The association of cumulative vasoactive drugs and neurodevelopmental outcomes in preterm Infants <29 weeks gestation.

OBJECTIVE: To assess the effect of cardiovascular medications on the neurodevelopment of preterm infants, as measured by calculated cumulative time of vasoactive-inotropic score (VISct). METHODS: A retrospective study was conducted on preterm infants who developed significant hypotension defined as a mean BP more than 2SDs below the mean for GA and received treatment with duration > 6 hours for each hypotensive episode, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). The composite Bayley III was reported from the high-risk follow-up clinic for the surviving infants between 18 to 21 months corrected age. RESULTS: VISct was significantly higher in infants with abnormal neurodevelopment. Cognitive Bayley was the most affected component with median (IQR) VISct 882.5(249,2047) versus 309(143,471) (p-value 0.012), followed by language function with VISct 786(261,1563.5), versus 343(106.75,473.75) (p-value 0.016) when those with Bayley III <85 were compared with those with normal Bayley IIIs. CONCLUSION: High VISct scores may have negative effect on cognitive and language neurodevelopmental outcomes.

Born into an isolating world: family-centred care for babies born to mothers with COVID-19.

Background: The benefits of facilitating breastmilk feeding and close contact between mother and neonate (family-centred care; FCC) in the perinatal period are well-established. The aim of this study was to determine how the delivery of FCC practices were impacted for neonates born to mothers with perinatal SARS-CoV-2 infection during the COVID-19 pandemic. Methods: Neonates born to mothers with confirmed SARS-CoV-2 infection during pregnancy were identified from the 'EsPnIC Covid paEdiatric NeonaTal REgistry' (EPICENTRE) multinational cohort between 10 March 2020 and 20 October 2021. The EPICENTRE cohort collected prospective data on FCC practices. Rooming-in and breastmilk feeding practice were the main outcomes, and factors influencing each were determined. Other outcomes included mother-baby physical contact prior to separation and the pattern of FCC components relative to time and local site guidelines. Findings: 692 mother-baby dyads (13 sites, 10 countries) were analysed. 27 (5%) neonates were positive for SARS-CoV-2 (14 (52%) asymptomatic). Most sites had policies that encouraged FCC during perinatal SARS-CoV-2 infection for most of the reporting period. 311 (46%) neonates roomed-in with their mother during the admission. Rooming-in increased over time from 23% in March-June 2020 to 74% in January-March 2021 (boreal season). 330 (93%) of the 369 separated neonates had no FCC physical contact with their mother prior, and 319 (86%) were asymptomatic. Maternal breastmilk was used for feeding in 354 (53%) neonates, increasing from 23% to 70% between March-June 2020 and January-March 2021. FCC was most impacted when mothers had symptomatic COVID-19 at birth. Interpretation: This is the largest report of global FCC practice during the COVID-19 pandemic to date. The COVID-19 pandemic may have impacted FCC despite low perinatal transmission rates. Fortunately, clinicians appear to have adapted to allow more FCC delivery as the COVID-19 pandemic progressed. Funding: The National Health and Medical Research Council (Australia): Grant ID 2008212 (DGT), Royal Children's Hospital Foundation: Grant ID 2019-1155 (EJP), Victorian Government Operational Infrastructure Support Program.

A vasoactive inotropic score predicts the severity of compromised systemic circulation and mortality in preterm infants.

OBJECTIVE: To validate the vasoactive inotropic score as a predictor of the severity of compromised systemic circulation and mortality in preterm infants. METHODS: A retrospective study was conducted on preterm infants with Compromised systemic circulation [hypotension±lactic acidosis±oliguria] who received a cardiovascular support, we calculated the vasoactive inotropic score (VIS) and cumulative exposure to cardiovascular medications over time (VISct). Receiver operator curve was constructed to predict the primary outcome which was death & refractory hypotension. RESULTS: VIS had an area under the curve of 0.73 (95% CI 0.85-0.98, p < 0.001). A VIS cut off of 25 has sensitivity and specificity of 66% and 92%, and positive and negative predictive values of 78.5% and 83%, respectively. CONCLUSION: High VIS predicts the severity of Compromised systemic circulation and mortality rate in preterm infants.

Delayed cord clamping: Time for physiologic implementation.

