'Leaving my comfort zone'. A qualitative study of physiotherapists' experiences blending an eHealth psychosocial intervention with face-to-face physiotherapy.

BACKGROUND: Many physiotherapists do not feel adequately equipped to address psychosocial risk factors in people with complex pain states. Hence, a biopsychosocial blended intervention (Back2Action) was developed to assist physiotherapists to manage people with persistent spinal pain and coexisting psychosocial risk factors associated with the development or maintenance of persistent pain. OBJECTIVE: This study aimed to gain insight into the experiences of physiotherapists with this blended psychosocial intervention. DESIGN: and methods: This was an interpretative qualitative study with a reflexive thematic analysis of semi-structured interviews with physiotherapists (N = 15) who delivered Back2Action. The interview started with the grand-tour question: "What was your experience in using Back2Action?" Physiotherapist were encouraged to provide examples, and follow-up questions were posed to ensure a deeper understanding could be reached. RESULTS: Four themes were constructed: Physiotherapists became increasingly aware of (1) their own implicit expectations, biases and skills, and underlying treatment paradigms, and (2) the implicit expectations from their patients towards them. This led to (3) creating a deeper and stronger therapeutic alliance with the patient, but also (4) an understanding that implementation of a true biopsychosocial intervention - even if offered in a blended form - requires more practice, confidence and resources. CONCLUSIONS: Back2Action is considered a valuable treatment to deliver a biopsychosocial intervention in primary care. Considering the high level of knowledge, skills and competency of the participating physiotherapists, the perceived barriers may be more difficult to overcome for more junior physiotherapists.

How people with persistent pain experience in-person physiotherapy blended with biopsychosocial digital health - A qualitative study on participants' experiences with Back2Action.

Background: A blended intervention consisting of in-person physiotherapy and psychologically-informed digital health, called Back2Action, was developed to optimise the management of people with persistent spinal pain who also have psychosocial risk factors associated with the development or maintenance of persistent pain. This study aimed to gain insights in how participants experienced this blended intervention. Methods: A qualitative study using semi-structured interviews was conducted. Eleven people with persistent non-specific spinal pain who received the blended intervention within a randomised clinical trial were included. All interviews were recorded, transcribed verbatim and analysed independently by two researchers. Data were analysed using a thematic analysis. Results: The analysis identified four themes: (1) Experiencing a better understanding of the relationship between own physical and mental health; (2) Importance of the physiotherapist's active involvement in biopsychosocial blended care, which describes the crucial role of physiotherapists in supporting participants in this; (3) Appreciation of digital health, to better understand persistent pain and make meaningful lifestyle changes; and (4) Trials and triumphs, revealing gains such as better coping, but also challenges with implementation of changes into long-term routines. Conclusion: Participants of the blended intervention experienced positive changes in thoughts and behaviours, which highlights the feasibility and acceptability of the blended intervention as a more holistic treatment within pain management. The differences in personal preferences for receiving psychologically-informed digital health poses challenges for implementation of blended biopsychosocial care in evidence-based practice.

Treatment sequences and drug costs from diagnosis to death in multiple myeloma.

Novel therapies for multiple myeloma (MM) have improved patient survival, but their high costs strain healthcare budgets. End-of-life phases of treatment are generally the most expensive, however, these high costs may be less justifiable in the context of a less pronounced clinical benefit. To manage drug expenses effectively, detailed information on end-of-life drug administration and costs are crucial. In this retrospective study, we analysed treatment sequences and drug costs from 96 MM patients in the Netherlands who died between January 2017 and July 2019. Patients received up to 16 lines of therapy (median overall survival: 56.5 months), with average lifetime costs of €209 871 (€3111/month; range: €3942-€776 185) for anti-MM drugs. About 85% of patients received anti-MM treatment in the last 3 months before death, incurring costs of €20 761 (range: €70-€50 122; 10% of total). Half of the patients received anti-MM treatment in the last 14 days, mainly fully oral regimens (66%). End-of-life treatment costs are substantial despite limited survival benefits. The use of expensive treatment options is expected to increase costs further. These data serve as a reference point for future cost studies, and further research is needed to identify factors predicting the efficacy and clinical benefit of continuing end-of-life therapy.

