Ethylene Polymerizations Catalyzed by Fluorinated "Sandwich" Diimine-Nickel and Palladium Complexes.

Nickel and palladium complexes bearing "sandwich" diimine ligands with perfluorinated aryl caps have been synthesized, characterized, and explored in ethylene polymerization reactions. The X-ray crystallographic analysis of the precatalysts 16 and 6b shows differences from their nonfluorinated analogues 17 and 19, with the perfluorinated aryl caps centered precisely over the nickel and palladium centers, which results in higher buried volumes of the metal centers relative to the nonfluorinated analogues. The sandwich diimine-palladium complexes 5a and 5b containing perfluorinated aryl caps polymerize ethylene in a controlled fashion with activities that are substantially increased compared with their nonfluorinated analogues. Migratory insertion rates in relevant methyl ethylene complexes agree with the activities exhibited in bulk polymerization experiments. DFT studies suggest that facility of ethylene rotation from its preferred orientation perpendicular to the Pd-alkyl bond into a parallel in-plane conformation contributes to the higher polymerization activity for 5b relative to 18a. For these palladium systems, polymer molecular weights can be controlled via hydrogen addition (hydrogenolysis), which is unusual for late-transition-metal-catalyzed olefin polymerizations with no catalyst deactivation occurring. Sandwich diimine-nickel complexes 6a and 6b with perfluorinated aryl caps show ethylene polymerization activities that are about half of those of classical tetraisopropyl-substituted catalyst 2 but again are more active than the analogous nonfluorinated sandwich complexes. Ethylene polymerizations exhibit living behavior, and branched ultrahigh-molecular-weight polyethylenes (UHMWPEs) with very low-molecular-weight distributions (less than 1.1) are obtained. The activated nickel catalysts are stable in the absence of monomer and show good long-term stability at 25 °C.

The long-run effects of financial development on income inequality: Evidence from the Asia-Pacific countries.

Income inequality is a vexing developmental challenge for governments and policymakers as it impedes social transformation and economic growth and development. Meanwhile, promoting financial development is generally regarded as an effective way to achieve inclusive and sustainable growth. This study examines the long-run effects of financial development, economic growth, and their combined effects on income inequality for 12 Asia-Pacific countries from 1990 to 2021. This paper employs various econometric techniques and different financial development proxies to ensure the findings' robustness. The paper also constructs a financial development index using the principal component analysis to fully capture the comprehensive effect of financial development on income inequality. Empirical results reveal that the impact of financial development on income inequality follows the inverted U-shaped relationship - financial development widens income inequality and only reduces income when surpassing its turning point. Findings further reveal that the nonlinear effect of financial development on income inequality is contingent upon the level of per capita income. Thus, policies promoting financial development to reduce income inequality should consider the existing level of per capita income.

Oral cavity cancer in young, non-smoking, and non-drinking patients: A contemporary review.

Oral squamous cell carcinoma (OSCC) in non-smoking and non-drinking (NSND) individuals appears to be distinct from the traditional head and neck squamous cell carcinoma (HNSCC). The incidence of this subset is increasing, as are the number of studies examining its characteristics. NSND OSCC individuals tend to be younger (<45 years) compared to traditional HNSCC patients. The proportion of females in the NSND OSCC cohort is also higher. The tongue is the predominantly affected subsite. Studies have revealed several gene mutations and unique epigenomic profiles but no definitive genetic etiology. Transcriptomic analysis has not found any causative viral agents. Other proposed etiologies include chronic dental trauma, microbiome abnormalities, marijuana consumption, and genetic disorders. There are international efforts to determine the relative prognostic outcome of this unique cohort, but no consensus has been reached. Here, we review the incidence, demographics, subsite, possible etiologies, prognosis, and therapy implications of the NSND OSCC cohort.

Does ignoring transmission dynamics lead to underestimation of the impact of interventions against mosquito-borne disease?

