Decision-analysis modeling of effectiveness and cost-effectiveness of pharmacologic thromboprophylaxis for surgical inpatients using variable risk assessment models or other strategies.

BACKGROUND: Surgical inpatients are at a risk of venous thromboembolism (VTE), which can be life-threatening or result in chronic complications. Thromboprophylaxis reduces the VTE risk but incurs costs and may increase bleeding risk. Risk assessment models (RAMs) are currently used to target thromboprophylaxis at high-risk patients. OBJECTIVES: To determine the balance of cost, risk, and benefit for different thromboprophylaxis strategies in adult surgical inpatients, excluding patients who underwent major orthopedic surgery or were under critical care and pregnant women. METHODS: Decision analytic modeling was performed to estimate the following outcomes for alternative thromboprophylaxis strategies: thromboprophylaxis usage; VTE incidence and treatment; major bleeding; chronic thromboembolic complications; and overall survival. Strategies compared were as follows: no thromboprophylaxis; thromboprophylaxis for all; and thromboprophylaxis given according to RAMs (Caprini and Pannucci). Thromboprophylaxis is assumed to be given for the duration of hospitalization. The model evaluates lifetime costs and quality-adjusted life-years (QALYs) within England's health and social care services. RESULTS: Thromboprophylaxis for all surgical inpatients had a 70% probability of being the most cost-effective strategy (at a £20 000 per QALY threshold). RAM-based prophylaxis would be the most cost-effective strategy if a RAM with a higher sensitivity (99.9%) were available for surgical inpatients. QALY gains were mainly due to reduced postthrombotic complications. The optimal strategy was sensitive to several other factors such as the risk of VTE, bleeding and postthrombotic syndrome, duration of prophylaxis, and patient age. CONCLUSION: Thromboprophylaxis for all eligible surgical inpatients seemed to be the most cost-effective strategy. Default recommendations for pharmacologic thromboprophylaxis, with the potential to opt-out, may be superior to a complex risk-based opt-in approach.

Risk assessment models for venous thromboembolism in hospitalised adult patients: a systematic review.

INTRODUCTION: Hospital-acquired thrombosis accounts for a large proportion of all venous thromboembolism (VTE), with significant morbidity and mortality. This subset of VTE can be reduced through accurate risk assessment and tailored pharmacological thromboprophylaxis. This systematic review aimed to determine the comparative accuracy of risk assessment models (RAMs) for predicting VTE in patients admitted to hospital. METHODS: A systematic search was performed across five electronic databases (including MEDLINE, EMBASE and the Cochrane Library) from inception to February 2021. All primary validation studies were eligible if they examined the accuracy of a multivariable RAM (or scoring system) for predicting the risk of developing VTE in hospitalised inpatients. Two or more reviewers independently undertook study selection, data extraction and risk of bias assessments using the PROBAST (Prediction model Risk Of Bias ASsessment Tool) tool. We used narrative synthesis to summarise the findings. RESULTS: Among 6355 records, we included 51 studies, comprising 24 unique validated RAMs. The majority of studies included hospital inpatients who required medical care (21 studies), were undergoing surgery (15 studies) or receiving care for trauma (4 studies). The most widely evaluated RAMs were the Caprini RAM (22 studies), Padua prediction score (16 studies), IMPROVE models (8 studies), the Geneva risk score (4 studies) and the Kucher score (4 studies). C-statistics varied markedly between studies and between models, with no one RAM performing obviously better than other models. Across all models, C-statistics were often weak (<0.7), sometimes good (0.7-0.8) and a few were excellent (>0.8). Similarly, estimates for sensitivity and specificity were highly variable. Sensitivity estimates ranged from 12.0% to 100% and specificity estimates ranged from 7.2% to 100%. CONCLUSION: Available data suggest that RAMs have generally weak predictive accuracy for VTE. There is insufficient evidence and too much heterogeneity to recommend the use of any particular RAM. PROSPERO REGISTRATION NUMBER: Steve Goodacre, Abdullah Pandor, Katie Sworn, Daniel Horner, Mark Clowes. A systematic review of venous thromboembolism RAMs for hospital inpatients. PROSPERO 2020 CRD42020165778. Available from https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=165778https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=165778.

