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Teaching is a complex endeavor, and the pandemic era stretched teachers to their limit, leaving them in need of supports that ignite both their passion and capacity. The typical top-down mandates found in many schools need to be replaced with processes that meet teachers where they are, helping them grow so their students can grow, too. Ann Mausbach and Kim Morrison present a differentiated approach to teacher learning that adapts to teachers’ learning need. They share conditions that allow for this approach to flourish and specific practices that promote a culture of support and deep impactful learning for teachers.

O presente estudo tem como finalidade a discussão acerca da importância do advento do juiz de garantias para o fortalecimento do sistema acusatório por meio da garantia ao princípio da imparcialidade do julgador. Para isso, será abordada, inicialmente, a relação entre o novo paradigma jurídico trazido pela Constituição Federal de 1988 e o sistema penal garantista adotado pelo ordenamento jurídico desde então. A partir desse raciocínio, o sistema acusatório será discutido como uma decorrência do garantismo exteriorizado pela Carta Magna e a sua relação com o princípio da imparcialidade. Por fim, as inovações jurídicas trazidas pelo Pacote Anticrime serão abordadas, a fim de se discutir o fortalecimento do sistema acusatório, por meio de uma previsão infraconstitucional expressa nesse sentido, bem como o advento de mecanismos de cunho garantista, como o juiz de garantias. Diante da discussão, pôde-se concluir que a figura do juiz de garantias é essencial para a garantia de um julgamento imparcial, a fim de que se evite o contato entre o julgador do caso e os elementos informativos juntados pela acusação durante a investigação preliminar. Utilizaram-se como métodos de abordagem o método dedutivo, bem como a pesquisa indireta bibliográfica.

Species from the Garcinia genus (Clusiaceae family) are used in the treatment of many diseases and metabolic disorders frequently associated with the oxidative stress. The characteristic metabolites found in this genus are xanthones and benzophenones, which have antioxidant properties, among relevant biological potentials. This review provides a specific vision about antioxidant activity of Garcinia species, reporting in vitro and in vivo assays, described from the last five years. The research about antioxidant properties of Garcinia species and their constituents can be directed in the development of new medicines and drugs.

In 2019 the Centers for Disease Control and Prevention (CDC) reported a series of 4 transfusion reactions that resulted from contamination of apheresis platelet products. Products involved in all 4 cases were contaminated with Acinetobacter calcoaceticus-baumannii complex (ACBC) and in 3 products Staphylococcus saprophyticus was found as well. CDC investigation found that bacterial isolates from the cases were genetically related and suggested a common source of contamination. The contamination of blood products with ACBC is rare and polymicrobial contamination of blood products even less common. ACBC and S. saprophyticus have been observed to adhere to one another and sediment out of suspension in vitro, a process referred to as coaggregation, and we hypothesized that there was an interaction between the strains from these cases that contributed to their co-contamination of blood products.To test the hypothesis of bacterial interaction, we performed coaggregation experiments and observed the growth characteristics of ACBC and S. saprophyticus strains recovered from contaminated blood products involved in a subset of the CDC cases.An increase in S. saprophyticus CFU concentration was observed after several days of co-culture with ACBC in LB and plasma; however, no other findings suggested coaggregation or augmentative growth interaction between the bacterial strains.Ultimately, an interaction between ACBC and S. saprophyticus that could help explain their co-occurrence and growth in contaminated platelet units was not found; however future studies of potential interactions may be warranted.

This study focuses on mimicking constitutive phosphorylation in the N-terminus of the myosin regulatory light chain (S15D-RLC) as a rescue strategy for mutation-induced cardiac dysfunction in transgenic (Tg) models of restrictive (RCM) and dilated (DCM) cardiomyopathy caused by mutations in essential (ELC, MYL3 gene) or regulatory (RLC, MYL2 gene) light chains of myosin. Phosphomimetic S15D-RLC was reconstituted in left ventricular papillary muscle (LVPM) fibers from two mouse models of cardiomyopathy, RCM-E143K ELC and DCM-D94A RLC, along with their corresponding Tg-ELC and Tg-RLC wild-type (WT) mice. The beneficial effects of S15D-RLC in rescuing cardiac function were manifested by the S15D-RLC-induced destabilization of the super-relaxed (SRX) state that was observed in both models of cardiomyopathy. S15D-RLC promoted a shift from the SRX state to the disordered relaxed (DRX) state, increasing the number of heads readily available to interact with actin and produce force. Additionally, S15D-RLC reconstituted with fibers demonstrated significantly higher maximal isometric force per cross-section of muscle compared with reconstitution with WT-RLC protein. The effects of the phosphomimetic S15D-RLC were compared with those observed for Omecamtiv Mecarbil (OM), a myosin activator shown to bind to the catalytic site of cardiac myosin and increase myocardial contractility. A similar SRX↔DRX equilibrium shift was observed in OM-treated fibers as in S15D-RLC-reconstituted preparations. Additionally, treatment with OM resulted in significantly higher maximal pCa 4 force per cross-section of muscle fibers in both cardiomyopathy models. Our results suggest that both treatments with S15D-RLC and OM may improve the function of myosin motors and cardiac muscle contraction in RCM-ELC and DCM-RLC mice.