New vector-control technologies to fight mosquito-borne diseases are urgently needed, the adoption of which depends on efficacy estimates from large-scale cluster-randomised trials (CRTs). The release of Wolbachia-infected mosquitoes is one promising strategy to curb dengue virus (DENV) transmission, and a recent CRT reported impressive reductions in dengue incidence following the release of these mosquitoes. Such trials can be affected by multiple sources of bias, however. We used mathematical models of DENV transmission during a CRT of Wolbachia-infected mosquitoes to explore three such biases: human movement, mosquito movement and coupled transmission dynamics between trial arms. We show that failure to account for each of these biases would lead to underestimated efficacy, and that the majority of this underestimation is due to a heretofore unrecognised bias caused by transmission coupling. Taken together, our findings suggest that Wolbachia-infected mosquitoes could be even more promising than the recent CRT suggested. By emphasising the importance of accounting for transmission coupling between arms, which requires a mathematical model, we highlight the key role that models can play in interpreting and extrapolating the results from trials of vector control interventions.

Small molecule allosteric modulation of the adenosine A1 receptor.

G protein-coupled receptors (GPCRs) represent the target for approximately a third of FDA-approved small molecule drugs. The adenosine A1 receptor (A1R), one of four adenosine GPCR subtypes, has important (patho)physiological roles in humans. A1R has well-established roles in the regulation of the cardiovascular and nervous systems, where it has been identified as a potential therapeutic target for a number of conditions, including cardiac ischemia-reperfusion injury, cognition, epilepsy, and neuropathic pain. A1R small molecule drugs, typically orthosteric ligands, have undergone clinical trials. To date, none have progressed into the clinic, predominantly due to dose-limiting unwanted effects. The development of A1R allosteric modulators that target a topographically distinct binding site represent a promising approach to overcome current limitations. Pharmacological parameters of allosteric ligands, including affinity, efficacy and cooperativity, can be optimized to regulate A1R activity with high subtype, spatial and temporal selectivity. This review aims to offer insights into the A1R as a potential therapeutic target and highlight recent advances in the structural understanding of A1R allosteric modulation.

Microplastics and trace metals in river sediment: Prevalence and correlation with multiple factors.

Microplastics (MPs), which are ubiquitous, are no longer novel emerging pollutants, yet our knowledge of them is insufficient. This study investigates the prevalence of MPs and trace metals in sediment belonging to Ma River, Vietnam, and their interaction with various parameters, including nutrients such as total carbon (TC), total nitrogen (TN), and total phosphorus (TP), grain sizes, and MPs in surface water. The study revealed that the abundance of MPs in sediment (MPs/S) is relatively high (i.e., 1328.3 ± 1925.5 items.kg-1 dry weight), while the concentration of MPs in surface water (MPs/W) was relatively low (i.e., 57.3 ± 55.8 items.m-3) compared to other areas. Notably, the study found that arsenic and cadmium concentrations exceeded baseline levels, indicating their anthropogenic origin. To interpret the relationship between MPs/S, metals, and the aforementioned parameters, principal component analysis and Pearson correlation analyses were employed. The results demonstrated a significant correlation between metals and nutrients, as well as small grain sizes such as clay and silt. It was observed that the majority of metals displayed co-occurrence with one another but showed weak associations with the levels of MPs present in both water and sediment. Additionally, a weak correlation was observed between MPs/W and MPs/S. In conclusion, these findings suggest that the distribution and behavior of MPs and trace metals in aquatic systems are influenced by multiple factors, including nutrient levels, grain size, and other chemical and physical characteristics of the environment. While certain metals may have natural sources, others may result from human activities such as mining, industrial discharge, and wastewater treatment plants. As a result, understanding the sources and aspects of metal contamination are critical for determining their relationship with MPs and developing effective strategies for mitigating their impact on aquatic ecosystems.

Expected endpoints from future chikungunya vaccine trial sites informed by serological data and modeling.

