High Levels Research Articles

Pubertal- and stress-dependent changes in cellular activation and expression of excitatory amino acid receptor subunits in the paraventricular nucleus of the hypothalamus in male and female rats.

Pubertal maturation is marked by significant changes in stress-induced hormonal responses mediated by the hypothalamic-pituitary-adrenal (HPA) axis, with prepubertal male and female rats often exhibiting greater HPA reactivity compared to adult males and females. Though the implications of these changes are unclear, elevated stress responsiveness might contribute to the stress-related vulnerabilities often associated with puberty. The current experiments sought to determine whether differences in cellular activation, as measured by FOS immunohistochemistry, or excitatory ionotropic glutamate receptor subunit expression, as measured by qRT-PCR, in the paraventricular nucleus (PVN) were associated with these noted pubertal shifts in stress reactivity in male and female rats. As the PVN is the key nucleus responsible for activating the hormonal stress response, we predicted greater cellular activation and higher expression levels of glutamate receptor subunits in the PVN of prepubertal males and females compared to their adult counterparts. Our FOS data revealed that while prepubertal males showed greater stress-induced activation in the PVN than adult males, prepubertal females showed less activation than adult females. Moreover, many of the NMDA, AMPA, and kainate receptor subunits measured, including Grin1, Grin2b, Gria1, Gria2, Grik1, and Grik2, had higher expression levels in adults, particularly in males. Though not supporting our initial predictions, these data do indicate that age and stress influence the activation of the PVN and the expression of glutamate receptor subunits important in its function. These data also suggest that the effects of age and stress are different in males and females. Though still far from a clear understanding of what mechanism(s) mediate pubertal shift in stress reactivity, these data add to our growing understanding of how age, stress, and sex influence HPA function.

Impact of agitation status during intensive care on functional outcomes and mortality in patients with cardiovascular disease

Abstract Background Agitation in patients during intensive care is a frequent complication. Several studies have reported that restlessness and agitation are risk factors for prolonged intensive care unit (ICU) stay and poor prognosis. Since patients with cardiovascular disease (CVD) requiring intensive care are ageing and thereby easily affected by responses, including changes in mental status, optimal management of sedation and agitation statuses during ICU stay is considered crucial. However, the influence of different agitation levels during CVD treatment in the ICU on clinical outcomes after ICU discharge is still unclear. Purpose To investigate the associations of the agitation level during ICU stay with mortality after ICU admission and functional outcomes at hospital discharge. Methods We studied 2236 patients (mean age 67.8±0.3 years) who were admitted to the ICU of a university hospital for CVD treatment and whose highest Richmond Agitation-Sedation Scale (RASS) ≥0, measured daily during ICU stay. In addition to clinical characteristics, we investigated the incidence of all-cause mortality during hospitalization and after hospital discharge. We also measured functional outcomes at discharge among 1625 patients, including 6 minutes walk distance (6MWD), Mini-Cog test, and Patient Health Questionnaire-2 (PHQ-2) as physical, cognitive, and mental functions, respectively. In statistical analysis, patients were divided into three groups based on the highest RASS levels during ICU stay in each patient (Calm: RASS=0, Restless: RASS=1, Agitation: RASS≥2). Kaplan-Meier analysis with a log-rank test and the multivariate Cox proportional hazard model were used to clarify whether higher agitation levels were associated with all-cause mortality. Moreover, the differences between the agitation levels and functional outcomes at hospital discharge were compared using the analysis of covariance. Results During the median follow-up of 1.9 years, all-cause death occurred in 280 patients (12.5%), with an incidence rate of 5.57/100 person-years. The Restless and Agitation groups showed higher mortality than the Calm group (P<0.001), and higher agitation levels in the ICU were significantly associated with a higher rate of all-cause mortality (adjusted hazard ratio: 1.37, 95% confidence interval: 1.19–1.57, P<0.001). Furthermore, as compared with the Calm group, the Restless and Agitation groups showed significantly lower levels of 6MWD (all P<0.001) and Mini-cog (P=0.004 and P<0.001, respectively) and a higher PHQ-2 (all P<0.001), even after adjusting for clinical confounders. Conclusions Agitation during ICU stay in CVD patients was associated with low functional outcomes at hospital discharge and high mortality rate after discharge, irrespective of agitation level. Detailed information on the agitation status during intensive care may be an important indicator in developing management and treatment strategies for patients with CVD admitted to ICU.

