M1 V star that has been recently found to host a transiting ultra-short period sub-Earth on a 7.7 hr orbit. With the aim of improving the planetary mass and radius and unveiling the inner architecture of the system, we performed an intensive radial velocity follow-up campaign with the HARPS spectrograph—collecting 371 high-precision measurements over a baseline of nearly 3 yr—and combined our Doppler measurements with new TESS observations from sectors 35 and 36. We found that GJ 367 b has a mass of M _b = 0.633 ± 0.050 M _⊕ and a radius of R _b = 0.699 ± 0.024 R _⊕ , corresponding to precisions of 8% and 3.4%, respectively. This implies a planetary bulk density of ρ _b = 10.2 ± 1.3 g cm ^−3 , i.e., 85% higher than Earth’s density. We revealed the presence of two additional non-transiting low-mass companions with orbital periods of ∼11.5 and 34 days and minimum masses of ${M}_{{\rm{c}}}\sin {i}_{{\rm{c}}}$ = 4.13 ± 0.36 M _⊕ and ${M}_{{\rm{d}}}\sin {i}_{{\rm{d}}}$ = 6.03 ± 0.49 M _⊕ , respectively, which lie close to the 3:1 mean motion commensurability. GJ 367 b joins the small class of high-density planets, namely the class of super-Mercuries, being the densest ultra-short period small planet known to date. Thanks to our precise mass and radius estimates, we explored the potential internal composition and structure of GJ 367 b, and found that it is expected to have an iron core with a mass fraction of ${0.91}_{-0.23}^{+0.07}$ . How this iron core is formed and how such a high density is reached is still not clear, and we discuss the possible pathways of formation of such a small ultra-dense planet.

ABSTRACTCandida species are the most prevalent cause of invasive fungal infections, of which Candida albicans is the most common. Translocation across the epithelial barrier into the bloodstream by intestinal-colonizing C. albicans cells serves as the main source for systemic infections. Understanding the fungal mechanisms behind this process will give valuable insights on how to prevent such infections and keep C. albicans in the commensal state in patients with predisposing conditions. This review will focus on recent developments in characterizing fungal translocation mechanisms, compare what we know about enteric bacterial pathogens with C. albicans, and discuss the different proposed hypotheses for how C. albicans enters and disseminates through the bloodstream immediately following translocation.

Abstract Background Despite important advancements in control and mechatronics of myoelectric prostheses, the communication between the user and his/her bionic limb is still unidirectional, as these systems do not provide somatosensory feedback. Electrotactile stimulation is an attractive technology to close the control loop since it allows flexible modulation of multiple parameters and compact interface design via multi-pad electrodes. However, the stimulation interferes with the recording of myoelectric signals and this can be detrimental to control. Methods We present a novel compact solution for simultaneous recording and stimulation through dynamic blanking of stimulation artefacts. To test the system, a feedback coding scheme communicating wrist rotation and hand aperture was developed specifically to stress the myoelectric control while still providing meaningful information to the subjects. Ten subjects participated in an experiment, where the quality of closed-loop myoelectric control was assessed by controlling a cursor in a two degrees of freedom target-reaching task. The benchmark performance with visual feedback was compared to that achieved by combining visual feedback and electrotactile stimulation as well as by using electrotactile feedback only. Results There was no significant difference in performance between visual and combined feedback condition with regards to successfully reached targets, time to reach a target, path efficiency and the number of overshoots. Therefore, the quality of myoelectric control was preserved in spite of the stimulation. As expected, the tactile condition was significantly poorer in completion rate (100/4% and 78/25% for combined and tactile condition, respectively) and time to reach a target (9/2 s and 13/4 s for combined and tactile condition, respectively). However, the performance in the tactile condition was still good, with no significant difference in path efficiency (38/8%) and the number of overshoots (0.5/0.4 overshoots), indicating that the stimulation was meaningful for the subjects and useful for closed-loop control. Conclusions Overall, the results demonstrated that the developed system can provide robust closed-loop control using electrotactile stimulation. The system supports different encoding schemes and allows placing the recording and stimulation electrodes next to each other. This is an important step towards an integrated solution where the developed unit will be embedded into a prosthetic socket.