Découverte le 30 septembre 2000 par Marc Delluc, spéléologue, qui y revient le 8 octobre, avec Hervé Durif et Fabrice Massoulier, repérant la présence de plusieurs panneaux gravés et vestiges humains dans des bauges à ours, la grotte de Cussac est une longue galerie avec une entrée médiane délimitant un secteur amont et un secteur aval (figure). Après le signalement de la découverte à Norbert Aujoulat, puis à la Direction Régionale des Affaires Culturelles d’Aquitaine (DRAC), l’urgence fut al...

We report the facile photochemical generation of a library of Ni(I)–bpy halide complexes (Ni(I)(ᴿbpy)X (R = t-Bu, H, MeOOC; X = Cl, Br, I) and benchmark their relative reactivity toward competitive oxidative addition and off-cycle dimerization pathways. Structure–function relationships between the ligand set and reactivity are developed, with particular emphasis on rationalizing previously uncharacterized ligand-controlled reactivity toward high energy and challenging C(sp²)–Cl bonds. Through a dual Hammett and computational analysis, the mechanism of the formal oxidative addition is found to proceed through an S_(N)Ar-type pathway, consisting of a nucleophilic two-electron transfer between the Ni(I) 3d(z²) orbital and the C_(aryl)–Cl σ* orbital, which contrasts the mechanism previously observed for activation of weaker C(sp²)–Br/I bonds. The bpy substituent provides a strong influence on reactivity, ultimately determining whether oxidative addition or dimerization even occurs. Here, we elucidate the origin of this substituent influence as arising from perturbations to the effective nuclear charge (Z_(eff)) of the Ni(I) center. Electron donation to the metal decreases Z_(eff), which leads to a significant destabilization of the entire 3d orbital manifold. Decreasing the 3d(z²) electron binding energies leads to a powerful two-electron donor to activate strong C(sp²)–Cl bonds. These changes also prove to have an analogous effect on dimerization, with decreases in Z_(eff) leading to more rapid dimerization. Ligand-induced modulation of Z_(eff) and the 3d(z²) orbital energy is thus a tunable target by which the reactivity of Ni(I) complexes can be altered, providing a direct route to stimulate reactivity with even stronger C–X bonds and potentially unveiling new ways to accomplish Ni-mediated photocatalytic cycles.

Young consumers (children and adolescents) play an increasingly important role in the functioning of the modern consumer market. Accordingly, it is becoming more important to promote sustainable, ecological consumption patterns among this group. The authors of the article analysed the results of a survey conducted on a group of 1326 children aged 9 to 15. The purpose was to diagnose the awareness and functioning patterns of consumption among the studied group of young consumers from the Polish market and to formulate a set of recommendations for the process of their ecological, economic and social education aimed at building sustainable consumption patterns. During the research process, an attempt was made to diagnose the ability to identify eleven selected, popular, pro-ecological graphic symbols placed on consumer products, aimed at assessing the skills of young consumers to identify products with better environmental parameters. The collected empirical data was analysed with the R-project program using the following methods: descriptive statistics, nonparametric Kruskal-Wallis test and Pearson Chi-square test of independence. As a result of the use of the comparative analysis method, the results of research in individual age groups of young consumers were compared and interpreted. After the research, the authors concluded that the education system lacks actions to consolidate the acquired knowledge in the field of ecolabeling, which results in large disproportions in the recognition of eco-labels both in individual age groups and in relation to selected symbols. It is disturbing that only 12.2% of the interviewed learners indicated the eco-label as a decisive factor in purchasing a food product. The authors of the article believe that among the group of young consumers, actions should be taken to raise awareness of sustainable consumption, and this requires consistent and differentiated steps at all levels of their education.

To analyze long-term results of two multicenter prospective single-arm trials (ARO-2010-01 and ARO-2013-04) investigating adjuvant hypofractionated radiotherapy (HF) with simultaneous integrated boost (SIB) after breast-conserving surgery (BCS).Eligible patients had histopathologically confirmed unifocal breast cancer planned for whole breast irradiation plus boost radiotherapy to the tumor bed. In both studies, a total dose of 40 Gy was applied to the whole breast and of 48 Gy to the tumor bed in 16 fractions of 2.5 and 3.0 Gy. Radiotherapy could be given either as three-dimensional conformal radiotherapy (3D-CRT) or as intensity-modulated radiotherapy (IMRT). The primary study objectives were feasibility and security within an observation period of six months. The current investigation focuses on long-term efficacy and toxicities.Between 2011 and 2014, both trials enrolled 300 patients in total. Data from 274 of these patients could be used for the current analysis. The median follow-up time was 60 months and the 5-year disease-free survival 92.1%. Three patients suffered a local recurrence (after 36-72 months) while a regional recurrence occurred in one patient (after 17 months). The 5-year local control rate in the breast was 99.6%. 63.5% of all patients did not report any late radiation-related toxicity, 28.5% reported grade 1 and 7.3% grade 2 toxicities. The highest late toxicity was grade 3 in 2 women (0.7%, telangiectasia and lymphedema of the breast).Our analysis demonstrates favorable efficacy and low rates of long-term side effects of HF with SIB after BCS. Randomized controlled phase III trials are ongoing.

