Piperine enhances contractile force in slow- and fast-twitch muscle.

Piperine has been shown to bind to myosin and shift the distribution of conformational states of myosin molecules from the super-relaxed state to the disordered relaxed state. However, little is known about the implications for muscle force production and potential underlying mechanisms. Muscle contractility experiments were performed using isolated muscles and single fibres from rats and mice. The dose-response effect of piperine on muscle force was assessed at several stimulation frequencies. The potentiation of muscle force was also tested in muscles fatigued by eccentric contractions. Potential mechanisms of force potentiation were assessed by measuring Ca2+ levels during stimulation in enzymatically dissociated muscle fibres, while myofibrillar Ca2+ sensitivity was assessed in chemically skinned muscle fibres. Piperine caused a dose-dependent increase in low-frequency force with no effect on high-frequency force in both slow- and fast-twitch muscle, with similar relative increases in twitch force, rate of force development and relaxation rate. The potentiating effect of piperine on low-frequency force was reversible, and piperine partially recovered low-frequency force in fatigued muscle. Piperine had no effect on myoplasmic free [Ca2+] levels in mouse muscle fibres, whereas piperine substantially augmented the force response to submaximal levels of [Ca2+] in rat MyHCII fibres and MyHCI fibres along with a minor increase in maximum Ca2+-activated force. Piperine enhances low-frequency force production in both fast- and slow-twitch muscle. The effects are reversible and can counteract muscle fatigue. The primary underlying mechanism appears to be an increase in Ca2+ sensitivity. KEY POINTS: Piperine is a plant alkaloid derived from black pepper. It is known to bind to skeletal muscle myosin and enhance resting ATP turnover but its effects on contractility are not well known. We showed for the first time a piperine-induced force potentiation that was pronounced during low-frequency electrical stimulation of isolated muscles. The effect of piperine was observed in both slow and fast muscle types, was reversible, and could counteract the force decrements observed after fatiguing muscle contractions. Piperine treatment caused an increase in myofibrillar Ca2+ sensitivity in chemically skinned muscle fibres, while we observed no effect on intracellular Ca2+ concentrations during electrical stimulation in enzymatically dissociated muscle fibres.

Psychosocial patient perspectives following major lower-limb amputation due to vascular aetiology: a protocol for a systematic meta-aggregation study.

INTRODUCTION: Persistent psychosocial problems in people with lower-limb amputation due to vascular aetiology indicate a great need for long-lasting holistic rehabilitation. An in-depth understanding of the psychosocial problems is essential for the guidance of health professionals in meeting and normalising patients' experiences and emotions. Furthermore, identifying the psychological problems may help develop effective rehabilitation and counselling programmes. This meta-aggregation study aims to explore the psychosocial perspectives of individuals who have undergone a major lower-limb amputation due to vascular aetiology during the post-discharge rehabilitation phase. METHODS AND ANALYSIS: A systematic meta-aggregation study will be performed to identify full-text, peer-reviewed journal articles reporting on patients' psychosocial perspectives on major lower-limb amputation due to vascular aetiology from post-discharge to several years afterward. The databases Embase, CINAHL Ultimate, APA PsycInfo, PubMed and Scopus will be searched with no limitations regarding the publication year. Studies that satisfy the eligibility criteria will be critically appraised using an acknowledged checklist and synthesised using the Joanna Briggs Institute three-phase approach for the synthesis of meta-aggregation studies. The GRADE-CERQual (Grading of Recommendations Assessment, Development and Evaluation- Confidence in Evidence from Reviews of Qualitative research) tool will be used to determine the level of confidence in the qualitative evidence, and the PRISMA (Preferred Reporting Items for Systematic Review and Meta-Analysis) reporting guidelines will be followed throughout the review process. ETHICS AND DISSEMINATION: Ethical approval is not required for the study, as the review is built on pre-existing available data in the literature. Findings from the review will be disseminated through publication in a peer-review journal. PROSPERO REGISTRATION NUMBER: CRD42022377114.

A Full Target-Mediated Drug Disposition (TMDD) Model to Explain the Changes in Recombinant Human Erythropoietin (rhEpo) Pharmacokinetics in Patients with Different Bone Marrow Integrity Following Hematopoietic Transplantation.