Maturational Patterns of Systolic Ventricular Deformation Mechanics by Two-Dimensional Speckle-Tracking Echocardiography in Preterm Infants over the First Year of Age.

BACKGROUND: The aim of this study was to determine the maturational changes in systolic ventricular strain mechanics by two-dimensional speckle-tracking echocardiography in extremely preterm neonates from birth to 1 year of age and discern the impact of common cardiopulmonary abnormalities on the deformation measures. METHODS: In a prospective multicenter study of 239 extremely preterm infants (<29 weeks gestation at birth), left ventricular (LV) global longitudinal strain (GLS) and global longitudinal systolic strain rate (GLSRs), interventricular septal wall (IVS) GLS and GLSRs, right ventricular (RV) free wall longitudinal strain and strain rate, and segmental longitudinal strain in the RV free wall, LV free wall, and IVS were serially measured on days 1, 2, and 5 to 7, at 32 and 36 weeks postmenstrual age, and at 1 year corrected age (CA). Premature infants who developed bronchopulmonary dysplasia or had echocardiographic findings of pulmonary hypertension were analyzed separately. RESULTS: In uncomplicated preterm infants (n = 103 [48%]), LV GLS and GLSRs remained unchanged from days 5 to 7 to 1 year CA (P = .60 and P = .59). RV free wall longitudinal strain, RV free wall longitudinal strain rate, and IVS GLS and GLSRs significantly increased over the same time period (P < .01 for all measures). A significant base-to-apex (highest to lowest) segmental longitudinal strain gradient (P < .01) was seen in the RV free wall and a reverse apex-to-base gradient (P < .01) in the LV free wall. In infants with bronchopulmonary dysplasia and/or pulmonary hypertension (n = 119 [51%]), RV free wall longitudinal strain and IVS GLS were significantly lower (P < .01), LV GLS and GLSRs were similar (P = .56), and IVS segmental longitudinal strain persisted as an RV-dominant base-to-apex gradient from 32 weeks postmenstrual age to 1 year CA. CONCLUSIONS: This study tracks the maturational patterns of global and regional deformation by two-dimensional speckle-tracking echocardiography in extremely preterm infants from birth to 1 year CA. The maturational patterns are ventricular specific. Bronchopulmonary dysplasia and pulmonary hypertension leave a negative impact on RV and IVS strain, while LV strain remains stable.

Development of a selected reaction monitoring mass spectrometry-based assay to detect asparaginyl endopeptidase activity in biological fluids.

Cancer Biomarkers have the capability to improve patient outcomes. They have potential applications in diagnosis, prognosis, monitoring of disease progression and measuring response to treatment. This type of information is particularly useful in the individualisation of treatment regimens. Biomarkers may take many forms but considerable effort has been made to identify and quantify proteins in biological fluids. However, a major challenge in measuring protein in biological fluids, such as plasma, is the sensitivity of the assay and the complex matrix of proteins present. Furthermore, determining the effect of proteases in disease requires measurement of their activity in biological fluids as quantification of the protein itself may not provide sufficient information. To date little progress has been made towards monitoring activity of proteases in plasma. The protease asparaginyl endopeptidase has been implicated in diseases such as breast cancer, leukaemia and dementia. Here we describe a new approach to sensitively and in a targeted fashion quantify asparaginyl endopeptidase activity in plasma using a synthetic substrate peptide protected from nonspecific hydrolysis using D-amino acids within the structure. Our selected reaction monitoring approach enabled asparaginyl endopeptidase activity to be measured in human plasma with both a high dynamic range and sensitivity. This manuscript describes a paradigm for future development of assays to measure protease activities in biological fluids as biomarkers of disease.

Pulmonary Artery Acceleration Time Provides a Reliable Estimate of Invasive Pulmonary Hemodynamics in Children.

