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Summary: Background: Continued phenotyping and ongoing molecular epidemiology are important in current and future monitoring of emerging SARS-CoV-2 lineages. Herein we developed pragmatic strategies to track the emergence, spread and phenotype of SARS-CoV-2 variants in Australia in an era of decreasing diagnostic PCR testing and focused cohort-based studies. This was aligned to longitudinal studies that span 4 years of the COVID-19 pandemic. Methods: Throughout 2023, we partnered with diagnostic pathology providers and pathogen genomics teams to identify relevant emerging or circulating variants in the New South Wales (NSW) community. We monitored emerging variants through viral culture, growth algorithms, neutralisation responses and changing entry requirements defined by ACE2 and TMPRSS2 receptor use. To frame this in the context of the pandemic stage, we continued to longitudinally track neutralisation responses at the population level using pooled Intravenous Immunoglobulins (IVIG) derived from in excess of 700,000 donations. Findings: In antibodies derived from recent individual donations and thousands of donations pooled in IVIGs, we observed continued neutralisation across prior and emerging variants with EG.5.1, HV.1, XCT and JN.1 ranked as the most evasive SARS-CoV-2 variants. Changes in the type I antibody site at Spike positions 452, 455 and 456 were associated with lowered neutralisation responses in XBB lineages. In longitudinal tracking of population immunity spanning three years, we observed continued maturation of neutralisation breadth to all SARS-CoV-2 variants over time. Whilst neutralisation responses initially displayed high levels of imprinting towards Ancestral and early pre-Omicron lineages, this was slowly countered by increased cross reactive breadth to all variants. We predicted JN.1 to have a marked transmission advantage in late 2023 and this eventuated globally at the start of 2024. We could not attribute this advantage to neutralisation resistance but rather propose that this growth advantage arises from the preferential utilisation of ACE2 pools that cannot engage TMPRSS2 at its Collectrin-Like Domain (CLD). Interpretation: The emergence of many SARS-CoV-2 lineages documented at the end of 2023 was found to be initially associated with lowered neutralisation responses. This continued to be countered by the gradual maturation of cross-reactive neutralisation responses over time. The later appearance and dominance of the divergent JN.1 lineage cannot be attributed to a lack of neutralisation responses alone, and our data supports that its dominance is a culmination of both lowered neutralisation and changes in ACE2/TMPRSS2 entry preferences. Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT).

Background: Structured and supervised physical exercise and cognitive training are two efficient ways to enhance cognition in older adults. Performing both within a combined intervention could maximize their effect on cognition due to their potential synergy on brain functions. During the COVID-19 pandemic, these interventions were particularly relevant due to the collateral impact of social restrictions regarding physical activity and the level of cognitive stimulation. However, the benefits of remotely monitored intervention combining physical exercise and cognitive training for older adult cognition remain to be demonstrated. Methods: 127 older adults (age: 65.20 ± 7.95) were randomized in two arms, encouraging self-engagement in six months of home-based physical exercise alone or combined with cognitive training, monitored by phone once a week. Neuropsychological assessment was performed under videoconference supervision at baseline and after three and six months. Composite Z-scores were calculated for processing speed, executive functioning, working, and episodic memory to assess changes after three and six months of training. The weekly metabolic expenditure of self-reported activities was estimated using the compendium of physical activity to distinguish participants performing higher and lower doses of exercise (median split). Results: 106 participants (83.46 %) completed the 6-month training. Results showed a greater Z-score change in executive functioning for participants in the combined arm than those who only exercised (F = 4.127, p = 0.046, ηp2 = 0.050). Group x Exercise dose interaction was observed for episodic memory Z-score change (F = 6.736, p = 0.011, ηp2 = 0.070), with a greater improvement for participants performing higher doses of exercise compared to those who performed a lower dose, only in exercise alone arm. Performing a higher dose of exercise increased the working memory Z-score change in both intervention arms compared to a lower dose (F = 7.391, p = 0.008, η p2 = 0.076). Conclusion: Remote combined training may lead to larger improvement in executive functioning than exercise alone. Physical exercise showed a dose-related improvement in working and episodic memory performances. The combination of cognitive interventions mitigated the effects of exercise on episodic memory. These results suggest that home-based exercise and cognitive training may help improve older adults' cognition. Trial registration: COVEPIC was retrospectively registered on December 03, 2020. Clinical trials Identifier: NCT04635462 - https://clinicaltrials.gov/ct2/show/record/NCT04635462?term=NCT04635462&draw=2&rank=1

