Cell-free DNA analysis in current cancer clinical trials: a review.

Cell-free DNA (cfDNA) analysis represents a promising method for the diagnosis, treatment selection and clinical follow-up of cancer patients. Although its general methodological feasibility and usefulness has been demonstrated, several issues related to standardisation and technical validation must be addressed for its routine clinical application in cancer. In this regard, most cfDNA clinical applications are still limited to clinical trials, proving its value in several settings. In this paper, we review the current clinical trials involving cfDNA/ctDNA analysis and highlight those where it has been useful for patient stratification, treatment follow-up or development of novel approaches for early diagnosis. Our query included clinical trials, including the terms 'cfDNA', 'ctDNA', 'liquid biopsy' AND 'cancer OR neoplasm' in the FDA and EMA public databases. We identified 1370 clinical trials (FDA = 1129, EMA = 241) involving liquid-biopsy analysis in cancer. These clinical trials show promising results for the early detection of cancer and confirm cfDNA as a tool for real-time monitoring of acquired therapy resistance, accurate disease-progression surveillance and improvement of treatment, situations that result in a better quality of life and extended overall survival for cancer patients.

Shock anafiláctico versus síndrome de Kounis durante el intraoperatorio de cirugía cardiaca: diagnóstico diferencial / Anaphylactic shock versus Kounis syndrome in cardiac surgery: Differential diagnosis

Pese a que fue descrito hace casi 3 décadas, ha sido en los últimos años cuando se ha producido un incremento notable en la comunicación de casos de síndromes coronarios agudos desarrollados en el contexto de reacciones alérgicas, entidad que es conocida como síndrome de Kounis. En este artículo nos planteamos esta posibilidad diagnóstica ante un fracaso biventricular agudo en el transcurso de una reacción anafiláctica durante el intraoperatorio de una cirugía valvular cardiaca

Although Kounis syndrome was described almost 3 decades ago, there has been a notable increase in the reports of cases of acute coronary syndromes developed in the context of allergic reactions, also known as Kounis syndrome. This article discusses the diagnostic possibility in the face of an acute biventricular failure in the course of an anaphylactic reaction during the intra-operative period of a cardiac valve surgery

Anaphylactic shock versus Kounis syndrome in cardiac surgery: Differential diagnosis. / Shock anafiláctico versus síndrome de Kounis durante el intraoperatorio de cirugía cardiaca: diagnóstico diferencial.

Although Kounis syndrome was described almost 3 decades ago, there has been a notable increase in the reports of cases of acute coronary syndromes developed in the context of allergic reactions, also known as Kounis syndrome. This article discusses the diagnostic possibility in the face of an acute biventricular failure in the course of an anaphylactic reaction during the intra-operative period of a cardiac valve surgery.

Social exclusion of the adolescent with overweight: study of sociocentric social networks in the classroom.

BACKGROUND: Multiple studies have shown the social consequences of suffering overweight, with social exclusion or isolation as some of the most important. In order to study the social patterns among adolescents, we have set as objectives to analyse the position of the individual within their network from a sociocentric perspective, comparing the relational pattern of the adolescents suffering from overweight with those who are normal weight. METHOD: This was a cross-sectional descriptive study using logistic regression and social network analysis. We analysed the contact patterns of 235 adolescents in 11 social networks, classifying contact into three levels of intensity: minimum, intermediate and maximum (friendship). The WHO reference was used for the variable of overweight. RESULTS: The prevalence of overweight was 30.2% (25.5% overweight and 4.7% obesity). An analysis of the relational patterns of individuals with overweight showed that at the minimum contact level, they established fewer relationships and less closeness (odds ratio [OR]: 2.32; confidence interval [CI] 95%: 1.17-4.66; p-value: 0.016). This effect was more marked in female adolescents. At intermediate contact level, they had few relationships and low prestige (OR: 3.29; CI: 95%; 1.03-10.51; p-value: 0.045, OR: 3.18; CI: 95%; 1.00-10.04; p-value: 0.049, respectively). At maximum contact level (friendship), female adolescents related little with other adolescents (OR: 3.78; CI: 95%; 1.07-13.32; p-value: 0.038). CONCLUSIONS: Adolescents with overweight take up peripheral positions within their social network, choosing by themselves not to establish contact with others. Social network analysis is crucial to detect adolescents with overweight at risk of exclusion and help alleviate psychological and social deficits.

