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Gaussian mixture models, which assume a Normal distribution for each component, are popular in antibody (or serological) data analysis to help determining antibody-positive and antibody-negative individuals. In this work, we advocate using finite mixture models based on Skew-Normal and Skew-t distributions for serological data analysis. These flexible mixing distributions have the advantage of describing right and left asymmetry often observed in the distributions of known antibody-negative and antibody-positive individuals, respectively. We illustrate the application of these alternative mixture models in a data set on the role of human herpesviruses in the Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Abstract Background Pheochromocytoma (PCC) is rare in cats and plasma (PL) and urinary (U) metanephrines (metanephrine [MN]; normetanephrine [NMN]) measurement is rarely described in cats. Objectives We evaluated the utility of PL and U MNs measurement in 10 healthy cats and a cat with a confirmed diagnosis of pheochromocytoma (PheoCat), using liquid chromatography with tandem mass spectrometry (LC‐MS‐MS). Methods Urine and EDTA PL samples collected from each of the 10 cats and the PheoCat were promptly stored at −80°C and remained frozen until analysis. To evaluate U MNs stability, an additional urine sample collected from the healthy cats was refrigerated for 24 hours before freezing. Urinary creatinine concentration (Creat) was assessed using the same spot urine samples to calculate U MNs‐to‐creatinine ratios. Results The PL‐MN and PL‐NMN median concentrations of the healthy cats were 2.73 and 7.02 nmol/L, respectively. The median U‐MN/Creat and U‐NMN/Creat ratios were 70 and 139 μg/g, respectively. The PheoCat had a PL‐MN of 3.68 nmol/L, PL‐NMN of 66.27 nmol/L, U‐MN/Creat of 179 μg/g, and U‐NMN/Creat of 1262 μg/g. The PheoCat had markedly increased concentrations of both PL and U MNs when compared to the healthy cats. No significant difference was found between U MNs measured in urine samples that underwent 24 hours of refrigeration in comparison to those that were frozen immediately. Conclusions We report preliminary reference intervals for PL and U MNs in cats using LC‐MS‐MS and the potential clinical applicability of these biomarkers for the diagnosis of PCC in cats.

Introduction: COVID-19-associated coagulopathy includes systemic and endothelial inflammation with coagulation dysregulation related to immunothrombosis. The aim of this study was to characterize this complication of SARS-CoV-2 infection in patients with moderate to severe COVID-19. Methods: An open-label, prospective observational study conducted in patients with COVID-19 moderate to severe acute respiratory failure admitted to an intensive care unit (ICU). Coagulation testing, including thromboelastometry, biochemical analysis and clinical variables, were collected at prespecified time points during the 30 days of ICU stay. Results: The study included 145 patients, 73.8% male, with a median age of 68 years (interquartile range - IQR 55 - 74). The most prevalent comorbidities were arterial hypertension (63.4%), obesity (44.1%) and diabetes (22.1%). Simplified acute physiology score II (SAPS II) was on average 43.5 (11 - 105) and sequential organ failure assessment (SOFA) at admission was 7.5 (0 - 14). During ICU stay, 66.9% of patients underwent invasive mechanical ventilation and 18.4% extracorporeal membrane oxygenation support; thrombotic and hemorrhagic events occurred in 22.1% and 15.1% of the patients respectively; anticoagulation with heparin was present in 99.2% of patients since early ICU stay. Death occurred in 35% of patients. Longitudinal studies revealed changes in almost all coagulation tests during the ICU stay. SOFA score, lymphocyte counts, some biochemical, inflammatory and coagulation parameters, including hypercoagulability and hypofibrinolysis seen in thromboelastometry, differed significantly (p < 0.05), between ICU admission and discharge. Hypercoagulability and hypofibrinolysis persisted throughout ICU hospitalization, showing higher incidence and severity in non-survivors. Conclusion: COVID-19-associated coagulopathy is characterized by hypercoagulability and hypofibrinolysis from ICU admission, and persisted throughout the clinical course in severe COVID-19. These changes were more pronounced in patients with higher disease burden and in non-survivors.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and multiple sclerosis (MS) are two complex and multifactorial diseases whose patients experience persistent fatigue, cognitive impairment, among other shared symptoms. The onset of these diseases has also been linked to acute herpesvirus infections or their reactivations. In this work, we re-analyzed a previously-described dataset related to IgG antibody responses to 6 herpesviruses (CMV – cytomegalovirus; EBV – Epstein-Barr virus; HHV6 – human herpesvirus-6; HSV1 and HSV2 – herpes simplex virus-1 and -2, respectively; VZV – varicella-zoster virus) from the United Kingdom ME/CFS biobank. The primary goal was to report the underlying symptomology and its association with herpesvirus IgG antibodies using data from 4 disease-trigger-based subgroups of ME/CFS patients (n = 222) and patients with MS (n = 46). The secondary objective was to assess whether serological data could distinguish ME/CFS and its subgroup from MS using a SuperLearner (SL) algorithm. There was evidence for a significant negative association between temporary eye insight disturbance and CMV antibody concentrations and for a significant positive association between bladder problems and EBV antibody concentrations in the MS group. In the ME/CFS or its subgroups, the most significant antibody-symptom association was obtained for increasing HSV1 antibody concentration and brain fog, a finding in line with a negative impact of HSV1 exposure on cognitive outcomes in both healthy and disease conditions. There was also evidence for a higher number of significant antibody-symptom associations in the MS group than in the ME/CFS group. When we combined all the serological data in an SL algorithm, we could distinguish three ME/CFS subgroups (unknown disease trigger, non-infection trigger, and an infection disease trigger confirmed in the lab at the time of the event) from the MS group. However, we could not find the same for the remaining ME/CFS group (related to an unconfirmed infection disease). In conclusion, IgG antibody data explains more the symptomology of MS patients than the one of ME/CFS patients. Given the fluctuating nature of symptoms in ME/CFS patients, the clinical implication of these findings remains to be determined with a longitudinal study. This study is likely to ascertain the robustness of the associations during natural disease course.

