Measurement invariance across countries of the Test of Memory Strategies (TMS): A contribution to the cross-national validity study.

Previous literature showed a complex interpretation of recall tasks due to the complex relationship between Executive Functions (EF) and Long Term Memory (M). The Test of Memory Strategies (TMS) could be useful for assessing this issue, because it evaluates EF and M simultaneously. This study aims to explore the validity of the TMS structure, comparing the models proposed by Vaccaro et al. (2022) and evaluating the measurement invariance according to three countries (Italy, Spain, and Portugal) through Confirmatory Factor Analysis (CFA). Four hundred thirty-one healthy subjects (Age mean = 54.84, sd = 20.43; Education mean = 8.85, sd =4.05; M = 177, F = 259) were recruited in three countries (Italy, Spain, and Portugal). Measurement invariance across three country groups was evaluated through Structural Equation modeling. Also, convergent and divergent validity were examined through the correlation between TMS and classical neuropsychological tests. CFA outcomes suggested that the best model was the three-dimensional model, in which list 1 and list2 reflect EF, list 3 reflects a mixed factor of EF and M (EFM) and list4 and list5 reflect M. This result is in line with the theory that TMS decreases EF components progressively. TMS was metric invariant to the country, but scalar invariance was not tenable. Finally, the factor scores of TMS showed convergent validity with the classical neuropsychological tests. The overall results support cross-validation of TMS in the three countries considered.

Reliability of a point of care testing blood gas analyzer for measurement of lactate levels in cerebrospinal fluid.

Analysis of cerebrospinal fluid (CSF), including lactate, is key for diagnosis of acute meningitis. Since blood gas analyzers (BGA) enable rapid and safe blood-lactate measurements, we evaluated the reliability of RAPIDPoint 500 BGA to provide a fast and accurate measure of CSF lactate. In this study, CSF lactate levels were measured by a reference assay and on RAPIDPoint 500 BGA. Comparability was evaluated through difference analysis, using Bland Altman test, and linear regression analysis, using the Passing Bablok test. Agreement rate according to CSF lactate (≥3.5 and <3.5 mmol/L) was calculated using kappa (κ) statistic. Population study included 98 CSF samples. Concerning difference analysis, according to Bland-Altman test, bias was 0.13 mmol/L (CI 95%: -0.26 to 0.52 mmol/L. In regression analysis, according to Passing-Bablok equation a systematic difference between both assays was found. In concordance analysis, the interrate realibility was very high (κ: 0.964). According to our resuls, although a systematic difference was detected when lactate levels were measured on RAPIDPoint 500 BGA, the results from Bland-Altman test and the high agreement rate support that this POCT analyzer could be useful for a early and safe detection of patients with high probability of increased CSF lactate level.

Design of Personalized Neoantigen RNA Vaccines Against Cancer Based on Next-Generation Sequencing Data.

The good clinical results of immune checkpoint inhibitors (ICIs) in recent cancer therapy and the success of RNA vaccines against SARS-nCoV2 have provided important lessons to the scientific community. On the one hand, the efficacy of ICI depends on the number and immunogenicity of tumor neoantigens (TNAs) which unfortunately are not abundantly expressed in many cancer subtypes. On the other hand, novel RNA vaccines have significantly improved both the stability and immunogenicity of mRNA and its efficient delivery, this way overcoming past technique limitations and also allowing a quick vaccine development at the same time. These two facts together have triggered a resurgence of therapeutic cancer vaccines which can be designed to include individual TNAs and be synthesized in a timeframe short enough to be suitable for the tailored treatment of a given cancer patient.In this chapter, we explain the pipeline for the synthesis of TNA-carrying RNA vaccines which encompasses several steps such as individual tumor next-generation sequencing (NGS), selection of immunogenic TNAs, nucleic acid synthesis, drug delivery systems, and immunogenicity assessment, all of each step comprising different alternatives and variations which will be discussed.

Antitumoral Effects of Tricyclic Antidepressants: Beyond Neuropathic Pain Treatment.

