Patients with rheumatic diseases may face 'discounting' (denying and patronising) or 'lack of understanding' because of having symptoms without external clinical signs, but instruments to assess such ...invalidation experiences are lacking.
To develop and evaluate the Illness Invalidation Inventory (3*I), to compare invalidation experiences of two groups of patients who differ in visual signs and laboratory findings-rheumatoid arthritis (RA) and fibromyalgia-and to examine the association of invalidation with health status.
A questionnaire (eight items with respect to five sources: spouse, family, medical professionals, work environment and social services) was constructed. It was completed by 142 patients with RA and 167 patients with fibromyalgia.
Principal axis factoring with oblimin rotation yielded two factors with high internal consistency (α>0.70): 'discounting' (five items) and 'lack of understanding' (three items). Patients with fibromyalgia experienced significantly more discounting and lack of understanding from their family, medical professionals, colleagues and social services than did patients with RA. Both patient groups experienced more invalidation from social services, colleagues and family than from medical professionals and spouses. More discounting and lack of understanding correlated with poorer mental well-being and social functioning in both patient groups. Discounting correlated with more physical disability and pain in patients with RA.
The 3*I is a brief, reliable instrument for assessing patients' perceptions of invalidation from different sources, which differ between patient groups and are associated with health status. Future validation research should clarify the clinical impact of invalidation on treatment adherence and outcome.
A cross-sectional study was performed to evaluate health-related quality of life (HRQOL) in children with congenital vascular malformations (CVM) and to investigate factors associated with an ...impaired HRQOL. Children (2–17 years) with CVMs who visited the HECOVAN expertise center between 2016–2018 were included. The PedsQL 4.0 Generic Core Scales were used and a score ≥ 1.0 SD below the normative mean was defined as an impaired HRQOL. Factors associated with impairment were investigated using univariate and multivariate logistic regression analysis. The median overall HRQOL was 84.8/100 (n = 207; 41% boys, 59% girls; self-reported IQR 73.9–92.4 and parent-reported IQR 71.4–92.4). Patients aged 13–17 years reported significantly worse physical functioning than those aged 8–12 years (median 84.4, IQR 71.1–93.8 versus median 90.6, IQR 81.3–96.9; p = 0.02). Parents reported a significantly lower overall HRQOL than their children (median 80.4, IQR 70.7–90.8 versus median 85.9, IQR 76.1–92.4; p = 0.001). HRQOL was impaired in 25% of patients. Impairment occurred significantly more often in lower extremity CVMs (38%, p = 0.01) and multifocal CVMs (47%, p = 0.01) compared to CVMs in the head/neck region (13%). Other associated factors included invasive management (31% versus 14%; p = 0.01), age at first treatment ≤ 5 years (48% versus 25%; p = 0.02) and ongoing treatment (38% versus 18%; p = 0.004). After correction for other factors, significance remained for lower extremity CVMs and ongoing invasive treatment.
Conclusions
: Overall median HRQOL was reasonable and not significantly different from the norm sample. Parental ratings were significantly lower than their children’s ratings. A quarter of the patients had an impaired HRQOL, which seemed to worsen with age. Independently associated factors included a lower extremity CVM and invasive management.
What is Known:
• Congenital vascular malformations could affect health-related quality of life (HRQOL).
• Studies on pediatric patients are limited and either very small or in combination with adult patient series.
What is New:
• This study raises awareness of an impaired HRQOL in 25% of pediatric patients with congenital vascular malformations.
• Associated factors included a lower extremity CVM and invasive management.
This retrospective study examines the outcomes of sclerotherapy in children with (veno)lymphatic malformations who received sclerotherapy between 2011 and 2016 (116 children, 234 procedures). ...Complication severity was classified using the Society of Interventional Radiology classification. Clinical response was rated on a scale of 0 (no change) to 3 (good improvement). The sclerosants used were bleomycin (
n
= 132; 56%), lauromacrogol (
n
= 42; 18%), doxycycline (
n
= 15; 6%), ethanol (
n
= 12; 5%), or a combination (
n
= 33; 14%). Four major and 25 minor complications occurred without significant differences between the agents. The median response rate per procedure was 2—some improvement—for all sclerosants. However, in pure LMs (67%), bleomycin and a combination of agents resulted in the best clinical response. On patient level, all had some or good clinical response. Mixed macrocystic and microcystic lesions showed a significantly lower clinical response (median 2 versus 3;
p
= 0.023 and
p
= 0.036, respectively) and required significantly more procedures (median 2 versus 1;
p
= 0.043 and
p
= 0.044, respectively) compared with lesions with one component.
Conclusion
: Sclerotherapy for (V)LMs in children is safe and effective. Bleomycin is the most frequently used agent in this clinic and seemed most effective for pure LMs. Mixed macrocystic and microcystic lesions are most difficult to treat effectively.