The effects of sediment depth and oxygen concentration on the use of organic matter: An experimental study using an infiltration sediment tank.

Water flowing through hyporheic river sediments or artificial recharge facilities promotes the development of microbial communities with sediment depth. We performed an 83-day mesocosm infiltration experiment, to study how microbial functions (e.g., extracellular enzyme activities and carbon substrate utilization) are affected by sediment depth (up to 50 cm) and different oxygen concentrations. Results indicated that surface sediment layers were mainly colonized by microorganisms capable of using a wide range of substrates (although they preferred to degrade carbon polymeric compounds, as indicated by the higher ß-glucosidase activity). In contrast, at a depth of 50 cm, the microbial community became specialized in using fewer carbon substrates, showing decreased functional richness and diversity. At this depth, microorganisms picked nitrogenous compounds, including amino acids and carboxyl acids. After the 83-day experiment, the sediment at the bottom of the tank became anoxic, inhibiting phosphatase activity. Coexistence of aerobic and anaerobic communities, promoted by greater physicochemical heterogeneity, was also observed in deeper sediments. The presence of specific metabolic fingerprints under oxic and anoxic conditions indicated that the microbial community was adapted to use organic matter under different oxygen conditions. Overall the heterogeneity of oxygen concentrations with depth and in time would influence organic matter metabolism in the sediment tank.

Actualización de las recomendaciones para la evaluación y tratamiento de la osteoporosis asociada a enfermedades endocrinas y nutricionales. Grupo de trabajo de osteoporosis y metabolismo mineral de la SEEN / Update of recommendations for evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions. Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology

Objetivo: Actualizar las recomendaciones previas formuladas por el Grupo de trabajo de osteoporosis y metabolismo mineral de la Sociedad Española de Endocrinología y Nutrición (SEEN) para la evaluación y el tratamiento de la osteoporosis asociada a diferentes enfermedades endocrinas y alteraciones nutricionales. Participantes: Miembros del Grupo de trabajo de osteoporosis y metabolismo mineral de la SEEN. Métodos: Las recomendaciones se formularon de acuerdo al sistema Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) para establecer tanto la fuerza de las recomendaciones como el grado de evidencia. Se realizó una búsqueda sistemática en PubMed de las nuevas acerca de cada enfermedad usando las siguientes palabras clave asociadas al nombre de cada proceso patológico: AND osteoporosis, fractures, bone mineral density, bone markers y treatment. Se revisaron artículos escritos en inglés con fechas de inclusión comprendidas entre el 18 de octubre de 2011 y el 30 de octubre de 2014. Tras la formulación de las recomendaciones estas se discutieron de forma conjunta por el Grupo de trabajo.Conclusiones: Esta actualización resume los nuevos datos acerca de la evaluación y tratamiento de la osteoporosis en las enfermedades endocrinas y nutricionales que se asocian a baja masa ósea o a un aumento del riesgo de fractura.(AU)

Objective: To update previous recommendations developed by the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition for the evaluation and treatment of osteoporosis associated to different endocrine and nutritional diseases. Participants: Members of the Working Group on Osteoporosis and Mineral Metabolism of the Spanish Society of Endocrinology and Nutrition. Methods: Recommendations were formulated according to the GRADE system (Grading of Recommendations, Assessment, Development, and Evaluation) to describe both the strength of recommendations and the quality of evidence. A systematic search was made in MEDLINE (Pubmed) using the following terms associated to the name of each condition: AND "osteoporosis", "fractures", "bone mineral density", and "treatment". Papers in English with publication date between 18 October 2011 and 30 October 2014 were included. The recommendations were discussed and approved by all members of the Working Group. Conclusions: This update summarizes the new data regarding evaluation and treatment of osteoporosis associated to endocrine and nutritional conditions.(AU)

Estudio piloto de la utilidad de la región medial de la proadrenomedulina (RM-proADM) en la valoración de la disnea de origen respiratorio en urgencias / Midregional proadrenomedull in plasma concentration in emergency patients with dyspnea due to respiratory disease: a pilot study

