Not so fast: Paradoxically increased variability in the glucose tolerance test due to food withdrawal in continuous glucose-monitored mice.

OBJECTIVE: This study was performed to determine the effect of fasting on reproducibility of the glucose tolerance test. Due to individual variation in animal feeding behaviors, fasting animals prior to metabolic and behavioral experiments is widely held to reduce inter-subject variation in glucose and metabolic parameters of preclinical rodent models. Reducing variability is especially important for studies where initial metabolite levels can influence the magnitude of experimental interventions, but fasting also imposes stress that may distort the variables of interest. One such intervention is the glucose tolerance test (GTT) which measures the maximum response and recovery following a bolus of exogenous glucose. We sought to investigate how fasting affects the response of individual mice to a GTT. METHODS: Using simultaneous continuous glucose monitoring (CGM) and indirect calorimetry, we quantified blood glucose, physical activity, body temperature, metabolic rates, and food consumption levels on a minute-to-minute basis in adult male mice for 4 weeks. We tested the effects of a 4-h or 18-h fast on the GTT to examine the effect of food withdrawal in light or dark photoperiods. Studies were also performed with 4-h fasting in additional mice without implanted CGM probes. RESULTS: Contrary to our expectations, a 4-h fast during the light photoperiod promotes a paradoxical increase in inter-animal variation in metabolic rate, physical activity, body temperature, glycemia, and glucose tolerance. This hyperglycemic and hyper-metabolic phenotype promotes increased corticosterone levels and is consistent with a behavioral stress response to food deprivation, even in well-fed mice. We find that mice undergoing an 18-h fast entered torpor, a hibernation-like state. In addition to low body temperature and metabolic rate, torpor is also associated with glucose levels 56 mg/dl lower than those seen in mice with ad libitum access to food. Moreover, the time spent in torpor affects the response to a GTT. CONCLUSION: Our results suggest fasting mice before glucose tolerance testing, and perhaps other experiments, can have the opposite of the intended effect where fasting can increase, rather than decrease, experimental variability.

Wide Complex Tachycardia and Cardiac Arrest During Endoscopy.

A 59-year-old man presented for implantable cardioverter-defibrillator placement after a wide QRS complex tachycardia cardiac arrest at an outside hospital. In this case report, we discuss the differential diagnosis of this patient's tachyarrhythmia and the electrophysiological studies that established the diagnosis and guided management. (Level of Difficulty: Intermediate.).

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.

BACKGROUND: Nearly 30,000 patients with coronavirus disease-2019 (COVID-19) have been hospitalized in New York City as of April 14th, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed. METHODS: We prospectively collected clinical, biomarker, and treatment data on critically ill adults with laboratory-confirmed-COVID-19 admitted to two hospitals in northern Manhattan between March 2nd and April 1st, 2020. The primary outcome was in-hospital mortality. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal-replacement-therapy, and time to clinical deterioration following hospital admission. The relationship between clinical risk factors, biomarkers, and in-hospital mortality was modeled using Cox-proportional-hazards regression. Each patient had at least 14 days of observation. RESULTS: Of 1,150 adults hospitalized with COVID-19 during the study period, 257 (22%) were critically ill. The median age was 62 years (interquartile range [IQR] 51-72); 170 (66%) were male. Two-hundred twelve (82%) had at least one chronic illness, the most common of which were hypertension (63%; 162/257) and diabetes mellitus (36%; 92/257). One-hundred-thirty-eight patients (54%) were obese, and 13 (5%) were healthcare workers. As of April 14th, 2020, in-hospital mortality was 33% (86/257); 47% (122/257) of patients remained hospitalized. Two-hundred-one (79%) patients received invasive mechanical ventilation (median 13 days [IQR 9-17]), and 54% (138/257) and 29% (75/257) required vasopressors and renal-replacement-therapy, respectively. The median time to clinical deterioration following hospital admission was 3 days (IQR 1-6). Older age, hypertension, chronic lung disease, and higher concentrations of interleukin-6 and d-dimer at admission were independently associated with in-hospital mortality. CONCLUSIONS: Critical illness among patients hospitalized with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extra-pulmonary organ dysfunction, and substantial in-hospital mortality.

Hippocampal Network Reorganization Underlies the Formation of a Temporal Association Memory.

