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Organochlorine (OC) contaminant concentrations in tissues and lipid profiles in blubber are summarised for 101 gray whales (Eschrichtius robustus) from the eastern North Pacific stock. Samples were obtained from presumably healthy gray whales during a 1994 subsistence hunt in the Russian Arctic (n = 17) and also from biopsy sampling of live animals from the Washington coast (n = 38). In addition, tissues were collected from two groups of animals (1988-1991, n = 22; and 1999, n = 24) that stranded along the west coast of the USA. These whales represent a diverse group of animals with respect to lipid stores, age, gender, health and reproductive status. Information about these biological factors is necessary before contaminant concentration data can be properly interpreted. Differences in blubber lipid levels and profiles were examined among these groups of whales. Significantly higher lipid levels were found in the blubber of subsistence animals that were sampled following summer feeding in the Bering and Chukchi Seas, compared to lipid levels in the biopsied and stranded animals. Lipid class profiles from blubber of presumably healthy gray whales (i.e. from subsistence and biopsy sampling) contained primarily triglycerides and were very different from those of stranded animals that showed lipid decomposition (increased proportions of free fatty acids, cholesterol and phospholipids). Furthermore, lipid class profiles were found to be a means of estimating the quality of a blubber sample from stranded cetaceans. An examination of how biological factors (e.g. gender, reproductive status, age) contribute to interpreting the differences found in contaminant concentrations among the gray whales was also undertaken. Although not statistically significant, higher (OC) concentrations were found in males compared to females, thus suggesting the tendency of the mother to shift her contaminant burden to her calf during gestation and lactation. Results also indicated that there was no significant increase in concentrations of contaminants in the blubber with increase in length (surrogate for age). Higher concentrations of OC contaminants were found in stranded juvenile gray whales, compared to juvenile subsistence whales, and were thought to result from retention of OCs in blubber of the stranded animals as lipid stores are mobilised for energy and total lipid levels decrease, rather than from a difference in diet or feeding areas. OC concentrations in various tissues (blubber, liver, kidney, muscle, brain) were similar on a lipid weight basis, except for brain, which had lower lipid-adjusted OCs because the blood-brain barrier limits contaminant transfer.

Neuronal activity propagates through the network during seizures, engaging brain dynamics at multiple scales. Such propagating events can be described through the avalanches framework, which can relate spatiotemporal activity at the microscale with global network properties. Interestingly, propagating avalanches in healthy networks are indicative of critical dynamics, where the network is organized to a phase transition, which optimizes certain computational properties. Some have hypothesized that the pathologic brain dynamics of epileptic seizures are an emergent property of microscale neuronal networks collectively driving the brain away from criticality. Demonstrating this would provide a unifying mechanism linking microscale spatiotemporal activity with emergent brain dysfunction during seizures. Here, we investigated the effect of drug-induced seizures on critical avalanche dynamics, usingin vivowhole-brain two-photon imaging of GCaMP6s larval zebrafish (males and females) at single neuron resolution. We demonstrate that single neuron activity across the whole brain exhibits a loss of critical statistics during seizures, suggesting that microscale activity collectively drives macroscale dynamics away from criticality. We also construct spiking network models at the scale of the larval zebrafish brain, to demonstrate that only densely connected networks can drive brain-wide seizure dynamics away from criticality. Importantly, such dense networks also disrupt the optimal computational capacities of critical networks, leading to chaotic dynamics, impaired network response properties and sticky states, thus helping to explain functional impairments during seizures. This study bridges the gap between microscale neuronal activity and emergent macroscale dynamics and cognitive dysfunction during seizures.SIGNIFICANCE STATEMENTEpileptic seizures are debilitating and impair normal brain function. It is unclear how the coordinated behavior of neurons collectively impairs brain function during seizures. To investigate this we perform fluorescence microscopy in larval zebrafish, which allows for the recording of whole-brain activity at single-neuron resolution. Using techniques from physics, we show that neuronal activity during seizures drives the brain away from criticality, a regime that enables both high and low activity states, into an inflexible regime that drives high activity states. Importantly, this change is caused by more connections in the network, which we show disrupts the ability of the brain to respond appropriately to its environment. Therefore, we identify key neuronal network mechanisms driving seizures and concurrent cognitive dysfunction.

Inland ships are an important source of NOx, especially for cities along busy waterways. The amount and effect of such emissions depend on the traffic density and NOx emission rates of individual vessels. Ship emission rates are typically derived using in situ land measurements in relation to NOx emission factors (e.g. the number of pollutants emitted by ships per unit of burnt fuel). In this study, a different approach is taken, and NOx emission rates are obtained (in g s−1). Within the EU LIFE project, CLean INland SHipping (CLINSH), a new approach to calculating the NOx emission rates from data of in situ measurement stations has been developed and is presented in this study. Peaks (i.e. elevated concentrations) of NOx were assigned to the corresponding source ships, using the AIS (automated identification system) signals they transmit. Each ship passage was simulated, using a Gaussian puff model, in order to derive the emission rate of the respective source ship. In total, over 32 900 ship passages have been monitored over the course of 4 years. The emission rates of NOx were investigated with respect to ship speed, ship size, and direction of travel. Comparisons of the onshore-derived emission rates and those on board for selected CLINSH ships show good agreement. The derived emission rates are of a similar magnitude to emission factors from previous studies. Most ships comply with existing limits due to grandfathering. The emission rates (in g s−1) can be directly used to investigate the effect of ship traffic on air quality, as the absolute emitted number of pollutants per unit of time is known. In contrast, for relative emission factors (in g kg−1 fuel), further knowledge about the fuel consumption of the individual ships is needed to calculate the number of pollutants emitted per unit of time.

