Increasing value and reducing waste by optimizing the development of complex interventions: Enriching the development phase of the Medical Research Council (MRC) Framework

This is the final version of the article. Available from Elsevier via the DOI in this record.Background In recent years there has been much emphasis on ‘research waste’ caused by poor question selection, insufficient attention to previous research results, and avoidable weakness in research design, conduct and analysis. Little attention has been paid to the effect of inadequate development of interventions before proceeding to a full clinical trial. Objective We therefore propose to enrich the development phase of the MRC Framework by adding crucial elements to improve the likelihood of success and enhance the fit with clinical practice Methods Based on existing intervention development guidance and synthesis, a comprehensive iterative intervention development approach is proposed. Examples from published reports are presented to illustrate the methodology that can be applied within each element to enhance the intervention design. Results A comprehensive iterative approach is presented by combining the elements of the MRC Framework development phase with essential elements from existing guidance including: problem identification, the systematic identification of evidence, identification or development of theory, determination of needs, the examination of current practice and context, modelling the process and expected outcomes leading to final element: the intervention design. All elements are drawn from existing models to provide intervention developers with a greater chance of producing an intervention that is well adopted, effective and fitted to the context. Conclusion This comprehensive approach of developing interventions will strengthen the internal and external validity, minimize research waste and add value to health care research. In complex interventions in health care research, flaws in the development process immediately impact the chances of success. Knowledge regarding the causal mechanisms and interactions within the intended clinical context is needed to develop interventions that fit daily practice and are beneficial for the end-user

Progressive neurological deficits in multiple myeloma: meningeal myelomatosis without MRI abnormalities

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Tissue culture response of CIMMYT elite bread wheat cultlvars and evaluation of regenerated plants

Six elite CIMMYT bread wheat genotypes Pavon 76, Seri M82, Opata M85, Mochis T88, Baviacora M93, and the advanced line Attila were evaluated for their response to in vitro tissue culture. Donor plants were grown at EI Batan and CIANO experiment stations in Mexico in 1992. Immature embryos, about 1.0 mm in length, were excised and placed scutellum side up on callus initiation media. Basal N6 medium supplemented with dicamba (E1), MS medium containing 2,40 (E3), or MS medium containing 2,40 plus different amino acids (E5) was used for callus initiation and maintenance. Plant regeneration and rooting were achieved on basal MS medium with IAA and BAP. Embryogenic calli with regeneration potentials of 10-92% were obtained on E3 and E5 media; each embryo produced 5-50 plants. A total of 800 regenerated plants were transferred to pots in the greenhouse for evaluation and seed production. Of the regenerated plants, 85% were morphologically normal. reached full maturity, and produced seeds. Seeds (R1) of 360 plants regenerated from Mochis T88, Baviacora M93, and Altila were planted in the field. Field observations indicated that embryos cultured on E3 medium resulted in 29% of the progeny producing deviating plants, compared with 21 % of those grown on E5 medium. These results will form the basis for future efforts aimed at transforming CIMMYT bread wheat varieties. IntroductionSix elite CIMMYT bread wheat genotypes Pavon 76, Seri M82, Opata M85, Mochis T88, Baviacora M93, and the advanced line Attila were evaluated for their response to in vitro tissue culture. Donor plants were grown at EI Batan and CIANO experiment stations in Mexico in 1992. Immature embryos, about 1.0 mm in length, were excised and placed scutellum side up on callus initiation media. Basal N6 medium supplemented with dicamba (E1), MS medium containing 2,40 (E3), or MS medium containing 2,40 plus different amino acids (E5) was used for callus initiation and maintenance. Plant regeneration and rooting were achieved on basal MS medium with IAA and BAP. Embryogenic calli with regeneration potentials of 10-92% were obtained on E3 and E5 media; each embryo produced 5-50 plants. A total of 800 regenerated plants were transferred to pots in the greenhouse for evaluation and seed production. Of the regenerated plants, 85% were morphologically normal. reached full maturity, and produced seeds. Seeds (R1) of 360 plants regenerated from Mochis T88, Baviacora M93, and Altila were planted in the field. Field observations indicated that embryos cultured on E3 medium resulted in 29% of the progeny producing deviating plants, compared with 21 % of those grown on E5 medium. These results will form the basis for future efforts aimed at transforming CIMMYT bread wheat varieties. Introductio

Diagnostic Laparoscopy as a Selection Tool for Patients with Colorectal Peritoneal Metastases to Prevent a Non-therapeutic Laparotomy During Cytoreductive Surgery

