Skin uses interdependent cellular networks for barrier integrity and host immunity, but most underlying mechanisms remain obscure. Herein, we demonstrate that the human parasitic helminth Schistosoma mansoni inhibited pruritus evoked by itch-sensing afferents bearing the Mas-related G-protein-coupled receptor A3 (MrgprA3) in mice. MrgprA3 neurons controlled interleukin (IL)-17+ γδ T cell expansion, epidermal hyperplasia and host resistance against S. mansoni through shaping cytokine expression in cutaneous antigen-presenting cells. MrgprA3 neuron activation downregulated IL-33 but induced IL-1β and tumor necrosis factor in macrophages and type 2 conventional dendritic cells partially through the neuropeptide calcitonin gene-related peptide. Macrophages exposed to MrgprA3-derived secretions or bearing cell-intrinsic IL-33 deletion showed increased chromatin accessibility at multiple inflammatory cytokine loci, promoting IL-17/IL-23-dependent changes to the epidermis and anti-helminth resistance. This study reveals a previously unrecognized intercellular communication mechanism wherein itch-inducing MrgprA3 neurons initiate host immunity against skin-invasive parasites by directing cytokine expression patterns in myeloid antigen-presenting cell subsets.

• MeSH
• dendritické buňky imunologie   MeSH
• interleukin 33 * metabolismus   imunologie   MeSH
• kůže imunologie   parazitologie   MeSH
• lidé MeSH
• makrofágy imunologie   metabolismus   MeSH
• myeloidní buňky imunologie   metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony imunologie   metabolismus   MeSH
• pruritus imunologie   MeSH
• receptory spřažené s G-proteiny * metabolismus   imunologie   genetika   MeSH
• Schistosoma mansoni * imunologie   MeSH
• schistosomiasis mansoni * imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. OBJECTIVE: The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. PATIENTS AND METHODS: The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. RESULTS: Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. CONCLUSIONS: The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

• MeSH
• dospělí MeSH
• humanizované monoklonální protilátky * terapeutické užití   farmakologie   MeSH
• karcinom z přechodných buněk farmakoterapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• metastázy nádorů MeSH
• monoklonální protilátky * terapeutické užití   farmakologie   MeSH
• protokoly antitumorózní kombinované chemoterapie terapeutické užití   farmakologie   MeSH
• retrospektivní studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

PURPOSE: Subretinal (SR) injection in porcine models is a promising avenue for preclinical evaluation of cell and gene therapies. Targeting of the subretinal fluid compartment (bleb) is critical to the procedure, especially if treatment of the cone-rich area centralis is required (i.e., visual streak [VS] in pigs). To our knowledge, this study is the first to investigate the influence of injection site placement on VS involvement in the pig eye. METHODS: We performed 23-gauge pars plana vitrectomy followed by SR injection in 41 eyes of 21 animals (Sus scrofa domesticus). In 27 eyes (65.9%), the injection site was placed superior to the VS, and in 14 eyes (34.1%) it was placed inferior to it. Using intraoperative imaging, blebs were classified based on their propagation behavior relative to the VS. RESULTS: In 79% of cases, blebs from inferior injection sites developed away from the VS, exhibiting a mean ± SEM vertical anisotropy (AP) of 0.67 ± 0.11. In contrast, blebs from superior injection sites tended to develop toward the VS with an AP of 1.27 ± 0.18 (P = 0.0070). Blebs developed away from the VS in only 41% of injections (P = 0.0212). Inferior blebs were orientated close to 0° (horizontal), whereas superior blebs displayed varied orientations with a mean angle of 56° (P = 0.0008). CONCLUSIONS: Bleb propagation was anisotropic (i.e., directionally biased) and dependent on injection site placement. Superior injection sites led to superior VS detachment. Morphological analysis suggested increased adhesion forces at the VS and superior vascular arcades. This study will aid the planning of surgeries for targeted subretinal delivery in pig models.