What is Known:
•
A variety of agents can be used for sclerotherapy of lymphatic malformations in children.
•
Macrocystic lesions have favorable outcomes compared with microcystic and mixed lesions.
What is New:
•
Bleomycin and a combination of agents seem to be most effective to treat lymphatic malformations in children.
•
Mixed macrocystic and microcystic lesions are more difficult to treat effectively compared with lesions with either one of these components.
Envenomation by elapid snakes primarily results in neurotoxic symptoms and, consequently, are the primary focus of therapeutic research concerning such venoms. However, mounting evidence suggests ...these venoms can additionally cause coagulopathic symptoms, as demonstrated by some Asian elapids and African spitting cobras. This study sought to investigate the coagulopathic potential of venoms from medically important elapids of the genera
(true cobras),
(rinkhals), and
(mambas). Crude venoms were bioassayed for coagulant effects using a plasma coagulation assay before RPLC/MS was used to separate and identify venom toxins in parallel with a nanofractionation module. Subsequently, coagulation bioassays were performed on the nanofractionated toxins, along with in-solution tryptic digestion and proteomics analysis. These experiments were then repeated on both crude venoms and on the nanofractionated venom toxins with the addition of either the phospholipase A
(PLA
) inhibitor varespladib or the snake venom metalloproteinase (SVMP) inhibitor marimastat. Our results demonstrate that various African elapid venoms have an anticoagulant effect, and that this activity is significantly reduced for cobra venoms by the addition of varespladib, though this inhibitor had no effect against anticoagulation caused by mamba venoms. Marimastat showed limited capacity to reduce anticoagulation in elapids, affecting only
and
venom at higher doses. Proteomic analysis of nanofractionated toxins revealed that the anticoagulant toxins in cobra venoms were both acidic and basic PLA
s, while the causative toxins in mamba venoms remain uncertain. This implies that while PLA
inhibitors such as varespladib and metalloproteinase inhibitors such as marimastat are viable candidates for novel snakebite treatments, they are not likely to be effective against mamba envenomings.
•Several xanthans were enzymatically hydrolyzed using cellulases.•The final degree of hydrolysis is solely controlled by the xanthan conformation.•Only disordered xanthan molecules are available for ...enzymatic hydrolysis.•At a given conformation, similar degradation levels are obtained for all xanthans.•Xanthans can be completely hydrolyzed to repeating units, independent on their primary structure.
Differently modified xanthans, varying in degree of acetylation and/or pyruvylation were incubated with the experimental cellulase mixture C1-G1 from Myceliophthora thermophila C1. The ionic strength and/or temperature of the xanthan solutions were varied, to obtain different xanthan conformations. The exact conformation at the selected incubation conditions was determined by circular dichroism. The xanthan degradation was analyzed by size exclusion chromatography. It was shown that at a fixed xanthan conformation, the backbone degradation by cellulases is equal for each type of xanthan. Complete backbone degradation is only obtained at a fully disordered conformation, indicating that only the secondary xanthan structure influences the final degree of hydrolysis by cellulases. It is thereby shown that, independently on the degree of substitution, xanthan can be completely hydrolyzed to oligosaccharides. These oligosaccharides can be used to further investigate the primary structure of different xanthans and to correlate the molecular structure to the xanthan functionalities.
Venomous snakebite is one of the world's most lethal neglected tropical diseases. Animal-derived antivenoms are the only standardized specific therapies currently available for treating snakebite ...envenoming, but due to venom variation, often this treatment is not effective in counteracting all clinical symptoms caused by the multitude of injected toxins. In this study, the coagulopathic toxicities of venoms from the medically relevant snake species
,
,
,
,
and
were assessed. The venoms were separated by liquid chromatography (LC) followed by nanofractionation and parallel mass spectrometry (MS). A recently developed high-throughput coagulation assay was employed to assess both the pro- and anticoagulant activity of separated venom toxins. The neutralization capacity of antivenoms on separated venom components was assessed and the coagulopathic venom peptides and enzymes that were either neutralized or remained active in the presence of antivenom were identified by correlating bioassay results with the MS data and with off-line generated proteomics data. The results showed that most snake venoms analyzed contained both procoagulants and anticoagulants. Most anticoagulants were identified as phospholipases A
s (PLA
s) and most procoagulants correlated with snake venom metalloproteinases (SVMPs) and serine proteases (SVSPs). This information can be used to better understand antivenom neutralization and can aid in the development of next-generation antivenom treatments.
