Return to work after COVID-19 infection - A Danish nationwide registry study.

OBJECTIVES: This study aimed to explore return to work after COVID-19 and how disease severity affects this. STUDY DESIGN: This is a Nationwide Danish registry-based cohort study using a retrospective follow-up design. METHODS: Patients with a first-time positive SARS-CoV-2 polymerase chain reaction test between 1 January 2020 and 30 May 2020, including 18-64 years old, 30-day survivors, and available to the workforce at the time of the first positive test were included. Admission types (i.e. no admission, admission to non-intensive care unit [ICU] department and admission to ICU) and return to work was investigated using Cox regression standardised to the age, sex, comorbidity and education-level distribution of all included subjects with estimates at 3 months from positive test displayed. RESULTS: Among the 7466 patients included in the study, 81.9% (6119/7466) and 98.4% (7344/7466) returned to work within 4 weeks and 6 months, respectively, with 1.5% (109/7466) not returning. Of the patients admitted, 72.1% (627/870) and 92.6% (805/870) returned 1 month and 6 months after admission to the hospital, with 6.6% (58/870) not returning within 6 months. Of patients admitted to the ICU, 36% (9/25) did not return within 6 months. Patients with an admission had a lower chance of return to work 3 months from positive test (relative risk [RR] 0.95, 95% confidence interval [CI] 0.94-0.96), with the lowest chance in patients admitted to an ICU department (RR 0.54, 95% CI 0.35-0.72). Female sex, older age, and comorbidity were associated with a lower chance of returning to work. CONCLUSION: Hospitalised patients with COVID-19 infection have a lower chance of returning to work with potential implications for postinfection follow-up and rehabilitation.

Viewing Prevention of Catheter-Associated Urinary Tract Infection as a System: Using Systems Engineering and Human Factors Engineering in a Quality Improvement Project in an Academic Medical Center.

BACKGROUND: Urinary tract infections (UTIs) are the most commonly reported health care-associated infection (HAI) in the United States. Among UTIs acquired in the hospital, approximately 75% are associated with urinary catheters, with an estimated 15%-25% of all hospitalized patients receiving urinary catheters during their hospitalization. Despite ambitious national goals to reduce these infections, catheter-associated urinary tract infection (CAUTI) has not decreased in the United States. METHODS: Systems engineering (SE) and human factors engi- neering (HFE) methods were used to reduce urinary catheter utilization and CAUTIs in a three-year (June 1, 2012-May 31, 2015) quality improvement project in a 610-bed academic medical center. These methods were used to define the factors leading to CAUTI and promote standardization of urinary catheter utilization, insertion, and maintenance. RESULTS: The total systemwide CAUTI count decreased from 135 cases at baseline to 74 cases at the end of the project's Year 1, to 59 cases at the end of Year 2, and 25 cases at the end of Year 3-alone, an 81.5% reduction from baseline. The control chart showed a steady decline in the CAUTI count within a few months after the project's start. By the end of Year 3, on the basis of an average attributable-per-patient cost of CAUTI ($1,007 per case), the estimated annual avoidable CAUTI costs decreased from approximately $135,945 to $25,175 per year. Urinary catheter utilization decreased by 27.3% during the same three-year period, and the systemwide CAUTI standardized infection ratio (SIR) decreased from 3.2 to 0.51 (84.1% from baseline). CONCLUSION: SE and HFE methods and principles can effectively decrease urinary catheter utilization and CAUTI incidence in an academic medical center hospital environment.

Pharmacokinetics of intra-articular betamethasone sodium phosphate and betamethasone acetate and endogenous hydrocortisone suppression in exercising horses.