• MeSH
• genetická terapie * metody   MeSH
• injekce nitrooční MeSH
• modely nemocí na zvířatech * MeSH
• prasata MeSH
• retina MeSH
• subretinální tekutina metabolismus   MeSH
• Sus scrofa MeSH
• vitrektomie * metody   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Working memory (WM) is essential for the temporary storage and processing of information required for complex cognitive tasks and relies on neuronal theta and gamma oscillations. Given the limited capacity of WM, researchers have investigated various methods to improve it, including transcranial alternating current stimulation (tACS), which modulates brain activity at specific frequencies. One particularly promising approach is theta-gamma peak-coupled-tACS (TGCp-tACS), which simulates the natural interaction between theta and gamma oscillations that occurs during cognitive control in the brain. The aim of this study was to improve WM in healthy young adults with TGCp-tACS, focusing on both behavioral and neurophysiological outcomes. Thirty-one participants completed five WM tasks under both sham and verum stimulation conditions. Electroencephalography (EEG) recordings before and after stimulation showed that TGCp-tACS increased power spectral density (PSD) in the high-gamma region at the stimulation site, while PSD decreased in the theta and delta regions throughout the cortex. From a behavioral perspective, although no significant changes were observed in most tasks, there was a significant improvement in accuracy in the 14-item Sternberg task, indicating an improvement in phonological WM. In conclusion, TGCp-tACS has the potential to promote and improve the phonological component of WM. To fully realize the cognitive benefits, further research is needed to refine the stimulation parameters and account for individual differences, such as baseline cognitive status and hormonal factors.

• MeSH
• chování fyziologie   MeSH
• dospělí MeSH
• elektrická stimulace MeSH
• elektroencefalografie MeSH
• gama rytmus EEG fyziologie   MeSH
• krátkodobá paměť * fyziologie   MeSH
• lidé MeSH
• mladý dospělý MeSH
• přímá transkraniální stimulace mozku * metody   MeSH
• theta rytmus EEG fyziologie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

• MeSH
• hrudní chirurgie * trendy   organizace a řízení   MeSH
• kardiochirurgické výkony * trendy   statistika a číselné údaje   MeSH
• lidé MeSH
• předpověď MeSH
• roboticky asistované výkony * trendy   statistika a číselné údaje   MeSH
• společnosti lékařské * trendy   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• úvodníky MeSH
• Geografické názvy
• Evropa MeSH

IMPORTANCE: Biosimilars may be lower-cost alternatives to originator biologic products, potentially offering expanded access or reduced economic burden, but have not been evaluated with aflibercept in diabetic macular edema (DME). OBJECTIVE: To compare efficacy and safety of MYL-1701P, an aflibercept biosimilar, with reference aflibercept (Eylea [Regeneron]) in DME. DESIGN, SETTING, AND PARTICIPANTS: This was a double-masked, randomized clinical trial that included participants at 77 centers across the US, Europe, Japan, and India. Included in the analysis were individuals 18 years and older with type 1 or type 2 diabetes with central DME and best-corrected visual acuity (BCVA) letter score of 73 to 38 in the study eye using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart. Study data were analyzed from October to December 2021. INTERVENTIONS: Formulations of MYL-1701P (0.5-mg vial) or reference aflibercept every 4 weeks for 5 consecutive intravitreal injections, followed by every 8 weeks through week 52. MAIN OUTCOMES AND MEASURES: The primary outcome was the adjusted difference in least squares mean (SE) change from baseline BCVA letter score at week 8 with an equivalence margin of -3 to +3 letters. Secondary outcomes included change in central subfield thickness (CST), BCVA, number of injections over 52 weeks, incidence of adverse events (AEs), and antidrug antibodies (ADAs). RESULTS: A total of 355 participants (mean [SD] age, 62.2 [9.2] years; 216 male [60.8%]) were randomized to MYL-1701P (179 participants [50.4%]) and aflibercept (176 participants [49.6%]). At week 8, mean (SE) change in BCVA was 6.60 (0.55) letters vs 6.56 (0.55) letters in the MYL-1701P vs aflibercept groups. The adjusted mean difference of 0.04 letters (90% CI, -1.16 to 1.24 letters) met the primary outcome. At week 8, mean (SE) change in CST was -112 (7) μm vs -124 (7) μm in the MYL-1701P vs aflibercept groups (adjusted mean difference, 12 μm; 90% CI, -3 to 26 μm). The incidence of treatment-emergent AEs in the MYL-1701P and aflibercept arms were ocular (30.9% [55 of 178] vs 29.5% [52 of 176]), serious ocular (0.6% [1 of 178] vs 1.1% [2 of 176]), nonocular (65.2% [116 of 178] vs 65.3% [115 of 176]), and serious nonocular (16.9% [30 of 178] vs 11.9% [21 of 176]). The mean (SD) total number of injections was 8.4 (2.1) vs 8.7 (1.8) in the MYL-1701P vs aflibercept groups. The incidence of treatment-induced or treatment-boosted ADAs was 2.8% (5 of 177) vs 5.7% (10 of 176) in the MYL-1701P vs aflibercept arms. CONCLUSIONS AND RELEVANCE: MYL-1701P demonstrated clinical equivalence in regard to efficacy, with comparable safety and immunogenicity, to reference aflibercept. These findings support use of MLY-1701P as an alternative to reference aflibercept. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03610646.