Abstract Muscle damage imposes stress on mitochondria resulting in mitochondrial fusion, fission, and mitophagy. Testosterone is a regulator of these processes. However, no study has examined the effect of sex‐specific resistance exercise (RE)‐induced hormonal response on mitochondrial dynamics and mitophagy after muscle damage in untrained men and women. Untrained men and women performed two sessions of 80 unilateral maximal eccentric knee extensions (ECC) followed by upper‐body RE (ECC+RE) aimed to induce hormonal changes and maintain a similar lower body demands between conditions or 20 min seated rest (ECC+REST). Vastus lateralis samples were analyzed for gene and protein expression of OPA1, MFN1, DRP1, PINK1, and Parkin at baseline (BL), 12 and 24 h. Testosterone area under the curve was greater for ECC+RE than ECC+REST in men and was greater in men than women for both conditions. A significant time × sex × condition effect was found for Parkin protein expression. At 12 and 24 h, Parkin was lower for ECC + REST than ECC + RE for men; whereas, Parkin was increased at 24 h for women regardless of condition. A significant time effect was found for OPA1 protein expression increasing at 12 and 24 h. A significant time × sex × condition effects were found for MFN1, DRP1, and PINK1 gene expression with increases at 12 h in men for ECC + RE. A significant time × sex effect was found for OPA1 gene expression with a decrease at 12 h in men, and 12 h expression in men was lower than women. RE‐induced hormonal changes promoted expression of fission, fusion, and mitophagy markers in men. With muscle damage, regardless of condition, expression of inner mitochondrial membrane fusion markers are promoted in both sexes; whereas, those for mitophagy were promoted in women but reduced in men.

Moderate paddling, as in long distance kayaking, constitutes an endurance activity, which shares energetic aspects with activities such as long distance running and road cycling. The aim of the present study was to investigate whether in moderate paddling there is a U-shaped relationship between oxygen uptake and stroke rate, and also whether elite kayakers apply a freely chosen stroke rate, which is energetically optimal. Eleven young male elite kayakers performed moderate kayak ergometry at preset target stroke rates of 65, 75, and 90 strokes min-1, and at a freely chosen stroke rate, while physiological responses including oxygen uptake were measured. The results showed that considering average values calculated across all participants, there was an approximately U-shaped relationship between oxygen uptake and target stroke rate with a minimum at 75 strokes min-1. The freely chosen stroke rate was 67.0 ± 6.1 strokes min-1. Thus, the freely chosen stroke rate, for the group in total, appeared to be lower and require higher oxygen uptake as compared to the energetically optimal preset target stroke rate. Eight out of 11 participants had a higher oxygen uptake (5.1% ± 6.7%, p = 0.028, across all participants) at their freely chosen stroke rate than at the preset target stroke rate, which resulted in the lowest oxygen uptake. In conclusion, an approximately U-shaped relationship between oxygen uptake and stroke rate for young elite kayakers during moderate ergometer kayaking was found. Additionally, the freely chosen stroke rate was systematically lower and, consequently, required higher oxygen uptake than the preset stroke rate, which resulted in the lowest oxygen uptake.