BACKGROUND: Pulmonary artery acceleration time (PAAT) is a noninvasive method to assess pulmonary hemodynamics, but it lacks validity in children. The aim of this study was to evaluate the accuracy of Doppler echocardiography-derived PAAT in predicting right heart catheterization (RHC)-derived pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR), and compliance in children. METHODS: Prospectively acquired and retrospectively measured Doppler echocardiography-derived PAAT and RHC-derived systolic PAP, mean PAP (mPAP), indexed PVR (PVRi), and compliance were compared using regression analysis in a derivation cohort of 75 children (median age, 5.3 years; interquartile range, 1.3-12.6 years) with wide ranges of pulmonary hemodynamics. To account for heart rate variability, PAAT was adjusted for right ventricular ejection time and corrected by the RR interval. Regression equations incorporating PAAT and PAAT/right ventricular ejection time from the derivation cohort were then evaluated for the accuracy of their predictive values for invasive pulmonary hemodynamics in a validation cohort of 50 age- and weight-matched children with elevated PAP and PVR. RESULTS: There were significant inverse correlations between PAAT and RHC-derived mPAP (r = -0.82) and PVRi (r = -0.78) and a direct correlation (r = 0.78) between PAAT and pulmonary compliance in the derivation cohort. For detection of pulmonary hypertension (PRVi > 3 Wood units · m2 and mPAP > 25 mm Hg), PAAT < 90 msec and PAAT/right ventricular ejection time < 0.31 resulted in sensitivity of 97% and specificity of 95%. In the derivation cohort, the regression equations relating PAAT with mPAP and PVRi were mPAP = 48 - 0.28 × PAAT and PVRi = 9 - 0.07 × PAAT. These PAAT-integrated equations predicted RHC-measured pulmonary hemodynamics in the validation cohort with good correlations (r = 0.88 and r = 0.83, respectively), small biases (<10%), and minimal coefficients of variation (<8%). CONCLUSIONS: PAAT inversely correlates with RHC-measured pulmonary hemodynamics and directly correlates with pulmonary arterial compliance in children. The study established PAAT-based regression equations in children to accurately predict RHC-derived PAP and PVR.

The Safety and Efficacy of a Sustainable Marine Extract for the Treatment of Thinning Hair: A Summary of New Clinical Research and Results from a Panel Discussion on the Problem of Thinning Hair and Current Treatments.

Alopecia and thinning hair are highly prevalent conditions affecting a large proportion of men and women. Diffused hair loss is often more difficult to diagnose in women, mostly due to over-reliance on the assumption of hormonal influences, and it is commonly treated with a multi-therapy approach. Clinical studies have demonstrated the effectiveness of a nutraceutical supplement to provide essential nutrients that aid in stimulating existing hair growth and reducing hair shedding. The supplement Viviscal® contains a proprietary blend of proteins, lipids, and glycosaminoglycans derived from sustainable marine sources. We present here a summary of studies that have examined the safety and efficacy of this nutraceutical; as well as discussions on hair loss and current therapies from a recently convened expert panel in dermatology and plastic surgery.

Right ventricular function in preterm and term neonates: reference values for right ventricle areas and fractional area of change.

BACKGROUND: Right ventricular (RV) fractional area of change (FAC) is a quantitative two-dimensional echocardiographic measurement of RV function. RV FAC expresses the percentage change in the RV chamber area between end-diastole (RV end-diastolic area [RVEDA]) to end-systole (RV end-systolic area [RVESA]). The objectives of this study were to determine the maturational (age- and weight-related) changes in RV FAC and RV areas and to establish reference values in healthy preterm and term neonates. METHODS: A prospective longitudinal study was conducted in 115 preterm infants (23-28 weeks' gestational age at birth, 500-1,500 g). RV FAC was measured at 24 hours of age, 72 hours of age, and 32 and 36 weeks' postmenstrual age (PMA). The maturational patterns of RVEDA, RVESA, and RV FAC were compared with those in 60 healthy full-term infants in a cross-sectional study (≥37 weeks, 3.5 ± 1 kg), who underwent echocardiography at birth (n = 25) and 1 month of age (n = 35). RVEDA and RVESA were traced in the RV-focused apical four-chamber view, and FAC was calculated using the formula 100 × [(RVEDA - RVESA)/RVEDA)]. Premature infants who developed chronic lung disease or had clinically and hemodynamically significant patent ductus arteriosus were excluded (n = 55) from the reference values. Intra- and interobserver reproducibility analysis was performed. RESULTS: RV FAC ranged from 26% at birth to 35% by 36 weeks' PMA in preterm infants (n = 60) and increased almost 2 times faster in the first month of age compared with healthy term infants (n = 60). Similarly, RVEDA and RVESA increased throughout maturation in both term and preterm infants. RV FAC and RV areas were correlated with weight (r = 0.81, P < .001) but were independent of gestational age at birth (r = 0.3, P = .45). RVEDA and RVESA were correlated with PMA in weeks (r = 0.81, P < .001). RV FAC trended lower in preterm infants with bronchopulmonary dysplasia (P = .04) but was not correlated with size of patent ductus arteriosus (P = .56). There was no difference in RV FAC based on gender or need for mechanical ventilation. CONCLUSIONS: This study establishes reference values of RV areas (RVEDA and RVESA) and RV FAC in healthy term and preterm infants and tracks their maturational changes during postnatal development. These measures increase from birth to 36 weeks' PMA, and this is reflective of the postnatal cardiac growth as a contributor to the maturation of cardiac function These measures are also linearly associated with increasing weight throughout maturation. This study suggests that two-dimensional RV FAC can be used as a complementary modality to assess global RV systolic function in neonates and facilitates its incorporation into clinical pediatric and neonatal guidelines.

