Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707

Interhemispheric modulation of somatosensory receptive fields: Evidence for plasticity in primary somatosensory cortex

Extracellular recordings were made from single and multiple neurons in primary somatosensory cortex (area 3b) of macaque monkeys and flying foxes. When a small region of area 3b (or adjacent area 1) in the opposite hemisphere was cooled, thereby blocking activity that is normally transferred via the corpus callosum, larger receptive fields (RFs) were immediately unmasked for most neurons, RF expansion presumably reflects the expression of afferent inputs that are normally inhibited, suggesting that callosal inputs provide a source of tonic inhibition that contributes to the shaping of neuronal RFs. Quantitative analyses of single neuron responses revealed other effects that were consistent with a release from inhibition, such as increases in response magnitude to stimulation of points within the original RF and decreases in response latency. An unexpected finding was the reversal of these unmasking effects with extended periods of cooling: RFs returned to their original dimensions and within-field response magnitude decreased. In contrast to the initial effects, this reversal of disinhibition cannot be readily explained by an unmasking of previously unexpressed inputs. Any explanation for the reversal requires an increase in the efficacy of interneuron-mediated inhibition, and presumably occurs in response to ongoing, altered patterns of activity

The @Community college enterprise : CCE ; a journal of research & practice

The interhemispheric connections of somatosensory cortex in the gray- headed flying fox (Pteropus poliocephalus) were examined. Injections of anatomical tracers were placed into five electrophysiologically identified somatosensory areas: the primary somatosensory area (SI or area 3b), the anterior parietal areas 3a and 1/2, and the lateral somatosensory areas SII (the secondary somatosensory area) and PV (pairetal ventral area). In two animals, the hemisphere opposite to that containing the injection sites was explored electrophysiologically to allow the details of the topography of interconnections to be assessed. Examination of the areal distribution of labeled cell bodies and/or axon terminals in cortex sectioned tangential to the pial surface revealed several consistent findings. First, the density of connections varied as a function of the body part representation injected. For example, the area 3b representation of the trunk and structures of the face are more densely interconnected than the representation of distal body parts (e.g., digit 1, D1). Second, callosal connections appear to be both matched and mismatched to the body part representations injected in the opposite hemisphere. For example, an injection of retrograde tracer into the trunk representation of area 3b revealed connections from the trunk representation in the opposite hemisphere, as well as from shoulder and forelimb/wing representations. Third, the same body part is differentially connected in different fields via the corpus callosum. For example, the D1 representation in area 3b in one hemisphere had no connections with the area 3b D1 representation in the opposite hemisphere, whereas the D1 representation in area 1/2 had relatively dense reciprocal connections with area 1/2 in the opposite hemisphere. Finally, there are callosal projections to fields other than the homotopic, contralateral field. For example, the D1 representation in area 1/2 projects to contralateral area 1/2, and also to area 3b and SII

Balanced inhibition and excitation underlies spike firing regularity in ventral cochlear nucleus chopper neurons

Publisher’s permission requested and denied.Ventral cochlear nucleus stellate cells respond to characteristic frequency (CF) tones with sustained (CS), transient (CT) or onset chopping (OC) activity. The mechanisms underlying these different response patterns are not fully understood, and the present study used in vivo intracellular recordings (n = 42) in urethane-anaesthetized rats to examine the possible influence of inhibition on action potential regularity. Hyperpolarization following the offset of a CF tone burst was used as a measure of on-CF inhibition. A cluster analysis based on several membrane potential features, including on-CF inhibition, discriminated three groups in addition to the CS response type - two types of CT responses and the OC type. The different patterns of firing regularity exhibited by CS/T neurons reflected different thresholds or degrees of overlap between these cells’ narrowly tuned excitatory and inhibitory inputs. CT cells with closely matched inhibitory and excitatory response areas showed substantial on-CF inhibition and the greatest decline in firing regularity during a CF tone, whereas those with a mismatch between their response areas showed lateral inhibition and a less marked decline in firing regularity. The presence of inhibition in CS neurons did not alter their firing regularity, possibly because of the lower threshold for excitation compared with inhibition. The latency, duration and frequency extent of sustained hyperpolarization in CS/T cells is inconsistent with the response properties of OC neurons, suggesting that another source(s) of inhibition influences firing regularity, and presumably response magnitude, in these neurons

Cortical synthesis of azimuth-sensitive single-unit responses with nonmonotonic level tuning: A thalamocortical comparison in the cat