About one third of patients suffering from Major Depressive Disorder (MDD) do not respond to any antidepressant medications and 75% experience relapses and general health deterioration. Importantly, inflammation can contribute to such negative outcomes, as well as to cause depression in patients who have been exposed to adverse childhood experiences and/or to viral infections, including COVID-19. Depressed patients also have an increased risk for developing comorbidities, such as cardio-metabolic dysfunctions, where inflammatory alterations, again, play a role in connecting MDD and these comorbid conditions.Here, we present our study protocol funded by the Italian Ministry of Health in the context of the PNRR call (M6/C2_CALL 2022; Project code: PNRR-MAD-2022-12375859). The project aims to clarify the role of inflammation: i) in the onset of depression in association with environmental factors; ii) in the mechanisms associated with treatment response/resistance; iii) in depression and its comorbidity. To reach all these aims, we will perform biochemical, transcriptomic, genetic variants analyses on inflammatory/immune genes, pharmacokinetics and machine learning techniques, taking advantage of different human cohorts (adolescent depressed patients exposed to childhood trauma; adult depressed patients; treatment resistant depression patients; both prevalent and incident depression cases identified within a large population cohort). Moreover, we will use in vitro models (primary cultures of astrocytes, neurons and microglia) treated with pro-inflammatory or stressful challenges and preventive compounds to clarify the underlying mechanisms.This 2-years project will increase the knowledge on the role of inflammation in the prevention and treatment of MDD and in comorbid disorders, and it will also provide experimental evidence for the development of novel targets and tools for innovative personalized intervention strategies.

Background: This study aims to evaluate the progression of morphological and functional alterations over time in patients with hypertrophic cardiomyopathy (HCM) using Cardiac Magnetic Resonance (CMR). Methods: A retrospective analysis was conducted on patients with HCM who underwent serial CMR at 1.5 Tesla. Left ventricular (LV) mass was measured during diastole, including papillary muscles and trabeculae assessment. Appearance of Late Gadolinium Enhancement (LGE) was volumetrically quantified using a 5-standard-deviation (SD) threshold. Results: Thirty-two patients, with a mean age of 44 ± 16 years (range: 11–70 years), were evaluated after an average follow-up period of 5.2 ± 2.4 years (range: 0.8–9.1 years). Significant increases were observed in LV mass (from 194 ± 56 g to 217 ± 60 g; p = 0.0001), septal wall thickness (from 18 ± 4 mm to 19 ± 4 mm; p = 0.01), LGE mass (from 6 ± 17 g to 8 ± 18 g; p = 0.006), and left atrial volume (from 109 ± 41 ml to 129 ± 40 ml; p = 0.0001). Both left and right ventricular ejection fractions (LVEF and RVEF) significantly decreased over time (LVEF: from 70 ± 9 % to 66 ± 9 %; p = 0.04 and RVEF: from 70 ± 7 % to 67 ± 9 %; p = 0.02). Multivariate regression analysis revealed that HCM mass gain was independently associated with age (B = -0.43; p = 0.02) and LGE mass (B = -0.46; p = 0.02). The median LV mass gain rate in adults was 1.7 g per year/BSA (IQR, 0.6–2.7) compared to 6.0 g per year/BSA (IQR, 0.5–11.6) in adolescents (mean age: 16 years; range: 11–20 years). A positive correlation was found between LV mass and LGE mass (B = 0.55; p = 0.001), while an inverse relationship was observed between LV mass gain and LGE mass gain rates (−0.37; p = 0.03). Conclusion: The range of morphological changes in HCM seems to reflect an age-related equilibrium between hypertrophy and fibrosis. The extent of changes in LV mass, fibrosis, and functional decline in HCM may help identify patients at risk, emphasizing the importance of ongoing follow-up studies.