The objective of this review is to identify and characterize the use of the natural environment/outdoor space by occupational therapists working in mental health care.Research has shown that the natural environment is beneficial for our health and can be used to benefit people who are experiencing mental health problems. Occupational therapists are well placed to assess and utilize the environment when treating people with mental health problems, but the use of the natural environment/outdoor space by occupational therapists working in mental health is unclear.The scoping review will include both primary research and gray literature relating to the use of the natural environment/outdoor space in mental health occupational therapy practice. The review will be limited to studies published in English. There will be no geographical or age restrictions.Embase (Ovid), MEDLINE (Ovid), CINAHL (EBSCO), PsycINFO (ProQuest), AMED (EBSCO), Trip Database, EMCARE (Ovid), and OTSeeker will be search for studies. Unpublished studies and gray literature will be searched using GreyNet and National Grey Literature Collection, alongside professional magazines and websites. Titles and abstracts will be screened by 2 independent reviewers for assessment against the inclusion criteria, followed by a full-text review and data extraction. Any disagreements will be discussed with a third reviewer. Data will be extracted using a data extraction tool developed by the reviewers and presented in a tabular format, accompanied by a narrative summary describing how the results relate to the review objective and question.

The need to extract permanent teeth as part of orthodontic treatment has been keenly debated over many decades. Changes in the frequency of extraction have been well documented; however, we continue to lack an understanding of what influences clinicians' decisions regarding extracting permanent teeth.Purposive sampling was undertaken to obtain representative views from primary care practitioners across Great Britain with a range of experience representing genders and wide geographic distribution. Twenty participants (9 female, 11 male) took part in in-depth, qualitative, 1-to-1 interviews based on a piloted topic guide. Interviews were conducted via video conferencing software with audio recording and verbatim transcription. Thematic analysis was performed with discussion and agreement to identify the main themes.Five main themes were identified: (1) patient-related factors, such as age and features of the malocclusion, (2) operator factors, including the level of experience, (3) setting, with regard to geographic location and method of remuneration, (4) mechanical approaches, including variations in appliance systems; and (5) self-directed ongoing education, including both formal continuing professional development and informal learning from peers. These factors acted as barriers, enablers, or both in relation to nonextraction treatment.Five key influences on extraction decisions among orthodontists in Great Britain were identified. Extraction choices appear to be influenced by various interrelated factors, evolving over time and with increased experience.

Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin.We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273.Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066).Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration.National Institute of Allergy and Infectious Diseases, bioMérieux.

Besides antiviral functions, type I IFN expresses potent anti-inflammatory properties and is being widely used to treat certain autoimmune conditions, such as multiple sclerosis. In a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis, administration of IFN-β effectively attenuates the disease development. However, the precise mechanisms underlying IFN-β–mediated treatment remain elusive. In this study, we report that IFN-induced protein with tetratricopeptide repeats 2 (Ifit2), a type I and type III IFN-stimulated gene, plays a previously unrecognized immune-regulatory role during autoimmune neuroinflammation. Mice deficient in Ifit2 displayed greater susceptibility to experimental autoimmune encephalomyelitis and escalated immune cell infiltration in the CNS. Ifit2 deficiency was also associated with microglial activation and increased myeloid cell infiltration. We also observed that myelin debris clearance and the subsequent remyelination were substantially impaired in Ifit2−/− CNS tissues. Clearing myelin debris is an important function of the reparative-type myeloid cell subset to promote remyelination. Indeed, we observed that bone marrow–derived macrophages, CNS-infiltrating myeloid cells, and microglia from Ifit2−/− mice express cytokine and metabolic genes associated with proinflammatory-type myeloid cell subsets. Taken together, our findings uncover a novel regulatory function of Ifit2 in autoimmune inflammation in part by modulating myeloid cell function and metabolic activity.

