Nickel-Based Catalysts for the Selective Monoarylation of Dichloropyridines: Ligand Effects and Mechanistic Insights.

This report describes a detailed study of Ni phosphine catalysts for the Suzuki-Miyaura coupling of dichloropyridines with halogen-containing (hetero)aryl boronic acids. With most phosphine ligands these transformations afford mixtures of mono- and diarylated cross-coupling products as well as competing oligomerization of the boronic acid. However, a ligand screen revealed that PPh2Me and PPh3 afford high yield and selectivity for monoarylation over diarylation as well as minimal competing oligomerization of the boronic acid. Several key observations were made regarding the selectivity of these reactions, including: (1) phosphine ligands that afford high selectivity for monoarylation fall within a narrow range of Tolman cone angles (between 136° and 157°); (2) more electron-rich trialkylphosphines afford predominantly diarylated products, while less-electron rich di- and triarylphosphines favor monoarylation; (3) diarylation proceeds via intramolecular oxidative addition; and (4) the solvent (MeCN) plays a crucial role in achieving high monoarylation selectivity. Experimental and DFT studies suggest that all these data can be explained based on the reactivity of a key intermediate: a Ni0-π complex of the monoarylated product. With larger, more electron-rich trialkylphosphine ligands, this π complex undergoes intramolecular oxidative addition faster than ligand substitution by the MeCN solvent, leading to selective diarylation. In contrast, with relatively small di- and triarylphosphine ligands, associative ligand substitution by MeCN is competitive with oxidative addition, resulting in selective formation of monoarylated products. The generality of this method is demonstrated with a variety of dichloropyridines and chloro-substituted aryl boronic acids. Furthermore, the optimal ligand (PPh2Me) and solvent (MeCN) are leveraged to achieve the Ni-catalyzed monoarylation of a broader set of dichloroarene substrates.

Mechanistic Origin of Ligand Effects on Exhaustive Functionalization During Pd-Catalyzed Cross-Coupling of Dihaloarenes.

We describe a detailed investigation into why bulky ligands-those that enable catalysis at "12e -" Pd0-tend to promote overfunctionalization during Pd-catalyzed cross-couplings of dihalogenated substrates. After one cross-coupling event takes place, PdL initially remains coordinated to the π system of the nascent product. Selectivity for mono- vs. difunctionalization arises from the relative rates of π-decomplexation versus a second oxidative addition. Under the Suzuki coupling conditions in this work, direct dissociation of 12e - PdL from the π-complex cannot outcompete oxidative addition. Instead, Pd must be displaced from the π-complex as 14e - PdL(L') by a second incoming ligand L'. The incoming ligand is another molecule of dichloroarene if the reaction conditions do not include π-coordinating solvents or additives. More overfunctionalization tends to result when increased ligand or substrate sterics raises the energy of the bimolecular transition state for separating 14e - PdL(L') from the mono-cross-coupled product. This work has practical implications for optimizing selectivity in cross-couplings involving multiple halogens. For example, we demonstrate that small coordinating additives like DMSO can largely suppress overfunctionalization and that precatalyst structure can also impact selectivity.

Response to COVID-19 vaccination imaged by PD-L1 PET scanning.

BACKGROUND: During a phase 0 clinical trial of an investigational programmed cell death ligand-1 (PD-L1) PET tracer in patients with non-small cell lung cancer (NSCLC), three patients received booster doses of COVID-19 vaccines before PD-L1 imaging. METHODS: Five patients underwent whole-body PET/CT imaging with a novel PD-L1 tracer, constructed by attaching 89Zr to the anti PD-L1 antibody durvalumab. Intramuscular (deltoid) booster doses of mRNA BNT162b2 COVID-19 mRNA vaccine were coincidentally given to three patients in the month before PD-L1 tracer injection. RESULTS: Two recently-vaccinated patients, in remission of NSCLC and receiving non-immunosuppressive cancer therapies (immunotherapy and tyrosine kinase inhibitor respectively), showed increasing PD-L1 tracer uptake in ipsilateral axillary lymph nodes. No asymmetric nodal uptake was seen in a third recently-vaccinated patient who was receiving immunosuppressive chemotherapy, or in two patients not recently-vaccinated. CONCLUSION: Immune response to mRNA BNT162b2 vaccination may involve regulation by PD-L1 positive immune cells in local draining lymph nodes in immunocompetent patients. TRIAL REGISTRATION: This trial was registered with the Australian New Zealand Clinical Trials Registry. Registration number ACTRN12621000171819. Date of Trial Registration 8/2/2021. Date of enrolment of 1st patient 11/4/2021. URL of trial registry record: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12621000171819 .

