Fibrinogen concentrate vs. fresh frozen plasma for the management of coagulopathy during thoraco-abdominal aortic aneurysm surgery: a pilot randomised controlled trial.

Major vascular surgery is frequently associated with significant blood loss and coagulopathy. Existing evidence suggests hypofibrinogenaemia develops earlier than other haemostatic deficiencies during major blood loss. The purpose of this study was to assess whether the use of an infusion of fibrinogen concentrate to prevent and treat hypofibrinogenaemia during surgery resulted in satisfactory haemostasis, removing or reducing the need for blood component transfusion. Twenty patients undergoing elective extent-4 thoraco-abdominal aortic aneurysm repair were randomly allocated to receive either fresh frozen plasma or fibrinogen concentrate to treat hypofibrinogenaemia during surgery. Coagulation was assessed during and after surgery by point-of-care and laboratory testing, respectively, and treatment was guided by pre-defined transfusion triggers. Despite blood losses of up to 11,800 ml in the patients who received the fibrinogen concentrate, none required fresh frozen plasma during surgery, and only two required platelet transfusions. The median (IQR [range]) allogeneic blood component administration during surgery and in the first 24 h postoperatively was 22.5 (14-28 [2-41]) units in patients allocated to fresh frozen plasma vs. 4.5 (3-11[0-17]) in patients allocated to fibrinogen concentrate (p = 0.011). All patients in both groups were assessed by the surgeon to have satisfactory haemostasis at the end of surgery. Mean (SD) postoperative fibrinogen concentrations were similar in patients allocated to fresh frozen plasma and fibrinogen concentrate (1.6 (0.3) g.l-1 vs. 1.6 (0.2) g.l-1 ; p = 0.36) but the mean (SD) international normalised ratio and activated partial thromboplastin time ratio were lower in patients allocated to fresh frozen plasma (1.1 (0.1) vs. 1.8 (0.3); p < 0.0001 and 1.1 (0.2) vs. 1.7 (0.5); p = 0.032, respectively). Fibrinogen concentrate may be used as an alternative to fresh frozen plasma in the treatment of coagulopathy during thoraco-abdominal aortic aneurysm repair.

X-ray ptychography using randomized zone plates.

We have developed a randomized grating condenser zone plate (GCZP) that provides a µm-scale probe for use in x-ray ptychography. This delivers a significantly better x-ray throughput than probes defined by pinhole apertures, while providing a clearly-defined level of phase diversity to the illumination on the sample, and helping to reduce the dynamic range of the detected signal by spreading the zero-order light over an extended area of the detector. The first use of this novel x-ray optical element has been demonstrated successfully for both amplitude and phase contrast imaging using soft x-rays on the TwinMic beamline at the Elettra synchrotron.

Dermal uptake of nicotine from air and clothing: Experimental verification.

This study aims to elucidate in greater detail the dermal uptake of nicotine from air or from nicotine-exposed clothes, which was demonstrated recently in a preliminary study. Six non-smoking participants were exposed to gaseous nicotine (between 236 and 304 µg/m3 ) over 5 hours while breathing clean air through a hood. Four of the participants wore only shorts and 2 wore a set of clean clothes. One week later, 2 of the bare-skinned participants were again exposed in the chamber, but they showered immediately after exposure instead of the following morning. The 2 participants who wore clean clothes on week 1 were now exposed wearing a set of clothes that had been exposed to nicotine. All urine was collected for 84 hours after exposure and analyzed for nicotine and its metabolites, cotinine and 3OH-cotinine. All participants except those wearing fresh clothes excreted substantial amounts of biomarkers, comparable to levels expected from inhalation intake. Uptake for 1 participant wearing exposed clothes exceeded estimated intake via inhalation by >50%. Biomarker excretion continued during the entire urine collection period, indicating that nicotine accumulates in the skin and is released over several days. Absorbed nicotine was significantly lower after showering in 1 subject but not the other. Differences in the normalized uptakes and in the excretion patterns were observed among the participants. The observed cotinine half-lives suggest that non-smokers exposed to airborne nicotine may receive a substantial fraction through the dermal pathway. Washing skin and clothes exposed to nicotine may meaningfully decrease exposure.

Partitioning of PCBs from air to clothing materials in a Danish apartment.