Previous evidence suggests that resistance training in combination with specific collagen peptides (CP) improves adaptive responses of the muscular apparatus. Although beneficial effects have been repeatedly demonstrated, the underlying mechanisms are not well understood. Therefore, the primary objective of the present randomized trial was to elucidate differences in gene expression pathways related to skeletal muscle signal transduction following acute high-load resistance exercise with and without CP intake. Recreationally active male participants were equally randomized to high-load leg extension exercise in combination with 15 g CP or placebo (PLA) supplementation. Muscle biopsies from the vastus lateralis muscle were obtained at baseline as well as 1, 4 and 24 h post exercise to investigate gene expression using next generation sequencing analysis. Several important anabolic pathways including PI3K-Akt and MAPK pathways were significantly upregulated at 1 and 4 h post-exercise. Significant between-group differences for both pathways were identified at the 4 h time point demonstrating a more pronounced effect after CP intake. Gene expression related to the mTOR pathway demonstrated a higher visual increase in the CP group compared to PLA by trend, but failed to achieve statistically significant group differences. The current findings revealed a significantly higher upregulation of key anabolic pathways (PI3K-Akt, MAPK) in human skeletal muscle 4 h following an acute resistance training combined with intake of 15 g of specific collagen peptides compared to placebo. Further investigations should examine potential relationships between upregulated gene expression and changes in myofibrillar protein synthesis as well as potential long-term effects on anabolic pathways on the protein level.

Abstract Background Infection with the cardiopulmonary nematode Angiostrongylus vasorum may cause severe disease in dogs, therefore prophylactic treatments are necessary to prevent infection in dogs at risk. A clinical field study was conducted to demonstrate the efficacy and safety of an oral combination of sarolaner, moxidectin and pyrantel (Simparica Trio ® ) for the prevention of A. vasorum infection in dogs (prevention study). A survey study was conducted concurrently to determine the infection pressure in the same areas. Methods Prevention and survey studies were both conducted at the same veterinary clinics in endemic hot spots for A. vasorum in Denmark and Italy. The prevention study was a randomized, placebo controlled, double masked study where 622 client-owned dogs were treated and tested at 30 days intervals for 10 months. In the survey study 1628 dogs that were at risk of infection and/or were suspected to be infected were tested by fecal and/or serological methods, and the percent of dogs positive for A. vasorum was calculated. Results In the prevention study, there were no adverse events related to treatment with Simparica Trio ® . Two placebo-treated animals became infected with A. vasorum during the 10-month study period, while none of the dogs in the combination product-treated group became infected. In the survey study, 12.2% of the study dogs were found positive to A. vasorum, indicating high exposure to the parasite during the period of the prevention study. Conclusions Monthly oral treatment with the combination of sarolaner, moxidectin and pyrantel (Simparica Trio ® ) was 100% effective in the prevention of natural infection with A. vasorum in dogs in highly endemic areas. In endemic areas, A. vasorum occurrence in dogs at risk is considerable.

The bright star λ Ser hosts a hot Neptune with a minimum mass of 13.6 M _⊕ and a 15.5 day orbit. It also appears to be a solar analog, with a mean rotation period of 25.8 days and surface differential rotation very similar to the Sun. We aim to characterize the fundamental properties of this system and constrain the evolutionary pathway that led to its present configuration. We detect solar-like oscillations in time series photometry from the Transiting Exoplanet Survey Satellite, and we derive precise asteroseismic properties from detailed modeling. We obtain new spectropolarimetric data, and we use them to reconstruct the large-scale magnetic field morphology. We reanalyze the complete time series of chromospheric activity measurements from the Mount Wilson Observatory, and we present new X-ray and ultraviolet observations from the Chandra and Hubble space telescopes. Finally, we use the updated observational constraints to assess the rotational history of the star and estimate the wind braking torque. We conclude that the remaining uncertainty on the stellar age currently prevents an unambiguous interpretation of the properties of λ Ser, and that the rate of angular momentum loss appears to be higher than for other stars with a similar Rossby number. Future asteroseismic observations may help to improve the precision of the stellar age.

