Septorhinoplasty and Septoplasty: Outcomes of a Large Cohort Using Autologous Versus Homologous Cartilage, 1999-2019.

This study describes the complication rate and use of autologous and/or homologous cartilage in a large 20-year cohort of septo(rhino)plasty surgeries in a Dutch hospital, in relation to postoperative complications of septo(rhino)plasty surgery described in previous studies. A retrospective medical chart review was conducted. 2606 patients, mean age 34.7 (± 13.2) and 59.9% male, underwent primary or revision septo(rhino)plasty surgery from 01/01/1999 to 01/09/2019. Follow-up was known in 1384 of 2606 patients (53.1%) with a mean duration of 47.5 months. Complication registration was complete for 1774 patients. The overall complication rate was 270 out of 1774 (15.2%). The use of autologous costal cartilage (ACC) was a risk factor for overall complication with an odds ratio (OR) of 11.1 (95% CI 0.03-0.30; P < 0.01) as compared to 5.9 (95% CI 0.06-0.45; P < 0.01) when using homologous costal cartilage (HCC). Infections were more likely when ACC (5/26 [19.2%]) was used than when HCC (1/28 [3.6%]) was used. Notable resorption of cartilage was more likely when HCC (9/28 [32.1%]) was used than when ACC (1/26 [3.8%]) was used. Both the use of autologous costal cartilage grafts (OR 11.1) and homologous costal cartilage grafts (OR 5.9) lead to an increased risk of complications. When choosing cartilage type for reconstruction in septo(rhino)plasty, it should be taken into account that both ACC and HCC are associated with a higher risk of complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Supporting the use of theory in cross-country health services research: a participatory qualitative approach using Normalisation Process Theory as an example.

OBJECTIVES: To describe and reflect on the process of designing and delivering a training programme supporting the use of theory, in this case Normalisation Process Theory (NPT), in a multisite cross-country health services research study. DESIGN: Participatory research approach using qualitative methods. SETTING: Six European primary care settings involving research teams from Austria, England, Greece, Ireland, The Netherlands and Scotland. PARTICIPANTS: RESTORE research team consisting of 8 project applicants, all senior primary care academics, and 10 researchers. Professional backgrounds included general practitioners/family doctors, social/cultural anthropologists, sociologists and health services/primary care researchers. PRIMARY OUTCOME MEASURES: Views of all research team members (n=18) were assessed using qualitative evaluation methods, analysed qualitatively by the trainers after each session. RESULTS: Most of the team had no experience of using NPT and many had not applied theory to prospective, qualitative research projects. Early training proved didactic and overloaded participants with information. Drawing on RESTORE's methodological approach of Participatory Learning and Action, workshops using role play, experiential interactive exercises and light-hearted examples not directly related to the study subject matter were developed. Evaluation showed the study team quickly grew in knowledge and confidence in applying theory to fieldwork.Recommendations applicable to other studies include: accepting that theory application is not a linear process, that time is needed to address researcher concerns with the process, and that experiential, interactive learning is a key device in building conceptual and practical knowledge. An unanticipated benefit was the smooth transition to cross-country qualitative coding of study data. CONCLUSION: A structured programme of training enhanced and supported the prospective application of a theory, NPT, to our work but raised challenges. These were not unique to NPT but could arise with the application of any theory, especially in large multisite, international projects. The lessons learnt are applicable to other theoretically informed studies.

Reporting mental health problems of undocumented migrants in Greece: A qualitative exploration.

BACKGROUND: Mental health problems are highly prevalent amongst undocumented migrants (UMs), and often part of their consultations with general practitioners (GPs). Little empirical data are available of how GPs and UMs engage around mental health in Greece, a country with a lack of balance between primary and secondary care and limited healthcare provisions for UMs. OBJECTIVES: To acquire insight in the barriers and levers in the provision of mental healthcare for UMs by GPs in Greece. METHODS: This was a qualitative study using semi-structured interviews with 12 GPs in Crete, Greece with clinical expertise in the care of UMs. All interviews were audio-taped and transcribed verbatim and were analysed using thematic content analysis. RESULTS: Greek GPs recognized many mental health problems in UMs and identified the barriers that prevented them from discussing these problems and delivering appropriate care: growing societal resistance towards UMs, budget cuts in healthcare, administrative obstacles and lack of support from the healthcare system. To overcome these barriers, Greek GPs provided UMs with free access to care and psychotropic drugs free of charge, and referred to other primary care professionals rather than to mental healthcare institutions. CONCLUSION: Greek GPs experienced substantial barriers in the provision of mental healthcare to UMs and political, economic and organizational factors played a major role.

