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Background Methods Results Conclusion Early onset rectal cancer (EORC) is increasing internationally. While EORC cancer presents with some distinct clinical features, there is currently insufficient evidence that age of onset should alter treatment. This study examines treatment patterns for EO versus late‐onset (LO) metastatic rectal cancer in Canterbury, New Zealand, to better understand appropriate treatment strategies and there effect on patient outcomes.A retrospective study on all patients diagnosed with stage 4 rectal adenocarcinoma in Canterbury from 2010 to 2021 was undertaken. Patients under 50 were compared to a control group aged 60–74, analysing treatment patterns, hospital stays, and survival outcomes.Between 2010 and 2021, there were 949 rectal cancer diagnoses in Canterbury, of which 23 were EO and 64 were LO with stage 4 cancer. Survival analysis revealed a significant difference in median survival times between EORC (47.9 months) and LORC patients (26.5 months; P = 0.03). There was no significant difference in the surgical or oncological management between age groups (P > 0.05). Mean admissions per 100 days of life was 0.45 in LORC and 0.44 in EORC (P = 0.9119). There was no significant difference in the median proportion of time spent in hospital between EO and LO groups (2.5 vs. 2.2 days for every 100 days of life, P = 0.88).Surgical and oncological treatments were similar for both EORC and LORC groups. The EO group exhibited better survival, with hospitalization burdens comparable for both. These findings underline the importance of maintaining an approach to metastatic RC balancing survival and quality of life. [ABSTRACT FROM AUTHOR]

A recent communication on Ru‐catalyzed C—H bond arylation with 4‐aminoantipyrine (AP) reported the synthesis of AP benzamides. In order to provide additional support to the published structures of AP benzamides, crystallization by high‐throughput (HTP) encapsulated nanodroplet crystallization (ENaCt) was undertaken. This allowed for conclusive structure determination by single‐crystal X‐ray diffraction analysis (SCXRD). This article describes the crystallization and X‐ray crystal structure of N‐(1,5‐dimethyl‐3‐oxo‐2‐phenyl‐2,3‐dihydro‐1H‐pyrazol‐4‐yl)‐2‐methylbenzamide, C19H19N3O2, as a benzamide bearing 4‐aminoantipyrine, providing structural confirmation. X‐ray structure analysis reveals intermolecular hydrogen‐bonding interactions between the AP benzamide N—H proton and the carbonyl O atom of the AP moiety. [ABSTRACT FROM AUTHOR]

The reaction of 7‐phenylbenzo[a]phenazine‐5(7H)‐one (rosindone) with one equivalent of a nitrating mixture (conc. H2SO4/HNO3) produced 6‐nitro‐7‐phenylbenzo[a]phenazine‐5(7H)‐one (NROS), as confirmed by 1H NMR spectroscopy. The selectivity of the reaction is assigned to an electronic effect. The attempted sulphonation of rosindone with chlorosulfonic acid produced the chlorinated derivative 6‐chloro‐7‐phenylbenzo[a]phenazine‐5(7H)‐one (CLROS), instead but in low yield. The nitro group of NROS was reduced with SnCl2 to produce a blue solid identified as 6‐amino‐7‐phenylbenzo[a]phenazine‐5(7H)‐one (AMROS). The X‐ray crystal structure confirmed the positioning of the amino group α to the carbonyl group. The reaction of rosindone with one equivalent of lithium trimethylsilylacetylide underwent a Michael addition to introduce the nucleophile β to the carbonyl group. The compound 6a‐ethynyl‐6a,7‐dihydrobenzo[a]phenazine‐5(6H)‐one (rac‐ACROS) was identified by an X‐ray crystal structure determination. Coupling of rac‐ACROS under standard Glazer conditions produced the dyad of the compound linked via the two ethynyl subunits. A different N‐phenyl group was readily introduced into the rosindone basic structure by the reaction of methyl 2‐((2‐aminophenyl)amino)benzoate with 2‐hydroxy‐1,4‐naphthoquinone to produce methyl 2‐(5‐oxobenzo[a]phenazine‐7(5H)‐yl)benzoate (MROS). [ABSTRACT FROM AUTHOR]

Background: Simultaneous alcohol and cannabis use is associated with riskier daily drinking. However, little research has tested momentary mechanisms through which simultaneous use predicts continued drinking during acute drinking episodes. The current study tested whether simultaneous use moments predicted within‐episode increases in subjective responses, craving, and continued drinking, and whether these relations were potentiated in social versus solitary settings. Methods: Emerging adults who co‐use alcohol and cannabis (N = 85) completed 21 days of ecological momentary assessment with event‐contingent reports during drinking episodes. Three‐level multilevel models tested whether simultaneous (vs. alcohol‐only) use moments indirectly predicted subsequent, continued drinking through subjective responses (i.e., high‐arousal positive/stimulant, high‐arousal negative/aggression, low‐arousal positive/relaxation, low‐arousal negative/impairment) and alcohol craving, and whether relations differed by social versus solitary contexts. Results: Within drinking episodes, simultaneous (vs. alcohol‐only) use moments were associated with increased stimulation, which was indirectly associated with continued drinking through increased alcohol craving. Additionally, the relation between simultaneous (vs. alcohol‐only) use and stimulating effects was potentiated during solitary drinking moments, whereas the relation between stimulating effects and craving was potentiated during social drinking moments. However, stimulating effects were higher in social contexts across all moments. Finally, simultaneous (vs. alcohol‐only) use moments were associated with increased relaxation, which was indirectly associated with a lower likelihood of continued drinking through lesser craving. Conclusions: Simultaneous use predicted both continued within‐episode drinking and cessation of drinking, with acute subjective effects and craving as mechanisms, dependent upon context. Just‐in‐time interventions should consider targeting affect, craving, and context in event‐specific interventions. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is the third most diagnosed cancer in the world, with an estimated 1.93 million cases diagnosed in 2020. While the overall CRC incidence in many countries is falling there has been a dramatic increase in CRC in those aged under 50 (early onset colorectal cancer, EOCRC). The reason for this increase in EOCRC is unknown. As the best predictor of survival is stage at diagnosis, early diagnosis is likely to be beneficial and population screening may facilitate this. Methods: A narrative review of the literature was undertaken. Results: Improving time to diagnosis in symptomatic patients is beneficial. However, by the time symptoms develop, over a third of patients already have metastatic disease. Screening asymptomatic patients (with Faecal Immunochemical test (FIT) and colonoscopy) has been proved to be effective in older patients (>60 years). In younger populations, the decreasing incidence rates of CRC previously made cost effectiveness, compliance and therefore benefit questionable. Now, with the increasing incidence of CRC in those under 50 years of age, modelling suggests screening with FIT and colonoscopy is cost effective from 40 years of age. There is evidence that some countries screening below 50 have prevented the rise in EOCRC incidence. Additionally the use of new and novel non‐invasive biomarkers may also be able to improve the accuracy of screening asymptomatic patients. Conclusion: Diagnosis of EOCRC once symptoms develop is often too late, and screening patients from age 40 is the best way to improve outcomes in this group. [ABSTRACT FROM AUTHOR]

Background: Pregnant women involved in decisions about their care report better health outcomes for themselves and their children. Shared decision‐making (SDM) is a priority for health services; however, there is limited research on factors that help and hinder SDM in hospital‐based maternity settings. The purpose of this study was to explore barriers and facilitators to SDM in a large tertiary maternity care service from the perspectives of multiple stakeholders. Methods: Qualitative semi‐structured interviews were undertaken with 39 participants including women, clinicians, health service administrators and decision‐makers, and government policymakers. The interview guide and thematic analysis were based on the Theoretical Domains Framework to identify barriers and facilitators to SDM. Results: Women expect to be included in decisions about their care. Health service administrators and decision‐makers, government policymakers, and most clinicians want to include them in decisions. Key barriers to SDM included lack of care continuity, knowledge, and clinician skills, as well as professional role and decision‐making factors. Key facilitators pertained to policy and guideline changes, increased knowledge, professional role factors, and social influences. Conclusion: This study revealed common barriers and facilitators to SDM and highlighted the need to consider perspectives outside the patient–clinician dyad. It adds to the limited literature on barriers and facilitators to SDM in hospital care settings. Organizational‐ and system‐wide changes to service delivery are necessary to facilitate SDM. These changes may be enabled by education and training, changes to policies and guidelines to include and support SDM, and adequately timed information provision to enable SDM conversations. [ABSTRACT FROM AUTHOR]