Diabetes, hypertension, and hospitalizations during pregnancy: a multivariate analysis

Abstract Introduction The study analyzes the correlation between socio-demographic variables and pathologies encountered by women during pregnancy. The presence of these pathologies is recorded at the time of compiling the CAP (Certificate of Assistance for Birth). Methods Data analysis pertains to the Certificate of Assistance for Birth (CAP) concerning residents in the territory of AUSL South-East Tuscany in the years 2021 and 2022. The number of women of childbearing age in Tuscany in 2022 is 150,959, while the number of births analyzed in the study is 9,053. The study conducts multivariate analysis between socio-demographic variables and pathological outcomes. Results Controlling for age, citizenship and other factors, the risk of gestational diabetes is significantly higher (p < 0.05) among mothers: over 40 years old (OR = 1.56), with citizenship in PFPM countries (OR = 1.60) and particularly, compared to Italians, among women from Indian subcontinent (OR = 3.73) and the Maghreb (OR = 2.04), with lower educational levels (OR = 1.28) compared to graduates, obese (OR = 2.43). The risk of gestational hypertension is significantly higher (p < 0.05) among mothers: over 40 years old (OR = 1.71), obese (OR = 2.50), nulliparous (OR = 1.60). The risk of one or more hospitalizations during pregnancy is significantly higher (p < 0.05) among mothers: not employed (OR = 1.31) and homemakers (OR = 1.32) compared to employed, from Indian subcontinent (OR = 1.82) and the Maghreb (OR = 1.75) compared to Italians, with gestational hypertension (OR = 2.06). Conclusions Unlike gestational diabetes and hospitalizations during pregnancy, gestational hypertension does not show significant associations with the mother’s socio-demographic characteristics. However, gestational diabetes and hospitalizations during pregnancy are correlated with different variables: they are more common among women over 40, foreigners, homemakers, with lower educational levels, obese, and with low family economic status. Key messages • It has been observed that some variables are also risk factors for adult age pathologies, such as diabetes and hypertension. • The importance of Early Childhood Development and early interventions can improve children’s health and well-being.

Chronic pain over time among Syrian refugees resettled in Norway

Abstract Background Chronic pain disproportionately impacts vulnerable groups such as migrants and refugees. This study investigates the long-term changes in chronic pain experienced by Syrian refugees in Norway and explores the factors influencing these changes. Methods This prospective cohort study used data from the CHART and Integration for Health studies, with data collection at three points: in Lebanon (Wave-1), one year (Wave-2), and four years post-arrival in Norway (Wave-3). All participants who completed surveys at these timepoints were included (n = 132). Chronic pain was measured by asking about pain lasting at least six months. Mixed-effects logistic regression was used to examine changes in prevalence and assess how age, gender, educational level (categorized as low, ≤9 years, and high, >9 years), and mental health symptoms (anxiety, depression, and post-traumatic disorders) affect these changes. Results Between Wave-1 and Wave-3, the proportion of participants reporting chronic pain increased from 31% to 53%, with an odds ratio of 3.6 (95% CI 2.2 - 5.8). There was an interaction between changes in chronic pain over time and participants’ educational level, where the increase in pain prevalence over time was more pronounced among participants with lower educational levels than higher levels. No modification with the other factors were detected. Conclusions The study observed an increase in the number of participants reporting chronic pain over time. Low educational level at baseline emerged as a useful indicator for identifying those at higher risk of chronic pain. Understanding this correlation can be crucial for guiding preventive strategies and optimizing resource allocation to assist those most vulnerable. Key messages • Chronic pain disproportionately impacts vulnerable groups such as refugees. • Refugees with lower education levels at baseline were more likely to experience chronic pain over time.

Unveiling social disparities in later life: Income’s Impact on mortality among the elderly in Italy

Abstract Background Income is an important predictor of adult mortality, as a proxy of living conditions, capability and access to health services. Previous studies show that mortality decreases by increasing income. In Italy, studies at a national level are missing. This study aims to investigate inequalities in mortality by income in Italy. Methods The analysis is based on the integration of the National Population Register (comprising the resident population as of Dec 31, 2018, and deaths in 2019) and the Income Statistical Register (representing perceived income during 2018). This integration enabled the availability of information on age, sex, residence, education, income, and vital status at the individual level for 13 million people aged 65 or above. Individuals were categorized according to their individual disposable income quintiles both before and after disability benefits. Inequalities by income are assessed by mortality rate ratios (MRR) estimated using negative binomial regression models controlling for demographic and socioeconomic features. The study is carried out within the Next Gen EU-funded project “Age-It Ageing well in an ageing society” (PE0000015), NRRF, M4.C2, Intervention 1.3. Results Considering income net of disability benefits, lower income levels are associated with higher mortality rates compared to the highest income level, for both sexes. Inequalities are more marked for men. The highest excess was observed for individuals with the lowest income (male MRR=1.65, 95%CI: 1.6-1.71; female MRR=1.43, 95%CI: 1.38-1.48). The excess decreases with increasing income. Conclusions The observed relationships between income and mortality are crucial for targeting policies to reduce health inequalities and promote the well-being of the elderly, the goal of which should be to improve access to social and health care and develop supportive policies for the most disadvantaged people. Further research will be devoted to the use of household income for individuals. Key messages • For the elderly, lower income levels are associated with higher mortality, with wider disparities in men. • The choice of definition of income is essential for an accurate assessment of the association between income and mortality.