Mental health problems of undocumented migrants in the Netherlands: A qualitative exploration of recognition, recording, and treatment by general practitioners.

OBJECTIVE: To explore the views and experiences of general practitioners (GPs) in relation to recognition, recording, and treatment of mental health problems of undocumented migrants (UMs), and to gain insight in the reasons for under-registration of mental health problems in the electronic medical records. DESIGN: Qualitative study design with semi-structured interviews using a topic guide. SUBJECTS AND SETTING: Sixteen GPs in the Netherlands with clinical expertise in the care of UMs. RESULTS: GPs recognized many mental health problems in UMs. Barriers that prevented them from recording these problems and from delivering appropriate care were their low consultation rates, physical presentation of mental health problems, high number of other problems, the UM's lack of trust towards health care professionals, and cultural differences in health beliefs and language barriers. Referrals to mental health care organizations were often seen as problematic by GPs. To overcome these barriers, GPs provided personalized care as far as possible, referred to other primary care professionals such as social workers or mental health care nurses in their practice, and were a little less restrictive in prescribing psychotropics than guidelines recommended. CONCLUSIONS: GPs experienced a variety of barriers in engaging with UMs when identifying or suspecting mental health problems. This explains why there is a gap between the high recognition of mental health problems and the low recording of these problems in general practice files. It is recommended that GPs address mental health problems more actively, strive for continuity of care in order to gain trust of the UMs, and look for opportunities to provide mental care that is accessible and acceptable for UMs.

Peptide vectors for gene delivery: from single peptides to multifunctional peptide nanocarriers.

The therapeutic use of nucleic acids relies on the availability of sophisticated delivery systems for targeted and intracellular delivery of these molecules. Such a gene delivery should possess essential characteristics to overcome several extracellular and intracellular barriers. Peptides offer an attractive platform for nonviral gene delivery, as several functional peptide classes exist capable of overcoming these barriers. However, none of these functional peptide classes contain all the essential characteristics required to overcome all of the barriers associated with successful gene delivery. Combining functional peptides into multifunctional peptide vectors will be pivotal for improving peptide-based gene delivery systems. By using combinatorial strategies and high-throughput screening, the identification of multifunctional peptide vectors will accelerate the optimization of peptide-based gene delivery systems.

Mental health problems of undocumented migrants (UMs) in The Netherlands: a qualitative exploration of help-seeking behaviour and experiences with primary care.

OBJECTIVE: To explore health-seeking behaviour and experiences of undocumented migrants (UMs) in general practice in relation to mental health problems. DESIGN: Qualitative study using semistructured interviews and thematic analysis. PARTICIPANTS: 15 UMs in The Netherlands, varying in age, gender, country of origin and education; inclusion until theoretical saturation was reached. SETTING: 4 cities in The Netherlands. RESULTS: UMs consider mental health problems to be directly related to their precarious living conditions. For support, they refer to friends and religion first, the general practitioner (GP) is their last resort. Barriers for seeking help include taboo on mental health problems, lack of knowledge of and trust in GPs competencies regarding mental health and general barriers in accessing healthcare as an UM (lack of knowledge of the right to access healthcare, fear of prosecution, financial constraints and practical difficulties). Once access has been gained, satisfaction with care is high. This is primarily due to the attitude of the GPs and the effectiveness of the treatment. Reasons for dissatisfaction with GP care are an experienced lack of time, lack of personal attention and absence of physical examination. Expectations of the GP vary, medication for mental health problems is not necessarily seen as a good practice. CONCLUSIONS: UMs often see their precarious living conditions as an important determinant of their mental health; they do not easily seek help for mental health problems and various barriers hamper access to healthcare for them. Rather than for medication, UMs are looking for encouragement and support from their GP. We recommend that barriers experienced in seeking professional care are tackled at an institutional level as well as at the level of GP.

Mental health problems in undocumented and documented migrants: a survey study.