• MeSH
• biosimilární léčivé přípravky * terapeutické užití   škodlivé účinky   MeSH
• diabetická retinopatie * farmakoterapie   diagnóza   patofyziologie   MeSH
• dvojitá slepá metoda MeSH
• inhibitory angiogeneze * aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• injekce intravitreální * MeSH
• lidé středního věku MeSH
• lidé MeSH
• makulární edém * farmakoterapie   patofyziologie   diagnóza   MeSH
• optická koherentní tomografie MeSH
• receptory vaskulárního endoteliálního růstového faktoru * aplikace a dávkování   MeSH
• rekombinantní fúzní proteiny * terapeutické užití   aplikace a dávkování   MeSH
• senioři MeSH
• vaskulární endoteliální růstový faktor A antagonisté a inhibitory   MeSH
• výsledek terapie MeSH
• zraková ostrost * fyziologie   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH

OBJECTIVES: Bridging from a temporary microaxial left ventricular assist device (tLVAD) to a durable left ventricular assist device (dLVAD) is playing an increasing role in the treatment of terminally ill patients with heart failure. Scant data exist about the best implant strategy. The goal of this study was to analyse differences in the dLVAD implant technique and effects on patient outcomes. METHODS: Data from 341 patients (19 European centres) who underwent a bridge-to-bridge implant from tLVAD to dLVAD between January 2017 and October 2022 were retrospectively analysed. The outcomes of the different implant techniques with the patient on cardiopulmonary bypass, extracorporeal life support or tLVAD were compared. RESULTS: A durable LVAD implant was performed employing cardiopulmonary bypass in 70% of cases (n = 238, group 1), extracorporeal life support in 11% (n = 38, group 2) and tLVAD in 19% (n = 65, group 3). Baseline characteristics showed no significant differences in age (P = 0.140), body mass index (P = 0.388), creatinine level (P = 0.659), the Model for End-Stage Liver Disease (MELD) score (P = 0.190) and rate of dialysis (P = 0.110). Group 3 had significantly fewer patients with preoperatively invasive ventilation and cardiopulmonary resuscitation before the tLVAD was implanted (P = 0.009 and P < 0.001 respectively). Concomitant procedures were performed more often in groups 1 and 2 compared to group 3 (24%, 37% and 5%, respectively, P < 0.001). The 30-day mortality data showed significantly better survival after an inverse probability of treatment weighting in group 3, but the 1-year mortality showed no significant differences among the groups (P = 0.012 and 0.581, respectively). Postoperative complications like the rate of right ventricular assist device (RVAD) implants or re-thoracotomy due to bleeding, postoperative respiratory failure and renal replacement therapy showed no significant differences among the groups. Freedom from the first adverse event like stroke, driveline infection or pump thrombosis during follow-up was not significantly different among the groups. Postoperative blood transfusions within 24 h were significantly higher in groups 1 and 2 compared to surgery on tLVAD support (P < 0.001 and P = 0.003, respectively). CONCLUSIONS: In our analysis, the transition from tLVAD to dLVAD without further circulatory support did not show a difference in postoperative long-term survival, but a better 30-day survival was reported. The implant using only tLVAD showed a reduction in postoperative transfusion rates, without increasing the risk of postoperative stroke or pump thrombosis. In this small cohort study, our data support the hypothesis that a dLVAD implant on a tLVAD is a safe and feasible technique in selected patients.