OBJECTIVE: The aim of this study was to evaluate the introduction of diagnostic laparoscopy (DLS) in patients with colorectal peritoneal metastases (PM) to prevent non-therapeutic laparotomies during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS + HIPEC). METHODS: Patients with histologically proven colorectal PM who underwent a laparotomy for potential CRS + HIPEC from January 2006 to January 2019 were retrospectively identified from a prospectively maintained database. In 2012, DLS was introduced in the preoperative work-up for CRS + HIPEC in our academic center. The rates of non-therapeutic laparotomies, major postoperative complications (Clavien-Dindo grade III or higher), and survival outcomes were investigated for patients who underwent a laparotomy before (cohort A) and after (cohort B) the introduction of DLS. In cohort B, the reasons to refrain from DLS were retrospectively explored from medical records. RESULTS: Overall, 172 patients were included [cohort A: 48 patients (27.9%); cohort B: 124 patients (72.1%)]. A significant drop in the rate of non-therapeutic laparotomies occurred in cohort B compared with cohort A (21.0 vs. 35.4%: p = 0.044), despite only 85 patients (68.5%) from cohort B undergoing DLS in our academic center. The most important reason to refrain from DLS was a recently performed DLS or laparotomy in the referring hospital (48.7%). Major postoperative complications, in-hospital mortality, and survival outcomes were similar for both cohorts. CONCLUSIONS: Performing DLS during the preoperative work-up for CRS + HIPEC prevents non-therapeutic laparotomies in patients with colorectal PM. We recommend performing this laparoscopic screening in an experienced HIPEC center

Epidemiology and outcome of infections with carbapenem-resistant Gram-negative bacteria treated with polymyxin B-based combination therapy

Introduction: Infections with carbapenem-resistant Gram-negative bacteria (CRGNB) are increasing and are associated with a high mortality. Synergistic effects of combination therapy with a polymyxin, carbapenem, and rifampin have been observed in in vitro studies. Clinical data are limited to retrospective studies.Methods: We performed an observational cohort study of patients over 18 y of age who were treated with polymyxin B combination therapy.Results: One hundred and four patients were studied. The mean age was 77 y; 73% had recently received antibiotics, 67% had recently been hospitalized, and 47% lived in a nursing facility. The most common infections were pneumonia and urinary tract infection due to Acinetobacter baumannii (33%), Klebsiella pneumoniae (24%), and Pseudomonas aeruginosa (11%). Treatment regimens included polymyxin B with a carbapenem in 48%, with additional rifampin in 23%. Clinical success was achieved in 50% and reinfection occurred in 25%. Treatment-related acute renal failure occurred in 14.4%. No treatment-related hemodialysis was needed. All-cause hospital mortality was 47% and mortality after 6 months was 77%. No significant difference was found between treatment regimens. Age (odds ratio (OR) 10.4 per 10 y, p = 0.04), severity of acute illness (OR 2.2 per point, p p = 0.04) were associated with hospital mortality. K. pneumoniae was associated with increased hospital survival compared to other CRGNB (p = 0.03).Conclusion: CRGNB infections are associated with previous antibiotic and health care exposure. Mortality is related to age and the severity of chronic and acute illness.Development Psychopathology in context: clinical setting

A tale of two worlds:assessing the vulnerability of enclave shielding runtimes

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Border skirmishes and the question of belonging: An authoethnographic account of everyday exclusion in multicultural society

Transnational migration has transformed most European countries, making the problem of how to 'integrate' an increasingly popular topic in public debates and social policy. It is assumed that as long as the newcomer learns the language, adapts to the local customs and finds work, s/he will be integrated and welcomed with open arms as a full-fledged member of society. Based on an autoethnography of our experiences as US-born, long-term and fully 'integrated' residents of the Netherlands, one of Europe's most multicultural societies, we have explored some of the subtle, well-intentioned practices of distancing and exclusion that are part of the fabric of everyday life. We will show how, contrary to the official discourse of integration, 'Dutch-ness' as a white/ethnic national identity is continuously constructed as a 'we', which excludes all 'others'. And, indeed, we have discovered that, paradoxically, the closer the 'other' comes to being completely assimilated into Dutch society, the more the symbolic borders of national belonging may need to be policed and tightened. © The Author(s) 2011

Long-Term Locoregional Vascular Morbidity After Isolated Limb Perfusion and External-Beam Radiotherapy for Soft Tissue Sarcoma of the Extremity

Background: Isolated limb perfusion (ILP) with tumor necrosis factor alpha (TNF-alpha) and melphalan, followed by delayed surgical resection and adjuvant external-beam radiotherapy is a limb salvage treatment strategy for locally advanced soft tissue sarcomas. The long-term vascular side effects of this combined procedure were evaluated. Methods: Thirty-two patients were treated for a locally advanced sarcoma of the upper (n = 5) or lower limb (n = 27). All patients underwent a noninvasive vascular work-up. Results: Five patients underwent a leg amputation, in two cases due to critical leg ischemia 10 years after ILP. With a median follow-up of 88 (range, 17-159) months, none of the patients with a salvaged lower leg (n = 22) experienced peripheral arterial occlusive disease. Ankle-brachial index (ABI) measurements in the involved leg (median, 1.02; range, .50-1.20) showed a significant decrease compared with the contralateral leg (median, 1.09; range, .91-1.36, P = .001). Pulsatility index (PI) was decreased in the treated leg in 17 of 22 patients at the femoral level (median, 6.30; range, 2.1-23.9 vs. median, 7.35; range, 4.8-21.9; P = .011) and in 19 of 20 patients at popliteal level (median, 8.35; range, 0-21.4 vs. median, 10.95; range, 8.0-32.6; P <.0005). In patients with follow-up of > 5 years, there was more often a decrease in ABI (P = .024) and PI at femoral level (P = .011). Conclusions: ILP followed by resection and external-beam radiotherapy can lead to major late vascular morbidity that requires amputation. Objective measurements show a time-related decrease of ABI and femoral PI in the treated extremity