BACKGROUND: Undocumented migrants (UM) frequently report mental health problems. It is unknown to what extent these migrants seek help for these problems in general practice and how these issues are explored, discussed, registered and treated by GPs. OBJECTIVE: To gain insight in the registration and treatment of mental health problems in general practice of UM compared to documented migrants (DM). METHODS: A survey study of general practice patient records of UM and DM in nine general practices in the Netherlands. Consultation rates, registration of mental health problems, prescription of psychotropic medication and referrals to mental health care institutions of UM and DM patients were compared. RESULTS: A total of 541 migrants were included (325 UM and 216 DM). UM consulted a GP significantly less than DM (3.1 versus 4.9 times per year). Only 20.6% of the UM had at least one mental health problem diagnosis registered compared to 44.0% of the DM. In both groups, ~10% mentioned at least one main mental health complaint during the consultation that was not coded in the record. No significant differences were found in the prescription of psychotropic medication between the two groups. UM were referred less to mental health care institutions but more often to psychiatrists than to psychologists. CONCLUSION: UM had less consultations with their GP, and in these consultations, less mental health problems were registered. UM were referred less to psychologists but more often to psychiatrists. GPs are advised to explore and register mental health problems more actively in UM.

PEG-pHPMAm-based polymeric micelles loaded with doxorubicin-prodrugs in combination antitumor therapy with oncolytic vaccinia viruses.

An enzymatically activatable prodrug of doxorubicin was covalently coupled, using click-chemistry, to the hydrophobic core of poly(ethylene glycol)-b-poly[N-(2-hydroxypropyl)-methacrylamide-lactate] micelles. The release and cytotoxic activity of the prodrug was evaluated in vitro in A549 non-small-cell lung cancer cells after adding ß-glucuronidase, an enzyme which is present intracellularly in lysosomes and extracellularly in necrotic areas of tumor lesions. The prodrug-containing micelles alone and in combination with standard and ß-glucuronidase-producing oncolytic vaccinia viruses were also evaluated in vivo, in mice bearing A549 xenograft tumors. When combined with the oncolytic viruses, the micelles completely blocked tumor growth. Moreover, a significantly better antitumor efficacy as compared to virus treatment alone was observed when ß-glucuronidase virus treated tumor-bearing mice received the prodrug-containing micelles. These findings show that combining tumor-targeted drug delivery systems with oncolytic vaccinia viruses holds potential for improving anticancer therapy.

Production and biomedical applications of virus-like particles derived from polyomaviruses.

Virus-like particles (VLPs), aggregates of capsid proteins devoid of viral genetic material, show great promise in the fields of vaccine development and gene therapy. These particles spontaneously self-assemble after heterologous expression of viral structural proteins. This review will focus on the use of virus-like particles derived from polyomavirus capsid proteins. Since their first recombinant production 27 years ago these particles have been investigated for a myriad of biomedical applications. These virus-like particles are safe, easy to produce, can be loaded with a broad range of diverse cargoes and can be tailored for specific delivery or epitope presentation. We will highlight the structural characteristics of polyomavirus-derived VLPs and give an overview of their applications in diagnostics, vaccine development and gene delivery.

A solid-phase platform for combinatorial and scarless multipart gene assembly.

With the emergence of standardized genetic modules as part of the synthetic biology toolbox, the need for universal and automatable assembly protocols increases. Although several methods and standards have been developed, these all suffer from drawbacks such as the introduction of scar sequences during ligation or the need for specific flanking sequences or a priori knowledge of the final sequence to be obtained. We have developed a method for scarless ligation of multipart gene segments in a truly sequence-independent fashion. The big advantage of this approach is that it is combinatorial, allowing the generation of all combinations of several variants of two or more modules to be ligated in less than a day. This method is based on the ligation of single-stranded or double-stranded oligodeoxynucleotides (ODN) and PCR products immobilized on a solid support. Different settings were tested to optimize the solid-support ligation. Finally, to show proof of concept for this novel multipart gene assembly platform a small library of all possible combinations of 4 BioBrick modules was generated and tested.

Π-π stacking increases the stability and loading capacity of thermosensitive polymeric micelles for chemotherapeutic drugs.

