FCSlib: an open-source tool for fluorescence fluctuation spectroscopy analysis for mobility, number and molecular brightness in R.

SUMMARY: FCSlib is an open-source R tool for fluorescence fluctuation spectroscopy data analysis. It encompasses techniques such as Fluorescence Correlation Spectroscopy, Number and Brightness, Pair Correlation Function and Pair Correlation of Molecular Brightness. AVAILABILITY AND IMPLEMENTATION: Source code available at https://cran.r-project.org/web/packages/FCSlib/ for Linux, Windows and macOS platforms. Sample data as well as a user's guide are available at https://github.com/FCSlib/FCSlib. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

The silent variants of pituitary tumors: demographic, radiological and molecular characteristics.

INTRODUCTION: Tumors of the anterior pituitary gland (PTs) are mostly benign tumors with a low prevalence, which has nevertheless increased with advances in brain radiology techniques. Nearly half of PTs are not associated with a clinical endocrine syndrome. These tumors have been indistinctly named non-functioning pituitary adenomas (NFPAs) or silent pituitary tumors (SPTs) and the mechanisms of silencing are not fully known. AIM: To study the frequency and characterize the silent variant of PTs in a large local series, and to assess their pituitary adenohypophyseal gene expression. METHODS: This observational, cross-sectional study was performed in a Pituitary Tumor Center of Excellence and involved 268 PTs. After identifying the different subtypes according to the immunohistochemical (IHC) expression of adenohypophyseal hormones, we studied their gene expression by RT-qPCR. RESULTS: We found that silent tumors were larger and more invasive, but not more proliferative than their functional counterparts. The RT-qPCR complements the IHC typification of PTs, reducing the proportion of null-cell subtype. Finally, some silent PT subtype variants showed lower specific adenohypophyseal hormone gene expression than their functional counterparts, which may contribute to the absence of endocrine manifestations. CONCLUSIONS: This paper highlights the importance of identifying the silent variant of the PTs subtypes. As expected, silent tumors were larger and more invasive than their functioning counterparts. However, there was no difference in the proliferation activity between them. Finally, the lower specific gene expression in the silent than in the functioning counterparts of some PTs subtypes gives insights into the silencing mechanisms of PTs.

Anaphylaxis: A Decade of a Nationwide Allergy Society Registry.

BACKGROUND AND OBJECTIVES: Anaphylaxis is an acute, life-threatening, multiorgan hypersensitivity reaction. Objective: The aim of this study was to identify the causes of anaphylaxis in Portugal in order to improve our knowledge of epidemiology and management. METHODS: We implemented a nationwide notification system for anaphylaxis over a 10-year period, with voluntary reporting by allergists. Data on 1783 patients with anaphylaxis were included. Etiopathogenesis, manifestations, and clinical management were characterized in detail for both children and adults. RESULTS: The mean age was 32.7 (20.3) years, and 30% were under 18 years of age; 58% were female. The mean age at the first anaphylaxis episode was 27.5 (20.4) years (ranging from 1 month to 88 years). The main culprits of anaphylaxis were foods (48%), drugs (37%) (main trigger in adults, 48%), and hymenoptera venom (7%). The main culprit foods were shellfish (27%), fresh fruit (17%), cow's milk (16%), tree nuts (15%), fish (8%), egg (7%), and peanut (7%). The main drugs were nonsteroidal anti-inflammatory drugs (43%), antibiotics (39%), and anesthetic agents (6%). Other causes included exercise (3%), latex (2%), cold-induced anaphylaxis (2%), and idiopathic anaphylaxis (2%). Most patients (80%) were admitted to the emergency department; only 43% received adrenaline. Anaphylaxis recurred in 41% of patients (21% with ≥3 anaphylactic episodes); 7% used an adrenaline autoinjector device. CONCLUSION: Food is the leading cause of anaphylaxis in Portugal, while drugs were the main elicitors in adults. We emphasize undertreatment with adrenaline and recurrent episodes, highlighting the need to improve diagnostic and therapeutic approaches to anaphylaxis.