The Stigma and Infertility-Related Stress of Chinese Infertile Women: A Cross-Sectional Study.

OBJECTIVES: This study was conducted to investigate the stigma status of infertile women in China and to determine the influencing factors. METHODS: 366 infertile women from the gynecological and reproductive departments of two tertiary hospitals completed socio-demographic questionnaires, the Infertility Stigma Scale (ISS) and the Mandarin Fertility Problem Inventory (M-FPI). RESULTS: The scores of stigma and infertility-related stress in infertile women were (52.51 ± 17.74) and (150.03 ± 17.51), respectively. Multiple regression analysis found that location of residence, regarding children as the most important thing in life, talking to others about infertility and infertility-related stress were the main influencing factors of stigma in infertile women, which explained 17.3% of the total variance. CONCLUSIONS: In the current study, the level of stigma in women with infertility was at the middle range. Location of residence, regarding children as the most important thing in life, whether to talk with others about infertility and infertility-related stress were the four main influencing factors of stigma.

Urinary Metabolite Diagnostic and Prognostic Liquid Biopsy Biomarkers of Lung Cancer in Non-smokers and Tobacco Smokers.

PURPOSE: Non-smokers account for 10-13% of all lung cancer cases in the United States. Etiology is attributed to multiple risk factors including exposure to secondhand smoking, asbestos, environmental pollution, and radon, but these exposures are not within the current eligibility criteria for early lung cancer screening by low-dose computed tomography (LDCT). EXPERIMENTAL DESIGN: Urine samples were collected from two independent cohorts comprising 846 participants (exploratory cohort) and 505 participants (validation cohort). The cancer urinary biomarkers, creatine riboside (CR) and N-acetylneuraminic acid (NANA) were analyzed and quantified using liquid chromatography-mass spectrometry to determine if non-smoker cases can be distinguished from sex and age-matched controls in comparison to tobacco smoker cases and controls, potentially leading to more precise eligibility criteria for LDCT screening. RESULTS: Urinary levels of CR and NANA were significantly higher and comparable in non-smokers and tobacco smoker cases as compared to population controls in both cohorts. Receiver Operating Characteristics (ROC) analysis for combined CR and NANA levels in non-smokers of the exploratory cohort resulted in better predictive performance with the area under the curve (AUC) of 0.94, whereas the validation cohort non-smokers had an AUC of 0.80. Kaplan-Meier survival curves showed that high levels of CR and NANA were associated with increased cancer-specific death in non-smokers as well as tobacco smoker cases in both cohorts. CONCLUSIONS: Measuring CR and NANA in urine liquid biopsies could identify non-smokers at high risk for lung cancer as candidates for LDCT screening and warrant prospective studies of these biomarkers.

Global patterns in small-scale cannabis growers' distribution practices: Exploring the grower-distributor nexus.

BACKGROUND: While the supply of cannabis is commonly assumed to be dominated by criminal gangs, a sizable share of the domestic cannabis supply is provided by small-scale growers. This article examines the nature and scope of small-scale growers' distribution practices, with a particular focus on cross-country differences and variations between different types of grower-distributors, i.e., "non-suppliers", "exclusive social suppliers", "sharers and sellers" and "exclusive sellers". METHODS: Based on a large convenience web survey sample of predominantly small-scale cannabis growers from 18 countries, this article draws on data from two subsamples. The first subsample includes past-year growers in all 18 countries who answered questions regarding their market participation (n = 8,812). The second subsample includes past-year growers in 13 countries, who answered additional questions about their supply practices (n = 2,296). RESULTS: The majority of the cannabis growers engaged in distribution of surplus products, making them in effect "grower-distributors". Importantly, many did so as a secondary consequence of growing, and social supply (e.g., sharing and gifting) is much more common than selling. While growers who both shared and sold ("sharers and sellers"), and especially those who only sold ("exclusive sellers"), grew a higher number of plants and were most likely to grow due to a wish to sell for profits, the majority of these are best described as small-scale sellers. That is, the profit motive for growing was often secondary to non-financial motives and most sold to a limited number of persons in their close social network. CONCLUSION: We discuss the implications of the findings on the structural process of import-substitution in low-end cannabis markets, including a growing normalization of cannabis supply.