'Give me something meaningful': GPs perspectives on how to improve an audit and feedback report provided by health insurers - an exploratory qualitative study.

BACKGROUND: Audit and feedback (A&F) is a valuable quality improvement strategy, which can contribute to de-implementation of low-value care. In the Netherlands, all health insurers collaboratively provide A&F to general practitioners (GPs), the 'Primary Care Practice Report' (PCPR). Unfortunately, the use of this report by GPs is limited. This study examined the thoughts of GPs on the usability of the PCPR and GPs recommendations for improving the PCPR. METHOD: We used an interpretative qualitative design, with think-aloud tasks to uncover thoughts of GPs on the usability of the PCPR and semistructured interview questions to ask GPs' recommendations for improvement of the PCPR. Interviews were audiorecorded and transcribed ad verbatim. Data were analysed using thematic content analysis. RESULTS: We identified two main themes: 'poor usability of the PCPR', and 'minimal motivation to change based on the PCPR'. The GPs found the usability of the PCPR poor due to the feedback not being clinically meaningful, the data not being recent, individual and reliable, the performance comparators offer insufficient guidance to assess clinical performance, the results are not discussed with peers and the definitions and visuals are unclear. The GPs recommended improving these issues. The GPs motivation to change based on the PCPR was minimal. CONCLUSIONS: The GPs evaluated the PCPR as poorly usable and were minimally motivated to change. The PCPR seems developed from the perspective of the reports' commissioners, health insurers, and does not meet known criteria for effective A&F design and user-centred design. Importantly, the GPs did state that well-designed feedback could contribute to their motivation to improve clinical performance.Furthermore, the GPs stated that they receive a multitude of A&F reports, which they hardly use. Thus, we see a need for policy makers to invest in less, but more usable A&F reports.

Evaluating ivosidenib for the treatment of acute myeloid leukemia.

INTRODUCTION: Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults, but the results for patients with AML are still unsatisfactory. The discovery of new mutations in AML, including IDH mutations, has opened the door for treatment with targeted agents. Ivosidenib is a selective, potent inhibitor of the IDH1 mutant protein. AREAS COVERED: This review summarizes the mechanism of action, safety profile and efficacy of ivosidenib for patients with IDH1-mutated AML. The authors then provide their expert perspectives on the use of the drug including their future perspectives. EXPERT OPINION: Ivosidenib is a promising, most probably practice changing, new drug for the treatment of IDH1-mutated AML. Current phase III trials are ongoing to evaluate the addition of ivosidenib to the current standards-of-care. In the near future, more drug combinations are awaited. Challenges for the future include the development of resistance and establishing the duration of maintenance therapy.

Combined PET-CT and axillary lymph node marking with radioactive iodine seeds (MARI procedure) for tailored axillary treatment in node-positive breast cancer after neoadjuvant therapy.

BACKGROUND: The treatment of axillary lymph node metastases after neoadjuvant systemic therapy (NST) remains debatable and axillary lymph node dissection (ALND) is still the standard of care. Marking axillary lymph nodes with radioactive iodine seeds (MARI procedure) is accurate in restaging the axilla after NST (false-negative rate 7 per cent). Here, the potential of tailored axillary treatment, determined by combining the results of PET-CT before NST with those of the MARI procedure after NST, was analysed. METHODS: A cohort of axillary node-positive patients was used to construct a hypothetical treatment algorithm based on a combination of PET-CT and the MARI procedure. In the algorithm, the number of fluorodeoxyglucose (FDG)-avid axillary lymph nodes (1-3 versus 4 or more) before NST and the tumour status of the MARI node (positive versus negative) after NST were used to tailor axillary treatment. All patients in the cohort underwent ALND, allowing estimation of potential overtreatment and undertreatment. RESULTS: A total of 93 patients were included in the study. Between one and three FDG-avid axillary lymph nodes were observed in 59 patients, and four or more in 34 patients. The MARI node was tumour-negative in 32 patients and showed residual disease in 61. Treatment according to the constructed algorithm would have resulted in 74 per cent of patients avoiding an ALND, with potential undertreatment in three patients (3 per cent) and overtreatment in 16 (17 per cent). CONCLUSION: Tailored axillary treatment after NST in node-positive patients, by combining PET-CT before NST and the MARI procedure after NST, has the potential for ALND to be avoided in 74 per cent of patients.

