Vadadustat for treatment of anemia in patients with dialysis-dependent chronic kidney disease receiving peritoneal dialysis.

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear. METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular event (MACE; defined as all-cause mortality or nonfatal myocardial infarction or stroke). The primary efficacy endpoint was mean change in hemoglobin from baseline to the primary evaluation period (Weeks 24-36). RESULTS: Of the 3923 patients randomized in the two INNO2VATE trials, 309 were receiving peritoneal dialysis (vadadustat, n = 152; darbepoetin alfa, n = 157) at baseline. Time to first MACE was similar in the vadadustat and darbepoetin alfa groups [hazard ratio 1.10; 95% confidence interval (CI) 0.62, 1.93]. In patients receiving peritoneal dialysis, the difference in mean change in hemoglobin concentrations was -0.10 g/dL (95% CI -0.33, 0.12) in the primary evaluation period. The incidence of treatment-emergent adverse events (TEAEs) was 88.2% versus 95.5%, and serious TEAEs was 52.6% versus 73.2% in the vadadustat and darbepoetin alfa groups, respectively. CONCLUSIONS: In the subgroup of patients receiving peritoneal dialysis in the phase 3 INNO2VATE trials, safety and efficacy of vadadustat were similar to darbepoetin alfa.

Does social thermal regulation constrain individual thermal tolerance in an ant species?

In ants, social thermal regulation is the collective maintenance of a nest temperature that is optimal for individual colony members. In the thermophilic ant Aphaenogaster iberica, two key behaviours regulate nest temperature: seasonal nest relocation and variable nest depth. Outside the nest, foragers must adapt their activity to avoid temperatures that exceed their thermal limits. It has been suggested that social thermal regulation constrains physiological and morphological thermal adaptations at the individual level. We tested this hypothesis by examining the foraging rhythms of six populations of A. iberica, which were found at different elevations (from 100 to 2,000 m) in the Sierra Nevada mountain range of southern Spain. We tested the thermal resistance of individuals from these populations under controlled conditions. Janzen's climatic variability hypothesis (CVH) states that greater climatic variability should select for organisms with broader temperature tolerances. We found that the A. iberica population at 1,300 m experienced the most extreme temperatures and that ants from this population had the highest heat tolerance (LT50 = 57.55°C). These results support CVH's validity at microclimatic scales, such as the one represented by the elevational gradient in this study. Aphaenogaster iberica maintains colony food intake levels across different elevations and mean daily temperatures by shifting its rhythm of activity. This efficient colony-level thermal regulation and the significant differences in individual heat tolerance that we observed among the populations suggest that behaviourally controlled thermal regulation does not constrain individual physiological adaptations for coping with extreme temperatures.

En hormigas, la termorregulación social es el mantenimiento colectivo de la temperatura del nido óptima para los individuos de la colonia. En la hormiga termófila Aphaenogaster iberica, hay dos comportamientos clave que regulan la temperatura del nido: la reubicación estacional y la profundidad variable del nido. Fuera del nido, las obreras recolectoras deben adaptar su actividad para evitar las temperaturas que excedan sus límites térmicos. Se ha sugerido que la termorregulación social limita las adaptaciones térmicas a nivel individual, fisiológicas y morfológicas. Examinamos esta hipótesis, estudiando los ritmos de actividad de recolección de alimento en seis poblaciones de A. iberica, a distinta altitud, desde 100 m a 2,000 m, en las montañas de Sierra Nevada, en el sur de España. Y analizamos la resistencia térmica de los individuos de estas poblaciones, en condiciones controladas. La Hipótesis de la Variabilidad Climática de Janzen (CVH) postula que una mayor variabilidad climática selecciona organismos con tolerancias térmicas más amplias. Encontramos que la población de 1,300 m era la que presentaba la mayor variabilidad climática, y que las hormigas de esta población tiene la mayor resistencia térmica individual (LT50 = 57.55°C), lo que confirma la validez de la CVH a una escala microclimática en el gradiente altitudinal estudiado. Encontramos que A. iberica puede compensar por la disminución de la temperatura media que acompaña al incremento en elevación. Las hormigas pueden cambiar sus ritmos de actividad sin afectar la entrada de alimento en la colonia, que tampoco se ve afectada por la elevación o la temperatura media diaria. A pesar de esta eficiente termorregulación a nivel de colonia, las diferencias estadísticamente significativas entre poblaciones observadas en la tolerancia térmica individual sugieren que la termorregulación controlada comportalmente no limita las adaptaciones fisiológicas individuales para enfrentarse a temperaturas extremas.

Mismatched training and test distributions can outperform matched ones.