Thermosensitive amphiphilic block copolymers self-assemble into micelles above their lower critical solution temperature in water, however, the micelles generally display mediocre physical stability. To stabilize such micelles and increase their loading capacity for chemotherapeutic drugs, block copolymers with novel aromatic monomers were synthesized by free radical polymerization of N-(2-benzoyloxypropyl methacrylamide (HPMAm-Bz) or the corresponding naphthoyl analogue (HPMAm-Nt), with N-(2-hydroxypropyl) methacrylamide monolactate, using a polyethylene glycol based macroinitiator. The critical micelle temperatures and critical micelle concentrations decreased with increasing the HPMAm-Bz/Nt content. The micelles of 30-50 nm were prepared by heating the polymer aqueous solutions from 0 to 50 °C and were colloidally stable for at least 48 h at pH 7.4 and 37 °C. Paclitaxel and docetaxel encapsulation was performed by mixing drug solutions in ethanol with polymer aqueous solutions and heating from 0 to 50 °C. The micelles had a drug loading capacity up to 34 wt % for docetaxel, which is among the highest loadings reported for polymeric micelles, with loaded micelle sizes ranging from 60 to 80 nm. The micelles without aromatic groups almost completely released loaded paclitaxel in 10 days, whereas the HPMAm-Bz/Nt containing micelles released 50% of the paclitaxel at the same time, which showed a better retention for the drug of the latter micelles. (1)H solid-state NMR spectroscopy data are compatible with π-π stacking between aromatic groups. The empty micelles demonstrated good cytocompatibility, and paclitaxel-loaded micelles showed high cytotoxicity to tumor cells. In conclusion, the π-π stacking effect introduced by aromatic groups increases the stability and loading capacity of polymeric micelles.

REsearch into implementation STrategies to support patients of different ORigins and language background in a variety of European primary care settings (RESTORE): study protocol.

BACKGROUND: The implementation of guidelines and training initiatives to support communication in cross-cultural primary care consultations is ad hoc across a range of international settings with negative consequences particularly for migrants. This situation reflects a well-documented translational gap between evidence and practice and is part of the wider problem of implementing guidelines and the broader range of professional educational and quality interventions in routine practice. In this paper, we describe our use of a contemporary social theory, Normalization Process Theory and participatory research methodology--Participatory Learning and Action--to investigate and support implementation of such guidelines and training initiatives in routine practice. METHODS: This is a qualitative case study, using multiple primary care sites across Europe. Purposive and maximum variation sampling approaches will be used to identify and recruit stakeholders-migrant service users, general practitioners, primary care nurses, practice managers and administrative staff, interpreters, cultural mediators, service planners, and policy makers. We are conducting a mapping exercise to identify relevant guidelines and training initiatives. We will then initiate a PLA-brokered dialogue with stakeholders around Normalization Process Theory's four constructs--coherence, cognitive participation, collective action, and reflexive monitoring. Through this, we will enable stakeholders in each setting to select a single guideline or training initiative for implementation in their local setting. We will prospectively investigate and support the implementation journeys for the five selected interventions. Data will be generated using a Participatory Learning and Action approach to interviews and focus groups. Data analysis will follow the principles of thematic analysis, will occur in iterative cycles throughout the project and will involve participatory co-analysis with key stakeholders to enhance the authenticity and veracity of findings. DISCUSSION: This research employs a unique combination of Normalization Process Theory and Participatory Learning and Action, which will provide a novel approach to the analysis of implementation journeys. The findings will advance knowledge in the field of implementation science because we are using and testing theoretical and methodological approaches so that we can critically appraise their scope to mediate barriers and improve the implementation processes.

High-content screening of peptide-based non-viral gene delivery systems.

High-content screening (HCS) uses high-capacity automated fluorescence imaging for the quantitative analysis of single cells and cell populations. Here, we developed an HCS assay for rapid screening of non-viral gene delivery systems as exemplified by the screening of a small library of peptide-based transfectants. These peptides were simultaneously screened for transfection efficiency, cytotoxicity, induction of cell permeability and the capacity to transfect non-dividing cells. We demonstrated that HCS is a valuable extension to the already existing screening methods for the in vitro evaluation of non-viral gene delivery systems with the added value that multiple parameters can be screened in parallel thereby obtaining more information from a single screening event, which will accelerate the development of novel gene delivery systems.