To the date, no reports exist of the pharmacokinetics (PK) of betamethasone (BTM) sodium phosphate and betamethasone acetate administered intra-articular (IA) into multiple joints in exercising horses. The purpose of the study was to determine the PK of BTM and HYD concentrations in plasma and urine after IA administration of a total of 30 mg BTM. Eight 4 years old Thoroughbred mares were exercised on a treadmill and BTM was administered IA. Plasma and urine BTM and HYD were determined via high performance liquid chromatography spectrometry for 6 weeks. Concentration-time profiles of BTM and HYD in plasma and urine were used to generate PK estimates for non-compartmental analyses and comparisons among times and HYD concentrations. BTM in plasma had greater Tmax (Tmax 0.8 h) vs. urine (Tmax 7.1 h). Urine BTM concentration (ng/mL) and amount (AUClast ; h × ng/mL) were greater than plasma. HYD was suppressed for at least 3 days (<1 ng/mL) for all horses. The time of last quantifiable concentration of BTM (Tlast ; hour) was not significantly different in plasma than urine. Use of highly sensitive HPLC-MS/MS assays enabled early detection and prolonged and consistent determination of BTM in plasma and urine.

Prejudices and perceptions: patient acceptance of mobile technology use in health care.

mHealth is transforming health care, yet few studies have evaluated patient and carer perceptions of the use of smartphones at the patient bedside. In this study, 70 patients and carers answered a short survey on health professionals' use of mobile devices. Half the participants were tolerant of doctors using such devices if it was work-related; others believed it was a distraction and not beneficial to patient care. Changes in practice and patient education may be needed to enable effective use of mobile devices in health.

Maximal entropy inference of oncogenicity from phosphorylation signaling.

Point mutations in the phosphorylation domain of the Bcr-Abl fusion oncogene give rise to drug resistance in chronic myelogenous leukemia patients. These mutations alter kinase-mediated signaling function and phenotypic outcome. An information theoretic analysis of the correlation of phosphoproteomic profiling and transformation potency of the oncogene in different mutants is presented. The theory seeks to predict the leukemic transformation potency from the observed signaling by constructing a distribution of maximal entropy of site-specific phosphorylation events. The theory is developed with special reference to systems biology where high throughput measurements are typical. We seek sets of phosphorylation events most contributory to predicting the phenotype by determining the constraints on the signaling system. The relevance of a constraint is measured by how much it reduces the value of the entropy from its global maximum, where all events are equally likely. Application to experimental phospho-proteomics data for kinase inhibitor-resistant mutants shows that there is one dominant constraint and that other constraints are not relevant to a similar extent. This single constraint accounts for much of the correlation of phosphorylation events with the oncogenic potency and thereby usefully predicts the trends in the phenotypic output. An additional constraint possibly accounts for biological fine structure.

Pharmacokinetics of oral ivabradine in healthy cats.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analytical method for the measurement of the novel heart rate-lowering drug ivabradine and its major metabolite, S-18982, was cross-validated in the plasma of eight healthy cats. Plasma concentrations were then determined after single and repeated oral administration of ivabradine. Individual plasma concentrations versus time from each cat were used in compartmental analysis using the commercially available software WinNonlin. Both ivabradine and S-18982 reached their maximum concentrations of 103.33 and 3.86 ng/mL within 1 h. Following repeated administration, areas under the plasma concentration-time curves for ivabradine and S-18982 did not significantly increase. Two-compartmental and one-compartmental models with first-order input and elimination provided the best fit to the data for ivabradine and S-18982, respectively. Both models were combined to produce a single 4-compartment model characterizing ivabradine and S-18982 pharmacokinetics. The results of this study indicate that repeated oral doses of ivabradine produced plasma drug concentrations suitable for 12-h dosing intervals in healthy cats. Furthermore, the analytical assay and combined ivabradine/S-18982 model provide tools for further evaluation of ivabradine pharmacokinetics and pharmacodynamics in future studies in cats.

Incidence of acute myocardial infarction-related cardiogenic shock during corona virus disease 19 (COVID-19) pandemic.