Simultaneous estimation of genotype error and uncalled deletion rates in whole genome sequence data.

Genotype data include errors that may influence conclusions reached by downstream statistical analyses. Previous studies have estimated genotype error rates from discrepancies in human pedigree data, such as Mendelian inconsistent genotypes or apparent phase violations. However, uncalled deletions, which generally have not been accounted for in these studies, can lead to biased error rate estimates. In this study, we propose a genotype error model that considers both genotype errors and uncalled deletions when calculating the likelihood of the observed genotypes in parent-offspring trios. Using simulations, we show that when there are uncalled deletions, our model produces genotype error rate estimates that are less biased than estimates from a model that does not account for these deletions. We applied our model to SNVs in 77 sequenced White British parent-offspring trios in the UK Biobank. We use the Akaike information criterion to show that our model fits the data better than a model that does not account for uncalled deletions. We estimate the genotype error rate at SNVs with minor allele frequency > 0.001 in these data to be [Formula: see text]. We estimate that 77% of the genotype errors at these markers are attributable to uncalled deletions [Formula: see text].

CRISPR-Cas13b-mediated suppression of hepatitis B virus replication and protein expression.

BACKGROUND & AIMS: New antiviral approaches are urgently required that target multiple aspects of the hepatitis B virus (HBV) replication cycle to improve rates of functional cure. HBV RNA represents a novel therapeutic target. Here, we programmed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas13b endonuclease, to specifically target the HBV pregenomic RNA (pgRNA) and viral mRNAs in a novel approach to reduce HBV replication and protein expression. METHODS: Cas13b CRISPR RNAs (crRNAs) were designed to target multiple regions of HBV pgRNA. Mammalian cells with replication competent wildtype HBV DNA of different genotypes, a HBV stable cell line, a HBV infection model and a hepatitis B surface antigen (HBsAg)-expressing stable cell line were transfected with PspCas13b-blue fluorescent protein (BFP) and crRNAs plasmids and the impact on HBV replication and protein expression was measured. WT HBV DNA, PspCas13b-BFP and crRNA plasmids were simultaneously hydrodynamically injected into mice, and sera HBsAg was measured. PspCas13b mRNA and crRNA were also delivered by lipid nanoparticles (LNP) in a HBsAg-expressing stable cell line and the impact on secreted HBsAg determined. RESULTS: Our HBV targeting crRNAs strongly suppressed HBV replication and protein expression in mammalian cells by up to 96% (p<0.0001). HBV protein expression was also reduced in an HBV stable cell line and in the HBV infection model. CRISPR-Cas13b crRNAs reduced HBsAg expression by 50% (p<0.0001) in vivo. LNP-encapsulated PspCas13b mRNA reduced secreted HBsAg by 87% (p=0.0168) in a HBsAg-expressing stable cell line. CONCLUSIONS: Together, these results show that CRISPR-Cas13b can be programmed to specifically target and degrade HBV RNAs to reduce HBV replication and protein expression, demonstrating its potential as a novel therapeutic option for chronic HBV infection. IMPACT AND IMPLICATIONS: There is an urgent need for new treatments that target multiple aspects of the HBV replication cycle. Here, we present CRISPR-Cas13b as a novel strategy to target HBV replication and protein expression paving the way for its development as a potential new treatment option for patients living with chronic hepatitis B.

Perceptions of Academic Grief in Baccalaureate Nursing Programs: An Instrument Development Study.