The biopsy 2 via dart, trocar or surgery 2 is becoming the preferred protocol for sampling skin and blubber of many cetacean species, because a small sample from a healthy animal may provide better information than a larger sample collected via necropsy from an ill or emaciated animal. Furthermore, the biopsy is often the only means of obtaining samples (e.g. for threatened or endangered species). Because biopsy darts collect only a small sample of tissue 2 and blubber can be heterogeneous in structure and composition 2 it is essential to compare the results obtained from biopsies to those found by analysing full-thickness blubber samples obtained via necropsy. This manuscript compares blubber stratification in two odontocete species, white whales (Delphinapterus leucas) and killer whales (Orcinus orca). Five parameters (i.e. lipid percent and classes, contaminant concentrations and profiles, fatty acid profiles) were measured by blubber depth. Results of these comparisons strongly suggest that biopsy results must be interpreted with caution and in conjunction with results from species-specific blubber depth profiling. For example, lipid classes measured in biopsy samples of white whales and killer whales were similar to those for equivalent-depth samples obtained by necropsy. In addition, lipid-adjusted contaminant concentrations measured in dart or trocar samples adequately represented those obtained by necropsy of both species. Conversely, the lipid content in biopsy samples was lower than that found in same-depth necropsied samples due to loss of lipid during sampling. Also, because of the high level of fatty acid stratification observed, fatty acid profiles from the outer blubber layer collected via biopsy from both species are less likely than the metabolically active inner layer to be useful in determining the prey species consumed by these odontocetes. This study demonstrates, for white and killer whales, that properly interpreted results from blubber biopsies can provide valuable information about the body condition, health and life history of individual animals.

Item does not contain fulltext BACKGROUND: Dyssynchrony-associated left ventricular systolic dysfunction is a major contributor to heart failure in congenital heart disease (CHD). Although conventional cardiac resynchronization therapy (CRT) has shown benefit, the comparative efficacy of cardiac conduction system pacing (CSP) is unknown. OBJECTIVES: The purpose of this study was compare the clinical outcomes of CSP vs conventional CRT in CHD with biventricular, systemic left ventricular anatomy. METHODS: Retrospective CSP data from 7 centers were compared with propensity score-matched conventional CRT control subjects. Outcomes were lead performance, change in left ventricular ejection fraction (LVEF), and QRS duration at 12 months. RESULTS: A total of 65 CSP cases were identified (mean age 37 ± 21 years, 46% men). The most common CHDs were tetralogy of Fallot (n = 12 [19%]) and ventricular septal defect (n = 12 [19%]). CSP was achieved after a mean of 2.5 ± 1.6 attempts per procedure (38 patients with left bundle branch pacing, 17 with HBP, 10 with left ventricular septal myocardial). Left bundle branch area pacing [LBBAP] vs HBP was associated with a smaller increase in pacing threshold (Δ pacing threshold 0.2 V vs 0.8 V; P = 0.05) and similar sensing parameters at follow-up. For 25 CSP cases and control subjects with baseline left ventricular systolic dysfunction, improvement in LVEF was non-inferior (Δ LVEF 9.0% vs 6.0%; P = 0.30; 95% confidence limits: -2.9% to 10.0%) and narrowing of QRS duration was more pronounced for CSP (Δ QRS duration 35 ms vs 14 ms; P = 0.04). Complications were similar (3 [12%] CSP, 4 [16%] conventional CRT; P = 1.00). CONCLUSIONS: CSP can be reliably achieved in biventricular, systemic left ventricular CHD patients with similar improvement in LVEF and greater QRS narrowing for CSP vs conventional CRT at 1 year. Among CSP patients, pacing electrical parameters were superior for LBBAP vs HBP.

In South Africa we have lived in a society where separation ofcommunities and racial groups has been the norm. Since 1994 theseparation is being bridged as more individuals encounter people withdifferent attitudes, value systems and cultural behavioural patterns insocial and business environments. This leads to new avenues ofunderstanding, but also to a wider scope for misunderstanding andunintentional miscommunication, especially in the business context.The way in which people communicate in a business setting, varies fromculture to culture. Such variation occurs in all stages of development andat all levels of culture. whether from one corporate culture to another, orfrom one region, state or country to another. Although most rules ofbusiness communication apply to the domestic business environment,Intercultural business communication requires knowledge and skills thatdiffer from those within a specific culture. It is impossible to know all thevariations in business communication in a multicultural business societylike South Africa, but businesspeople can and should prepare themselvesfor those experiences they are most likely to face in employee andcustomer relations when conducting business in more than one culture.This article probes the possibility of diminishing businessmiscommunication in South Africa, by focussing on awareness of barriersto multicultural marketing and management communication. Businesscommunication is defined as consisting of management as well asmarketing communication. A pilot survey on existing businesscommunication strategies in a large South African province is discussed.This has pointed towards a more comprehensive research project, with the aim of providing a three-tier model for effective multicultural marketingcommunication strategies in a post-Mande/a South Africa.