Objetivos: La adrenomedulina (ADM) es un biomarcador cuyos niveles han demostrado tener valor pronóstico en diferentes patologías, particularmente en aquéllas de etiología infecciosa. Los niveles de la región medial de la proADM (RMproADM) son un reflejo de los de la ADM y tienen una mayor estabilidad plasmática. El objetivo de este estudio es analizar la relación entre los niveles de RMproADM y la gravedad de pacientes con disnea de origen respiratorio. Método: Estudio piloto, analítico, observacional, prospectivo y sin intervención de pacientes con disnea de origen respiratorio atendidos en un servicio de urgencias hospitalario (SUH). Se recogieron variables sociodemográficas, nivel de prioridad según el Sistema de Triaje de Manchester (STM) y variables relacionadas con su patología durante su asistencia en el SUH, incluidas las determinaciones analíticas. Se reservó parte del plasma para la posterior determinación de la RMproADM. Se hizo un seguimiento para ver el diagnóstico de alta, reingreso y fallecimiento en los 7 días tras la asistencia en el SUH. Como variables para medir la gravedad del proceso se utilizó el nivel de prioridad asignado por el STM. Resultados: Se incluyeron 50 pacientes [edad 69 (22) años y 52% hombres]. Veintiocho pacientes (56%) ingresaron y 17 (34%) tenían una prioridad 2 en el triaje. Los ingresados tenían una forma de presentación que los situaba en un nivel de gravedad superior a los que se iban de alta, mientras que no había diferencias en la mayoría de los parámetros medidos en el caso de la prioridad 2 del triaje comparados con las prioridades 3 y 4. Los niveles de RM-proADM eran mayores en los pacientes ingresados (..)(AU)

Background and objective: Adrenomedullin (ADM) is a prognostic biomarker that has proven useful in various diseases, particularly infections. The midregional proADM (MR-proADM) plasma concentration reflects the ADM level and is a more stable measure. This study aimed to explore the relationship between MR-proADM and severity of disease in patients with dyspnea due to respiratory disease. Patients and methods: Prospective, observational (no intervention), analytical pilot study in hospital emergency department patients with shortness of breath caused by respiratory disease. We recorded sociodemographic data, priority according to the Manchester triage system (MTS), and clinical data (including laboratory findings) collected in the emergency department. A plasma sample was reserved for later determination of MR-proADM concentration. The patients were followed for 7 days after the emergency department visit in order to record the discharge diagnosis,readmission, or exitus. The assigned MTS priority level was used as a measure of severity. Results: Fifty patients with a mean (SD) age of 69 (22) years were studied; 52% were men. Twenty-eight patients (56%)were admitted and 17 (34%) were assigned an MTS priority level of 2. The initial clinical picture indicated greater severity of disease in admitted patients than in discharged patients; the number of variables studied did not differ (AU) (..)

Optimal reconstruction of concentrations, gradients and reaction rates from particle distributions.

Random walk particle tracking methodologies to simulate solute transport of conservative species constitute an attractive alternative for their computational efficiency and absence of numerical dispersion. Yet, problems stemming from the reconstruction of concentrations from particle distributions have typically prevented its use in reactive transport problems. The numerical problem mainly arises from the need to first reconstruct the concentrations of species/components from a discrete number of particles, which is an error prone process, and then computing a spatial functional of the concentrations and/or its derivatives (either spatial or temporal). Errors are then propagated, so that common strategies to reconstruct this functional require an unfeasible amount of particles when dealing with nonlinear reactive transport problems. In this context, this article presents a methodology to directly reconstruct this functional based on kernel density estimators. The methodology mitigates the error propagation in the evaluation of the functional by avoiding the prior estimation of the actual concentrations of species. The multivariate kernel associated with the corresponding functional depends on the size of the support volume, which defines the area over which a given particle can influence the functional. The shape of the kernel functions and the size of the support volume determines the degree of smoothing, which is optimized to obtain the best unbiased predictor of the functional using an iterative plug-in support volume selector. We applied the methodology to directly reconstruct the reaction rates of a precipitation/dissolution problem involving the mixing of two different waters carrying two aqueous species in chemical equilibrium and moving through a randomly heterogeneous porous medium.

Thin healthy women have a similar low bone mass to women with anorexia nervosa.

