[Risk stratification nomogram for COVID-19 patients with interstitial pneumonia in the emergency department : A retrospective multicenter study]. / Nomogramm zur Risikostratifizierung von COVID-19-Patienten mit interstitieller Pneumonie in der Notaufnahme : Eine retrospektive multizentrische Studie.

BACKGROUND: There is currently no reliable method to identify which COVID-19 patients in the emergency department will experience rapid disease progression and death. AIM: The aim of this work is to investigate predictive risk factors for 30-day mortality in COVID-19 (coronavirus disease 2019) patients with interstitial pneumonia using patient history, and clinical and laboratory parameters and to develop a nomogram for risk stratification in the emergency department. METHODS: A retrospective, multicenter study was conducted in a cohort of 164 patients with COVID-19 pneumonia in the emergency departments of hospitals in Merano and Bressanone from 1 March 2020 to 31 March 2020. Patients were diagnosed as positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) using fluorescence reverse transcription polymerase chain reaction (RT-PCR). A nomogram for risk stratification of 30-day mortality of COVID-19 patients was developed based on the parameters studied. RESULTS: In all, 35 (21.3%) of 164 COVID-19 patients with interstitial pneumonia died within 30 days of admission to the emergency department. Multivariate analysis method revealed that cognitive deterioration (odds ratio [OR]: 8.330; p = 0.004), lymphocytopenia (OR: 4.229; p = 0.049), renal function deterioration (OR: 4.841; p = 0.028), peripheral oxygen saturation < 93% (OR: 17.871; p = 0.002), age > 75 years (OR: 2.925; p = 0.032), elevated C­reactive protein (OR: 6.504; p = 0.005), low monocyte count (OR: 0.504; p = 0.004), and comorbidity (OR 5.862; p = 0.019) were associated with 30-day mortality. Using these eight parameters, a nomogram was developed that showed good discrimination with an area under the ROC curve of 0.937. CONCLUSION: The initial evaluation of the patient history, and the clinical and laboratory data collected in the emergency department provides important prognostic information for risk stratification of COVID-19 patients in the emergency department and for early identification of patients with risk for critical disease course.

Effect of Ritonavir on (99m)Technetium-Mebrofenin Disposition in Humans: A Semi-PBPK Modeling and In Vitro Approach to Predict Transporter-Mediated DDIs.

A semiphysiologically based pharmacokinetic (semi-PBPK) model was developed to describe a unique blood, liver, and bile clinical data set for the hepatobiliary imaging agent (99m)Technetium-mebrofenin ((99m)Tc-mebrofenin), and to simulate sites/mechanisms of a (99m)Tc-mebrofenin-ritonavir drug-drug interaction (DDI). The transport inhibitor ritonavir (multiple-dose: 2 × 300 mg) significantly increased systemic (99m)Tc-mebrofenin exposure as compared with control (4,464 ± 1,861 vs. 1,970 ± 311 nCi min/ml; mean ± SD), without affecting overall hepatic exposure or biliary recovery. A novel extrahepatic distribution compartment was required to characterize (99m)Tc-mebrofenin disposition. Ritonavir inhibited (99m)Tc-mebrofenin accumulation in human sandwich-cultured hepatocytes (SCH) (half maximal inhibitory concentration (IC50) = 3.46 ± 1.53 µmol/l). Despite ritonavir accumulation in hepatocytes, intracellular binding was extensive (97. 6%), which limited interactions with multidrug resistance protein 2 (MRP2)-mediated biliary excretion. These in vitro data supported conclusions from modeling/simulation that ritonavir inhibited (99m)Tc-mebrofenin hepatic uptake, but not biliary excretion, at clinically relevant concentrations. This integrated approach, utilizing modeling, clinical, and in vitro data, emphasizes the importance of hepatic and extrahepatic distribution, assessment of inhibitory potential in relevant in vitro systems, and intracellular unbound concentrations to assess transporter-mediated hepatic DDIs.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e20; doi:10.1038/psp.2012.21; advance online publication 2 January 2013.

Selection of the in vitro culture media influences mRNA expression of Hedgehog genes, Il-6, and important genes regarding reactive oxygen species in single murine preimplantation embryos.