Fluorescent dyes are routinely used to visualize DNA or RNA in various experiments, and some dyes also act as photosensitizers capable of catalyzing oxidation reactions. The present studies explored whether the common labeling dyes fluorescein, rhodamine, BODIPY, or cyanine3 (Cy3) can function as photosensitizers to oxidize nucleic acid polymers. Photoirradiation of each dye in the presence of the guanine (G) heterocycle, which is the most sensitive toward oxidation, identified slow rates of nucleobase oxidation in the nucleoside and DNA contexts. For all four fluorophores studied, the only product detected was spiroiminodihydantoin (Sp) suggesting the dyes functioned as Type II photosensitizers and generate singlet oxygen (

Two decades of measurements of spectral reflectance of solar radiation at the top of the atmosphere and a complementary record of cloud properties from satellite passive remote sensing have been analyzed for their pan-Arctic, regional, and seasonal changes. The pan-Arctic loss of brightness, which is explained by the retreat of sea ice during the current warming period, is not compensated by a corresponding increase in cloud cover. A systematic change in the thermodynamic phase of clouds has taken place, shifting towards the liquid phase at the expense of the ice phase. Without significantly changing the total cloud optical thickness or the mass of condensed water in the atmosphere, liquid water content has increased, resulting in positive trends in liquid cloud optical thickness and albedo. This leads to a cooling trend by clouds being superimposed on top of the pan-Arctic amplified warming, induced by the anthropogenic release of greenhouse gases, the ice–albedo feedback, and related effects. Except over the permanent and parts of the marginal sea ice zone around the Arctic Circle, the rate of surface cooling by clouds has increased, both in spring (−32 % in total radiative forcing for the whole Arctic) and in summer (−14 %). The magnitude of this effect depends on both the underlying surface type and changes in the regional Arctic climate.

Objective: Web-based dietary interventions could support healthy eating. The Advice, Ideas and Motivation for My Eating (Aim4Me) trial investigated the impact of three levels of personalised web-based dietary feedback on diet quality in young adults. Secondary aims were to investigate participant retention, engagement and satisfaction. Design: Randomised controlled trial. Setting: Web-based intervention for young adults living in Australia. Participants: 18–24-year-olds recruited across Australia were randomised to Group 1 (control: brief diet quality feedback), Group 2 (comprehensive feedback on nutritional adequacy + website nutrition resources) or Group 3 (30-min dietitian consultation + Group 2 elements). Australian Recommended Food Score (ARFS) was the primary outcome. The ARFS subscales and percentage energy from nutrient-rich foods (secondary outcomes) were analysed at 3, 6 and 12 months using generalised linear mixed models. Engagement was measured with usage statistics and satisfaction with a process evaluation questionnaire. Results: Participants (n 1005, 85 % female, mean age 21·7 ± 2·0 years) were randomised to Group 1 (n 343), Group 2 (n 325) and Group 3 (n 337). Overall, 32 (3 %), 88 (9 %) and 141 (14 %) participants were retained at 3, 6 and 12 months, respectively. Only fifty-two participants (15 % of Group 3) completed the dietitian consultation. No significant group-by-time interactions were observed (P > 0·05). The proportion of participants who visited the thirteen website pages ranged from 0·6 % to 75 %. Half (Group 2 = 53 %, Group 3 = 52 %) of participants who completed the process evaluation (Group 2, n 111; Group 3, n 90) were satisfied with the programme. Conclusion: Recruiting and retaining young adults in web-based dietary interventions are challenging. Future research should consider ways to optimise these interventions, including co-design methods.

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression. Significance: Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1–AXL axis and to stimulate lymphovascular angiogenesis.

The TROPOspheric Monitoring Instrument (TROPOMI) on board the Sentinel-5 Precursor satellite enables the accurate determination of atmospheric methane (CH4) and carbon monoxide (CO) abundances at high spatial resolution and global daily sampling. Due to its wide swath and sampling, the global distribution of both gases can be determined in unprecedented detail. The scientific retrieval algorithm Weighting Function Modified Differential Optical Absorption Spectroscopy (WFMD) has proven valuable in simultaneously retrieving the atmospheric column-averaged dry-air mole fractions XCH4 and XCO from TROPOMI's radiance measurements in the shortwave infrared (SWIR) spectral range. Here we present recent improvements of the algorithm which have been incorporated into the current version (v1.8) of the TROPOMI/WFMD product. This includes processing adjustments such as increasing the polynomial degree to 3 in the fitting procedure to better account for possible spectral albedo variations within the fitting window and updating the digital elevation model to minimise topography-related biases. In the post-processing, the machine-learning-based quality filter has been refined using additional data when training the random forest classifier to further reduce scenes with residual cloudiness that are incorrectly classified as good. In particular, the cloud filtering over the Arctic ocean is considerably improved. Furthermore, the machine learning calibration, addressing systematic errors due to simplifications in the forward model or instrumental issues, has been optimised. By including an additional feature associated with the fitted polynomial when training the corresponding random forest regressor, spectral albedo variations are better accounted for. To remove vertical stripes in the XCH4 and XCO data, an efficient orbit-wise destriping filter based on combined wavelet–Fourier filtering has been implemented, while optimally preserving the original spatial trace gas features. The temporal coverage of the data records has been extended to the end of April 2022, covering a total length of 4.5 years since the start of the mission, and will be further extended in the future. Validation with the ground-based Total Carbon Column Observing Network (TCCON) demonstrates that the implemented improvements reduce the pseudo-noise component of the products, resulting in an improved random error. The XCH4 and XCO products have similar spatial coverage from year to year including high latitudes and the oceans. The analysis of annual growth rates reveals accelerated growth of atmospheric methane during the covered period, in line with observations at marine surface sites of the Global Monitoring Division of NOAA's Earth System Research Laboratory, which reported consecutive annual record increases over the past 2 years of 2020 and 2021.

