Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected, as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen

Interviews for the assessment of long-term incapacity for work: a study on adherence to protocols and principles

<p>Abstract</p> <p>Background</p> <p>Assessments for long-term incapacity for work are performed by Social Insurance Physicians (SIPs) who rely on interviews with claimants as an important part of the process. These interviews are susceptible to bias. In the Netherlands three protocols have been developed to conduct these interviews. These protocols are expert- and practice-based. We studied to what extent these protocols are adhered to by practitioners.</p> <p>Methods</p> <p>We compared the protocols with one another and with the ICF and the biopsychosocial approach. The protocols describe semi-structured interviews with comparable but not identical topics. All protocols prescribe that the client's opinion on his capacity for work, and his arguments, need to be determined and assessed. We developed a questionnaire to elicit the adherence SIPs have to the protocols, their underlying principles and topics. We conducted a survey among one hundred fifty-five experienced SIPs in the Netherlands.</p> <p>Results</p> <p>Ninety-eight SIPs responded (64%). All respondents used some form of protocol, either one of the published protocols or their own mix. We found no significant relation between training and the use of a particular protocol. Ninety percent use a semi-structured interview. Ninety-five percent recognise having to verify what the claimant says and eighty-three percent feel the need to establish a good relation (p = 0.019). Twelve topics are basically always addressed by over eighty percent of the respondents. The claimant's opinion of being fit for his own work or other work, and his claim of incapacity and his health arguments for that claim, reach a hundred percent. Description of claimants' previous work reaches ninety-nine percent.</p> <p>Conclusion</p> <p>Our study shows professional consensus among experienced Dutch SIPs about the principle of assessment on arguments, the principle of conducting a semi-structured interview and the most crucial interview topics. This consensus can be used to further develop a protocol for interviewing in the assessment of incapacity for work in social insurance. Such a protocol can improve the quality of the assessments in terms of transparency and reproducibility, as well as by enabling clients to better prepare themselves for the assessments.</p

Systematic development of a communication skills training course for physicians performing work disability assessments: from evidence to practice

<p>Abstract</p> <p>Background</p> <p>Physicians require specific communication skills, because the face-to-face contact with their patients is an important source of information. Although physicians who perform work disability assessments attend some communication-related training courses during their professional education, no specialised and evidence-based communication skills training course is available for them. Therefore, the objectives of this study were: 1) to systematically develop a training course aimed at improving the communication skills of physicians during work disability assessment interviews with disability claimants, and 2) to plan an evaluation of the training course.</p> <p>Methods</p> <p>A physician-tailored communication skills training course was developed, according to the six steps of the Intervention Mapping protocol. Data were collected from questionnaire studies among physicians and claimants, a focus group study among physicians, a systematic review of the literature, and meetings with various experts. Determinants and performance objectives were formulated. A concept version of the training course was discussed with several experts before the final training course programme was established. The evaluation plan was developed by consulting experts, social insurance physicians, researchers, and policy-makers, and discussing with them the options for evaluation.</p> <p>Results</p> <p>A two-day post-graduate communication skills training course was developed, aimed at improving professional communication during work disability assessment interviews. Special focus was on active teaching strategies, such as practising the skills in role-play. An adoption and implementation plan was formulated, in which the infrastructure of the educational department of the institute that employs the physicians was utilised. Improvement in the skills and knowledge of the physicians who will participate in the training course will be evaluated in a randomised controlled trial.</p> <p>Conclusions</p> <p>The feasibility and practical relevance of the communication skills training course that was developed seem promising. Such a course may be relevant for physicians in many countries who perform work disability assessments. The development of the first training course of this type represents an important advancement in this field.</p

Outpatient parenteral antifungal therapy (OPAT) for invasive fungal infections with intermittent dosing of liposomal amphotericin B

