Higher vs lower doses of dexamethasone in patients with COVID-19 and severe hypoxia (COVID STEROID 2) trial: Protocol and statistical analysis plan.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has resulted in millions of deaths and overburdened healthcare systems worldwide. Systemic low-dose corticosteroids have proven clinical benefit in patients with severe COVID-19. Higher doses of corticosteroids are used in other inflammatory lung diseases and may offer additional clinical benefits in COVID-19. At present, the balance between benefits and harms of higher vs. lower doses of corticosteroids for patients with COVID-19 is unclear. METHODS: The COVID STEROID 2 trial is an investigator-initiated, international, parallel-grouped, blinded, centrally randomised and stratified clinical trial assessing higher (12 mg) vs. lower (6 mg) doses of dexamethasone for adults with COVID-19 and severe hypoxia. We plan to enrol 1,000 patients in Denmark, Sweden, Switzerland and India. The primary outcome is days alive without life support (invasive mechanical ventilation, circulatory support or renal replacement therapy) at day 28. Secondary outcomes include serious adverse reactions at day 28; all-cause mortality at day 28, 90 and 180; days alive without life support at day 90; days alive and out of hospital at day 90; and health-related quality of life at day 180. The primary outcome will be analysed using the Kryger Jensen and Lange test adjusted for stratification variables and reported as adjusted mean differences and median differences. The full statistical analysis plan is outlined in this protocol. DISCUSSION: The COVID STEROID 2 trial will provide evidence on the optimal dosing of systemic corticosteroids for COVID-19 patients with severe hypoxia with important implications for patients, their relatives and society.

Rapid suppression of bone formation marker in response to sleep restriction and circadian disruption in men.

We describe the time course of bone formation marker (P1NP) decline in men exposed to ~ 3 weeks of sleep restriction with concurrent circadian disruption. P1NP declined within 10 days and remained lower with ongoing exposure. These data suggest even brief exposure to sleep and circadian disruptions may disrupt bone metabolism. INTRODUCTION: A serum bone formation marker (procollagen type 1 N-terminal, P1NP) was lower after ~ 3 weeks of sleep restriction combined with circadian disruption. We now describe the time course of decline. METHODS: The ~ 3-week protocol included two segments: "baseline," ≥ 10-h sleep opportunity/day × 5 days; "forced desynchrony" (FD), recurring 28 h day (circadian disruption) with sleep restriction (~ 5.6-h sleep per 24 h). Fasted plasma P1NP was measured throughout the protocol in nine men (20-59 years old). We tested the hypothesis that PINP would steadily decline across the FD intervention because the magnitude of sleep loss and circadian misalignment accrued as the protocol progressed. A piecewise linear regression model was used to estimate the slope (ß) as ΔP1NP per 24 h with a change point mid-protocol to estimate the initial vs. prolonged effects of FD exposure. RESULTS: Plasma P1NP levels declined significantly within the first 10 days of FD ([Formula: see text] = - 1.33 µg/L per 24 h, p < 0.0001) and remained lower than baseline with prolonged exposure out to 3 weeks ([Formula: see text] = - 0.18 µg/L per 24 h, p = 0.67). As previously reported, levels of a bone resorption marker (C-telopeptide (CTX)) were unchanged. CONCLUSION: Sleep restriction with concurrent circadian disruption induced a relatively rapid decline in P1NP (despite no change in CTX) and levels remained lower with ongoing exposure. These data suggest (1) even brief sleep restriction and circadian disruption can adversely affect bone metabolism, and (2) there is no P1NP recovery with ongoing exposure that, taken together, could lead to lower bone density over time.

