Search

Abstract As genotype databases increase in size, so too do the number of detectable segments of identity by descent (IBD): segments of the genome where two individuals share an identical copy of one of their two parental haplotypes, due to shared ancestry. We show that given a large enough genotype database, these segments of IBD collectively overlap entire chromosomes, including instances of IBD that span multiple chromosomes, and can be used to accurately separate the alleles inherited from each parent across the entire genome. The resulting phase is not an improvement over state-of-the-art local phasing methods, but provides accurate long-range phasing that indicates which of two haplotypes in different regions of the genome, including different chromosomes, was inherited from the same parent. We are able to separate the DNA inherited from each parent completely, across the entire genome, with 98% median accuracy in a test set of 30,000 individuals. We estimate the IBD data requirements for accurate genome-wide phasing, and we propose a method for estimating confidence in the resulting phase. We show that our methods do not require the genotypes of close family, and that they are robust to genotype errors and missing data. In fact, our method can impute missing data accurately and correct genotype errors.

The article examines canine gastrointestinal stromal tumors (GISTs) for gross, histologic and immunohistochemical features including CD34, AgNOR and Ki67 labeling to assist in the diagnosis, provide prognostic information and offer target for therapy. Positive correlations were noted between proliferation indicators AgNOR, Ki67 and mitotic index, and significant differences were noted in such proliferation indices between small and large intestinal tumors. It believes that the study is the first report to describe CD34 immunoreactivity in canine GISTs.

Acute respiratory distress syndrome (ARDS) results in decreased quality of life, including increased risk of pulmonary hypertension (PH). In animal models, ARDS can be induced by lipopolysaccharide (LPS), which can disrupt the pulmonary endothelium and epithelium and induce inflammation. We tested whether in vivo administration or ex vivo treatment with LPS alters the reactivity of intrapulmonary arteries and airways to constrictors relevant to both ARDS and PH, using the precision cut lung slice (PCLS) technique. Mice were administered LPS (10μg/50μl, intranasal) or saline daily for 4d before collection of bronchoalveolar lavage fluid (BALF) or preparation of PCLS. Alternatively, PCLS from naïve mice were left untreated or treated ex vivo with LPS (10μg/mL) or tumour necrosis factor (TNF, 10ng/mL) for 18h. Contraction to endothelin-1 (ET-1), U46619 (a stable mimetic of TXA 2 ) or serotonin (5HT) were quantified. In vivo LPS administration increased BAL total inflammatory cells 5-fold, neutrophils 125-fold and protein 2-fold, as well as the thickness of the pulmonary arterial smooth muscle layer. After in vivo LPS, contraction of intrapulmonary arteries in PCLS to ET-1 and U46619, but not 5HT, increased, while bronchoconstrictor responses were unchanged. In PCLS treated with LPS ex vivo , these differential effects on pulmonary artery and airway contraction were maintained. While LPS increased TNF secretion from PCLS, TNF treatment only increased U46619-induced vasoconstriction. This study demonstrates the potential contributions of LPS-induced inflammation and vascular remodelling to altered intrapulmonary artery reactivity to specific agonists with implications for ARDS-associated PH.