Lifestyle factors before and after colorectal cancer treatment and their association with fatigue

Abstract Background As colorectal cancer (CRC) survivorship increases, so does the challenge of managing cancer-related fatigue, a prevalent condition that severely impacts survivors’ ability to work and overall quality of life. This study delves into the relationship between lifestyle behaviors, assessed using the HEALTHY lifestyle score, and its influence on fatigue among CRC patients. Methods Data was derived from MIRANDA, a multicenter cohort study that enrolls adult CRC patients during a 3-week in-patient rehab within a year after primary CRC treatment. Up to date, n = 438 participants provided information on lifestyle factors at the rehabilitation start (baseline) and then every three months for the first year. The predictors were the HEALTHY lifestyle score and its components (diet, alcohol consumption, physical activity, BMI, and smoking status) calculated at three time points: before surgery, after surgery, and 12 months following rehabilitation. The outcome was fatigue, assessed using the Functional Assessment of Chronic Illness Therapy - Fatigue (FACIT-F-FS) scale. Results Participants with a higher HEALTHY lifestyle score after CRC surgery had statistically significantly lower fatigue levels. The components that contributed most to this finding were smoking and physical activity. Participants who engaged in exercise post-surgery or did not smoke before their cancer diagnosis experienced lower fatigue levels during rehabilitation. Conclusions Lifestyle modifications, such as increasing physical activity and smoking cessation, are crucial in preventing or reducing fatigue among CRC patients. Tailored public health initiatives that advocate for these lifestyle adjustments and their incorporation into CRC rehabilitation protocols could significantly advance survivor care, ultimately leading to better health outcomes. Key messages • The HEALTHY score is associated with fatigue of CRC patients during rehabilitation, highlighting the crucial role of lifestyle changes after CRC treatment. • Smoking cessation and physical activity programs may be the most effective measures for decreasing the fatigue burden of these patients.

Remnant cholesterol, clinical characteristics and mortality in 41.767 patients from LIPIDOGRAM 2004-2015 studies - the factor analysis for mixed data cluster analysis

Abstract Introduction Remnant cholesterol (remnant-C) contributes to residual cardiovascular risk and is produced by metabolism of triglyceride rich proteins. Aim To assess association between clinical characteristics of patients with elevated remnant-C in a large cohort of patients under the care of primary care physicians. Methods The LIPIDOGRAM studies were carried out in the primary care in Poland in 2004, 2006 and 2015. Patients (n=47,398) recruited in all 16 administrative regions in Poland and physicians were proportionally distributed to the number of inhabitants in each administrative region. Each patient was asked to fill the questionnaire on risk factors, chronic diseases, treatment and lifestyle. In the present analysis we included patients with body mass index (BMI )>18.5 kg/m2 aged 18-75 years. We set the cut-off point of fasting remnant cholesterol at >30 mg/dL (>0.77 mmol/L) that differentiated subjects at high risk of cardiovascular events. We carried out Factor Analysis for Mixed Data (FAMD) cluster analysis to discern groups of patients with similar clinical profiles. Results 41,767 patients, for which we had all relevant data, were included in the analysis. Follow-up rate was 97.8%. Three FAMD-derived clinical characteristics patterns accounted for 47.8% of the total variance and were retained for further analysis. The first pattern was associated with higher prevalence of metabolic syndrome (MetS), higher waist circumference, higher levels of non-HDL-C and remnant-C levels. The second pattern was distinguished by lipid parameters, particularly higher HDL-C levels, and was not significantly associated with comorbid conditions. The third pattern was linked to male sex, previous myocardial infarction, smoking, age, lower remnant-C levels, and reduced prevalence of obesity. All patterns were associated with 5-year mortality. The hazard ratio (HR) for mortality per 1 standard deviation (SD) increase in the first pattern score was 1.18 (95% CI: 1.16-1.22, p<0.001). Patients with clinical characteristics corresponding to second pattern had more favorable outcome HR (per 1SD score increase) – 0.75, 95%CI (0.73-0.78, p<0.001). Patients in third cluster, similarly to patients in cluster 1 had increased mortality HR (per 1SD score) – 1.10, (95%CI:1.06-1.15, p <0.001). Higher (>0.77 mmol/l / 30 mg/dl) remnant-C cholesterol significantly contributed to classification of patients into first and third clusters. It was positively associated with first pattern (r=0.64, p<0.001), but negatively with the third pattern (r=0.39, p<0.001). Conclusions Elevated Remnant-C was associated with clinical pattern typical for metabolic syndrome. Interestingly, lower remnant-C levels in patients with comorbidities and more advanced age may not automatically be indicative of a better prognosis – this requires further investigation.Figure 1.Figure 2.