Delayed cord clamping has been shown to be beneficial in both preterm and term babies. Practice guidelines have not been consistent between centers and the practice of delayed cord clamping has not been standardized. The concept of physiologic-based cord clamping emerged into practice as well. Cord milking has different physiological effect and might be harmful in preterm babies.

The impact of targeted oxygen reduction test in preterm infants on reducing the oxygen exposure.

BACKGROUND: Caring for infants on respiratory support is a challenge in the middle-income countries, applying a protocol of targeted oxygen reduction test (tORT) guided by daily assessment of oxygen histograms is novel and practical approach. OBJECTIVE: To study the impact of tORT guided by daily assessment of oxygen histograms as a quality improvement project aiming to decrease days on oxygen support, and duration of hospital admission in preterm infants. STUDY DESIGN: A quality project conducted in neonatal intensive care units (NICU) of two hospitals, from 2017- 2018 (Epochs II). After a period of observation of a cohort of preterm Infants, 2016-2017 (Epoch I). The main aims were to reduce days on oxygen and hospital admission days. All infants in Epoch II underwent daily assessment of oxygen histograms and a trial of oxygen reduction if applicable as per a predefined protocol. Comparison was made between these two Epochs, and the primary outcome was the time to successful discontinuation of oxygen support. RESULTS: Fifty-nine infants were included; 30 underwent the protocolized tORT (Epoch II) with a median (IQR) of 4 (2-6) tORC per infant. Postanal age at presentation (time of initial tORT assessment was performed at the postnatal age of 8 (5, 13) days. Days on oxygen and total numbers of hospital days were significantly less in Epoch II. Oxygen histograms significantly improved after tORT. CONCLUSIONS: Applying tORT guided by oxygen histograms may have a significant impact on oxygen exposure and hospitalization days of patients admitted to the NICU.

Targeted Neonatal Echocardiography-Guided Therapy in Vein of Galen Aneurysmal Malformation: A Report of Two Cases with a Review of Physiology and Approach to Management.

Vein of Galen malformation results in predictable changes in physiology which exist on a continuum. Severe pulmonary hypertension may present as hypoxemia; however, excessive reduction in pulmonary vascular resistance may precipitate progressive pulmonary overcirculation and impaired systemic blood flow. Right ventricular performance and the patency and direction of the ductus arteriosus may play a crucial role in postductal organ perfusion. Physiological stabilization may be complex and variable over time. The utilization of targeted neonatal echocardiography to guide treatment decisions may improve the ability to provide therapy tailored to the specific disease pathophysiology and monitor serially as conditions change. An enhanced approach to physiological stabilization may reduce the risk of unexpected decompensation and allow for thoughtful, controlled endovascular embolization in appropriate candidates.

Pre-symptomatic targeted treatment of patent ductus arteriosus in preterm newborns: A systematic review and meta-analysis.

BACKGROUND: A clinically significant patent ductus arteriosus (PDA) is associated with significant morbidity and mortality in premature newborns. Symptomatic PDAs are often treated with prostaglandin synthesis inhibitors (PSI), but controversy remains if PSIs should also be used to manage early, asymptomatic PDAs. OBJECTIVE: To systematically identify, critically appraise, and evaluate the efficacy and safety of pharmacological management of pre-symptomatic PDA in preterm newborns after confirmed patency by echocardiography. STUDY DESIGN: Systematic review and meta-analysis. SEARCH METHODS: We searched MEDLINE (Ovid), EMBASE (Ovid), Cochrane Central Register of Controlled Trials (Wiley), from date of inception to February 2017. Supplemental searching was performed in Scopus and Web of Science to identify additional relevant citations. We also searched conference proceedings, reference lists of relevant articles and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: We included only randomized controlled trials (RCTs) that compared the use of indomethacin or ibuprofen to placebo for treatment of pre-symptomatic PDA in preterm newborns (<32 weeks gestational age and <1500gms). DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials, assessed risk of bias and extracted trial-level data. Outcomes are reported as risk ratios from random-effects models. Absolute risk reduction (ARR) is additionally reported for significant outcomes.We included seven trials (466 newborns). Targeted medical treatment did not significantly reduce mortality rates (RR 0.85, 95% CI 0.50 to 1.43; ARR -2.38%, 95% CI -8.04% to 3.29%; I2 0% 6 studies; 442 newborns), but it did significantly reduce the overall incidence of developing symptomatic PDA (RR 0.39, 95% CI 0.21 to 0.73; ARR -34.3%, 95% CI -50.8% to -17.8%; I2 0%; 3 studies; 97 newborns) compared to placebo. Other efficacy or safety outcomes were not significantly different. CONCLUSIONS: Targeted medical treatment of pre-symptomatic PDA decreases the incidence of developing symptomatic PDA, but not neonatal mortality. Further studies are essential to confirm these results.

