Ambient temperature modulates body weight changes in patients with advanced oncological diseases and anorexia cachexia syndrome.

OBJECTIVE: To assess the impact of ambient temperature (AT) on the evolution of bodyweight in patients with heterogeneous types of cancer in advanced stages of the disease (stages III and IV) and anorexia- cachexia syndrome (ACS). METHODS: A prospective naturalistic multicenter study of patients undergoing oncological treatment at four hospitals during a three-year period (2017-2020) in the Autonomous Community of Extremadura in southwestern Spain with a continentalized Mediterranean climate of mild and relatively rainy winters, and particularly hot and sunny summers. Bodyweight changes were obtained from the medical records of 84 oncological patients (59 men and 25 women, age range 37-91 yrs). Mean monthly AT was used to examine the association of weight changes across cold and warm bimesters -BIMs (December and January, vs. July and August), Trimesters -TRIMs (July to September vs. December to February), and Semesters -SEMs (May to October vs. November to April). Weight changes between two consecutive weight measures were categorized as weight gain, weight loss, or no weight change. Differences across cold and warm seasons were analysed using parametric (ANOVA), and nonparametric statistics (Chi-square and binomial z tests). An alpha-rate of 0.05 was used for all analyses. RESULTS: A weight loss trend was observed during BIMs cold periods in comparison to warm ones (p 0.04). However, differences in average bodyweight were not significant. The negative impact of cold periods was more marked in men than in women, (p = 0.05; p = 0.03, for cold vs. warm BIMs and TRIMs, respectively). In contrast, significantly higher weight gain percentages were found in women during warm TRIMs and SEMs (p = 0.03, and p = 0.01, respectively). As for the number of patients dying during the study (N = 56; 39 men, 17 women), there were a significant interaction between temperature (cold/warm), and mean weight F (1, 499) = 6.06, p = 0.01, which revealed a pattern of weight loss in the cold semester as opposed to weight gain during the warm SEM months. CONCLUSIONS: AT temperature modulated body weight changes in patients with advanced oncological disease and ACS. Two main limitations of the study were the absence of information on diets as a moderating factor of weight loss/gain, and the lack of the patients' weight measurements closest to the date of diagnosis prior to admittance to the study. As for the practical implications, it remains to be seen whether an adjunctive heat supply will serve a buffering effect on weight loss during colder seasons for patients with advanced cancer and ACS.

Anorexia nervosa and microbiota: systematic review and critical appraisal.

PURPOSE: Recent studies have reported a gut microbiota imbalance or dysbiosis associated with anorexia nervosa (AN), which has prompted an appraisal of its aetiological role, and the reformulation of AN as a metabo-psychiatric disorder. Thus, the aim of this paper was to critically review the current scientific findings regarding the role of microbiota in anorexia nervosa. METHODS: A systematic study of peer-reviewed literature published in four databases between 2009 and 2022 was conducted according to PRISMA guidelines. Both human and animal studies were included. RESULTS: A total of 18 studies were included. In animal models, both the preclinical and clinical findings were inconsistent regarding microbiota composition, faecal metabolite concentrations, and the effects of human faecal microbiota transplants. CONCLUSION: The methodological limitations, lack of standardisation, and conceptual ambiguity hinder the analysis of microbiota as a key explanatory factor for AN. LEVEL OF EVIDENCE: Level I, systematic review.

Information and behavioral responses during a pandemic: Evidence from delays in Covid-19 death reports.

Providing information is important for managing epidemics, but issues with data accuracy may hinder its effectiveness. Focusing on Covid-19 in Mexico, we ask whether delays in death reports affect individuals' beliefs and behavior. Exploiting administrative data and an online survey, we provide evidence that behavior, and consequently the evolution of the pandemic, are considerably different when death counts are presented by date reported rather than by date occurred, due to non-negligible reporting delays. We then use an equilibrium model incorporating an endogenous behavioral response to illustrate how reporting delays lead to slower individual responses, and consequently, worse epidemic outcomes.