Following muscle damage, autophagy is crucial for muscle regeneration. Hormones (e.g., testosterone, cortisol) regulate this process and sex differences in autophagic flux exist in the basal state. However, to date, no study has examined the effect of a transient hormonal response following eccentric exercise-induced muscle damage (EE) between untrained young men and women. Untrained men (n = 8, 22 ± 3 years) and women (n = 8, 19 ± 1 year) completed two sessions of 80 unilateral maximal eccentric knee extensions followed by either upper body resistance exercise (RE; designed to induce a hormonal response; EE + RE) or a time-matched rest period (20 min; EE + REST). Vastus lateralis biopsy samples were collected before (BL), and 12 h, and 24 h after RE/REST. Gene and protein expression levels of selective markers for autophagic initiation signaling, phagophore initiation, and elongation/sequestration were determined. Basal markers of autophagy were not different between sexes. For EE + RE, although initiation signaling (FOXO3) and autophagy-promoting (BECN1) genes were greater (p < 0.0001; 12.4-fold, p = 0.0010; 10.5-fold, respectively) for women than men, autophagic flux (LC3-II/LC3-I protein ratio) did not change for women and was lower (p < 0.0001 3.0-fold) than men. Furthermore, regardless of hormonal changes, LC3-I and LC3-II protein content decreased (p = 0.0090; 0.547-fold, p = 0.0410; 0.307-fold, respectively) for men suggesting increased LC3-I lipidation and autophagosome degradation whereas LC3-I protein content increased (p = 0.0360; 1.485-fold) for women suggesting decreased LC3-I lipidation. Collectively, our findings demonstrated basal autophagy was not different between men and women, did not change after EE alone, and was promoted with the acute hormonal increase after RE only in men but not in women. Thus, the autophagy response to moderate muscle damage is promoted by RE-induced hormonal changes in men only.

Skeletal muscle mass is determined by the balance between muscle protein synthesis (MPS) and degradation. Several intracellular signaling pathways control this balance, including mammalian/mechanistic target of rapamycin (mTOR) complex 1 (C1). Activation of this pathway in skeletal muscle is controlled, in part, by nutrition (e.g., amino acids and alcohol) and exercise (e.g., resistance exercise (RE)). Acute and chronic alcohol use can result in myopathy, and evidence points to altered mTORC1 signaling as a contributing factor. Moreover, individuals who regularly perform RE or vigorous aerobic exercise are more likely to use alcohol frequently and in larger quantities. Therefore, alcohol may antagonize beneficial exercise-induced increases in mTORC1 pathway signaling. The purpose of this review is to synthesize up-to-date evidence regarding mTORC1 pathway signaling and the independent and combined effects of acute alcohol and RE on activation of the mTORC1 pathway. Overall, acute alcohol impairs and RE activates mTORC1 pathway signaling; however, effects vary by model, sex, feeding, training status, quantity, etc., such that anabolic stimuli may partially rescue the alcohol-mediated pathway inhibition. Likewise, the impact of alcohol on RE-induced mTORC1 pathway signaling appears dependent on several factors including nutrition and sex, although many questions remain unanswered. Accordingly, we identify gaps in the literature that remain to be elucidated to fully understand the independent and combined impacts of alcohol and RE on mTORC1 pathway signaling.

Nutritional ingredients with defined mechanisms of action can be useful in the recovery of the body from the physical demands of a habitual training plan. The purpose of this study was to determine the effect of dietary supplementation with optimized curcumin, pomegranate ellagitannins, and MSM (R + MSM) on immune-associated mRNA during early recovery (i.e., up to 8 h post-exercise) following all-out running efforts (5-km, 10-km, and 21.1-km). Subjects (N = 14) were randomized to either a supplement (R + MSM) or a control group using an open label design. The study was completed over a period of 31-day prior to a scheduled half-marathon race. Venous blood samples were collected into PAXgene tubes at baseline, subsequent samples were collected at 2, 4, and 8 h after each running effort. A 574-plex mRNA Immunology Array (NanoString) was measured for each sample and ROSALIND® Advanced Analysis Software was used to examined changes in 31 annotated immune response pathways and specific mRNA changes. The greatest change in immune pathways occurred at 2 h (GSS > 3) followed by 4 h (GSS 2–3) and 8 h (GSS 1–2). R + MSM was associated with an increase in innate immunity (CAMP, LTF, TIRAP, CR1, IL1R1, CXCR1, PDCDILG2, and GNLY) and a blunted/smaller increase in damage-associated molecular pattern (DAMP) signaling/inflammation (TLR4, TLR5, S100A8, S100A9, and IFP35). We also found changes in immune-associated mRNA that have not been previously linked to exercise recovery (SOCS1, SOCS2, MME, CECAM6, MX1, IL-1R2, KLRD1, KLRK1, and LAMP3). Collectively these results demonstrate that supplementation with a combination of optimized curcumin, pomegranate ellagitannins, and methylsulfonylmethane resulted in changes that may improve biological recovery from all-out running efforts.