Is DCIS breast cancer, and how do I treat it?

Ductal carcinoma in situ (DCIS) is a pre-invasive stage of breast cancer with a heterogeneous clinical behaviour. Since the introduction of mammographic screening programmes, the incidence of DCIS has shown a dramatic increase. Treatment should focus on the prevention of progression to invasive disease. If progression occurs, poorly differentiated DCIS frequently gives rise to grade III invasive breast cancer, whereas well differentiated DCIS more often recurs as grade I invasive disease. However, at present, validated diagnostic test are lacking to predict progression accurately. The majority of women with DCIS are suitable for breast conserving therapy. Obtaining clear surgical margins is the most important goal of a local excision. Radiotherapy is effective in reducing the risk of local recurrence with about 50 % in all subgroups of patients with DCIS. (Breast cancer specific) survival of women with DCIS is excellent, and radiotherapy does not further improve this. Future research should be directed in enabling to select women who have a high risk of--invasive--recurrence, so in which radiotherapy should be standard part of the breast conserving approach, and those women with a more indolent lesion, in which after surgery a watchful waiting approach can be followed.

Radioguided occult lesion localisation (ROLL) in breast-conserving surgery after neoadjuvant chemotherapy.

BACKGROUND: An important benefit of neoadjuvant chemotherapy, as compared to adjuvant chemotherapy, in breast cancer patients is down staging of the primary tumour, which allows for more breast-conserving surgery. When a tumour becomes non-palpable after this down staging, precise localisation of the original tumour bed is crucial to be able to perform breast-conserving surgery. Radioguided Occult Lesion Localisation with (99m)Technetium (ROLL-(99m)Tc) is commonly used to perform breast-conserving surgery in patients with non-palpable breast tumours. We modified this technique to use it in the neoadjuvant setting. The present analysis was performed to assess its feasibility and analyse the number of patients in which a mastectomy was correctly withheld using this technique. METHODS: A retrospective analysis was performed for all patients who were treated with neoadjuvant chemotherapy between 2007 and 2010 in our institute and underwent breast-conserving surgery with the ROLL-(99m)Tc technique afterwards. The status of the margins and the weight of the resected specimen were assessed. RESULTS: The median weight of the resected specimen in these 83 patients was 53 g (range: 11-204 g). Eleven of the 58 patients with residual disease revealed positive margins at pathological examination. However, in only 5 of those 11 patients a secondary mastectomy was indicated. This means that in 94% of all included patients a mastectomy was correctly withheld. CONCLUSION: The ROLL-(99m)Tc technique is a feasible technique that can be used to perform breast-conserving surgery after neoadjuvant chemotherapy in a carefully selected group of patients.

Techniques for wound closure at caesarean section: a randomized clinical trial.

OBJECTIVE: It is unclear which technique for skin closure should be used at caesarean section (CS) in order to get the best cosmetic result. STUDY DESIGN: We conducted a randomized controlled trial to assess the cosmetic result of different techniques for skin closure after CS. A two-center single-blind randomized controlled trial was performed in The Netherlands. Women undergoing their first CS were eligible for the trial. In a factorial design, women were randomly allocated to (1) closure of the fat layer versus non-closure and (2) staples or intracutaneous stitches for skin closure. The cosmetic result was assessed using the Patient and Observer Scar Assessment Scale (POSAS). RESULTS: We included 124 women. In the stitches group 63% [39/62] women judged the scar as satisfactory, versus 63% [38/60] in the staples group (RR 1.01; 95% CI 0.64-1.6). When the subcutaneous fat layer was closed, 52% [33/63] of the women scored the scar as satisfactory, versus 75% [44/59] of the women in whom the fat layer was not separately closed (RR 0.53; 95% CI 0.32-0.89). This effect was independent of the subcutaneous thickness (p-value for interaction 0.64). Of the secondary outcomes, subcutaneous closure of the fat layer was associated with a longer admission time (median 4 days; IQR 3-5 versus 3 days; IQR 3-5, p-value 0.023). CONCLUSIONS: The choice of staples or stitches does not affect the cosmetic result after a caesarean section. Closing of the subcutaneous fat layer, however, negatively affects the cosmetic result and is associated with a longer admission time.