In learning theory, the training and test sets are assumed to be drawn from the same probability distribution. This assumption is also followed in practical situations, where matching the training and test distributions is considered desirable. Contrary to conventional wisdom, we show that mismatched training and test distributions in supervised learning can in fact outperform matched distributions in terms of the bottom line, the out-of-sample performance, independent of the target function in question. This surprising result has theoretical and algorithmic ramifications that we discuss.

Neurofibromatosis Type I Presenting with Incomplete Ileal Volvulus in a Pediatric Patient.

BACKGROUND Neurofibromatosis 1 is a neurocutaneous disorder with multisystemic manifestations. When patients are lacking overt cutaneous manifestations, diagnosis may be delayed and may complicate diagnosis and management of atypical presentations of this disease. It is thus important to strive to obtain relevant and/or complete history to arrive at the appropriate diagnosis. Furthermore, maintaining an index of suspicion in cases of vague abdominal pain may guide the clinician in establishing the correct diagnosis of mesenteric plexiform neurofibroma in the setting of known/presumed neurofibromatosis 1 patients presenting with acute and/or chronic vague abdominal symptoms. CASE REPORT This is a case of a teenage boy who presented with acute, vague abdominal pain over a period of 2 weeks. Laboratory tests and physical exam findings in primary and secondary care settings were unremarkable, and thus the patient was discharged home only to continue with abdominal pain, thus seeking additional medical care. After admission to our facility and exhaustive history taking, physical examination, and imaging, a prospective diagnosis of neurofibromatosis with mesenteric neurofibroma was made. Upon surgical exploration, a mesenteric mass with corresponding volvulized, ischemic small bowel was removed. Histopathology confirmed a plexiform neurofibroma. The patient recovered adequately and was discharged home without complications. CONCLUSIONS This case highlights the importance of exhaustive history taking to obtain an accurate diagnosis as well as the importance of a high index of clinical suspicion for mesenteric neurofibromatosis in patients with presumed or known neurofibromatosis and presenting with vague abdominal symptoms.

Behavioral responses to a repetitive visual threat stimulus express a persistent state of defensive arousal in Drosophila.

The neural circuit mechanisms underlying emotion states remain poorly understood. Drosophila offers powerful genetic approaches for dissecting neural circuit function, but whether flies exhibit emotion-like behaviors has not been clear. We recently proposed that model organisms may express internal states displaying "emotion primitives," which are general characteristics common to different emotions, rather than specific anthropomorphic emotions such as "fear" or "anxiety." These emotion primitives include scalability, persistence, valence, and generalization to multiple contexts. Here, we have applied this approach to determine whether flies' defensive responses to moving overhead translational stimuli ("shadows") are purely reflexive or may express underlying emotion states. We describe a new behavioral assay in which flies confined in an enclosed arena are repeatedly exposed to an overhead translational stimulus. Repetitive stimuli promoted graded (scalable) and persistent increases in locomotor velocity and hopping, and occasional freezing. The stimulus also dispersed feeding flies from a food resource, suggesting both negative valence and context generalization. Strikingly, there was a significant delay before the flies returned to the food following stimulus-induced dispersal, suggestive of a slowly decaying internal defensive state. The length of this delay was increased when more stimuli were delivered for initial dispersal. These responses can be mathematically modeled by assuming an internal state that behaves as a leaky integrator of stimulus exposure. Our results suggest that flies' responses to repetitive visual threat stimuli express an internal state exhibiting canonical emotion primitives, possibly analogous to fear in mammals. The mechanistic basis of this state can now be investigated in a genetically tractable insect species.

Colectomía videolaparoscópica ¿opción válida? / Videolaparoscopic colectomy: Is it a valid option?

La videolaparoscopía (VL) se está convirtiendo en el nuevo método de abordaje para el cirujano colorrectal y general por las ventajas que presenta en el posoperatorio. Se presenta en este trabajo el resultado de la primera colectomía derecha asistida por VL en la Primera Cátedra de Clínica Quirúrgica del Hospital de Clínicas, Asunción, Paraguay; y se valoran las publicaciones hechas. Ingresó una paciente de 66 años, con el diagnóstico de adenoma velloso del colon derecho. Se realizó la colectomía derecha por VL, seguida de una laparotomía mediana supra-trans e infraumbilical (10 cm de longitud); y anastomosis manual ileotransversa. Tiempo operatorio: cinco horas. Presentó transito intestinal a las 36 horas; dieta por vía oral a las 48 horas; el requerimiento de analgésicos en forma similar a la cirugía convencional, alta al cuarto día del posoperatorio. La anatomía patológica confirmó el diagnóstico. La factibilidad de este método no justifica plenamente su aplicación, y es fundamental una valoración estricta para definir su rol en la enfermedad maligna