Direct RNA sequencing with a commercial nanopore platform was used to sequence RNA containing uridine (U), pseudouridine (Ψ), or N1-methylpseudouridine (m1Ψ) generated by in vitro transcription (IVT). The base calling data as well as the ionic currents and dwell times for U, Ψ, or m1Ψ as they translocated through the helicase and nanopore proteins identified diagnostic signatures for Ψ and m1Ψ; however, the two modifications yielded similar patterns although both were different from U. Understanding the nanopore signatures for Ψ and m1Ψ enabled a running start T7 RNA polymerase assay to study how competing mixtures of UTP with ΨTP or m1ΨTP lead to nucleotide selection in all possible adjacent sequence contexts. For UTP vs. ΨTP, ΨTP was favorably incorporated in singly-modified contexts, while doubly-modified contexts found high yields of ΨTP insertion on the 5′ side and lower yields on the 3′ side. For UTP vs. m1ΨTP, UTP was favorably selected except in 5′-XA (X = U or m1Ψ) where the ratio was determined by their relative NTP concentrations. Experiments with chemically-modified triphosphates and DNA templates designed based on the structure of T7 RNA polymerase provide a model to explain the observations. These results may aid in future efforts that employ IVT to make therapeutic mRNAs with sub-stochiometric amounts of m1Ψ.

In response to breast cancer diagnostic regional wait times exceeding both national and provincial standards and to symptomatic patient referrals for diagnostic mammography taking longer than abnormal screening mammography referrals, the Rae Fawcett Breast Health Clinic (RFBHC) was opened in 2017 in a mid-sized Canadian hospital serving both urban and rural-remote communities. We investigated whether the RFBHC improved wait times to breast cancer diagnosis, improved compliance with national and provincial breast cancer standards, and decreased the wait time disparity associated with referral source. Statistical analyses of wait time differences were conducted between patients who were diagnosed with breast cancer prior to and after the RFBHC establishment. Study group compliance with national and provincial standards and wait time differences by referral source were also analysed. A survey was administered to assess overall patient experience with the RFBHC and clinic wait times. RFBHC patients had a shorter mean wait to breast cancer diagnosis (24.4 vs. 45.7 days, p ≤ 0.001) and a shorter mean wait to initial breast cancer treatment (49.1 vs. 78.9 days, p ≤ 0.001) than pre-RFBHC patients. After the RFBHC establishment, patients who attended the RFBHC had a shorter mean wait time to breast cancer diagnosis (24.4 vs. 36.9 days, p = 0.005) and to initial treatment (49.1 vs. 73.1 days, p ≤ 0.001) than patients who did not attend the clinic. Compliance with national and provincial breast cancer standards improved after the RFBHC establishment and the wait time disparity between screening mammography referrals and symptomatic patient referrals decreased. Survey results indicate that the RFBHC is meeting patient expectations. We concluded that the establishment of a breast health clinic in a Canadian center serving urban and rural-remote communities improved breast diagnostic services.

Climatic extremes are becoming increasingly common against a background trend of global warming. In the oceans, marine heatwaves (MHWs)-discrete periods of anomalously warm water-have intensified and become more frequent over the past century, impacting the integrity of marine ecosystems globally. We review and synthesize current understanding of MHW impacts at the individual, population, and community levels. We then examine how these impacts affect broader ecosystem services and discuss the current state of research on biological impacts of MHWs. Finally, we explore current and emergent approaches to predicting the occurrence and impacts of future events, along with adaptation and management approaches. With further increases in intensity and frequency projected for coming decades, MHWs are emerging as pervasive stressors to marine ecosystems globally. A deeper mechanistic understanding of their biological impacts is needed to better predict and adapt to increased MHW activity in the Anthropocene. Expected final online publication date for the

Paul Crutzen received his doctorate in meteorology from the University of Stockholm in 1968 and was awarded the Nobel Prize in Chemistry in 1995. In addition to chemistry and atmospheric science, however, the breadth of his accomplishments has also been recognized by biologists, Earth system scientists, and geologists. This tribute provides some insight into Crutzen’s career and how it contributed to so many scientific disciplines. In addition, we offer a road map showing how these diverse contributions were woven together over the course of more than five decades of research. The citation for the 1995 Nobel Prize reads that it was given for “work in atmospheric chemistry, particularly concerning the formation and decomposition of ozone.” The inclusion of the wording “formation … of ozone” applies only to him among the three laureates (Crutzen, Mario Molina, and F. Sherwood Rowland). His research on tropospheric chemistry led to seminal studies of tropical biomass burning, which eventually evolved into the concept later known as “nuclear winter,” a topic in the forefront of far-ranging popular discussions in the 1980s. Last, Crutzen’s proposal for the emergence of the “Anthropocene” as a new geological epoch that would terminate the 11,700-yr-old Holocene is considered by the Earth system science community to be the most pronounced trademark of his remarkable career. Crutzen also received American Meteorological Society’s Battan Award for his coauthorship of Atmosphere, Climate, and Change, recognized by the organization as the best book for general audiences. In the later years of his career, as a member of the Pontifical Academy of Sciences, Crutzen was a key player in the formulation of Laudato Si’, Pope Francis’s encyclical on climate change, which was released in advance of the Conference of Parties (COP 21) meeting that announced the formulation of the Paris Climate Accords in 2015.