Sex differences in patients with acute myocardial infarction under 65 years of age: a Spanish cohort

Abstract Background Myocardial infarction (MI) clinical presentation and prognosis usually vary between men and women. Studying different age groups may be of interest. Aim Compare clinical characteristics and prognosis between men and women under 65 years old (y/o) with MI. Methods observational prospective study, including all patients admitted for MI between 2016 and 2023. Median follow-up was 43months[20-71]. Results Out of a total of 1064 patients, 436 were younger than 65 y/o (98 were women and 338 were men). The median age was similar in both sexes: 53.4[41-65] vs 54.2[43-65], p=0.24. A higher percentage of men were married (76.6 vs 59.2%, p<0.01), while a greater proportion of women were widowed (7.9 vs 1.3%, p<0.01). Men showed higher rates of permanent employment (71.4vs54.9%, p=0.01) and night shifts (58vs26.1%, p<0.01), whereas women had a higher unemployment rate (26.8vs15.2%, p=0.03) and reported higher levels of stress (70.3 vs 42.4%, p<0.01). The percentage of smokers was similar in both sexes (84.6% in men vs 75.8% in women, p=0.06), but there were more cocaine users in the male group (10.8vs1.4%, p=0.01). Women had a higher prevalence of autoimmune diseases (20.4 vs 6.2%, p<0.01), allergies (17.3 vs 5.6%, p<0.01), psychiatric illnesses (25.8 vs 9.9%, p<0.01), and migraines (15.6 vs 1.8%, p<0.01). Men had more history of previous coronary angioplasty (9.5 vs 3.1%, p=0.05). At admission, men presented with higher levels of creatine kinase (1175.2±1490.1 vs 766.5±1084.5 U/L, p=0.02), haemoglobin (15.2±1.6 vs 14±1.4 g/dl, p<0.01) and serum creatinine (1.2±1.4 vs 0.8±0.5 mg/dl, p<0.01), while women exhibited higher cholesterol levels (186.5±51.6 vs 174.9±44.5 mg/dl, p=0.03). Coronary dissection and myocardial infarction with non-obstructive coronary arteries were more frequent in women (14.3 vs 2.1%, p<0.01 and 27.6 vs 11.5%, p<0.01, respectively). Women also underwent additional tests at a higher rate, such as cardiac magnetic resonance (14.3 vs 4%, p<0.01) and vasospasm test (7.6vs1.9%, p=0.02). During hospitalization, men underwent drug-eluting stent implantation more frequently (66.7vs23.8%, p<0.01). At discharge, they were more likely to receive antiplateles (93.7vs84.5%, p<0.01), beta-blockers (81.7vs.71.1%, p=0.03), angiotensin-converting enzyme inhibitors (63.2vs49.5%, p=0.02) and statins (96.4vs84.5%, p<0.01). The rest of variables, which showed no significant differences, are in Table 1. Prognosis was similar in both sexes: death from any cause (HR 0.7, 95%CI[0.1-3.4]), cardiovascular readmission (HR 1.2, 95%CI[0.5-2.7]), reinfarction (HR 1.9, 95%CI[0.3-10.3]), stroke (HR 1, 95%CI[0.1-11.9]). Conclusion The clinical profile of men and women with MI is clearly different. The investigation into the underlying mechanisms of MI occasionally necessitates more extensive testing in women. Additionally, the treatment plans at discharge diverge between the two genders. Nevertheless, the prognosis appears to be similar for both sexes.

Quality of Life and Symptoms of Hospitalized Hematological Cancer Patients

Patients with hematological malignancies undergo intensive treatment and prolonged hospitalization, thus having a variety of physical and psychosocial symptoms and worse quality of life (QOL). This study aimed to assess the QOL and investigate the symptoms of hospitalized hematological cancer patients. A cross-sectional study was conducted in the hematology clinics and day units of two general hospitals of Heraklion, Crete. Adult patients with hematological malignancy and an adequate understanding of the Greek language participated. A demographic questionnaire, the European Organization for Research and Treatment for Cancer quality assessment questionnaire (EORTC QLQ-C30), and the MD Anderson Symptom Inventory (MDASI) were used. The sample consisted of 120 patients—42.5% were women, with a mean age of 65.6 years. The mean time from diagnosis was 33 months. The global health status of QoL had an average value of 47.1. The highest levels of QOL were found in the subscale of cognitive function (72.8) and the lowest in the role function (46.1). For the EORTC QLQ-C30 symptoms scale, the lowest score was found in nausea-vomiting (11.0) and the highest in fatigue (59.1). In the MDASI, in part I (core symptoms), higher levels but also medium intensities were reported at fatigue (78.3%, mean 3.5), drowsiness (65.0, mean 3.3), and distress (65.8%, mean 2.8). In part II, enjoyment of life (85.8%, mean 5.1) had the highest, and relation with other people (67.5%, mean 3.7) had the lowest scores. The increase in the severity of the core symptoms (part I) was related to females (rho = 0.193, p <0.05) and comorbidities (rho = 0.220, p < 0.05). It was also associated with a significant decrease in all functional domains and increased fatigue (rho = 0.571, p < 0.05) in the EORTC QLQ-C30 questionnaire. The increased global health status was related to males (rho = −0.185, p < 0.05) and physical functioning with younger age (rho = −0.331, p < 0.05), higher education (rho = 0.239, p < 0.05), fewer months from diagnosis (rho = −0.199, p < 0.05), and low comorbidity (rho = −0.209, p < 0.05). Finally, multiple linear regression analysis revealed that the total average symptom score of the MDASI was the most significant factor influencing the global health status of the EORTC QLQ-C30 (β = −4.91, p < 0.001). The increased global health status of the EORTC QLQ C30 was not significantly related (p > 0.05) to the social characteristics of the patients, such as education or employment, which requires further validation. The QoL of hematological cancer patients significantly decreases during treatments due to a considerable number of symptoms that must be taken into consideration for high-quality, individualized care.