Background and Purpose: Nursing students and graduates experience grief when not achieving curricular benchmarks or passing the NCLEX-RN. This study developed the perceptions of academic grief (PAG) instrument for baccalaureate nursing program completers experiencing academic failure. Methods: Content analysis methods generated items and achieved face validity. Focus group interview and experts' judgment of item relevance established content validity. A purposeful sample of registered nurses (RNs) and nursing students (N = 70) completed the pilot test on the 40-item instrument. Results: The highest ranked items included being disappointed, trying again to prove they could become a nurse, life investment in nursing school, and fear of failing again. The Cronbach's alpha coefficient was .94. Conclusions: The instrument was developed to measure nursing students' and RNs' academic grief. The PAG showed beginning reliability and validity and needs additional testing.

A Chinese version of the infertility self-efficacy scale: Reliability and validity assessment.

Objective: To translate, cross-culturally adapt and test the reliability and validity of a Chinese version of the Infertility Self-Efficacy scale. Methods: The Infertility Self-Efficacy (ISE) scale was translated into Chinese using forward and backward translations, expert consultation, cognitive interviews and a pilot study. To test the scale's reliability and validity, 515 infertile women in two hospitals were recruited to evaluate the Chinese version of the scale. Content validity was assessed by means of expert consultation. Exploratory factor and confirmatory factor analyses were performed using SPSS 26.0 and Amos 24.0. Reliability tests of the scale included Cronbach's alpha coefficient, split-half reliability and test-retest reliability. Results: The Chinese version of the ISE scale contains 16 items and one dimension. Content validity of the scale was 0.96. Results of exploratory factor analysis suggested that the one factor model was suitable for the scale, and factor loading of all items was greater than 0.4. Model fitting parameters of confirmatory factor analysis of the ISE scale were χ2/df = 2.710, Root Mean Square Error Approximation (RMSEA) = 0.079, Standardized Root Mean Square Residual (SRMR) = 0.042, Comparative Fit Index (CFI) = 0.953, and Tucker-Lewis Index (TLI) = 0.939. Cronbach's alpha coefficient of the Chinese ISE was 0.980; split-half coefficient was 0.972 and retest reliability was 0.848 (P < 0.01). Conclusion: The Chinese ISE scale is a reliable and valid instrument to evaluate the self-efficacy of infertile Chinese women.

The roles of the kynurenine pathway in COVID-19 neuropathogenesis.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the highly contagious respiratory disease Corona Virus Disease 2019 (COVID-19) that may lead to various neurological and psychological disorders that can be acute, lasting days to weeks or months and possibly longer. The latter is known as long-COVID or more recently post-acute sequelae of COVID (PASC). During acute COVID-19 infection, a strong inflammatory response, known as the cytokine storm, occurs in some patients. The levels of interferon-γ (IFN-γ), interferon-ß (IFN-ß), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-α) are particularly increased. These cytokines are known to activate the enzyme indoleamine 2,3-dioxygenase 1 (IDO-1), catalysing the first step of tryptophan (Trp) catabolism through the kynurenine pathway (KP) leading to the production of several neurotoxic and immunosuppressive metabolites. There is already data showing elevation in KP metabolites both acutely and in PASC, especially regarding cognitive impairment. Thus, it is likely that KP involvement is significant in SARS-CoV-2 pathogenesis especially neurologically.

Understanding adherence to continuous positive airway pressure in patients with obstructive sleep apnea post-stroke: A prospective study based on the Andersen model.

Adherence to continuous positive airway pressure (CPAP) in patients with obstructive sleep apnea (OSA) post-stroke is often problematic, despite potential benefits. This study aimed to evaluate CPAP adherence in patients with OSA post-stroke based on the Andersen behavioral model of health services utilization. A total of 227 eligible participants were recruited from a Chinese hospital. After baseline assessment, participants were followed for 6 months to determine short-term CPAP adherence. Those with good short-term adherence were followed for an additional 6 months to explore long-term adherence and influencing factors. Short-term CPAP adherence rate was 33%. Being married or living with a partner, having an associate degree or baccalaureate degree or higher, and stronger health beliefs independently predicted short-term CPAP adherence. Only 25% of participants from the adherent group showed good long-term adherence. The factor associated with long-term CPAP adherence was participants not using alcohol. Adherence to CPAP is suboptimal among patients having OSA post-stroke. Addressing unfavorable predisposing factors and modifying health beliefs are suggested.