Is Somatostatin Receptor and Dopamine Receptor profiling useful in the management of silent somatotroph tumors?

Silent somatotroph tumors (sSTs) are pituitary neuroendocrine tumors (PitNETs) which do not give rise to the clinical syndrome of acromegaly. Differently to their functioning counterparts, the adjuvant medical treatment with somatostatin analogues (SSAs) or dopamine receptors agonists (DAs) has been scarcely addressed in these tumors. As preliminary results of an ongoing research on silencing mechanisms involved in the pathogenesis of sSTs, we have characterized by qRT-PCR the expression of SSTRs and DRDs in a large series of 18 silent and 68 functioning STs. Although the expression of SSTR2 and SSTR5 was lower in sSTs than in functioning ones, we found a negative correlation between SSTR2 and the tumor size of the sSTs. Additionally, levels of expression of DRD2 were similar between the two subtypes suggesting a possible basis for the treatment of these tumors with SSAs and DAs.

Occupation and cancer of the larynx: a systematic review and meta-analysis.

The aim of the study was to explore the relationship between occupational exposure, defined by occupational categories and job title, and laryngeal cancer. A systematic review and meta-analysis of 21 tobacco and alcohol-adjusted case-control studies including data from 6,906 exposed cases and 10,816 exposed controls was performed to investigate the frequency of laryngeal cancer in different occupations. Job classifications were harmonized using the International Standard Classification of Occupations. Pooled odds ratios (OR [95 % confidence intervals (CI)]) were calculated for the different occupational groups. A significantly increased risk of laryngeal cancer was observed for the occupational category of 'production-related workers, transport equipment operators, and laborers' (OR=1.3 [1.2-1.4]); particularly at risk were occupations as: miners (OR=1.6 [1.2-2.1]), tailors (OR=1.7 [1.2-2.3]), blacksmith and toolmakers (OR=1.5 [1.2-1.7]), painters (OR=1.4 [1.1-1.9]), bricklayers and carpenters (OR=1.3 [1.2-1.5]), and transport equipment operators (OR=1.3 [1.2-1.5]). Individuals working as 'professional, technical, and related workers' (OR=0.7 [0.6- 0.8]), 'administrative and managerial workers' (OR=0.6 [0.4-0.7]), or 'clerical and related workers' (OR=0.8 [0.7-0.9]) had laryngeal cancer less frequently. Occupational exposure, defined by occupational categories and job title, is likely to be an independent risk factor for laryngeal cancer. Further research on specific occupations with increased risk of laryngeal cancer is warranted to explore the underlying mechanisms.

Functional patterns of cytomegalovirus (CMV) pp65 and immediate early-1-specific CD8(+) T cells that are associated with protection from and control of CMV DNAemia after allogeneic stem cell transplantation.

BACKGROUND: The functional profile of cytomegalovirus (CMV)-specific CD8(+) T cells that associate with protection from and control of CMV DNAemia in allogeneic stem cell transplant (allo-SCT) recipients remains incompletely characterized. METHODS: We enumerated pp65 and immediate early (IE)-1-specific CD8(+) T cells expressing interferon-gamma, tumor necrosis factor-alpha, and CD107a, by flow cytometry in 94 patients at days +30 and +60 after allo-SCT. RESULTS: Fifty of 94 patients had CMV DNAemia within the first 100 days after transplant. CMV-specific CD8(+) T-cell responses (of any functional type) were more likely to be detected in patients who did not display CMV DNAemia than in those who did (P = 0.04). Qualitatively, no major differences in the functional signature of CMV-specific CD8(+) T cells were noted between patients who had or did not have CMV DNAemia. Patients displaying levels of polyfunctional CD8(+) T cells at day +30 >0.30 cell/µL had a lower risk of CMV DNAemia (positive predictive value 76%, and negative predictive value 43%). CONCLUSION: The presence of polyfunctional CD8(+) T cells (either expressing CD107a or not) was associated with lower levels of CMV replication, and higher frequency of self-resolved episodes. The data reported further clarify the role of polyfunctional CD8(+) T cells in control of CMV DNAemia in allo-SCT recipients.