Polychlorinated biphenyl (PCB) contamination of buildings continues to pose an exposure threat, even decades after their application in the form of calks and other building materials. In this research, we investigate the ability of clothing to sorb PCBs from contaminated air and thereby influence exposure. The equilibrium concentration of PCB-28 and PCB-52 was quantified for nine used clothing fabrics exposed for 56 days to air in a Danish apartment contaminated with PCBs. Fabric materials included pure materials such as cotton and polyester, or blends of polyester, cotton, viscose/rayon, and/or elastane. Air concentrations were fairly stable over the experimental period, with PCB-28 ranging from 350 to 430 ng/m3 and PCB-52 ranging from 460 to 550 ng/m3 . Mass accumulated in fabric ranged from below detection limits to 4.5 mg/g of fabric. Cotton or materials containing elastane sorbed more than polyester materials on a mass basis. Mass-normalized partition coefficients above detection limits ranged from 105.7 to 107.0  L/kg. Clothing acts as a reservoir for PCBs that extends dermal exposure, even when outside or in uncontaminated buildings.

Advanced buffer materials for indoor air CO2 control in commercial buildings.

In this study, we evaluated solid sorbents for their ability to passively control indoor CO2 concentration in buildings or rooms with cyclic occupancy (eg, offices, bedrooms). Silica supported amines were identified as suitable candidates and systematically evaluated in the removal of CO2 from indoor air by equilibrium and dynamic techniques. In particular, sorbents with various amine loadings were synthesized using tetraethylenepentamine (TEPA), poly(ethyleneimine) (PEI) and a silane coupling agent 3-aminopropyltriethoxysilane (APS). TGA analysis indicates that TEPA impregnated silica not only displays a relatively high adsorption capacity when exposed to ppm level CO2 concentrations, but also is capable of desorbing the majority of CO2 by air flow (eg, by concentration gradient). In 10 L flow-through chamber experiments, TEPA-based sorbents reduced outlet CO2 by up to 5% at 50% RH and up to 93% of CO2 adsorbed over 8 hours was desorbed within 16 hours. In 8 m3 flow-through chamber experiments, 18 g of the sorbent powder spread over a 2 m2 area removed approximately 8% of CO2 injected. By extrapolating these results to real buildings, we estimate that meaningful reductions in the CO2 can be achieved, which may help reduce energy requirements for ventilation and/or improve air quality.

Impact of surface ozone interactions on indoor air chemistry: A modeling study.

An INdoor air Detailed Chemical Model was developed to investigate the impact of ozone reactions with indoor surfaces (including occupants), on indoor air chemistry in simulated apartments subject to ambient air pollution. The results are consistent with experimental studies showing that approximately 80% of ozone indoors is lost through deposition to surfaces. The human body removes ozone most effectively from indoor air per square meter of surface, but the most significant surfaces for C6 -C10 aldehyde formation are soft furniture and painted walls owing to their large internal surfaces. Mixing ratios of between 8 and 11 ppb of C6 -C10 aldehydes are predicted to form in apartments in various locations in summer, the highest values are when ozone concentrations are enhanced outdoors. The most important aldehyde formed indoors is predicted to be nonanal (5-7 ppb), driven by oxidation-derived emissions from painted walls. In addition, ozone-derived emissions from human skin were estimated for a small bedroom at nighttime with concentrations of nonanal, decanal, and 4-oxopentanal predicted to be 0.5, 0.7, and 0.7 ppb, respectively. A detailed chemical analysis shows that ozone-derived surface aldehyde emissions from materials and people change chemical processing indoors, through enhanced formation of nitrated organic compounds and decreased levels of oxidants.

Measurements of dermal uptake of nicotine directly from air and clothing.