First Accurate Normalization of the ß-delayed α Decay of

The ^{12}C(α,γ)^{16}O reaction plays a central role in astrophysics, but its cross section at energies relevant for astrophysical applications is only poorly constrained by laboratory data. The reduced α width, γ_{11}, of the bound 1^{-} level in ^{16}O is particularly important to determine the cross section. The magnitude of γ_{11} is determined via sub-Coulomb α-transfer reactions or the ß-delayed α decay of ^{16}N, but the latter approach is presently hampered by the lack of sufficiently precise data on the ß-decay branching ratios. Here we report improved branching ratios for the bound 1^{-} level [b_{ß,11}=(5.02±0.10)×10^{-2}] and for ß-delayed α emission [b_{ßα}=(1.59±0.06)×10^{-5}]. Our value for b_{ßα} is 33% larger than previously held, leading to a substantial increase in γ_{11}. Our revised value for γ_{11} is in good agreement with the value obtained in α-transfer studies and the weighted average of the two gives a robust and precise determination of γ_{11}, which provides significantly improved constraints on the ^{12}C(α,γ) cross section in the energy range relevant to hydrostatic He burning.

Quality of life in childhood, adolescence and adult food allergy: Patient and parent perspectives.

BACKGROUND: Studies of children with food allergy typically only include the mother and have not investigated the relationship between the amount of allergen needed to elicit a clinical reaction (threshold) and health-related quality of life (HRQL). Our aims were (i) to compare self-reported and parent-reported HRQL in different age groups, (ii) to evaluate the impact of severity of allergic reaction and threshold on HRQL, and (iii) to investigate factors associated with patient-reported and parent-reported HRQL. METHODS: Age-appropriate Food Allergy Quality of Life Questionnaires (FAQLQ) were completed by 73 children, 49 adolescents and 29 adults with peanut, hazelnut or egg allergy. Parents (197 mothers, 120 fathers) assessed their child's HRQL using the FAQLQ-Parent form. Clinical data and threshold values were obtained from a hospital database. Significant factors for HRQL were investigated using univariate and multivariate regression. RESULTS: Female patients reported greater impact of food allergy on HRQL than males did. Egg and hazelnut thresholds did not affect HRQL, but lower peanut threshold was associated with worse HRQL. Both parents scored their child's HRQL better than the child's own assessment, but whereas mother-reported HRQL was significantly affected by limitations in the child's social life, father-reported HRQL was affected by limitations in the family's social life. Severity of allergic reaction did not contribute significantly to HRQL. CONCLUSION: The risk of accidental allergen ingestion and limitations in social life are associated with worse HRQL. Fathers provide a unique perspective and should have a greater opportunity to contribute to food allergy research.

24-hour profile of serum sclerostin and its association with bone biomarkers in men.

The osteocyte's role in orchestrating diurnal variations in bone turnover markers (BTMs) is unclear. We identified no rhythm in serum sclerostin (osteocyte protein). These results suggest that serum sclerostin can be measured at any time of day and the osteocyte does not direct the rhythmicity of other BTMs in men. INTRODUCTION: The osteocyte exerts important effects on bone remodeling, but its rhythmicity and effect on the rhythms of other bone cells are not fully characterized. The purpose of this study was to determine if serum sclerostin displays rhythmicity over a 24-h interval, similar to that of other bone biomarkers. METHODS: Serum sclerostin, FGF-23, CTX, and P1NP were measured every 2 h over a 24-h interval in ten healthy men aged 20-65 years. Maximum likelihood estimates of the parameters in a repeated measures model were used to determine if these biomarkers displayed a diurnal, sinusoidal rhythm. RESULTS: No discernible 24-h rhythm was identified for sclerostin (p = 0.99) or P1NP (p = 0.65). CTX rhythmicity was confirmed (p < 0.001), peaking at 05:30 (range 01:30-07:30). FGF-23 levels were also rhythmic (p < 0.001), but time of peak was variable (range 02:30-11:30). The only significant association identified between these four bone biomarkers was for CTX and P1NP mean 24-h metabolite levels (r = 0.65, p = 0.04). CONCLUSIONS: Sclerostin levels do not appear to be rhythmic in men. This suggests that in contrast to CTX, serum sclerostin could be measured at any time of day. The 24-h profiles of FGF-23 suggest that a component of osteocyte function is rhythmic, but its timing is variable. Our results do not support the hypothesis that osteocytes direct the rhythmicity of other bone turnover markers (CTX), at least not via a sclerostin-mediated mechanism.