Our aim was to build a mechanistic full target-mediated drug disposition (TMDD) model for rhEpo to better understand rhEpo disposition, Epo receptor (EpoR) synthesis, and degradation in hematopoietic transplant patients with four distinct bone marrow conditions. All PK data were analyzed simultaneously using the nonlinear mixed effect modeling approach with NONMEM. The final model was a two-compartmental full TMDD model, which adequately characterizes rhEpo PK in patients and provides insight into the dynamics of free EpoR, rhEpo-EpoR, and total EpoR. The model predicted association rate constant (kon), dissociation rate constant (koff), and internalization rate constant (kint) were 0.0276 pM-1h-1, 0.647 h-1, and 0.255h-1, respectively, which were supported by experimental data. Also, the EpoR degradation rate constant (kdeg) was estimated to be 0.461 h-1. EpoR production rate was estimated to be 37.5 pM/h for adults at pre-ablation baseline and 5.91 pM/h, and 4.19 pM/h in the early post-transplant post-engraftment, and late post-transplant full engraftment. Our model provides extensive information on the dynamics of free EpoR, total EpoR and rhEpo-EpoR, and proven to be more robust and can provide more physiologically relevant binding parameters than previous models.

Anthroposophic Medicinal Products: A Literature Review of Features, Similarities and Differences to Conventional Medicinal Products, Scientific and Regulatory Assessment.

Background: Regulatory assessment of anthroposophic medicinal products (AMPs) can be challenging due to their specific features. Objective: The aim of this paper is therefore to provide adequate scientific information on AMPs for regulatory purposes. Methods: A literature review was executed with database searches in PubMed, Cinahl, Merkurstab, Anthromedics, and https://iaap-pharma.org/. Search terms were: anthroposophic medicinal products, anthroposophic medicines, anthroposophic pharmacy. There was no language restriction; searches were executed from onset until June 11, 2020. In addition, experts were invited to suggest relevant literature. Results: Eighty-seven of 660 identified publications were included. The system of anthroposophic medicine (AM) with its conceptual background and various aspects of AMPs was described: definition, pharmaceutical properties, an example of AMP development, use in clinical practice, similarities with and differences to conventional medicinal products, societal aspects, scientific and regulatory assessment. Conclusion: AMPs are part of the integrative whole medical system of AM. AMPs are manufactured according to Good Manufacturing Practice and national drug regulations and have an excellent safety status; the limited available evidence suggests clinical benefits. Current drug regulation of AMPs in the EU and most European countries does not take the special properties of AMPs into account. Future research should focus on appropriate methodologies for the evaluation of effects of AMPs as part of the AM whole medical system, the scientific quality of its non-atomistic holistic ontological position, and the integration of AM and conventional medicine in clinical practice. Future policies should focus on appropriate ways of addressing regulatory challenges to AMPs.

Measuring Knee Joint Laxity in Three Degrees-of-Freedom In Vivo Using a Robotics- and Image-Based Technology.

Accurate and reliable information about three-dimensional (3D) knee joint laxity can prevent misdiagnosis and avoid incorrect treatments. Nevertheless, knee laxity assessments presented in the literature suffer from significant drawbacks such as soft tissue artifacts, restricting the knee within the measurement, and the absence of quantitative knee ligament property information. In this study, we demonstrated the applicability of a novel methodology for measuring 3D knee laxity, combining robotics- and image-based technology. As such technology has never been applied to healthy living subjects, the aims of this study were to develop novel technology to measure 3D knee laxity in vivo and to provide proof-of-concept 3D knee laxity measurements. To measure tibiofemoral movements, four healthy subjects were placed on a custom-built arthrometer located inside a low dose biplanar X-ray system with an approximately 60 deg knee flexion angle. Anteroposterior and mediolateral translation as well as internal and external rotation loads were subsequently applied to the unconstrained leg, which was placed inside a pneumatic cast boot. Bone contours were segmented in the obtained X-rays, to which subject-specific bone geometries from magnetic resonance imaging (MRI) scans were registered. Afterward, tibiofemoral poses were computed. Measurements of primary and secondary laxity revealed considerable interpersonal differences. The method differs from those available by the ability to accurately track secondary laxity of the unrestricted knee and to apply coupled forces in multiple planes. Our methodology can provide reliable information for academic knee ligament research as well as for clinical diagnostics in the future.