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.

One-year outcomes from a phase 3 randomized trial of ravulizumab in adults with paroxysmal nocturnal hemoglobinuria who received prior eculizumab.

Ravulizumab every 8 weeks showed non-inferiority to eculizumab every 2 weeks in a 26-week, phase 3, randomized controlled trial in adults with paroxysmal nocturnal hemoglobinuria (PNH) who were clinically stable on eculizumab (NCT03056040). We report results from the first 26 weeks of the extension period in which patients continued ravulizumab (n = 96) or switched from eculizumab to ravulizumab (n = 95). At week 52, mean (SD) lactate dehydrogenase levels increased 8.8% (29%) with ravulizumab-ravulizumab and 5.8% (27%) with eculizumab-ravulizumab from primary evaluation period baseline. During the extension period, four patients (ravulizumab-ravulizumab, n = 3; eculizumab-ravulizumab, n = 1) experienced breakthrough hemolysis, but none associated with serum free C5 ≥ 0.5 µg/mL. Mean Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scores remained stable through week 52. During the extension period, proportions of patients avoiding transfusion remained stable (ravulizumab-ravulizumab, 86.5%; eculizumab-ravulizumab, 83.2%); 81.2% and 81.1%, respectively, had stabilized hemoglobin. All patients maintained serum free C5 levels < 0.5 µg/mL. Adverse events were generally similar between groups, and rates were lower in the extension period. Adults with PNH on stable eculizumab therapy who received ravulizumab over 52 weeks experienced durable efficacy, with consistent efficacy in patients who received eculizumab during the primary evaluation period and then switched to ravulizumab. Ravulizumab was well tolerated.

Differential effects of heat in the phases of the light-dark cycle in the activity-based anorexia model.

BACKGROUND: This research builds on the studies on ambient temperature as a key influence in the recovery of rodents exposed to the activity-based anorexia (ABA) model. The ABA model is an experimental paradigm in which rodents under a restricted feeding schedule and with free access to an activity wheel show signs that parallel those of anorexia nervosa in humans. OBJECTIVE: The present study focuses on the effects of applying heat during the different phases of the dark-light cycle in the activity levels, body weight, food intake, body temperature, and recovery rates of 30 male rats submitted to ABA. METHOD: After reaching a 20% weight loss criterion, animals were randomly assigned to three experimental conditions: (a) continuous warming, (b) warming exclusively during the light phase, or (c) warming exclusively during the dark phase. RESULTS: Differential effects were found depending on the modalities of warming: in comparison with either light or dark warming, continuous warming significatively decreased activity, facilitated weight gain, and maintained body temperature. Transient effects of warming were found both in the groups warmed either during light or dark periods exclusively. DISCUSSION: The results suggest that both light and dark warming did not promote recovery in animals exposed to ABA. Evidence about the beneficial effects of continuous warming are in line with previous research and reinforces adding external heat as a useful tool in the treatment of anorexia nervosa.

Seasonal BMI differences between restrictive and purging anorexia nervosa subtypes.

OBJECTIVE: Seasonal differences in anorexia nervosa is an area of research which has received scarce attention in the literature. The aim of this study was to explore patterns of seasonal variation in body weight in anorexia nervosa patients admitted to an eating disorders unit from January 2007 to December 2011. METHOD: Anorexia nervosa restrictive (ANR) and binge eating/purging (ANBP) subtypes were compared with respect to BMI on admission during the Warm and Cold Semester, and in terms of lenght of hospital stay. RESULTS: The main result was that BMI differences between ANBP and ANR patients were due to bodyweight differences during the colder months of the year (p < 0.01) whereas no difference in bodyweight on admission was observed between both subtypes during the Warm Semester months. Furthermore, ANR patients' bodyweight was lower when admitted during the Cold compared to the Warm Semester (p < 0.05). Length of stay was significantly associated with reduced BMI in ANR patients (p < 0.01), but not so for ANBP patients. DISCUSSION: To our knowledge, this is the first study in the literature providing data on seasonal variations in the BMI on admission of anorexia nervosa patients, and in the length of hospitalization.