In recent decades, there has been an increased interest in developing a vaccine for chikungunya. However, due to its unpredictable transmission, planning for a chikungunya vaccine trial is challenging. To inform decision making on the selection of sites for a vaccine efficacy trial, we developed a new framework for projecting the expected number of endpoint events at a given site. In this framework, we first accounted for population immunity using serological data collated from a systematic review and used it to estimate parameters related to the timing and size of past outbreaks, as predicted by an SIR transmission model. Then, we used that model to project the infection attack rate of a hypothetical future outbreak, in the event that one were to occur at the time of a future trial. This informed projections of how many endpoint events could be expected if a trial were to take place at that site. Our results suggest that some sites may have sufficient transmission potential and susceptibility to support future vaccine trials, in the event that an outbreak were to occur at those sites. In general, we conclude that sites that have experienced outbreaks within the past 10 years may be poorer targets for chikungunya vaccine efficacy trials in the near future. Our framework also generates projections of the numbers of endpoint events by age, which could inform study participant recruitment efforts.

A domain-knowledge modeling of hospital-acquired infection risk in Healthcare personnel from retrospective observational data: A case study for COVID-19.

INTRODUCTION: Hospital-acquired infections of communicable viral diseases (CVDs) have been posing a tremendous challenge to healthcare workers globally. Healthcare personnel (HCP) is facing a consistent risk of viral infections, and subsequently higher rates of morbidity and mortality. MATERIALS AND METHODS: We proposed a domain-knowledge-driven infection risk model to quantify the individual HCP and the population-level risks. For individual-level risk estimation, a time-variant infection risk model is proposed to capture the transmission dynamics of CVDs. At the population-level, the infection risk is estimated using a Bayesian network model constructed from three feature sets, including individual-level factors, engineering control factors, and administrative control factors. For model validation, we investigated the case study of the Coronavirus disease, in which the individual-level and population-level infection risk models were applied. The data were collected from various sources such as COVID-19 transmission databases, health surveys/questionaries from medical centers, U.S. Department of Labor databases, and cross-sectional studies. RESULTS: Regarding the individual-level risk model, the variance-based sensitivity analysis indicated that the uncertainty in the estimated risk was attributed to two variables: the number of close contacts and the viral transmission probability. Next, the disease transmission probability was computed using a multivariate logistic regression applied for a cross-sectional HCP data in the UK, with the 10-fold cross-validation accuracy of 78.23%. Combined with the previous result, we further validated the individual infection risk model by considering six occupations in the U.S. Department of Labor O*Net database. The occupation-specific risk evaluation suggested that the registered nurses, medical assistants, and respiratory therapists were the highest-risk occupations. For the population-level risk model validation, the infection risk in Texas and California was estimated, in which the infection risk in Texas was lower than that in California. This can be explained by California's higher patient load for each HCP per day and lower personal protective equipment (PPE) sufficiency level. CONCLUSION: The accurate estimation of infection risk at both individual level and population levels using our domain-knowledge-driven infection risk model will significantly enhance the PPE allocation, safety plans for HCP, and hospital staffing strategies.

Probative Evidence and Quantitative Energetics for the Unimolecular Mechanism of the 1,5-Sigmatropic Hydrogen Shift of Cyclopentadiene.

While the 1,5-sigmatropic hydrogen shift in cyclopentadiene is generally thought to be a unimolecular pericyclic reaction, Yamabe proposed a more complex bimolecular mechanism proceeding through the exo dimer of cyclopentadiene. DFT computations by Yamabe were claimed to show that the bimolecular mechanism was kinetically more favorable than the unimolecular mechanism. Reinvestigation of the unimolecular concerted mechanism and Yamabe's bimolecular mechanism with ωB97X-D and DLPNO-CCSD(T) calculations demonstrates a 25 kcal/mol preference for the unimolecular mechanism relative to the bimolecular mechanism. While Yamabe's calculations were performed with the less accurate B3LYP functional, the incorrect conclusion was the result of a different error discovered here. We have also computed corrections for tunneling that result in computed activation barriers within 1.5 kcal/mol of the experimental values.

Projecting vaccine demand and impact for emerging zoonotic pathogens.