In this preliminary study, we have investigated whether dermal uptake of nicotine directly from air or indirectly from clothing can be a meaningful exposure pathway. Two participants wearing only shorts and a third participant wearing clean cotton clothes were exposed to environmental tobacco smoke (ETS), generated by mechanically "smoking" cigarettes, for three hours in a chamber while breathing clean air from head-enveloping hoods. The average nicotine concentration (420 µg/m3 ) was comparable to the highest levels reported for smoking sections of pubs. Urine samples were collected immediately before exposure and 60 hour post-exposure for bare-skinned participants. For the clothed participant, post-exposure urine samples were collected for 24 hour. This participant then entered the chamber for another three-hour exposure wearing a hood and clothes, including a shirt that had been exposed for five days to elevated nicotine levels. The urine samples were analyzed for nicotine and two metabolites-cotinine and 3OH-cotinine. Peak urinary cotinine and 3OH-cotinine concentrations for the bare-skinned participants were comparable to levels measured among non-smokers in hospitality environments before smoking bans. The amount of dermally absorbed nicotine for each bare-skinned participant was conservatively estimated at 570 µg, but may have been larger. For the participant wearing clean clothes, uptake was ~20 µg, and while wearing a shirt previously exposed to nicotine, uptake was ~80 µg. This study demonstrates meaningful dermal uptake of nicotine directly from air or from nicotine-exposed clothes. The findings are especially relevant for children in homes with smoking or vaping.

Diagnostic accuracy of DXA compared to conventional spine radiographs for the detection of vertebral fractures in children.

OBJECTIVES: In children, radiography is performed to diagnose vertebral fractures and dual energy x-ray absorptiometry (DXA) to assess bone density. In adults, DXA assesses both. We aimed to establish whether DXA can replace spine radiographs in assessment of paediatric vertebral fractures. METHODS: Prospectively, lateral spine radiographs and lateral spine DXA of 250 children performed on the same day were independently scored by three radiologists using the simplified algorithm-based qualitative technique and blinded to results of the other modality. Consensus radiograph read and second read of 100 random images were performed. Diagnostic accuracy, inter/intraobserver and intermodality agreements, patient/carer experience and radiation dose were assessed. RESULTS: Average sensitivity and specificity (95 % confidence interval) in diagnosing one or more vertebral fractures requiring treatment was 70 % (58-82 %) and 97 % (94-100 %) respectively for DXA and 74 % (55-93 %) and 96 % (95-98 %) for radiographs. Fleiss' kappa for interobserver and average kappa for intraobserver reliability were 0.371 and 0.631 respectively for DXA and 0.418 and 0.621 for radiographs. Average effective dose was 41.9 µSv for DXA and 232.7 µSv for radiographs. Image quality was similar. CONCLUSION: Given comparable image quality and non-inferior diagnostic accuracy, lateral spine DXA should replace conventional radiographs for assessment of vertebral fractures in children. KEY POINTS: • Vertebral fracture diagnostic accuracy of lateral spine DXA is non-inferior to radiographs. • The rate of unreadable vertebrae for DXA is lower than for radiographs. • Effective dose of DXA is significantly lower than radiographs. • Children prefer DXA to radiographs. • Given the above, DXA should replace radiographs for paediatric vertebral fracture assessment.

Dermal uptake of phthalates from clothing: Comparison of model to human participant results.

In this research, we extend a model of transdermal uptake of phthalates to include a layer of clothing. When compared with experimental results, this model better estimates dermal uptake of diethylphthalate and di-n-butylphthalate (DnBP) than a previous model. The model predictions are consistent with the observation that previously exposed clothing can increase dermal uptake over that observed in bare-skin participants for the same exposure air concentrations. The model predicts that dermal uptake from clothing of DnBP is a substantial fraction of total uptake from all sources of exposure. For compounds that have high dermal permeability coefficients, dermal uptake is increased for (i) thinner clothing, (ii) a narrower gap between clothing and skin, and (iii) longer time intervals between laundering and wearing. Enhanced dermal uptake is most pronounced for compounds with clothing-air partition coefficients between 104 and 107 . In the absence of direct measurements of cotton cloth-air partition coefficients, dermal exposure may be predicted using equilibrium data for compounds in equilibrium with cellulose and water, in combination with computational methods of predicting partition coefficients.

Cell-type specific examination of central amygdala dopamine receptor 2 expressing neurons as a translational target for pharmacological enhancement of extinction / 中国药理学与毒理学杂志

Behavioral and molecular characterization of cell- type specific populations governing fear learning and behavior is a promising avenue for the rational identification of potential therapeutics for fear-related disorders. Identification of cell-type specific changes in neuronal translation following fear learning allows for targeted pharmacological intervention during fear extinction learning, mirroring possible treatment strategies in humans. Here we identify the central amygdala (CeA) Drd2-expressing population as a fear-supporting population that is molecularly distinct from other, previously identified fear-supporting CeA populations. Sequencing of actively translating transcripts of Drd2 neurons identifies mRNAs that are differentially regulated following fear learning including Npy5r, Rxrg, Sst5r, Fgf3, ErbB4, Fkbp14, Dlk1,Ssh3 and Adora2a. Direct pharmacological manipulation of NPY5R, RXR, and ADORA2A confirms their importance in fear behavior and validates the present approach of identifying pharmacological targets for the modulation of emotional learning.