Prevalence and burden of difficult-to-treat and severe asthma in Australia: A national population survey.

BACKGROUND AND OBJECTIVE: Most evidence about difficult-to-treat and severe asthma (DTTA) comes from clinical trials and registries. We aimed to identify people with DTTA from a large nationally representative asthma population and describe their characteristics and healthcare utilization compared with people whose asthma was not 'difficult-to-treat'. METHODS: We conducted a cross-sectional survey of Australians aged ≥18 years with current asthma from large web-based survey panels. Enrolment was stratified by gender, age-group and state/territory based on national population data for people with asthma. Difficult-to-treat or severe asthma was defined by poor symptom control, exacerbations and/or oral corticosteroid/biologic use despite medium/high-dose inhaled therapy. Outcomes included exacerbations, healthcare utilization, multimorbidity, quality of life and coronavirus disease of 2019 (COVID-19)-related behaviour. Weighted data were analysed using SAS version 9.4. RESULTS: The survey was conducted in February-March 2021. The weighted sample comprised 6048 adults with current asthma (average age 47.3 ± SD 18.1 years, 59.9% female), with 1313 (21.7%) satisfying ≥1 DTTA criteria. Of these, 50.4% had very poorly controlled symptoms (Asthma Control Test ≤15), 36.2% were current smokers, and 85.4% had ≥1 additional chronic condition, most commonly anxiety/depression. More than twice as many participants with DTTA versus non-DTTA had ≥1 urgent general practitioner (GP) visit (61.4% vs. 27.5%, OR 4.8 [4.2-5.5, p < 0.0001]), or ≥1 emergency room visit (41.9% vs. 17.9%, OR 3.8 [3.3-4.4, p < 0.0001]) in the previous 12 months. CONCLUSION: Our findings emphasize the burden of uncontrolled symptoms, current smoking, multimorbidity and healthcare utilization in people with DTTA in the community, who may be under-represented in registries or clinical trials.

Adjusting for principal components can induce spurious associations in genome-wide association studies in admixed populations.

Principal component analysis (PCA) is widely used to control for population structure in genome-wide association studies (GWAS). Top principal components (PCs) typically reflect population structure, but challenges arise in deciding how many PCs are needed and ensuring that PCs do not capture other artifacts such as regions with atypical linkage disequilibrium (LD). In response to the latter, many groups suggest performing LD pruning or excluding known high LD regions prior to PCA. However, these suggestions are not universally implemented and the implications for GWAS are not fully understood, especially in the context of admixed populations. In this paper, we investigate the impact of pre-processing and the number of PCs included in GWAS models in African American samples from the Women's Women's Health Initiative SNP Health Association Resource and two Trans-Omics for Precision Medicine Whole Genome Sequencing Project contributing studies (Jackson Heart Study and Genetic Epidemiology of Chronic Obstructive Pulmonary Disease Study). In all three samples, we find the first PC is highly correlated with genome-wide ancestry whereas later PCs often capture local genomic features. The pattern of which, and how many, genetic variants are highly correlated with individual PCs differs from what has been observed in prior studies focused on European populations and leads to distinct downstream consequences: adjusting for such PCs yields biased effect size estimates and elevated rates of spurious associations due to the phenomenon of collider bias. Excluding high LD regions identified in previous studies does not resolve these issues. LD pruning proves more effective, but the optimal choice of thresholds varies across datasets. Altogether, our work highlights unique issues that arise when using PCA to control for ancestral heterogeneity in admixed populations and demonstrates the importance of careful pre-processing and diagnostics to ensure that PCs capturing multiple local genomic features are not included in GWAS models.

Theoretical approaches in the development of interventions to promote breastfeeding: A scoping review.