Growing evidence shows that nerves play an active role in cancer development and progression by altering crucial molecular pathways and cell functions. Conversely, the use of neurotropic drugs, such as tricyclic antidepressants (TCAs), may modulate these molecular signals with a therapeutic purpose based on a direct antitumoral effect and beyond the TCA use to treat neuropathic pain in oncology patients. In this review, we discuss the TCAs' safety and their central effects against neuropathic pain in cancer, and the antitumoral effects of TCAs in in vitro and preclinical studies, as well as in the clinical setting. The current evidence points out that TCAs are safe and beneficial to treat neuropathic pain associated with cancer and chemotherapy, and they block different molecular pathways used by cancer cells from different locations for tumor growth and promotion. Likewise, ongoing clinical trials evaluating the antineoplastic effects of TCAs are discussed. TCAs are very biologically active compounds, and their repurposing as antitumoral drugs is a promising and straightforward approach to treat specific cancer subtypes and to further define their molecular targets, as well as an interesting starting point to design analogues with increased antitumoral activity.

Palliative care knowledge test for nurses and physicians: validation and cross-cultural adaptation.

BACKGROUND: Palliative care knowledge is essential in primary healthcare due to the increasing number of patients who require attention in the final stage of their life. Health professionals (physicians and nurses) need to acquire specific knowledge and abilities to provide high-quality palliative care. The development of education programmes in palliative care is necessary. The Palliative Care Knowledge Test (PCKT) is a questionnaire that evaluates the basic knowledge about palliative care, but it has not been adapted into Spanish, and its effectiveness and utility for Spanish culture have not been analysed. OBJECTIVE: The aim of this study was to report the translation into Spanish and a psychometric analysis of the PCKT. METHODS: The questionnaire survey was validated with a group of 561 physicians and nurses. The PCKT Spanish Version (PCKT-SV) was obtained from a process, including translation, back translation and revision by experts and a pilot study. The content validity and reliability of the questionnaire were analysed. RESULTS: The results showed internal consistency and reliability indexes similar to those obtained by the original version of PCKT. CONCLUSION: The PCKT-SV is a useful instrument for measuring Spanish-speaking physician and nurse knowledge of palliative care, and it is suitable to evaluate the effectiveness of training activities in palliative care.

Physicians' and Nurses' Knowledge in Palliative Care: Multidimensional Regression Models.

The increase in life expectancy has led to a growth in the number of people in need of palliative care. Health professionals must possess appropriate knowledge and skills. This study aimed to assess knowledge in palliative care through the Palliative Care Knowledge Test Spanish Version (PCKT-SV)®. A cross-sectional analytical study was conducted in 40 primary care health services. A total of 600 PCKT-SV questionnaires were distributed among health professionals; 561 of them (226 nurses and 335 physicians) were properly filled up. Sociodemographic information, education, and work experience were also recorded. A total of 34.41% of the nurses and 67.40% of the physicians showed good or excellent knowledge of palliative care. Physicians' scores for pain, dyspnea, and psychiatric disorders were higher than those of the nurses. Nurses scored significantly better in philosophy. Professionals with continuous training in palliative care showed a higher level of knowledge. Age and work experience of physicians and undergraduate training in nurses had significant weight in knowledge. Developing continuous training and enhancing undergraduate training in palliative care will lead to improved patient care at the end of life.

Increased concentrations of procalcitonin in patients with paracetamol intoxication.