Inter- and intrarater reliability of measuring lengthening of magnetically controlled growing rods on digital radiographs.

PURPOSE: The aim of this study was to determine inter- and intraobserver reliability of delta rod extension, and total rod length measured on digital x-rays in patients with early onset scoliosis (EOS) treated with magnetically controlled growing rods (MCGR). For the last decade, patients with EOS have been treated with MCGR. Replacement of MCGR relies heavily on the measurement done at every lengthening session. Only a few studies have looked at inter- and intraobserver reliability of rod lengthening, and none have used the delta extension before. METHODS: 202 radiographs presented in random order were rated and measured twice with at least a 14-day interval and differing order of the radiographs. The measuring was done at both rods. All x-rays came from 15 patients diagnosed with EOS and treated with MCGR from 2009 until 2019. The total extension length and the delta extension (the difference in total extension length between two lengthening in succession) were measured, and the intraclass correlation coefficient (ICC) calculated for both measurements RESULTS: Intrarater ICC scores varied from moderate to good, but non-significantly. Interrater reliability increased significantly from moderate (ICC 0.72 [0.68; 0.76] and 0.73 [0.69; 0.77] to excellent (ICC 0.91 [0.88; 0.93] and 0.97 [0.96: 0.98]), when examining delta extension every sixth instead of every second month. CONCLUSION: Measuring rod lengthening on x-rays can be done every 6 months, with an ample reliability. The ICC's for the delta extension with 2-3 months interval were only moderately precise, compared to the near perfect ICC's for the total extension length.

Organ failure, aetiology and 7-day all-cause mortality among acute adult patients on arrival to an emergency department: a hospital-based cohort study.

BACKGROUND: Organ failure is both a frequent and dangerous condition among adult patients on arrival to an emergency department (ED). The risk of an unfavourable outcome could depend on the underlying aetiology. Knowledge of the relation between aetiology and prognosis could improve the risk stratification at arrival. OBJECTIVES: To describe the relation between organ failure, aetiology and prognosis through 7-day all-cause mortality. METHODS: An observational three-year cohort study at the ED at Odense University Hospital, Denmark, including all acute adult patients.First-measured vital signs and laboratory values were included to evaluate the presence of the following organ failures: respiratory, coagulation, hepatic, circulatory, cerebral or renal.The primary outcome was 7-day all-cause mortality. Aetiological disease categories were based on primary discharge diagnoses. We described the association between 7-day mortality, aetiology category, site of organ failures and number of patients at risk. RESULTS: Of 40 423 patients with a first-time visit at the ED, 5883(14.6%) had an organ failure on arrival. The median age was 69 (IQR 54-80), and 50% were men. The most frequent aetiology was infection (1495, 25.4%). Seven-day all-cause mortality ranged between aetiologies from 0.0% (95% confidence interval [CI], 0.0-14.2) allergy) to 45.6% (95% CI, 41.3-50.0) (cardiac). Combining aetiology and site of organ failure, 7-day all-cause mortality was the highest in the cardiac category, from 14.8% (95% CI, 4.2-3.7) with hepatic failure to 79.2% (95% CI, 73.6-84.1) with cerebral failure. The combination of infection and respiratory failure characterised most patients (n = 949). CONCLUSION: Infection was the most prevalent aetiology, and 7-day all-cause mortality was highly associated with the site of organ failure and aetiology.

Comparison of interventions for lumbar disc herniation: a systematic review with network meta-analysis.