The association between cancer literacy and cancer screening behaviours: a systematic review

Abstract Background This study aimed at investigating the association between cancer literacy (CL) and adherence to cancer screening programs. Methods PubMed, Scopus and Web of Science were searched. Any study, published until March 2024, that investigated the associations between CL and cancer screening intention or uptake in any target population were eligible. For CL measurement, both validated and ad hoc tools were considered. For each outcome, articles were grouped according to the type of cancer investigated and results were narratively synthesized. Results A total of 3426 records were retrieved. After deduplication and screening process, six studies were included. Population enrolled was heterogeneous as well as the tool used to measure CL. Four studies explored the relationship between CL and screening uptake, one focused solely on screening intention and another investigated both intention and uptake. Significant association was found between CL and screening intention in the two studies included, with higher literacy levels correlating to increased intent for screening. A significant association between higher CL and skin cancer screening uptake was reported, while the uptake of prostate cancer screening was not significantly associated with CL levels. By contrast, mixed results were obtained investigating breast, cervix and colorectal screening uptake. Conclusions Higher levels of cancer literacy appeared to be associated with screening intention, while its association with screening uptake was found barely significant for any screening type, suggesting that other factors influence the actual screening uptake. However, the scarce number of studies, along with the absence of validated tools and the heterogeneity of target populations, limits the generalizability of the results. Further research, differentiating screening types and timelines and using multivariate models, is needed to clarify the role of CL in screening behaviours. Key messages • Higher levels of cancer literacy appear to be associated with screening intention, suggesting its importance in promoting motivation for early cancer detection. • Association between cancer literacy and screening uptake was found barely significant for any screening type, suggesting that other factors influence actual screening uptake, urging further research.

Stress-induced coronary spasms: evaluating the role of serum cortisol in variant angina

Abstract Background and purpose Variant angina is a type of angina pectoralis caused by vasospasm, and the patients were recommended to take lifelong medication to suppress spasms. In addition to risk factors, mental stress can be a precipitating factor in vasospasm. We can analyze whether mental stress can affect vasospasm by analyzing the relationship between serum cortisol levels, the major stress hormone, and coronary artery vasospasm. Methods We prospectively enrolled patients who were admitted for coronary angiography from October 2022 to August 2023. We divided them into 2 groups: variant angina and those who had other angiographic findings such as insignificant, stable angina, unstable angina, or non ST segment elevation myocardial infarction. The primary endpoint was the norepinephrine, cortisol, and adrenocorticotropic hormone (ACTH) level at admission, cortisol and ACTH level at Day 1 after admission, and after discharge when visiting the outpatient clinic. We used students' t-tests to examine the differences between groups. Results A total of 196 patients were enrolled, and 23 patients were diagnosed with variant angina. The variant angina group showed significantly higher serum cortisol levels on Day1 than the other diagnosis group (10.1±3.4 µg/dL vs. 8.4±4.1 µg/dL, p-value 0.044). There were no significant differences between baseline norepinephrine, ACTH, cortisol levels, Day 1 ACTH, and serum ACTH, cortisol levels after discharge. However, the serum cortisol levels showed an increased trend than other diagnosis group (baseline cortisol 9.7±3.5 vs. 8.3±4.1, p-value 0.082; after discharge cortisol 9.3±2.7 vs. 8.6±3.6, p-value0.294). Conclusions The variant angina group had a higher level of serum cortisol level than other diagnosis groups. Also, this trend was sustained at baseline and after discharge. Further research with a large cohort is warranted.

Determinants of Long COVID illness duration and service use-an Irish retrospective cohort study

Abstract The Follow-up After Disease Acquisition (FADA) study is a retrospective cohort study of COVID-19 recovery, aimed to characterise the nature and severity of Long COVID (LC) in an Irish community-based sample. Duration analysis is conducted applying Cox’s proportional hazards model to those self-reported recovered from LC (n = 577) and a Gompertz distribution parametric model, determined best fit by AIC, for those still ill with LC (n = 928) at time of survey completion. A negative binomial model is estimated to understand the variation of services accessed for LC. The Hazard in this instance is recovery(<1 = contributing factor to duration). Factors significantly contributing to duration of illness are never married (Hazard Ratio (HR):0.689;p:0.01) higher physical activity levels prior to first C-19 infection (HR:0.964; p:0.06) and number of COVID-19 infections (H:0.926;p:0.07). Those that contract more recent variants are likely to recover quicker from their LC illness (baseline Wildtype. Alpha HR:1.7;p:0.0; Delta HR:3.36;p:0.0; Omicron HR:3.8; p:0.0). In variation of services used for LC, there are some major differences between those self-reporting as recovered from LC at time of survey completion and those still ill. Of those recovered, men, those sickest with LC and sick longest use a wider variation of services. Single people use a significantly narrower range of health services to combat their illness. For those still ill higher education, higher levels of physical activity pre COVID-19, healthcare workers, higher rates of comorbidity, those sick longest and those whose health has been most impacted by LC use a wider variation of services. A poorer health rating negatively impacts variation of services accessed for LC illness. More recent strains of COVID-19 are significantly less likely to lead to LC, this offers hope for the future, albeit more research is required to investigate factors to improve recovery rates for those already experiencing LC. Key messages • Those with Long COVID that recover quickly are fundamentally different to those that do not. • The number of COVID-19 infections is a key indicator of length of Long COVID illness, we need to protect our most vulnerable and put appropriate safeguards in place for healthcare provision.