European guidelines for prevention and management of influenza in hematopoietic stem cell transplantation and leukemia patients: summary of ECIL-4 (2011), on behalf of ECIL, a joint venture of EBMT, EORTC, ICHS, and ELN.

Influenza may cause severe disease and mortality in leukemia patients and in hematopoietic stem cell transplantation recipients. The 4th European Conference of Infections in Leukemia (ECIL-4) has developed evidence-based guidelines for prevention and management of influenza infections in these patients. Real-time reverse-transcription polymerase chain reaction is the diagnostic test of choice, as it is the most sensitive and specific test for influenza. The risks for severe influenza and fatal outcome include lymphopenia, older age, influenza soon after transplantation or chemotherapy, steroid treatment, and lack of early antiviral therapy. Neuraminidase inhibitors (oral oseltamivir or inhalation of zanamivir) are currently the most effective therapeutic agents for influenza. Main preventive measures include annual vaccination of patients, household contacts, and hospital staff. This review summarizes ECIL-4's main recommendations.

Fresh or frozen grafts for allogeneic stem cell transplantation: conceptual considerations and a survey on the practice during the COVID-19 pandemic from the EBMT Infectious Diseases Working Party (IDWP) and Cellular Therapy & Immunobiology Working Party (CTIWP).

The COVID-19 pandemic has had a significant impact on medical practices, including the delivery of allogeneic hematopoietic cell transplantation (HCT). In response, transplant centers have made changes to their procedures, including an increased use of cryopreservation for allogeneic haematopoietic progenitor cell (HPC) grafts. The use of cryopreserved grafts for allogeneic HCT has been reviewed and analysed in terms of potential benefits and drawbacks based on existing data on impact on cell subsets, hematological recovery, and clinical outcomes of approximately 2000 patients from different studies. A survey of European Society for Blood and Marrow Transplantation centers was also conducted to assess changes in practice during the pandemic and any unnecessary burdens on HPC donors. Before the pandemic, only 7.4% of transplant centers were routinely cryopreserving HPC products, but this percentage increased to 90% during the pandemic. The results of this review and survey suggest that cryopreservation of HPC grafts is a viable option for allogeneic HCT in certain situations, but further research is needed to determine long-term effects and ethical discussions are required to balance the needs of donors and patients when using frozen allografts.

Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

Detection of glucose abnormalities in patients with acute coronary heart disease: study of reliable tools in clinical practice.

AIM: To investigate the prevalence of glucose abnormalities in patients with acute coronary syndrome and to assess the reliability of certain clinical or analytical variables to predict a pathologic result of oral glucose tolerance test (OGTT) at 3 months from discharge. SUBJECTS AND METHODS: Prospective study of 102 patients admitted to the coronary care units. Patients were classified according to the American Diabetes Association criteria. Three months after discharge, an OGTT was performed to non-diabetic patients. RESULTS: Forty-six (45.1%) patients were identified as diabetic (5 previously undiagnosed) and 56 (54.9%) as non-diabetic. OGTT identified 22% of diabetes, 33% of impaired glucose tolerance, and 45% of normal glucose tolerance. Fasting glucose (r=0.55, p<0.001), glycated hemoglobin (HbA1c) (r=0.46, p<0.001), low HDL cholesterol (HDLc) levels (r=-0.34, p<0.02), waist-hip ratio (r=0.45, p<0.01), high systolic blood pressure (r=0.5, p<0.01), and presence of acute myocardial infarction (r=0.46, p<0.001) at admission resulted significant to predict a pathologic result of OGTT. CONCLUSIONS: Glucose abnormalities are frequent in acute coronary syndrome patients. Certain clinical and analytical markers at admission such as fasting glucose, HbA1c, HDL-c<40 mg/dl, waist-hip ratio, and systolic blood pressure, are useful to recognize patients with a higher predisposition to present a pathologic result in OGTT at 3 months from discharge.

Quality of life: a potentially useful measure to indicate subclinical flares in Crohn disease.