BACKGROUND: Implants for use in disc herniation surgery have been commercially available for some time. Several clinical trials have shown promising results. There are now a wide variety of surgical methods for treating lumbar disc herniation. PURPOSE: The objective of this systematic review was to compare all current surgical methods for disc herniation, including newer methods with implants for annulus repair and dynamic stabilization. STUDY DESIGN: Systematic review and network meta-analysis. METHODS: PRISMA-P guidelines were followed in this review. Literature search in PubMed, Embase, and Cochrane library databases identified eligible randomized controlled trials (RCT) studies comparing interventions for lumbar disc surgery. The investigated outcomes were: changes in pain score, disability score and reoperation rate with a minimum follow-up of 1 year. Risk of bias was assessed in concordance with Cochrane Neck and Back Review Group recommendation. A network meta-analysis was performed using gemtc and BUGSnet software, and each outcome evaluated using Confidence in Network Meta-Analysis (CINeMA). RESULTS: Thirty-two RCT studies, with 4,877 participants, and eight different interventions were identified. A significant difference was seen in change of pain score, as all treatments were superior to conservative treatment and percutaneous discectomy. This difference was only found to be of clinically importance when comparing conservative treatment and dynamic stabilization. There was no significant difference in reoperation rates or change in disability score, regardless of treatment. However, SUCRA plots showed a trend in ranking annulus repair and dynamic stabilization highest. Risk of bias assessment showed that 15 studies had a high overall risk of bias. Meta-regression with risk of bias as covariate did not indicate any influence in risk of bias on the model. Confidence in Network Meta-Analysis evaluation showed a high level of confidence for all treatment comparisons. CONCLUSIONS: With this network meta-analysis, we have aimed to compare all treatments for herniated lumbar disc in one large comprehensive systematic review and network meta-analysis. We have compared across the three main outcomes: disability score, pain score and reoperation rate. We were not able to rank one single treatment as the best. Most of the treatment performed at the same level. However percutaneous discectomy and conservative treatment consistently performed worse than the other treatments. In general, the CINeMA evaluation according to the GRADE recommendations gave a high level of confidence for the study comparisons.

Emissions of ultrafine particles from five types of candles during steady burn conditions.

Emissions from candles are of concern for indoor air quality. In this work, five different types of pillar candles were burned under steady burn conditions in a new laboratory scale system for repeatable and controlled comparison of candle emissions (temperature ~25°C, relative humidity ~13%, O2 >18%, air exchange rate 1.9 h-1 ). Burn rate, particle number concentrations, mass concentrations, and mode diameters varied between candle types. Based on the results, the burning period was divided in two phases: initial (0-1 h) and stable (1-6 h). Burn rates were in the range 4.4-7.3 and 4.7-7.1 g/h during initial and stable phase, respectively. Relative particle number emissions, mode diameters, and mass concentrations were higher during the initial phase compared to the stable phase for a majority of the candles. We hypothesize that this is due to elevated emissions of wick additives upon ignition of the candle together with a slightly higher burn rate in the initial phase. Experiments at higher relative humidity (~40%) gave similar results with a tendency toward larger particle sizes at the higher relative humidity. Chemical composition with respect to inorganic salts was similar in the emitted particles (dry conditions) compared to the candlewicks, but with variations between different candles.

Level of vital and laboratory values on arrival, and increased risk of 7-day mortality among adult patients in the emergency department: a population-based cohort study.

OBJECTIVES: The aim of the study was to provide evidence for, at which vital and laboratory values, increased risk of 7-day mortality in acute adult patients on arrival to an emergency department (ED). DESIGN: A population-based cohort study. SETTING: ED at Odense University Hospital, Denmark. PARTICIPANTS: All patients ≥18 years with a first-time contact within the study period, 1 April 2012 to 31 March 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was 7-day all-cause mortality.Variables were first recorded vital and laboratory values included in risk stratification scores; respiratory frequency, blood pressure, heart rate, Glasgow Coma Scale, temperature, saturation, creatinine, PaO2, platelet count and bilirubin. The association between values and mortality was described using a restricted cubic spline. A predefined 7-day mortality of 2.5% was chosen as a relevant threshold. RESULTS: We included 40 423 patients, 52.5% women, median age 57 (IQR 38-74) years and 7-day mortality 2.8%. Seven-day mortality of 2.5% had thresholds of respiratory frequency <12 and >18/min, systolic blood pressure <112 and >192 mm Hg, heart rate <54 and >102 beats/min, temperature <36.0°C and >39.8°C, saturation <97%, Glasgow Coma Scale score <15, creatinine <41 and >98 µmol/L for PaO2 <9.9 and >12.3 kPa, platelet count <165 and >327×109/L and bilirubin >12 µmol/L. CONCLUSION: Vital values on arrival, outside the normal ranges for the measures, are indicative of increased risk of short-term mortality, and most of the value thresholds are included in the lowest urgency level in triage and risk stratification scoring systems.

Neonatal Umbilical Arterial Catheter Removal Is Accompanied by a Marked Decline in Phlebotomy Blood Loss.