Green, Yellow, and Red risk perception in everyday life - a communication tool.

BACKGROUND: Adolescents have the highest risk for food allergy-related fatalities. Our main aim was to investigate the level of risk in everyday social situations as perceived by adolescents/young adults with peanut allergy, their families, and their friends. METHODS: The web-based 'Colours Of Risks' (COR) questionnaire was completed by 70 patients (aged 12-23 years), 103 mothers and fathers, 31 siblings (aged 12-26 years), and 42 friends (aged 12-24 years). COR deals with six main contexts (home, school/university, work, visiting/social activities, special occasions/parties, and vacations), each with 1-12 items. Response categories are green (I feel safe), yellow (I feel uncertain), or red (I feel everything is risky). RESULTS: There was a high level of agreement between participants in defining situations as safe, uncertain, or risky, but female patients and mothers rated fewer situations as safe compared to male patients and fathers. Being with close friends and family, and attending planned parties without alcohol were perceived as situations of low risk. While 94% of patients took an epinephrine auto-injector (EAI) into risky situations, only 65% took it into safe situations. In contrast to the close family, 31% of the friends did not know the patient had an EAI, and fewer knew how to administer the EAI. CONCLUSION: Young adults with peanut allergy face challenges when moving from the safe home with ready assistance if needed, to independence with unpredictable surroundings and less certain help. Perceived 'safe' situations may in fact be the riskiest, as patients often do not take the EAI with them.

23Na(α,p)26Mg Reaction Rate at Astrophysically Relevant Energies.

The production of 26Al in massive stars is sensitive to the 23Na(α,p)26Mg cross section. Recent experimental data suggest the currently recommended cross sections are underestimated by a factor of ∼40. We present here differential cross sections for the 23Na(α,p)26Mg reaction measured in the energy range E(c.m.)=1.7-2.5 MeV. Concurrent measurements of Rutherford scattering provide absolute normalizations that are independent of variations in target properties. Angular distributions are measured for both p0 and p1 permitting the determination of total cross sections. The results show no significant deviation from the statistical model calculations upon which the recommended rates are based. We therefore retain the previous recommendation without the increase in cross section and resulting stellar reaction rates by a factor of 40, impacting the 26Al yield from massive stars by more than a factor of 3.

Different colors of light lead to different adaptation and activation as determined by high-density EEG.

Light adaptation is crucial for coping with the varying levels of ambient light. Using high-density electroencephalography (EEG), we investigated how adaptation to light of different colors affects brain responsiveness. In a within-subject design, sixteen young participants were adapted first to dim white light and then to blue, green, red, or white bright light (one color per session in a randomized order). Immediately after both dim and bright light adaptation, we presented brief light pulses and recorded event-related potentials (ERPs). We analyzed ERP response strengths and brain topographies and determined the underlying sources using electrical source imaging. Between 150 and 261 ms after stimulus onset, the global field power (GFP) was higher after dim than bright light adaptation. This effect was most pronounced with red light and localized in the frontal lobe, the fusiform gyrus, the occipital lobe and the cerebellum. After bright light adaptation, within the first 100 ms after light onset, stronger responses were found than after dim light adaptation for all colors except for red light. Differences between conditions were localized in the frontal lobe, the cingulate gyrus, and the cerebellum. These results indicate that very short-term EEG brain responses are influenced by prior light adaptation and the spectral quality of the light stimulus. We show that the early EEG responses are differently affected by adaptation to different colors of light which may contribute to known differences in performance and reaction times in cognitive tests.

Practical implementation of automated closed-loop insulin delivery: A French position statement.