Surgical complications of skin sparing mastectomy and immediate prosthetic reconstruction after neoadjuvant chemotherapy for invasive breast cancer.

BACKGROUND: Neoadjuvant chemotherapy is gaining acceptance as an option for breast cancer treatment, particularly in young women. These women may seek immediate breast reconstruction after mastectomy even though it is not known whether such preoperative chemotherapy may be detrimental to post-reconstruction wound healing. Therefore, we set out to assess the influence of neoadjuvant chemotherapy for invasive breast cancer on the short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction. METHODOLOGY: The short-term surgical outcome of 48 immediate breast reconstructions in 37 women treated with neoadjuvant chemotherapy from 2006 through 2009 was prospectively compared to that of 215 immediate reconstructions in 176 women who were operated in the same period without neoadjuvant chemotherapy. RESULTS: The overall rate of short-term postoperative complications was significantly less among neoadjuvantly treated women (15% vs. 29%; p = 0.042) but this did not result in a reduction of loss of prostheses (8% vs. 11%; p = 0.566). CONCLUSION: Because neoadjuvant chemotherapy is not associated with an increase in short-term complications after skin sparing mastectomy and immediate prosthetic reconstruction in patients with invasive breast cancer, such combined surgical therapy may be offered as treatment option for this particular group of patients also.

[Outcomes of disciplinary proceedings against gynaecologists: comparison between the periods 1980-1991 and 1992-2003]. / Uitkomsten van de tuchtrechtspraak over gynaecologen: vergelijkingen tussen 1980-1991 en 1992-2003.

In a study of the archives of the Chief Inspector for Healthcare in The Netherlands during the period 1992-2003, the number of complaints against gynaecologists submitted to disciplinary boards (n = 371) was found to be higher than during the period of 1980-1991 (n = 240). On the other hand, the number of complaints per gynaecologist had decreased from 6.3 complaints per 100 gynaecologists in 1992 to 2.6/100 in 2003. The number ofcomplaints declared legitimate relative to the number of submitted complaints remained the same in both periods (55/240 (23%) in 1980-1991 and 84/371 (23%) in 1992-2003), although the percentage ofcomplaints ruled as legitimate did increase during the course of the second period from 14 between 1992-1997 to 28 during the 1998-2003 period. Interesting points included the number of rulings regarding the death of an infant (40%), the interpretation of the cardiotocography recording, the need to keep medical records up to date (in particular the informed consent) and the fact that almost 50% of complaints ruled to be legitimate related to how the locum position was arranged, the role of the duty gynaecologist and that of the house officer.

Stepped care vs. matched care for mood and anxiety disorders: a randomized trial in routine practice.

OBJECTIVE: The effectiveness of two versions of stepped care [with either brief therapy (BT) or cognitive behavioural therapy (CBT) as a first step] is studied in comparison with the traditional matched care approach (CAU) for patients with mood and anxiety disorders. METHOD: A randomized trial was performed in routine mental health care in 12 settings, including 702 patients. Patients were interviewed once in 3 months for 18-24 months (response rate 69%). RESULTS: Overall, patients' health improved significantly over time: 51% had achieved recovery from the DSM-IV disorder(s) after 1 year and 66% at the end of the study. Respectively, 50% and 60% had 'normal' SCL90 and SF36 scores. Cognitive behavioural therapy and BT patients achieved recovery more often than CAU patients (ORs between 1.26 and 1.48), although these results were not statistically significant. CONCLUSION: Stepped care, with BT or CBT as a first step, is at least as effective as matched care.

Comparison of EQ-5D and SF-6D utilities in mental health patients.