BACKGROUND: Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. METHODS: We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies to assess sustainable vaccine manufacturing needs, vaccine stockpile requirements, and the potential impact of the outbreak response. This framework incorporates geographically variable zoonotic spillover rates, human-to-human transmission, and the implementation of reactive vaccination campaigns in response to disease outbreaks. As proof of concept, we applied the framework to four priority pathogens: Lassa virus, Nipah virus, MERS coronavirus, and Rift Valley virus. RESULTS: Annual vaccine regimen requirements for a population-wide strategy ranged from > 670,000 (95% prediction interval 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. CONCLUSIONS: Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios. Uncertainties in our model estimates highlight several knowledge gaps that need to be addressed to target vulnerable populations more accurately. These include surveillance gaps that mask the true geographic distribution of each pathogen, details of key routes of spillover from animal reservoirs to humans, and the role of human-to-human transmission outside of healthcare settings. In addition, our estimates are based on the current epidemiology of each pathogen, but pathogen evolution could alter vaccine stockpile requirements.

Economic growth, renewable energy and financial development in the CPTPP countries.

The trade agreement is generally considered an effective mechanism to encourage trading activities. However, trade activities may lead to environmental degradation because more trade is generally associated with more energy consumption. In addition, financial development with an increased flow of capital among members is required to fund trading activities. Renewable energy can be a moderating factor to balance the effects of trade activities and financial development on the economy and the environment. This paper focuses on the inter-relationship between growth-energy-finance nexus for the CPTPP members in the 1971-2020 period. While the energy-growth-environment nexus has been extensively investigated, the energy-growth-finance relationship has been largely ignored in existing literature, particularly for the CPTPP countries. Our findings can be summarized as follows. First, we find that renewable energy consumption does reduce CO2 emission while financial development does not necessarily increase environmental degradation. Second, financial development is found to cause renewable energy usage bilaterally. Finally, when different proxies are used for financial development, a bilateral causality relationship between renewable energy usage, financial development and economic growth is confirmed. These important findings imply that the governments of the CPTPP countries should encourage renewable energy usage to achieve the dual objectives from the CPTPP trade agreement: (i) to increase trade activities; and (ii) to support further financial development within the region. These two objectives together support economic growth.

Topical vancomycin reduces surgical site infections in patients subjected to craniotomy for primary brain tumor resection: A comprehensive cancer center experience.

BACKGROUND: Craniotomies for resection of neoplastic lesions are at increased risk for surgical site infections (SSIs) as compared to non-neoplastic pathologies. SSIs can be detrimental due to delay in pivotal adjuvant therapies. OBJECTIVE: The purpose of this study was to determine the rate of SSI in primary brain tumors, to analyze risk factors, and to evaluate effectiveness of topical vancomycin in reducing SSIs. METHODS: A retrospective cohort study was conducted at a National Cancer Institutedesignated Comprehensive Cancer Center. Patients with primary brain tumors (n = 799) who were subjected to craniotomy from 2004 to 2014 were included. Patient demographics, tumor characteristics, use of topical vancomycin and clinical outcomes were analyzed. RESULTS: Topical vancomycin was associated with a significantly lower rate of SSI (0.8%) compared to standard care (5%), ( p = 0.00071; OR = 0.15; 95% CI = 0.02 - 0.5). Narcotic use ( p = 0.043; OR = 2.24; 95% CI = 0.96 - 4.81), previous brain radiation ( p = 0.043; OR = 2.08; 95% CI = 1.02 - 4.29), length of hospitalization ( p = 0.01; OR= 1.04; 95% CI = 1.01 - 1.08), and 30 day re-operation ( p = 1.58 ×10 -10; OR = 15.23; 95% CI = 7.06 - 32.71) were associated with increased risk for SSI. CONCLUSION: Topical vancomycin effectively reduced the rate of SSI in patients subjected to craniotomy for primary brain tumor resection. Furthermore, preoperative narcotic use, previous head/brain radiation, length of hospitalization, and 30-day reoperation were associated with increased risk of SSI.

