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Recently updated COVID-19 mRNA vaccines encode the spike protein of the omicron subvariant XBB.1.5 and are recommended for patients with inflammatory bowel disease (IBD) on immunosuppressive treatment. Nonetheless, their immunogenicity in patients with IBD against rapidly expanding virus variants remains unknown. This prospective multicenter cohort study is the first study to investigate the immunogenicity of XBB.1.5-adapted vaccines in patients with IBD. Systemic and mucosal antibodies targeting the receptor-binding domains (RBDs) of the omicron subvariants XBB.1.5, EG.5.1, and BA.2.86, as well as their neutralization were quantified before and two to four weeks after vaccination with monovalent XBB.1.5-adapted mRNA vaccines. Vaccination increased levels of serum anti-RBD IgG targeting XBB.1.5, EG.5.1, and BA.2.86 (1.9-fold, 1.8-fold, and 2.6-fold, respectively) and enhanced corresponding neutralization responses (2.3-fold, 3.1-fold, and 3.5-fold, respectively). Following vaccination, anti-TNF-treated patients had reduced virus neutralization compared to patients on treatments with other cellular targets. 11.1% and 16.7% of patients lacked EG.5.1 and BA.2.86 neutralization, respectively; all these patients received anti-TNF treatment. At mucosal sites, vaccination induced variant-specific anti-RBD IgG but failed to induce RBD-targeting IgA. Our findings provide a basis for future vaccine recommendations while highlighting the importance of frequent booster vaccine adaptation and the need for mucosal vaccination strategies in patients with IBD.

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BACKGROUND: There is growing interest in nurse practitioner (NP) turnover with some reports indicating it is as high as 15% annually. However, there is a lack of generalizability and other conceptual weaknesses in the literature. These weaknesses support the development of a framework to operationalize NP turnover for administrators to develop workplace initiatives to reduce turnover. PURPOSE: To describe the demographic and job characteristics of four NP voluntary turnover groups (i.e., dynamic leavers, static leavers, dynamic stayers, and static stayers) representing voluntary turnover intention and actual turnover among US NPs. METHODOLOGY: A cross-sectional, descriptive secondary analysis of NPs ( N = 86,632) from the 2018 National Sample Survey of Registered Nurses (NSSRN) was used to delineate and describe four NP voluntary turnover groups. RESULTS: Nurse practitioners who left nursing (static leavers) were older and had the most work experience. Nurse practitioners who changed jobs and stayed in nursing (dynamic leavers) were younger, less experienced, and reported the least job satisfaction. Nurse practitioners who remained in their positions (stayers) regardless of whether they reported turnover intentions or not earned the most and reported the most job satisfaction. CONCLUSIONS: Four NP voluntary turnover groups were defined and described to distinguish voluntary turnover intentions from actual turnover. IMPLICATIONS: Characterizing NP voluntary turnover can help administrators mitigate losses and project organizational needs associated with NP turnover. A framework developed from the 2018 NSSRN can be used to research and develop key initiatives to strengthen the NP workforce.