Objective: Musculoskeletal (MSK) disorders affect ~50% of US adults and 75% of those over the age of 65, representing a sizable economic and disability burden. Outcome measures, both objective and subjective, help clinicians and investigators determine whether interventions to treat MSK conditions are effective. This narrative review qualitatively compared the responsiveness of different types of outcome measures, a key measurement characteristic that assesses an outcome measure's ability to detect change in patient status. Methods: We evaluated elective orthopedic interventions as a model for assessing responsiveness because the great majority of patients improves following surgery. We searched for articles reporting responsiveness (quantified as effect size [ES]) of subjective and objective outcome measures after orthopedic surgery and included 16 articles reporting 17 interventions in this review. Results: In 14 of 17 interventions, subjective function measures had an ES 10% greater than that of objective function measures. Two reported a difference in ES of <10%. The sole intervention that demonstrated higher ES of objective function used a composite measure. Sixteen interventions reported measures of subjective pain and/or mixed measures and subjective function. In nine interventions, subjective pain had a higher ES than subjective function by >10%, in three, subjective function had a higher ES than subjective pain by >10%, and in the remaining four, the difference between pain and function was <10%. Conclusion: These findings reinforce the clinical observation that subjective pain generally changes more than function following elective orthopedic surgery. They also suggest that subjective function measures are more responsive than objective function measures, and composite scores may be more responsive than individual performance tests. [ABSTRACT FROM AUTHOR]

Background: Respiratory syncytial virus (RSV) is a substantial cause of infant morbidity and mortality due to seasonal peaks of bronchiolitis across the United States. Clinical and viral surveillance plays a pivotal role in helping hospital systems prepare for expected surges in RSV bronchiolitis. Existing surveillance efforts have shown a geographic pattern of RSV positivity across the United States, with cases typically starting in the southeast and spreading north and west. Public health measures implemented due to the COVID‐19 pandemic disrupted viral transmission across the nation and altered the expected seasonality of RSV. The impact of these changes on the geographic progression of infant RSV bronchiolitis across the United States has not been described. Methods: Here, we used clinical and viral surveillance data from four health care systems located in different regions of the United States to describe the geographic progression of infant RSV bronchiolitis across the country from 2015 to 2023. Results: Prior to widespread circulation of SARS‐CoV‐2, infant RSV bronchiolitis followed an established geographic pattern associated with seasonal epidemics originating in Florida and spreading north (North Carolina and New York) and later westward (Nevada). Although public health and social measures implemented during the COVID‐19 pandemic disrupted the seasonality of RSV disease, infant RSV bronchiolitis epidemics progressed across the nation in a pattern identical to the prepandemic era. Conclusions: Our findings highlight the importance of ongoing clinical and viral surveillance to optimally track the onset of RSV epidemics and allow health care systems to prepare for expected RSV bronchiolitis surges. [ABSTRACT FROM AUTHOR]

Background: We investigated the effectiveness of Nurse‐Family Partnership (NFP), a prenatal‐to‐age‐two‐years home‐visiting programme, in British Columbia (BC), Canada. Methods: For this randomised controlled trial, we recruited participants from 26 public health settings who were: <25 years, nulliparous, <28 weeks gestation and experiencing socioeconomic disadvantage. We randomly allocated participants (one‐to‐one; computer‐generated) to intervention (NFP plus existing services) or comparison (existing services) groups. Prespecified outcomes were prenatal substance exposure (reported previously); child injuries (primary), language, cognition and mental health (problem behaviour) by age two years; and subsequent pregnancies by 24 months postpartum. Research interviewers were masked. We used intention‐to‐treat analyses. (ClinicalTrials.gov, NCT01672060.) Results: From 2013 to 2016 we enrolled 739 participants (368 NFP, 371 comparison) who had 737 children. Counts for child injury healthcare encounters [rate per 1,000 person‐years or RPY] were similar for NFP (223 [RPY 316.17]) and comparison (223 [RPY 305.43]; rate difference 10.74, 95% CI ‐46.96, 68.44; rate ratio 1.03, 95% CI 0.78, 1.38). Maternal‐reported language scores (mean, M [SD]) were statistically significantly higher for NFP (313.46 [195.96]) than comparison (282.77 [188.15]; mean difference [MD] 31.33, 95% CI 0.96, 61.71). Maternal‐reported problem‐behaviour scores (M [SD]) were statistically significantly lower for NFP (52.18 [9.19]) than comparison (54.42 [9.02]; MD ‐2.19, 95% CI −3.62, −0.75). Subsequent pregnancy counts were similar (NFP 115 [RPY 230.69] and comparison 117 [RPY 227.29]; rate difference 3.40, 95% CI ‐55.54, 62.34; hazard ratio 1.01, 95% CI 0.79, 1.29). We observed no unanticipated adverse events. Conclusions: NFP did not reduce child injuries or subsequent maternal pregnancies but did improve maternal‐reported child language and mental health (problem behaviour) at age two years. Follow‐up of long‐term outcomes is warranted given that further benefits may emerge across childhood and adolescence. [ABSTRACT FROM AUTHOR]

Wastewater‐based surveillance has become an important tool for research groups and public health agencies investigating and monitoring the COVID‐19 pandemic and other public health emergencies including other pathogens and drug abuse. While there is an emerging body of evidence exploring the possibility of predicting COVID‐19 infections from wastewater signals, there remain significant challenges for statistical modeling. Longitudinal observations of viral copies in municipal wastewater can be influenced by noisy datasets and missing values with irregular and sparse samplings. We propose an integrative Bayesian framework to predict daily positive cases from weekly wastewater observations with missing values via functional data analysis techniques. In a unified procedure, the proposed analysis models severe acute respiratory syndrome coronavirus‐2 RNA wastewater signals as a realization of a smooth process with error and combines the smooth process with COVID‐19 cases to evaluate the prediction of positive cases. We demonstrate that the proposed framework can achieve these objectives with high predictive accuracies through simulated and observed real data. [ABSTRACT FROM AUTHOR]

Background: With recent changes in tobacco and marijuana use patterns, it becomes crucial to understand how the prenatal co‐use of these substances impacts birth outcomes. The goal of this study was to examine the risk of adverse birth outcomes among infants born to women who used tobacco and marijuana concurrently throughout pregnancy compared to infants of women who used tobacco alone. Methods: This study involved a retrospective chart review of pregnant women identified via self‐report or biochemical testing who used tobacco products alone (N = 71) or tobacco and marijuana simultaneously (N = 127) at any point throughout pregnancy. Differences in birth outcomes between these groups, including APGAR (appearance, pulse, grimace, activity, and respiration) scores, respiratory distress, neonatal intensive care unit admission, intrauterine growth restriction, birth weight, birth length, head circumference, gestational age, and length of hospital stay, were analyzed using linear regression and odds ratio analysis. Results: There were no significant differences in outcomes for infants of women who used tobacco and marijuana compared to infants of women who used tobacco alone during pregnancy. Rates of adverse birth outcomes were high among women who used tobacco compared to what would be expected in unexposed pregnancies. Conclusions: Tobacco and marijuana co‐use during pregnancy was not associated with an additional risk of adverse birth outcomes compared to tobacco use alone. Women should be educated on potential risks of marijuana, and especially, tobacco use during pregnancy. These results will inform clinical recommendations for pregnant women using tobacco and marijuana, aiming to decrease preventable adverse outcomes for patients and infants. [ABSTRACT FROM AUTHOR]