Alignment and component position after patient-matched instrumentation versus conventional total knee arthroplasty.

PURPOSE: To compare patient-matched instrumentation (PMI) with conventional total knee arthroplasty (TKA) in terms of limb alignment and component position. METHODS: Nine men and 36 women (mean age, 69.5 years) who underwent PMI TKA were compared with 20 men and 25 women (mean age, 69.3 years) who underwent conventional TKA by the same team of surgeons with the same prosthesis and protocols in terms of limb alignment and component position using the Perth protocol computed tomography, as well as bone resection measurements, operating time, and the number of trays used. RESULTS: The PMI and conventional TKA groups were comparable in terms of age, body mass index, tourniquet time, operating time, and the number of trays used. For limb alignment and component position, the 2 groups differed significantly in sagittal femoral component position (2.4º vs. 0.9º, p=0.0008) and the percentage of knees with femoral component internally rotated ≥1° with respect to the transepicondylar axis (20% vs. 55%, p=0.001). The difference was not significant in terms of limb alignment, coronal and rotational femoral component position, or coronal and sagittal tibial component position. Intra-operatively, all patient-matched cutting blocks demonstrated acceptable fit and stability. No instrument-related adverse events or complications were encountered. One (2.2%) femur and 6 (13.3%) tibiae were recut 2 mm for optimal ligament balancing. Two femoral components were upsized to the next size, and 2 tibial components were upsized and 2 downsized to the next size. CONCLUSION: PMI was as accurate as conventional instrumentation in TKA. There was no significant difference in limb alignment or femoral and tibial component position in the coronal and sagittal planes between PMI and conventional TKA. PMI had a higher tendency to achieve correct femoral component rotation.

Dermal uptake directly from air under transient conditions: advances in modeling and comparisons with experimental results for human subjects.

To better understand the dermal exposure pathway, we enhance an existing mechanistic model of transdermal uptake by including skin surface lipids (SSL) and consider the impact of clothing. Addition of SSL increases the overall resistance to uptake of SVOCs from air but also allows for rapid transfer of SVOCs to sinks like clothing or clean air. We test the model by simulating di-ethyl phthalate (DEP) and di-n-butyl phthalate (DnBP) exposures of six bare-skinned (Weschler et al. 2015, Environ. Health Perspect., 123, 928) and one clothed participant (Morrison et al. 2016, J. Expo. Sci. Environ. Epidemiol., 26, 113). The model predicts total uptake values that are consistent with the measured values. For bare-skinned participants, the model predicts a normalized mass uptake of DEP of 3.1 (µg/m2 )/(µg/m3 ), whereas the experimental results range from 1.0 to 4.3 (µg/m2 )/(µg/m3 ); uptake of DnBP is somewhat overpredicted: 4.6 (µg/m2 )/(µg/m3 ) vs. the experimental range of 0.5-3.2 (µg/m2 )/(µg/m3 ). For the clothed participant, the model predicts higher than observed uptake for both species. Uncertainty in model inputs, including convective mass transfer coefficients, partition coefficients, and diffusion coefficients, could account for overpredictions. Simulations that include transfer of skin oil to clothing improve model predictions. A dynamic model that includes SSL is more sensitive to changes that impact external mass transfer such as putting on and removing clothes and bathing.

Benefit-cost analysis of commercially available activated carbon filters for indoor ozone removal in single-family homes.

This study involved the development of a model for evaluating the potential costs and benefits of ozone control by activated carbon filtration in single-family homes. The modeling effort included the prediction of indoor ozone with and without activated carbon filtration in the HVAC system. As one application, the model was used to predict benefit-to-cost ratios for single-family homes in 12 American cities in five different climate zones. Health benefits were evaluated using disability-adjusted life-years and included city-specific age demographics for each simulation. Costs of commercially available activated carbon filters included capital cost differences when compared to conventional HVAC filters of similar particle removal efficiency, energy penalties due to additional pressure drop, and regional utility rates. The average indoor ozone removal effectiveness ranged from 4 to 20% across the 12 target cities and was largely limited by HVAC system operation time. For the parameters selected in this study, the mean predicted benefit-to-cost ratios for 1-inch filters were >1.0 in 10 of the 12 cities. The benefits of residential activated carbon filters were greatest in cities with high seasonal ozone and HVAC usage, suggesting the importance of targeting such conditions for activated carbon filter applications.