Antimicrobial resistance is one of the top 10 global public-health threats. Especially high rates of resistance have been reported for isolates from ICU patients, requiring expanded treatment options in this setting. We evaluated the activity of ceftolozane/tazobactam and comparators against Gram-negative isolates collected from patients with lower respiratory tract infections (LRTIs) in ICUs in seven Asian countries.In 2017-2019, up to 100 consecutive, aerobic Gram-negative LRTI isolates were collected per year at each of 37 hospitals. MICs were determined using the Clinical and Laboratory Standards Institute reference broth microdilution method.Overall, ceftolozane/tazobactam was active against 72% of 1408 Enterobacterales and 86% of 761 Pseudomonas aeruginosa isolates. Susceptibility to the non-carbapenem β-lactam comparators, including piperacillin/tazobactam, was 52-67% among Enterobacterales isolates, and the activity of all β-lactam comparators, including meropenem, was 57-70% among P. aeruginosa. Ceftolozane/tazobactam maintained activity against 61% of meropenem-nonsusceptible and 64% of piperacillin/tazobactam-nonsusceptible P. aeruginosa. At the country-level, ceftolozane/tazobactam activity ranged from90% against Enterobacterales from Hong Kong and South Korea to64% in Thailand and Vietnam, and from90% against P. aeruginosa from South Korea, Malaysia, Philippines and Taiwan to75% in Thailand and Vietnam. Correspondingly, the proportions of carbapenemase-positive isolates among Enterobacterales and P. aeruginosa isolates were highest in Thailand and Vietnam.Ceftolozane/tazobactam provides a potential treatment option for ICU patients in Asia, which is especially important considering the reduced activity of commonly used β-lactams against the studied ICU isolates. Knowledge of local resistance patterns should inform empirical therapy decision-making.

International audience; Infection spreading in cell culture occurs due to virus replication in infected cells and its random motion in the extracellular space. Multiplicity of infection experiments in cell cultures are conventionally used for the characterization of viral infection by the number of viral plaques and the rate of their growth. We describe this process with a delay reaction-diffusion system of equations for the concentrations of uninfected cells, infected cells, virus, and interferon. Time delay corresponds to the duration of viral replication inside infected cells. We show that infection propagates in cell culture as a reaction-diffusion wave, we determine the wave speed and prove its existence. Next, we carry out numerical simulations and identify three stages of infection progression: infection decay during time delay due to virus replication, explosive growth of viral load when infected cells begin to reproduce it, and finally, wave-like infection progression in cell culture characterized by a constant or slowly growing total viral load. The modelling results are in agreement with the experimental data for the coronavirus infection in a culture of epithelial cells and for some other experiments. The presence of interferon produced by infected cells decreases the viral load but does not change the speed of infection progression in cell culture. In the 2D modelling, the total viral load grows faster than in the 1D case due to the increase of plaque perimeter.

Subglacial processes in Antarctica are difficult to directly observe and are one of the sources of uncertainty when modelling the response of ice sheets to environmental forcing. Subglacial processes pertain to the type of basal sliding or friction law used, where especially the contrast between viscous (linear) and plastic (Coulomb) sliding makes the latter far more responsive to changes at the marine boundary (Ritz et al., 2015; Brondex et al., 2019; Bulthuis et al., 2019; Sun et al., 2020; Kazmierczak et al., 2022).Besides the type of sliding, physical basal conditions, such as basal temperatures, bed properties (hard or soft), subglacial water flow and drainage, till properties, and mechanics, also directly affect the ice sheet flow (Clarke, 2005, Cuffey and Patterson, 2010, Kazmierczak et al., 2022), by affecting the effective pressure (Bueler and Brown, 2009, Winkelmann et al., 2011, van der Wel et al., 2013).In this study, we investigate how variations in effective pressure determines the evolution of the main marine basins of the West Antarctic Ice Sheet (Pine Island and Thwaites glacier) which are currently exhibiting the largest ice mass loss of the Antarctic ice sheet.For this purpose, we employ different types of subglacial hydrology for soft and hard bed configurations, which we adapt to simulate individual drainage basins of the Antarctic ice sheet at a km-scale resolution, thus allowing for proper migration of the grounding line (e.g., Pattyn et al., 2013). These hydrological representations are included in a generalized basal sliding law (Zoet et al., 2020), implemented in the the f.ETISh/Kori model (Pattyn, 2017; Sun et al., 2020). Results are compared to results from a pan-Antarctic ice sheet model (Kazmierczak et al., 2022) and demonstrate the importance of detailed bed topography influencing the subglacial conditions upstream of the grounding line.