AIMS: The hospitalization of patients with MI has decreased during global lockdown due to the COVID-19 pandemic. Whether this decrease is associated with more severe MI, e.g. MI-CS, is unknown. We aimed to examine the association of Corona virus disease (COVID-19) pandemic and incidence of acute myocardial infarction with cardiogenic shock (MI-CS). METHODS: On March 11, 2020, the Danish government announced national lock-down. Using Danish nationwide registries, we identified patients hospitalized with MI-CS. Incidence rates (IR) and incidence rate ratios (IRR) were used to compare MI-CS before and after March 11 in 2015-2019 and in 2020. RESULTS: We identified 11,769 patients with MI of whom 696 (5.9%) had cardiogenic shock in 2015-2019. In 2020, 2132 MI patients were identified of whom 119 had cardiogenic shock (5.6%). The IR per 100,000 person years before March 11 in 2015-2019 was 9.2 (95% CI: 8.3-10.2) and after 8.9 (95% CI: 8.0-9.9). In 2020, the IR was 7.5 (95% CI: 5.8-9.7) before March 11 and 7.7 (95% CI: 6.0-9.9) after. The IRRs comparing the 2020-period with the 2015-2019 period before and after March 11 (lockdown) were 0.81 (95% CI: 0.59-1.12) and 0.87 (95% CI: 0.57-1.32), respectively. The IRR comparing the 2020-period during and before lockdown was 1.02 (95% CI: 0.74-1.41). No difference in 7-day mortality or in-hospital management was observed between study periods. CONCLUSION: We could not identify a significant association of the national lockdown on the incidence of MI-CS, along with similar in-hospital management and mortality in patients with MI-CS.

Patterns of human local cerebral glucose metabolism during epileptic seizures.

Ictal patterns of local cerebral metabolic rate have been studied in epileptic patients by positron computed tomography with 18F-labeled 2-fluoro-2-deoxy-D-glucose. Partial seizures were associated with activation of anatomic structures unique to each patient studied. Ictal increases and decreases in local cerebral metabolism were observed. Scans performed during generalized convulsions induced by electroshock demonstrated a diffuse ictal increase and postictal decrease in cerebral metabolism. Petit mal absences were associated with a diffuse increase in cerebral metabolic rate. The ictal fluorodeoxyglucose patterns obtained from patients do not resemble autoradiographic patterns obtained from common experimental animal models of epilepsy.

Positron emission tomography: human brain function and biochemistry.

Positron emission tomography (PET) is an analytical imaging technique that provides a way of making in vivo measurements of the anatomical distribution and rates of specific biochemical reactions. This ability of PET to measure and image dynamic biochemistry builds a bridge between the basic and clinical neurosciences founded on the commonality of the types of measurements made. Clinical findings with PET in humans are suggesting hypotheses that can be tested rigorously in the basic science laboratory.

Maturational changes in cerebral function in infants determined by 18FDG positron emission tomography.

2-Deoxy-2[18F]fluoro-D-glucose positron emission tomography performed in human infants during development revealed progressive changes in local cerebral glucose utilization. In infants 5 weeks of age and younger, glucose utilization was highest in the sensorimotor cortex, thalamus, midbrain-brainstem, and cerebellar vermis. By 3 months, glucose metabolic activity had increased in the parietal, temporal, and occipital cortices and the basal ganglia, with subsequent increases in frontal and various association regions occurring by 8 months. These functional changes measured with positron emission tomography are in agreement with behavioral, neurophysiological, and anatomical alterations known to occur during infant development.

Metabolic mapping of the brain's response to visual stimulation: studies in humans.

These studies demonstrated increasing glucose metabolic rates in the human primary (PVC) and associative (AVC) visual cortex as the complexity of visual scenes increased. The metabolic response of the AVC increased more rapidly with scene complexity than that of the PVC, indicating the greater involvement of the higher order AVC for complex visual interpretations. Increases in local metabolic activity by as much as a factor of 2 above that of control subjects with eyes closed indicate the wide range and metabolic reserve of the visual cortex.

In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET).