Methamphetamine absorption by skin lipids: accumulated mass, partition coefficients, and the influence of fatty acids.

Occupants of former methamphetamine laboratories, often residences, may experience increased exposure through the accumulation of the methamphetamine in the organic films that coat skin and indoor surfaces. The objectives of this study were to determine equilibrium partition coefficients of vapor-phase methamphetamine with artificial sebum (AS-1), artificial sebum without fatty acids (AS-2), and real skin surface films, herein called skin oils. Sebum and skin oil-coated filters were exposed to vapor-phase methamphetamine at concentrations ranging from 8 to 159 ppb, and samples were analyzed for exposure time periods from 2 h to 60 days. For a low vapor-phase methamphetamine concentration range of ~8-22 ppb, the equilibrium partition coefficient for AS-1 was 1500 ± 195 µg/g/ppb. For a high concentration range of 98-112 ppb, the partition coefficient was lower, 459 ± 80 µg/g/ppb, suggesting saturation of the available absorption capacity. The low partition coefficient for AS-2 (33 ± 6 µg/g/ppb) suggests that the fatty acids in AS-1 and skin oil are responsible for much high partition coefficients. We predict that the methamphetamine concentration in skin lipids coating indoor surfaces can exceed recommended surface remediation standards even for air concentrations well below 1 ppb.

A rare case of paediatric stridor caused by achalasia.

OBJECTIVE: This paper reports a case of achalasia in a 12-year-old girl who presented with stridor. CASE REPORT: An otherwise healthy 12-year-old girl presented to the ENT clinic with an 18-month history of dysphagia and noisy breathing on eating. Flexible fibre-optic examination showed a normal larynx with normal vocal fold movements. Fibre-optic endoscopic evaluation of swallowing was normal initially, but biphasic stridor occurred after several swallows. Microlaryngoscopy, bronchoscopy and upper oesophagoscopy showed a dilated oesophagus with normal mucosa. Bronchoscopy showed tracheomalacia of the distal trachea, which reduced the airway by approximately 75 per cent. This was caused by posterior compression from redundant oesophageal mucosa with dilatation as a result of retained fluids. Videofluoroscopy suggested achalasia, which was confirmed by oesophageal manometry. Her symptoms improved following a Heller's myotomy. CONCLUSION: This is the first paediatric case in the English literature of achalasia presenting with stridor. The condition was correctable with surgical intervention.

UK service level audit of insulin pump therapy in paediatrics.

AIM: To conduct an audit of insulin pump therapy in the UK after the issue of guidelines for the use of continuous subcutaneous insulin infusion by NICE in 2008 (Technology Appraisal 151). METHODS: All centres in the UK, providing pump services to children and young people were invited to participate in an online audit. Audit metrics were aligned to NICE Technology Appraisal 151 and an electronic data collection tool was used. RESULTS: Of the 176 UK centres identified as providing pump services, 166 (94.3%) participated in the study. A total of 5094 children and young people were identified as using continuous subcutaneous insulin infusion (19% of all paediatric patients with Type 1 diabetes), with a median (range) of 16.9 (0.67-69.4)% per centre. Units had a median of 0.58 consultant sessions, 0.43 full-time equivalent diabetic specialist nurses, and 0.1 full-time equivalent dieticians delivering the pump service. The majority of this time was not formally funded. Families could access 24-h clinical and technical support (83% units), although the delivery varied between consultant, diabetic specialist nurse and company representatives. Only 53% of units ran, or accessed, structured education programmes for continuous subcutaneous insulin infusion use. Most units (86%) allowed continuous subcutaneous insulin infusion use for paediatric inpatients, but only 56% had written guidelines for this scenario. Nine percent of units had encountered funding refusal for a patient fulfilling NICE (Technology Appraisal 151) criteria. CONCLUSION: The number of children and young people on continuous subcutaneous insulin infusion therapy is consistent with numbers estimated by NICE. There is a worrying lack of funded healthcare professional time. The audit also identified gaps in the provision of structured education and absence of written inpatient guidelines.