Bites from elapid snakes typically result in neurotoxic symptoms in snakebite victims. Neurotoxins are, therefore, often the focus of research relating to understanding the pathogenesis of elapid ...bites. However, recent evidence suggests that some elapid snake venoms contain anticoagulant toxins which may help neurotoxic components spread more rapidly. This study examines the effects of venom from the West African black-necked spitting cobra (
) on blood coagulation and identifies potential coagulopathic toxins. An integrated RPLC-MS methodology, coupled with nanofractionation, was first used to separate venom components, followed by MS, proteomics and coagulopathic bioassays. Coagulation assays were performed on both crude and nanofractionated
venom toxins as well as PLA
s and 3FTx purified from the venom. Assays were then repeated with the addition of either the phospholipase A
inhibitor varespladib or the snake venom metalloproteinase inhibitor marimastat to assess whether either toxin inhibitor is capable of neutralizing coagulopathic venom activity. Subsequent proteomic analysis was performed on nanofractionated bioactive venom toxins using tryptic digestion followed by nanoLC-MS/MS measurements, which were then identified using Swiss-Prot and species-specific database searches. Varespladib, but not marimastat, was found to significantly reduce the anticoagulant activity of
venom and MS and proteomics analyses confirmed that the anticoagulant venom components mostly consisted of PLA
proteins. We, therefore, conclude that PLA
s are the most likely candidates responsible for anticoagulant effects stimulated by
venom.
Coagulation assays currently employed are often low throughput, require specialized equipment and/or require large blood/plasma samples. This study describes the development, optimization and early ...application of a generic low-volume and high-throughput screening (HTS) assay for coagulation activity. The assay is a time-course spectrophotometric measurement which kinetically measures the clotting profile of bovine or human plasma incubated with Ca
and a test compound. The HTS assay can be a valuable new tool for coagulation diagnostics in hospitals, for research in coagulation disorders, for drug discovery and for venom research. A major effect following envenomation by many venomous snakes is perturbation of blood coagulation caused by haemotoxic compounds present in the venom. These compounds, such as anticoagulants, are potential leads in drug discovery for cardiovascular diseases. The assay was implemented in an integrated analytical approach consisting of reversed-phase liquid chromatography (LC) for separation of crude venom components in combination with parallel post-column coagulation screening and mass spectrometry (MS). The approach was applied for the rapid assessment and identification of profiles of haemotoxic compounds in snake venoms. Procoagulant and anticoagulant activities were correlated with accurate masses from the parallel MS measurements, facilitating the detection of peptides showing strong anticoagulant activity.
ObjectiveIt is known that doctors who receive complaints may have feelings of anger, guilt, shame and depression, both in the short and in the long term. This might lead to functional impairment. ...Less is known about the impact of the disciplinary process and imposed measures. Previous studies of disciplinary proceedings have mainly focused on identifying characteristics of disciplined doctors and on sentencing policies. Therefore, the aim of this study is to explore what impact the disciplinary process and imposed measures have on healthcare professionals.DesignSemistructured interview study, with purposive sampling and inductive qualitative content analysis.Participants16 healthcare professionals (9 medical specialists, 3 general practitioners, 2 physiotherapists and 2 psychologists) that were sanctioned by the disciplinary tribunal.SettingThe Netherlands.ResultsProfessionals described feelings of misery and insecurity both during the process as in its aftermath. Furthermore, they reported to fear receiving new complaints and provide care more cautiously after the imposed measure. Factors that may enhance psychological and professional impact are the publication of measures online and in newspapers, media coverage, the feeling of treated as guilty before any verdict has been reached, and the long duration of the process.ConclusionsThis study shows that the disciplinary process and imposed measures can have a profound psychological and professional impact on healthcare professionals. Although a disciplinary measure is meant to have a corrective effect, our results suggest that the impact that is experienced by professionals might hamper optimal rehabilitation afterwards. Therefore, organising emotional support should be considered during the disciplinary process and in the period after the verdict.
High-throughput screening platforms for the identification of bioactive compounds in mixtures have become important tools in the drug discovery process. Miniaturization of such screening systems may ...overcome problems associated with small sample volumes and enhance throughput and sensitivity. Here we present a new screening platform, coined picofractionation analytics, which encompasses microarray bioassays and mass spectrometry (MS) of components from minute amounts of samples after their nano liquid chromatographic (nanoLC) separation. Herein, nanoLC was coupled to a low-volume liquid dispenser equipped with pressure-fed solenoid valves, enabling 50-nL volumes of column effluent (300 nL/min) to be discretely deposited on a glass slide. The resulting fractions were dried and subsequently bioassayed by sequential printing of nL-volumes of reagents on top of the spots. Unwanted evaporation of bioassay liquids was circumvented by employing mineral oil droplets. A fluorescence microscope was used for assay readout in kinetic mode. Bioassay data were correlated to MS data obtained using the same nanoLC conditions in order to assign bioactives. The platform provides the possibility of freely choosing a wide diversity of bioassay formats, including those requiring long incubation times. The new method was compared to a standard bioassay approach, and its applicability was demonstrated by screening plasmin inhibitors and fibrinolytic bioactives from mixtures of standards and snake venoms, revealing active peptides and coagulopathic proteases.
PDF