Various preference-based measures of health are available for use as an outcome measure in cost-utility analysis. The aim of this study is to compare two such measures EQ-5D and SF-6D in mental health patients. Baseline data from a Dutch multi-centre randomised trial of 616 patients with mood and/or anxiety disorders were used. Mean and median EQ-5D and SF-6D utilities were compared, both in the total sample and between severity subgroups based on quartiles of SCL-90 scores. Utilities were expected to decline with increased severity. Both EQ-5D and SF-6D utilities differed significantly between patients of adjacent severity groups. Mean utilities increased from 0.51 at baseline to 0.68 at 1.5 years follow-up for EQ-5D and from 0.58 to 0.70 for SF-6D. For all severity subgroups, the mean change in EQ-5D utilities as well as in SF-6D utilities was statistically significant. Standardised response means were higher for SF-6D utilities. We concluded that both EQ-5D and SF-6D discriminated between severity subgroups and captured improvements in health over time. However, the use of EQ-5D resulted in larger health gains and consequent lower cost-utility ratios, especially for the subgroup with the highest severity of mental health problems.

Radiation-enhanced vascular endothelial growth factor (VEGF) secretion in glioblastoma multiforme cell lines--a clue to radioresistance?

OBJECTIVE: Postoperative radiotherapy is standard treatment for patients with a glioblastoma multiforme (GBM). However, a GBM is radioresistant and almost always recurs, even after a high dose of radiation. A GBM is characterized by its extensive neo-angiogenesis, which can be attributed to the high levels of vascular endothelial growth factor (VEGF). The scope of this study is to investigate the VEGF secretion by GBM cells with different radiosensitivity after irradiation. METHODS: Three human GBM cell lines (U251, U251-NG2 and U87) were irradiated with single doses of 0, 5, 10 and 20 Gy of gamma-rays from a (137)Cs source. VEGF levels in medium were measured by ELISA at 24, 48 and 72 h after radiation. Cell survival was measured by the XTT assay 7 days after irradiation. RESULTS: Following single dose radiation, the VEGF levels showed a dose dependent increase in U251, U251-NG2 and U87 glioma cells. Both base-line and radiation-enhanced VEGF levels were about 10-fold higher in U87 compared to U251 and U251-NG2 cells. In addition, in the XTT assay, the U87 was more radioresistant than both U251 and U251-NG2 cell lines (dose modifying factor (DMF) = 1.6 and 1.7 resp). CONCLUSION: Irradiation enhanced VEGF secretion in all three tested glioma cell lines (up to eight times basal levels). It is tempting to associate the radiation-enhanced VEGF secretion with an increased angiogenic potential of the tumor, which may be a factor in radioresistance.

Bioavailability of contaminants estimated from uptake rates into soil invertebrates.

It is often argued that the concentration of a pollutant inside an organism is a good indicator of its bioavailability, however, we show that the rate of uptake, not the concentration itself, is the superior predictor. In a study on zinc accumulation and toxicity to isopods (Porcellio scaber) the dietary EC(50) for the effect on body growth was rather constant and reproducible, while the internal EC(50) varied depending on the accumulation history of the animals. From the data a critical value for zinc accumulation in P. scaber was estimated as 53 microg/g/wk. We review toxicokinetic models applicable to time-series measurements of concentrations in invertebrates. The initial slope of the uptake curve is proposed as an indicator of bioavailability. To apply the dynamic concept of bioavailability in risk assessment, a set of representative organisms should be chosen and standardized protocols developed for exposure assays by which suspect soils can be evaluated.

Common mental disorders and use of general health services: a review of the literature on population-based studies.

OBJECTIVE: To review population-based studies on the association between common mental disorders and the use of general (non-mental) health care services. METHOD: Literature search in Medline and PsychLit databases. Only studies with a prospective design and correction for somatic morbidity were included for review. RESULTS: On the most general level of outcomes considered and in the majority of studies, mental disorders were associated with higher service use. This general tendency is not consistently reflected in the use of specific health care services, but is materialized in different patterns of out-patient and in-patient service utilization, which vary from study to study. Findings for the elderly were less clear-cut than for other age groups. CONCLUSION: Mental disorders are related to higher general health care service use on a global, aggregated level. These associations are not specific for certain types of services.

Two metal-binding peptides from the insect Orchesella cincta (Collembola) as a result of metallothionein cleavage.