Recurrent epistaxis in a nine-year-old boy: benign or malignant?

OBJECTIVE: We present the case of a rare cause of epistaxis in a paediatric patient, together with the diagnostic and management challenges associated with this condition. CASE REPORT: A previously well nine-year-old boy presented with a six-month history of intermittent unilateral epistaxis. Radiological investigation and endoscopic biopsy confirmed a highly malignant nasopharyngeal mass consistent with carcinoma. The tumour continued to grow rapidly. Whilst awaiting intervention, the patient experienced a further significant haemorrhage requiring surgical intervention. CONCLUSION: Nasopharyngeal carcinoma is a rare cause of epistaxis amongst children in the UK. Early flexible nasendoscopy can help delineate both benign and sinister causes of symptoms in this region.

Accumulation of gas-phase methamphetamine on clothing, toy fabrics, and skin oil.

UNLABELLED: To better understand methamphetamine exposure and risk for occupants of former residential clandestine methamphetamine laboratories, we measured the dynamic accumulation of methamphetamine in skin oil, cotton and polyester (PE) clothing, upholstery, and toy fabric (substrates) exposed to 15-30 ppb (91-183 µg/m(3)) neutral methamphetamine in air for up to 60 days. The average equilibrium partition coefficients at 30% RH, in units of µg of methamphetamine per gram of substrate per ppb, are 3.0 ± 0.2 for a PE baby blanket, 5.6 ± 3.5 for a PE fabric toy, 3.7 ± 0.2 for a PE shirt, 18.3 ± 8.0 for a PE/cotton upholstery fabric, and 1200 ± 570 in skin oil. The partition coefficients at 60% RH are 4.5 ± 0.4, 5.2 ± 2.1, 4.5 ± 0.6, 36.1 ± 3.6, and 1600 ± 1100 µg/(g ppb), respectively. There was no difference in the partition coefficient for a clean and skin-oil-soiled cotton shirt [15.3 ± 2.1 µg/(g ppb) @ 42 days]. Partition coefficients for skin oil may be sensitive to composition. 'Mouthing' of cloth is predicted to be the dominant exposure pathway [60 µg/(kg body weight*ppb)] for a toddler in former meth lab, and indoor air concentrations would have to be very low (0.001 ppb) to meet the recommended reference dose for children. PRACTICAL IMPLICATIONS: Gas-phase methamphetamine transfers to and accumulates on clothing, toys and other fabrics significantly increases risk of ingestion of methamphetamine. Current remediation methods should consider measurement of postremediation gas-phase air concentrations of methamphetamine in addition to surface wipe samples.

Morbidity and mortality associated with subglottic laryngotracheal stenosis in granulomatosis with polyangiitis (Wegener's granulomatosis): a single-centre experience in the United Kingdom.

OBJECTIVES: We aimed to determine the prevalence of symptomatic subglottic laryngotracheal stenosis in patients with granulomatosis with polyangiitis (Wegener's granulomatosis); we also wanted to characterise the clinical outcomes and surgical interventions required, and the relapse rate in our cohort. METHODS: We undertook a retrospective clinical review of all granulomatosis with polyangiitis patients with symptomatic subglottic laryngotracheal stenosis attending St Thomas' Hospital, London, United Kingdom. RESULTS: Symptomatic subglottic laryngotracheal stenosis developed in 16 per cent of granulomatosis with polyangiitis patients attending our clinic. The median age of patients at diagnosis was 44 years (range: 34-81 years); 78 per cent of those presenting with subglottic laryngotracheal stenosis were women and 22 per cent were men. All patients were white; 67 per cent of patients were proteinase 3-antineutrophil cytoplasmic antibody-positive and 67 per cent developed relapsing disease requiring repeated surgical intervention. Subglottic laryngotracheal stenosis relapse was not associated with active systemic vasculitis elsewhere. CONCLUSION: Subglottic laryngotracheal stenosis is an uncommon but significant complication of granulomatosis with polyangiitis. Management of subglottic laryngotracheal stenosis requires a multi-disciplinary approach, with both rheumatological and otolaryngological expertise involved, given the relapsing nature of the disease.