Automated closed-loop (CL) insulin therapy has come of age. This major technological advance is expected to significantly improve the quality of care for adults, adolescents and children with type 1 diabetes. To improve access to this innovation for both patients and healthcare professionals (HCPs), and to promote adherence to its requirements in terms of safety, regulations, ethics and practice, the French Diabetes Society (SFD) brought together a French Working Group of experts to discuss the current practical consensus. The result is the present statement describing the indications for CL therapy with emphasis on the idea that treatment expectations must be clearly defined in advance. Specifications for expert care centres in charge of initiating the treatment were also proposed. Great importance was also attached to the crucial place of high-quality training for patients and healthcare professionals. Long-term follow-up should collect not only metabolic and clinical results, but also indicators related to psychosocial and human factors. Overall, this national consensus statement aims to promote the introduction of marketed CL devices into standard clinical practice.

Biomechanical aspects of the posteromedial split in bicondylar tibial plateau fractures-a finite-element investigation.

PURPOSE: To gain principal insight into fixation techniques of a posteromedial split fragment in bicondylar tibial plateau fractures. METHODS: A computer simulation was performed, applying the finite-element method (FEM) to compare four methods of fixation of the posteromedial split fragment: lateral plate (model 1), lateral plate and kickstand screw (model 2), lateral plate and two antero-posterior lag screws (model 3), and lateral and posteromedial plate (model 4). The displacement of the fragment and material stresses in implants and bone under 2500 N axial load were analyzed. RESULTS: Maximal displacement of the posteromedial split fragment of 2.8 mm was found with a sole lateral plate. An added kickstand screw decreased the displacement to 1.46 mm. Added lag screws improved stability by a factor 4, with a maximal displacement of 0.76 mm. The double-plate configuration revealed 0.27 mm, a decrease of the displacement by a factor 10 compared to model 1. An additional analysis of posteromedial fragment displacements with osteoporotic bone, simulated by dividing the elastic modulus of the bone by a factor 2, turned out to be of relevant impact. For model 1, the calculations did not converge. The influence of bone quality was found to be 70% in model 2, 60% in model 3, and 40% in model 4. CONCLUSIONS: The results indicate that the additional fixation of a posteromedial split fracture by plate osteosynthesis might be advantageous in bicondylar tibial plateau fractures treated with lateral plating. This might be even more important in patients with low bone quality.

Impact of long-term daylight deprivation on retinal light sensitivity, circadian rhythms and sleep during the Antarctic winter.

Long-term daylight deprivation such as during the Antarctic winter has been shown to lead to delayed sleep timing and sleep fragmentation. We aimed at testing whether retinal sensitivity, sleep and circadian rest-activity will change during long-term daylight deprivation on two Antarctic bases (Concordia and Halley VI) in a total of 25 healthy crew members (mean age: 34 ± 11y; 7f). The pupil responses to different light stimuli were used to assess retinal sensitivity changes. Rest-activity cycles were continuously monitored by activity watches. Overall, our data showed increased pupil responses under scotopic (mainly rod-dependent), photopic (mainly L-/M-cone dependent) as well as bright-blue light (mainly melanopsin-dependent) conditions during the time without direct sunlight. Circadian rhythm analysis revealed a significant decay of intra-daily stability, indicating more fragmented rest-activity rhythms during the dark period. Sleep and wake times (as assessed from rest-activity recordings) were significantly delayed after the first month without sunlight (p < 0.05). Our results suggest that during long-term daylight deprivation, retinal sensitivity to blue light increases, whereas circadian rhythm stability decreases and sleep-wake timing is delayed.

Can short-wavelength depleted bright light during single simulated night shifts prevent circadian phase shifts?