Background & Aims: Disorders of gut‐brain interaction (DGBI) are complex conditions that result in decreased quality of life and a significant cost burden. Linaclotide, a guanylin cyclase C (GCC) receptor agonist, is approved as a DGBI treatment. However, its efficacy has been limited and variable across DGBI patients. Microbiota and metabolomic alterations are noted in DGBI patients, provoking the hypothesis that the microbiota may impact the GCC response to current therapeutics. Methods: Human‐derived intestinal organoids were grown from pediatric DGBI, non‐IBD colon biopsies (colonoids). Colonoids were treated with 250 nM linaclotide and assayed for cGMP to develop a model of GCC activity. Butyrate was administered to human colonoids overnight at a concentration of 1 mM. Colonoid lysates were analyzed for cGMP levels by ELISA. For the swelling assay, colonoids were photographed pre‐ and post‐treatment and volume was measured using ImageJ. Principal coordinate analyses (PCoA) were performed on the Bray–Curtis dissimilarity and Jaccard distance to assess differences in the community composition of short‐chain fatty acid (SCFA) producing microbial species in the intestinal microbiota from pediatric patients with IBS and healthy control samples. Key Results: Linaclotide treatment induced a significant increase in [cGMP] and swelling of patient‐derived colonoids, demonstrating a human in vitro model of linaclotide‐induced GCC activation. Shotgun sequencing analysis of pediatric IBS patients and healthy controls showed differences in the composition of commensal SCFA‐producing bacteria. Butyrate exposure significantly dampened linaclotide‐induced cGMP levels and swelling in patient‐derived colonoids. Conclusions & Inferences: Patient‐derived colonoids demonstrate that microbiota‐derived butyrate can dampen human colonic responses to linaclotide. This study supports incorporation of microbiota and metabolomic assessment to improve precision medicine for DGBI patients. [ABSTRACT FROM AUTHOR]

The methodology described in this article enables a type of holistic fleet optimization that simultaneously considers the composition and activity of a fleet through time as well as the design of individual systems within the fleet. Often, real‐world system design optimization and fleet‐level acquisition optimization are treated separately due to the prohibitive scale and complexity of each problem. This means that fleet‐level schedules are typically limited to the inclusion of predefined system configurations and are blind to a rich spectrum of system design alternatives. Similarly, system design optimization often considers a system in isolation from the fleet and is blind to numerous, complex portfolio‐level considerations. In reality, these two problems are highly interconnected. To properly address this system‐fleet design interdependence, we present a general method for efficiently incorporating multi‐objective system design trade‐off information into a mixed‐integer linear programming (MILP) fleet‐level optimization. This work is motivated by the authors' experience with large‐scale DOD acquisition portfolios. However, the methodology is general to any application where the fleet‐level problem is a MILP and there exists at least one system having a design trade space in which two or more design objectives are parameters in the fleet‐level MILP. [ABSTRACT FROM AUTHOR]

Background: The overall incidence of colorectal cancer is decreasing in much of the world, yet the incidence in those under 50 years of age is increasing (early onset colorectal cancer (EOCRC)). The reasons for this are unclear. This study was undertaken to describe the clinical, pathological and familial characteristics of patients with EOCRC and their oncological outcomes and compare this with previously published data on late onset colorectal cancer (LOCRC). Methods: A retrospective review of all patients diagnosed with EOCRC in Canterbury between 2010 and 2017 was conducted. Data was collected on demographics, family history, treatment, and oncologic outcomes. Kaplan–Meier survival curves were calculated to assess overall survival based on disease stage. Results: During the study period (2010–2017) there were 3340 colorectal cancers diagnosed in Canterbury, of which 201 (6%) were in patients under 50 years (range: 17–49). Of these, 87 (43.3%) were female and 125 (62.2%) were aged between 40 and 49 years. 28 (13.9%) were associated with hereditary conditions. Of the 201 patients, 139 (69.2%) had rectal or left‐sided cancers. 142 (70.6%) patients presented with either stage 3 or 4 disease and the 5‐year overall survival by stage was 79.1% and 14.4%, respectively. Conclusion: EOCRC is increasing and usually presents as distal left sided cancers, and often at an advanced stage. They do not appear to have the common risk factors of family history or inherited pre‐disposition for colorectal cancer. Planning by healthcare providers for this epidemiological change is imperative in investigating symptomatic patients under 50 and optimizing early detection and prevention. [ABSTRACT FROM AUTHOR]

Definitive identification of fentanyl analogs based on mass spectral comparison is challenging given the high degree of structural and, hence, spectral similarity. To address this, a statistical method was previously developed in which two electron‐ionization (EI) mass spectra are compared using the unequal variance t‐test. Normalized intensities of corresponding ions are compared, testing the null hypothesis (H0) that the difference in intensity is equal to zero. If H0 is accepted at all m/z values, the two spectra are statistically equivalent at the specified confidence level. If H0 is not accepted at any m/z value, then there is a significant difference in intensity at that m/z value between the two spectra. In this work, the statistical comparison method is applied to distinguish EI spectra of valeryl fentanyl, isovaleryl fentanyl, and pivaloyl fentanyl. Spectra of the three analogs were collected over a 9‐month period and at different concentrations. At the 99.9% confidence level, the spectra of corresponding isomers were statistically associated. Spectra of different isomers were statistically distinct, and ions responsible for discrimination were identified in each comparison. To account for inherent instrument variations, discriminating ions for each pairwise comparison were ranked based on the magnitude of the calculated t‐statistic (tcalc) value. For a given comparison, ions with higher tcalc values are those with the greatest difference in intensity between the two spectra and, therefore, are considered more reliable for discrimination. Using these methods, objective discrimination among the spectra was achieved and ions considered most reliable for discrimination of these isomers were identified. [ABSTRACT FROM AUTHOR]

Despite the ubiquity of poverty, its causes remain largely misunderstood and many attribute poverty to individual shortcomings. This stigma not only predicts negative physical and mental health outcomes for those living in poverty, it also psychologically distances them from the economically advantaged. Thus, solutions to the problem of poverty should include efforts to reduce stigma among the economically advantaged, who are often crucial decision‐makers with the power and resources to act as allies. The current research utilized an intensive and immersive intervention designed to challenge the attributions that underpin poverty stigma. In two studies, we tested the effectiveness of this intervention. Results of both studies demonstrate that participation in the intervention consistently predicted more favorable attributions for poverty, and that these changes in attributions, in turn, had meaningful positive effects on participants' support for poverty‐reducing policies and willingness to engage in poverty‐related allyship. [ABSTRACT FROM AUTHOR]

Cover crop grazing can be used as a strategy to meet nutritional requirements for livestock while simultaneously enhancing soil ecosystem services without sacrificing subsequent crop yield. Field research was conducted in east‐central Mississippi from 2019 to 2021 on a sandy loam soil to assess the impacts that grazing, tillage, and cover crop species had on corn (Zea mays L.) grain yield and soil characteristics. The main plot was grazed (G) and un‐grazed (UG) cover crops, tillage (conventional and no‐till [NT]) was the subplot, and cover crop species the sub‐subplots. Cover crops were grazed using beef (Bos taurus) heifers at a stocking density of approximately 3300 kg ha−1 each growing season as forage mass (FM) allowed. No differences were observed in FM among cover crop treatments; however, FM, crude protein (CP), and total digestible nutrients (TDN) were affected by tillage and grazing. Corn grain yield was unaffected by grazing or tillage but was impacted by cover crop treatment. Cereal rye (Secale cereale L.; 11.99 Mg ha−1), crimson clover (Trifolium incarnatum L.; 11.67 Mg ha−1), and cereal rye + radish (Raphanus sativus L.; 12.07 Mg ha−1) had greater grain yield compared to the un‐planted control (10.99 Mg ha−1). The combination of G × no‐till (NT) resulted in greater penetration resistance (71.07 J); however, G plots contributed to greater organic matter(OM) concentrations. Overall, our data suggest that complimenting G and NT practices does not impact subsequent corn grain yield and could add value to cover cropping systems. Core Ideas: Grazing cover crops and no‐till do not affect corn grain yield.Grazing cover crops increases organic matter concentration.Cover crop species affects corn grain yield. [ABSTRACT FROM AUTHOR]

Objective: To determine if an association between ionized magnesium (iMg) and total magnesium (tMg) exists in healthy and hospitalized dogs admitted through an emergency service and to assess the associations between iMg and tMg with total protein, albumin, ionized calcium, and total calcium. Design: Prospective cohort study. Setting: Veterinary teaching hospital. Animals: Sixty‐nine dogs were enrolled. The healthy control group (group 1) included 24 dogs, and the hospitalized group (group 2) included 45 dogs. Interventions: None. Measurements and Main Results: For both groups, signalment, a venous blood gas, and serum biochemistry were obtained. In addition, the presumptive diagnosis was recorded for group 2. Blood was obtained prior to any therapeutic interventions. Group 1 tMg was within the reference interval (RI), and the values for iMg were used to provide a healthy group range (HGR) of 0.44–0.50 mmol/L. Group 2 tMg was within the RI, but iMg was below the calculated HGR range (group 2 median iMg = 0.4 mmol/L; range = 0.27–0.70). There was a significant positive correlation between iMg and tMg in each group (group 1: r = 0.6713, P = 0.0003; group 2: r = 0.5312, P = 0.0002). Ionized Mg and tMg were not significantly associated with any of the other evaluated variables in either group. Conclusions: Ionized Mg and tMg were significantly associated in both healthy and hospitalized dogs, but the relationship was weaker in the hospitalized dogs compared with the healthy population. For hospitalized dogs, the relationship was weak enough to question the validity of using iMg and tMg interchangeably to track magnesium status. [ABSTRACT FROM AUTHOR]