Veterinary pathology credentials serve as a concise means attesting to educational attainments and experiences indicating a readiness for professional practice. Given the cost, time, and stress associated with obtaining different qualifications, pathologists must consider what credentials enhance their readiness. In this commentary, the authors describe how their various degrees and certifications have facilitated their individual and organizational success. The minimum credentials for proficient veterinary pathology practice are a veterinary medical degree (DVM or equivalent) and advanced pathology training (residency and/or on-the-job "apprenticeship") ideally culminating in board certification in pathology (American College of Veterinary Pathologists [ACVP] diplomate status or equivalent). Graduate degrees (MS, PhD, MPH, etc) and/or other qualifications in allied biomedical fields (eg, board certification in internal medicine, laboratory animal medicine, poultry medicine, preventive medicine, or toxicology) may improve employability by affirming specialty knowledge in another complementary discipline. The authors note that pathology positions may be obtained without a long list of degrees or certifications, and that more credentials may provide occupational flexibility for some employers. However, a good work ethic, experience in the field, ability to adapt to changes, job satisfaction, good attitude, and demonstrated productivity are also important, and indeed, they are often the paramount criteria for career success as a veterinary pathologist., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Diet is associated with major adverse cardiovascular events (MACE)., Objective: We evaluated the associations between empirically derived dietary patterns and MACE., Design: Prospective cohort study., Setting: The Concord Health and Ageing in Men Project, Sydney, Australia., Participants: 539 community-dwelling older Australian men aged 75 years and older., Methods: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Cox regression analyses were conducted between MACE and the three dietary patterns identified from factor analysis. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality., Results: At a median of 5.3 (IQR 4.6-6.3) years of follow-up, the incidences were: five-point MACE 31.2% (n = 168); four-point MACE excluding all-cause mortality 17.8% (n = 96); all-cause mortality 20.1% (n = 111); CCF 11.3% (n = 61); MI 3.7% (n = 20); stroke 3.2% (n = 17); and coronary revascularisation 3.1% (n = 15). In fully adjusted analyses, compared to the bottom tertile, the middle tertile of 'vegetables-legumes-seafood' dietary pattern was associated with reduced five-point MACE (HR 0.67 [95% CI: 0.45, 0.99, P = .047]), and CCF (HR 0.31 [95% CI: 0.15, 0.65, P = .002]), whilst the middle tertile of 'wholegrains-milk-other fruits' dietary pattern was associated with increased five-point MACE (HR 1.78 [95% CI: 1.17, 2.70, P = .007]), four-point MACE (HR 1.92 [95% CI: 1.12, 3.30, P = .018]), and CCF (HR 2.33 [95% CI: 1.17, 4.65, P = .016]). For the 'discretionary-starchy vegetables-processed meats' dietary pattern, a higher score was associated with increased five-point MACE (HR 1.33 [95% CI: 1.09, 1.62, P = .004]), and all-cause mortality (HR 1.63 [95% CI: 1.26, 2.12, P < .001]), and compared to the bottom tertile, the top tertile was associated with increased all-cause mortality (HR 2.26 [95% CI: 1.27, 4.00, P = .005])., Conclusion: Older men may benefit from consuming a 'vegetables-legumes-seafood' dietary pattern rather than 'discretionary-starchy vegetables-processed meats' and 'wholegrains-milk-other fruits' dietary patterns for the prevention of MACE., (Copyright © 2023. Published by Elsevier Masson SAS.)

Prostate cancer is ranked second in the world for cancer-related deaths in men, highlighting the lack of effective therapies for advanced-stage disease. Toll-like receptors (TLRs) and immunity have a direct role in prostate cancer pathogenesis, but TLR9 has been reported to contribute to both the progression and inhibition of prostate tumorigenesis. To further understand this apparent disparity, we have investigated the effect of TLR9 stimulation on prostate cancer progression in an immune-competent, syngeneic orthotopic mouse model of prostate cancer. Here, we utilized the class B synthetic agonist CPG-1668 to provoke a TLR9-mediated systemic immune response and demonstrate a significant impairment of prostate tumorigenesis. Untreated tumors contained a high abundance of immune-cell infiltrates. However, pharmacological activation of TLR9 resulted in smaller tumors containing significantly fewer M1 macrophages and T cells. TLR9 stimulation of tumor cells in vitro had no effect on cell viability or its downstream transcriptional targets, whereas stimulation in macrophages suppressed cancer cell growth via type I IFN. This suggests that the antitumorigenic effects of CPG-1668 were predominantly mediated by an antitumor immune response. This study demonstrated that systemic TLR9 stimulation negatively regulates prostate cancer tumorigenesis and highlights TLR9 agonists as a useful therapeutic for the treatment of prostate cancer.