International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

The impact of integrated evaluation of hemodynamics using targeted neonatal echocardiography with indices of tissue oxygenation: a new approach.

OBJECTIVE: To study the impact of integrated evaluation of hemodynamics (IEH) using targeted neonatal echocardiography, together with regional tissue oxygenation, fractional oxygen extraction using near-infrared spectroscopy on the management of infants with compromised hemodynamics. STUDY DESIGN: Retrospective cohort comparison of two groups of infants with compromised hemodynamics. EPOCH 1: did not undergo IEH (January 2012 to March 2014); EPOCH 2: underwent IEH (April 2014 to December 2015). The primary outcome was the time to recovery. RESULTS: In all, 340 infants were included; 158 underwent IEH with a median (IQR) of 2 (1 to 3) evaluations per infant. Reasons for assessment included PDA (60%), compromised systemic circulation (14%) and clinically suspected pulmonary hypertension (22%). The time to recovery was shorter in IEH group in patients with compromised systemic circulation median (IQR), 32 h (24 to 63) compared with none IEH group 71 h (36 to 96), pulmonary hypertension 63 h (14.2 to 102) in IEH group compared with 68 h (24 to 240) in none IEH group, there were fewer PDA-related complications in preterm infants with PDA in IEH group. CONCLUSION: IEH was associated with shorter time to clinical recovery in infants with compromised hemodynamics.

Fabrication and characterisation of biomimetic, electrospun gelatin fibre scaffolds for tunica media-equivalent, tissue engineered vascular grafts.

It is increasingly recognised that biomimetic, natural polymers mimicking the extracellular matrix (ECM) have low thrombogenicity and functional motifs that regulate cell-matrix interactions, with these factors being critical for tissue engineered vascular grafts especially grafts of small diameter. Gelatin constitutes a low cost substitute of soluble collagen but gelatin scaffolds so far have shown generally low strength and suture retention strength. In this study, we have devised the fabrication of novel, electrospun, multilayer, gelatin fibre scaffolds, with controlled fibre layer orientation, and optimised gelatin crosslinking to achieve not only compliance equivalent to that of coronary artery but also for the first time strength of the wet tubular acellular scaffold (swollen with absorbed water) same as that of the tunica media of coronary artery in both circumferential and axial directions. Most importantly, for the first time for natural scaffolds and in particular gelatin, high suture retention strength was achieved in the range of 1.8-1.94 N for wet acellular scaffolds, same or better than that for fresh saphenous vein. The study presents the investigations to relate the electrospinning process parameters to the microstructural parameters of the scaffold, which are further related to the mechanical performance data of wet, crosslinked, electrospun scaffolds in both circumferential and axial tubular directions. The scaffolds exhibited excellent performance in human smooth muscle cell (SMC) proliferation, with SMCs seeded on the top surface adhering, elongating and aligning along the local fibres, migrating through the scaffold thickness and populating a transverse distance of 186 µm and 240 µm 9 days post-seeding for scaffolds of initial dry porosity of 74 and 83%, respectively.

Phase II multicentre trial of oral quisinostat, a histone deacetylase inhibitor, in patients with previously treated stage IB-IVA mycosis fungoides/Sézary syndrome.

BACKGROUND: Quisinostat is a hydroxamate, second-generation, orally available pan-histone deacetylase inhibitor. OBJECTIVES: To evaluate the efficacy and safety of oral quisinostat in patients with previously treated cutaneous T-cell lymphoma (CTCL). METHODS: Patients received quisinostat 8 mg or 12 mg on days 1, 3 and 5 of each week in 21-day treatment cycles. Primary efficacy end point was cutaneous response rate (RR) based on the modified Severity Weighted Assessment Tool (mSWAT). Secondary end points included global RR, duration of response (DOR) in skin, progression-free survival (PFS), pruritus relief, safety and pharmacodynamic markers. RESULTS: Eight of 26 (25 evaluable) patients achieved ≥ 50% reduction in mSWAT score at least once, with confirmed cutaneous response in six (RR 24%). There was a low global RR of 8%. DOR in skin ranged from 2·8 to 6·9 months. Median PFS was 5·1 months. Pruritus relief was more frequent in cutaneous responders (67%) than nonresponders (32%). Serial tumour biopsies revealed an increase in acetylated tubulin, indicating a target effect of histone deacetylase 6. Twenty-one of 26 (81%) patients were withdrawn from the study before or at clinical cut-off; five (19%) continued to receive treatment with quisinostat. The most common drug-related adverse events were nausea, diarrhoea, asthenia, hypertension, thrombocytopenia and vomiting. Grade 3 drug-related adverse events included hypertension, lethargy, pruritus, chills, hyperkalaemia and pyrexia. CONCLUSIONS: Quisinostat 12 mg three times weekly is active in the treatment of patients with relapsed or refractory CTCL, with an acceptable safety profile. Combination therapy with other drugs active in CTCL may be appropriate.

Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies.

BACKGROUND: To determine the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies. DESIGN: In this Phase I, open-label, dose-finding study, patients refractory to standard therapy received trabectedin (3-h intravenous infusion, 0.4-1.3 mg/m(2), day 1) and capecitabine (2,000 or 1,600 mg/m(2)/day orally, days 2-15) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. Antitumor response was assessed every two cycles; adverse events (AEs) were recorded throughout. RESULTS: Forty patients received 149 cycles of treatment (median 2; range 1-11) at nine dose levels. Gastrointestinal dose-limiting toxicities in two patients at two dose levels with capecitabine at 2,000 mg/m(2)/day prompted dose reduction to 1,600 mg/m(2)/day and initiation of new trabectedin dose escalation at 0.6 mg/m(2). The MTD was capecitabine 1,600 mg/m(2)/day + trabectedin 1.1 mg/m(2). Common grade 3-4 drug-related AEs were neutropenia (20%), nausea (18%), diarrhea (15%) and palmar-plantar erythrodysesthesia (15%). One patient with cholangiocarcinoma achieved a sustained partial response, and 18 patients maintained stable disease (six for ≥6 months). CONCLUSIONS: The combination of trabectedin and capecitabine is generally well tolerated, without pharmacokinetic interactions, and shows some activity in patients with advanced cancers.

Bortezomib in a phase 1 trial for patients with relapsed AL amyloidosis: cardiac responses and overall effects.

BACKGROUND: Bortezomib is approved for the treatment of multiple myeloma and a role has been suggested in the treatment of systemic AL amyloidosis (AL). METHODS: In this phase 1 dose-escalation portion of the first prospective study of single-agent bortezomib in AL, 31 patients with relapsed disease, including 14 (45%) with cardiac involvement, received bortezomib in seven dose cohorts on once-weekly (0.7, 1.0, 1.3, 1.6 mg/m(2)) and twice-weekly (0.7, 1.0, 1.3 mg/m(2)) schedules. Electrocardiographic, Holter and echocardiographic studies were evaluated in all patients to determine safety and response. RESULTS: During therapy (median treatment period 210 days), no patient developed significant ventricular or supraventricular rhythm disturbance on 24-h Holter monitoring; however, no patient satisfied study criteria for cardiac response using echocardiographic assessment or New York Heart Association classification. Seven patients (23%) had a ≥ 10% fall in left ventricular ejection fraction, but only one met criteria for cardiac deterioration. The predominant cardiac adverse events were peripheral edema (23%), orthostatic hypotension (13%) and hypotension (10%). Two patients developed grade 3 congestive heart failure, which resolved following treatment interruption. In this Phase 1 portion, the maximum tolerated dose of bortezomib on either schedule was not reached. Hematologic responses occurred in 14 patients (45%), including seven (23%) complete responses. In non-responders mean left ventricular wall thickness increased during the course of treatment. CONCLUSION: AL is frequently rapidly progressive; in these patients who had relapsed or progressed following previous conventional therapies, these results suggest that bortezomib may slow the progression of cardiac amyloid with limited toxicity.

Selected novel anticancer treatments targeting cell signaling proteins.

Empirical approaches to discovery of anticancer drugs and cancer treatment have made limited progress in the cure of cancer in the last several decades. Recent advances in technology and expanded knowledge of the molecular basis of tumorigenesis and metastasis have provided unique opportunities to design novel compounds that rationally target the abnormal molecular and biochemical signals leading to cancer. Several such novel agents have completed advanced stages in clinical development. The excellent clinical results achieved by some of these compounds are creating new paradigms in management of patients with neoplastic diseases. Clinical development of these agents also raises challenges to the traditional methods of drug evaluation and measurement of efficacy.

Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model.

Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.

Enhanced expression of tissue factor activity in the atherosclerotic aortas of cholesterol-fed rabbits.

Tissue factor (TF) is an initiation cofactor of the extrinsic pathway of coagulation. Although the overexpression of TF antigen and mRNA have been previously demonstrated in atherosclerotic lesions using both immunohistochemical and in situ hybridization techniques, it still remains unclear as to whether TF activity is overexpressed in atherosclerotic plaque in vivo. In thoracic aortas obtained from cholesterol-fed rabbits for 10-20 weeks, the TF-mediated activation of factor X was quantitatively assessed on the intimal surface of the aortas ex vivo using a chromogenic substrate S-2222 and the findings were then compared with the immunohistochemical distribution of TF antigen. Non-atherosclerotic intimas showed only a weak amount of TF activity, while the adventitia contained a significantly high amount of activity. In the atherosclerotic intimas where TF antigen was overexpressed by foamy and non-foamy macrophages and smooth muscle cells but not by endothelial cells, TF activity was apparently enhanced to a level similar to that in the adventitia. Scanning electron microscopy revealed a perturbation of the intimal surface of the atherosclerotic aorta. These findings suggest that TF activity is apparently enhanced in subendothelial atherosclerotic lesions and, therefore, endothelial denudation, which results in the exposure of active TF to flowing blood, leads to thrombosis and its sequelae in atherosclerotic lesions.

Procoagulant properties of atherosclerotic aortas.

TF protein was overexpressed by macrophages and smooth muscle cells and deposited in the extracellular matrix of atheroclerotic intimas. TF activity was also enhanced in the atherosclerotic intima, probably resulting in either thrombus formation or intimal fibrin deposition after the exposure of flowing blood and imbibed fibrinogen to TF in atherosclerotic lesions. These findings further support the hypothesis that the coagulation and fibrinolysis systems can play an essential role in the initiation and progression of atherosclerosis, and the clinical implications of this phenomenon may thus contribute to future investigations in the prevention and treatment of atherosclerotic diseases.

Expression of tissue factor and interleukin-1 beta in a novel rabbit model of disseminated intravascular coagulation induced by carrageenan and lipopolysaccharide.

Thrombus formation and the sequential expression of tissue factor (TF), interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1 ra) in several organs were examined immunohistochemically and morphometrically in a novel model of disseminated intravascular coagulation (DIC) developed by modifying the generalized Shwartzman reaction (GSR) in rabbits. The new model [carrageenan (CA)-lipopolysaccharide (LPS)] was induced by the administration of a priming dose of intraperitoneal CA, 10 mg/kg, followed 24 h later by a provocative dose of LPS 25 micrograms/kg, while GSR was induced by the intravenous injection of two doses of LPS 25 micrograms/kg. CA was detected predominantly within macrophages in the spleen and liver. Fibrin thrombi were formed as early as 1 h after the second LPS treatment in all examined organs reaching a peak at 3-9 h and their prevalence was higher in the CA-LPS group (p < 0.05). The sequential expressions of TF and IL-1 beta correlated well with each other in both groups reaching a peak at 3-9 h with the CA-LPS group showing a more pronounced expression than the GSR group. Macrophages in the liver, spleen and lungs, and Bowman's epithelial cells expressed both proteins, while IL-1 beta was also expressed by endothelial and epithelial cells. IL-1 ra was expressed by the same cells expressing IL-1 beta, however, its expression continued to increase gradually over 24 h. The mortality rate was lower (p < 0.05) and neutrophilic sequestration less prominent in the CA-LPS group than in the GSR group. These findings indicate that CA efficiently replaced the priming LPS treatment and the consequently enhanced production of IL-1 beta may have resulted in the upregulation of TF expression leading to the high level of thrombi in this new model which may provide a tool for further studies on the role of cytokines in DIC.

Spectrophotometric determination of theophylline formulations.

Minophylline (theophylline ethanoate of piperazine) and aminophylline (theophylline ethylenediamine) were determined spectrophotometrically in dosage forms without interference from excipients and/or preservatives. A mixture of minophylline, in about 30-fold concentration, with phenobarbital was assayed for both components with good accuracy and high reproducibility.