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Background: Food allergy in infants and young children places a significant burden on primary care. This study evaluated a dietetic‐led paediatric food allergy service, which attempts to provide more rapid access to the dietitian and reduce the need for general practitioner (GP) and secondary care appointments. Methods: Two community dietetic services for children referred with food allergy were compared. The first was dietetic‐led care where dietitians train community children's nurses to recognise potential cases of food allergy, undertake basic diagnostic assessment and subsequently refer to the dietitian. The other was a more traditional dietetic community service where patients were referred predominantly by the GP or secondary care. Results: In dietetic‐led care 86 patients were seen, compared to 96 in dietetic community care. Dietetic‐led care received fewer referrals from the GP, 36% versus 67% (p < 0.001); GP appointments for allergy‐related conditions prior to dietetic referral were lower, 3 versus 6 visits (p = 0.001); and input from secondary care was also lower, 8 versus 25 patients (p = 0.002) compared with dietetic community care. Children referred to dietetic‐led care were younger, 78% <6 months versus 40% (p < 0.001) in dietetic community care. Conclusions: Dietetic‐led care describes a model that has the potential to reduce GP and secondary care appointments, identify patients more quickly and reduce the time to receive dietetic input, thereby resolving symptoms more quickly and reducing prescribed medications. This model demonstrates the importance of integrated care and multidisciplinary working, offering a solution to reducing GP workload while maintaining or improving patient care. Key points: The prevalence of paediatric food allergy is increasing and is an area that has a high impact on the general practitioner (GP) workload.Dietitians play a central role in the management of food allergies in infants and children.Healthcare can be organised in a variety of ways; here a dietetic‐led service is compared to a traditional model of dietetic community care to show the advantages of each.A dietetic‐led model, which focuses on integration of care and multidisciplinary working, offers a potential solution to reduce part of the GP workload while maintaining or improving patient care. [ABSTRACT FROM AUTHOR]

A course on negotiation and dispute resolution might also focus on specific negotiation principles and techniques from the course. This article presents an employment negotiation exercise suitable for use in numerous business courses. By using the negotiation process to figure out what resources and abilities each party brings to the table and aligning their interests, both parties are able to leave the negotiation better off through the creation of value. Many different negotiation techniques and principles can be illustrated by this exercise, but here we set out some specific negotiation issues that could be emphasized in this exercise. In integrative negotiations, more than one party can achieve their goals, and there is an opportunity to create value between the parties through the negotiation process. [Extracted from the article]

Aromatic amides can be used to construct light‐harvesting materials with valuable optical properties. The amide bond is formed using well‐known coupling agents in near quantitative yield, as illustrated here through the synthesis of two boron dipyrromethene derivatives bearing an amide linkage. The primary concern with acyl amides is rotation around the C−N bond, leading to cis and trans isomers. Using NMR spectroscopy, quantum chemical calculations and critical comparison to simpler benzamides, the stereochemistry of the target compounds has been addressed. The N‐cyclohexyl derivative gave diffraction quality crystals that established a trans geometry for the amide bond. Quantum chemical calculations support the trans geometry as being the lowest‐energy structure in solution but indicate that inversion of the aryl ring is an important structural feature. Indeed, rotation around the C(sp2)−C(aryl) bond has a strong influence on the solution‐phase NMR spectra. The amide connection has minimal effect on the photophysical properties. [ABSTRACT FROM AUTHOR]

The target mono‐BF2 complex is weakly emissive in fluid solution because radiationless decay of the excited‐singlet state is promoted through an intramolecular N⋅⋅⋅H−N hydrogen bond. The lack of mirror symmetry for this compound is attributed to vibronic effects, as reported previously for the bis‐BF2 complex (BOPHY). Red‐shifted fluorescence is observed from single crystals, the emission quantum yield approaching 30 % with a fluorescence lifetime of 2 ns. The large Stokes shift of 5,700 cm−1 helps minimize self‐absorption. Crystallography indicates that the internal fold and twist angles are increased substantially in the crystal, but the hydrogen bond is weakened relative to solution. The crystal structure is compiled from pairs of head‐to‐tail molecules having a shift of ca. 4.1 Å and closest approach of ca. 3.5 Å. These molecular pairs are arranged in columns, which, in turn, assemble into sheets. The proximity favors excitonic coupling between individual molecules, with the coupling strength obtained by analysis of the absorption spectrum reaching ca. 1,000 cm−1. Both the ideal dipole approximation and the extended dipole methodology seriously overestimate the coupling strength, but the atomic transition charge density procedure leads to good agreement with experiment. Emission is attributed to the closely coupled molecular pair functioning in an excimer‐like manner with the exciton trapped in a local minimum. Increasing temperature causes a slight blue shift and loss of fluorescence. [ABSTRACT FROM AUTHOR]

Background: Cytology smears are commonly collected during endobronchial ultrasound–guided transbronchial needle aspiration (EBUS TBNA) procedures but are rarely used for molecular testing. Studies are needed to demonstrate their great potential, in particular for the prediction of malignant cell DNA content and for utility in molecular diagnostics using large gene panels. Methods: A prospective study was performed on samples from 66 patients with malignant lymph nodes who underwent EBUS TBNA. All patients had air‐dried, Diff‐Quik cytology smears and formalin‐fixed, paraffin‐embedded cell blocks collected for cytopathology and molecular testing. One hundred eighty‐five smears were evaluated by microscopy to estimate malignant cell percentage and abundance and to calculate smear size and were subjected to DNA extraction. DNA from 56 smears from 27 patients was sequenced with the TruSight Oncology 500 assay (Illumina). Results: Each microscopy parameter had a significant effect on the DNA yield. An algorithm was developed that predicted a >50‐ng DNA yield of a smear with an area under the curve of 0.86. Fifty DNA samples (89%) with varying malignant yields were successfully sequenced. Low‐malignant‐cell content (<25%) and smear area (<15%) were the main reasons for failure. All standard‐of‐care mutations were detected in replicate smears from individual patients, regardless of malignant cell content. Tier 1/2 mutations were discovered in two cases where standard‐of‐care specimens were inadequate for sequencing. Smears were scored for tumor mutation burden. Conclusions: Microscopy of Diff‐Quik smears can triage samples for comprehensive panel sequencing, which highlights smears as an excellent alternative to traditional testing with cell blocks. Diff‐Quik cytology smears are a valuable source of material for molecular testing in lung and other cancers. Even smears yielding low‐malignant‐cell content are of great use in high‐depth, targeted gene panel sequencing assays. [ABSTRACT FROM AUTHOR]

Background: The Acquired Preparedness Model (APM) posits that highly impulsive individuals develop stronger positive alcohol expectancies, which in turn predicts heavier drinking. However, most acquired preparedness studies have focused solely on between‐person relations, despite the theory suggesting that there are potential developmental‐specific within‐person relations. Thus, the current study tested the APM from late adolescence into adulthood, while disaggregating within‐ from between‐person relations. Methods: Data come from a multigenerational study of familial alcohol use disorder (N=653) spanning three waves 5 years apart. Participants reported their lack of conscientiousness, sensation seeking, positive alcohol expectancies, and binge drinking at each wave. First, missing data techniques were used to create a "ghost timepoint," allowing the specification of four developmental‐specific timepoints representing late adolescence (age 18 to 20), emerging adulthood (age 21 to 25), young adulthood (age 26 to 29), and adulthood (age 30 to 39). Second, a Random‐Intercept Cross‐Lagged Panel Model tested between‐person and within‐person relations among variables. Results: At the between‐person level, lower conscientiousness and sensation seeking were correlated with higher positive expectancies, and positive expectancies were correlated with more binge drinking. There were no within‐person prospective relations among conscientiousness, sensation seeking, and positive expectancies. However, within‐person increases in lack of conscientiousness during late adolescence predicted within‐person increases in emerging adult binge drinking, and within‐person increases in late adolescent and emerging adult binge drinking predicted within‐person increases in lack of conscientiousness during emerging and young adulthood, respectively. Similarly, within‐person increases in late adolescent and young adult sensation seeking predicted within‐person increases in binge drinking during emerging adulthood and adulthood, respectively. Binge drinking did not reciprocally predict sensation seeking. Conclusions: Findings suggest that acquired preparedness effects may be between persons rather than within persons. However, several within‐person developmental‐specific relations among conscientiousness, sensation seeking, and binge drinking were observed, outside of expectancies. Findings are discussed in terms of theory and prevention. [ABSTRACT FROM AUTHOR]