BACKGROUND: While quality of life (QoL) is a well-recognised outcome measure of Crohn disease (CD) activity, its influence on other outcome measures, including exacerbation of CD is poorly understood. If QoL measures were to be associated with intestinal inflammatory activity, they might be useful for early detection of subclinical flares. AIMS: We hypothesised that low QoL might be associated with subsequent CD flares. METHODS: A cohort of 318 adult CD patients was observed for 1 year after assessment of baseline characteristics. Data were collected in Swiss university hospitals, regional hospitals and private practices. At inclusion, patients completed the Inflammatory Bowel Disease QoL Questionnaire (gastrointestinal QoL; range: 32 to 224 points) and the Short Form-36 Health Survey (general QoL; range: 35 to 145 points). During follow up, flares were recorded. Binary logistic regression was performed to estimate the relation between QoL and the odds of subsequent flares. RESULTS: A twofold decrease in the odds of flares (99% CI: 1.1; 4.0) per standard deviation of gastrointestinal QoL and a threefold decrease (99% CI: 1.5; 6.2) per standard deviation of general QoL were observed. CONCLUSIONS: The close association between QoL and subsequent flares suggests that QoL measures might be useful in detecting upcoming flares before they become clinically apparent.

Targeted use of intraoperative frozen-section analysis lowers the frequency of completion thyroidectomy.

BACKGROUND: The impact of intraoperative frozen section (iFS) analysis on the frequency of completion thyroidectomy for the management of thyroid carcinoma is controversial. Although specialized endocrine centres have published their respective results, there are insufficient data from primary and secondary healthcare levels. The aim of this study was to analyse the utility of iFS analysis. METHODS: In the Prospective Evaluation Study Thyroid Surgery (PETS) 2 study, 22 011 operations for benign and malignant thyroid disease were registered prospectively in 68 European hospitals from 1 July 2010 to 31 December 2012. Group 1 consisted of 569 patients from University Medical Centre (UMC) Mainz, and group 2 comprised 21 442 patients from other PETS 2 participating hospitals. UMC Mainz exercised targeted but liberal use of iFS analysis for suspected malignant nodules. iFS analysis was compared with standard histological examination regarding the correct distinction between benign and malignant disease. The percentage of completion thyroidectomies was assessed for the participating hospitals. RESULTS: iFS analysis was performed in 35.70 per cent of patients in group 1 versus 21.80 per cent of those in group 2 (risk ratio (RR) 1.6, 95 per cent c.i. 1.5 to 1.8; P < 0.001). Sensitivity of iFS analysis was 75.0 per cent in group 1 versus 63.50 per cent in group 2 (RR 1.2, 1.2 to 1.3; P = 0.040). Completion surgery was necessary in 8.10 per cent of patients in group 1 versus 20.8 per cent of those in group 2 (RR 0.4, 0.2 to 0.7; P = 0.001). CONCLUSION: iFS analysis is a useful tool in determining the appropriate surgical management of thyroid disease. Targeted use of iFS was associated with a significantly higher sensitivity for the detection of malignancy, and with a significantly reduced necessity for completion surgery.

Management of CMV, HHV-6, HHV-7 and Kaposi-sarcoma herpesvirus (HHV-8) infections in patients with hematological malignancies and after SCT.

These recommendations were prepared by the European Conference on Infections in Leukaemia following a predefined methodology. Literature searches were made to identify studies pertinent to management of CMV, HHV-6, -7 and -8 infections. For CMV, 76 studies were reviewed: 72 published and 4 presented as abstracts. Twenty-nine of these studies were prospective randomized trials. For the other herpesviruses, HHV-6, -7 and -8, no randomized controlled trial has been performed, although data from some studies with other primary endpoints have been used to assess the management of HHV-6 infection. Works presented only as abstracts were used to a very limited extent. The quality of evidence and level of recommendation were graded according to the Center for Disease Control (CDC) criteria.

The role of IGF-1 and the distribution of body fat in decreasing the number of prostate rebiopsies. / Papel del IGF-1 y la distribución de la grasa corporal para disminuir el número de rebiopsias prostáticas.