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target.

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.

Fluconazole worsened lung inflammation, partly through lung microbiome dysbiosis in mice with ovalbumin-induced asthma

Innate immunity in asthma may be influenced by alterations in lung microbiota, potentially affecting disease severity. This study investigates the differences in lung inflammation and microbiome between asthma-ovalbumin (OVA) administered with and without fluconazole treatment in C57BL/6 mice. Additionally, the role of inflammation was examined in an in vitro study using a pulmonary cell line. At 30 days post-OVA administration, allergic asthma mice exhibited increased levels of IgE and IL-4 in serum and lung tissue, higher pathological scores, and elevated eosinophils in bronchoalveolar lavage fluid (BALF) compared to control mice. Asthma inflammation was characterized by elevated serum IL-6, increased lung cytokines (TNF-α, IL-6, IL-10), and higher fungal abundance confirmed by polymerase chain reaction (PCR). Fluconazole-treated asthma mice displayed higher levels of cytokines in serum and lung tissue (TNF-α and IL-6), increased pathological scores, and a higher number of mononuclear cells in BALF, with undetectable fungal levels compared to untreated mice. Lung microbiome analysis revealed similarities between control and asthma mice; however, fluconazole-treated asthma mice exhibited higher Bacteroidota levels, lower Firmicutes, and reduced bacterial abundance. Pro-inflammatory cytokine production was increased in supernatants of the pulmonary cell line (NCI-H292) after co-stimulation with LPS and beta-glucan (BG) compared to LPS alone. Fluconazole treatment in OVA-induced asthma mice exacerbated inflammation, partially due to fungi and Gram-negative bacteria, as demonstrated by LPS+BG-activated pulmonary cells. Therefore, fluconazole should be reserved for treating fungal asthma rather than asthma caused by other etiologies.

The association of NT-proBNP levels in atrial fibrillation patients and 3-year risk of heart hospitalization and death

Abstract Background NT-proBNP-levels are often elevated in patients with atrial fibrillation (AF), but their clinical use and interpretation for predicting subsequent cardiovascular events has not been explored in an all-comers setting. Aim To determine whether NT-proBNP levels are associated with the risk of subsequent heart failure (CHF) and/or death in patients with AF and its relation to prior CHF diagnosis Method All patients with new-onset AF (defined by ICD-code I48) who had an NT-proBNP-level within +/- 14 days of the date of the AF date measured in a regional laboratory repository between 2000-2021 were included in the analysis cohort. Patients were categorized into NT-proBNP level (pg/mL) <1000, 1000-1999, ≥2000. If several NT-proBNP-levels were measured, the maximal value was used. The association between NT-proBNP level and the outcome CHF hospitalization and/or death within 3 years of diagnosis was assessed in Cox regression analyses adjusted for baseline characteristic and medications. Since there was an interaction (p<0.001) between Nt-proBNP-level and prior/new-onset CHF at time of AF diagnosis and no known CHF, two separate analyses were performed in patients with or new-onset CHF and those without prior CHF. Results There were 10559 patients with AF and no CHF, and 11 257 with AF and CHF. There were 14% of patients with new-onset CHF at time of new-onset AF diagnosis. These were grouped together with patients with known CHF. Patients with no prior CHF were younger (76 years (95% CI 68-83) vs 80 (72-87), p<0.001), and healthier with less often diabetes (18.4% vs 24.5%, p<0.001), prior myocardial infarction (12.0% vs 24.3%), a lower CHA2DS2-VASc score (3.0 vs 5.0, p<0.001) and a lower median NT-proBNP level (1650 pg/mL (95% CI 702-3549) vs 4240 pg/mL (2160-8860), p<0.001). Among patients with AF and no prior CHF, the incidence rate in the lowest NT-proBNP level was low, but increased with higher levels (Table). Adjusting for covariates and medications, the risk of both CHF hospitalization and CHF/death compared to the reference category NTproBNP< 1000 pg/mL was nearly 2 and 3 times higher among those who with initial NT-proBNP level 1000-1999 and ≥ 2000. Among patients with AF and known CHF, the incidence rate of CHF hospitalization or CHF hospitalization/death at the same NT-proBNP-strata was several times higher compared to patients without known CHF. Adjusting for covariates, the risk increased for CHF hospitalization or CHF/hospitalization similarly for each strata as for patients without known CHF. AF patients without known HF but with the highest elevation of NTproBNP-level had a risk of subsequent hospitalization of heart failure which was higher than those with known heart failure and lowest NTproBNP-level. Conclusion A higher NTproBNP-level in patients with AF identifies patients at higher risk of CHF hospitalization and/or death in both patients with no and prior CHF.Table

The Protein/Carbohydrate Ratio in the Diet Affects Zootechnical Performance and the Regulation of Intermediary Metabolism in Juveniles Tambaqui (Colossoma macropomum).