Durum wheat is among the cereal crops most susceptible to Fusarium Head Blight (FHB), a fungal disease that can lead to significant yield losses. Despite this, only limited research efforts have been directed towards understanding FHB resistance in durum wheat. Wheat grains naturally contain phenolic compounds, and anthocyanins are particularly present in the so-called pigmented wheat genotypes, such as purple pericarp ones. In this study the effects of the biotic stress caused by Fusarium graminearum infection on phenylpropanoid biosynthetic pathway in durum wheat spikes were explored, considering three genotypes with different susceptibility (including a purple pericarp genotype), and two time points (an early stage time point: 2 days post infection, and a late stage time point: 21 days post infection). At early infection stage, the F. graminearum infection triggered upregulation of all the considered genes involved in the phenylpropanoid pathway in the resistant genotype, while, in the purple pericarp genotype, the infection caused an increase in quercetin accumulation in the soluble fraction of spike extract. At late infection stage, the infection caused (in all the genotypes) a degradation of secondary cell wall and the release of the hydroxycinnamic acids esterified with arabinoxylans (ferulic acid and p-coumaric acid) and lignin-derived monomers (vanillic acid). Furthermore, chalcone synthase gene (CHS) and the transcription factor Ppm1 (Purple pericarp MYB 1) were boosted in the pigmented genotype due to infection at late infection stage. These findings contribute to the understanding of host-pathogen interactions for future breeding programs focused on improving FHB resistance in durum wheat varieties, with a particular focus on pigmented genotypes.

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3–9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.

BackgroundApproximately one-third of trauma-related deaths are due to traumatic brain injury (TBI), particularly among young adults and elderly patients. Management strategies may vary across different age groups, potentially influencing short-term neurological outcomes. This study aims to investigate age-related disparities in treatment approaches and 3-month neurological outcomes among TBI patients.MethodsWe conducted a retrospective study on TBI patients requiring Intensive Care Unit (ICU) admission from January 1, 2015, to January 1, 2024, in a tertiary University hospital. Patient demographics, major comorbidities, ICU admission parameters, interventions and ICU complications were collected. An unfavorable neurological outcome at 3 months (UO) was defined as a Glasgow Outcome Scale (GOS) score of 1–3. A high therapy intensity level (TIL) was defined as a TIL basic of 3–4. A multivariable logistic regression model and a Cox proportional Hazard Regression model were used to assess the association of age and TIL with neurological outcome and mortality. A sensitivity analysis on low TIL (0–2) and high TIL subgroups was also conducted.ResultsWe enrolled 604 TBI patients, of which 240 (40%) had UO. The highest prevalence of UO was found in patients aged ≥80 years (53/94, 56%), followed by patients aged 50–79 years (104/255, 41%). The age group 35–49 years had the lowest rate of UO (38/127, 30%). Older patients (age ≥ 80 years) received less frequently high TIL than others (p = 0.03). In the multivariable analysis, age ≥ 80 years [OR: 3.42 (95% CI 1.72–6.81)] was independently associated with UO, while age ≥ 80 years [HR 5.42 (95% CI 3.00–9.79)] and age 50–79 years [HR 2.03, (95% CI 1.19–3.48)] were independently associated with mortality. Although there was no interaction between age groups and TIL on outcome, an exploratory analysis showed that in the high TIL subgroup of patients, age had no independent impact on the outcome, whereas, in the low TIL group, age ≥ 80 years was independently associated with UO [OR: 3.65 (95% CI: 1.64–8.14)].ConclusionOlder age, especially in the setting of low intensity treatment, may impact short-term neurological outcome of traumatic brain-injured patients.

A presente pesquisa objetiva aprofundar a articulação do Fator E para o processo de ensino-aprendizagem, guiando-se a partir da seguinte questão norteadora: “Qual o papel da espontaneidade no processo de ensino aprendizagem?” Para tanto, foi realizada uma pesquisa qualitativa exploratória em formato de estudo de caso, considerando três contextos educacionais da autora: ensino, pesquisa e extensão. As experiências utilizadas no trabalho advêm da formação de psicólogos(as) e psicodramatistas e foram apresentadas por meio de análise temática. A espontaneidade na educação é essencial para evitar a repetição de conservas cristalizadas no papel psi e para a abertura da transformação social. O fator E amplia a conexão dos envolvidos com o aqui e agora, e com o reconhecimento dos papéis desempenhados.