Background: Diet may be associated with frailty., Objective: We aimed to evaluate the associations between empirically derived dietary patterns and frailty in older men., Design: Prospective cohort study., Setting: The Concord Health and Ageing in Men Project, Sydney, Australia., Participants: 785 community-dwelling older Australian men aged 75 years and older., Methods: Men underwent dietary assessment using a validated dietitian-administered diet history questionnaire. Factor analysis identified three dietary patterns. Multinomial logistic regression was conducted between frailty and dietary patterns for cross-sectional analyses and longitudinal analyses over a 3-year follow-up. Frailty was defined by the Fried frailty phenotype., Results: Of the 785 men, pre-frailty was prevalent in 47.1% (n = 370), and frailty in 8.3% (n = 65). In fully adjusted cross-sectional analyses, the top tertile and a higher 'vegetables-legumes-seafood' dietary pattern score were associated with reduced prevalence of frailty (OR 0.34 [95% CI: 0.12, 0.93, P = .036]) and OR 0.50 [95% CI: 0.30, 0.83, P = .007] respectively). The top tertile of the 'discretionary-starchy vegetables-processed meats' dietary pattern was also associated cross-sectionally with increased prevalence of pre-frailty (OR 1.75 [95% CI: 1.08, 2.83, P = .022]). Of the 296 robust men in fully adjusted longitudinal analyses, the incidence of pre-frailty was 52.4% (n = 155), and frailty was 5.4% (n = 16) over a 3-year follow-up. The middle tertile of the 'vegetables-legumes-seafood' dietary pattern had a non-significant trend towards reduced incident pre-frailty (OR 0.52 [95% CI: 0.27, 1.00, P = .050])., Conclusion: Consumption of a 'vegetables-legumes-seafood' dietary pattern appears to be less favoured by frail older men., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Objective: Diets with a low proportion of energy from protein have shown to cause overconsumption of non-protein energy, known as Protein Leverage. Older adults are susceptible to nutritional inadequacy. The aim was to investigate associations between protein to non-protein ratio (P:NP) and intakes of dietary components and assess the nutritional adequacy of individuals aged 65-75 years from the Nutrition for Healthy Living (NHL) Study., Design: Cross-sectional. Nutritional intakes from seven-day weighed food records were compared with the Nutrient Reference Values for Australia and New Zealand, Australian Guide to Healthy Eating, Australian Dietary Guidelines and World Health Organisation Free Sugar Guidelines. Associations between P:NP and intakes of dietary components were assessed through linear regression analyses., Setting: NHL Study., Participants: 113 participants., Results: Eighty-eight (59 female and 29 male) with plausible dietary data had a median (interquartile range) age of 69 years (67-71), high education level (86 %) and sources of income apart from the age pension (81 %). Substantial proportions had intakes below recommendations for dairy and alternatives (89 %), wholegrain (89 %) and simultaneously exceeded recommendations for discretionary foods (100 %) and saturated fat (92 %). In adjusted analyses, P:NP (per 1 % increment) was associated with lower intakes of energy, saturated fat, free sugar and discretionary foods and higher intakes of vitamin B 12 , Zn, meat and alternatives, red meat, poultry and wholegrain % (all P < 0·05)., Conclusions: Higher P:NP was associated with lower intakes of energy, saturated fat, free sugar and discretionary. Our study revealed substantial nutritional inadequacy in this group of higher socio-economic individuals aged 65-75 years.