The mechanisms by which organisms adapt their growth according to the availability of oxygen are incompletely understood. Here the authors identify the D rosophila fat body as a tissue regulating growth in response to oxygen sensing via a mechanism involving Hph inhibition, HIF1-a activation and insulin secretion.

Objective The objective of this study is to evaluate patient and provider satisfaction with telemedicine encounters across 3 otolaryngology practices. Study Design Cross-sectional survey. Setting A military community hospital, an academic military hospital, and a nonmilitary academic center. Methods A telephone-based survey of patients undergoing telemedicine encounters for routine otolaryngology appointments was performed between April and July 2020. Patients were asked about their satisfaction, the factors affecting care, and demographic information. A provider survey was emailed to staff otolaryngologists. The survey asked about satisfaction, concerns for reimbursement or liability, encounters best suited for telemedicine, and demographic information. The results were analyzed with descriptive statistics and a multivariable logistic linear regression model to determine odds ratios. Results A total of 325 patients were surveyed, demonstrating high satisfaction with telemedicine (average score, 4.49 of 5 [best possible answer]). Patients perceived “no negative impact” or “minor negative impact” on the encounter due to the lack of a physical examination or face-to-face interaction (1.86 and 1.95 of 5, respectively). High satisfaction was consistent across groups for distance to travel, age, and reason for referral. A total of 25 providers were surveyed, with an average satisfaction score of 3.44 of 5. Providers reported “slight” to “somewhat” concern about reimbursement (40%) and liability (32%). Conclusion Given patients’ and providers’ levels of satisfaction, there is likely a role for telemedicine in otolaryngology practice that may benefit patient care independent of the COVID-19 pandemic.

This narrative review aims to describe Angiostrongylus vasorum-induced hemostatic dysfunction of dogs with emphasis on clinical and laboratory findings as well as potential therapeutic strategies for the bleeding patient. Canine angiostrongylosis (CA) is a disease with potentially high morbidity and mortality in endemic areas and with fatal outcome often associated with either severe respiratory compromise, pulmonary hypertension and right-sided heart failure, or hemostatic dysfunction with severe bleeding. The most common signs of hemorrhage are hematomas, petecchiation, ecchymoses, oral mucosal membrane bleeding and scleral bleeding, while intracranial and pulmonary hemorrhage are among the most severe. The pathophysiological mechanisms underlying hemostatic dysfunction in these patients are presently researched. While the larval effect on platelets remains unknown, the parasite appears to induce dysregulation of hemostatic proteins, with studies suggesting a mixture of pro-coagulant protein consumption and hyperfibrinolysis. Importantly, not all dogs display the same hemostatic abnormalities. Consequently, characterizing the hemostatic state of the individual patient is necessary, but has proven difficult with traditional coagulation tests. Global viscoelastic testing shows promise, but has limited availability in general practice. Treatment of A. vasorum-infected dogs with hemostatic dysfunction relies on anthelmintic treatment as well as therapy directed at the individual dog’s specific hemostatic alterations.