Knowing the attitudes and behaviors of nursing students in relation to vaccination is important because they will soon be determinant for the health literacy of the population. Vaccination remains the most effective response in the fight against communicable diseases, including COVID-19 and influenza. The objective of this study is to analyze the attitudes and behaviors of Portuguese nursing students with regard to vaccination. A cross-sectional study was carried out, with data collection from nursing students at a university in Lisbon, Portugal. A sample of 216 nursing students was obtained, representing 67.1% of the students enrolled in this university. What stands out from the results of the questionnaire “Attitudes and Behaviors in Relation to Vaccination among Students of Health Sciences” is that for the majority of students the answers were positive; in addition, 84.7% had a completed vaccination schedule for COVID-19. Being a nursing student, being in the final years of the course and being a woman are the factors that most influence the positive attitude of the students. The results obtained are motivating, because these students will be the future health professionals most likely to integrate health promotion programs through vaccination.

Aromatase inhibitors (AI) are extensively used as adjuvant endocrine therapy in post-menopausal women with hormone receptor-positive early breast cancer (HR+ EBC), but their impact on bone health is not negligible. This work aimed to assess bone loss, fracture incidence, and risk factors associated with these events, as well as the prognostic influence of fractures. We have conducted a retrospective cohort study of women with HR+ EBC under adjuvant therapy with AI, during a 3-year period. Four-hundred-and-fifty-one eligible women were reviewed (median age 68 years). Median time under AI was 40 months. A fracture event occurred in 8.4%, mostly in the radium and femoral neck and in older women (mean 74 vs. 68 years, p = 0.006). Age (OR 1.01, 95% CI 1.01–1.07, p = 0.024) and time under AI (OR 1.02, 95% CI 1.00–1.04, p = 0.037) were independent predictors of fracture, with a fair discrimination (AUC 0.71). Analysis of disease-free survival according to fracture event varied between groups, disfavoring the fracture cohort (at 73 months, survival 78.6%, 95% CI, 47.6–92.4 vs. 95.6%, 95% CI, 91.2–97.8, p = 0.027). The multivariate model confirmed the prognostic impact of fracture occurrence (adjusted HR of 3.17, 95% CI 1.10–9.11; p = 0.032). Bone health is often forgotten, despite its great impact in survivorship. Our results validate the pathophysiologic link between EBC and bone metabolism, which translates into EBC recurrence. Further research in this area may help refine these findings. Moreover, early identification of women at higher risk for fractures is warranted.