Triazole resistant A. fumigatus has been documented in many parts of the world. In the Netherlands, incidence is now above 10% and results in the need for long-term parenteral therapy with liposomal amphotericin B (LAmB). The long terminal half-life of LAmB suggests that intermittent dosing could be effective, making the application of outpatient antifungal therapy (OPAT) possible. Here, we report our experience with the use of OPAT for Invasive Fungal Infections (IFI). All adult patients treated with LAmB with a 2 or 3 times weekly administration via the outpatient departments in four academic tertiary care centers in the Netherlands and Belgium since January 2010 were included in our analysis. Patient characteristics were collected,\ud as well as information about diagnostics, therapy dose and duration, toxicity, treatment history and outcome of the IFI. In total, 18 patients were included. The most frequently used regimen (67%) was 5 mg/kg 3 times weekly. A partial response to the daily treatment prior to discharge was confirmed by CT-scan in 17 (94%) of patients. A favorable outcome was achieved in 13 (72%) patients. Decrease in renal function occurred in 10 (56%) cases but was reversible in all and was treatment limiting in one patient only. The 100-day mortality and 1-year mortality after initiation of OPAT were 0% and 6%, respectively. In a selected population, and after confirmation of initial response to treatment, our data support the use of OPAT with LAmB for treatment of IFI in an intermittent dosing regimen

Identifying factors relevant in the assessment of return-to-work efforts in employees on long-term sickness absence due to chronic low back pain: a focus group study

ABSTRACT: BACKGROUND: Efforts undertaken during the return to work (RTW) process need to be sufficient to prevent unnecessary applications for disability benefits. The purpose of this study was to identify factors relevant to RTW Effort Sufficiency (RTW-ES) in cases of sick-listed employees with chronic low back pain (CLBP). METHODS: Using focus groups consisting of Labor Experts (LE's) working at the Dutch Social Insurance Institute, arguments and underlying grounds relevant to the assessment of RTW-ES were investigated. Factors were collected and categorized using the International Classification of Functioning, Disability and Health (ICF model). RESULTS: Two focus groups yielded 19 factors, of which 12 are categorized in the ICF model under activities (e.g. functional capacity) and in the personal (e.g. age, tenure) and environmental domain (e.g. employer-employee relationship). The remaining 7 factors are categorized under intervention, job accommodation and measures. CONCLUSIONS: This focus group study shows that 19 factors may be relevant to RTW-ES in sick-listed employees with CLBP. Providing these results to professionals assessing RTW-ES might contribute to a more transparent and systematic approach. Considering the importance of the quality of the RTW process, optimizing the RTW-ES assessment is essential

Multicentre study and systematic review: Allopurinol exposure during pregnancy

BACKGROUND: Data about the safety of allopurinol in pregnant women are sparsely reported. AIMS: To investigate the risk of adverse pregnancy outcome and congenital abnormalities after in utero exposure to allopurinol in inflammatory bowel disease (IBD) pregnancies and in general. METHODS: We collected safety data of patients with IBD who were treated with allopurinol during pregnancy between January 2013 and March 2022. Additionally, we performed a systematic review about the teratogenic potential of allopurinol. RESULTS: We collected data from 42 allopurinol-exposed pregnancies, including one twin pregnancy; in all women, allopurinol was combined with a thiopurine. Six pregnancies (14.3%) resulted in miscarriage and one in stillbirth at 32 weeks. A congenital anomaly was observed in one newborn (coarctation of the aorta discovered postpartum). Three pregnancies, including the twin pregnancy, ended in moderate preterm delivery and one in very preterm delivery. Five neonates (15.2%) were small for gestational age. From our literature search, we identified an additional 102 allopurinol-exposed pregnancies resulting in 129 live births, including 36 infants from our cohort. Ten infants (7.8%) were born with a congenital anomaly. Two (1.6%) had a comparable pattern of multiple anomalies. The systematic review sub-analysis including only infants born to mothers with IBD (n = 76) revealed that 2.6% of infants had congenital anomalies after in utero exposure to a low dose of allopurinol. CONCLUSIONS: Overall, the teratogenicity of allopurinol remains inconclusive. Children conceived by mothers treated for IBD with allopurinol/thiopurine co-therapy do not seem to have an increased risk of congenital anomalies

Evidence-based guidelines in the evaluation of work disability: an international survey and a comparison of quality of development

