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Abstract Combining radiation therapy with immunotherapy is a strategy to improve both treatments. The purpose of this study was to compare responses for two syngeneic head and neck cancer (HNC) tumor models in mice following X-ray or proton irradiation with or without immune checkpoint inhibition (ICI). MOC1 (immunogenic) and MOC2 (less immunogenic) tumors were inoculated in the right hind leg of each mouse (C57BL/6J, n = 398). Mice were injected with anti-PDL1 (10 mg/kg, twice weekly for 2 weeks), and tumors were treated with single-dose irradiation (5–30 Gy) with X-rays or protons. MOC2 tumors grew faster and were more radioresistant than MOC1 tumors, and all mice with MOC2 tumors developed metastases. Irradiation reduced the tumor volume in a dose-dependent manner. ICI alone reduced the tumor volume for MOC1 with 20% compared to controls, while no reduction was seen for MOC2. For MOC1, there was a clear treatment synergy when combining irradiation with ICI for radiation doses above 5 Gy and there was a tendency for X-rays being slightly more biologically effective compared to protons. For MOC2, there was a tendency of protons being more effective than X-rays, but both radiation types showed a small synergy when combined with ICI. Although the responses and magnitudes of the therapeutic effect varied, the optimal radiation dose for maximal synergy appeared to be in the order of 10–15 Gy, regardless of tumor model.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Purpose CHEK2 c.1100delC is associated with an increased breast cancer risk in women. While this variant is prevalent in the Netherlands (1% in the general population), knowledge of aetiology and prognosis of breast cancer and other tumours in CHEK2 c.1100delC carriers is lacking. The nationwide HEreditary Breast and Ovarian cancer study the Netherlands (Hebon) cohort aims to answer study questions in families with an increased risk of breast cancer and ovarian cancer. While initially focusing on BRCA1/2-variant families, Hebon gradually expanded to include pathogenic variants in other genes associated with breast and/or ovarian cancer over time. This provides an excellent setting to establish a cohort to ultimately study the impact of CHEK2 c.1100delC on cancer risk prediction and surveillance, breast cancer treatment and prognosis.Participants We invited all heterozygous and homozygous CHEK2 c.1100delC indexes and tested female relatives. 1802 women were included, of whom 1374 were heterozygotes and 938 were breast cancer cases. Pedigrees were collected from all clinical genetic departments. Furthermore, participants completed a detailed questionnaire on hormonal and lifestyle factors, family history, cancer diagnosis and treatment.Findings to date Mean age at study inclusion was 53 years. Linkage with the Netherlands Cancer Registry showed a younger age at diagnosis in homozygotes (mean age 41.7 years) and heterozygotes (47.9 years) than non-carriers (51.2 years). Furthermore, carriers were more often diagnosed with grade 2, oestrogen receptor-positive breast cancer and more often developed contralateral breast cancer than non-carriers. Most women consumed alcohol regularly and about half never smoked.Future plans Further data linkages with the Netherlands Cancer Registry will allow prospective follow-up and breast cancer risk assessment in unaffected women at the time of genetic testing, risk of contralateral breast cancer and survival in patients with breast cancer. Also, linkage with the nationwide network and registry of histopathology and cytopathology in The Netherlands (PALGA) allows us to retrieve tumour samples to study tumourigenesis.