BACKGROUND: The aim of this paper was to determine the influence of different in vitro culture media on mRNA expression of Hedgehog genes, il-6, and important genes regarding reactive oxygen species in single mouse embryos. METHODS: Reverse transcription of single embryos either cultured in vitro from day 0.5 until 3.5 (COOK's Cleavage medium or Vitrolife's G-1 PLUS medium) or in vivo until day 3.5 post coitum. PCR was carried out for ß-actin followed by nested-PCR for shh, ihh, il-6, nox, gpx4, gpx1, and prdx2. RESULTS: The number of murine blastocysts cultured in COOK medium which expressed il-6, gpx4, gpx1, and prdx2 mRNA differed significantly compared to the in vivo group. Except for nox, the mRNA profile of the Vitrolife media group embryos varied significantly from the in vivo ones regarding the number of blastocysts expressing the mRNA of shh, ihh, il-6, gpx4, gpx1 and prdx2. CONCLUSIONS: The present study shows that different in vitro culture media lead to different mRNA expression profiles during early development. Even the newly developed in vitro culture media are not able to mimic the female reproductive tract. The question of long-term consequences for children due to assisted reproduction techniques needs to be addressed in larger studies.

Cortical control of thermoregulatory sympathetic activation.

Thermoregulation enables adaptation to different ambient temperatures. A complex network of central autonomic centres may be involved. In contrast to the brainstem, the role of the cortex has not been clearly evaluated. This study was therefore designed to address cerebral function during a whole thermoregulatory cycle (cold, neutral and warm stimulation) using 18-fluordeoxyglucose-PET (FDG-PET). Sympathetic activation parameters were co-registered. Ten healthy male volunteers were examined three times on three different days in a water-perfused whole-body suit. After a baseline period (32 degrees C), temperature was either decreased to 7 degrees C (cold), increased to 50 degrees C (warm) or kept constant (32 degrees C, neutral), thereafter the PET examination was performed. Cerebral glucose metabolism was increased in infrapontine brainstem and cerebellar hemispheres during cooling and warming, each compared with neutral temperature. Simultaneously, FDG uptake decreased in the bilateral anterior/mid-cingulate cortex during warming, and in the right insula during cooling and warming. Conjunction analyses revealed that right insular deactivation and brainstem activation appeared both during cold and warm stimulation. Metabolic connectivity analyses revealed positive correlations between the cortical activations, and negative correlations between these cortical areas and brainstem/cerebellar regions. Heart rate changes negatively correlated with glucose metabolism in the anterior cingulate cortex and in the middle frontal gyrus/dorsolateral prefrontal cortex, and changes of sweating with glucose metabolism in the posterior cingulate cortex. In summary, these results suggest that the cerebral cortex exerts an inhibitory control on autonomic centres located in the brainstem or cerebellum. These findings may represent reasonable explanations for sympathetic hyperactivity, which occurs, for example, after hemispheric stroke.

Stress and thermoregulation: different sympathetic responses and different effects on experimental pain.

Stress and thermoregulation both activate the sympathetic nervous system (SNS) but might differently affect pain. Studies investigating possible interactions in patients are problematic because of the high prevalence of SNS disturbances in patients. We therefore analyzed the influence of these different sympathetic challenges on experimentally-induced pain in healthy subjects. SNS was activated in two different ways: by mental stress (Stroop task, mental arithmetic task), and by thermoregulatory stimulation using a water-perfused thermal suit (7 degrees C, 32 degrees C, or 50 degrees C). Attentional effects of the mental stress tasks were controlled by using easy control tasks. Both, stress and thermoregulatory stimuli, robustly activated SNS parameters. However, the patterns of activation were different. While stress co-activated heart rate, blood pressure, peripheral vasoconstriction and sweating, thermal stimulation either increased blood pressure (cold) or heart rate and sweating (warm). Only stress was able to induce a significant reduction of pain. The control tasks neither activated the SNS nor altered pain perception. Our results suggest that (1) different patterns of sympathetic activation can be recorded after stress and thermoregulatory challenges and (2) that only stress is able to interfere with sensation of experimental pain. Whether SNS activation is causally responsible for analgesia needs to be further investigated.