Pseudomonas aeruginosais intrinsically resistant to many classes of antibiotics, reflecting the restrictive nature of its outer membrane and the action of its numerous efflux systems. However, the dynamics of compound uptake, retention and efflux in this bacterium remain incompletely understood. Here, we exploited the sensor capabilities of a Z-nucleotide sensing riboswitch to create an experimental system able to identify physicochemical and structural properties of compounds that permeate the bacterial cell, avoid efflux, and perturb the folate cycle orde novopurine synthesis. In a first step, a collection of structurally diverse compounds enriched in antifolate drugs was screened for ZTP riboswitch reporter activity in efflux-deficientP. aeruginosa, allowing us to identify compounds that entered the cell and disrupted the folate pathway. These initial hits were then rescreened using isogenic efflux-proficient bacteria, allowing us to separate efflux substrates from efflux avoiders. We confirmed this categorization by measuring intracellular levels of select compounds in the efflux-deficient and - proficient strain using high resolution LC-MS. This simple yet powerful method, optimized for high throughput screening, enables the discovery of numerous permeable compounds that avoid efflux and paves the way for further refinement of the physicochemical and structural rules governing efflux in this multi-drug resistant Gram-negative pathogen.ImportanceTreatment ofPseudomonas aeruginosainfections has become increasingly challenging. The development of novel antibiotics against this multi-drug resistant bacterium is a priority, but many drug candidates never achieve effective concentrations in the bacterial cell due due to its highly restrictive outer membrane and the action of multiple efflux pumps. Here, we develop a robust and simple reporter system inP. aeruginosato screen chemical libraries and identify compounds that either enter the cell and remain inside, or enter the cell and are exported by efflux systems. This approach enables developing rules of compound uptake and retention inP. aeruginosathat will lead to more rational design of novel antibiotics.

An analysis of peak lumbar load data collected from the existing peer-reviewed literature on rear impact crash tests was performed. Values for peak lumbar tension/compression, peak lumbar sagittal forces, and peak lumbar flexion/extension moments were aggregated from each study. The trends in the accumulated data were analyzed as functions of the changes in velocity (delta-Vs) measured during the crash tests. The data were further analyzed to identify differences in trends found across variations in the testing conditions used across studies. These testing conditions included type of anthropometric test device (ATD) used, type of ATD pelvis used, ATD seating position, production year of seat used, type of seat used, and type of seat restraint used. Data were also aggregated from peer-reviewed research quantifying peak lumbar compression in human subjects performing various tasks, including activities of daily living (ADLs), tasks related to sports and exercise, and industrial tasks typical of manual labor. The peak lumbar compression data from rear impact tests with ATDs was compared with the corresponding peak load data from the studies with human subjects. Linear regressions of the aggregated data from rear impact crash tests with impact severities between 5-45 km/h indicated some relationships between peak lumbar loads and delta-V. However, the relatively low R2 values observed from these regressions suggest that other variables may contribute to the variance in peak lumbar loading with respect to delta-V. It appears that individuals performing ADLs may experience peak lumbar compression similar to the compression measured in ATDs in rear impact crash tests with impact severities between 5-45 km/h. Aggregated peak lumbar compressive loading values in tasks related to sports, exercise, and industry were largely greater than the aggregated peak loads from crash testing.

Stromal antigen 2 (STAG2), in healthy somatic cells, functions in sister chromatid cohesion, DNA damage repair, and genome organization, but its role in muscle-invasive bladder cancer (MIBC) remains unknown. Here, using whole-exome and targeted sequencing (n = 119 bladder cancer clinical samples), we found several STAG2 mutations in MIBC that correlate with loss of protein expression. The analysis of a bladder cancer tissue microarray (n = 346) revealed that decreased STAG2 protein expression is associated with improved overall and progression-free survival for patients with MIBC. In mouse xenograft studies, STAG2 knockdown (KD) decelerated MIBC tumor growth, whereas STAG2 overexpression accelerated tumor growth. In cell line studies, STAG2 loss augmented treatment with cisplatin, a first-line therapy for MIBC. STAG2 KD or overexpression did not alter degree of aneuploidy, copy-number variations, or cell-cycle distribution. However, unbiased RNA-sequencing analysis revealed that STAG2 KD altered gene expression. STAG2 KD led to significant downregulation of several gene sets, such as collagen containing extracellular matrix, external encapsulating structure organization, and regulation of chemotaxis. Therefore, we investigated the effect of STAG2 KD on cell migration and invasion in vitro. We found that STAG2 KD minimized cell speed, displacement, and invasion. Altogether, our results present a noncanonical function of STAG2 in promoting cell motility and invasion of MIBC cells. This work forms the basis for additional investigation into the role of STAG2 in transcriptional regulation and how it becomes dysregulated in STAG2-mutant MIBC.Significance:The cohesin component STAG2 regulates cell motility and invasion. STAG2 expression is associated with decreased MIBC survival and may be a useful biomarker to guide bladder cancer treatment.

