Seasonal Patterns of Body Temperature Daily Rhythms in Group-Living Cape Ground Squirrels Xerus inauris

Organisms respond to cyclical environmental conditions by entraining their endogenous biological rhythms. Such physiological responses are expected to be substantial for species inhabiting arid environments which incur large variations in daily and seasonal ambient temperature (Ta). We measured core body temperature (Tb) daily rhythms of Cape ground squirrels Xerus inauris inhabiting an area of Kalahari grassland for six months from the Austral winter through to the summer. Squirrels inhabited two different areas: an exposed flood plain and a nearby wooded, shady area, and occurred in different social group sizes, defined by the number of individuals that shared a sleeping burrow. Of a suite of environmental variables measured, maximal daily Ta provided the greatest explanatory power for mean Tb whereas sunrise had greatest power for Tb acrophase. There were significant changes in mean Tb and Tb acrophase over time with mean Tb increasing and Tb acrophase becoming earlier as the season progressed. Squirrels also emerged from their burrows earlier and returned to them later over the measurement period. Greater increases in Tb, sometimes in excess of 5°C, were noted during the first hour post emergence, after which Tb remained relatively constant. This is consistent with observations that squirrels entered their burrows during the day to ‘offload’ heat. In addition, greater Tb amplitude values were noted in individuals inhabiting the flood plain compared with the woodland suggesting that squirrels dealt with increased environmental variability by attempting to reduce their Ta-Tb gradient. Finally, there were significant effects of age and group size on Tb with a lower and less variable Tb in younger individuals and those from larger group sizes. These data indicate that Cape ground squirrels have a labile Tb which is sensitive to a number of abiotic and biotic factors and which enables them to be active in a harsh and variable environment

Targeted Gene Expression Profiling Predicts Meningioma Outcomes and Radiotherapy Responses

Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P \u3c 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses

DeltaScan for the Assessment of Acute Encephalopathy and Delirium in ICU and non-ICU Patients, a Prospective Cross-Sectional Multicenter Validation Study

OBJECTIVES: To measure the diagnostic accuracy of DeltaScan: a portable real-time brain state monitor for identifying delirium, a manifestation of acute encephalopathy (AE) detectable by polymorphic delta activity (PDA) in single-channel electroencephalograms (EEGs). DESIGN: Prospective cross-sectional study. SETTING: Six Intensive Care Units (ICU's) and 17 non-ICU departments, including a psychiatric department across 10 Dutch hospitals. PARTICIPANTS: 494 patients, median age 75 (IQR:64-87), 53% male, 46% in ICUs, 29% delirious. MEASUREMENTS: DeltaScan recorded 4-minute EEGs, using an algorithm to select the first 96 seconds of artifact-free data for PDA detection. This algorithm was trained and calibrated on two independent datasets. METHODS: Initial validation of the algorithm for AE involved comparing its output with an expert EEG panel's visual inspection. The primary objective was to assess DeltaScan's accuracy in identifying delirium against a delirium expert panel's consensus. RESULTS: DeltaScan had a 99% success rate, rejecting 6 of the 494 EEG's due to artifacts. Performance showed and an Area Under the Receiver Operating Characteristic Curve (AUC) of 0.86 (95% CI: 0.83-0.90) for AE (sensitivity: 0.75, 95%CI=0.68-0.81, specificity: 0.87 95%CI=0.83-0.91. The AUC was 0.71 for delirium (95%CI=0.66-0.75, sensitivity: 0.61 95%CI=0.52-0.69, specificity: 72, 95%CI=0.67-0.77). Our validation aim was an NPV for delirium above 0.80 which proved to be 0.82 (95%CI: 0.77-0.86). Among 84 non-delirious psychiatric patients, DeltaScan differentiated delirium from other disorders with a 94% (95%CI: 87-98%) specificity. CONCLUSIONS: DeltaScan can diagnose AE at bedside and shows a clear relationship with clinical delirium. Further research is required to explore its role in predicting delirium-related outcomes

Liquid chromatography-tandem mass spectrometric assay for the T790M mutant EGFR inhibitor osimertinib (AZD9291) in human plasma