The use of carbohydrates in animal feed is a way to save protein in the diet. This study evaluated the effect of protein/starch ratio on the performance, hepatic metabolism, and body composition of juvenile tambaqui (Colossoma macropomum). Six isoenergetic experimental diets were formulated containing three levels of digestible protein (P: 230, 260 and 290 g kg- 1) and two levels of starch (S: 180 and 280 g kg- 1): P23S18, P23S28, P26S18, P26S28, P29S18 and P29S28. Juveniles tambaqui (N = 288; initial weight = 30.0 ± 3.8 g) were fed experimental diets for 90 days and the zootechnical performance was evaluated. Nine fish from each treatment group were sampled to determine somatic indices, blood metabolites, tissue energy reserves, body composition and activity of key hepatic enzymes. Blood triglycerides, hepatosomatic index, liver and muscle lipids, and hepatic glycogen increased significantly with starch while blood glucose, triglycerides and cholesterol, muscle lipids were significantly impacted by protein levels. Fish-fed S28 had increased feed intake (1714-1829 g; p < 0.0001) and fish-fed diet P26S18 had a higher protein efficiency rate (23.62%; p = 0.0356). Fish fed P23 had lower crude protein retention in the carcass (p = 0.0018) and high lipogenesis and lipid deposition in the muscle (p = 0.0069). These results suggest that dietary carbohydrates have a protein-sparing effect. Tambaqui adapted well to diets containing starch, even at higher levels, resulting in an overall increase in lipogenesis from S18 to S28. Thus, we recommend P26S18 as a cost-effective feed that ensures both zootechnical performance and quality of the final product.

Atrial fibrillation screening to prevent stroke in persons with low-normal thyrotropin

Abstract Background Screening for atrial fibrillation (AF) has been proposed as a method to prevent strokes in high-risk individuals. Recent trials were unable to prove efficacy for stroke prevention but suggested that a more refined approach may be beneficial. Low-normal thyroid-stimulating hormone (TSH) is a marker for AF and stroke risk and may be used to select individuals for AF screening. Purpose To explore TSH as a tool to select individuals for AF screening to prevent stroke. Methods Post hoc analysis of a clinical trial enrolling 6004 participants with stroke risk factors but no known AF randomized 1:3 to implantable loop recorder (ILR) screening for AF and initiation of oral anticoagulation (OAC) upon AF detection versus usual care (control group). The primary outcome was stroke or systemic embolism (SE). Secondary outcomes included the combination of stroke, SE, or cardiovascular (CV) death, all-cause death, AF diagnosis, and OAC initiation. All outcomes were adjudicated. Results Baseline TSH was measured in 6003 participants (99.98%); 1500 randomized to ILR vs 4503 to control. The mean age was 75±4 years, 2836 (47%) were women. The tertiles of TSH were at ≤1.2, 1.2-1.9, and &amp;gt;1.9 mIU/L. Participants in the first tertile had slightly higher levels of the thyroid hormones (T3, T4, and free T4), were slightly younger, had more smoking pack-years, and higher pulse rate compared to other tertiles. The median follow-up duration was 5.4 (4.9-5.8) years, and no participants were lost to follow-up. AF was diagnosed in 476 (31.7%) participants in the ILR group vs 550 (12.2%) in the control group and this difference was similar across tertiles (p-interaction=0.44). Similar patters were observed for OAC initiation. In the first TSH tertile, participants in the ILR group were significantly less likely to experience the primary outcome (hazard ratio 0.52 [0.30–0.90]; p=0.019) or the combination of stroke, SE, or CV death (hazard ratio 0.54 [0.35–0.84]; p=0.006, respectively) compared to control, while there was no effect in participants with higher TSH (p-interaction 0.029 and 0.014, respectively) and there was no effect on all-cause death in any tertile. When TSH was modelled as a continuous variable, the effect of ILR screening gradually increased with decreasing TSH, with the upper bound of the confidence interval reaching HR&amp;lt;1 at TSH&amp;lt;1.2-1.5 mIU/L. Sensitivity analyses excluding participants with baseline TSH outside reference range (0.3-4.0 mIU/L) and/or treated with thyroid hormone replacement or antithyroid agents yielded similar results. Conclusion In persons with stroke risk factors and TSH &amp;lt;1.2-1.5 mIU/L, ILR screening for AF and anticoagulation upon detection led to significantly decreased stroke risk. There was no effect in persons with higher TSH, though the yield of screening was similar across levels. This suggests that low-normal TSH may indicate benefit from AF screening while higher levels may lead to overdiagnosis.TableFigure

Finally, some hope. Communicating systemic aspects of climate‐change mitigation

AbstractClimate communication, including from museums, often advocates individual lifestyle changes, and while these are necessary, the biggest emissions reductions will come from the systemic transition to renewable energy sources. The importance of this systemic change and its attainability has been under‐communicated in the public discourse, although bodies like the Intergovernmental Panel on Climate Change have increased their focus on it. We tested a message focusing on systemic aspects and actions that individuals can do to accelerate the renewable energy transition against a message advocating lifestyle change and a neutral message on the science of climate change. The neutral message elicited the highest levels of negative emotions, whereas the systemic message elicited higher levels of hope. These higher hope levels mediated increased behavioral intentions for doing the suggested system‐aimed actions and for making lifestyle changes. Our results suggest that museums and climate communicators should prominently feature systemic aspects of climate change mitigation.