Episodic memory requires linking events in time, a function dependent on the hippocampus. In "trace" fear conditioning, animals learn to associate a neutral cue with an aversive stimulus despite their separation in time by a delay period on the order of tens of seconds. But how this temporal association forms remains unclear. Here we use two-photon calcium imaging of neural population dynamics throughout the course of learning and show that, in contrast to previous theories, hippocampal CA1 does not generate persistent activity to bridge the delay. Instead, learning is concomitant with broad changes in the active neural population. Although neural responses were stochastic in time, cue identity could be read out from population activity over longer timescales after learning. These results question the ubiquity of seconds-long neural sequences during temporal association learning and suggest that trace fear conditioning relies on mechanisms that differ from persistent activity accounts of working memory.

Epidemiology, clinical course, and outcomes of critically ill adults with COVID-19 in New York City: a prospective cohort study.

BACKGROUND: Over 40 000 patients with COVID-19 have been hospitalised in New York City (NY, USA) as of April 28, 2020. Data on the epidemiology, clinical course, and outcomes of critically ill patients with COVID-19 in this setting are needed. METHODS: This prospective observational cohort study took place at two NewYork-Presbyterian hospitals affiliated with Columbia University Irving Medical Center in northern Manhattan. We prospectively identified adult patients (aged ≥18 years) admitted to both hospitals from March 2 to April 1, 2020, who were diagnosed with laboratory-confirmed COVID-19 and were critically ill with acute hypoxaemic respiratory failure, and collected clinical, biomarker, and treatment data. The primary outcome was the rate of in-hospital death. Secondary outcomes included frequency and duration of invasive mechanical ventilation, frequency of vasopressor use and renal replacement therapy, and time to in-hospital clinical deterioration following admission. The relation between clinical risk factors, biomarkers, and in-hospital mortality was modelled using Cox proportional hazards regression. Follow-up time was right-censored on April 28, 2020 so that each patient had at least 28 days of observation. FINDINGS: Between March 2 and April 1, 2020, 1150 adults were admitted to both hospitals with laboratory-confirmed COVID-19, of which 257 (22%) were critically ill. The median age of patients was 62 years (IQR 51-72), 171 (67%) were men. 212 (82%) patients had at least one chronic illness, the most common of which were hypertension (162 [63%]) and diabetes (92 [36%]). 119 (46%) patients had obesity. As of April 28, 2020, 101 (39%) patients had died and 94 (37%) remained hospitalised. 203 (79%) patients received invasive mechanical ventilation for a median of 18 days (IQR 9-28), 170 (66%) of 257 patients received vasopressors and 79 (31%) received renal replacement therapy. The median time to in-hospital deterioration was 3 days (IQR 1-6). In the multivariable Cox model, older age (adjusted hazard ratio [aHR] 1·31 [1·09-1·57] per 10-year increase), chronic cardiac disease (aHR 1·76 [1·08-2·86]), chronic pulmonary disease (aHR 2·94 [1·48-5·84]), higher concentrations of interleukin-6 (aHR 1·11 [95%CI 1·02-1·20] per decile increase), and higher concentrations of D-dimer (aHR 1·10 [1·01-1·19] per decile increase) were independently associated with in-hospital mortality. INTERPRETATION: Critical illness among patients hospitalised with COVID-19 in New York City is common and associated with a high frequency of invasive mechanical ventilation, extrapulmonary organ dysfunction, and substantial in-hospital mortality. FUNDING: National Institute of Allergy and Infectious Diseases and the National Center for Advancing Translational Sciences, National Institutes of Health, and the Columbia University Irving Institute for Clinical and Translational Research.

Distinct Contribution of Adult-Born Hippocampal Granule Cells to Context Encoding.

Adult-born granule cells (abGCs) have been implicated in cognition and mood; however, it remains unknown how these cells behave in vivo. Here, we have used two-photon calcium imaging to monitor the activity of young abGCs in awake behaving mice. We find that young adult-born neurons fire at a higher rate in vivo but paradoxically exhibit less spatial tuning than their mature counterparts. When presented with different contexts, mature granule cells underwent robust remapping of their spatial representations, and the few spatially tuned adult-born cells remapped to a similar degree. We next used optogenetic silencing to confirm the direct involvement of abGCs in context encoding and discrimination, consistent with their proposed role in pattern separation. These results provide the first in vivo characterization of abGCs and reveal their participation in the encoding of novel information.