Introduction: Treatment of autoimmune pancreatitis (AIP) is based solely on consensus and has yet to become standardized. Consequently, therapeutic regimens vary greatly between countries and centers, and largely depend on the experience of the physician. At this moment, the optimal regimen for inducing disease remission and preventing relapse is unknown.Objectives: The primary objective of this study is to describe current treatment regimens used in Europe, and to compare their effectiveness in inducing remission and preventing and treating relapse. The secondary objectives are: to identify risk factors for relapse; to assess the diagnostic accuracy of the Unified-AIP criteria; to assess the performance of the M-ANNHEIM score for predicting relapse; and to assess long-term outcomes including pancreatic exocrine insufficiency and pancreatic cancer.Methods: This is an international, retrospective, observational cohort study, performed in over 40 centers from 16 European countries. Eligible are all patients diagnosed with AIP from 2005 onwards, regardless of the used diagnostic criteria. Data on study subjects will be retrieved from the hospital's electronic medical records and registered with a standardized, web-based, electronic case report form (eCRF). To compare the effectiveness of treatment regimens in inducing remission, preventing relapse, and treating relapse, subjects will be stratified in groups based on: type of therapy; initial therapy dose; cumulative therapy dose; therapy tapering speed and duration; and having received maintenance therapy or not.Ethics and Dissemination: Ethical and/or institutional review board approvals are obtained by all participating centers according to local regulations. The study complies with the General Data Protection Regulation (GDPR). All manuscripts resulting from the study will be submitted to peer-reviewed journals.Conclusion: This is the first pan-European retrospective registry for AIP. It will produce the first large-scale data on treatment of European patients with AIP, providing answers on the use and effectiveness of treatment regimens. In the future, this collaboration may provide a network for continuation into a prospective European registry.

Aim: Previous reports suggest that low-load muscle exercise performed under blood flow restriction (BFR) may lead to endurance adaptations. However, only few and conflicting results exist on the magnitude and timing of microvascular adaptations, overall indicating a lack of angiogenesis with BFR training. The present study, therefore, aimed to examine the effect of short-term high-frequency BFR training on human skeletal muscle vascularization.Methods: Participants completed 3 weeks of high-frequency (one to two daily sessions) training consisting of either BFR exercise [(BFRE) n = 10, 22.8 ± 2.3 years; 20% one-repetition maximum (1RM), 100 mmHg] performed to concentric failure or work-matched free-flow exercise [(CON) n = 8, 21.9 ± 3.0 years; 20% 1RM]. Muscle biopsies [vastus lateralis (VL)] were obtained at baseline, 8 days into the intervention, and 3 and 10 days after cessation of the intervention to examine capillary and perivascular adaptations, as well as angiogenesis-related protein signaling and gene expression.Results: Capillary per myofiber and capillary area (CA) increased 21–24 and 25–34%, respectively, in response to BFRE (P < 0.05–0.01), while capillary density (CD) remained unchanged. Overall, these adaptations led to a consistent elevation (15–16%) in the capillary-to-muscle area ratio following BFRE (P < 0.05–0.01). In addition, evaluation of perivascular properties indicated thickening of the perivascular basal membrane following BFRE. No or only minor changes were observed in CON.Conclusion: This study is the first to show that short-term high-frequency, low-load BFRE can lead to microvascular adaptations (i.e., capillary neoformation and changes in morphology), which may contribute to the endurance effects previously documented with BFR training. The observation of perivascular membrane thickening suggests that high-frequency BFRE may be associated with significant vascular stress.