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BACKGROUND: Vaccine-elicited immune responses are impaired in patients with inflammatory bowel disease (IBD) treated with anti-TNF biologics. AIMS: To assess vaccination efficacy against the novel omicron sublineages BQ.1.1 and XBB.1.5 in immunosuppressed patients with IBD. METHODS: This prospective multicentre case-control study included 98 biologic-treated patients with IBD and 48 healthy controls. Anti-spike IgG concentrations and surrogate neutralisation against SARS-CoV-2 wild-type, BA.1, BA.5, BQ.1.1, and XBB.1.5 were measured at two different time points (2-16 weeks and 22-40 weeks) following third dose vaccination. Surrogate neutralisation was based on antibody-mediated blockage of ACE2-spike protein-protein interaction. Primary outcome was surrogate neutralisation against tested SARS-CoV-2 sublineages. Secondary outcomes were proportions of participants with insufficient surrogate neutralisation, impact of breakthrough infection, and correlation of surrogate neutralisation with anti-spike IgG concentration. RESULTS: Surrogate neutralisation against all tested sublineages was reduced in patients with IBD who were treated with anti-TNF biologics compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.001) at visit 1. Anti-TNF therapy (odds ratio 0.29 [95% CI 0.19-0.46]) and time since vaccination (0.85 [0.72-1.00]) were associated with low, and mRNA-1273 vaccination (1.86 [1.12-3.08]) with high wild-type surrogate neutralisation in a ß-regression model. Accordingly, higher proportions of patients treated with anti-TNF biologics had insufficient surrogate neutralisation against omicron sublineages at visit 1 compared to patients treated with non-anti-TNF biologics and healthy controls (each p ≤ 0.015). Surrogate neutralisation against all tested sublineages decreased over time but was increased by breakthrough infection. Anti-spike IgG concentrations correlated with surrogate neutralisation. CONCLUSIONS: Patients with IBD who are treated with anti-TNF biologics show impaired neutralisation against novel omicron sublineages BQ.1.1 and XBB.1.5 and may benefit from prioritisation for future variant-adapted vaccines.

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Artificial intelligence is a rapidly expanding area of research, with the disruptive potential to transform traditional approaches in the pharmaceutical industry, from drug discovery and development to clinical practice. Machine learning, a subfield of artificial intelligence, has fundamentally transformed in silico modelling and has the capacity to streamline clinical translation. This paper reviews data-driven modelling methodologies with a focus on drug formulation development. Despite recent advances, there is limited modelling guidance specific to drug product development and a trend towards suboptimal modelling practices, resulting in models that may not give reliable predictions in practice. There is an overwhelming focus on benchtop experimental outcomes obtained for a specific modelling aim, leaving the capabilities of data scraping or the use of combined modelling approaches yet to be fully explored. Moreover, the preference for high accuracy can lead to a reliance on black box methods over interpretable models. This further limits the widespread adoption of machine learning as black boxes yield models that cannot be easily understood for the purposes of enhancing product performance. In this review, recommendations for conducting machine learning research for drug product development to ensure trustworthiness, transparency, and reliability of the models produced are presented. Finally, possible future directions on how research in this area might develop are discussed to aim for models that provide useful and robust guidance to formulators.

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Background: Montessori education is the oldest and most widely implemented alternative education in the world, yet its effectiveness has not been clearly established. Objectives: The primary objective of this review was to examine the effectiveness of Montessori education in improving academic and nonacademic outcomes compared to traditional education. The secondary objectives were to determine the degree to which grade level, Montessori setting (public Montessori vs. private Montessori), random assignment, treatment duration, and length of follow-up measurements moderate the magnitude of Montessori effects. Search Methods: We searched for relevant studies in 19 academic databases, in a variety of sources known to publish gray literature, in Montessori-related journals, and in the references of studies retrieved through these searches. Our search included studies published during or before February 2020. The initial search was performed in March 2014 with a follow-up search in February 2020. Selection Criteria: We included articles that compared Montessori education to traditional education, contributed at least one effect size to an academic or nonacademic outcome, provided sufficient data to compute an effect size and its variance, and showed sufficient evidence of baseline equivalency-through random assignment or statistical adjustment-of Montessori and traditional education groups. Data Collection and Analysis: To synthesize the data, we used a cluster-robust variance estimation procedure, which takes into account statistical dependencies in the data. Otherwise, we used standard methodological procedures as specified in the Campbell Collaboration reporting and conduct standards. Main Results: Initial searches yielded 2012 articles, of which 173 were considered in detail to determine whether they met inclusion/exclusion criteria. Of these, 141 were excluded and 32 were included. These 32 studies yielded 204 effect sizes (113 academic and 91 nonacademic) across 132,249 data points. In the 32 studies that met minimum standards for inclusion, including evidence of baseline equivalence, there was evidence that Montessori education outperformed traditional education on a wide variety of academic and nonacademic outcomes. For academic outcomes, Hedges' g effect sizes, where positive values favor Montessori, ranged from 0.26 for general academic ability (with high quality evidence) to 0.06 for social studies. The quality of evidence for language (g = 0.17) and mathematics (g = 0.22) was also high. The effect size for a composite of all academic outcomes was 0.24. Science was the only academic outcome that was deemed to have low quality of evidence according to the GRADE approach. Effect sizes for nonacademic outcomes ranged from 0.41 for students' inner experience of school to 0.23 for social skills. Both of these outcomes were deemed as having low quality of evidence. Executive function (g = 0.36) and creativity (g = 0.26) had moderate quality of evidence. The effect size for a composite of all nonacademic outcomes was 0.33. Moderator analyses of the composite academic and nonacademic outcomes showed that Montessori education resulted in larger effect sizes for randomized studies compared to nonrandomized studies, for preschool and elementary settings compared to middle school or high school settings, and for private Montessori compared to public Montessori. Moderator analyses for treatment duration and duration from intervention to follow-up data collection were inconclusive. There was some evidence for a lack of small sample-size studies in favor of traditional education, which could be an indicator of publication bias. However, a sensitivity analysis indicated that the findings in favor of Montessori education were nonetheless robust. Authors' Conclusions: Montessori education has a meaningful and positive impact on child outcomes, both academic and nonacademic, relative to outcomes seen when using traditional educational methods.