OBJECTIVE: To assess the usefulness of IGF-1 and internal organ fat measured by bioelectrical impedance audiometry to avoid rebiopsies in patients with persistently high prostate-specific antigen (PSA) levels. MATERIAL AND METHOD: A prospective study was conducted with 92 patients who underwent prostate rebiopsy due to high PSA levels with negative results in the rectal examination and a lack of preneoplastic lesions. The patients previously had their IGF-1 levels measured and had undergone an impedance audiometry test using the abdominal Fat Analyser AB-140 TANITA system. We calculated the receiver operating characteristic (ROC) curves for the PSA levels, %PSA, internal organ fat and IGF-1 and PSA density. RESULTS: Twenty-five patients were diagnosed with prostate cancer. These patients had significantly higher PSA, PSAd and IGF-1 values and a tendency towards higher internal organ fat levels and lower %PSA readings (p=.001, p=.003, p=.001, p=.24 and P=0.28, respectively). The ROC curve showed an area under the curve for IGF-1 and PSA of .82 and .81, respectively. Using the cutoff points for 95% sensitivity and using the 3 criteria as an indication of rebiopsy, 74% of the biopsies would have been spared, leaving undiagnosed only 1 patient with clinically significant cancer -Gleason score>7 (4+3)-. The positive and negative predictive values for the set of variables were higher than for each one separately (PPV: 66/NPV: 63). The cost of both determinations was 82 euros. CONCLUSIONS: Our results suggest that measuring IGF-1 could significantly decrease the number of unnecessary rebiopsies in an inexpensive and safe manner.

Multiple myeloma patients in long-term complete response after autologous stem cell transplantation express a particular immune signature with potential prognostic implication.

The proportion of multiple myeloma patients in long-term complete response (LTCR-MM) for more than 6 years after autologous stem cell transplantation (ASCT) is small. To evaluate whether this LTCR is associated with a particular immune signature, peripheral blood samples from 13 LTCR-MM after ASCT and healthy blood donors (HBD) were analysed. Subpopulations of T-cells (naïve, effector, central memory and regulatory), B-cells (naïve, marginal zone-like, class-switched memory, transitional and plasmablasts) and NK-cells expressing inhibitory and activating receptors were quantified by multiparametric flow cytometry (MFC). Heavy/light chains (HLC) were quantified by nephelometry. The percentage of CD4+ T-cells was lower in patients, whereas an increment in the percentage of CD4+ and CD8+ effector memory T-cells was associated with the LTCR. Regulatory T-cells and NK-cells were similar in both groups but a particular redistribution of inhibitory and activating receptors in NK-cells were found in patients. Regarding B-cells, an increase in naïve cells and a corresponding reduction in marginal zone-like and class-switched memory B-cells was observed. The HLC values were normal. Our results suggest that LTCR-MM patients express a particular immune signature, which probably reflects a 'high quality' immune reconstitution that could exert a competent anti-tumor immunological surveillance along with a recovery of the humoral immunity.

[Consensus opinion on antifungal prophylaxis in haematologic patients: Results of the PROMIC project]. / Posicionamiento y actitudes de manejo sobre la profilaxis antifúngica en el paciente hematológico (proyecto PROMIC).

OBJECTIVE: Invasive fungal disease (IFD) is an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis (AFP) is indicated for a number of clinical scenarios in this group of patients. The aim of this study was to reach a consensus on IFD prophylaxis in haematological patients in order to optimize their management. METHODS: A committee of experts in haematology and infectious diseases compiled a survey of 79 items with controversial aspects about antifungal prophylaxis in haematological patients. The survey was evaluated in two rounds by a panel of experts following a modified Delphi methodology. RESULTS: Forty-four experts in haematology and infectious diseases answered the survey. After two evaluation rounds, consensus was reached in 67 of the 79 items (84.8%), specifically 48 items were consensually agreed on (60.7%) and 19 were disagreed on (24.0%). Consensus was reached on prophylaxis candidates profiles and questions related to indications, mechanisms of action, spectrum of activity, toxicity and interactions of antifungal were elucidated. The usefulness of micafungin in IFD prophylaxis was particularly analysed. The consensus reached was that micafungin is an antifungal to be considered in this context as its safety profile and lower interaction potential may be advantageous. CONCLUSIONS: A broad consensus was found in the management of IFD prophylaxis in the haematological patient. This consensus provides practical indications about its optimal management and can help determine the profile of patients eligible for this type of intervention.