Mechanisms behind the phenomenon of Arctic amplification are widely discussed. To contribute to this debate, the (AC)3 project was established in 2016 (www.ac3-tr.de/). It comprises modeling and data analysis efforts as well as observational elements. The project has assembled a wealth of ground-based, airborne, shipborne, and satellite data of physical, chemical, and meteorological properties of the Arctic atmosphere, cryosphere, and upper ocean that are available for the Arctic climate research community. Short-term changes and indications of long-term trends in Arctic climate parameters have been detected using existing and new data. For example, a distinct atmospheric moistening, an increase of regional storm activities, an amplified winter warming in the Svalbard and North Pole regions, and a decrease of sea ice thickness in the Fram Strait and of snow depth on sea ice have been identified. A positive trend of tropospheric bromine monoxide (BrO) column densities during polar spring was verified. Local marine/biogenic sources for cloud condensation nuclei and ice nucleating particles were found. Atmospheric–ocean and radiative transfer models were advanced by applying new parameterizations of surface albedo, cloud droplet activation, convective plumes and related processes over leads, and turbulent transfer coefficients for stable surface layers. Four modes of the surface radiative energy budget were explored and reproduced by simulations. To advance the future synthesis of the results, cross-cutting activities are being developed aiming to answer key questions in four focus areas: lapse rate feedback, surface processes, Arctic mixed-phase clouds, and airmass transport and transformation.

APE1 complexed with an abasic site in G-quadruplex (G4) topologies displays differences in binding constants, enzyme cleavage yields, and gene regulation. APE1 tightly binds parallel G4s to regulate transcription that is not found with hybrid G4s.

Biodegradable active food packaging addresses key environmental issues including plastic waste and food waste.

Rivers that do not flow year-round are the predominant type of running waters on Earth. Despite a burgeoning literature on natural flow intermittence (NFI), knowledge about the hydrological causes and ecological effects of human-induced, anthropogenic flow intermittence (AFI) remains limited. NFI and AFI could generate contrasting hydrological and biological responses in rivers because of distinct underlying causes of drying and evolutionary adaptations of their biota. We first review the causes of AFI and show how different anthropogenic drivers alter the timing, frequency and duration of drying, compared with NFI. Second, we evaluate the possible differences in biodiversity responses, ecological functions, and ecosystem services between NFI and AFI. Last, we outline knowledge gaps and management needs related to AFI. Because of the distinct hydrologic characteristics and ecological impacts of AFI, ignoring the distinction between NFI and AFI could undermine management of intermittent rivers and ephemeral streams and exacerbate risks to the ecosystems and societies downstream.

Children with glomerular disease have unique risk factors for compromised bone health. Studies addressing skeletal complications in this population are lacking.This retrospective cohort study utilized data from PEDSnet, a national network of pediatric health systems with standardized electronic health record data for more than 6.5 million patients from 2009 to 2021. Incidence rates (per 10,000 person-years) of fracture, slipped capital femoral epiphysis (SCFE), and avascular necrosis/osteonecrosis (AVN) in 4598 children and young adults with glomerular disease were compared with those among 553,624 general pediatric patients using Poisson regression analysis. The glomerular disease cohort was identified using a published computable phenotype. Inclusion criteria for the general pediatric cohort were two or more primary care visits 1 year or more apart between 1 and 21 years of age, one visit or more every 18 months if followed3 years, and no chronic progressive conditions defined by the Pediatric Medical Complexity Algorithm. Fracture, SCFE, and AVN were identified using SNOMED-CT diagnosis codes; fracture required an associated x-ray or splinting/casting procedure within 48 hours.We found a higher risk of fracture for the glomerular disease cohort compared with the general pediatric cohort in girls only (incidence rate ratio [IRR], 1.6; 95% CI, 1.3 to 1.9). Hip/femur and vertebral fracture risk were increased in the glomerular disease cohort: adjusted IRR was 2.2 (95% CI, 1.3 to 3.7) and 5 (95% CI, 3.2 to 7.6), respectively. For SCFE, the adjusted IRR was 3.4 (95% CI, 1.9 to 5.9). For AVN, the adjusted IRR was 56.2 (95% CI, 40.7 to 77.5).Children and young adults with glomerular disease have significantly higher burden of skeletal complications than the general pediatric population.