An association between anorexia nerviosa (AN) and low bone mass has been demonstrated. Bone loss associated with AN involves hormonal and nutritional impairments, though their exact contribution is not clearly established. We compared bone mass in AN patients with women of similar weight with no criteria for AN, and a third group of healthy, normal-weight, age-matched women. The study included forty-eight patients with AN, twenty-two healthy eumenorrhoeic women with low weight (LW group; BMI < 18.5 kg/m2) and twenty healthy women with BMI >18.5 kg/m2 (control group), all of similar age. We measured lean body mass, percentage fat mass, total bone mineral content (BMC) and bone mineral density in lumbar spine (BMD LS) and in total (tBMD). We measured anthropometric parameters, leptin and growth hormone. The control group had greater tBMD and BMD LS than the other groups, with no differences between the AN and LW groups. No differences were found in tBMD, BMD LS and total BMC between the restrictive (n 25) and binge-purge type (n 23) in AN patients. In AN, minimum weight (P = 0.002) and percentage fat mass (P = 0.02) explained BMD LS variation (r2 0.48) and minimum weight (r2 0.42; P = 0.002) for tBMD in stepwise regression analyses. In the LW group, BMI explained BMD LS (r2 0.72; P = 0.01) and tBMD (r2 0.57; P = 0.04). We concluded that patients with AN had similar BMD to healthy thin women. Anthropometric parameters could contribute more significantly than oestrogen deficiency in the achievement of peak bone mass in AN patients.

Effects of raloxifene therapy on circulating osteoprotegerin and RANK ligand levels in post-menopausal osteoporosis.

Previous in vitro studies suggest that the anti-resorptive effect of raloxifene might be mediated by changes in several cytokines involved in the bone remodeling process. In this context, the osteoprotegerin (OPG)- receptor activator of NF kappa B ligand (RANKL) system is considered a key component in the osteoclastogenesis regulation. The aim of this study was to determine the effects of raloxifene treatment on serum concentrations of OPG, receptor RANKL and its relationship with biochemical markers of bone turnover and bone mineral density (BMD) in previously untreated women with post-menopausal osteoporosis. We selected 47 post-menopausal women (mean age 63+/-7 yr) with densitometric criteria of osteoporosis. We determined at baseline, 3, 6, and 12 months anthropometric parameters, biochemical markers of bone turnover, serum levels of 25(OH) D, serum levels of OPG and RANKL. BMD (dual-energy x-ray absorptiometry) in lumbar spine (LS) femoral neck and total hip was measured at baseline and 12 months after raloxifene (60 mg/day) treatment. Serum levels of OPG decreased in the 3rd and 6th month of treatment (p<0.001) and returned to basal levels in the 12th month. There was a significant decrease of RANKL levels and OPG/RANKL ratio after 1 yr of raloxifene treatment. In addition, BMD in LS increased significantly (2.5%) in the 12th month of treatment (p=0.031). Finally, the biochemical markers of bone turnover (total alkaline phosphatase, bone alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase, urine cross-linked carboxi-terminal telopeptide of type I collagen) decreased significantly from the 3rd month of treatment. In conclusion, our results support the hypothesis that raloxifene may inhibit osteoclast activity, at least partly modulating the OPG-RANKL system.

Incidentaloma adrenal e hipertensión arterial / Adrenal incidentaloma and high blood pressure

El incidentaloma adrenal se define como el hallazgo casual de una lesión adrenal evidenciada durante un estudio de imagen abdominal y su incidencia en la población general es del 4-6 %. Entre las etiologías posibles se incluyen lesiones benignas o malignas que pueden ser hormonalmente activas o inactivas. Datos recientes sugieren que la incidencia de hiperaldosteronismo primario (HAP) en pacientes hipertensos puede alcanzar hasta un 10 %, representando una de las causas más frecuentes de hipertensión arterial secundaria. En la mayoría de los casos el HAP es causado por un adenoma adrenal productor de aldosterona (APA) o hiperplasia bilateral idiopática. Evidencias recientes sugieren que la aldosterona ejerce un efecto deletéreo directo sobre el sistema cardiovascular incrementando la incidencia de eventos cardiovasculares y cerebrovasculares. Se expone el caso clínico de una mujer de 38 años con hipertensión arterial secundaria a un APA que se presentó como una masa adrenal incidentalmente descubierta