Introduction. Malnutrition is underdiagnosed in chronic obstructive pulmonary disease. Objectives. This study aimed to evaluate the nutritional status of COPD patients and the link between dyspnea and nutritional status. Methods. This longitudinal observational study included patients hospitalized with exacerbated COPD. Nutritional status was assessed using Nutrition Risk Screening 2002, anthropometric, and biochemical assessments, in the first 48 hours of hospitalization. Results. Thirty patients were evaluated. According to the Nutrition Risk Screening 2002, half of the patients were at increased risk of malnutrition. 36.7% were classified as malnourished if we only considered the body mass index. From the evaluation of the tricipital skin fold, 69.0% were classified as malnourished, with 48.3% having severe malnutrition. According to the serum albumin level, 29.6% had malnutrition criteria. A significant association between dyspnea and increasing age (p=0.037) was found. There was a strong association between the fold classification and the degrees of severity of dyspnea (Fisher exact test: 13.60, p=0.001, V Cramer = 0.826). Most patients were malnourished and had higher grades of dyspnea. Tricipital skinfold reflects subcutaneous adipose tissue; this anthropometric measurement seems to be a good method to classify the nutritional status of COPD patients. It classified the biggest portion of patients as malnourished. Conclusion. The number of patients classified as malnourished changed with the method under analysis. The tricipital skin fold parameter was strongly associated with the dyspnea score. Most patients had adipose tissue and muscular mass depletion.

Introduction of EGFR-TKI has changed the treatment paradigm for NSCLC patient with activating mutations of EGFR exons 18–21, replacing chemotherapy as standard first line treatment. Given the delays in molecular study results we sometimes face the need to start treatment in very symptomatic patients with high tumor burden. The reason for this retrospective study is to analyze the survival impact of performing an induction cytotoxic therapy until obtaining the molecular profile (EGFR mutation), followed by targeted therapy.This is a retrospective analysis of 31 patients who did upfront chemotherapy (ChT) before switching to EGFR TKI upon the molecular profile result. The calculated survival endpoints were progression-free survival (PFS), duration of TKI response and overall survival (OS).All patients were treated with upfront chemotherapy with a median of one cycle (range 1–3) followed by a first generation EGFR-TKI. Median PFS was 13 months (95% CI, 6.6–19.4) and median OS 33 months (95% CI, 11.9–54.0). After first line progression 14 patients were treated with Osimertinib. In this subgroup median OS was 52 months (95% CI, 34.0–69.9). In the multivariable Cox model, only body mass index retained independent prognostic significance for progression-free survival (p = 0.045).Survival outcomes in this cohort are in line with published data regarding first generation EGFR-TKI, both in terms of PFS and OS. Despite the limitations of this study, starting with upfront chemotherapy doesn't seem detrimental in terms of survival outcomes, with the potential advantage of symptomatic control. To our knowledge, this is the first study to address this strategy, which requires further confirmation.

The evidence of an association between Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and chronic herpesviruses infections remains inconclusive. Two reasons for the lack of consistent evidence are the large heterogeneity of the patients' population with different disease triggers and the use of arbitrary cutoffs for defining seropositivity. In this work we re-analyzed previously published serological data related to 7 herpesvirus antigens. Patients with ME/CFS were subdivided into four subgroups related to the disease triggers: S0-42 patients who did not know their disease trigger; S1-43 patients who reported a non-infection trigger; S2-93 patients who reported an infection trigger, but that infection was not confirmed by a lab test; and S3-48 patients who reported an infection trigger and that infection was confirmed by a lab test. In accordance with a sensitivity analysis, the data were compared to those from 99 healthy controls allowing the seropositivity cutoffs to vary within a wide range of possible values. We found a negative association between S1 and seropositivity to Epstein-Barr virus (VCA and EBNA1 antigens) and Varicella-Zoster virus using specific seropositivity cutoff. However, this association was not significant when controlling for multiple testing. We also found that S3 had a lower seroprevalence to the human cytomegalovirus when compared to healthy controls for all cutoffs used for seropositivity and after adjusting for multiple testing using the Benjamini-Hochberg procedure. However, this association did not reach statistical significance when using Benjamini-Yekutieli procedure. In summary, herpesviruses serology could distinguish subgroups of ME/CFS patients according to their disease trigger, but this finding could be eventually affected by the problem of multiple testing.