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BACKGROUND: Immunosuppressed patients with inflammatory bowel disease (IBD) experience increased risk of vaccine-preventable diseases such as COVID-19. AIMS: To assess humoral and cellular immune responses following SARS-CoV-2 booster vaccination in immunosuppressed IBD patients and healthy controls. METHODS: In this prospective, multicentre, case-control study, 139 IBD patients treated with biologics and 110 healthy controls were recruited. Serum anti-SARS-CoV-2 spike IgG concentrations were measured 2-16 weeks after receiving a third mRNA vaccine dose. The primary outcome was to determine if humoral immune responses towards booster vaccines differ in IBD patients under anti-TNF versus non-anti-TNF therapy and healthy controls. Secondary outcomes were antibody decline, impact of previous infection and SARS-CoV-2-targeted T cell responses. RESULTS: Anti-TNF-treated IBD patients showed reduced anti-spike IgG concentrations (geometric mean 2357.4 BAU/ml [geometric SD 3.3]) when compared to non-anti-TNF-treated patients (5935.7 BAU/ml [3.9]; p < 0.0001) and healthy controls (5481.7 BAU/ml [2.4]; p < 0.0001), respectively. In multivariable modelling, prior infection (geometric mean ratio 2.00 [95% CI 1.34-2.90]) and vaccination with mRNA-1273 (1.53 [1.01-2.27]) increased antibody concentrations, while anti-TNF treatment (0.39 [0.28-0.54]) and prolonged time between vaccination and antibody measurement (0.72 [0.58-0.90]) decreased anti-SARS-CoV-2 spike antibodies. Antibody decline was comparable in IBD patients independent of anti-TNF treatment and antibody concentrations could not predict breakthrough infections. Cellular and humoral immune responses were uncoupled, and more anti-TNF-treated patients than healthy controls developed inadequate T cell responses (15/73 [20.5%] vs 2/100 [2.0%]; p = 0.00031). CONCLUSIONS: Anti-TNF-treated IBD patients have impaired humoral and cellular immunogenicity following SARS-CoV-2 booster vaccination. Fourth dose administration may be beneficial for these patients.