BACKGROUND: Umbilical arterial catheters (UACs) are frequently used in critically ill neonates. UAC are convenient, reliable, and allow for caregiver convenience in performing painless arterial blood sampling. We hypothesized that UAC removal in extremely low birth weight (ELBW) neonates will result in significantly less phlebotomy blood loss (PBL) after correcting for severity of illness. STUDY DESIGN AND METHODS: PBL was measured at a single center in 99 ELBW infants who survived to day 28. Individual infant's paired daily PBL for the two 24-h periods before and after UAC removal were compared using the paired t test. Daily PBL up to 7 days before and 7 days after UAC removal were compared using a logistic regression with mixed model analysis for repeated measures. Cumulative 28-day phlebotomy loss was evaluated by multiple linear regression analysis. RESULTS: PBL 24 h before and after UAC removal were 1.7 mL (95% CI 1.5-1.9) and 0.9 mL (95% CI 0.8-1.0; p < 0.0001), respectively. Cumulative 28-day PBL increased by 2.2 mL (±0.7) per day that a UAC was present with or without correction for severity of illness (p < 0.001). CONCLUSION: UAC removal is independently associated with a marked decline in PBL. We speculate the ease and convenience of UAC blood sampling lead to more frequent blood testing and greater PBL.

HOW MANY DOSEMETERS ARE NEEDED FOR CORRECT MEAN ORGAN DOSE ASSESSMENT WHEN PERFOMING PHANTOM DOSIMETRY? A PHANTOM STUDY EVALUATING LIVER ORGAN DOSE AND INVESTIGATING TLD NUMBERS AND WAYS OF DOSEMETER PLACEMENT.

This study evaluated repeated mean organ dose measurements of the liver by phantom dosimetry and statistical modelling in order to find a way to reduce the number of dosemeters needed for precise organ dose measurements. Thermoluminescent dosemeters were used in an adult female phantom exposed to a biplanar x-ray source at three different axial phantom rotations. Generalised mixed linear effect modelling was used for statistical analysis. A subgroup of five to six organ-specific locations out of 28 yielded mean liver organ doses within 95% confidence intervals of measurements based on all 28 liver-specific dosemeter locations. No statistical difference of mean liver dose was observed with rotation of the phantom either 10° clockwise or counter-clockwise as opposed to the coronal plane. Phantom dosimetry handling time during organ dose measurements can be markedly reduced, in this case the liver, by 79% (22/28), while still providing precise mean organ dose measurements.

Vertebral Osteomyelitis: A Mortality Analysis Comparing Surgical and Conservative Management.

STUDY DESIGN: Retrospective cohort study. OBJECTIVES: To compare the mortality between patients treated for vertebral osteomyelitis (VO) with either surgical or conservative management and to construct a predictive model for mortality after VO. METHODS: All patients with a diagnosis of VO in Region North Denmark from 2004 to 2014 were followed for at least 2 years or until death. They were all treated according to a standardized guideline for the choice of treatment modality. Nineteen dichotomized variables with possible influence on the mortality were registered for all patients in the study. LASSO (least absolute shrinkage and selection operator) penalized Cox regression analysis was used to build a predictive model for 2-year survival after VO. RESULTS: A total of 125 patients were eligible for inclusion, mean age 67 years, 36 women. 75 were treated surgically. Twenty-one patients were dead 2 years after the diagnosis. Kaplan-Meier estimate of 2-year survival was 0.82 [0.75, 0.88]. Any difference in mortality between surgically and conservatively treated patients was nonsignificant at 1 and 2 years (univariate Cox regression analysis). Significant factors included in the predictive model after LASSO penalized Cox regression analysis was Charlson Comorbidity Index (CCI), cardiovascular disease, C-reactive protein (CRP) normalization, thoracic infection, and Karnofsky score. The area under the curve (AUC) for the predictive model ranged from 0.74 to 0.77. CONCLUSION: Patients undergoing surgical management for vertebral osteomyelitis according to standardized and agreed-upon guidelines had no higher mortality than those allocated to conservative treatment. The predictive model included 5 variables associated with an increased mortality: CCI, CRP normalization, cardiovascular disease, thoracic infection, and Karnofsky score.