Adrenal incidentaloma is defined as the casual finding of an adrenal lesion seen during an abdominal imaging study and its incidence in the general population is 4-6 %. Benign or malignant lesions, that may be hormonally active or inactive, are found among the possible etiologies. Recent data suggest that the incidence of primary hyperaldosteronism (PHA) in hypertense patients may reach up to 10 %, thus representing one of the most frequent causes of secondary high blood pressure. In most of the cases, PHA is caused by an adrenal aldosterone producing adenoma (APA) or bilateral idiopathic hyperplasia. Recent evidence suggests that aldosterone has a direct harmful effect on the cardiovascular system, increasing the incidence of cardiovascular and cerebrovascular events. The clinical case of a 38-year old woman with HBP secondary to APA that presented as an incidentally discovered adrenal mass is presented

Carcinoma corticosuprarrenal / Adrenocortical cancer

El carcinoma corticosuprarrenal es una entidad de baja frecuencia (0,5-2 casos/millón de habitantes/año) que sin embargo plantea importantes desafíos diagnósticos y terapéuticos. Suele tratarse de masas tumorales grandes (> 6 cm), detectadas en estadios avanzados y frecuentemente funcionantes. La hipersecreción hormonal se expresa habitualmente con cuadros de hipercortisolismo (síndrome de Cushing) aislado o combinado con hiperandrogenismo. El curso clínico suele ser rápidamente progresivo. El diagnóstico se fundamenta en la clínica, las determinaciones hormonales y las técnicas de imagen. A pesar del tratamiento quirúrgico, uso del mitotane y citostáticos, el pronóstico es malo, con una supervivencia baja a corto plazo. Presentamos el caso de una mujer joven con un cuadro clínico de hipertensión arterial secundaria, hipercortisolismo e hiperandrogenismo inducidos por un carcinoma corticosuprarrenal

Adrenocortical cancer is a rare condition (0.5-2 cases/million/year). However, it raises important diagnostic and therapeutic challenges. This is generally a large, and frequently functioning, tumor (> 6 cm), detected in advanced stages. The hormonal hypersecretion is usually evident as either isolated hypercortisolism (Cushing's syndrome) or in combination with hyperandrogenism. The clinical outcome is usually rapidly progressive. Diagnosis is based on the clinical features, hormone measurements and imaging techniques. In spite of the surgical treatment and use of mitotane and cytostatic drugs, the prognosis is poor with low short-term survival. We present the case of a woman with secondary arterial hypertension, hypercortisolism and hyperandrogenism caused by an adrenocortical carcinoma

Neurofibromatosis tipo 1 y feocromocitoma / Type 1 neurofibromatosis and pheochromocytoma

No disponible

Islote óseo gigante vertebral / Vertebral giant bone island

No disponible

Densitometría ósea: indicaciones e interpretación / Bone densitometry: indications interpretation

La osteoporosis es una enfermedad caracterizada por un compromiso de la resistencia ósea que predispone a fracturas por fragilidad. Las alteraciones de la densidad y la calidad óseas contribuyen al contribuyen al desarrollo de la enfermedad. En la actualidad la medida de la densidad mineral ósea mediante absorciometría dual de rayos x (DXA) constituye el patrón oro en el diagnóstico de la osteoporosis por su capacidad para predecir riesgo de fracturas. En la práctica clínica los resultados de la densitometría deben ser evaluados conjuntamente con otros factores de riesgo para decidir las intervenciones terapéuticas (AU)

Osteoporosis is characterized by reduced bone resistance that predisposes individuals to fragility fractures. Alterations in bone density and quality contribute to the development of the disease. Because of its ability to predict the risk of fractures, measurement of bone mineral density through dual-energy x-ray absorptiometry is currently the gold standard in the diagnosis of osteoporosis. In clinical practice, therapeutic decisions should be based on the results of densitometry together with evaluation of other risk factors (AU)