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Importance: Elderly patients, especially men, are at risk of increased morbidity from coronavirus disease 2019 (COVID-19). Long-term data on troponin I levels in longitudinal observational studies of outpatients with mild to moderate COVID-19 are scarce. Objective: This controlled cohort study aimed to evaluate the course of troponin I concentrations over a long period in convalescent COVID-19 outpatients with mild to moderate symptoms. Setting and participants: In this cohort study, individuals with PCR-confirmed, mild to moderate SARS-CoV-2 infection as well as control individuals with confirmed negative PCR and negative SARS-CoV-2 serology were included. Study visits were performed from April 2020 through July 2021 (initialized during the first wave of the corona pandemic in Switzerland). A study visit in patients comprised blood draws every week in the first month and additionally after 8 weeks. This course was repeated in patients observed long-term. Results: This study enrolled 278 individuals from the Canton of St. Gallen, Switzerland, aged 12-92 years (59.5% women), who had mild to moderate COVID-19 symptoms (outpatients only) and a diagnosis confirmed by positive RT-PCR. Fifty-four of the participants with confirmed SARS-CoV-2 infection were followed for 14 months with repeat cycles of the testing protocol. In addition, 115 symptomatic patients that were PCR and serology negative were enrolled in the same time period as a control group. In COVID-19 patients, low-level troponin I concentrations (cTnI) were significantly increased from baseline until week 9 after positive RT-PCR diagnosis in men older than 54 years [ΔcTnI = 5.0 ng/L (median); 95% CI 4.1-6.0; p = 0.02]. The troponin I concentration remained elevated throughout 14 months in men older than 54 years within the cohort with a prolonged observation period. This statistically significant change in troponin I concentration was not dependent on co-morbidities in this group. ALT, Creatinine, BNP, and D-Dimer values after convalescence did not differ in comparison to the control cohort. Conclusion: In this analysis of individuals with confirmed SARS-CoV-2 infection, hs troponin I levels of men aged 54 or older significantly increased after infection. They remained elevated for at least 14 months after diagnosis. This suggests the possibility of an ongoing, long-term, low-grade myocardial injury. Further studies with focus on elderly patients and a prolonged observational period are necessary to elucidate whether the phenomenon observed is associated with detectable structural changes to the heart muscle or is without further clinical consequences.

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BACKGROUND: Based on current and future research priorities to inform Ph.D. education, emerging and priority areas were developed through the Idea Festival Advisory Committee of the Council for the Advancement of Nursing Science. PURPOSE: The purpose of this study was to examine the bibliographic, methodologic, study topic characteristics, and emerging and priority areas of two randomly selected samples of nursing doctoral dissertations from the Proquest Digital Dissertations and Theses database between January 2017 and September 2018. METHODS: Using human- (N = 101) and computer-coding (N = 242), we analyzed text data using descriptive statistics and data visualization. FINDINGS: Health behavior (32.7%) and quantitative sciences (17.8%) were the most common emerging and priority areas, and translation science and -omics/microbiome were absent. Health, practice, education, and leadership were four study topic themes. DISCUSSION: This approach may serve as a metric for the state of Ph.D. nursing education. A replication study is recommended in three to five years.

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The understanding of the regional and local dimensions of vulnerability due to climate change is essential to develop appropriate and targeted adaptation efforts. We assessed the local dimensions of vulnerability in the tropical state of Kerala, India, using a purposely developed vulnerability index, which accounts for both environmental and socio-economic factors. The large extents of coastal wetlands and lagoons and high concentration of mangrove forests make the state environmentally vulnerable. Low human development index, large population of socially deprived groups, which are dependent on the primary sector, and high population density make the state vulnerable from a socio-economic point of view. The present study investigates climate change vulnerability at the district level in the State of Kerala relying on a purposely developed composite vulnerability index that encompasses both socio-economic and environmental factors. The Kerala coast contains the socio-economically and ecologically most vulnerable regions, as demonstrated by a composite vulnerability index.

