Field and Laboratory Studies Provide Insights into the Meaning of Day-Time Activity in a Subterranean Rodent (Ctenomys aff. knighti), the Tuco-Tuco

South American subterranean rodents (Ctenomys aff. knighti), commonly known as tuco-tucos, display nocturnal, wheel-running behavior under light-dark (LD) conditions, and free-running periods >24 h in constant darkness (DD). However, several reports in the field suggested that a substantial amount of activity occurs during daylight hours, leading us to question whether circadian entrainment in the laboratory accurately reflects behavior in natural conditions. We compared circadian patterns of locomotor activity in DD of animals previously entrained to full laboratory LD cycles (LD12∶12) with those of animals that were trapped directly from the field. In both cases, activity onsets in DD immediately reflected the previous dark onset or sundown. Furthermore, freerunning periods upon release into DD were close to 24 h indicating aftereffects of prior entrainment, similarly in both conditions. No difference was detected in the phase of activity measured with and without access to a running wheel. However, when individuals were observed continuously during daylight hours in a semi-natural enclosure, they emerged above-ground on a daily basis. These day-time activities consisted of foraging and burrow maintenance, suggesting that the designation of this species as nocturnal might be inaccurate in the field. Our study of a solitary subterranean species suggests that the circadian clock is entrained similarly under field and laboratory conditions and that day-time activity expressed only in the field is required for foraging and may not be time-dictated by the circadian pacemaker

In silico assessment of biomedical products: the conundrum of rare but not so rare events in two case studies

In silico clinical trials, defined as “The use of individualized computer simulation in the development or regulatory evaluation of a medicinal product, medical device, or medical intervention,” have been proposed as a possible strategy to reduce the regulatory costs of innovation and the time to market for biomedical products. We review some of the the literature on this topic, focusing in particular on those applications where the current practice is recognized as inadequate, as for example, the detection of unexpected severe adverse events too rare to be detected in a clinical trial, but still likely enough to be of concern. We then describe with more details two case studies, two successful applications of in silico clinical trial approaches, one relative to the University of Virginia/Padova simulator that the Food and Drug Administration has accepted as possible replacement for animal testing in the preclinical assessment of artificial pancreas technologies, and the second, an investigation of the probability of cardiac lead fracture, where a Bayesian network was used to combine in vivo and in silico observations, suggesting a whole new strategy of in silico-augmented clinical trials, to be used to increase the numerosity where recruitment is impossible, or to explore patients’ phenotypes that are unlikely to appear in the trial cohort, but are still frequent enough to be of concern

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Neuro-cardiac interaction in malignant ventricular arrhythmia and sudden cardiac death

Sudden cardiac death as a result of lethal ventricular arrhythmias is a major cause of death in cardiac diseases such as heart failure and prior myocardial infarct. Activity of the autonomic nervous system is often abnormal where sympathetic activity is upregulated and vagal activity reduced in these conditions. The abnormal autonomic state has been shown to be a strong prognostic marker of increased mortality and propensity to lethal arrhythmias, for which there is no effective prevention. Research effort over the years has established good evidence for a causal link between autonomic disturbance and ventricular arrhythmias. However, the detailed electrophysiological mechanisms by which ventricular fibrillation occurs are still not clear and molecular processes which are modulated by autonomic nerve influences that either predispose the heart to or protect it from these arrhythmias are not fully understood. This review presents data from studies investigating the link between activity of the autonomic nervous system and ventricular arrhythmias, from seminal findings in classical studies to ongoing investigations, in the quest for a better understanding of the arrhythmogenic mechanisms underlying neurocardiac interactions with a view to the development of effective preventative and therapeutic strategies which are very much needed

Is less more? Assessing the utility of early clinical and radiographic follow-up for operative supracondylar humerus fractures.

PurposePostoperative protocols following surgical management of supracondylar humerus fractures (SCFs) are often based upon surgeon preference rather than clinical merit. The purpose of this study is to determine the utility of early clinical and radiographic follow-up.MethodsA retrospective review of patients who underwent closed reduction and percutaneous pinning (CRPP) for SCF between 2009 and 2015 was performed using a database of prospectively-collected consecutive patient data. Previously undiagnosed neuropathies documented at the first postoperative visit were identified. Unscheduled visits and postoperative complications were compared between patients who were seen at one week and those with delayed first clinic visits.ResultsOf 873 patients, 823 (94.3%) were seen within ten days of surgery (early follow-up) and 50 (5.7%) had a delayed first clinic appointment. Among patients seen for early follow-up, 12 (1.5%) had a previously undocumented neuropathy diagnosed but only eight (1%) had an alteration of management secondary to clinical findings. Greater than 90% of patients seen for early follow-up had radiographs performed, but only one had an alteration in management due to radiographic findings. Patients seen for early follow-up had the same rate of unscheduled visits (2.9% versus 4%, p = 0.66) and postoperative complications (1.6% versus 0%, p > 0.99) as those with delayed first appointments. Radiographic parameters were comparable at final follow-up (Baumann's angle 74.5° versus 73.7°, p = 0.40; lateral humeral condylar angle 40.2° versus 41.2°, p = 0.53).ConclusionThe early follow-up visit after CRPP of SCF rarely leads to alterations in care and does not reduce unscheduled visits or late complications.Level of evidenceLevel IV

Is less more? Assessing the utility of early clinical and radiographic follow-up for operative supracondylar humerus fractures.

PurposePostoperative protocols following surgical management of supracondylar humerus fractures (SCFs) are often based upon surgeon preference rather than clinical merit. The purpose of this study is to determine the utility of early clinical and radiographic follow-up.MethodsA retrospective review of patients who underwent closed reduction and percutaneous pinning (CRPP) for SCF between 2009 and 2015 was performed using a database of prospectively-collected consecutive patient data. Previously undiagnosed neuropathies documented at the first postoperative visit were identified. Unscheduled visits and postoperative complications were compared between patients who were seen at one week and those with delayed first clinic visits.ResultsOf 873 patients, 823 (94.3%) were seen within ten days of surgery (early follow-up) and 50 (5.7%) had a delayed first clinic appointment. Among patients seen for early follow-up, 12 (1.5%) had a previously undocumented neuropathy diagnosed but only eight (1%) had an alteration of management secondary to clinical findings. Greater than 90% of patients seen for early follow-up had radiographs performed, but only one had an alteration in management due to radiographic findings. Patients seen for early follow-up had the same rate of unscheduled visits (2.9% versus 4%, p = 0.66) and postoperative complications (1.6% versus 0%, p > 0.99) as those with delayed first appointments. Radiographic parameters were comparable at final follow-up (Baumann's angle 74.5° versus 73.7°, p = 0.40; lateral humeral condylar angle 40.2° versus 41.2°, p = 0.53).ConclusionThe early follow-up visit after CRPP of SCF rarely leads to alterations in care and does not reduce unscheduled visits or late complications.Level of evidenceLevel IV