A rat in the labyrinth of anorexia nervosa: contributions of the activity-based anorexia rodent model to the understanding of anorexia nervosa.

Activity-based anorexia (ABA) is an analogous animal model of anorexia nervosa where food-restricted rats develop excessive running activity when given free access to a running wheel; their body weight sharply decreases, and finally self-starvation and death ensue unless animals are removed from the experimental conditions. The parallel of this animal model with major signs in the human disorder has been the focus of much attention from researchers and clinicians as a platform for translational research. The paper reviews the historical antecedents of ABA, research characterizing its occurrence, and its main limitations and strengths as a model of AN. As a symptomatic model of AN, the ABA model can provide clinicians with innovative and alternative routes for improving the treatment of AN.

Heat exposure following encoding can interfere with subsequent recognition memory.

Correlational studies suggest that high temperatures may impair online cognitive performance and learning processes. Here, we tested the hypothesis that heat exposure blocks offline memory consolidation. We report two studies, including a pre-registered replication. First, during a study phase, participants were familiarized with neutral and negatively valenced images. One day later, half of the participants were exposed to high temperatures in a sauna session at 50 °C. Recognition memory was tested 24 h later. We found that participants exposed to high temperature showed an impairment in recognition memory performance, relative to a control group of participants that were not exposed to heat or that had a sauna at 28 °C. This occurred for both emotional and neutral items. These results indicate that heat exposure impairs memory consolidation, thereby opening the possibility of using heat exposure as an agent for the treatment of clinical mental disorders.

Heat makes a difference in activity-based anorexia: a translational approach to treatment development in anorexia nervosa.

OBJECTIVE: To test the effect of raising ambient temperature (AT) on activity-based anorexia (ABA) and to extend to female rats previous findings reported in male animals. METHOD: Two studies are reported in which female rats were submitted to food restriction and free access to an activity wheel either separately or in combination under changing (21-32 °C) or constant AT (21 °C). RESULTS: Warming ABA animals reversed running activity, preserved food-intake, and enabled female rats to recover from acute weight loss. Moreover, sedentary food-restricted warmed rats maintained a body weight equivalent to the levels of animals housed at standard AT in spite of 20% reduced food-intake. DISCUSSION: The replication on female rats corroborates the effect previously reported for males, which is indicative of the robust effect of AT in recovering rats from ABA. The findings reported here represent strong preclinical evidence in favor of heat supply as a useful adjunctive component for the treatment of anorexia nervosa (AN).

The effects of microtubule stabilizing and recovery agents on vitrified bovine oocytes.

Oocyte vitrification, while beneficial for research and species conservation applications, has limited success due to cryoinjury to the meiotic spindle. This study aimed to improve meiotic spindle recovery in vitrified bovine oocytes by investigating the effects of treatment with either a microtubule stabilizing agent, or a microtubule recovery agent. In the first two experiments, either paclitaxel or epothilone B were used to treat bovine oocytes before vitrification. Both compounds have microtubule stabilizing properties and are known antimitotic compounds used to disrupt microtubule dynamics in rapidly proliferating cancer cells. Paclitaxel treatment at 2.0 µM significantly increased the proportion of oocytes with normal microtubule distribution and chromosome arrangement after warming. Treatment with 1.0 µM had no effect and 0.5 µM had a negative effect on meiotic spindle recovery. Epothilone B treatment at all concentrations significantly increased the proportion of oocytes with meiotic spindle disruption and abnormally dispersed chromosomes. In the second set of experiments, Rho-associated coiled-coil kinase inhibition and glutathione accumulation were investigated as recovery treatments after vitrification. Oocytes were incubated with either Y-27632 or combinations of cysteine and cysteamine for 4 h after warming. Treatment with 5 µM and 10 µM of Y-27632 to inhibit rho-associated coiled-coil kinase activity significantly increased the proportion of vitrified oocytes with normal microtubule distribution and chromosome arrangement. When oocytes were incubated with 20 µM of Y-27632 there was no effect on spindle recovery. Incubation with 100 µM of cysteamine also had no effect on spindle recovery while 0.6 mM of cysteine and both 0.6 mM of cysteine and 100 µM of cysteamine significantly increased oocytes with normal microtubule distribution and chromosome arrangement.