Ambulatory Outpatient Management of patients with low risk febrile neutropaenia.

Patients with febrile neutropenia are a heterogeneous group with only a minority developing significant medical complications. Scoring systems, such as the Multinational Association for Supportive Care in Cancer (MASCC) score, have been developed and validated to identify low risk patients. Caring for patients with low risk febrile neutropenia in an ambulatory setting is proven to be safe and effective. Benefits include admission avoidance, cost savings and reduced risk of nosocomial infections, as well as improved patient experience and satisfaction. Implementation of an ambulatory pathway for low risk febrile neutropenia provides an excellent opportunity for Acute Physicians and Oncologists to collaborate in delivering care for this group of patients.

Doppler echocardiography inaccurately estimates right ventricular pressure in children with elevated right heart pressure.

BACKGROUND: Doppler echocardiography (DE) is widely used as a surrogate for right heart catheterization (RHC), the gold standard, to assess and monitor elevated right heart pressure in children. However, its accuracy has not been prospectively validated in children. The objectives of this study were to evaluate the accuracy of DE in predicting simultaneously measured right ventricular (RV) pressure by RHC in pediatric patients and to determine if the degree of RV hypertension affects the accuracy of DE in assessing right heart pressure. METHODS: Eighty children (age range, 0-17.9 years; median age, 5.5 years) with two-ventricle physiology and a wide range of right heart pressures underwent simultaneous DE and RHC. The pressure gradient between the right ventricle and the right atrium was directly measured by RHC and simultaneously estimated by DE using tricuspid regurgitation. Patients were then grouped on the basis of RHC-measured RV systolic pressure (RVSP): group 1 (n = 43), with RVSP < 1/2 systemic systolic blood pressure (SBP); group 2 (n = 37), with RVSP ≥ 1/2 SBP; group 3 (n = 56), with RVSP < 2/3 SBP; and group 4 (n = 24), with RVSP ≥ 2/3 SBP. Correlation and Bland-Altman analyses were performed on all groups. Accuracy was predefined as 95% limits of agreement within ±10 mm Hg. RESULTS: Despite a reasonable correlation between DE and RHC in all groups, there was poor agreement between techniques as RVSP/SBP increased. DE was inaccurate in one of 43 patients in group 1 (2%) versus nine of 37 in group 2 (24%) and was inaccurate in one of 56 patients in group 3 (2%) versus eight of 24 in group 4 (33%). Overestimation and underestimation occurred equally in all groups. CONCLUSION: DE inaccurately estimates RV pressure in children with elevated right heart pressure. It should not be relied on as the sole method of assessing right heart hemodynamics in children with RV hypertension.

The burden of cancer on the acute medical unit.