Objectives: Paracetamol intoxication is one of the causes of elevated procalcitonin concentrations unrelated to infection. We report a case series of two patients intoxicated with paracetamol whose laboratory data revealed a significant elevation of serum procalcitonin concentrations without clinical, radiological and/or biological evidence of infection. The underlying mechanism by which paracetamol triggers an increase in procalcitonin concentrations is still unclear. Case presentation: We report two cases of paracetamol intoxication. Both patients were admitted to the Emergency Department (ED) and subsequently transferred to the Intensive Care Unit (ICU). The patients exhibited elevated procalcitonin levels during the first hours of admission without clinical and/or microbiological evidence of infection that could explain such increase. Notably, only Case 1 developed liver injury, with alterations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin and esterified bilirubin concentrations, which were not observed in Case 2. Conclusions: The two patients showed elevated procalcitonin concentrations resulting from paracetamol intoxication, although only a patient exhibited signs of liver injury. These findings suggest that increased procalcitonin levels induced by a paracetamol overdose cannot be fully explained by hepatocyte injury alone, but other mechanisms involving other organs and tissues may also be associated. In any case, although this mechanism is not well understood, it is important to be aware of this limitation when using procalcitonin as a biomarker of infection in patients intoxicated with paracetamol.

Biology and Therapeutic Targets of Colorectal Serrated Adenocarcinoma; Clues for a Histologically Based Treatment against an Aggressive Tumor.

Serrated adenocarcinoma (SAC) is a tumor recognized by the WHO as a histological subtype accounting for around 9% of colorectal carcinomas. Compared to conventional carcinomas, SACs are characterized by a worse prognosis, weak development of the immune response, an active invasive front and a frequent resistance to targeted therapy due to a high occurrence of KRAS or BRAF mutation. Nonetheless, several high-throughput studies have recently been carried out unveiling the biology of this cancer and identifying potential molecular targets, favoring a future histologically based treatment. This review revises the current evidence, aiming to propose potential molecular targets and specific treatments for this aggressive tumor.

A Randomized, Double-Blind, Placebo Controlled Trial to Determine the Effectiveness a Polyphenolic Extract (Hibiscus sabdariffa and Lippia citriodora) in the Reduction of Body Fat Mass in Healthy Subjects.

: The location and quantity of body fat determine the health risks, limiting people with obesity. Recently, polyphenols have attracted the attention of the scientific community because of their potential use for the reduction of obesity. A proprietary formula comprised of a blend of Lippia citriodora and Hibiscus sabdariffa has been recognized for its high content of polyphenols, powerful antioxidant molecules that may prevent weight gain and could be helpful for the treatment of obesity, as proven previously by in vivo models. The aim of the present study is to determine if the supplementation with Lippia citriodora and Hibiscus sabdariffa is useful for the treatment of obesity and/or weight control in subjects without a controlled diet. The intake of the extract for 84 days reduced body weight, the body mass index, and the fat mass measured with both bioimpedance and densitometry. This decrease in fat mass was observed to a greater extent, being significant, in the fat mass of the trunk (chest and torso).

Health status and nutritional development of adopted Ethiopian children living in southern Spain: A prospective cohort study.

OBJECTIVE: The first aim of this study was to evaluate the health status and anthropometrical development of adopted children from Ethiopia living in southern Spain. A second aim was to evaluate the association between these parameters and adherence to the Mediterranean dietary pattern. METHODS: The study sample included 53 adopted children from Ethiopia and a matched sample of 54 native-born children. A physical examination of the children, including height and weight, was conducted in Ethiopia at the time of entry into the adoption process. Height and weight were re-measured at the first day of adoption and 6, 12, and 24 mo after adoption. After 2 y of follow-up, another physical examination was performed, including the KIDMED test, to measure adherence to the Mediterranean diet. RESULTS: Skin and digestive conditions were the most prevalent disorders in Ethiopian children before adoption and at the end of follow-up. Baseline anthropometric characteristics indicated a low wasting prevalence (7.5%); however, stunted growth was more prevalent (35.8%). After 6 mo, the weight-for-age of Ethiopian children was restored (change from baseline P < 0.001), and not significantly different from the Spanish children at 1-y after adoption. Height-for-age also increased from baseline (P < 0.001. A higher KIDMED score was associated with increased weight-for-age (r = 0.279; P = 0.045) and height-for-age (r = 0.385; P = 0.004). CONCLUSIONS: This prospective study of adopted Ethiopian children confirmed a rapid growth development that occurred from the beginning of the adoption process and continued after the 2-y of follow-up. A higher adherence to the Mediterranean diet was associated with better growth development, which reinforces the importance of a balanced and adequate diet in growing children.