Burden is in the eye of the beholder: Sensitivity of yellow fever disease burden estimates to modeling assumptions.

Estimates of disease burden are important for setting public health priorities. These estimates involve numerous modeling assumptions, whose uncertainties are not always well described. We developed a framework for estimating the burden of yellow fever in Africa and evaluated its sensitivity to modeling assumptions that are often overlooked. We found that alternative interpretations of serological data resulted in a nearly 20-fold difference in burden estimates (range of central estimates, 8.4 × 104 to 1.5 × 106 deaths in 2021­2030). Uncertainty about the vaccination status of serological study participants was the primary driver of this uncertainty. Even so, statistical uncertainty was even greater than uncertainty due to modeling assumptions, accounting for a total of 87% of variance in burden estimates. Combined with estimates that most infections go unreported (range of 95% credible intervals, 99.65 to 99.99%), our results suggest that yellow fever's burden will remain highly uncertain without major improvements in surveillance.

Constructing Saturated Guanidinum Heterocycles by Cycloaddition of N-Amidinyliminium Ions with Indoles.

We report that structurally complex guanidinium heterocycles can be prepared in one step by regio- and stereoselective [4 + 2]-cycloadditions of N-amidinyliminium ions with indoles or benzothiophene. In contrast to reactions of these heterodienes with alkenes, density functional theory (DFT) calculations show that these cycloadditions take place in a concerted asynchronous fashion. The [4 + 2]-cycloaddition of N-amidinyliminium ions (1,3-diaza-1,3-dienes) with indoles and benzothiophene are distinctive, as related [4 + 2]-cycloadditions of N-acyliminium ions (1-oxa-3-aza-1,3-dienes) are apparently unknown.

Impacts of K-12 school reopening on the COVID-19 epidemic in Indiana, USA.

In the United States, schools closed in March 2020 due to COVID-19 and began reopening in August 2020, despite continuing transmission of SARS-CoV-2. In states where in-person instruction resumed at that time, two major unknowns were the capacity at which schools would operate, which depended on the proportion of families opting for remote instruction, and adherence to face-mask requirements in schools, which depended on cooperation from students and enforcement by schools. To determine the impact of these conditions on the statewide burden of COVID-19 in Indiana, we used an agent-based model calibrated to and validated against multiple data types. Using this model, we quantified the burden of COVID-19 on K-12 students, teachers, their families, and the general population under alternative scenarios spanning three levels of school operating capacity (50 %, 75 %, and 100 %) and three levels of face-mask adherence in schools (50 %, 75 %, and 100 %). Under a scenario in which schools operated remotely, we projected 45,579 (95 % CrI: 14,109-132,546) infections and 790 (95 % CrI: 176-1680) deaths statewide between August 24 and December 31. Reopening at 100 % capacity with 50 % face-mask adherence in schools resulted in a proportional increase of 42.9 (95 % CrI: 41.3-44.3) and 9.2 (95 % CrI: 8.9-9.5) times that number of infections and deaths, respectively. In contrast, our results showed that at 50 % capacity with 100 % face-mask adherence, the number of infections and deaths were 22 % (95 % CrI: 16 %-28 %) and 11 % (95 % CrI: 5 %-18 %) higher than the scenario in which schools operated remotely. Within this range of possibilities, we found that high levels of school operating capacity (80-95 %) and intermediate levels of face-mask adherence (40-70 %) resulted in model behavior most consistent with observed data. Together, these results underscore the importance of precautions taken in schools for the benefit of their communities.

Over 100 Years of Rift Valley Fever: A Patchwork of Data on Pathogen Spread and Spillover.