Pleiotropic Anticancer Properties of Scorpion Venom Peptides: Rhopalurus princeps Venom as an Anticancer Agent.

To date, the success of conventional chemotherapy, radiotherapy, and targeted biological therapies in cancer treatment is not satisfactory. The main reasons for such outcomes rely on low target selectivity, primarily in chemo- and radiotherapy, ineffectiveness to metastatic disease, drug resistance, and severe side effects. Although immune checkpoint inhibitors may offer better clinical promise, success is still limited. Since cancer is a complex systemic disease, the need for new therapeutic modalities that can target or block several steps of cancer cell characteristics, modulate or repolarize immune cells, and are less toxic to healthy tissues is essential. Of these promising therapeutic modalities are pleiotropic natural products in which scorpion venom (SV) is an excellent example. SV consists of complex bioactive peptides that are disulfide-rich of different peptides' length, potent, stable, and exerts various multi-pharmacological actions. SV peptides also contain ion channel inhibitors. These ion channels are dysregulated and overexpressed in cancer cells, and play essential roles in cancer development and invasion, as well as depolarizing immune cells. Furthermore, SV has been found to induce cancer cell apoptosis, and inhibit cancer cells proliferation, invasion, metastasis, and angiogenesis. In the current review, we are presenting data that show the pleiotropic effect of SV against different types of human cancer as well as revealing one potential anticancer agent, Rhopalurus princeps venom. Furthermore, we are addressing what is needed to be done to translate these potential cancer therapeutics to the clinic.

Cumulative radiation exposure during current scoliosis management.

INTRODUCTION: Patients undergoing scoliosis management are exposed to repeated radiological imaging. Previous studies have shown an increase in incidence of cancer among these patients. The primary aim of this study was to evaluate the radiographic examinations and cumulative radiation dose to which scoliotic patients are exposed. A secondary aim was to compare in-house algorithms of scoliosis management and radiographic follow-up to international spine centres and current consensus literature. MATERIALS AND METHODS: A single-centre retrospective review evaluating type and frequency of radiographic imaging and total cumulative radiation exposure to patients treated for scoliosis. Inclusions: patients followed for idiopathic scoliosis in the years 2013-2016. A survey asking for information on management and radiological follow-up algorithms was sent to a number of international spine centres for comparison with the in-house algorithm. RESULTS: Patients who underwent surgery received an approximately ten-fold higher median cumulative radiation dose than those treated conservatively. A variety of radiological follow-up algorithms among eight spine centres was observed. CONCLUSIONS: Cumulative radiation dose during scoliosis treatment varies substantially depending on radiographic follow-up protocol, intraoperative and ancillary imaging. By using low-dose X-ray systems in combination with a low-dose protocol for intraoperative navigation, it is possible to keep exposure to patients at a minimum while still providing optimal care. FUNDING: none. TRIAL REGISTRATION: not relevant.

Development and Evaluation of a Subject-Specific Lower Limb Model With an Eleven-Degrees-of-Freedom Natural Knee Model Using Magnetic Resonance and Biplanar X-Ray Imaging During a Quasi-Static Lunge.

Musculoskeletal (MS) models can be used to study the muscle, ligament, and joint mechanics of natural knees. However, models that both capture subject-specific geometry and contain a detailed joint model do not currently exist. This study aims to first develop magnetic resonance image (MRI)-based subject-specific models with a detailed natural knee joint capable of simultaneously estimating in vivo ligament, muscle, tibiofemoral (TF), and patellofemoral (PF) joint contact forces and secondary joint kinematics. Then, to evaluate the models, the predicted secondary joint kinematics were compared to in vivo joint kinematics extracted from biplanar X-ray images (acquired using slot scanning technology) during a quasi-static lunge. To construct the models, bone, ligament, and cartilage structures were segmented from MRI scans of four subjects. The models were then used to simulate lunges based on motion capture and force place data. Accurate estimates of TF secondary joint kinematics and PF translations were found: translations were predicted with a mean difference (MD) and standard error (SE) of 2.13 ± 0.22 mm between all trials and measures, while rotations had a MD ± SE of 8.57 ± 0.63 deg. Ligament and contact forces were also reported. The presented modeling workflow and the resulting knee joint model have potential to aid in the understanding of subject-specific biomechanics and simulating the effects of surgical treatment and/or external devices on functional knee mechanics on an individual level.