Metallothionein (MT) is an ubiquitous heavy metal-binding protein which has been identified in animals, plants, protists, fungi and bacteria. In insects, primary structures of MTs are known only for Drosophila and the collembolan, Orchesella cincta. The MT cDNA from O. cincta encodes a 77 amino acid protein with 19 cysteines. Isolations of the protein itself have demonstrated the presence of two smaller metal-binding peptides, whose amino acid sequences correspond to parts of the cDNA, and which apparently result from cleavage of the native protein. The present study was undertaken to complete the picture of cleavage sites within the MT protein by applying protein isolation techniques in combination with mass spectrometry and N-terminal sequence analysis. Further, recombinant expression allowed us to study the intrinsic stability of the MT and to perform in vitro cleavage studies. The results show that the MT from O. cincta is specifically cleaved at two sites, both after the amino acid sequence Thr-Gln (TQ). One of these sites is located in the N-terminal region and the other in the linker region between two putative metal-binding clusters. When expressed in Escherichia coli, the recombinant O. cincta MT can be isolated in an uncleaved form; however, this protein can be cleaved in vitro by the proteolytic activity of O. cincta. In combination with other studies, the results suggest that the length of the linker region is important for the stability of MT as a two domain metal-binding protein.

Biomarkers in terrestrial invertebrates for ecotoxicological soil risk assessment.

This review has served to present the most recent information on a selected series of biomarker studies undertaken on soil invertebrates during two extensive European-funded scientific consortia, BIOPRINT and BIOPRINT-II. The goals were to develop and validate methods for the analysis of markers of stress in a range of soil-dwelling organisms. We have discussed the potential and limitations of the following invertebrate biomarkers for soil risk assessment purposes: heat shock proteins, histological and ultrastructural markers, metallothioneins and metal-binding proteins, esterases, lysosomal integrity, and the novel biomarker histidine. The hsp response in soil invertebrates is especially suitable to indicate the effects of exposure to comparatively low concentrations for a range of toxicants and can be regarded as a biomarker of general stress. The application of MTs and other metal-binding proteins as biomarkers for exposure in soil invertebrates has been well described, and new methods are being developed for analyzing MT induction both at the protein and molecular level, and reliable and reproducible methods are now available. (Cd)-MT is well characterized for the springtails and its MT concentration is a useful biomarker for exposure as well as for effect. For snails, (Cd)-MT can accumulate in the midgut gland over extended periods of time and therefore its concentration is a biomarker not only for recent intoxication but also for events of cadmium exposure that snails may have experienced a long time before the measurement took place. Cellular and histological alterations can be regarded as reflecting the "health" state of a cell, which may be a measure for the presence of toxicants. Histopathological work on terrestrial invertebrates, however, is still scarce. Isozymes have been poorly studied in soil invertebrates despite their promising role as potential biomarkers in aquatic organisms. Among the large diversity of isozymes, the most well studied are esterases that are frequently used a biomarkers of exposure to various classes of pesticides. Many other isozymes offer potentials for biomarker research, such as glucosephosphate isomerase and phosphoglucomutase, both enzymes necessary for the glycolytic pathway. The lysosomal system has been identified as a particular target for the toxic effects of xenobiotics, although it has yet a limited application in soil invertebrates. This marker is nonspecific, responding equally sensitively to organic or inorganic contamination; however, if used in combination with an earthworm immnunocompetence assay such as total immunoactivity of the coelomocytes, then it is possible to be more specific as to the likely nature of contamination. Free histidine was positively correlated with increasing copper exposure and total copper burden in earthworms from a semifield study. Histidine may thus act as a biomarker of exposure. The transient responses and confounding factors of biomarkers obscure a proper interpretation of biomarker responses under field conditions. These factors are still very poorly understood and require more study. For risk assessment purposes it is recommended that the aforementioned biomarkers may show promise when included in a suite of biomarkers among different soil invertebrate species. It is recommended that a risk assessment protocol draw upon ranking of biomarker responses on a defined scale. It is also hoped that the problems outlined in this review will aid the direction of future research on soil invertebrate biomarkers.