Objectives Methotrexate (MTX) is one of the most commonly used medications to treat rheumatoid arthritis (RA). However, the effect of MTX treatment on cellular immune responses remains incompletely understood. This raises concerns about the vulnerability of these patients to emerging infections and following vaccination.Methods In the current study, we investigated the impact of MTX treatment in patients with immune-mediated inflammatory disease on B and CD4 T cell SARS-CoV-2 vaccination responses. Eighteen patients with RA and two patients with psoriatic arthritis on MTX monotherapy were included, as well as 10 patients with RA without immunosuppressive treatment, and 29 healthy controls. CD4 T and B cell responses were analysed 7 days and 3–6 months after two SARS-CoV-2 messenger RNA vaccinations. High-dimensional flow cytometry analysis was used to analyse fresh whole blood, an activation-induced marker assay to measure antigen-specific CD4 T cells, and spike probes to study antigen-specific B cells.Results Seven days following two SARS-CoV-2 vaccinations, total B and T cell counts were similar between MTX-treated patients and controls. In addition, spike-specific B cell frequencies were unaffected. Remarkably, the frequency of antigen-specific CD4 T cells was reduced in patients using MTX and correlated strongly with anti-RBD IgG antibodies. These results suggest that decreased CD4 T cell activity may result in slower vaccination antibody responses in MTX-treated patients.Conclusion Taken together, MTX treatment reduces vaccine-induced CD4 T cell activation, which correlates with lower antibody responses.Trial registration number NL8900.

Interprofessional education is one of the interventions used to increase health care students’ motivation for working with older patients. Previous research about such interventions has been conducted without the use of control groups and has given inconclusive results. The objective of the present curricular resource was: Does geriatric paper-based interprofessional education influence students’ interest in treating older people? During a one-year period, undergraduate fourth-year medical and third-year nursing students wrote four health care plans for four different paper-based older patient cases. In the intervention group students were paired up in interprofessional couples. In the control group students made the assignment alone. Interest for working with older patients was measured on a 5-point Likert scale before and one year after the intervention. In both groups, no significant change was found. Before-interest score of the interprofessional group was relatively high (3.8) so the non-significant results may be due to a ceiling effect. Nursing students’ interest in treating older people at the start of the research was higher than medical students’ interest.

Abstract Three-dimensional facial stereophotogrammetry provides a detailed representation of craniofacial soft tissue without the use of ionizing radiation. While manual annotation of landmarks serves as the current gold standard for cephalometric analysis, it is a time-consuming process and is prone to human error. The aim in this study was to develop and evaluate an automated cephalometric annotation method using a deep learning-based approach. Ten landmarks were manually annotated on 2897 3D facial photographs. The automated landmarking workflow involved two successive DiffusionNet models. The dataset was randomly divided into a training and test dataset. The precision of the workflow was evaluated by calculating the Euclidean distances between the automated and manual landmarks and compared to the intra-observer and inter-observer variability of manual annotation and a semi-automated landmarking method. The workflow was successful in 98.6% of all test cases. The deep learning-based landmarking method achieved precise and consistent landmark annotation. The mean precision of 1.69 ± 1.15 mm was comparable to the inter-observer variability (1.31 ± 0.91 mm) of manual annotation. Automated landmark annotation on 3D photographs was achieved with the DiffusionNet-based approach. The proposed method allows quantitative analysis of large datasets and may be used in diagnosis, follow-up, and virtual surgical planning.

Abstract Background The increasingly complex patient care in the twenty-first century is delivered by interprofessional health care teams. Interprofessional collaboration can be taught during interprofessional education. However, whether a long-term change in collaborative competencies can be achieved by interprofessional education has not been studied sufficiently. Our research questions were: How does motivation for interprofessional collaboration and interprofessional collaborative skills change up to one year after an interprofessional educational intervention? How are they related to each other? Methods During a one-year period, undergraduate medical and nursing students attended four interprofessional (intervention) or uniprofessional (control group) education sessions. Self-determination Theory was used as the theoretical framework. Autonomous and controlled motivation scores for interprofessional collaboration were calculated using the Academic Self-Regulation Questionnaire, before (T1), directly after (T2) and one year post-intervention (T3). At T3, the students also filled out the Interprofessional Collaborative Competencies Attainment Survey (ICCAS), which measured the perceived attainment of collaborative competencies by a retrospective pre-test/post-test design. We used linear mixed effects models to analyse the motivation scores and linear regression for the relation between motivation and competence. Results In the interprofessional group, autonomous motivation scores of the participants were significantly lower at T2 vs. T1. Controlled motivation scores were significantly higher at T3 vs. T1. Controlled motivation scores for T2 were significantly higher in the uniprofessional group than in the interprofessional group. Perceived competence was related to higher autonomous motivation scores. At T3 the interprofessional collaborative competencies seemed to have grown more among students in the interprofessional group. Conclusions The perceived growth in interprofessional collaboration competence lasted at least up to one year after the intervention, and was measurable with the ICCAS. The growth was significantly more in the IPE students than in the UPE students. The few differences found in motivation scores for interprofessional collaboration were probably caused by an imbalance of nursing versus medical students over the different time points. This finding indicates that classroom based IPE can contribute to interprofessional collaboration skills of nursing and medical students at least up to one year after an intervention.