Measurement invariance-the notion that the measurement properties of a scale are equal across groups, contexts, or time-is an important assumption underlying much of psychology research. The traditional approach for evaluating measurement invariance is to fit a series of nested measurement models using multiple-group confirmatory factor analyses. However, traditional approaches are strict, vary across the field in implementation, and present multiplicity challenges, even in the simplest case of two groups under study. The alignment method was recently proposed as an alternative approach. This method is more automated, requires fewer decisions from researchers, and accommodates two or more groups. However, it has different assumptions, estimation techniques, and limitations from traditional approaches. To address the lack of accessible resources that explain the methodological differences and complexities between the two approaches, we introduce and illustrate both, comparing them side by side. First, we overview the concepts, assumptions, advantages, and limitations of each approach. Based on this overview, we propose a list of four key considerations to help researchers decide which approach to choose and how to document their analytical decisions in a preregistration or analysis plan. We then demonstrate our key considerations on an illustrative research question using an open dataset and provide an example of a completed preregistration. Our illustrative example is accompanied by an annotated analysis report that shows readers, step-by-step, how to conduct measurement invariance tests using R and Mplus. Finally, we provide recommendations for how to decide between and use each approach and next steps for methodological research. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Background: Nutritional intake can influence major adverse cardiovascular events (MACE). Dietary iron is found in two forms: haem-iron (HI) only found in animal sources and non-haem iron (NHI) present mostly in plant sources., Objective: We evaluated the associations between dietary iron intakes with MACE and iron status biomarkers., Design: Prospective cohort study., Setting: The Concord Health and Ageing in Men Project, Sydney, Australia., Participants: 539 community-dwelling older Australian men aged 75 years and older., Methods: Men underwent nutritional assessment using a validated diet history questionnaire. Entries were converted to food groups and nutrients. The dietary calculation was used to derive HI and NHI intakes from total iron intakes. Analyses of iron intakes with iron status biomarkers were conducted using linear regression, and with MACE and individual endpoints were conducted using Cox regression. Five-point MACE comprised of all-cause mortality, myocardial infarction (MI), congestive cardiac failure (CCF), coronary revascularisation, and/or ischaemic stroke. Four-point MACE included the four endpoints of MI, CCF, coronary revascularisation, and/or ischaemic stroke, and excluded all-cause mortality., Results: At a median of 5.3 (4.6 - 6.3) years follow-up, the incidences were: 31.2% (n = 168) five-point MACE, 17.8% (n = 96) four-point MACE excluding all-cause mortality, 20.1% (n = 111) all-cause mortality, 11.3% (n = 61) CCF, and 3.1% (n = 15) coronary revascularisation. In adjusted analyses, higher HI intake (per 1mg increment) was associated with increased five-point MACE (HR: 1.45 [95% CI: 1.16, 1.80, P = .001]), four-point MACE excluding all-cause mortality (HR: 1.64 [95% CI: 1.26, 2.15, P <.001]), all-cause mortality (HR: 1.51 [95% CI: 1.15, 1.99, P = .003]), CCF (HR: 2.08 [95% CI: 1.45, 2.98, P <.001]), and coronary revascularisation (HR: 1.89 [95% CI: 1.15, 3.10, P = .012]). Compared with the bottom tertile of NHI intake, the middle tertile of NHI intake was associated with reduced risk of all-cause mortality (HR: 0.56 [95% CI: 0.33, 0.96, P = .035]). Total iron intake was not associated with MACE and individual endpoints. Dietary iron intakes were not associated with serum iron and haemoglobin., Conclusion: Higher haem iron intake was independently associated with increased risks of five-point MACE, four-point MACE excluding all-cause mortality, all-cause mortality, CCF, and coronary revascularisation in older men over 5 years., Competing Interests: The authors declare no conflicts of interest.

Background: Sexual assault remains a highly prevalent crime worldwide and has the potential to cause a number of short and longer-term health sequelae. Complainants of recent sexual assault may undergo forensic and/or medical examinations for medical treatment or evidence collection, or both. However, the frequency and severity of acute health concerns requiring medical intervention in these patients at the time of examination is not well understood and has implications for their clinical care and safety., Aims & Objectives: To examine the frequency and severity of acute concomitant health concerns at the time of forensic examination following an allegation of recent sexual assault in post-pubertal (age >13 years) individuals, through a review of existing literature. Concomitant health concerns considered in this review include ano-genital and extra-genital injury, and acute substance intoxication., Methods: Four online databases (PubMed, Ovid Medline, CINAHL, Embase) were systematically searched with key terms regarding the topics of sexual assault, forensic examination, injury and intoxication. Articles were assessed for relevance based on inclusion and exclusion criteria., Results: Of 562 titles, 53 full-text publications met the inclusion criteria. Frequency of ano-genital and extra-genital injury was highly variable across studies, and severity was inconsistently assessed and rarely reported. Medical treatment or transfer to acute care settings was more commonly required for extra-genital injuries. Non-fatal strangulation (NFS) was found to represent an increasingly frequent feature of sexual assault cases. NFS complainants often exhibit signs and symptoms of potentially lethal complications requiring urgent review in acute care settings. Substance use around the time of sexual assault was commonly reported by patients and detected in toxicological screens, and could have significant implications on patient and staff safety at the time of examination., Conclusion: The findings of this review highlight the clinical significance of acute concomitant health concerns following an allegation of recent sexual assault. Ano-genital and extra-genital injury, NFS and both voluntary and involuntary substance use may be more frequent and severe than previously understood. Further investigation into the assessment and management of these acute health needs is required to elucidate their clinical significance and inform evidence-based care for complainants of sexual assault., (Copyright © 2022 Elsevier Ltd and Faculty of Forensic and Legal Medicine. All rights reserved.)