Supplementary methods, Supplementary Figures S1-S3, and Supplementary tables

We report the facile photochemical generation of a library of Ni(I)–bpy halide complexes (Ni(I)(Rbpy)X (R = t-Bu, H, MeOOC; X = Cl, Br, I) and benchmark their relative reactivity toward competitive oxidative addition and off-cycle dimerization pathways. Structure-function relationships between ligand set and reactivity are developed, with a particular emphasis on rationalizing previously uncharacterized ligand-controlled reactivity toward high energy and challenging C(sp2)–Cl bonds. Through a dual Hammett and computational analysis, the mechanism of the formal oxidative addition is found to proceed through an SNAr-type pathway, consisting of a nucleophilic two-electron transfer between the Ni(I) 3d(z2) orbital and the Caryl–Cl σ* orbital, which contrasts the mechanism previously observed for activation of weaker C(sp2)–Br/I bonds. The bpy substituent provides a strong influence on reactivity, ultimately determining whether oxidative addition or dimerization even occur. Here we elucidate the origin of this substituent influence as arising from perturbations to the effective nuclear charge (Zeff) of the Ni(I) center. Electron donation to the metal decreases Zeff, which leads to a significant destabilization of the entire 3d orbital manifold. Decreasing the 3d(z2) electron binding energies leads to a powerful two-electron donor to activate strong C(sp2)–Cl bonds. These changes also prove to have an analogous effect on dimerization, with decreases in Zeff leading to more rapid dimerization. Ligand-induced modulation of Zeff and the 3d(z2) orbital energy is thus a tunable target by which the reactivity of Ni(I) complexes can be altered, providing a direct route to stimulate reactivity with even stronger C–X bonds and potentially unveiling new ways to accomplish Ni-mediated photocatalytic cycles.

Objectives To investigate the differentiation of premalignant from benign colorectal polyps detected by CT colonography using deep learning. Methods In this retrospective analysis of an average risk colorectal cancer screening sample, polyps of all size categories and morphologies were manually segmented on supine and prone CT colonography images and classified as premalignant (adenoma) or benign (hyperplastic polyp or regular mucosa) according to histopathology. Two deep learning models SEG and noSEG were trained on 3D CT colonography image subvolumes to predict polyp class, and model SEG was additionally trained with polyp segmentation masks. Diagnostic performance was validated in an independent external multicentre test sample. Predictions were analysed with the visualisation technique Grad-CAM++. Results The training set consisted of 107 colorectal polyps in 63 patients (mean age: 63 ± 8 years, 40 men) comprising 169 polyp segmentations. The external test set included 77 polyps in 59 patients comprising 118 polyp segmentations. Model SEG achieved a ROC-AUC of 0.83 and 80% sensitivity at 69% specificity for differentiating premalignant from benign polyps. Model noSEG yielded a ROC-AUC of 0.75, 80% sensitivity at 44% specificity, and an average Grad-CAM++ heatmap score of ≥ 0.25 in 90% of polyp tissue. Conclusions In this proof-of-concept study, deep learning enabled the differentiation of premalignant from benign colorectal polyps detected with CT colonography and the visualisation of image regions important for predictions. The approach did not require polyp segmentation and thus has the potential to facilitate the identification of high-risk polyps as an automated second reader. Key Points • Non-invasive deep learning image analysis may differentiate premalignant from benign colorectal polyps found in CT colonography scans. • Deep learning autonomously learned to focus on polyp tissue for predictions without the need for prior polyp segmentation by experts. • Deep learning potentially improves the diagnostic accuracy of CT colonography in colorectal cancer screening by allowing for a more precise selection of patients who would benefit from endoscopic polypectomy, especially for patients with polyps of 6–9 mm size.