The effectiveness of sin food taxes: Evidence from Mexico.

We measure the effect of a large nationwide tax reform on sugar-added drinks and caloric-dense food introduced in Mexico in 2014. Using scanner data containing weekly purchases of 47,973 barcodes by 8,130 households and an RD design, we find that calories purchased from taxed drinks and taxed food decreased respectively by 2.7% and 3%. However, this was compensated by increases from untaxed categories, such that total calories purchased did not change. We find increases in cholesterol (12.6%), sodium (5.8%), saturated fat (3.1%), carbohydrates (2%), and proteins (3.8%).

Activity-Based Anorexia Induces Browning of Adipose Tissue Independent of Hypothalamic AMPK.

Anorexia nervosa (AN) is an eating disorder leading to malnutrition and, ultimately, to energy wasting and cachexia. Rodents develop activity-based anorexia (ABA) when simultaneously exposed to a restricted feeding schedule and allowed free access to running wheels. These conditions lead to a life-threatening reduction in body weight, resembling AN in human patients. Here, we investigate the effect of ABA on whole body energy homeostasis at different housing temperatures. Our data show that ABA rats develop hyperactivity and hypophagia, which account for a massive body weight loss and muscle cachexia, as well as reduced uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT), but increased browning of white adipose tissue (WAT). Increased housing temperature reverses not only the hyperactivity and weight loss of animals exposed to the ABA model, but also hypothermia and loss of body and muscle mass. Notably, despite the major metabolic impact of ABA, none of the changes observed are associated to changes in key hypothalamic pathways modulating energy metabolism, such as AMP-activated protein kinase (AMPK) or endoplasmic reticulum (ER) stress. Overall, this evidence indicates that although temperature control may account for an improvement of AN, key hypothalamic pathways regulating thermogenesis, such as AMPK and ER stress, are unlikely involved in later stages of the pathophysiology of this devastating disease.

Severe and Enduring Anorexia Nervosa: Enduring Wrong Assumptions?

To the extent that severe and lasting anorexia nervosa (SE-AN) is defined in terms of refractoriness to the best treatments available, it is mandatory to scrutinize the proven effectiveness of the treatments offered to patients. The array of so-called current evidence-based treatments for anorexia nervosa (AN) encompasses the entire spectrum of treatments ranging from specialized brand-type treatments to new treatments adapted to the specific characteristics of people suffering from AN. However, after several randomized control trials, parity in efficacy is the characteristic among these treatments. To further complicate the landscape of effective treatments, this "tie score" extends to the treatment originally conceived as control conditions, or treatment as usual conditions. In retrospection, one can understand that treatments considered to be the best treatments available in the past were unaware of their possible iatrogenic effects. Obviously, the same can be said of the theoretical assumptions underpinning such treatments. In either case, if the definition of chronicity mentioned above is applied, it is clear that the responsibility for the chronicity of the disorder says more about the flagrant inefficacy of the treatments and the defective assumptions underpinning them, than the nature of the disorder itself. A historical analysis traces the emergence of the current concept of "typical" AN and Hilde Bruch's contribution to it. It is concluded that today's diagnostic criteria resulting from a long process of acculturation distort rather than capture the essence of the disorder, as well as marginalizing and invalidating patients' perspectives.

Temperature but not leptin prevents semi-starvation induced hyperactivity in rats: implications for anorexia nervosa treatment.