Objectives The aim of this study was to establish whether early pulmonary rehabilitation after severe exacerbation of chronic obstructive pulmonary disease (COPD) reduces mortality and hospital admissions, and increases physical performance and quality of life compared to rehabilitation initiated later in the stable phase of COPD. Methods In a randomised controlled trial of 150 patients hospitalised with an exacerbation of COPD, participants were allocated to pulmonary rehabilitation either within 2 weeks after discharge or the same rehabilitation programme but initiated 2 months after discharge. Results Early pulmonary rehabilitation did not prolong time to first hospital admission or time to death (hazard ratio 0.79, 95% CI 0.47–1.23, p=0.33) compared to rehabilitation in stable phase. However, 2 months after inclusion, pulmonary rehabilitation resulted in a significantly better improvement in the incremental shuttle walk test (33.9 m, 95% CI 4.18–63.7, p=0.02) compared to that in the stable phase. The difference in the endurance shuttle walk test was of borderline significance (140 s, 95% CI −2.03–282.76, p=0.05), but there was no significant difference concerning the COPD assessment test (−1.43 points, 95% CI −3.44–0.59, p=0.17). Conclusion Early pulmonary rehabilitation after acute exacerbation of COPD led to a faster improvement in physical performance compared to rehabilitation initiated later in the stable phase, but did not improve survival or prolong time to hospital readmission.

At the University of Copenhagen, companion animal emergency medicine is taught in a clinical environment after students’ completion of basic theoretical and clinical courses. Students are often anxious about emergency shift partici-pation and the prospect of being the responsible veterinarian in emergency sit-uations. This study aimed to investigate whether inclusion of virtual patients in addition to real-life patients would increase students’ perceived self-efficacy in emergency medicine. Sixty-seven students were divided into two groups, one of which participated in regular emergency rotations, while the other also learned in a Virtual Emergency Clinic (VEC). Participating students were given a ques-tionnaire regarding course experience and self-efficacy, with responses on a 10-point Likert scale. The VEC group expressed a higher level of knowledge and sig-nificantly higher level of exposure to and ability to handle emergency patients. In addition, virtual problem-based learning appeared to increase veterinary students’ self-efficacy with regard to managing emergency patients in their fu-ture careers.

The formation of nanodomains in the plasma membrane are thought to be part of membrane proteins regulation and signaling. Plasma membrane proteins are often investigated by analyzing the lateral mobility. k-space ICS (kICS) is a powerful image correlation spectroscopy (ICS) technique and a valuable supplement to fluorescence correlation spectroscopy (FCS). Here, we study the diffusion of aquaporin-9 (AQP9) in the plasma membrane, and the effect of different membrane and cytoskeleton affecting drugs, and therefore nanodomain perturbing, using kICS. We measured the diffusion coefficient of AQP9 after addition of these drugs using live cell Total Internal Reflection Fluorescence imaging on HEK-293 cells. The actin polymerization inhibitors Cytochalasin D and Latrunculin A do not affect the diffusion coefficient of AQP9. Methyl-β-Cyclodextrin decreases GFP-AQP9 diffusion coefficient in the plasma membrane. Human epidermal growth factor led to an increase in the diffusion coefficient of AQP9. These findings led to the conclusion that kICS can be used to measure diffusion AQP9, and suggests that the AQP9 is not part of nanodomains.

The current manuscript sets out a series of guidelines for blood flow restriction exercise, focusing on the methodology, application and safety of this mode of training. With the emergence of this technique and the wide variety of applications within the literature, the aim of this review is to set out a current research informed guide to blood flow restriction training to practitioners. This covers the use of blood flow restriction to enhance muscular strength and hypertrophy via training with resistance and aerobic exercise and preventing muscle atrophy using the technique passively. The authorship team for this article was selected from the researchers focused in blood flow restriction training research with expertise in exercise science, strength and conditioning and sports medicine.

In this study, we explore the use of line FRAP to detect diffusion in synthetic lipid membranes. The study of the dynamics of these membrane lipids can, however, be challenging. The diffusion in two different synthetic membranes consisting of the lipid mixtures 1:1 DOPC:DPPC and 2:2:1 DOPC:DPPC:Cholesterol was studied with line FRAP. A correlation between diffusion coefficient and temperature was found to be dependent on the morphology of the membrane. We suggest line FRAP as a promising accessible and simple technique to study diffusion in plasma membranes.