Introduction: Palliative radical cystectomy (pRC) may be offered to selected bladder cancer (BC) patients with grievous local symptoms. However, there is only scarce information on perioperative complications and prognosis, especially in the case of metastatic spread. We intended to analyze morbidity and oncological outcome in this patient subgroup. Materials: Patients undergoing pRC because of BC with radiologic evidence of metastases were included in this retrospective study. Perioperative adverse events (AEs) were graded by the Clavien-Dindo Classification system. All patients underwent CT-based surveillance, and questionnaires were sent for survival follow-up in predefined intervals. Oncological outcome and predictive markers were assessed in univariate and multivariate analyses, using log-rank tests and Cox-regression analyses. Results: Between 2004 and 2016, 77 patients were identified. Median age at surgery was 70 years (IQR 66–77) and the median follow-up time was 12 months (IQR 4–44). Preoperative staging revealed pulmonary, hepatic, bone, peritoneal, and various other metastasis in 46/77 (60%), 14/77 (18%), 11/77 (14%), 5/77 (7%), and 11/77 (14%) cases, respectively. Most frequently observed symptoms at the time of pRC were severe gross hematuria (n = 41) and intense pain (n = 11). Most AEs were of minor grade (83%). The median length of stay was 20 days. Median CSS was 13 months with a 5-year CSS of 34%. Intriguingly and unsuspectedly, preoperatively suspicious lung lesions were confirmed during surveillance only in 33%, respectively. In multivariate analysis, intraoperative blood transfusions (HR = 2.25, 95% CI: 1.09–4.63, p = 0.028) were significantly associated with decreased CSS. The best outcome was observed in patients with only subpleural metastases (CSS 80 months, p = 0.039) and normal CRP- and Hb values. Conclusion: pRC can be performed with acceptable perioperative morbidity and mortality. Pulmonary lesions seem to have a risk of false-positive results and should be biopsied in all uncertain cases. Localization of lung metastases together with preoperative CRP- and Hb levels seem to play a prognostic role.

Herein, we would like to present deoxyfluorinating reagents such as DAST and PyFluor and their successful use as tools for selective modification of γ-amino-α-hydroxyphosphonates. Depending on the deoxyfluorinating reagent applied, an intramolecular cyclization leading to phosphonates containing the 1,3-oxazinan-2-one moiety or direct nucleophilic deoxyfluorination yielding the α-fluorinated derivatives of γ-aminophosphonates was observed. The obtained compounds may be used as precursors in the preparation of medicinally important compounds

Background: Atrial fibrillation (AF) and renal impairment share a bidirectional relationship with important pathophysiological interactions. We evaluated the impact of renal impairment in a contemporary cohort of patients with AF. Methods: We utilised the ESC-EHRA EORP-AF Long-Term General Registry. Outcomes were analysed according to renal function by CKD-EPI equation. The primary endpoint was a composite of thromboembolism, major bleeding, acute coronary syndrome and all-cause death. Secondary endpoints were each of these separately including ischaemic stroke, haemorrhagic event, intracranial haemorrhage, cardiovascular death and hospital admission. Results: A total of 9306 patients were included. The distribution of patients with no, mild, moderate and severe renal impairment at baseline were 16.9%, 49.3%, 30% and 3.8%, respectively. AF patients with impaired renal function were older, more likely to be females, had worse cardiac imaging parameters and multiple comorbidities. Among patients with an indication for anticoagulation, prescription of these agents was reduced in those with severe renal impairment, p 2 decrease), that was most notable in patients with eGFR 2 (HR 2.21 [95% CI, 1.23–3.99] compared to eGFR ≥90 ml/min/1.73 m 2). Conclusion: A significant proportion of patients with AF suffer from concomitant renal impairment which impacts their overall management. Furthermore, renal impairment is an independent predictor of major adverse events including thromboembolism, major bleeding, acute coronary syndrome and all-cause death in patients with AF.

Objectives This study reports antimicrobial activity for ceftazidime-avibactam and comparators against carbapenemase-producing Enterobacterales (N = 1,992) and carbapenemase-producing Pseudomonas aeruginosa (N = 784) collected in Africa/Middle East, Asia/South Pacific, Europe and Latin America (2016-2018). Methods MICs and susceptibility were determined using broth microdilution methodology and EUCAST breakpoints. Genes encoding carbapenemases were detected using multiplex PCR assays. Results No isolates of carbapenemase-producing, MBL-negative Enterobacterales from Africa/Middle East or Latin America were resistant to ceftazidime-avibactam; resistance rates in Europe and Asia/South Pacific were ≤ 4.5%. Colistin had the lowest resistance rate among MBL-positive isolates (6.0%-11.4%). Enterobacterales isolates collected in Latin America predominantly carried a KPC carbapenemase (77.6%), whereas in Africa/Middle East OXA-48-like carbapenemases were most frequently detected (55.9%), and in Asia/South Pacific most isolates carried NDM carbapenemases (56.2%). Among all Enterobacterales carrying KPC carbapenemases, the lowest rate of resistance was to ceftazidime-avibactam (1.5%), and among isolates carrying NDM carbapenemases, to colistin (10.8%). Among carbapenemase-producing, MBL-negative P. aeruginosa, resistance rates to ceftazidime-avibactam were 8.6% for isolates collected in Europe and 53.2% in Latin America. Isolates in each region most frequently carried VIM carbapenemases, ranging from 41.7% of isolates in Asia/South Pacific to 86.2% in Africa/Middle East. No P. aeruginosa carrying KPC or NDM carbapenemases, and 1.0% of isolates carrying GES carbapenemases, were resistant to colistin. Conclusion Given the limited therapeutic options to treat infections caused by carbapenemase-positive Enterobacterales and P. aeruginosa, continued surveillance of ceftazidime-avibactam activity, as well as that of agents such as colistin, is crucial.