The hypothesis linking hyperactivity with weight loss associated hypoleptinemia in anorexia nervosa gained momentum after a study showing that leptin suppressed semi-starvation induced hyperactivity in rats. Alternatively, ambient temperature is a key modulating factor of activity in semi-starved rats. The aim of the study is to compare the efficacy of leptin with increased ambient temperature in the prevention of hyperactivity in semi-starved rats. 74 Sprague-Dawley male rats were employed in two experiments with the difference residing in the length of baseline. After an extended (28 days), or shorter (14 days) baseline with free access to food and the running wheel, housed at 21 °C, animals were either ad-lib feed or food restricted (60% of food ingested during previous week) and infused with same amount of leptin at 21 °C, 25 °C, or vehicle at 21 °C, 25 °C and 32 °C for a week. Animals housed at 32 °C significantly reduced wheel running and weight loss during food restriction while animals given leptin did not yield no differences in activity or weight loss. Moreover, unlike animals housed at 32 °C, body temperature of leptin infused animals housed at 21 °C was significantly reduced during food restriction. Furthermore, leptin treated rats without a preceding stable pattern of activity displayed a severe dysregulation of circadian rhythm in activity and a collapse of body temperature. Housing temperature plays a more critical role than leptin in the regulation of semi-starvation induced hyperactivity in rats, which may be of relevance for the management of hyperactivity in anorexia nervosa.

Patient preferences and quality of life implications of ravulizumab (every 8 weeks) and eculizumab (every 2 weeks) for the treatment of paroxysmal nocturnal hemoglobinuria.

BACKGROUND: Eculizumab has transformed management of paroxysmal nocturnal hemoglobinuria (PNH) since its approval. However, its biweekly dosing regimen remains a high treatment burden. Ravulizumab administered every 8 weeks demonstrated noninferiority to eculizumab in two phase 3 trials. In regions where two PNH treatment options are available, it is important to consider patient preference. OBJECTIVE: The aim of this study was to assess patient preference for ravulizumab or eculizumab. METHODS: Study 302s (ALXN1210-PNH-302s) enrolled PNH patients who participated in the extension period of phase 3 study ALXN1210-PNH-302. In the parent study, eculizumab-experienced adult PNH patients received ravulizumab or eculizumab during a 26-week primary evaluation period. All patients in the extension period received ravulizumab. In study 302s, patient treatment preference was evaluated using an 11-item PNH-specific Patient Preference Questionnaire (PNH-PPQ©). Of 98 patients, 95 completed PNH-PPQ© per protocol for analysis. RESULTS: Overall, 93% of patients preferred ravulizumab whereas 7% of patients either had no preference (6%) or preferred eculizumab (1%) (P < 0.001). For specific aspects of treatment, ravulizumab was preferred (in comparison to no preference or eculizumab) on infusion frequency (98% vs. 0% vs. 2%), ability to plan activities (98% vs. 0% vs. 2%), and overall quality of life (88% vs. 11% vs. 1%), among other aspects. Most participants selected frequency of infusions as the most important factor determining preference (43%), followed by overall quality of life (23%). CONCLUSION: This study shows that a substantial proportion of patients preferred ravulizumab over eculizumab and provides an important patient perspective on PNH treatment when there is more than one treatment option.

Voluntary Compliance, Pollution Levels, and Infant Mortality in Mexico.

The increasing body of evidence from high income countries linking pollution to health outcomes (Ken Chay and Michael Greenstone 2003; Janet Currie and Matthew Neidell 2004), has raised concerns about the health impact of adverse air quality in developing countries, where, in general, environmental regulation is less stringent and health monitoring and treatment are less accessible. These concerns have, in turn, encouraged consideration of the effectiveness of alternative mechanisms for improving air quality while limiting the adverse impact on economic growth. However, the analysis of both the effects of pollution on health and the effectiveness of pollution abatement policies faces particular empirical challenges in low- and middle-income contexts, given the scarcity of reliable measures of pollution concentrations. The primary source of good quality data on air quality, ground monitoring, tends to be limited to larger metropolitan areas with monitors placed at sentinel sites that may or may not yield a representative picture of population exposure. This paper calls attention to, and makes use of, newly available procedures for extracting measures of air quality from satellite imagery. In particular, satellite-based measures of aerosol optical depth (AOD) are used to obtain estimates of air quality for the whole Mexican territory at a detailed geographic scale, and these estimates are related to measures of participation in a voluntary certification program at the level of the county. The resulting estimates are then combined with estimates of the relationship between participation in the certification program and infant mortality due to respiratory causes to obtain a rough estimate of the relationship between air quality and infant health in Mexico.