Background: Nutritional intake could influence the development of frailty. The aim was to evaluate the associations between dietary iron intakes and changes in dietary iron intakes with frailty., Methods: Cross-sectional analyses involved 785 men with Fried frailty phenotype (FP) and 758 men with Rockwood frailty index (FI) data aged 75 years and older at nutrition assessment from the Concord Health and Ageing in Men Project prospective cohort study. Of these, 563 men who were FP robust or prefrail, and 432 men who were FI nonfrail were included in the longitudinal analyses for more than 3 years. Dietary intake was assessed at both timepoints using a validated diet history questionnaire. The dietary calculation was used to derive heme iron and nonheme iron intakes from total iron intakes. The associations were evaluated through binary logistic regression., Results: Incidence of FP frailty was 15.3% (n = 86). In longitudinal analyses, maintaining total iron intakes (medium tertile -2.61-0.81 mg/d), increases in total iron and nonheme iron intakes (high tertiles ≥0.82 mg/d and ≥0.80 mg/d), and changes in nonheme iron intake (1 mg increment) were associated with reduced risks of incident FP frailty (OR: 0.47 [95% confindence interval (CI): 0.24, 0.93, p = .031], OR 0.48 [95% CI: 0.23, 0.99, p = .048], OR 0.41 [95% CI: 0.20, 0.88, p = .022], and OR 0.89 [95% CI: 0.82, 0.98, p = .017])., Conclusion: Maintaining or increases in total dietary iron and increases or changes in dietary nonheme iron intakes more than 3 years were associated with reduced incidence of FP frailty in older men., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America.)

Influenza A virus (IAV) infection during pregnancy initiates significant aortic endothelial and vascular smooth muscle dysfunction, with inflammation and T cell activation, but the details of the mechanism are yet to be clearly defined. Here we demonstrate that IAV disseminates preferentially into the perivascular adipose tissue (PVAT) of the aorta in mice. IAV mRNA levels in the PVAT increased at 1-3 days post infection (d.p.i) with the levels being ~4-8 fold higher compared with the vessel wall. IAV infection also increased Ly6Clow patrolling monocytes and Ly6Chigh pro-inflammatory monocytes in the vessel wall at 3 d.p.i., which was then followed by a greater homing of these monocytes into the PVAT at 6 d.p.i. The vascular immune phenotype was characteristic of a "vascular storm"- like response, with increases in neutrophils, pro-inflammatory cytokines and oxidative stress markers in the PVAT and arterial wall, which was associated with an impairment in endothelium-dependent relaxation to acetylcholine. IAV also triggered a PVAT compartmentalised elevation in CD4+ and CD8+ activated T cells. In conclusion, the PVAT of the aorta is a niche that supports IAV dissemination and a site for perpetuating a profound innate inflammatory and adaptive T cell response. The manifestation of this inflammatory response in the PVAT following IAV infection may be central to the genesis of cardiovascular complications arising during pregnancy., Competing Interests: The authors have declared that no competing interests exist.

Macrophages undergo a metabolic switch from oxidative phosphorylation to glycolysis when exposed to gram-negative bacterial lipopolysaccharide (LPS), which modulates antibacterial host defence mechanisms. Here, we show that LPS treatment of macrophages increased the classical oxidative burst response via the NADPH oxidase (NOX) 2 enzyme, which was blocked by 2-deoxyglucose (2-DG) inhibition of glycolysis. The inhibition of the pentose phosphate pathway with 6-aminonicotinamide (6-AN) also suppressed the LPS-induced increase in NOX2 activity and was associated with a significant reduction in the mRNA expression of NOX2 and its organizer protein p47phox. Notably, the LPS-dependent enhancement in NOX2 oxidase activity was independent of both succinate and mitochondrial reactive oxygen species (ROS) production. LPS also increased type I IFN-β expression, which was suppressed by 2-DG and 6-AN and, therefore, is dependent on glycolysis and the pentose phosphate pathway. The type I IFN-β response to LPS was also inhibited by apocynin pre-treatment, suggesting that NOX2-derived ROS promotes the TLR4-induced response to LPS. Moreover, recombinant IFN-β increased NOX2 oxidase-dependent ROS production, as well as NOX2 and p47phox expression. Our findings identify a previously undescribed molecular mechanism where both glycolysis and the pentose phosphate pathway are required to promote LPS-induced inflammation in macrophages.