During the past 100 years, Rift Valley fever virus (RVFV), a mosquito-borne virus, has caused potentially lethal disease in livestock, and has been associated with significant economic losses and trade bans. Spillover to humans occurs and can be fatal. Here, we combined data on RVF disease in humans (22 countries) and animals (37 countries) from 1931 to 2020 with seroprevalence studies from 1950 to 2020 (n = 228) from publicly available databases and publications to draw a more complete picture of the past and current RVFV epidemiology. RVFV has spread from its original locus in Kenya throughout Africa and into the Arabian Peninsula. Throughout the study period seroprevalence increased in both humans and animals, suggesting potentially increased RVFV exposure. In 24 countries, animals or humans tested positive for RVFV antibodies even though outbreaks had never been reported there, suggesting RVFV transmission may well go unnoticed. Among ruminants, sheep were the most likely to be exposed during RVF outbreaks, but not during periods of cryptic spread. We discuss critical data gaps and highlight the need for detailed study descriptions, and long-term studies using a one health approach to further convert the patchwork of data to the tale of RFV epidemiology.

Management trends and outcomes of pineal germinoma in a multi-institutional Australian cohort.

Pineal germinoma is rare with high cure rates following craniospinal radiotherapy. Efforts to reduce the radiotherapy dose and field via combination with chemotherapy suggest comparable disease control and reduced neurocognitive impairments, while the efficacy of immunotherapy in pineal germinoma remains undetermined. This report aimed to review clinical outcomes in patients treated for pineal germinoma in Queensland, Australia, and assess for Programmed Death-Ligand1 (PD-L1) expression. Patients who commenced radiation and/or chemotherapy for pineal germinoma from 2005 to 2017 were retrospectively identified using Queensland Oncology Online database. Demographic, diagnostic, treatment, and outcome data was obtained from electronic medical records. PD-L1 immuno-histochemistry was performed on available specimens. Eighteen patients with long-term follow-up data were identified. Median age at diagnosis was 16.8 years (range 9-46 years). Diagnosis was made histologically in fifteen patients, and radiologically in three. All patients underwent radiotherapy (median 36 Gy (range 21-54 Gy)) with lower median dose delivered with whole ventricle irradiation (12/18patients) than craniospinal irradiation (5/18patients). Sixteen patients received chemotherapy preceding radiotherapy. All patients are alive at median 7.25 years from primary treatment completion (range 2.03-13.1 years). Relapse occurred in three patients (16.67%) following treatment response, all of whom achieved remission following high-dose chemotherapy with stem-cell support and craniospinal radiotherapy. Post-treatment functional outcomes were similarly excellent. PD-L1 expression was low (1-49% cells) or negative in 87% of tumours tested but results were confounded by specimen quality and availability. Reduced-dose radiotherapy with chemotherapy does not compromise outcome and is standard of care at this institution. Immunotherapy is unlikely to become standard treatment in the near future.

Targeting KRAS4A splicing through the RBM39/DCAF15 pathway inhibits cancer stem cells.

The commonly mutated human KRAS oncogene encodes two distinct KRAS4A and KRAS4B proteins generated by differential splicing. We demonstrate here that coordinated regulation of both isoforms through control of splicing is essential for development of Kras mutant tumors. The minor KRAS4A isoform is enriched in cancer stem-like cells, where it responds to hypoxia, while the major KRAS4B is induced by ER stress. KRAS4A splicing is controlled by the DCAF15/RBM39 pathway, and deletion of KRAS4A or pharmacological inhibition of RBM39 using Indisulam leads to inhibition of cancer stem cells. Our data identify existing clinical drugs that target KRAS4A splicing, and suggest that levels of the minor KRAS4A isoform in human tumors can be a biomarker of sensitivity to some existing cancer therapeutics.

Seeking Help From Formal Sources Among Teen Dating Violence Victims: Exploring the Role of Incident and Victim Characteristics.

Most teen dating violence (TDV) victims do not seek help after their victimization experience. While research has identified that victims are more likely to turn to informal versus formal sources, there is a lack of knowledge about what factors are predictive of help-seeking from formal sources. The current study explored the impact of incident and victim characteristics on help-seeking from formal sources among middle and high school TDV victims (N = 2,174). Findings indicate that the severity and location of the victimization significantly increase the likelihood of help-seeking from formal sources.