Nonmedical prescription stimulant use (NMPSU) is a rising trend among college-age adults (18-25 years old). Survey research has identified several reasons for use, including enhancing cognitive, athletic, and social performance. Less is known about how relative reinforcing value differs based on the self-reported reasons for use. The commodity purchase task (CPT) is used to assess demand for substances such as alcohol and cigarettes and has been extended for NMPSU among college student users. However, this work has not been replicated for NMPSU or expanded to determine how reason for use affects drug demand. The aim of this study was to develop a novel functional purchase task (FPT) to measure demand for preferred stimulant-like drug effects (e.g., focus, academic achievement, energy). Undergraduate students (n = 116) recruited from two universities who endorsed lifetime NMPSU completed five hypothetical stimulant purchase tasks, one for stimulant medication and four based on their ordinal ranking of eight possible reasons for stimulant use. Results support using a CPT to measure the reinforcing value of prescription stimulants and found demand predicts past year NMPSU, but not other variables associated with use. Furthermore, there are multiple reinforcing functions of NMPSU among college students, and more preferred reasons for use corresponded with higher demand intensity and inelasticity on the FPT at the aggregate level but less so at the individual participant level. These results suggest the need for further work exploring the utility of a functional approach to measure demand as reinforcing value. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

BACKGROUND AND AIMS: Adipose tissue secretes adipokines such as adiponectin and leptin, playing important roles in energy metabolism. The longitudinal associations between such adipokines and body fat accumulation have not been established, especially during adolescence and young adulthood and in diverse populations. The study aims to assess the longitudinal association between body fat measured with dual X-ray absorptiometry and plasma adipokines from adolescence to young adulthood. METHODS AND RESULTS: Among Hispanic/Latino participants (N=537) aged 16.8 (SD: 0.3) years of the Santiago Longitudinal Study, we implemented structural equation modeling to estimate the sex-specific associations between adiposity (body fat percent (BF%) and proportion of trunk fat (PTF)) and adipokines (adiponectin and leptin levels) during adolescence (16y) and these values after 6 years of follow-up (22y). In addition, we further investigated whether the associations differed by baseline insulin resistance (IR) status. We found evidence for associations between 16y BF% and 22y leptin levels (β(SE): 0.58(0.06) for females; 0.53(0.05) for males), between 16y PTF and 22y adiponectin levels (β(SE): −0.31(0.06) for females; −0.18(0.06) for males) and between 16y adiponectin levels and 22y BF% (β(SE): 0.12(0.04) for both females and males). CONCLUSION: We observed dynamic relationships between adiposity and adipokines levels from late adolescence to young adulthood in a Hispanic/Latino population further demonstrating the importance of this period of the life course in the development of obesity.

Introduction Varicose veins (VV) negatively impact quality of life (QoL) and have risks of major complications including bleeding, ulceration and phlebitis. During the COVID-19 pandemic, the VSGBI (Vascular Society of Great Britain and Ireland) and GIRFT (Get It Right First Time) classified VVs as lowest priority for intervention. Objective This study aims to determine harm caused and the impact on the QoL on patients waiting for their VVs procedures for more than 1 year. Methods This was a prospective study conducted at the Norfolk and Norwich University Hospital (NNUH). Patients with VVs awaiting intervention for >1 year were included in the study. Patients with CEAP C6 disease were considered to be too high risk to be invited for treatment during the Covid-19 pandemic. Patients were sent QoL questionnaires and underwent a telephone consultation to assess harm. Both generic (EQ-VAS and EQ-5D) and disease-specific (AVVQ and CIVIQ-14) instruments were utilised. There were no control groups available for comparison. Results 275 patients were identified (37.1% male) with median time on waiting list of 60 weeks (IQR 56–65). 19 patients (6.9%) came to major harm, including phlebitis (3.6%), bleeding (1.8%) and ulceration (1.8%). Fifty-two patients (18.9%) had minor harm, including worsening pain (12.7%) and swelling (6.2%). 6.9% reported psychological harm. Rising CEAP stage was also associated with worsening level of harm in patients with C5-6 disease ( p < 0.0001). Only 8.7% stated they would decline surgery during the pandemic. 104 QoL questionnaires were returned. Median EQ-VAS and EQ-5D was 75 (IQR: 60–85) and 0.685 (0.566–0.761), respectively. Median AVVQ score was 23.2 (14.9–31.0) and CIVIQ-14 score was 33 (21–44). ConclusionsThis study highlights the impact of delaying VVs surgery during a pandemic. A significant rate of both major and minor as well as psychological harm was reported. In addition, VVs had a significant detriment to quality of life.

Purpose Mental health (MH) and caring can be demanding for those directly and indirectly impacted. An under-researched area is that of professionals’ personal experiences of caring for a loved one with MH difficulties. This study aims to provide an in-depth exploration of psychologists’ experiences of caring and its impact on clinical practice. Design/methodology/approach A total of 11 psychologists with experiences of caring for a loved one with a diagnosed MH condition and/or MH distress participated in semi-structured interviews focused on caring experiences and its impact. Transcripts were analysed using thematic analysis. Findings Themes identified were as follows: personal and professional roles; the emergence of a carer identity; carer stress and strain; impact on professional practice; and dual positioning. Originality/value This study highlighted the knowledge and value of listening to professionals with lived experiences. Their ability to understand stigmatisation through personal caring experiences may facilitate the mitigation of this for vulnerable people attending clinical services.