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Vector borne diseases are a threat to human health. Little attention has been paid to the prevention of these diseases. We attempted to identify the significant wetland characteristics associated with the spread of chikungunya, dengue fever and malaria in Kerala, a tropical region of South West India using multivariate analyses (hierarchical cluster analysis, factor analysis and multiple regression). High/medium turbid coastal lagoons and inland water-logged wetlands with aquatic vegetation have significant effect on the incidence of chikungunya while dengue influenced by high turbid coastal beaches and malaria by medium turbid coastal beaches. The high turbidity in water is due to the urban waste discharge namely sewage, sullage and garbage from the densely populated cities and towns. The large extent of wetland is low land area favours the occurrence of vector borne diseases. Hence the provision of pollution control measures at source including soil erosion control measures is vital. The identification of vulnerable zones favouring the vector borne diseases will help the authorities to control pollution especially from urban areas and prevent these vector borne diseases. Future research should cover land use cover changes, climatic factors, seasonal variations in weather and pollution factors favouring the occurrence of vector borne diseases.

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The study on bioaccumulation of heavy metals in a lake reveals that during the nonrainy season, accumulation of cadmium in plankton is high in the upstream of the lake where anoxic freshwater condition exists resulting from inflow of urban wastes. Stern action is required to stop the bypass of sewage from the old sewer system especially in the commercial areas of Thiruvananthapuram city, either by augmenting the sewerage system or by treating sewage at the source. During monsoon season, the accumulation of heavy metals-namely lead and nickel, followed by cadmium and chromium-is high in phytoplankton resulting from high nitrate content caused by heavy rainfall. During postmonsoon, lead and nickel accumulation is high. The study emphasizes the need for stormwater management practices for the removal of lead in urban runoff from roads caused by vehicular exhaust, tire wear, and wastes from service stations and workshops.

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While a plethora of ligands are known for the well studied α7 and α4ß2 nicotinic acetylcholine receptor (nAChR), only very few ligands address the related α3ß2 nAChR expressed in the central nervous system and at the neuromuscular junction. Starting with the public database ChEMBL organized in the chemical space of Molecular Quantum Numbers (MQN, a series of 42 integer value descriptors of molecular structure), a visual survey of nearest neighbors of the α7 nAChR partial agonist N-(3R)-1-azabicyclo[2.2.2]oct-3-yl-4-chlorobenzamide (PNU-282,987) pointed to N-(2-halobenzyl)-3-aminoquinuclidines as possible nAChR modulators. This simple "chemical space walk" was performed using a web-browser available at www.gdb.unibe.ch . Electrophysiological recordings revealed that these ligands represent a new and to date most potent class of positive allosteric modulators (PAMs) of the α3ß2 nAChR, which also exert significant effects in vivo. The present discovery highlights the value of surveying chemical space neighbors of known drugs within public databases to uncover new pharmacology.

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The chemical universe database GDB-13 enumerates 977 million organic molecules up to 13 atoms of C, N, O, Cl, and S that are virtually possible following simple rules for chemical stability and synthetic feasibility. Analogs of nicotine were identified in GDB-13 using the city-block distance in MQN-space (CBD(MQN)) as a similarity measure, combined with a restriction eliminating problematic structural elements. The search was carried out with a Web browser available at www.gdb.unibe.ch . This virtual screening procedure selected 31 504 analogs of nicotine from GDB-13, from which 48 were known nicotinic ligands reported in Chembl. An additional 60 virtual screening hits were purchased and tested for modulation of the acetylcholine signal at the human α7 nAChR expressed in Xenopus oocytes, which led to the identification of three previously unknown inhibitors. These experiments demonstrate for the first time the use of GDB-13 for ligand discovery.

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Lakes are seriously affected due to urban pollution. The study of the morphological features of a lake system helps to identify its environmental status. The objective of the present study is to analyse the influence of morphometry on water quality in a lake (Akkulam-Veli Lake, Thiruvananthapuram, Kerala). The morphological features namely mean depth, surface area, volume, shoreline length, shoreline development and index of basin permanence have been evaluated. Correlation analysis has been conducted to determine the relationship between morphological features and water quality. Regression analysis has been conducted to find out the extent of influence of morphometric features on water quality. The study revealed that the lake is less affected by wind-induced wave action due to various reasons. The depth and volume have significant role in the water quality. The nitrogen fixation of blue green algae can be observed from the morphological features. The morphology has greater role in the water quality of a lake system.