Perception of stress among healthcare workers in hospitals in Belgrade during COVID-19 pandemic

Abstract Background The COVID-19 pandemic has affected healthcare institutions and workers, exposing them to unfamiliar and hazardous conditions, increased workloads, and changing directives. This has led to work-related stress, resulting in burnout, depression, anxiety disorders, and other health issues among healthcare workers. Methods This cross-sectional study utilized an anonymous questionnaire with closed-ended questions. To assess stress levels among healthcare workers, a Likert-type scale was used. Over 6.000 healthcare workers completed the questionnaire in 2022. The relationship between the dependent variable (perceived stress level) and predictors was modelled using generalized ordinal univariate and multivariate logistic regression. Results Almost a third (30.7%) of respondents felt a very high amount of tension, stress, or pressure while performing their jobs under the conditions of the COVID-19 epidemic, while 422 (6.8%) did not feel tension, stress, or pressure at all. In the multivariate logistic regression model, statistically significant predictors of higher levels of perceived stress in the conditions of the COVID-19 epidemic include female sex (OR = 0,80), older age (OR = 1.19), being in a managerial position (OR = 1.32), lower satisfaction with available work time (OR = 0.82), patient relations (OR = 0.81), financial compensation (OR = 0.83), and cooperation with colleagues (OR = 0.93). Conclusions Through the identification of potential stress predictors, valuable insights are gained to aid policymakers in the planning and enhancement of healthcare personnel’s work during pandemics, as well as in situations characterized by heightened stress levels. Key messages • These findings emphasize supporting healthcare workers during the pandemic. • Strategies for reducing stress should be directed towards healthcare professionals who experience higher stress levels.

Monocyte response to mitochondrial DAMPs in elderly subjects: a possible contribution to chronic inflammation and atherosclerosis

Abstract Background Aging is an important risk factor for atherosclerosis and persists as an independent contributor when all other known factors are controlled. Circulating free mitochondrial DNA (cf-mtDNA) can activate immune cells, including monocytes, that promote plaque formation and produce proinflammatory cytokines [1]. Several receptors, including TLR9, AIM2, NLRP3, cGAS can bind cf-mtDNA and activate downstream pathways, leading to the activation of proinflammatory genes [2]. We previously showed that mtDNA increases with age, and at the highest concentrations observed in plasma, can enhance the pro-inflammatory effect of bacterial PAMPs [3]. Nevertheless, it is unknown if the pathways triggered by mtDNA are functionally preserved in elderly, and if it can synergize with oxidized low-density lipoproteins (ox-LDL), which are known to interact with TLR4 and TLR2, in concert with scavenger receptors to regulate the inflammatory microenvironment in atherosclerosis. Purpose This study aims to understand if and how the cf-mtDNA activates monocytes triggering an inflammatory response, if monocyte from young and old donors present a different response to mtDNA if age-related difference in the functional activity of these cells. Methods We selected 10 old subjects (74.4 ± 2.4 y.o.; 2M:8F) without a history of cardiovascular or peripheral arterial diseases, 4 ultranonagenarians (98.3 ± 4.7 y.o.; 1M:3F) and 9 sex-matched young controls (28.4 ± 7.3 y.o.; 0M:9F). Monocytes were isolated from blood samples, and inflammatory response to mtDNA alone or in combination with LPS was assessed, by analyzing TLR9 expression, NF-kB activation and the release in the supernatants of a panel of proinflammatory cytokines. Results Monocyte expression of the mtDNA receptor TLR9 showed a slight reduction with aging, and is similar in old subjects and ultranonagenarians. mtDNA was internalized only in cells pre-treated with LPS and co-localized with TLR9. When internalization occurred, monocytes treated with mtDNA+LPS, released pro-inflammatory cytokines at higher levels than cells treated with LPS alone. Monocytes from elderly subjects showed a partial impairment in mtDNA uptake, and a lower capability to activate TLR9 downstream pathway. However, the capability to secrete pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) was not compromised, and NF-kB translocation into the nucleus after treatment with mtDNA is preserved, suggesting that compensatory mechanisms allowed mtDNA-driven activation of monocytes in elderly people. Conclusions The capability of mtDNA to promote an inflammatory response is preserved in elderly people and is still present in ultranonagenarians subjects. As mtDNA plasma levels increase with aging, mtDNA likely act as proinflammatory agents in aged people and can contribute to maintain inflammation in the atherosclerotic plaques. Further studies will clarify if mtDNA can act synergistically with ox-LDL to promote monocyte activation.