1. Azimuth and sound pressure level (SPL) tuning to noise stimulation was characterized in single-unit samples obtained from primary auditory cortex (AI) and in areas of the medial geniculate body (MGB) that project to AI. The primary aim of the study was to test the hypothesis that AI is an important site of synthesis of single-unit responses that exhibit both azimuth sensitivity (tendency for directionally restricted responsiveness) and nonmonotonic (NM) level tuning (tendency for decreased responsiveness with increasing SPL). This was accomplished by comparing the proportions of such responses in AI and MGB. 2. Samples consisted of high-best-frequency (BF) single units located in MGB (n = 217) and AI (n = 216) of barbiturate- anesthetized cats. The MGB sample was obtained mainly from recording sites located in two nuclei that project to AI, the ventral nucleus (VN, n = 118) and the lateral part of the posterior group of thalamic nuclei (Po, n = 84). In addition, a few MGB units were obtained from the medial division (n = 8) or uncertain locations (n = 7). Each unit's responses were studied using noise bursts presented from azimuthal sound directions distributed throughout 180° of the frontal hemifield at 0° elevation. SPL was varied over an 80- dB range in steps of ≤20 dB at each location. Similarities and differences in azimuth and level tuning were evaluated statistically by comparing the AI sample with the entire MGB sample. If they were found to differ, the AI, VN, and Po samples were compared. 3. Azimuth function modulation was used as a measure of azimuth sensitivity, and its mean was greater in AI than in MGB. NM strength was defined as the percentage reduction in level function value at 75 dB SPL and its mean was greater in AI (showing a greater tendency for decreased responsiveness) than in MGB. Azimuth sensitive (AS) NM units were identified by jointly categorizing each sample according to both azimuth sensitivity (sensitive and insensitive categories) and NM strength (NM and monotonic categories). AS NM units were much more common in the AI sample than in any of the MGB samples, suggesting that some such responses are synthesized in AI. 4. A vast majority of AI NM units have been reported to be AS, showing a preferential association (linkage) between these two response properties. This finding was confirmed in AI, but was not found to be the case in MGB. This suggests that a linkage between these response properties emerges in the cortex, presumably as a result of synthesis of NM AS responses. Although the functional significance of the linkage is unknown. NM responses may reflect excitatory/inhibitory antagonism that provides AS AI neurons with sensitivity to stimulus features beyond that which is present in MGB. 5. Breadth of azimuth tuning of AS cells was measured as the portion of the frontal hemifield over which azimuth function values were >75% of maximum (preferred azimuth range, PAR). PARs were broadly distributed in each structure, and mean PAR was narrower in AI than in MGB. A preferred level range (PLR) was defined for NM level functions as the range over which values were >75% of maximum, and mean PLRs were similar in each sample. There was a weak, but significant, positive correlation between PARs and PLRs in AI but not in MGB. This further suggests a linkage between azimuth and level tuning in AI that does not exist in MGB. 6. Best azimuth (midpoint of the PAR) was used to classify cells as contralateral preferring, ipsilateral preferring, midline preferring, or multipeaked. Samples from AI and MGB exhibited similar distributions of these categories. Contralateral-preferring cells represented a majority of each sample, whereass midline-preferring, ipsilateral- preferring, and multipeaked cells each represented smaller proportions. This suggests that the azimuth preference distribution in AI largely reflects that in MGB. 7. A best SPL was defined as the midpoint of the PLR. This was broadly distributed with respect to best azimuths and BFs in both MGB and AI. Mean best SPLs in different structures were similar. Best SPL was positively correlated with PLR size in both AI and MGB, showing that variation in best SPL reflected, at least in part, variation in breadth of level tuning

Spontaneous and stimulus-evoked intrinsic optical signals in primary auditory cortex of the cat

Spontaneous and tone-evoked changes in light reflectance were recorded from primary auditory cortex (A1) of anesthetized cats (barbiturate induction, ketamine maintenance). Spontaneous 0.1-Hz oscillations of reflectance of 540- and 690-nm light were recorded in quiet. Stimulation with tone pips evoked localized reflectance decreases at 540 nm in 3/10 cats. The distribution of patches activated by tones of different frequencies reflected the known tonotopic organization of auditory cortex. Stimulus-evoked reflectance changes at 690 nm were observed in 9/10 cats but lacked stimulus-dependent topography. In two experiments, stimulus-evoked optical signals at 540 nm were compared with multiunit responses to the same stimuli recorded at multiple sites. A significant correlation (P < 0.05) between magnitude of reflectance decrease and multiunit response strength was evident in only one of five stimulus conditions in each experiment. There was no significant correlation when data were pooled across all stimulus conditions in either experiment. In one experiment, the spatial distribution of activated patches, evident in records of spontaneous activity at 540 nm, was similar to that of patches activated by tonal stimuli. These results suggest that local cerebral blood volume changes reflect the gross tonotopic organization of A1 but are not restricted to the sites of spiking neurons