Background/Aims The role of very early (≤12 hours) endoscopy in nonvariceal upper gastrointestinal bleeding is controversial. We aimed to compare results of very early and early (12–24 hours) endoscopy in patients with upper gastrointestinal bleeding demonstrating low-risk versus high-risk features and nonvariceal versus variceal bleeding. Methods This retrospective study included patients with nonvariceal and variceal upper gastrointestinal bleeding. The primary outcome was a composite of inpatient death, rebleeding, or need for surgery or intensive care unit admission. Endoscopy timing was defined as very early and early. We performed the analysis in two subgroups: (1) high-risk vs. low-risk patients and (2) variceal vs. nonvariceal bleeding. Results A total of 102 patients were included, of whom 59.8% underwent urgent endoscopy. Patients who underwent very early endoscopy received endoscopic therapy more frequently (p=0.001), but there was no improvement in other clinical outcomes. Furthermore, patients at low risk and with nonvariceal bleeding who underwent very early endoscopy had a higher risk of the composite outcome. Conclusions Very early endoscopy does not seem to be associated with improved clinical outcomes and may lead to poorer outcomes in specific populations with upper gastrointestinal bleeding. The actual benefit of very early endoscopy remains controversial and should be further clarified.

Leptospirosis is a zoonosis of global importance caused by Leptospira species. Rodents are the main reservoirs, known to shed the bacteria in urine, thus contaminating water and soil and infecting other animals and people. Leptospirosis has been re-emerging in both developing and developed countries including Europe. It has been hypothesized that cats could be asymptomatic carriers of Leptospira. This study aims to evaluate cats’ exposure to Leptospira in Lisbon, Portugal, by measuring IgG titres and correlating them with possible factors that may increase the risk of exposure in urban cats. Two hundred and forty-three samples were collected from the biobank. An ELISA test followed by a seroprevalence analysis using a finite mixture model was performed to detect and measure anti-Leptospira IgG antibodies titres. In parallel, a survey was conducted to identify possible risk factors for seropositivity.According to the ELISA test protocol, only twenty-three cats (9.5%; 95% CI =(6.1%;13.9%)) could be considered as seropositive to Leptospira antigens. However, when the same data were analysed by the best different mixture models, one hundred and forty-four cats (59.3%; 95%CI = (52.8%; 65.5%)) could be classified as intermediate and high antibody responders to Leptospira antigens. Seropositivity to Feline Immunodeficiency Virus infection (FIV) was found to be the only significant risk factor associated with anti-Leptospira IgG antibodies. In conclusion, the present studies raises the possibility of a higher exposure of cats to Leptospira than previously thought due to the identification of a subpopulation of cats with intermediate antibody levels.

Spiritual distress may ascend from unmet spiritual needs. The use of instruments to measure spiritual distress seems to facilitate the approach to spirituality, such as the Spiritual Distress Scale (SDS) that has been used worldwide. No instrument to assess spiritual distress in cancer patients is currently available in Portugal. This study aims to conduct the translation, adaptation and validation of the SDS in Portuguese cancer patients undergoing chemotherapy. Methodological study based on Sousa and Rojjanasrirat (2011), a seven-step approach, started with the linguistic translation to the psychometric tests. The main participants (55.4%) were older than 60 years; about 64.7% were females, married (68.0%), and 86.7% were Catholic. Moderate spiritual distress was experienced by 49.3% of the participants. Linguistic and conceptual equivalences were obtained. The SDS European Portuguese version has an overall Cronbach’s alpha of 0.91, and the subscales were as follows: “relationship with self” (0.92), “relationship with others” (0.63), “relationship with God” (0.64) and “facing death” (0.85). Four factors emerged after Varimax rotation. Overall, these results indicate that the SDS European Portuguese version has good psychometric characteristics and can used in assessing spiritual distress in cancer patients.

Gaussian mixture models are widely employed in serological data analysis to discern between seropositive and seronegative individuals. However, serological populations often exhibit significant skewness, making symmetric distributions like Normal or Student-t distributions unreliable. In this study, we propose finite mixture models based on Skew-Normal and Skew-t distributions for serological data analysis. Although these distributions are well established in the literature, their application to serological data needs further exploration, with emphasis on the determination of the threshold that distinguishes seronegative from seropositive populations. Our previous work proposed three methods to estimate the cutoff point when the true serological status is unknown. This paper aims to compare the three cutoff techniques in terms of their reliability to estimate the true threshold value. To attain this goal, we conducted a Monte Carlo simulation study. The proposed cutoff points were also applied to an antibody dataset against four SARS-CoV-2 virus antigens where the true serological status is known. For this real dataset, we also compared the performance of our estimated cutoff points with the ROC curve method, commonly used in situations where the true serological status is known.