The burden of cancer is increasing, with a significant increase in cancer-related emergencies and patients with known malignancy presenting to the acute medical unit (AMU). We performed a retrospective analysis at a university hospital in the north west of England in May 2011. We examined 300 consecutive admissions to determine the number of, and reason for, cancer patients presenting to the AMU. Patients with cancer had a statistically significantly longer average length of inpatient stay than patients without cancer (8.8 days vs 7.2 days, p<0.01). As the incidence and prevalence of cancer increases, the challenge of improving the experience, safety and outcomes of patients with cancer becomes more important. Development of successful acute oncology services with close working with acute physicians will be essential in order to achieve this.

The utility of porous graphitic carbon as a stationary phase in proteomics workflows: two-dimensional chromatography of complex peptide samples.

We present the first investigation into the utility of porous graphitic carbon (PGC) as a stationary phase in proteomic workflows involving complex samples. PGC offers chemical and physical robustness and is capable of withstanding extremes of pH and higher temperatures than traditional stationary phases, without the likelihood of catastrophic failure. In addition, unlike separations driven by ion exchange mechanisms, there is no requirement for high levels of non-volatile salts such as potassium chloride in the elution buffers, which must be removed prior to LC-MS analysis. Here we present data which demonstrate that PGC affords excellent peptide separation in a complex whole cell lysate digest sample, with good orthogonality to a typical low pH reversed-phase system. As strong cation exchange (SCX) is currently the most popular first dimension for 2D peptide separations, we chose to compare the performance of a PGC and SCX separation as the first dimension in a comprehensive 2D-LC-MS/MS workflow. A significant increase, in the region of 40%, in peptide identifications is reported with off-line PGC fractionation compared to SCX. Around 14,000 unique peptides were identified at an estimated false discovery rate of 1% (n=3 replicates) from starting material constituting only 100 µg of protein extract.

RAC2, AEP, and ICAM1 expression are associated with CNS disease in a mouse model of pre-B childhood acute lymphoblastic leukemia.

We developed a murine model of CNS disease to obtain a better understanding of the pathogenesis of CNS involvement in pre-B-cell acute lymphoblastic leukemia (ALL). Semiquantitative proteomic discovery-based approaches identified unique expression of asparaginyl endopeptidase (AEP), intercellular adhesion molecule 1 (ICAM1), and ras-related C3 botulinum toxin substrate 2 (RAC2), among others, in an invasive pre-B-cell line that produced CNS leukemia in NOD-SCID mice. Targeting RAC2 significantly inhibited in vitro invasion and delayed disease onset in mice. Induced expression of RAC2 in cell lines with low/absent expression of AEP and ICAM1 did not result in an invasive phenotype or murine CNS disease. Flow cytometric analysis identified an enriched population of blast cells expressing ICAM1/lymphocyte function associated antigen-1 (LFA-1)/CD70 in the CD10(+)/CD19(+) fraction of bone marrow aspirates obtained from relapsed compared with normal controls and those with primary disease. CD10(+)/CD19(+) fractions obtained from relapsed patients also express RAC2 and give rise to CNS disease in mice. Our data suggest that combinations of processes are involved in the pathogenesis of CNS disease in pre-B-cell ALL, support a model in which CNS disease occurs as a result of external invasion, and suggest that targeting the processes of adhesion and invasion unique to pre-B cells may prevent recurrences within the CNS.

The optimal antigen response of chimeric antigen receptors harboring the CD3zeta transmembrane domain is dependent upon incorporation of the receptor into the endogenous TCR/CD3 complex.

Chimeric Ag receptors (CARs) expressed in T cells permit the redirected lysis of tumor cells in an MHC-unrestricted manner. In the Jurkat T cell model system, expression of a carcinoembryonic Ag-specific CD3zeta CAR (MFEzeta) resulted in an increased sensitivity of the transduced Jurkat cell to generate cytokines when stimulated through the endogenous TCR complex. This effect was driven through two key characteristics of the MFEzeta CAR: 1) receptor dimerization and 2) the interaction of the CAR with the endogenous TCR complex. Mutations of the CAR transmembrane domain that abrogated these interactions resulted in a reduced functional capacity of the MFEzeta CAR to respond to carcinoembryonic Ag protein Ag. Taken together, these results indicate that CARs containing the CD3zeta transmembrane domain can form a complex with the endogenous TCR that may be beneficial for optimal T cell activation. This observation has potential implications for the future design of CARs for cancer therapy.

A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug L-asparaginase.

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.