Noninvasive delivery of near‐infrared light (IRL) to human tissues has been researched as a treatment for several acute and chronic disease conditions. We recently showed that use of specific IRL wavelengths, which inhibit the mitochondrial enzyme cytochrome c oxidase (COX), leads to robust neuroprotection in animal models of focal and global brain ischemia/reperfusion injury. These life‐threatening conditions can be caused by an ischemic stroke or cardiac arrest, respectively, two leading causes of death. To translate IRL therapy into the clinic an effective technology must be developed that allows efficient delivery of IRL to the brain while addressing potential safety concerns. Here, we introduce IRL delivery waveguides (IDWs) which meet these demands. We employ a low‐durometer silicone that comfortably conforms to the shape of the head, avoiding pressure points. Furthermore, instead of using focal IRL delivery points via fiberoptic cables, lasers, or light‐emitting diodes, the distribution of the IRL across the entire area of the IDW allows uniform IRL delivery through the skin and into the brain, preventing "hot spots" and thus skin burns. The IRL delivery waveguides have unique design features, including optimized IRL extraction step numbers and angles and a protective housing. The design can be scaled to fit various treatment areas, providing a novel IRL delivery interface platform. Using fresh (unfixed) human cadavers and isolated cadaver tissues, we tested transmission of IRL via IDWs in comparison to laser beam application with fiberoptic cables. Using the same IRL output energies IDWs performed superior in comparison to the fiberoptic delivery, leading to an up to 95% and 81% increased IRL transmission for 750 and 940 nm IRL, respectively, analyzed at a depth of 4 cm into the human head. We discuss the unique safety features and potential further improvements of the IDWs for future clinical implementation. [ABSTRACT FROM AUTHOR]

EMC1 encodes subunit 1 of the endoplasmic reticulum (ER) membrane protein complex (EMC), a transmembrane domain insertase involved in membrane protein biosynthesis. Variants in EMC1 are described as a cause of global developmental delay, hypotonia, cortical visual impairment, and commonly, cerebral atrophy on MRI scan. We report an individual with severe global developmental delay and progressive cerebellar atrophy in whom exome sequencing identified a heterozygous essential splice‐site variant in intron‐3 of EMC1 (NM_015047.3:c.287‐1G>A). Whole genome sequencing (WGS) identified a deep intronic variant in intron‐20 of EMC1 (NM_015047.3:c.2588‐771C>G) that was poorly predicted by in silico programs to disrupt pre‐mRNA splicing. Reverse Transcription‐PCR (RT‐PCR) revealed stochastic activation of a pseudo‐exon associated with the c.2588‐771C>G variant and mis‐splicing arising from the c.287‐1G>A variant. This case highlights the utility of WGS and RNA studies to identify and assess likely pathogenicity of deep intronic variants and expands the genotypic and phenotypic spectrum of EMC1‐related disorders. [ABSTRACT FROM AUTHOR]

CCR4‐NOT is a versatile eukaryotic protein complex that controls multiple steps in gene expression regulation from synthesis to decay. In yeast, CCR4‐NOT has been implicated in stress response regulation, though this function in other organisms remains unclear. In a genome‐wide RNAi screen, we identified a subunit of the CCR4‐NOT complex, ccf‐1, as a requirement for the C. elegans transcriptional response to cadmium and acrylamide stress. Using whole‐transcriptome RNA sequencing, we show that the knockdown of ccf‐1 attenuates the activation of a broad range of stress‐protective genes in response to cadmium and acrylamide, including those encoding heat shock proteins and xenobiotic detoxification. Consistently, survival assays show that the knockdown of ccf‐1 decreases C. elegans stress resistance and normal lifespan. A yeast 2‐hybrid screen using a CCF‐1 bait identified the homeobox transcription factor PAL‐1 as a physical interactor. Knockdown of pal‐1 inhibits the activation of ccf‐1 dependent stress genes and reduces C. elegans stress resistance. Gene expression analysis reveals that knockdown of ccf‐1 and pal‐1 attenuates the activation of elt‐2 and elt‐3 under stress that encode master transcriptional co‐regulators of stress response in the C. elegans, and that overexpression of ELT‐2 can suppress ccf‐1's requirement for gene transcription in a stress‐dependent manner. Our findings reveal a new role for CCR4‐NOT in the environmental stress response and define its role in stress resistance and longevity in C. elegans. [ABSTRACT FROM AUTHOR]

Background: Donor‐derived cell free DNA (dd‐cfDNA) and gene expression profiling (GEP) offer noninvasive alternatives to rejection surveillance after heart transplantation; however, there is little evidence on the paired use of GEP and dd‐cfDNA for rejection surveillance. Methods: A single center, retrospective analysis of adult heart transplant recipients. A GEP cohort, transplanted from January 1, 2015 through December 31, 2017 and eligible for rejection surveillance with GEP was compared to a paired testing cohort, transplanted July 1, 2018 through June 30, 2020, with surveillance from both dd‐cfDNA and GEP. The primary outcomes were survival and rejection‐free survival at 1 year post‐transplant. Results: In total 159 patients were included, 95 in the GEP and 64 in the paired testing group. There were no differences in baseline characteristics, except for less use of induction in the paired testing group (65.6%) compared to the GEP group (98.9%), P <.01. At 1‐year, there were no differences between the paired testing and GEP groups in survival (98.4% vs. 94.7%, P =.23) or rejection‐free survival (81.3% vs. 73.7% P =.28). Conclusions: Compared to post‐transplant rejection surveillance with GEP alone, pairing dd‐cfDNA and GEP testing was associated with similar survival and rejection‐free survival at 1 year while requiring significantly fewer biopsies. [ABSTRACT FROM AUTHOR]

Wastewater‐based SARS‐CoV‐2 surveillance enables unbiased and comprehensive monitoring of defined sewersheds. We performed real‐time monitoring of hospital wastewater that differentiated Delta and Omicron variants within total SARS‐CoV‐2‐RNA, enabling correlation to COVID‐19 cases from three tertiary‐care facilities with >2100 inpatient beds in Calgary, Canada. RNA was extracted from hospital wastewater between August/2021 and January/2022, and SARS‐CoV‐2 quantified using RT‐qPCR. Assays targeting R203M and R203K/G204R established the proportional abundance of Delta and Omicron, respectively. Total and variant‐specific SARS‐CoV‐2 in wastewater was compared to data for variant specific COVID‐19 hospitalizations, hospital‐acquired infections, and outbreaks. Ninety‐six percent (188/196) of wastewater samples were SARS‐CoV‐2 positive. Total SARS‐CoV‐2 RNA levels in wastewater increased in tandem with total prevalent cases (Delta plus Omicron). Variant‐specific assessments showed this increase to be mainly driven by Omicron. Hospital‐acquired cases of COVID‐19 were associated with large spikes in wastewater SARS‐CoV‐2 and levels were significantly increased during outbreaks relative to nonoutbreak periods for total SARS‐CoV2, Delta and Omicron. SARS‐CoV‐2 in hospital wastewater was significantly higher during the Omicron‐wave irrespective of outbreaks. Wastewater‐based monitoring of SARS‐CoV‐2 and its variants represents a novel tool for passive COVID‐19 infection surveillance, case identification, containment, and potentially to mitigate viral spread in hospitals. [ABSTRACT FROM AUTHOR]