In single night shifts, extending habitual wake episodes leads to sleep deprivation induced decrements of performance during the shift and re-adaptation effects the next day. We investigated whether short-wavelength depleted (=filtered) bright light (FBL) during a simulated night shift would counteract such effects. Twenty-four participants underwent a simulated night shift in dim light (DL) and in FBL. Reaction times, subjective sleepiness and salivary melatonin concentrations were assessed during both nights. Daytime sleep was recorded after both simulated night shifts. During FBL, we found no melatonin suppression compared to DL, but slightly faster reaction times in the second half of the night. Daytime sleep was not statistically different between both lighting conditions (n = 24) and there was no significant phase shift after FBL (n = 11). To conclude, our results showed positive effects from FBL during simulated single night shifts which need to be further tested with larger groups, in more applied studies and compared to standard lighting.

Diurnal variations of hormonal secretion, alertness and cognition in extreme chronotypes under different lighting conditions.

Circadian rhythms in physiology and behavior are modulated by external factors such as light or temperature. We studied whether self-selected office lighting during the habitual waking period had a different impact on alertness, cognitive performance and hormonal secretion in extreme morning and evening chronotypes (N = 32), whose preferred bed- and wake-up times differed by several hours. The self-selected lighting condition was compared with constant bright light and a control condition in dim light. Saliva samples for hormonal analyses, subjective ratings of alertness, wellbeing, visual comfort and cognitive performance were regularly collected. Between the self-selected and the bright, but not the dim lighting condition, the onset of melatonin secretion in the evening (as marker for circadian phase) was significantly different for both chronotypes. Morning chronotypes reported a faster increase in sleepiness during the day than evening chronotypes, which was associated with higher cortisol secretion. Wellbeing, mood and performance in more difficult cognitive tasks were better in bright and self-selected lighting than in dim light for both chronotypes, whereas visual comfort was best in the self-selected lighting. To conclude, self-selection of lighting at work might positively influence biological and cognitive functions, and allow for inter-individual differences.

Interconversions between active, inert and substrate forms of denatured/refolded type-1 plasminogen activator inhibitor.

The latent form of type-1 plasminogen activator inhibitor (PAI-1) acquires inhibitory activity by denaturation followed by refolding. We show here that the reactions of denatured/refolded PAI-1 with plasminogen activators are affected by low concentrations of SDS, which may remain after using SDS for denaturation. Without SDS, the active fraction of denatured/refolded PAI-1 comprised around 60%. Increasing SDS concentrations led to conversions to an inert form without inhibitory activity; then to a substrate form, that is being cleaved proteolytically in the reactive centre by the activators without complex formation, and finally to a second inert form. The first two conversions were associated with changes of the reactivity with monoclonal antibodies and of the thermal stability, respectively. Our results define clearly different interconvertible forms of denatured/refolded PAI-1, distinguish these from the latent and the reactive-centre-cleaved forms, and provide conditions for reproducibly producing reactive-centre-cleaved PAI-1 and PAI-1/activator complexes.

Investigation of marmoset hybrids (Cebuella pygmaea x Callithrix jacchus) and related Callitrichinae (Platyrrhini) by cross-species chromosome painting and comparative genomic hybridization.

We report on the cytogenetics of twin offspring from an interspecies cross in marmosets (Callitrichinae, Platyrrhini), resulting from a pairing between a female Common marmoset (Callithrix jacchus, 2n = 46) and a male Pygmy marmoset (Cebuella pygmaea, 2n = 44). We analyzed their karyotypes by multi-directional chromosome painting employing human, Saguinus oedipus and Lagothrix lagothricha chromosome-specific probes. Both hybrid individuals had a karyotype with a diploid chromosome number of 2n = 45. As a complementary tool, interspecies comparative genomic hybridization (iCGH) was performed in order to screen for genomic imbalances between the hybrids and their parental species, and between Callithrix argentata and S. oedipus, respectively. These genomic imbalances were confined to centromeric and telomeric heterochromatin, while euchromatic chromosome regions appeared balanced in all species investigated. When comparing marmosets and tamarins, sequence divergence of centromeric heterochromatin was already clearly noticeable. In the C. argentata and C. pygmaea genomes numerous subtelomeric regions were affected by amplification of different repetitive sequences. Cross-species FISH with a microdissection-derived C. pygmaea repetitive probe revealed species specificity of this repetitive sequence at the molecular cytogenetic level of resolution.