A method for the quantitative analysis by ultra-performance liquid chromatography-tandem mass spectrometry of the highly selective irreversible covalent inhibitor of EGFR-TK, osimertinib in human plasma was developed and validated, using pazopanib as an internal standard. The validation was performed in a range from 1 to 1000ng/ml, with the lowest level corresponding to the lower limit of quantitation. Gradient elution was performed on a 1.8μm particle trifunctional bonded C18 column by 1% (v/v) formic acid in water, and acetonitrile as mobile phase. The analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with the heated electrospray interface. Within-day precisions ranged from 3.4 to 10.3%, and between-day precisions from 3.8 to 10.4%, accuracies were 95.5-102.8%. Plasma (either lithium heparin or sodium EDTA) pretreatment was performed by salting-out assisted liquid-liquid extraction using acetonitrile and magnesium sulfate. This method was used to analyze the osimertinib blood plasma levels of five adult patients with metastatic T790M mutated non-small cellular lung carcinoma for therapeutic drug monitoring purposes

Postoperatief delirium herkennen bij ouderen

Objective: To determine the degree of agreement between delirium experts on the diagnosis of delirium based on exactly the same information, and to assess the sensitivity of delirium screening methods used by clinical nurses. Design: Prospective observational longitudinal study. Method: Older patients (≥ 60 years) who underwent major surgery were included. During the first three days after surgery they had a standardised cognitive screening test which was recorded on video. Two delirium experts independently evaluated these videos and the information from the patient records. They classified the patients as having 'no delirium', 'possible delirium' or 'delirium'. If there was disagreement, a third expert was consulted. The final classification, based on consensus of two or three delirium experts, was compared with the result of the delirium screening carried out by the clinical nurses. Results: A total of 167 patients were included and 424 postoperative classifications were obtained. The agreement between the experts was 0.61(95% confidence interval (CI):0.53-0.68), based on Cohen's kappa. In 89 (21.0%) of the postoperative classifications there was no agreement between the experts and a third expert was consulted. The nurses using the delirium screening tools recognised 32% of the cases that had been classified as delirium by the experts. Conclusion: There was considerable disagreement between the classifications of individual delirium experts, based on exactly the same information, indicating the difficulty of the diagnosis. Furthermore, the sensitivity of the delirium screening tools used by the clinical nurses was poor. Further research should focus on the development of objective methods for recognising delirium

Postoperatief delirium herkennen bij ouderen

Objective: To determine the degree of agreement between delirium experts on the diagnosis of delirium based on exactly the same information, and to assess the sensitivity of delirium screening methods used by clinical nurses. Design: Prospective observational longitudinal study. Method: Older patients (≥ 60 years) who underwent major surgery were included. During the first three days after surgery they had a standardised cognitive screening test which was recorded on video. Two delirium experts independently evaluated these videos and the information from the patient records. They classified the patients as having 'no delirium', 'possible delirium' or 'delirium'. If there was disagreement, a third expert was consulted. The final classification, based on consensus of two or three delirium experts, was compared with the result of the delirium screening carried out by the clinical nurses. Results: A total of 167 patients were included and 424 postoperative classifications were obtained. The agreement between the experts was 0.61(95% confidence interval (CI):0.53-0.68), based on Cohen's kappa. In 89 (21.0%) of the postoperative classifications there was no agreement between the experts and a third expert was consulted. The nurses using the delirium screening tools recognised 32% of the cases that had been classified as delirium by the experts. Conclusion: There was considerable disagreement between the classifications of individual delirium experts, based on exactly the same information, indicating the difficulty of the diagnosis. Furthermore, the sensitivity of the delirium screening tools used by the clinical nurses was poor. Further research should focus on the development of objective methods for recognising delirium

Liquid chromatography-tandem mass spectrometric assay for the T790M mutant EGFR inhibitor osimertinib (AZD9291) in human plasma