Purpose: To perform a systematic review that provides an overview of the current literature on fatigue behavior of removable partial denture (RPD) clasp materials based on different retentive areas. Materials and methods: The review followed the Preferred Reporting Items for Systematic Review and Meta‐Analyses (PRISMA) guidelines. Electronic searches were done via PubMed, Scopus, and OVID for studies reporting on RPD clasps and the fatigue failure of clasp materials. Inclusion criteria were English language with full text and in vitro studies only. Exclusion criteria were studies that did not assess the fatigue of RPD clasp materials. A quality assessment and selection of full‐text articles were performed according to Consolidated Standards of Reporting Trials criteria. Results: A total of 182 articles were initially identified and screened. After applying inclusion and exclusion criteria, 15 articles were selected for the final analysis. Seven of the included studies utilized a vertical insertion/removal testing approach. Ten studies used the constant deflection test. Three studies used untapered specimens, and 12 studies used tapered specimens. Ten studies performed post‐test analysis. Conclusions: Cobalt‐chromium (CoCr) is the strongest material in terms of fatigue in relation to the undercut depth and the modern, digitally manufactured RPD clasp materials also exhibit comparable fatigue behavior. Recent RPD clasp materials such as polyetheretherketone (PEEK) or laser sintered CoCr, however, require further study in terms of their fatigue behavior. In order to improve the quality of future studies, a standardized and calibrated fatigue testing method is needed with standardized specimen size and shape, which will reduce the risk of bias and enable meta‐analysis for bulk comparison between studies. [ABSTRACT FROM AUTHOR]

Helically chiral boron‐chelated dipyrromethene (BODIPY) dyes are known to exhibit solution phase circularly polarized luminescence (CPL), but examples are limited to a few synthetically accessible molecular architectures. We report a B−N chelation, SNAr, Suzuki cross‐coupling, B−O chelation cascade reaction for the synthesis of understudied helically chiral, N,N,O,C‐boron chelated, "confused" BODIPYs, from readily accessible 3,5‐dibromo‐BODIPY starting materials. Using this approach we have prepared a series of helically chiral "confused" BODIPYs with variation of the 3,5‐subsitutents. Following resolution by chiral HPLC, absolute stereochemistry was assigned through comparison of the experimental and calculated ECD spectra, and solution phase chiroptical properties including CPL were determined (|glum| from 2.1 to 3.7×10−3; BCPL from 11.3 to 27.2). [ABSTRACT FROM AUTHOR]

Background and aims: Dickkopf‐1 (DKK1) is associated with poor prognosis in intrahepatic cholangiocarcinoma (iCCA), but the mechanisms behind this are unclear. Here, we show that DKK1 plays an immune regulatory role in vivo and inhibition reduces tumour growth. Methods: Various in vivo GEMM mouse models and patient samples were utilized to assess the effects of tumour specific DKK1 overexpression in iCCA. DKK1‐driven changes to the tumour immune microenvironment were characterized by immunostaining and gene expression analysis. DKK1 overexpressing and damage‐induced models of iCCA were used to demonstrate the therapeutic efficacy of DKK1 inhibition in these contexts using the anti‐DKK1 therapeutic, DKN‐01. Results: DKK1 overexpression in mouse models of iCCA drives an increase in chemokine and cytokine signalling, the recruitment of regulatory macrophages, and promotes the formation of a tolerogenic niche with higher numbers of regulatory T cells. We show a similar association of DKK1 with FOXP3 and regulatory T cells in patient tissue and gene expression data, demonstrating these effects are relevant to human iCCA. Finally, we demonstrate that inhibition of DKK1 with the monoclonal antibody mDKN‐01 is effective at reducing tumour burden in two distinct mouse models of the disease. Conclusion: DKK1 promotes tumour immune evasion in iCCA through the recruitment of immune suppressive macrophages. Targeting DKK1 with a neutralizing antibody is effective at reducing tumour growth in vivo. As such, DKK1 targeted and immune modulatory therapies may be an effective strategy in iCCA patients with high DKK1 tumour expression or tolerogenic immune phenotypes. [ABSTRACT FROM AUTHOR]

Objective: To investigate the fatigue behavior of cast and laser‐sintered cobalt‐chromium (CoCr) and polyetheretherketone (PEEK) material for a removable partial denture (RPD) clasps. Methods: Dumbbell‐shaped specimens were digitally designed with the center part of the dumbbell being a half‐round shape at the cross‐sectional dimension of 1.25 mm to simulate a typical clasp design and dimensions. A fatigue machine with an offset axis rotation system simulated a typical undercut depth of 0.25, 0.50, and 0.75 mm. Each group was subjected to 30,000 fatigue cycles (simulating 21 years) or till specimen failure. Before testing, the stress value at each undercut depth for each specimen was established in a universal testing machine and SN curves were plotted for each group. Data were statistically analyzed using Kruskal–Wallis and post hoc tests. The fractured surfaces were analyzed using SEM. Results: The average fatigue cycles with 0.25, 0.50, and 0.75 mm undercuts were 27,155 ± 6277, 9298 ± 4033, 5642 ± 8785 for cast CoCr and 26,765 ± 6150, 11,318 ± 7931, 2861 ± 4803, for laser‐sintered CoCr, respectively. Apart from three specimens, the PEEK groups did not fail during the simulation period. Clasps with 0.25 mm deflection showed significantly higher fatigue resistance than other groups (p <.001). There was no significant difference in fatigue behavior between the cast and laser‐sintered CoCr. Microporosities at the fractured site along with irregular crack propagation were observed for cast and laser‐sintered CoCr specimens. Fatigue‐induced broken polymer crosslinking chains were observed in PEEK specimens. Conclusion: PEEK material exhibited the highest fatigue resistance and significantly lower deflection resistance. Cast and laser‐sintered CoCr showed similar fatigue resistance and behavior. [ABSTRACT FROM AUTHOR]

Objective: Existing gene panels were developed to understand the etiology of epilepsy, and further benefits will arise from an effective pharmacogenomics panel for personalizing therapy and achieving seizure control. Our study assessed the cost‐effectiveness of a pharmacogenomics panel for patients with drug‐resistant epilepsy, compared with usual care. Methods: A cost–utility analysis was employed using a discrete event simulation model. The microsimulation model aggregated the costs and benefits of genetically guided treatment versus usual care for 5000 simulated patients. The 10‐year model combined data from various sources including genomic databases on prevalence of variants, population‐level pharmaceutical claims on antiseizure medications, published long‐term therapy retention rates, patient‐level cost data, and systematic reviews. Incremental cost per quality‐adjusted life‐year (QALY) gained was computed. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model parameters. Results: The mean cost of the genetically guided treatment option was AU$98 199 compared with AU$95 386 for usual care. Corresponding mean QALYs were 4.67 compared with 4.28 for genetically guided and usual care strategies, respectively. The incremental cost per QALY gained was AU$7381. In probabilistic sensitivity analyses, the incremental cost per QALY gained was AU$6321 (95% uncertainty interval = AU$3604–AU$9621), with a 100% likelihood of being cost‐effective in the Australian health care system. The most influential drivers of the findings were the monthly health care costs associated with reduced seizures, costs when seizures continued, and the quality‐of‐life estimates under genetically guided and usual care strategies. Significance: This early economic evaluation of a pharmacogenomics panel to guide treatment for drug‐resistant epilepsy could potentially be cost‐effective in the Australian health care system. Clinical trial evidence is necessary to confirm these findings. [ABSTRACT FROM AUTHOR]

The clinical classification of variants may change with new information, however, there is limited guidance on how often significant changes in variant classification occur. We used ClinVar to examine how variant classification changes over time. We developed a custom parser and accessed variant data from ClinVar between January 2015 and July 2021. The ClinVar‐assigned "aggregate" classification of variants in 121 hereditary cancer genes was harmonized across releases to align to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology terms. Aggregate classification categories were grouped as: benign/likely benign (B/LB); likely pathogenic/pathogenic (LP/P); variant of uncertain significance (VUS); conflicting interpretations of pathogenicity (Conflicting); or Other. We profiled changes in aggregate variant classification between consecutive semi‐annual ClinVar releases. The proportion of variants that changed aggregate classification between semi‐annual ClinVar releases ranged from 0.6% to 6.4%. The most frequent changes were "VUS to conflicting," "other to LP/P," and "B/LB to Conflicting." A limited number of variants changed aggregate classification from "LP/P to B/LB," or vice versa. Our analysis indicates need for regular reassessment of clinical variant interpretations. The parser developed for this project will facilitate extraction of relevant interpretation data from ClinVar. [ABSTRACT FROM AUTHOR]