Varón XYY con azoospermia / An XYY male with azoospermia

Las anomalías que involucran a los cromosomas sexuales son las más frecuentes entre el conjunto de todas las alteraciones cromosómicas. Aproximadamente 1 de cada 1.000 varones es portador de un cromosoma Y adicional, ya sea en forma pura (47,XYY) o en diversas variantes demo-saicismos. Existe una notable variabilidad en la presentación clínica y el pronóstico de cada una de las aneuploidías que comprometen a los cromosomas sexuales. En individuos con cariotipo XYY se han descrito variables características fenotípicas y conductuales. La función gonadal y reproductiva de los varones XYY adultos suele ser normal y habitualmente son fértiles. Se describe el caso de un varón de 45 años con esterilidad primaria por azoospermia con aplasia de células germinales en la biopsia de testículo. El estudio citogenético mostró un cariotipo XYY y no se evidenciaron microdelecciones de la región AZF delos cromosomas Y. Se reseñan los principales aspectos del síndrome XYY y se destaca su variable presentación clínica (AU)

The anomalies that involve sexualchromosomes are the most frequent of all chromosomal alterations. Approximately 1in every 1000 males carries an additional Y chromosome, either in pure form (47, XYY)or in diverse mosaicisms variants . There is wide variability in the clinical presentation and prognosis of sexual chromosome anomalies. In XYY males various phenotypic and behavioral characteristics have been described. The gonadal and reproductive functions in adult XYY males are usually normal and these individuals are usually fertile. We describe the case of a 45-year-old man with primary infertility due to azoospermia with germ cell aplasia in testicular biopsy. Cytogenetic study showed an XYY karyotype without micro deletions of the AZF region of Y chromosomes. The main aspects of XYY syndrome are outlined, and its variable clinical presentation is emphasized (AU)

Hiperprolactinemia / Hiperprolactinemia

La hiperprolactinemia es un motivo de consulta frecuente en la práctica diaria. Las causas de hiperprolactinemia son múltiples; la causa más frecuente es la toma de fármacos, por lo que es necesario realizar una historia clínica detallada a fin de orientar al diagnóstico. En la mujer, los síntomas más frecuentes son la oligomenorrea/amenorrea, la galactorrea y la infertilidad, mientras que en el varón predominan los síntomas compresivos (pérdida de visión, cefaleas, déficits neurológicos). Una historia clínica detallada, junto con la exploración clínica y la determinación de bioquímica básica, tirotropina y test de embarazo, permite excluir todas las causas de hiperprolactinemia excepto las secundarias a la enfermedad hipotálamo-hipofisaria. Cuando no se encuentra causa de la hiperprolactinemia debe realizarse una resonancia magnética nuclear del área hipotálamo-hipofisaria, y sólo en caso de que ésta sea negativa se diagnosticará al paciente de hiperprolactinemia idiopática. El tratamiento debe ser etiológico en las hiperprolactinemias secundarias. El tratamiento médico con agonistas dopaminérgicos es, hoy día, el tratamiento de elección en los prolactinomas y en la hiperprolactinemia idiopática. La cirugía transesfenoidal sólo está indicada en casos de resistencia o intolerancia a los agonistas dopaminérgicos y en algunos casos de microadenoma pregestación. La radioterapia sólo está indicada en tumores resistentes muy invasivos, que no responden a cirugía o tratamiento médico (AU)

Hyperprolactinemia is a frequent problem in daily clinical practice. There are several causes of hyperprolactinemia, the most common of which are medications. Consequently, a detailed history must be taken to guide diagnosis. In women the main symptoms are the association of oligomenorrhea/amenorrhea, galactorrhea and infertility while men usually present compression symptoms (vision loss, headache or neurological deficit). A thorough history and physical examination, routine laboratory investigations thyroid–stimulatinghormone determination, and pregnancy test allow can rule out all causes of hyperprolactinemia except hypothalamus–pituitary disease. When no evident cause of secondary hyperprolactinemia is found, hypothalamus-pituitary magnetic resonance imaging (MRI) should be performed and patients should be diagnosed with idiopathic hyperprolactinemia only when MRI is negative. Treatment of secondary hyperprolactinemia should be etiologic. Medical therapy with dopamine agonists is currently the treatment of choice for prolactinomas and idiopathic hyperprolactinemia. Transsphenoidal surgery is suitable only when there is resistance or intolerance to dopamine agonists and in some cases of pre-gestational microadenoma. Radiotherapy is suitable in highly invasive, resistant tumors that have not responded to medical or surgical treatment (AU)