• MeSH
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• podpůrné srdeční systémy * MeSH
• retrospektivní studie MeSH
• senioři MeSH
• srdeční selhání * chirurgie   terapie   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH

The aim of this study was to develop and validate methods for the determination of vitamins B2, B9, E and A in serum using liquid chromatography with mass spectrometry (MS) detection. Vitamin analysis was performed using an ultra performance liquid chromatography combined with tandem MS. The compounds were separated on a BEH C18 RP column (2.1 × 100 mm, 1.7 μm) using a gradient elution with an analysis time of 10 min. Sample preparation included protein precipitation with ethanol. The concentration range in human serum was as follows: riboflavin 5-1000 nmol/L, folic acid 2.5-250 nmol/L, α-tocopherol 0.5-100 μmol/L and all-trans-retinol 25-2500 nmol/L. Accuracy and precision were validated according to Food and Drug Administration guidelines, with coefficients of variation ranging from 3.1-11.7% and recoveries from 94.4-107.5%. Routine monitoring of the complex range of vitamins in bariatric medicine is still not common. This is despite the fact that patients are at risk for glitch deficits, especially of a neurological nature. An analytical method that allows for the complex measurement of both water-soluble and fat-soluble vitamins is important and necessary for the clinical monitoring of bariatric patients. The method we have described could benefit both clinical practice and nutritional research.

• MeSH
• alfa-tokoferol * krev   MeSH
• bariatrická chirurgie MeSH
• chromatografie kapalinová metody   MeSH
• kyselina listová * krev   MeSH
• lidé MeSH
• limita detekce MeSH
• lineární modely MeSH
• reprodukovatelnost výsledků MeSH
• riboflavin * krev   MeSH
• tandemová hmotnostní spektrometrie * metody   MeSH
• vitamin A * krev   MeSH
• vysokoúčinná kapalinová chromatografie metody   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Calcineurin-nuclear factor of activated T cells (CN-NFAT) inhibitors are widely clinically used drugs for immunosuppression, but besides their required T cell response inhibition, they also undesirably affect innate immune cells. Disruption of innate immune cell function can explain the observed susceptibility of CN-NFAT inhibitor-treated patients to opportunistic fungal infections. Neutrophils play an essential role in innate immunity as a defense against pathogens; however, the effect of CN-NFAT inhibitors on neutrophil function was poorly described. Thus, we tested the response of human neutrophils to opportunistic fungal pathogens, namely Candida albicans and Aspergillus fumigatus, in the presence of CN-NFAT inhibitors. Here, we report that the NFAT pathway members were expressed in neutrophils and mediated part of the neutrophil response to pathogens. Upon pathogen exposure, neutrophils underwent profound transcriptomic changes with subsequent production of effector molecules. Importantly, genes and proteins involved in the regulation of the immune response and chemotaxis, including the chemokines CCL2, CCL3, and CCL4 were significantly upregulated. The presence of CN-NFAT inhibitors attenuated the expression of these chemokines and impaired the ability of neutrophils to chemoattract other immune cells. Our results amend knowledge about the impact of CN-NFAT inhibition in human neutrophils.