The objective of this phenomenological study was to describe families' experiences of supporting veterans and emergency service first responders (ESFRs) (known also as public safety personnel) to seek help for a mental health problem. In‐depth semi‐structured open‐ended interviews were undertaken with 25 family members of Australian veterans and ESFRs. Fourteen participants were family members of police officers. Data were analysed thematically. Participants described a long and difficult journey of supporting the person's help‐seeking across six themes. Traumatic exposures, bullying in the workplace and lack of organisational support experienced by veterans/ESFRs caused significant family distress. Families played a vital role in help‐seeking but were largely ignored by veteran/ESFR organisations. The research provides a rich understanding of distress and moral injury that is experienced not only by the service members but is transferred vicariously to their family within the mental health help‐seeking journey. Veteran and ESFR organisations and mental health services need to shift from a predominant view of distress as located within an individual (intrapsychic) towards a life‐course view of distress as impacting families and which is more relational, systemic, cultural and contextual. [ABSTRACT FROM AUTHOR]

Background: Language regression, broadly defined as the loss of acquired language skills in early childhood, is a distinctive feature of autism. Little is known about the factors underlying regression or the prognosis of children who exhibit regression. We examine potential predictors of language regression and test its association with language development in a prospective longitudinal sample of children with autism spectrum disorder (ASD) from diagnosis to age 10 years. Methods: We analysed data from Pathways in ASD, a prospective longitudinal study of 421 children enrolled around the time of an autism diagnosis between 2 and 5 years. Autism Diagnostic Interview‐Revised data were available for 408 children, of whom 90 (22%) were classified as having language regression. Results: Demographic and other health factors including caregiver education, family income, child sex, reported seizures, and age of enrolment did not differ between children with and without language regression. Children with language regression walked earlier and attained first words sooner than those without regression. However, both groups attained phrase speech at comparable ages. Those with regression exhibited greater delays in expressive and receptive communication over the follow‐up period, although this effect was attenuated when accounting for baseline differences in motor and cognitive ability. Overall, those with language regression continued to exhibit expressive but not receptive communication delay compared to those without regression. Communication trajectories were heterogeneous to age 10 years, irrespective of regression status. Conclusions: Although language regression can be alarming, our findings confirm that its occurrence does not necessarily foreshadow worse developmental outcomes relative to those without regression. Although a discrepancy in age‐equivalent communication skills may persist, this can be expected to be of less practical importance with rising average levels of skills. Future studies need to account for the significant variability in language trajectories by considering factors beyond developmental regression. [ABSTRACT FROM AUTHOR]

Ditetrelenes R2E=ER2 (E=Si, Ge, Sn, Pb) substituted by multiple N/P/O/S‐donor groups are extremely rare due to their propensity to disaggregate into their tetrylene monomers R2E. We report the synthesis of the first fully phosphanyl‐substituted digermene {(Mes)2P}2Ge=Ge{P(Mes)2}2 (3, Mes=2,4,6‐Me3C6H2), which adopts a highly unusual structure in the solid state, that is both strongly trans‐bent and highly twisted. Variable‐temperature 31P{1H} NMR spectroscopy suggests that 3 persists in solution, but is subject to a dynamic equilibrium between two conformations, which have different geometries about the Ge=Ge bond (twisted/non‐twisted) due to a difference in the nature of their π‐stacking interactions. Compound 3 undergoes unprecedented, spontaneous decomposition in solution to give a unique GeI cluster {(Mes)2P}4Ge4⋅5 CyMe (7). [ABSTRACT FROM AUTHOR]

Synthetically straightforward π‐extension of helically chiral N,N,O,O‐boron chelated borondipyrromethenes (BODIPYs) has been achieved by incorporation of naphthyl rings into the BODIPY 3‐ and 5‐positions. The effect of this extension on the photophysical and chiroptical properties is strongly dependent on the regiochemistry of the naphthyl substituents (4 exo, 4 lin, 4 endo). The most helicene‐like regioisomer 4 endo is a near infra‐red (NIR) emitter (λemmax=751 nm) with an emission band between 675–875 nm, displaying circularly polarised luminescence (CPL) with a luminescence dissymmetry factor, |glum|=5.7×10−3 and CPL brightness, BCPL=27, rivalling the best NIR CPL‐emitting small organic molecules reported to date. [ABSTRACT FROM AUTHOR]

Objective: Reductions in substance involvement into adulthood are thought to represent a normative maturing out of substance use. However, patterns and predictors of maturing out of alcohol and cannabis co‐use remain largely unstudied. Therefore, the current study tested developmental trajectories of alcohol and cannabis use from late adolescence into adulthood and whether late adolescent personality traits predicted trajectory class membership. Methods: Data come from a longitudinal study of family history of alcohol disorder (N = 458). Age bands were created to model trajectories of drinking quantity, negative alcohol consequences, and cannabis use frequency from late adolescence (age 18–22) to young adulthood (age 23–28) and adulthood (age 29–36). Participants reported on their sensation seeking, conscientiousness, and neuroticism during late adolescence and their typical drinking quantity, negative alcohol consequences, and cannabis use frequency at each age band. Results: Three trajectory classes were derived from an initial Parallel Process Growth Mixture Model: (1) low‐risk maturing out of alcohol‐only use, (2) high‐risk maturing out of co‐use, and (3) high‐risk switchers who increased their cannabis use into adulthood. Late adolescent sensation seeking was associated with higher odds of being in both co‐use trajectories, whereas a lack of conscientiousness was associated with higher odds of being a co‐use switcher. Conclusions: We identified heterogeneity in trajectories of co‐use, which suggests that a lack of maturing out of alcohol involvement may be accompanied by increased cannabis use. Moreover, late adolescent personality traits may predispose individuals toward riskier developmental trajectories of substance use into adulthood. [ABSTRACT FROM AUTHOR]

β‐catenin signaling, and angiogenesis are associated with colospheroid (CSC), development. CSCs, spheroids derived from colon cancer cells, are responsible for metastasis, drug resistance, and disease recurrence. Whether dysregulating β‐catenin and inhibiting angiogenesis reduce CSC growth is unknown. In this study, the molecular mechanism of CSC growth inhibition was evaluated using a novel combination of melatonin (MLT) and andrographolide (AGP). These drugs have anticarcinogenic, antioxidant, and antimetastatic properties. CSCs were obtained from two metastatic colon cancer cell lines (HT29 and HCT‐15). The viability and stemness were monitored (FDA propidium iodide staining and immunoblot for CD44, CD133, Nanog, Sox2, and Oct4). The drug combination synergistically diminished stemness via increased reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential and ATP level. MLT + AGP induced cell death by inhibiting β‐catenin expression and its downregulatory signals, Cyclin D1, c‐Myc. MLT + AGP treated cells exhibited translocation of phospho‐β‐catenin to the nucleus and dephosphorylated‐β‐catenin. Downregulation of β‐catenin activation and its transcription factors (TCF4 and LEF1) and GTP binding/G‐protein related activity were found in the dual therapy. Angiogenic inhibition is consistent with downregulation of VEGF messenger RNA transcripts (VEGF189), phosphorylated VEGF receptor protein expression, matrigel invasion, and capillary tube inhibition. In vivo, the intravenous injection of MLT + AGP slowed HT29 metastatic colon cancer. Histopathology indicated significant reduction in microvascular density and tumor index. Immunohistochemistry for caspase 7, and β‐catenin found increased apoptosis and downregulation of β‐catenin signals. The mechanism(s) of decreased colospheroids growth were the inhibition of the Wnt/β‐catenin pathway. Our results provide a rationale for using MLT in combination with AGP for the inhibition of CRCs. [ABSTRACT FROM AUTHOR]