Prevalence of organ failure and mortality among patients in the emergency department: a population-based cohort study.

OBJECTIVES: The aim was to describe population-based incidence and emergency department-based prevalence and 1-year all-cause mortality of patients with new organ failure present at arrival. DESIGN: This was a population-based cohort study of all citizens in four municipalities (population of 230 000 adults). SETTING: Emergency department at Odense University Hospital, Denmark. PARTICIPANTS: We included all adult patients who arrived from 1 April 2012 to 31 March 2015. PRIMARY AND SECONDARY OUTCOME MEASURES: Organ failure was defined as a modified Sequential Organ Failure Assessment score≥2 within six possible organ systems: cerebral, circulatory, renal, respiratory, hepatic and coagulation.The primary outcome was prevalence of organ failure, and secondary outcomes were 0-7 days, 8-30 days and 31-365 days all-cause mortality. RESULTS: We identified in total 175 278 contacts, of which 70 399 contacts were further evaluated for organ failure. Fifty-two per cent of these were women, median age 62 (IQR 42-77) years. The incidence of new organ failure was 1342/100 000 person-years, corresponding to 5.2% of all emergency department contacts.The 0-7-day, 8-30-day and 31-365-day mortality was 11.0% (95% CI: 10.2% to 11.8%), 5.6% (95% CI: 5.1% to 6.2%) and 13.2% (95% CI: 12.3% to 14.1%), respectively, if the patient had one or more new organ failures at first contact in the observation period, compared with 1.4% (95% CI: 1.3% to 1.6%), 1.2% (95% CI: 1.1% to 1.3%) and 5.2% (95% CI: 5.0% to 5.4%) for patients without. Seven-day mortality ranged from hepatic failure, 6.5% (95% CI: 4.9% to 8.6%), to cerebral failure, 33.8% (95% CI: 31.0% to 36.8%), the 8-30-day mortality ranged from cerebral failure, 3.9% (95% CI: 2.8% to 5.3%), to hepatic failure, 8.6% (95% CI: 6.6% to 10.8%) and 31-365-day mortality ranged from cerebral failure, 9.3% (95% CI: 7.6% to 11.2%), to renal failure, 18.2% (95% CI: 15.5% to 21.1%). CONCLUSIONS: The study revealed an incidence of new organ failure at 1342/100 000 person-years and a prevalence of 5.2% of all emergency department contacts. One-year all-cause mortality was 29.8% among organ failure patients.

Target-mediated disposition population pharmacokinetics model of erythropoietin in premature neonates following multiple intravenous and subcutaneous dosing regimens.

Routine erythropoietin (Epo) therapy for neonatal anemia is presently controversial due to its modest response. We speculate that an important contributor to this modest response is that previous clinical study designs were not driven by rigorous mechanistic and kinetic insights into the complex pharmacokinetics (PK) and pharmacodynamics (PD) of Epo in this population. To address this therapeutic opportunity, we conducted a prospective clinical study to investigate the PK of Epo in very-low-birth-weight (VLBW) premature neonates using a unique Epo dosing algorithm that accounts for complex neonatal erythropoietic physiology. Twenty-seven subjects received up to 10 intravenous or subcutaneous exogenous doses of Epo (600 or 1200 U/kg) during the first 4 weeks of life. Subjects were administered two doses of Epo 1200 U/kg on days 2 and 16, and eight doses of Epo 600 U/kg on days 4, 5, 6, 7, 9, 14, 15, and 28 following birth. We have developed for the first time a mechanistic, target-mediated disposition model that provides novel insights into the mechanisms driving Epo PK in VLBW neonates. Epo association rate, kon, was estimated to be 0.00610 pM-1h-1, and the dissociation rate koff was 0.112 h-1. Internalization of the Epo-target complex (kint) and the total receptor concentration (Rmax) were estimated to be 0.118 h-1 and 133 pM, respectively. Following s.c. administration, the absorption rate (ka) of Epo was 0.0738h-1 and bioavailability was 78.0%. Our mechanism-based population pharmacokinetic analysis provided quantitative insight into Epo kinetics in VLBW neonates; the information gained will assist in deriving dosing strategies for neonatal anemia and for neuroprotection efficacy studies.