Development of an application for mobile phones (App) based on the collaboration between the Spanish Society of Rheumatology and Spanish Society of Family Medicine for the referral of systemic autoimmune diseases from primary care to rheumatology. / Desarrollo de una aplicación para teléfonos móviles (app) basada en la colaboración Sociedad Española de Reumatología/Sociedad Española de Medicina de Familia y Comunitaria para derivación de enfermedades autoinmunes sistémicas.

Management of systemic autoimmune diseases is challenging for physicians in their clinical practice. Although not common, they affect thousands of patients in Spain. The family doctor faces patients with symptoms and non-specific cutaneous, mucous, joint, vascular signs or abnormal laboratory findings at the start of the disease process and has to determine when to refer patients to the specialist. To aid in disease detection and better referral, the Spanish Society of Rheumatology and the Spanish Society of Family Medicine has created a group of experts who selected 26 symptoms, key signs and abnormal laboratory findings which were organized by organ and apparatus. Family doctors and rheumatologists with an interest in autoimmune systemic diseases were selected and formed mixed groups of two that then elaborated algorithms for diagnostic guidelines and referral. The algorithms were then reviewed, homogenized and adapted to the algorithm format and application for cell phone (apps) download. The result is the current Referral document of systemic autoimmune diseases for the family doctor in paper format and app (download). It contains easy-to-use algorithms using data from anamnesis, physical examination and laboratory results usually available to primary care, that help diagnose and refer patients to rheumatology or other specialties if needed.

Amylin as a potential link between type 2 diabetes and alzheimer disease.

OBJECTIVE: Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and ß-amyloid (Aß) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. METHODS: We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aß and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aß interact with amylin in either the pancreas or brain of these subjects. RESULTS: Cytoplasmic tau and Aß protein deposits were detected in pancreatic ß cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aß and tau in both the pancreas and hippocampus. INTERPRETATION: The presence of both tau and Aß inclusions in pancreatic ß cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.

In vivo randomized trial of three marketed milk preparations enriched with calcium and vitamins (D and K) on bone mass and bone turnover markers from biological fluids in premenopausal Caucasian women.

INTRODUCTION: osteoporosis is a metabolic bone disease that leads to increased bone fragility and increased risk of fracture. OBJECTIVES: the aim of the present research was to determine the effectiveness of a diary intake of three different dairy products (250 ml) enriched with vitamins and calcium on decreasing bone mass. METHOS: the present study is a comparative trial of three dairy products fortified with calcium and vitamin D, parallel, randomized, double-blind andsingle-center. Bone mass content (BMC), bone mass density (BMD), T-score and Z-score were measured in different locations, besides biochemical markers along 18 months in premenopausal women. Two hundred and ten volunteers from all the three groups were submitted to the same monitoring procedures, consisting on blood extraction, urine collection and energy X-ray absorptiometry (DEXA) done in the laboratory. The monitoring was carried on three times, first at month 0 (baseline), the second at month 9 (in the middle of the treatment) and, finally, at month 18 (the end of the treatment). RESULTS: the majority of anatomical locations showed both BMC and BMD decrease ranging between 0.5% and 1.5%. The T-score and the Z-scoreincreased in lumbar spine after the treatment with the dairy products. Moreover, the most noteworthy change on the biomarkers of bone resorption was showed by plasmatic tartrate-resistant acid phosphatase (TRAP), with and increase between 20.7% and 29.5% after the intake of the different products. CONCLUSIONS: therefore, the intake of the three dairy products improves the bone mass in lumbar spine, leading to important changes in the concentration of biomarkers of bone resorption. Especially, tartrate-resistant acid phosphatase seems to be strongly influenced by the intake of every dairy product. However, no significant differences were found between the different dairy products used in the present study. Therefore, the intake of dairy product seems to be more determinant than micronutrients supplementation.