Background and aim: Opioid agonist medications for treatment of opioid use disorder (OUD) can improve human immunodeficiency virus (HIV) outcomes and reduce opioid use. We tested whether outpatient antagonist treatment with naltrexone could achieve similar results. Design Open‐label, non‐inferiority randomized trial. Setting: Six US HIV primary care clinics. Participants: A total of 114 participants with untreated HIV and OUD (62% male; 56% black, 12% Hispanic; positive for fentanyl (62%), other opioids (47%) and cocaine (60%) at baseline). Enrollment halted early due to slow recruitment. Intervention: HIV clinic‐based extended‐release naltrexone (XR‐NTX; n = 55) versus treatment as usual (TAU) with buprenorphine or methadone (TAU; n = 59). Measurements Treatment group differences were compared for the primary outcome of viral suppression (HIV RNA ≤ 200 copies/ml) at 24 weeks and secondary outcomes included past 30‐day use of opioids at 24 weeks. Findings Fewer XR‐NTX participants initiated medication compared with TAU participants (47 versus 73%). The primary outcome of viral suppression was comparable for XR‐NTX (52.7%) and TAU (49.2%) [risk ratio (RR) = 1.064; 95% confidence interval (CI) = 0.748, 1.514] at 24 weeks. Non‐inferiority could not be demonstrated, as the lower confidence limit of the RR did not exceed the pre‐specified margin of 0.75 in intention‐to‐treat (ITT) analysis. The main secondary outcome of past 30‐day opioid use was comparable for XR‐NTX versus TAU (11.7 versus 14.8 days; mean difference = −3.1; 95% CI = –8.7, 1.1) in ITT analysis. Among those initiating medication, XR‐NTX resulted in fewer days of opioid use compared with TAU in the past 30 days (6.0 versus 13.6, mean difference = −7.6; 95% CI = –13.8, −0.2). Conclusions: A randomized controlled trial found supportive, but not conclusive, evidence that human immunodeficiency virus clinic‐based extended‐release naltrexone is not inferior to treatment as usual for facilitating human immunodeficiency virus viral suppression. Participants who initiated extended‐release naltrexone used fewer opioids than those who received treatment as usual. [ABSTRACT FROM AUTHOR]

Species are responding to global climate change in varied and nuanced ways. However, how species‐specific responses to climate change= affect interactions among species remains poorly understood. It is important to understand species interactions under potential climate change scenarios because those interactions can in turn alter community dynamics.In this study, we conducted two complementary experiments to examine how simulated warming might alter larval intraguild predation (IGP) rates and resulting adult assemblage composition in three species of North American dragonflies: Pachydiplax longipennis, Plathemis lydia and Libellula luctuosa.First, using both P. longipennis and L. luctuosa, we isolated interspecific and intraspecific pairs of larval dragonflies of different size differentials to determine how the size and species identity might influence IGP rates.In tandem, we conducted a year‐long mesocosm experiment with all three species to assess how simulated warming and heat waves influenced the resulting adult dragonfly assemblages.IGP trials revealed that P. longipennis individuals were much more likely to engage in IGP than L. luctuosa, regardless of size differential. In the mesocosm experiment, emerging adult assemblages were dominated by P. longipennis individuals, a pattern that was most pronounced in the control treatment.Our results indicate that while P. longipennis may be the competitively dominant species under current ambient conditions, warming may alter this dynamic and lessen the dominance of this species on the resulting assemblage composition. [ABSTRACT FROM AUTHOR]

Objective: Type 2 diabetes (T2D) is associated with significant end‐organ damage and ectopic fat accumulation. Multiparametric magnetic resonance imaging (MRI) can provide a rapid, noninvasive assessment of multiorgan and body composition. The primary objective of this study was to investigate differences in visceral adiposity, ectopic fat accumulation, body composition, and relevant biomarkers between people with and without T2D. Methods: Participant demographics, routine biochemistry, and multiparametric MRI scans of the liver, pancreas, visceral and subcutaneous adipose tissue, and skeletal muscle were analyzed from 266 participants (131 with T2D and 135 without T2D) who were matched for age, gender, and BMI. Wilcoxon and χ2 tests were performed to calculate differences between groups. Results: Participants with T2D had significantly elevated liver fat (7.4% vs. 5.3%, p = 0.011) and fibroinflammation (as assessed by corrected T1 [cT1]; 730 milliseconds vs. 709 milliseconds, p = 0.019), despite there being no differences in liver biochemistry, serum aspartate aminotransferase (p = 0.35), or alanine transaminase concentration (p = 0.11). Significantly lower measures of skeletal muscle index (45.2 cm2/m2 vs. 50.6 cm2/m2, p = 0.003) and high‐density lipoprotein cholesterol (1.1 mmol/L vs. 1.3 mmol/L, p < 0.0001) were observed in participants with T2D. Conclusions: Multiparametric MRI revealed significantly elevated liver fat and fibroinflammation in participants with T2D, despite normal liver biochemistry. This study corroborates findings of significantly lower measures of skeletal muscle and high‐density lipoprotein cholesterol in participants with T2D versus those without T2D. [ABSTRACT FROM AUTHOR]

Ventricular arrhythmias can cause death in heart failure (HF). A trigger is the occurrence of Ca2+ waves which activate a Na+‐Ca2+ exchange (NCX) current, leading to delayed after‐depolarisations and triggered action potentials. Waves arise when sarcoplasmic reticulum (SR) Ca2+ content reaches a threshold and are commonly induced experimentally by raising external Ca2+, although the mechanism by which this causes waves is unclear and was the focus of this study. Intracellular Ca2+ was measured in voltage‐clamped ventricular myocytes from both control sheep and those subjected to rapid pacing to produce HF. Threshold SR Ca2+ content was determined by applying caffeine (10 mM) following a wave and integrating wave and caffeine‐induced NCX currents. Raising external Ca2+ induced waves in a greater proportion of HF cells than control. The associated increase of SR Ca2+ content was smaller in HF due to a lower threshold. Raising external Ca2+ had no effect on total influx via the L‐type Ca2+ current, ICa‐L, and increased efflux on NCX. Analysis of sarcolemmal fluxes revealed substantial background Ca2+ entry which sustains Ca2+ efflux during waves in the steady state. Wave frequency and background Ca2+ entry were decreased by Gd3+ or the TRPC6 inhibitor BI 749327. These agents also blocked Mn2+ entry. Inhibiting connexin hemi‐channels, TRPC1/4/5, L‐type channels or NCX had no effect on background entry. In conclusion, raising external Ca2+ induces waves via a background Ca2+ influx through TRPC6 channels. The greater propensity to waves in HF results from increased background entry and decreased threshold SR content. Key points: Heart failure is a pro‐arrhythmic state and arrhythmias are a major cause of death.At the cellular level, Ca2+ waves resulting in delayed after‐depolarisations are a key trigger of arrhythmias. Ca2+ waves arise when the sarcoplasmic reticulum (SR) becomes overloaded with Ca2+.We investigate the mechanism by which raising external Ca2+ causes waves, and how this is modified in heart failure.We demonstrate that a novel sarcolemmal background Ca2+ influx via the TRPC6 channel is responsible for SR Ca2+ overload and Ca2+ waves.The increased propensity for Ca2+ waves in heart failure results from an increase of background influx, and a lower threshold SR content.The results of the present study highlight a novel mechanism by which Ca2+ waves may arise in heart failure, providing a basis for future work and novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Objectives: There is an urgent need to be able to identify individuals with asymptomatic Leishmania donovani infection, so their risk of progressing to VL and transmitting parasites can be managed. This study examined transcriptional markers expressed by CD4+ T cells that could distinguish asymptomatic individuals from endemic controls and visceral leishmaniasis (VL) patients. Methods: CD4+ T cells were isolated from individuals with asymptomatic L. donovani infection, endemic controls and VL patients. RNA was extracted and RNAseq employed to identify differentially expressed genes. The expression of one gene and its protein product during asymptomatic infection were evaluated. Results: Amphiregulin (AREG) was identified as a distinguishing gene product in CD4+ T cells from individuals with asymptomatic L. donovani infection, compared to VL patients and healthy endemic control individuals. AREG levels in plasma and antigen‐stimulated whole‐blood assay cell culture supernatants were significantly elevated in asymptomatic individuals, compared to endemic controls and VL patients. Regulatory T (Treg) cells were identified as an important source of AREG amongst CD4+ T‐cell subsets in asymptomatic individuals. Conclusion: Increased Treg cell AREG expression was identified in individuals with asymptomatic L. donovani infection, suggesting the presence of an ongoing inflammatory response in these individuals required for controlling infection and that AREG may play an important role in preventing inflammation‐induced tissue damage and subsequent disease in asymptomatic individuals. [ABSTRACT FROM AUTHOR]