A Nano-Dose Protocol For Cobb Angle Assessment in Children With Scoliosis: Results of a Phantom-based and Clinically Validated Study.

STUDY DESIGN: This was a prospective validation study with technical notes. OBJECTIVE: This study aimed to validate a new ultra-low-dose full-spine protocol for reproducible Cobb angle measurements-the "nano-dose" protocol. SUMMARY OF BACKGROUND DATA: Scoliosis is a 3-dimensional (3D) deformity of the spine characterized by 3D clinical parameters. Nevertheless, 2D Cobb angle remains an essential and widely used radiologic measure in clinical practice. Repeated imaging is required for the assessment and follow-up of scoliosis patients. The resultant high dose of absorbed radiation increases the potential risk of developing radiation-induced cancer in such patients. Micro-dose radiographic imaging is already available in clinical practice, but the radiation dose delivered to the patient could be further reduced. METHODS: An anthropomorphic child phantom was used to establish an ultra-low-dose protocol in the EOS Imaging System still allowing Cobb angle measurements, defined as nano-dose. A group of 23 consecutive children presenting for scoliosis assessment, 12 years of age or younger, were assessed with standard-dose or micro-dose and additional nano-dose full-spine imaging modalities. Intraobserver and interobserver reliability of determining the reliability of 2D Cobb angle measurements was performed. The dosimetry was performed in the anthropomorphic phantom to confirm theoretical radiation dose reduction. RESULTS: A nano-dose protocol was established for reliable Cobb angle measurements. Dose area product with this new nano-dose protocol was reduced to 5 mGy×cm, corresponding to one sixth of the micro-dose protocol (30 mGy×cm) and <1/40th of the standard-dose protocol (222 mGy×cm). Theoretical dose reduction, for posteroanterolateral positioning was confirmed using phantom dosimetry. Our study showed good reliability and repeatability between the 2 groups. Cobb variability was <5 degrees from the mean using 95% confidence intervals. CONCLUSIONS: We propose a new clinically validated nano-dose protocol for routine follow-up of scoliosis patients before surgery, keeping the radiation dose at a bare minimum, while allowing for reproducible Cobb angle measurements.

Toxicokinetics of Chiral PCB 136 and Its Hydroxylated Metabolites in Mice with a Liver-Specific Deletion of Cytochrome P450 Reductase.

Exposure to polychlorinated biphenyls (PCBs) has been implicated in adverse human health effects, including developmental neurotoxicity. Several neurotoxic PCBs are chiral and undergo atropisomeric enrichment in vivo due to atropselective metabolism by cytochrome P450 enzymes. Here we study how the liver-specific deletion of the cytochrome P450 reductase ( cpr) gene alters the toxicokinetics of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) in mice. Male and female mice with a liver-specific deletion of cpr (KO) and congenic wild-type (WT) mice were exposed to a single oral dose of racemic PCB 136 (6.63 mg/kg). Levels and chiral signatures of PCB 136 and its hydroxylated metabolites were determined 1-48 h after PCB exposure in whole blood. Blood levels of PCB 136 were typically higher in M-WT compared to F-WT mice. At the later time points, F-KO mice had significantly higher PCB 136 levels than F-WT mice. 2,2',3',4,6,6'-Hexachlorobiphenyl-3-ol (3-150), 2,2',3,3',6,6'-hexachlorobiphenyl-4-ol (4-136), 2,2',3,3',6,6'-hexachlorobiphenyl-5-ol (5-136), and 4,5-dihydroxy-2,2',3,3',6,6'-hexachlorobiphenyl (4,5-136) were detected in blood, with 5-136 and 4-136 being major metabolites. At later time points, the sum of HO-PCB (∑HO-PCB) levels exceeded PCB 136 levels in the blood; however, higher ∑HO-PCB than PCB 136 levels were observed later in KO than WT mice. PCB 136 and its major metabolites displayed atropisomeric enrichment in a manner that depended on the time point, sex, and genotype. Toxicokinetic analysis revealed sex and genotype-dependent differences in toxicokinetic parameters for PCB 136 atropisomers and its metabolites. The results suggest that mice with a liver-specific deletion of the cpr gene can potentially be used to assess how an altered metabolism of neurotoxic PCB congeners affects neurotoxic outcomes following exposure of the offspring to PCBs via the maternal diet.