Anaphylaxis: A Decade of a Nationwide Allergy Society Registry

Background: Anaphylaxis is an acute, life-threatening, multiorgan hypersensitivity reaction.Objective: The aim of this study was to identify the causes of anaphylaxis in Portugal in order to improve our knowledge of epidemiology and management.Methods: We implemented a nationwide notification system for anaphylaxis over a 10-year period, with voluntary reporting by allergists. Data on 1783 patients with anaphylaxis were included. Etiopathogenesis, manifestations, and clinical management were characterized in detail for both children and adults.Results: The mean age was 32.7 (20.3) years, and 30% were under 18 years of age; 58% were female. The mean age at the first anaphylaxis episode was 27.5 (20.4) years (ranging from 1 month to 88 years). The main culprits of anaphylaxis were foods (48%), drugs (37%) (main trigger in adults, 48%), and hymenoptera venom (7%). The main culprit foods were shellfish (27%), fresh fruit (17%), cow’s milk (16%), tree nuts (15%), fish (8%), egg (7%), and peanut (7%). The main drugs were nonsteroidal anti-inflammatory drugs (43%), antibiotics (39%), and anesthetic agents (6%). Other causes included exercise (3%), latex (2%), cold-induced anaphylaxis (2%), and idiopathic anaphylaxis (2%). Most patients (80%) were admitted to the emergency department; only 43% received adrenaline. Anaphylaxis recurred in 41% of patients (21% with ≥3 anaphylactic episodes); 7% used an adrenaline autoinjector device.Conclusions: Food is the leading cause of anaphylaxis in Portugal, while drugs were the main elicitors in adults. We emphasize undertreatment with adrenaline and recurrent episodes, highlighting the need to improve diagnostic and therapeutic approaches to anaphylaxis (AU)

Antecedentes: La anafilaxia es una reacción de hipersensibilidad sistémica potencialmente mortal.Objetivo: El objetivo de este estudio fue el identificar las causas de la anafilaxia en Portugal para mejorar el conocimiento de la epidemiologíay del manejo de la enfermedad.Métodos: Durante un período de 10 años, se implementó un sistema nacional de notificación de anafilaxia, por parte de los alergólogos,mediante la emisión de informes voluntarios. Se recogieron datos de 1.783 pacientes con anafilaxia, pediátricos y adultos, relativos a laetiopatogenia, las manifestaciones clínicas y el manejo clínico de la misma.Resultados: La edad media fue de 32,7 ± 20,3 años, siendo el 30% de los pacientes menores de 18 años. El 58% fueron mujeres. Laedad media del primer episodio de anafilaxia fue de 27,5 ± 20,4 años (desde 1 mes hasta 88 años). Los principales agentes responsablesde anafilaxia fueron los alimentos (48%), los medicamentos (37%), que fue el principal desencadenante en los pacientes adultos, y losvenenos de himenópteros (7%). Los principales alimentos responsables fueron: mariscos (27%), frutas frescas (17%), leche de vaca (16%),nueces (15%), pescado (8%), huevo (7%) y cacahuete (7%). Los principales fármacos, fueron los antiinflamatorios no esteroideos (43%),antibióticos (39%) y anestésicos (6%). Entre otras causas implicadas se incluyó: ejercicio físico (3%), látex (2%), frío (2%) e idiopática (2%). La mayoría de los pacientes fueron atendidos en el servicio de urgencias (80%), y solo el 43% recibió tratamiento con adrenalina.La recurrencia de la anafilaxia ocurrió en el 41% de los pacientes (21% con ≥3 episodios anafilácticos). El 7% utilizó un dispositivoautoinyector de adrenalina.Conclusiones: Los alimentos son la principal causa de anafilaxia en Portugal y en el subgrupo de pacientes adultos, lo son los medicamentos