The current study investigated the motives that underlie support for COVID-19 preventive behaviorsin a large, cross-cultural sample of 12,758 individuals from 34 countries. We hypothesized that the associations of empathic prosocial concern and fear of disease, with support towards preventive COVID-19 behaviors would be moderated by the individual-level and country-level trust in the government. Results suggest that the association between fear of disease and support for COVID-19 preventive behaviors was strongest when trust in the government was weak (both at individual and country-level). Conversely, the association with empathic prosocial concern was strongest when trust was high, but this moderation was only found at individual-level scores of governmental trust. We discuss how both fear and empathy motivations to support preventive COVID-19 behaviors may be shaped by socio-cultural context, and outline how the present findings may contribute to a better understanding of collective action during global crises.

Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. A new amending regulation, which introduces a phased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices and a later date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021. The combined use of CE-IVDs, in-house IVDs, and RUO products are a cornerstone of diagnostics in pathology departments and crucial for optimal patient care. The IVDR not only regulates the manufacture and placement on the market of industrially manufactured IVDs, but also imposes conditions on the manufacture and use of IH-IVDs for internal use by healthcare facilities.Our work provides an overview of the background and structure of the IVDR and identifies core areas that need to be interpreted and fleshed out in the context of the legal framework as well as expert knowledge.The gaps and ambiguities in the IVDR crucially require the expertise of professional societies, alliances, and individual stakeholders to successfully facilitate the implementation and use of the IVDR in pathology departments and to avoid aberrant developments.HINTERGRUND: Die Verordnung (EU) 2017/746 über In-vitro-Diagnostika (IVDR) wurde vom Europäischen Parlament und dem Rat der Europäischen Union am 5. April 2017 erlassen und ist am 26. Mai 2017 in Kraft getreten. Eine neue Änderungsverordnung, die eine schrittweise Einführung der IVDR mit neuen Übergangsbestimmungen für bestimmte In-vitro-Diagnostika (IVD) und einen späteren Geltungsbeginn mancher Anforderungen für hausinterne Produkte für Gesundheitseinrichtungen regelt, wurde am 15. Dezember 2021 beschlossen. Die kombinierte Verwendung von CE-IVDs, hausinternen IVDs und Research-use-only(RUO)-Produkten führt in Pathologien zu einem validen Befund, der für die optimale Patientenversorgung notwendig ist. Die IVDR regelt nun nicht nur die Herstellung und das Inverkehrbringen von industriell hergestellten IVDs, sondern stellt auch Bedingungen für die Herstellung und Verwendung von Inhouse-IVDs (IH-IVDs) für den internen Gebrauch von Gesundheitseinrichtungen.Dieser Artikel gibt einen Überblick über die Hintergründe und Rahmenbedingungen der IVDR und zeigt Kernbereiche auf, die der inhaltlichen Ausgestaltung unter Berücksichtigung inhaltlicher und rechtlicher Rahmenbedingungen bedürfen.Die Leerstellen und Unbestimmtheiten innerhalb der IVDR erfordern zwingend die Expertise der Fachgesellschaften, akademischen Verbünde und Fachexperten, um eine erfolgreiche Umsetzung der IVDR in den Instituten und Einrichtungen für Pathologie zu erreichen und Fehlentwicklungen zu vermeiden.

Bacteriophage therapy, which uses lytic viruses as antimicrobials, has received renewed interest to address the emerging antimicrobial resistance (AMR) crisis. Cystic fibrosis (CF), a disease complicated by recurrentP. aeruginosapulmonary infections that cause lung function decline, is an example where AMR is already a clinical problem. While bacteria evolve bacteriophage resistance, we developed a strategy to select bacteriophages that target bacterial cell surface receptors that contribute to antibiotic resistance or virulence. Thus, in addition to killing bacteria, these phages steer surviving, evolved bacteria to antibiotic re-sensitivity or attenuated virulence. Here, we present outcomes from nine CF adults treated with nebulized bacteriophage therapy for AMRP. aeruginosausing this personalized approach. Results showed that phage therapy: 1) reduced sputumP. aeruginosa, 2) showed evidence for predicted trade-offs in most subjects, and 3) improved lung function, which may reflect the combined effects of decreased bacterial sputum density and phage-driven evolved trade-offs.