[Diagnostic and therapeutic management in a series of 1156 patients with the diagnosis of prostate cancer in Castilla y Leon during 2014.] / Manejo diagnóstico y actitud terapeútica de 1156 pacientes diagnosticados de cáncer de próstata en la comunidad de Castilla y León durante el año 2014.

OBJECTIVES: To evaluate the current clinical practice for patients with Prostate Cancer (CP) in the Health Areas of Castilla y León (CyL) in 2014. METHODS: A retrospective multicenter study was designed to provide data on the diagnosis and treatment of PC in CyL: 87.8% of patients were screened. Descriptive statistics on variables related to characteristics of the patient, the tumor and the treatment modality of the first line to which it was submitted are provided. RESULTS: A total of 1156 new cases of PC were analyzed with a mean age of 68.2 years and a mean PSA of 8.40 ng/ml. The Gleason score (GS) showed 538 (46.2%), 418 (35.9 %) and 200 (17.1%) patients for GS ≤ 6, 7 and  ≥ 8 respectively. 91% of patients (1053 patients) are diagnosed at a localized stage. 56 (4.8%) patients received treatment with active surveillance/ watchful waiting, 423 (36.6%) radical prostatectomy (PR), 348 (30.1%) radiotherapy (RT), 98 (8.4%) brachytherapy (BT) and 170 (14.7%) hormone therapy (HT) respectively. CONCLUSIONS: Differed strategies still accounted for a small percentage of treatments. PR and RT/BT were of choice in patients with localized stages of the disease and younger than 70 years. More advanced stages and older patients were treated with HT mainly. Age is postulated as the main factor involved in therapeutic decision making.

OBJETIVO: Conocer la práctica clínica real en pacientes con Cáncer de Próstata (CP) en las Áreas Sanitarias de Castilla y León (CyL) en el año 2014. MATERIAL Y MÉTODOS: Se diseña un estudio multicéntrico con carácter retrospectivo para disponer de datos sobre el diagnóstico y tratamiento del CP en CyL: se logra una cobertura del 87,8% de los pacientes comunitarios. Se aporta estadística descriptiva sobre las variables referentes a características del paciente, del tumor y de la modalidad de tratamiento de primera línea a la que fue sometido. RESULTADOS: Se analizan 1.156 nuevos casos de CP con una edad media de 68,2 años y una mediana de PSA de 8,4 ng/ml. La puntuación de Gleason (PG) muestra 538 (46,2%), 418 (35,9%) y 200 (17,1%) pacientes para PG ≤  6, 7 y  ≥ 8 respectivamente. El 91,0% de los pacientes (1.053 pacientes) son diagnosticados en estadio localizado. 56 pacientes (4,8%) son tratados con estrategias diferidas (EDs), vigilancia activa/ observación, 423 (36,6%) con prostatectomia radical (PR), 348 (30,1%) con radioterapia, 98 (8,4%) con braquiterapia (BT) y 170 (14,7%) con hormonoterapia (HT). CONCLUSIONES: Las EDs aún supusieron un porcentaje pequeño de los tratamientos. PR y RT/BT fueron de elección en pacientes con estadios localizados de la enfermedad y menores de 70 años. Estadios más avanzados y pacientes mayores fueron tratados con HT principalmente. La edad se postula como el principal factor implicado en la toma de decisiones terapéuticas.