<p>Abstract</p> <p>Background</p> <p>In social insurance, the evaluation of work disability is becoming stricter as priority is given to the resumption of work, which calls for a guarantee of quality for these evaluations. Evidence-based guidelines have become a major instrument in the quality control of health care, and the quality of these guidelines' development can be assessed using the AGREE instrument. In social insurance medicine, such guidelines are relatively new. We were interested to know what guidelines have been developed to support the medical evaluation of work disability and the quality of these guidelines.</p> <p>Methods</p> <p>Five European countries that were reported to use guidelines were approached, using a recent inventory of evaluations of work disability in Europe. We focused on guidelines that are disease-oriented and formally prescribed in social insurance medicine. Using the AGREE instrument, these guidelines were appraised by two researchers. We asked two experts involved in guideline development to indicate if they agreed with our results and to provide explanations for insufficient scores.</p> <p>Results</p> <p>We found six German and sixteen Dutch sets of disease-oriented guidelines in official use. The AGREE instrument was applicable, requiring minor adaptations. The appraisers reached consensus on all items. Each guideline scored well on 'scope and purpose' and 'clarity and presentation'. The guidelines scored moderately on 'stakeholder involvement' in the Netherlands, but insufficiently in Germany, due mainly to the limited involvement of patients' representatives in this country. All guidelines had low scores on 'rigour of development', which was due partly to a lack of documentation and of existing evidence. 'Editorial independence' and 'applicability' had low scores in both countries as a result of how the production was organised.</p> <p>Conclusion</p> <p>Disease-oriented guidelines in social insurance medicine for the evaluation of work disability are a recent phenomenon, so far restricted to Germany and the Netherlands. The AGREE instrument is suitably applicable to assess the quality of guideline development in social insurance medicine, but some of the scoring rules need to be adapted to the context of social insurance. Existing guidelines do not meet the AGREE criteria to a sufficient level. The way patients' representatives can be involved needs further discussion. The guidelines would profit from more specific recommendations and, for providing evidence, more research is needed on the functional capacity of people with disabilities.</p

Increased ERK signalling promotes inflammatory signalling in primary airway epithelial cells expressing Z α1-antitrypsin.

Overexpression of Z α1-antitrypsin is known to induce polymer formation, prime the cells for endoplasmic reticulum stress and initiate nuclear factor kappa B (NF-κB) signalling. However, whether endogenous expression in primary bronchial epithelial cells has similar consequences remains unclear. Moreover, the mechanism of NF-κB activation has not yet been elucidated. Here, we report excessive NF-κB signalling in resting primary bronchial epithelial cells from ZZ patients compared with wild-type (MM) controls, and this appears to be mediated by mitogen-activated protein/extracellular signal-regulated kinase, EGF receptor and ADAM17 activity. Moreover, we show that rather than being a response to protein polymers, NF-κB signalling in airway-derived cells represents a loss of anti-inflammatory signalling by M α1-antitrypsin. Treatment of ZZ primary bronchial epithelial cells with purified plasma M α1-antitrypsin attenuates this inflammatory response, opening up new therapeutic options to modulate airway inflammation in the lung

Blood coagulation and beyond:Position paper from the Fourth Maastricht Consensus Conference on Thrombosis

The 4th Maastricht Consensus Conference on Thrombosis (MCCT), included the following themes: Theme 1: The coagulome as a critical driver of cardiovascular disease Blood coagulation proteins also play divergent roles in biology and pathophysiology, related to specific organs, including brain, heart, bone marrow and kidney. Four investigators shared their views on these organ-specific topics. Theme 2: Novel mechanisms of thrombosis Mechanisms linking factor XII to fibrin, including their structural and physical properties, contribute to thrombosis, which is also affected by variation in microbiome status. Virus infections associated-coagulopathies perturb the hemostatic balance resulting in thrombosis and/or bleeding. Theme 3: How to limit bleeding risks: insights from translational studies This theme included state of the art methodology for exploring the contribution of genetic determinants of a bleeding diathesis; determination of polymorphisms in genes that control the rate of metabolism by the liver of P2Y12 inhibitors, to improve safety of antithrombotic therapy. Novel reversal agents for direct oral anticoagulants are discussed. Theme 4: Hemostasis in extracorporeal systems: how to utilize ex vivo models? Perfusion flow chamber and nanotechnology developments are developed for studying bleeding and thrombosis tendencies. Vascularised organoids are utilized for disease modeling and drug development studies. Strategies for tackling extracorporeal membrane oxygenation (ECMO) associated coagulopathy are discussed. Theme 5: Clinical dilemmas in thrombosis and antithrombotic management Plenary presentations addressed controversial areas, ie thrombophilia testing, thrombosis risk assessment in hemophilia, novel antiplatelet strategies and clinically tested factor XI(a) inhibitors,both possibly with reduced bleeding risk. Finally, Covid-19 associated coagulopathy is revisited.</p