The study of neural repair and neuroplasticity in rodents would be enhanced by the ability to assess neuronal function in vivo. Positron emission tomography (PET) is used to study brain plasticity in humans, but the limited resolution and sensitivity of conventional scanners have generally precluded the use of PET to study neuroplasticity in rodents. We now demonstrate that microPET, a PET scanner developed for use with small animals, can be used to assess metabolic activity in different regions of the conscious rodent brain using [18F]fluorodeoxyglucose (FDG) as the tracer, and to monitor changes in neuronal activity. Limbic seizures result in dramatically elevated metabolic activity in the hippocampus, whereas vibrissal stimulation results in more modest increases in FDG uptake in the contralateral neocortex. We also show that microPET can be used to study lesion-induced plasticity of the brain. Cerebral hemidecortication resulted in diminished relative glucose metabolism in the neostriatum and thalamus ipsilateral to the lesion, with subsequent, significant recovery of metabolic function. These studies demonstrate that microPET can be used for serial assessment of metabolic function of individual, awake rats with a minimal degree of invasiveness, and therefore, has the potential for use in the study of brain disorders and repair.

Milk, fat, protein, somatic cell score, and days open among Holstein, Brown Swiss, and their crosses.

The objectives of this study were to compare Holstein (HO), Brown Swiss (BS), and their crosses for milk, fat, and protein yields, somatic cell score (SCS), days open (DO), and age at first calving (AFC), and to estimate the effects of heterosis and recombination. First through fifth lactation records were obtained from 19 herds milking crosses among BS and HO. The edited data set included 6,534 lactation records from 3,473 cows of the following breed combinations: 2,125 pure HO, 926 pure BS, 256 BS sire x HO dam (SH), 105 backcrosses to BS (SX), 18 HO sire x BS dam, and 43 backcrosses to HO. Least squares means for daily milk, fat, and protein yields, mature-equivalent milk, fat, and protein yields, SCS, DO, and AFC were calculated for breed combinations with a model that included fixed effects of age within parity (except for AFC), days in milk for daily yield and SCS, herd-year-season of calving, and breed combination. Cow and error were random effects. Breed combination was replaced with regressions on coefficients for heterosis and recombination in a second analysis. Last, data were analyzed with a 5-trait animal model that included a single pedigree file for both breeds and coefficients for heterosis and recombination. The least squares means for fat production were 1.21, 1.15, 1.27, and 1.16 kg for HO, BS, SH, and SX, respectively, which corresponds to a heterosis estimate of 7.30% and a recombination estimate of -3.76%. Heterosis and recombination estimates for protein production were 5.63% and -3.31%, respectively. Heterosis estimates increased for fat yield (10.38%) and protein yield (7.07%) when maternal grandsire identification from a known artificial insemination sire was required. Regression coefficients indicated an 11.44-d reduction in DO due to heterosis. Heterosis estimates for SCS were inconsistent. Regression on heterosis for SCS was significant and favorable (-0.22) when the breed of sire was BS, but nonsignificant and unfavorable when sire breed was HO (0.43). Heterosis estimates were favorable for all traits, whereas recombination effects tended to be unfavorable for yield traits. Reduced performance of future generations did not appear to be the result of inseminating crossbred cows with inferior sires. Results indicated that first-generation crosses among BS and HO compared favorably with HO. Yield in subsequent generations was somewhat below expectations, perhaps due to recombination loss in HO.

An evaluation of the core physical exam in patients with minor peripheral chief complaints.

OBJECTIVE: We sought to determine (1) how often and why emergency medicine resident physicians perform core physical exams in patients with minor peripheral chief complaints (MCCs); and (2) the clinical impact this practice. METHODS: This prospective observational study was conducted at an urban emergency department with a 4 year emergency medicine residency. Charts of all emergency department patients presenting with MCCs in June-September 2003 were reviewed by blinded assistants for documentation of (1) core physical exams; (2) abnormal core physical exam findings; and (3) additional work up, treatment or follow up related to abnormal core physical exam findings. In May-June 2004 all emergency medicine residents were asked how often they perform core physical exams on emergency department patients with MCCs and their motivating factors for this practice. RESULTS: 297 patients met MCC inclusion/exclusion criteria. Among the 591 total cardiac, lung and abdominal exams performed, 8 (1.4%, 95% confidence interval (CI) 0.7% to 2.7%) were abnormal and only 1 (0.1%, 95% CI 0% to 0.1%) finding led to further testing (ECG); none prompted change in treatment or follow up. All 46 eligible emergency medicine residents were evaluated; 72% (33) performed core physical exams in half or more patients with MCCs. Their primary reasons were to screen the underserved emergency department population, the belief that such exams are standard of care, and establishment of physician-patient rapport. CONCLUSIONS: Because they want to screen an underserved population, establish rapport, and meet what they believe is a standard of care, most emergency medicine residents performed core exams on patients with MCCs. Abnormal core physical exam findings are unusual and rarely lead to further testing or change in management.