• MeSH
• Aspergillus fumigatus imunologie   MeSH
• Candida albicans imunologie   MeSH
• chemotaxe MeSH
• kalcineurin * metabolismus   MeSH
• lidé MeSH
• mykózy imunologie   MeSH
• neutrofily * imunologie   metabolismus   MeSH
• signální transdukce * MeSH
• transkripční faktory NFATC * metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Úvod: Včasná detekce pomocí platných screeningových nástrojů může představovat příležitost k odhalení mírné kognitivní poruchy (mild cognitive impairment; MCI) jako rizikového faktoru demence a tím zpomalit progresi kognitivního poklesu u starších dopělích. Cíl: Cílem této studie bylo vyhodnotit Trail Walking Test (TWT) k detekci pravděpodobné MCI (probable MCI; pMCI) u starších jedinců a zhodnotit jeho použitelnost jako screeningového nástroje. Metodika: Studie se zúčastnilo 61 osob rozdělených pomocí Montrealského kognitivního testu (Montreal Cognitive Assessment; MoCA) do tří skupin: starší dospělí s intaktními kognitivními funkcemi (ICA, MoCA > 25); starší dospělí s pMCI (MoCA ≤ 25); a kontrolní skupina mladých jedinců (healthy young adults; HYA). Všichni účastníci absolvovali Trail Making Test a tři varianty TWT se zvyšující se složitostí. Plocha pod křivkou (area under the curve; AUC), senzitivita, specificita a Youdenovy indexy byly použity k vyhodnocení schopnosti každého testu předpovídat projev pravděpodobné mírné kognitivní poruchy u starších jedinců. Na korekciu optimizmu predikcie bola vykonaná interná validácia AUC a vypočítala sa príslušná korigovaná AUC (AUCVAL). Výsledky: Skupina pMCI dosáhla významně horších výsledků ve všech hodnocených variantách TMT a TWT než skupiny ICA a HYA (p < 0,001). Zjistili jsme, že všechny verze testů TMT (např. TMT-A a TMT-B) a TWT (např. TWT-1,2,3) mají velmi dobrou detekční schopnost rozlišení osob s pMCI od kontrolních skupin ICA a HYA hodnocené dohromady s hodnotami AUC v rozmezí od 0,81 do 0,876, které se obecně zvyšují s rostoucí složitostí duálního úkolu. Nejlepší detekční schopnosti však bylo dosaženo, když byla jako kontrolní skupina použita pouze HYA (AUC: 0,894–0,975). Screeningové testy TMT pro detekci pMCI zůstaly validní i po korekcích pomocí bootstrappingu (AUCs: 0,829–0,839). Zatímco varianta testu TWT-2 vykazovala přínos oproti TWT-1, přidaná hodnota TWT-3 oproti TWT-2 byla v naší studii omezená. Závěr: TWT je platným nástrojem pro screening pMCI u starších dospělých. Jeho použití může zlepšit včasnou detekci pMCI v klinických i neklinických podmínkách. Zatímco zvyšující se složitost testu zvyšuje jeho prediktivní výkonnost, na základě našich zjištění se zdá, že existuje hranice, za kterou se přidaná hodnota složitějších duálních úloh snižuje.

Background: Early detection of mild cognitive impairment (MCI) as a risk factor for dementia using valid screening tools can present an opportunity for timely intervention to slow the progression of cognitive decline in older adults. Aim: The aim of this study was to evaluate the Trail Walking Test (TWT) that includes a dual task to predict probable MCI (pMCI) in older adults and to evaluate its usability as a screening tool. Methods: The study was conducted on a sample of 61 subjects categorized using the Montreal Cognitive Assessment (MoCA) into three groups: older adults with intact cognitive ability (ICA, MoCA > 25); older adults with pMCI (MoCA ≤ 25); and “healthy young adults (HYA) ”. All participants completed the Trail Making Test (TMT) and three variants of the TWT with increasing complexity. Area under the receiver operating curve (AUC), sensitivity, specificity and Youden indices were used to evaluate the capacity of each test to predict pMCI in older adults. Internal validation was performed to calculate AUCs corrected for optimism (AUCVAL). Results: The pMCI group performed significantly worse in all evaluated variations of the TMT and TWT than the ICA and HYA groups (P < 0.001). We found that all versions of the TMT (e. g., TMT-A and TMT-B) and TWT tests (e. g., TWT-1, 2, 3) have very good ability to discriminate between people with pMCI and all controls (e. g., ICA and HYA combined) with AUCs ranging from 0.81 to 0.876, generally increasing with increasing complexity of the dual task. Best performance was achieved when only HYA were used as a control group (AUCs: 0.894–0.975). The validity of these tools to predict pMCI remained very good after corrections using bootstrapping (AUCs: 0.829–0.839). While TWT-2 showed more benefits over TWT-1, the added value of TWT-3 over TWT-2 has been limited in this study. Conclusions: The dual component TWT is a valid screening tool for pMCI in older adults. Its use may improve early detection of pMCI in clinical and non-clinical settings. While increasing complexity of the test increases its predicting performance, based on our findings there seems to be a cutoff beyond which the added value of more complex dual tasks diminishes.

• MeSH
• dospělí MeSH
• kognitivní dysfunkce * diagnóza   MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• test cesty statistika a číselné údaje   MeSH
• test chůzí * metody   statistika a číselné údaje   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• klinická studie MeSH