Comparison of acute non-visual bright light responses in patients with optic nerve disease, glaucoma and healthy controls.

This study examined the effect of optic nerve disease, hence retinal ganglion cell loss, on non-visual functions related to melanopsin signalling. Test subjects were patients with bilateral visual loss and optic atrophy from either hereditary optic neuropathy (n = 11) or glaucoma (n = 11). We measured melatonin suppression, subjective sleepiness and cognitive functions in response to bright light exposure in the evening. We also quantified the post-illumination pupil response to a blue light stimulus. All results were compared to age-matched controls (n = 22). Both groups of patients showed similar melatonin suppression when compared to their controls. Greater melatonin suppression was intra-individually correlated to larger post-illumination pupil response in patients and controls. Only the glaucoma patients demonstrated a relative attenuation of their pupil response. In addition, they were sleepier with slower reaction times during nocturnal light exposure. In conclusion, glaucomatous, but not hereditary, optic neuropathy is associated with reduced acute light effects. At mild to moderate stages of disease, this is detected only in the pupil function and not in responses conveyed via the retinohypothalamic tract such as melatonin suppression.

The implications of Epstein-Barr virus in multiple sclerosis--a review.

The objective of this article is to bring together knowledge about Epstein-Barr virus (EBV) in relation to multiple sclerosis (MS) in order to evaluate its implications in this disease. All MS patients are EBV seropositive, but EBV is not normally detected in the brain. EBV can explain many of the epidemiological dogmas known in MS. In addition, other studies point towards the involvement of EBV in MS. Despite this, other co-actors seem also to be involved. We still need to know whether EBV may be an initiating factor in MS or whether it is a factor in the pathogenesis. Possible ways of EBV involvement are discussed: direct involvement, an autoimmune inducing factor or a transactivating factor. A current treatment study of MS patients with a specific herpes antiviral drug may add further information to the etiology and pathogenesis of MS.

Characterization of retroviruses from patients with multiple sclerosis.

These studies were performed to characterize retroviruses found in cell lines spontaneously developed from peripheral blood mononuclear cells (PBMNC) from 6 multiple sclerosis patients, a patient with progressive myelopathy and a healthy control. The cell lines are B-lymphoblastoid and produce Epstein-Barr virus (EBV) particles or express EBV proteins. The B-lymphoblastoid cell lines are also characterized by production of low, fluctuating amounts of retrovirus. The low productivity complicates purification and characterization, but implementation of product-enhanced reverse transcriptase (PERT) assays has provided a highly useful tool for monitoring retrovirus production. By electron microscopy, the retroviral particles appear type-C-like. Functional assays indicate the presence of Pol, Gag and Env. Indirect ELISA demonstrates a significant relation between disease activity and reactivity towards retroviral peptides. Molecular characterization is primarily based on RT-PCR, cloning, sequencing and Northern- or Southern analyses. Molecular characterization is continuing.

Type-1 inhibitor of plasminogen activators. Distinction between latent, activated and reactive centre-cleaved forms with thermal stability and monoclonal antibodies.

Type-1 inhibitor of plasminogen activators (PAI-1) occurs in purified preparations in a latent form that can be activated with denaturants; in vivo, latency is prevented by binding to vitronectin. We have compared latent, denaturant-activated and reactive centre-cleaved human PAI-1 with respect to thermal stability and affinity to monoclonal antibodies. By both criteria, latent and cleaved PAI-1 are very similar or indistinguishable, and clearly different from active PAI-1. Our findings suggest that the conformations of latent and reactive centre-cleaved PAI-1 are similar and resemble the so-called relaxed (R) serpin conformation, while that of active PAI-1 is different and resembles the stressed (S) serpin conformation.