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PURPOSE Zanubrutinib is a potent, irreversible next-generation Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target kinase inhibition. We hypothesized that complete/sustained BTK occupancy may improve efficacy outcomes and increased BTK specificity may minimize off-target inhibition-related toxicities. PATIENTS AND METHODS ALPINE (ClinicalTrials.gov identifier: NCT03734016 ) is a global, randomized, open-label phase III study of zanubrutinib versus ibrutinib in patients with relapsed/refractory chronic lymphocytic leukemia. The primary end point was investigator-assessed overall response rate (ORR). The preplanned interim analysis was scheduled approximately 12 months after the first 415 patients were enrolled. RESULTS Between November 1, 2018, and December 14, 2020, 652 patients were enrolled. We present the interim analysis of the first 415 enrolled patients randomly assigned to receive zanubrutinib (n = 207) or ibrutinib (n = 208). At 15 months of median follow-up, ORR (partial or complete response) was significantly higher with zanubrutinib (78.3%; 95% CI, 72.0 to 83.7) versus ibrutinib (62.5%; 95% CI, 55.5 to 69.1; two-sided P < .001). ORR was higher with zanubrutinib versus ibrutinib in subgroups with del(17p)/ TP53 mutations (80.5% v 50.0%) and del(11q) (83.6% v 69.1%); 12-month progression-free survival in all patients was higher with zanubrutinib (94.9%) versus ibrutinib (84.0%; hazard ratio, 0.40; 95% CI, 0.23 to 0.69). Atrial fibrillation rate was significantly lower with zanubrutinib versus ibrutinib (2.5% v 10.1%; two-sided P = .001). Rates of cardiac events, major hemorrhages, and adverse events leading to treatment discontinuation/death were lower with zanubrutinib. CONCLUSION Zanubrutinib had a significantly higher ORR, lower atrial fibrillation rate, and improved progression-free survival and overall cardiac safety profile versus ibrutinib. These data support improved efficacy/safety outcomes with selective BTK inhibition.

This dissertation examines some aspects of the relationship between ˜í¬™ calculus and universal algebra. Motivated by the desire to understand the implementation of abstract data types in functional languages we use ˜í¬™ algebras, or models of the pure ˜í¬™˜í‚⧠calculus, as a universe in which models for specifications are to be constructed. Given an arbitrary ˜í¬™ algebra M we construct from it a cartesian closed category with sum objects which we call C(M) . The objects of C(M) are interpreted as types while the arrows can be thought of as effective functions. Unlike set theory where the semantics of an abstract data type is often chosen to be the (isomorphism) class of initial models the simple model of types and functions presented here contains no initial object. This means more care is required when choosing the semantics of an abstract data type. In particular the category C(M) , which is an extension of the cartesian closed monoids of [Koy82, LS86, Bar84] is cartesian closed (4.1.6) and so the basic properties of functional languages such as currying and higher order functions can be modelled. Using the idea of a T-algebra [LS81, SP82] we construct algebras as the greatest fixed points of endofunctors over C(M) (4.2.5). While in general systems of equations do not always exhibit computational properties in many cases they do, especially if a set of Church-Rosser and strongly normalising rewrite rules can be extracted from the equations by a technique such as the Knuth-Bendix completion procedure [KB70]. It is known [KS81] that a Church-Rosser strongly normalising set of rewrite rules is associated with the word problem in the free algebra and if the word problem is solvable then there is a recursive function taking each term in the free algebra to its normal form. We construct models for systems of Church-Rosser, strongly normalising sets of rewrite rules based on this characterisation of the word problem (4.3.14). Secondly a calculus, ˜í¬™˜í¬£E , is given for reasoning about these models. ˜í¬™˜í¬£E is a simply typed ˜í¬™ calculus augmented with the operations and equations of the original specification. It is shown that this calculus is a conservative extension of the usual equational calculus if a strongly normalising and Church-Rosser set of rewrite rules can be generated from the original equations (5.2.10). Thirdly, given a specification and an arbitrary model of that specification in C(M) , the soundness of deduction in ˜í¬™˜í¬£E is proved (6.1.5). Finally, a theorem relating the equational theory to ˜í¬™˜í¬£E , namely that for every model of the equational theory there exists a unique model of ˜í¬™˜í¬£E .

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Distant spreading of tumor cells to the central nervous system in non-small cell lung cancer (NSCLC) occurs frequently and poses major clinical issues due to limited treatment options. RNAs displaying differential expression in brain metastasis versus primary NSCLC may explain distant tumor growth and may potentially be used as therapeutic targets. In this study, we conducted systematic microRNA expression profiling from tissue biopsies of primary NSCLC and brain metastases from 25 patients. RNA analysis was performed using the nCounter Human v3 miRNA Expression Assay, NanoString technologies, followed by differential expression analysis and in silico target gene pathway analysis. We uncovered a panel of 11 microRNAs with differential expression and excellent diagnostic performance in brain metastasis versus primary NSCLC. Five microRNAs were upregulated in brain metastasis (miR-129-2-3p, miR-124-3p, miR-219a-2-3p, miR-219a-5p, and miR-9-5p) and six microRNAs were downregulated in brain metastasis (miR-142-3p, miR-150-5p, miR-199b-5p, miR-199a-3p, miR-199b-5p, and miR-199a-5p). The differentially expressed microRNAs were predicted to converge on distinct target gene networks originating from five to twelve core target genes. In conclusion, we uncovered a unique microRNA profile linked to two target gene networks. Our results highlight the potential of specific microRNAs as biomarkers for brain metastasis in NSCLC and indicate plausible mechanistic connections.

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