Abstract Objective and Rationale Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, manifests with chronic intestinal inflammation and frequent sequential fibrosis. Current pharmacological therapies may show harmful side effects and are not useful for prevention or resolution of fibrosis. Thus, the use of alternative therapies is emerging as a novel useful approach. Previous results suggest that Scutellaria baicalensis Georgi (SBG) and Boswellia serrata (BS) display anti‐inflammatory properties. The aim of this study was to investigate in intestinal epithelial cells and fibroblasts the anti‐inflammatory and anti‐fibrotic potential of SBG and BS, alone or in combination. Methods Human colorectal adenocarcinoma cells (HT29), human intestinal epithelial cells (HIEC6) and human colon fibroblasts (CCD‐18Co) were used. Cells were pretreated with SBG and BS and then exposed to pro‐inflammatory and pro‐fibrotic cytokines. Results SBG and BS extracts significantly decreased pro‐inflammatory cytokine expression and improved epithelial restitution in HT29 and HIEC6 cells. Besides, fibrotic marker expression, including SNAIL, ACTA2, ZNF281, was strongly reduced. Colon myofibroblasts treated with SBG and BS showed a significant decrease of fibrotic markers as well. Conclusions SBG and BS extracts significantly reduce inflammation and impair fibrosis in intestinal epithelial cells and colon myofibroblasts. No cooperative effect is observed.

BackgroundObesity and frailty are prevalent geriatric conditions that share some pathophysiological mechanisms and are associated with adverse clinical outcomes. The relationship between frailty, obesity, and polymorphism remains inadequately explored. Single nucleotide polymorphisms (SNPs) offer insights into genetic predispositions that may influence the development of both frailty and obesity.MethodsWe aimed at investigating whether SNPs associated with frailty also play a role in obesity. Data were collected from the FRASNET cross-sectional study, which included community-dwelling older individuals residing in Milan and nearby areas. Participants were recruited through random sampling. They underwent multidimensional geriatric assessments, which included the collection of blood samples for SNP analysis. Frailty was assessed using the frailty index, and body composition was evaluated using bioelectrical impedance analysis and anthropometric measures.ResultsSNPs related to frailty and linked to the renin–angiotensin system (CYP11B2 rs1799998, AGT rs5051, and AGTR1 rs2131127), apoptosis pathways (CASP8 rs6747918), growth hormone signaling (GHR rs6180), inflammation (TLR4 rs5030717, CD33 rs3865444, and FN1 rs7567647), adducin (ADD3 rs3731566), and the 9p21–23 region (rs518054) were found to be associated with various measures of obesity in community-dwelling older adults.ConclusionsFrailty-related SNPs contribute to obesity in community-dwelling older adults. We identified a novel association between adducin SNPs and visceral fat, which has not been previously reported. Detecting genetic predispositions to obesity and frailty early could aid in identifying individuals at risk, facilitating the adoption of preventive interventions. This represents an initial step toward promoting early intervention strategies.

Couples in which wives have more education than their husbands have been found to be more likely than other couples to divorce. But this relationship varies across time and place. We compare the relationship between spouses’ relative education and marital dissolution across four birth cohorts born between 1951 and 1990 in East and West Germany using 37 waves of the German Socio-Economic Panel (1984-2021) and Cox proportional hazard models. The comparison between East and West Germany provides contrasting levels and trends in women’s education, employment, and gender cultures, with East Germany persistently being a more gender egalitarian context compared to West Germany. Our results show that marriages in which wives have more education than their husbands are less stable in West Germany, but not in East Germany, where the point estimates indicate that these couples are more stable than other couples, but this association is not statistically significant. We do not find evidence of cohort change in these associations in either East or West Germany. These findings are consistent with the idea that the consequences of non-traditional gender arrangements are weaker in more egalitarian contexts and confirm that notable differences between East and West Germany persist after reunification. * This article belongs to a special issue on “Changes in Educational Homogamy and Its Consequences”.

Up to 17 GPa, the crystalline phases of N2 are characterized by pronounced orientational disorder, whereas the higher-pressure phases of molecular N2 are ordered. This raises the question about long-term relaxation of orientational disorder within the low- to intermediate-pressure regime. Here, this question is addressed by comparing synthetic with natural, chemically pure, solid N2 that resides as inclusions in diamonds at 300 K for about 108 years at pressures up to 11 GPa. It is shown that disorder prevails at 8.7 GPa, 300 K, where both synthetic and natural N2 assume the same structure. However, at 10.8 GPa, natural solid N2 exhibits monoclinic distortion and partial orientational ordering of the molecules, both of which are not observed in synthetic material. This difference is interpreted as the result of long-term structural relaxation. The ordering mechanism is examined and placed into the context of the δ- to ε-N2 transition. We present explanations for the absence of complete ordering of δ-N2. [ABSTRACT FROM AUTHOR]