PROBLEM AND BACKGROUND: There is a low world rate of exclusive breastfeeding and a short duration of breastfeeding. More studies have constructed interventions to improve breastfeeding behavior, but the actual effect is not significant. AIM: The purpose of this review is identifying the ways that various theories have an influence on theory-based breastfeeding intervention studies. METHODS: A scoping review using Arksey and O'Malley's framework explored breastfeeding promotion practices. PubMed, The Cochrane Library, Web of Science, Embase, and CINAHL databases were searched from database creation to March 9, 2024. Building on previous research, key terms were used to search the literature. Data analysis involved descriptive and interpretive summaries of theories used and the proposed interventions. FINDINGS: An online search yielded 906 articles, with 28 meeting the inclusion criteria for the scoping review, including 5 reviews and 23 articles. Reviews demonstrated that interventions based on theories were more effective. Articles promoting breastfeeding used theories of self-efficacy (n = 9), theory of planned behavior (n = 8), social cognitive theory (n = 5) and individual and family self-management theory (n = 1). These theories were used in developing specific content of the intervention program (n = 20, 86.9%), constructing the framework of the program (n = 10, 43.5%), and evaluating outcomes (n = 19, 82.6%). Most interventions focused on education, professional support, and/or peer support for breastfeeding. CONCLUSION AND DISCUSSION: Theory can guide decisions and play a role in selecting a methodology or lens. Researchers should make deliberate choices in the use of a theory that relates to aspects of breastfeeding behavior. Future interventions based on theories should be more varied and effective and need to consider families' and social factors.

Relationships Between Anxiety, Attention, and Reading Performance in Children.

Many studies link anxiety in children with reading difficulties, but some facets of anxiety have been found to be positively associated with reading achievement. Attentional Control Theory offers a potential explanation for these seemingly contradictory findings, positing that anxiety can both interfere in attentional processes and enhance effort and use of compensatory processing strategies. The current study examines the relationships between anxiety, attentional control, and reading performance (word reading/decoding and passage comprehension) in a racially-diverse sample of 251 s-grade students, 152 of whom had not met reading benchmarks using screening measures. Results showed that harm avoidance was positively associated with reading performance and physical symptoms of anxiety were negatively associated with reading performance. These links were attenuated when including attentional control in the model, suggesting mediation and lending support to Attentional Control Theory. Further research is needed to confirm causal mediation effects between anxiety, attentional control, and reading performance.

A New Look at Resilience in Nursing Students: Stress, Social Media, and Student Athletes.

ABSTRACT: Resilience in nursing students is important for academic and practice success and a necessary subcompetency in the American Association of Colleges of Nursing 2021 Essentials. This study examined levels of resilience and identified related factors in prelicensure nursing students. Data were collected via an online survey that included a descriptive questionnaire with resilience and stress scales. Significant findings include negative relationships between resilience and stress, and resilience and social media use; positive relationships between stress and social media use, specifically TikTok use; and high resilience levels in student athletes. Specific implications for nursing education and future research are discussed.

Transient loss of satiety effects of leptin in middle-aged male mice.

Extensive research is undertaken in rodents to determine the mechanism underlying obesity-induced leptin resistance. While body weight is generally tightly controlled in these studies, the effect of age of experimental animals has received less attention. Specifically, there has been little investigation into leptin regulation of food intake in middle-aged animals, which is a period of particular relevance for weight gain in humans. We investigated whether the satiety effects of leptin remained constant in young (3 months), middle-aged (12 months) or aged (18-22 months) male mice. Although mean body weight increased with age, leptin concentrations did not significantly increase in male mice beyond 12 months of age. Exogenous leptin administration led to a significant reduction in food intake in young mice but had no effect on food intake in middle-aged male mice. This loss of the satiety effect of leptin appeared to be transient, with leptin administration leading to the greatest inhibition of food intake in the aged male mice. Subsequently, we investigated whether these differences were due to changes in leptin transport into the brain with ageing. No change in leptin clearance from the blood or transport into the brain was observed, suggesting the emergence of central resistance to leptin in middle age. These studies demonstrate the presence of dynamic and age-specific changes in the satiety effects of leptin in male mice and highlight the requirement for age to be carefully considered when undertaking metabolic studies in rodents.