Distributional shifts in species ranges provide critical evidence of ecological responses to climate change. Assessments of climate-driven changes typically focus on broad-scale range shifts (e.g. poleward or upward), with ecological consequences at regional and local scales commonly overlooked. While these changes are informative for species presenting continuous geographic ranges, many species have discontinuous distributions-both natural (e.g. mountain or coastal species) or human-induced (e.g. species inhabiting fragmented landscapes)-where within-range changes can be significant. Here, we use an ecosystem engineer species (Sabellaria alveolata) with a naturally fragmented distribution as a case study to assess climate-driven changes in within-range occupancy across its entire global distribution. To this end, we applied landscape ecology metrics to outputs from species distribution modelling (SDM) in a novel unified framework. SDM predicted a 27.5% overall increase in the area of potentially suitable habitat under RCP 4.5 by 2050, which taken in isolation would have led to the classification of the species as a climate change winner. SDM further revealed that the latitudinal range is predicted to shrink because of decreased habitat suitability in the equatorward part of the range, not compensated by a poleward expansion. The use of landscape ecology metrics provided additional insights by identifying regions that are predicted to become increasingly fragmented in the future, potentially increasing extirpation risk by jeopardising metapopulation dynamics. This increased range fragmentation could have dramatic consequences for ecosystem structure and functioning. Importantly, the proposed framework-which brings together SDM and landscape metrics-can be widely used to study currently overlooked climate-driven changes in species internal range structure, without requiring detailed empirical knowledge of the modelled species. This approach represents an important advancement beyond predictive envelope approaches and could reveal itself as paramount for managers whose spatial scale of action usually ranges from local to regional.

To determine the impact of offering elective labour induction at 39 weeks gestation on perinatal and maternal outcomes in nulliparous people with low-risk pregnancies.The charts of all pregnant people who delivered at Brockville General Hospital between September 2018 and December 2021 were retrospectively reviewed. Perinatal and maternal outcomes of low-risk nulliparous pregnant people who underwent elective induction at 39 weeks and over were extracted and compared with those of low-risk nulliparous pregnant people who underwent expectant management. Exclusion criteria included multiparous people, high-risk pregnancies, multiple gestations, deliveries at less than 39 weeks gestation, and elective cesarean deliveries. Univariate and multivariate analysis was performed.A total of 174 patients were included. Of these patients, 56 (32.2%) underwent elective induction of labour between 39Our results suggest that elective induction of labour at 39 weeks gestation and over in low-risk nulliparous people is associated with lower risks of cesarean delivery, composite adverse maternal outcomes, and composite adverse perinatal outcomes than expectant management.

Septic arthritis (SA) of the native ankle joint can result in serious morbidity and mortality but is a poorly quantified issue with little literature available on its clinical features, treatment and outcomes. This was a 10-y review (N ≥ 30) of adults with SA of the native ankle joint presenting to a single center from December 2009 to January 2019. Patients with prior ankle surgery, prosthetic infection, inoculation from trauma, not initially treated at our institution or lost to follow-up were excluded. Thirty-six patients met inclusion criteria. This is the largest cohort of adult native ankle joint SA in the literature. Mean age was 63.5 y (range 28-93 y). Patients most often presented with pain (91.7%), swelling (61.1%), and fever (22%). Staphylococcus aureus was the most common causative pathogen (63.9%). Readmission rate was 60%. The 1-y mortality rate was 14.3% with Charlson Comorbidity Index and age identified as independent predictors of mortality. No statistically significant predictors were found for returns to theatre. When assessing ankle pain in elderly patients, and those with poor physiology, high clinical index of suspicion should be maintained for this potentially life-threatening condition. We recommend development of evidence-based clinical guidelines for adult native ankle joint SA and establishment of a prospective multi-center database to enable further research in this field.

Business organisations are increasingly viewing knowledge as their most valuable andstrategic resource to remain competitive. Every organisation has both explicit knowledge,referring to carefully analysed and defined knowledge, and tacit knowledge, referringto complex knowledge, difficult to specify and often unrecorded. Tacit knowledgebecomes embedded in an individual's personal expertise and cannot be expressed throughthe normal use of words. But it is precisely the tacit knowledge that often delivers asustainable competitive advantage, as it is this part that competitors have difficultyin replicating. Many organisations are realizing that they must explicitly manage their knowledgeresources and capabilities, and they have initiated a range of knowledge managementprogrammes. An important managerial responsibility resides in managing the knowledgetransfercontext, including the assessment of all knowledge possessed by a firm. Thisnecessitates the conversion of tacit knowledge into explicit knowledge. This article looks at the tacit knowledge literature and focuses on the existing methods of converting tacit knowledge into implicit knowledge in organisations. A pilot surveyon existing tacit knowledge articulation in a large South African province is discussed.This has pointed towards a more comprehensive research project, with the aim ofproviding a model for tacit knowledge communication strategies in South Africanmulticultural firms.

The binding interaction between the DNA repair enzyme apurinic/apyrimidinic endonuclease-1 (APE1) with promoter G-quadruplex (G4) folds bearing an abasic site (AP) can serve as a gene regulatory switch during oxidative stress. Prior fluorescence-based analysis in solution suggested APE1 binds the