A method for the quantitative analysis by ultra-performance liquid chromatography-tandem mass spectrometry of the highly selective irreversible covalent inhibitor of EGFR-TK, osimertinib in human plasma was developed and validated, using pazopanib as an internal standard. The validation was performed in a range from 1 to 1000ng/ml, with the lowest level corresponding to the lower limit of quantitation. Gradient elution was performed on a 1.8μm particle trifunctional bonded C18 column by 1% (v/v) formic acid in water, and acetonitrile as mobile phase. The analyte was detected in the selected reaction monitoring mode of a triple quadrupole mass spectrometer after positive ionization with the heated electrospray interface. Within-day precisions ranged from 3.4 to 10.3%, and between-day precisions from 3.8 to 10.4%, accuracies were 95.5-102.8%. Plasma (either lithium heparin or sodium EDTA) pretreatment was performed by salting-out assisted liquid-liquid extraction using acetonitrile and magnesium sulfate. This method was used to analyze the osimertinib blood plasma levels of five adult patients with metastatic T790M mutated non-small cellular lung carcinoma for therapeutic drug monitoring purposes

Recognition of Delirium in Postoperative Elderly Patients: A Multicenter Study

OBJECTIVES: To evaluate to what extent delirium experts agree on the diagnosis of delirium when independently assessing exactly the same information and to evaluate the sensitivity of delirium screening tools in routine daily practice of clinical nurses. DESIGN: Prospective observational longitudinal study. SETTING: Three medical centers in the Netherlands. PARTICIPANTS: Elderly postoperative adults (n = 167). MEASUREMENTS: A researcher examined participants daily (Postoperative Day 1-3) for delirium using a standardized cognitive assessment and interview including the Delirium Rating Scale Revised-98 as global impression without any cut-off values that was recorded on video. Two delirium experts independently evaluated the videos and clinical information from the last 24 hours in the participants' record and classified each assessment as delirious, possibly delirious, or not delirious. Interrater agreement between the delirium experts was determined using weighted Cohen's kappa. When there was no consensus, a third expert was consulted. Final classification was based on median score and compared with the results of the Confusion Assessment Method for Intensive Care Unit and Delirium Observation Scale that clinical nurses administered. RESULTS: Four hundred twenty-four postoperative assessments of 167 participants were included. The overall kappa was 0.61 (95% confidence interval = 0.53-0.68). There was no agreement between the experts for 89 (21.0%) assessments and a third delirium expert was needed for the final classification. Delirium screening that nurses performed detected 32% of the assessments that the experts diagnosed as (possibly) delirious. CONCLUSION: There was considerable disagreement in classification of delirium by experts who independently assessed exactly the same information, showing the difficulty of delirium diagnosis. Furthermore, the sensitivity of daily delirium screening by clinical nurses was poor. Future research should focus on development of objective instruments to diagnose delirium

The Impact of Non-Pharmacological Interventions on Delirium in Neurological Intensive Care Unit Patients: A Single-Center Interrupted Time Series Trial

Background: Delirium is a pathobiological brain process that is frequently observed in Intensive Care Unit (ICU) patients, and is associated with longer hospitalization as well as long-term cognitive impairment. In neurological ICU patients, delirium may be more treatment-resistant due to the initial brain injury. This study examined the effects of a multicomponent non-pharmacological nursing intervention program on delirium in neurological ICU patients. Methods: A single-center interrupted time series trial was conducted in adult neurological ICU patients at high risk for developing delirium who were non-delirious at admission. A multicomponent nursing intervention program focusing on modifiable risk factors for delirium, including the optimalization of vision, hearing, orientation and cognition, sleep and mobilization, was implemented as the standard of care, and its effects were studied. The primary outcome was the number of delirium-free and coma-free days alive at 28 days after ICU admission. The secondary outcomes included delirium incidence and duration, ICU and hospital length-of-stay and duration of mechanical ventilation. Results: Of 289 eligible patients admitted to the ICU, 130 patients were included, with a mean age of 68 ± 11 years, a mean APACHE-IV score of 79 ± 25 and a median predicted delirium risk (E-PRE-DELIRIC) score of 42 [IQR 38–50]). Of these, 73 were included in the intervention period and 57 in the control period. The median delirium- and coma-free days alive were 15 days [IQR 0–26] in the intervention group and 10 days [IQR 0–24] in the control group (level change −0.48 days, 95% confidence interval (95%CI) −7 to 6 days, p = 0.87; slope change −0.95 days, 95%CI −2.41 to 0.52 days, p = 0.18). Conclusions: In neurological ICU patients, our multicomponent non-pharmacological nursing intervention program did not change the number of delirium-free and coma-free days alive after 28 days