Non-immunosuppressive FTY720-derivative OSU-2S mediates reactive oxygen species-mediated cytotoxicity in canine B-cell lymphoma.

OSU-2S is a FTY720 (Fingolimod) derivative that lacks immunosuppressive properties but exhibits strong anti-tumour activity in several haematological and solid tumour models. We have recently shown OSU-2S to mediate potent cytotoxicity in human mantle cell lymphoma cell lines and primary cells. We report here the pre-clinical activity of OSU-2S in spontaneous B-cell lymphoma of dogs which shares many characteristics of human lymphoma. OSU-2S mediated apoptosis in canine B-cell lines and primary B-cell lymphoma cells obtained from spontaneous lymphoma bearing dogs. OSU-2S induced reactive oxygen species (ROS) in canine lymphoma cells and inhibition of ROS partially rescued OSU-2S-mediated cell death. These studies provide a rational basis for the use of spontaneous lymphoma in pet dogs as a preclinical large animal model for the development of OSU-2S as small molecule for treating people and dogs with lymphoma.

Influence of OATP1B1 Function on the Disposition of Sorafenib-ß-D-Glucuronide.

The oral multikinase inhibitor sorafenib undergoes extensive UGT1A9-mediated formation of sorafenib-ß-D-glucuronide (SG). Using transporter-deficient mouse models, it was previously established that SG can be extruded into bile by ABCC2 or follow a liver-to-blood shuttling loop via ABCC3-mediated efflux into the systemic circulation, and subsequent uptake in neighboring hepatocytes by OATP1B-type transporters. Here we evaluated the possibility that this unusual process, called hepatocyte hopping, is also operational in humans and can be modulated through pharmacological inhibition. We found that SG transport by OATP1B1 or murine Oatp1b2 was effectively inhibited by rifampin, and that this agent can significantly increase plasma levels of SG in wildtype mice, but not in Oatp1b2-deficient animals. In human subjects receiving sorafenib, rifampin acutely increased the systemic exposure to SG. Our study emphasizes the need to consider hepatic handling of xenobiotic glucuronides in the design of drug-drug interaction studies of agents that undergo extensive phase II conjugation.

Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial.

High-dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

The plasma binding protein for vitamin D is a site of discrimination against vitamin D-2 compounds by the chick.

The binding of 25-hydroxy-[26,27-3H]vitamin D-3 and 25-hydroxy-[26,27-3H]vitamin D-2 to the vitamin D binding protein in the plasma of both rats and chicks has been studied. In the case of rats, sucrose density gradient analysis, competitive displacement, and Scatchard analysis demonstrate that 25-hydroxyvitamin D-3 and 25-hydroxyvitamin D-2 are bound equally well to the vitamin D binding protein. In contrast, 25-hydroxyvitamin D-2 is poorly bound, while 25-hydroxyvitamin D-3 is tightly bound to the vitamin D binding protein in chick plasma. On the other hand, the chick intestinal receptor binds 1,25-dihydroxyvitamin D-2 and 1,25-dihydroxyvitamin D-3 equally well with a KD of 7.10(-11) M for both compounds. These results strongly suggest that the failure of the plasma transport protein in chicks to bind the vitamin D-2 compounds may be responsible for their relative ineffectiveness in these animals.