Interaction of amyloidogenic proteins in pancreatic ß cells from subjects with synucleinopathies.

Parkinson's disease patients experience a wide range of non-motor symptoms that may be provoked by deposits of phosphorylated α-synuclein in the peripheral nervous system. Pre-existing diabetes mellitus might be a risk factor for developing Parkinson's disease, and indeed, nearly 60% of Parkinson's disease patients are insulin resistant. Thus, we have investigated whether phosphorylated α-synuclein is deposited in pancreatic tissue of subjects with synucleinopathies. We studied pancreatic tissue from 39 subjects diagnosed with Parkinson's disease, Lewy body Dementia or incidental Lewy bodies disease, as well as that from 34 subjects with diabetes mellitus and a normal neuropathological examination, and 52 subjects with a normal neuropathological examination. We examined the pancreatic accumulation of phosphorylated α-synuclein and of the islet amyloid polypeptide precursor (IAPP), an amyloidogenic protein that plays an unknown role in diabetes mellitus, but that can promote α-synuclein amyloid deposition in vitro. Moreover, we performed proximity ligation assays to assess whether these two proteins interact in the pancreas of these subjects. Cytoplasmic phosphorylated α-synuclein deposits were found in the pancreatic ß cells of 14 subjects with Parkinson's disease (93%), in 11 subjects with Lewy body Dementia (85%) and in 8 subjects with incidental Lewy body disease (73%). Furthermore, we found similar phosphorylated α-synuclein inclusions in 23 subjects with a normal neuropathological examination but with diabetes mellitus (68%) and in 9 control subjects (17%). In addition, IAPP/α-synuclein interactions appear to occur in patients with pancreatic inclusions of phosphorylated α-synuclein. The presence of phosphorylated α-synuclein inclusions in pancreatic ß cells provides a new evidence of a mechanism that is potentially common to the pathogenesis of diabetes mellitus, PD and DLB. Moreover, the interaction of IAPP and α-synuclein in the pancreatic ß cells of patients may represent a novel target for the development of strategies to treat these diseases.

Evaluation of the thyroid nodule with high-resolution ultrasonography and elastography without fine needle aspiration biopsy. / Evaluación del nódulo tiroideo con ecografía y elastografía de alta resolución sin la punción-aspiración con aguja fina.

INTRODUCTION: Fine needle aspiration biopsy (FNAB) is the gold standard screening technique used in the diagnostic protocol for thyroid nodules. However, it is not free of complications. OBJECTIVE: To identify thyroid nodules in which FNAB could be avoided during the diagnostic process by means of the use of a high-resolution ultrasonography or elastography. MATERIAL AND METHOD: A prospective, non-randomized study was carried out. Single thyroid nodules and dominant nodules of multinodular goiter were included. Patients who had undergone thyroid surgery in the past were excluded. All patients underwent a high-resolution ultrasound and elastography, and, subsequently, a FNAB. We analyzed the ultrasound variables in 2D and Doppler, followed by the elastographic variables, and the results of the FNAB according to Bethesda. To correlate the data, the nodules were classified as benign or malignant. Student's t test, the Chi-square test and a logistic regression analysis were applied for the statistical analysis. RESULTS: A total of 221 thyroid nodules were analyzed, 32 of which were malignant (14%). The most predictive ultrasound findings of malignancy (P<.05) were a hypoechoic or complex echostructure (OR=11.832), the presence of microcalcifications (OR=9.637) and chaotic vascularization observed in the Doppler (OR=46.464). With regard to the elastography, elastographic patterns i and ii were seen to be associated with benignity (P=.0004 and P<.0001, respectively). When type i or ii elastography was combined with an ultrasound showing a non-hypoechoic nor complex echostructure, without microcalcifications nor chaotic vascularization in the Doppler ultrasound, 100% of the cases were benign with a specificity of 100% and a sensitivity of 14%. CONCLUSIONS: The combination of a high-resolution ultrasound with an elastography makes it possible to select cases where a FNAB does not have to be performed. Cases susceptible to a periodic follow-up without the use of a FNAB are those without a hypoechoic nor complex structure, no microcalcifications, non-chaotic vascularization and a type i or ii elastography.