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A family of chiral C(2)-symmetric disulfoxide ligands possessing biaryl atropisomeric backbones has been synthesized by using the Andersen methodology. Complete characterization includes X-ray crystallographic studies of all ligands and some of their rhodium complexes. Their synthesis, optical purity, electronic properties, and catalytic behavior in the prototypical rhodium-catalyzed 1,4-addition of phenylboronic acid to 2-cyclohexen-1-one are presented through an in depth study of this ligand class. Density functional theory calculations on the step of the catalytic cycle that determines the enantioselectivity are presented and reinforce the first hypothetical explanations for the high levels of asymmetric induction observed.

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AIM: To investigate extracellular matrix (ECM) characteristics of cortical bone and articular cartilage of patients with Morquio syndrome A, a lysosomal storage disease caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase. PATIENTS AND METHODS: Cartilage, bone, and fibroblasts from 2 unrelated patients with Morquio syndrome were used. Histological analysis on bone and cartilage was carried out by means of light and electron microscopy. Lysyl hydroxylation and cross-linking of collagen present in bone, cartilage, and fibroblast cultures was determined by reverse-phase high performance liquid chromatography. RESULTS: No histological or biochemical differences were seen in cortical bone; furthermore, no differences were seen in the amount and modification of collagen deposited by fibroblasts. Articular cartilage showed major differences: collagen fibrils show a wider range of fibril diameter, the fibrils are in mean thicker, the lysyl hydroxylation level of the triple helix is strongly decreased, the total amount of pyridinolines is in the lower ranges, and the ratio hydroxylysylpyridinoline to lysylpyridinoline is decreased. Changes were also observed with respect to the arrangement of proteoglycans in the extracellular matrix surrounding the chondrocytes. CONCLUSION: The collagen of bone and the collagen deposited by fibroblasts is normal, whereas the ECM of cartilage in Morquio syndrome A patients is affected. Thus, deficiency in N-acetylgalactosamine-6-sulfate sulfatase has an impact on the phenotypic properties of chondrocytes, resulting in the formation of cartilage that is more prone to degeneration, being an explanation for the occurrence of osteoarthritis in Morquio syndrome A patients at early age.

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From zero to hero? Sulfoxides are generally not considered useful ligand entities in asymmetric metal catalysis. However, a chiral disulfoxide as a chelating ligand in the rhodium-catalyzed 1,4-addition of aryl boronic acids to cyclic, alpha,beta-unsaturated ketones and esters gives impressive catalytic results, thus opening the door to future applications of this new chiral ligand class.

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OBJECTIVE: To explore how rheumatoid arthritis (RA) antirheumatic drug-specific knowledge and numeric literacy, patient trust in physician, and demographic and disease-related factors relate to the confidence of patient decision-making related to disease modifying antirheumatic drugs (DMARD). METHODS: Data were analyzed from 628 randomly selected patients with RA receiving care in community rheumatology practices, who responded to a multicenter, cross-sectional mail survey. We used multiple regression models to predict patient confidence in DMARD decision-making related to their most recently initiated DMARD. RESULTS: Significant positive correlation was found between confidence in DMARD decision and trust in physician, DMARD-specific knowledge, and disease duration, but not risk-related numeric literacy, sex, or education. Negative correlations were found with disease severity and current bother with DMARD side effects. A multiple linear regression model of confidence in DMARD decision had an overall R = 0.788, R2 = 0.620 (p < 0.001). The 4 dependent variables contributing significantly to the model were female sex, Medicaid insurance status, satisfaction with RA disease control, and trust in physician, with standardized beta = 0.077, -0.089, 0.147, and 0.687, respectively. CONCLUSION: In this sample of community patients with RA, the patient trust in physician had substantially greater effect on confidence in DMARD decision than DMARD-specific knowledge, disease-related factors, or demographic characteristics.

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