Endosomal NOX2 oxidase-dependent ROS production promotes influenza pathogenicity, but the role of NOX4 oxidase, which is highly expressed in the lung endothelium, is largely unknown. The aim of this study was to determine if endothelial NOX4 expression can influence viral pathology in vivo , using a mouse model of influenza infection. WT and transgenic endothelial NOX4 overexpressing mice (NOX4 TG) were infected intranasally with the Hong Kong H3N2 X-31 influenza A virus (10 4 PFU; HK x-31) or PBS control. Mice were culled at either 3 or 7 days post-infection to analyse: airway inflammation by bronchoalveolar lavage fluid (BALF) cell counts; NOX4, as well as inflammatory cytokine and chemokine gene expression by QPCR; and ROS production by an L-012-enhanced chemiluminescence assay. Influenza A virus infection of WT mice resulted in a significant reduction in lung NOX4 mRNA at day 3, which persisted until day 7, when compared to uninfected mice. Influenza A virus infection of NOX4 TG mice resulted in significantly less weight loss than that of WT mice at 3-days post infection. Viral titres were decreased in infected NOX4 TG mice compared to the infected WT mice, at both 3- and 7-days post infection and there was significantly less lung alveolitis, peri-bronchial inflammation and neutrophil infiltration. The oxidative burst from BALF inflammatory cells extracted from infected NOX4 TG mice was significantly less than that in the WT mice. Expression of macrophage and neutrophil chemoattractants CXCL10, CCL3, CXCL1 and CXCL2 in the lung tissue were significantly lower in NOX4 TG mice compared to the WT mice at 3-days post infection. We conclude that endothelial NOX4 oxidase is protective against influenza morbidity and is a potential target for limiting influenza A virus-induced lung inflammation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Hendricks, To, Luong, Liong, Erlich, Shah, Liong, O’Leary, Brooks, Vlahos and Selemidis.)

There is an urgent need to develop effective therapeutic strategies including immunomodulators to combat influenza A virus (IAV) infection. Influenza A viruses increase ROS production, which suppress anti-viral responses and contribute to pathological inflammation and morbidity. Two major cellular sites of ROS production are endosomes via the NOX2-oxidase enzyme and the electron transport chain in mitochondria. Here we examined the effect of administration of Cgp91ds-TAT, an endosome-targeted NOX2 oxidase inhibitor, in combination with mitoTEMPO, a mitochondrial ROS scavenger and compared it to monotherapy treatment during an established IAV infection. Mice were infected with IAV (Hkx31 strain; 10 4 PFU/mouse) and 24 h post infection were treated with Cgp91ds-TAT (0.2 mg/kg), mitoTEMPO (100 μg) or with a combination of these inhibitors [Cgp91ds-TAT (0.2 mg/kg)/mitoTEMPO (100 μg)] intranasally every day for up to 2 days post infection (pi). Mice were euthanized on Days 3 or 6 post infection for analyses of disease severity. A combination of Cgp91ds-TAT and mitoTEMPO treatment was more effective than the ROS inhibitors alone at reducing airway and neutrophilic inflammation, bodyweight loss, lung oedema and improved the lung pathology with a reduction in alveolitis following IAV infection. Dual ROS inhibition also caused a significant elevation in Type I IFN expression at the early phase of infection (day 3 pi), however, this response was suppressed at the later phase of infection (day 6 pi). Furthermore, combined treatment with Cgp91ds-TAT and mitoTEMPO resulted in an increase in IAV-specific CD8 + T cells in the lungs. In conclusion, this study demonstrates that the reduction of ROS production in two major subcellular sites, i.e. endosomes and mitochondria, by intranasal delivery of a combination of Cgp91ds-TAT and mitoTEMPO, suppresses the severity of influenza infection and highlights a novel immunomodulatory approach for IAV disease management., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 To, Erlich, Liong, Liong, Luong, Oseghale, Miles, Papagianis, Quinn, Bozinovski, Vlahos, Brooks, O’Leary, Brooks and Selemidis.)