Brain delivery of microencapsulated GDNF induces functional and structural recovery in parkinsonian monkeys.

Glial cell line-derived neurotrophic factor (GDNF) remains the most potent neurotrophic factor for dopamine neurons. Despite its potential as treatment for Parkinson's disease (PD), its clinical application has been hampered by safety and efficacy concerns associated with GDNF's short in vivo half-life and with significant brain delivery obstacles. Drug formulation systems such as microparticles (MPs) may overcome these issues providing protein protection from degradation and sustained drug release over time. We therefore sought to evaluate the efficacy and safety of GDNF delivered via injectable biodegradable MPs in a clinically relevant model of PD and to investigate the mechanism contributing to their beneficial effects. MPs were injected unilaterally into the putamen of parkinsonian monkeys with severe nigrostriatal degeneration. Notably, a single administration of the microencapsulated neurotrophic factor achieved sustained GDNF levels in the brain, providing motor improvement and dopaminergic function restoration. This was reflected by a bilateral increase in the density of striatal dopaminergic neurons 9 months after treatment. Moreover, GDNF was retrogradely transported to the substantia nigra increasing bilaterally the number of dopaminergic and total neurons, regardless of the severe degeneration. GDNF-MP injection within the putamen elicited no adverse effects such as immunogenicity, cerebellar degeneration or weight loss. MPs are therefore a safe, efficient vehicle for sustained protein delivery to the brain, supporting the therapeutic benefit of GDNF when encapsulated within MPs for brain repair. Overall, these findings constitute important groundwork for GDNF-MP clinical development.

The CarD/CarG regulatory complex is required for the action of several members of the large set of Myxococcus xanthus extracytoplasmic function σ factors.

Extracytoplasmic function (ECF) σ factors are critical players in signal transduction networks involved in bacterial response to environmental changes. The Myxococcus xanthus genome reveals ∼45 putative ECF-σ factors, but for the overwhelming majority, the specific signals or mechanisms for selective activation and regulation remain unknown. One well-studied ECF-σ, CarQ, binds to its anti-σ, CarR, and is inactive in the dark but drives its own expression from promoter P(QRS) on illumination. This requires the CarD/CarG complex, the integration host factor (IHF) and a specific CarD-binding site upstream of P(QRS). Here, we show that DdvS, a previously uncharacterized ECF-σ, activates its own expression in a CarD/CarG-dependent manner but is inhibited when specifically bound to the N-terminal zinc-binding anti-σ domain of its cognate anti-σ, DdvA. Interestingly, we find that the autoregulatory action of 11 other ECF-σ factors studied here depends totally or partially on CarD/CarG but not IHF. In silico analysis revealed possible CarD-binding sites that may be involved in direct regulation by CarD/CarG of target promoter activity. CarD/CarG-linked ECF-σ regulation likely recurs in other myxobacteria with CarD/CarG orthologous pairs and could underlie, at least in part, the global regulatory effect of the complex on M. xanthus gene expression.

[Treatment of patients with osteoarthritis]. / Tratamiento del paciente con artrosis.

The therapeutic management of patients with osteoarthritis aims to decrease pain and inflammation, improve physical function, and to apply safe and effective treatments. A patient-centered approach implies the active participation of the patient in the design of the treatment plan and in timely and informed decision-making at all stages of the disease. The nucleus of treatment is patient education, physical activity and therapeutic exercise, together with weight control in overweight or obese patients. Self-care by the individual and by the family is fundamental in day-to-day patient management. The use of physical therapies, technical aids (walking sticks, etc.) and simple analgesics, opium alkaloids, and antiinflammatory drugs have demonstrated effectiveness in controlling pain, improving physical function and quality of life and their use is clearly indicated in the treatment of osteoarthritis. Conservative surgery and joint replacement is indicated when treatment goals are not achieved in specific patients.