Context: Cardiometabolic diseases are leading causes of death and morbidity. Aging increases the risk of disease development. Diet has protective and causal effects on cardiometabolic health., Objective: To consolidate the current evidence on the short- and long-term effects of dietary patterns on cardiometabolic health in adults aged ≥ 65 years., Data Sources: The Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Scopus, Global Health, and Pre-Medline databases, along with ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched., Data Extraction: A total of 40 042 records were identified. Quality assessment involved using the revised Cochrane risk-of-bias tool for randomized trials and Joanna Briggs Institute checklists. The certainty of evidence was assessed using Grading of Recommendations, Assessment, Development, and Evaluation., Results: Thirteen articles were included (n = 5 cohort studies and n = 3 randomized controlled trials). The low-fat dietary pattern reduced adiposity; however, no effects were evident for hypertension incidence, composite coronary heart disease incidence (including myocardial infarction, coronary heart disease, and coronary revascularization), high-density lipoprotein cholesterol level, and increased blood pressure in the long term. The Mediterranean dietary pattern resulted in reduced triglyceride levels and systolic blood pressure, and had no effects on diastolic blood pressure and glucose in the short term. Other dietary patterns had inconclusive effects., Conclusions: The Mediterranean dietary pattern showed the most benefits without harm on cardiometabolic health in older adults. The current body of evidence is small, indicating the need for more research to confirm these findings at a high certainty of evidence, and to include dietary patterns combined with other dietary components, subgroups with cardiometabolic disease or risk factors, longer follow-up, and outcomes that have not yet been investigated. Studies including these factors may help identify the most effective dietary pattern for cardiometabolic health benefits in older adults, to inform future guidelines., Systematic Review Registration: PROSPERO registration no. CRD42020141400., (© The Author(s) 2021. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Because of the misspecification of models and specificity of operationalizations, many studies produce claims of limited utility. We suggest a path forward that requires taking a few steps back. Researchers can retool large-scale replications to conduct the descriptive research which assesses the generalizability of constructs. Large-scale construct validation is feasible and a necessary next step in addressing the generalizability crisis.

Background and Objectives: Adolescents with cardiac disease are at risk for life-changing complications and premature death. The importance of advance care planning (ACP) in adults with congenital heart disease and in pediatric patients with HIV and cancer has been demonstrated. ACP preferences of adolescents with heart disease have not been evaluated. We describe ACP preferences of adolescents with heart disease and compare with those of their caregivers., Methods: Outpatient adolescents aged 12 to 18 years with heart failure, cardiomyopathy, heart transplantation, or who were at risk for cardiomyopathy, as well as their caregivers, completed self-administered questionnaires which evaluated participants' opinions regarding content and timing of ACP discussions, preferences for end-of-life communication, and emotional responses to ACP., Results: Seventy-eight adolescents and 69 caregivers participated, forming 62 adolescent-caregiver dyads. Adolescents and caregivers reported that adolescent ACP discussions should occur early in the disease course (75% and 61%, respectively). Adolescents (92%) wanted to be told about terminal prognosis, whereas only 43% of caregivers wanted the doctor to tell their child this information. Most adolescents (72%) and caregivers (67%) anticipated that discussing ACP would make the adolescent feel relieved the medical team knew their wishes. Most caregivers (61%) believed that adolescents would feel stress associated with ACP discussions, whereas only 31% of adolescents anticipated this., Conclusions: Adolescents and their caregivers agree that ACP should occur early in disease course. There are discrepancies regarding communication of prognosis and perceived adolescent stress related to ACP discussions. Facilitated conversations between patient, caregiver, and providers may align goals of care and communication preferences., Competing Interests: FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose., (Copyright © 2022 by the American Academy of Pediatrics.)

Standardization of tumor assessment lays the foundation for validation of grading systems, permits reproducibility of oncologic studies among investigators, and increases confidence in the significance of study results. Currently, there is minimal methodological standardization for assessing tumors in veterinary medicine, with few attempts to validate published protocols and grading schemes. The current article attempts to address these shortcomings by providing standard guidelines for tumor assessment parameters and protocols for evaluating specific tumor types. More detailed information is available in the Supplemental Files, the intention of which is 2-fold: publication as part of this commentary, but more importantly, these will be available as "living documents" on a website (www.vetcancerprotocols.org), which will be updated as new information is presented in the peer-reviewed literature. Our hope is that veterinary pathologists will agree that this initiative is needed, and will contribute to and utilize this information for routine diagnostic work and oncologic studies. Journal editors and reviewers can utilize checklists to ensure publications include sufficient detail and standardized methods of tumor assessment. To maintain the relevance of the guidelines and protocols, it is critical that the information is periodically updated and revised as new studies are published and validated with the intent of providing a repository of this information. Our hope is that this initiative (a continuation of efforts published in this journal in 2011) will facilitate collaboration and reproducibility between pathologists and institutions, increase case numbers, and strengthen clinical research findings, thus ensuring continued progress in veterinary oncologic pathology and improving patient care.