Abstract CINAC-patients present renal proximal tubular cell lysosomal lesions which are also observed in patients experiencing calcineurin inhibitor (CNI) nephrotoxicity, suggesting that CINAC is a toxin-induced nephropathy. An alternative hypothesis advocates chronic dehydration as a major etiological factor for CINAC. Here, we evaluated histological and molecular changes in dehydrated versus toxin exposed rats. Wistar rats were divided in 3 groups. Group 1 (n = 6) had free access to drinking water (control group). Group 2 (n = 8) was water deprived for 10 h per 24 h, 5 days/week and placed in an incubator (37 °C) for 30 min/h during water deprivation. Group 3 (n = 8) underwent daily oral gavage with cyclosporine (40 mg/kg body weight). After 28 days, renal function, histopathology and proteomic signatures were analysed. Cyclosporine-treated rats developed focal regions of atrophic proximal tubules with associated tubulo-interstitial fibrosis. PASM staining revealed enlarged argyrophilic granules in affected proximal tubules, identified as lysosomes by immunofluorescent staining. Electron microscopy confirmed the enlarged and dysmorphic phenotype of the lysosomes. Overall, these kidney lesions resemble those that have been previously documented in farmers with CINAC. Dehydration resulted in none of the above histopathological features. Proteomic analysis revealed that dehydration and cyclosporine both induce injury pathways, yet of a clear distinct nature with a signature of toxicity only for the cyclosporine group. In conclusion, both cyclosporine and dehydration are injurious to the kidney. However, dehydration alone does not result in kidney histopathology as observed in CINAC patients, whereas cyclosporine administration does. The histopathological analogy between CINAC and calcineurin inhibitor nephrotoxicity in rats and humans supports the involvement of an as-yet-unidentified environmental toxin in CINAC etiology.

BackgroundPatients undergoing spinal surgery report high levels of insecurity, pain, stress, and anxiety before and after surgery. Unfortunately, there is no guarantee that surgery will resolve all issues; postsurgical recovery often entails moderate to severe postoperative pain, and some patients undergoing spinal surgery do not experience (long-term) pain relief after surgery. Therefore, focusing on sustainable coping skills and resilience is crucial for these patients. A digital health intervention based on acceptance and commitment therapy (ACT) and positive psychology (PP) was developed to enhance psychological flexibility and well-being and reduce postsurgical pain. ObjectiveThe objective of this study was 3-fold: to explore the potential benefits for patients undergoing spinal surgery of the digital ACT and PP intervention Strength Back (research question [RQ] 1), explore the feasibility of a future randomized controlled trial in terms of recruitment and dropout (RQ 2), and assess the acceptability of Strength Back by patients undergoing spinal surgery (RQ 3). MethodsWe used a nonrandomized experimental design with an intervention group (n=17) and a control group (n=20). To explore the potential benefits of the intervention, participants in both groups filled out questionnaires before and after surgery. These questionnaires included measurements of pain intensity (Numeric Pain Rating Scale), pain interference (Multidimensional Pain Inventory), anxiety and depression (Hospital Anxiety and Depression Scale), valued living (Engaged Living Scale), psychological flexibility (Psychological Inflexibility in Pain Scale), and mental well-being (Mental Health Continuum–Short Form). Semistructured interviews combined with log data and scores on the Twente Engagement With eHealth Technologies Scale were used to assess the acceptability of the intervention. ResultsA significant improvement over time in emotional (V=99; P=.03) and overall (V=55; P=.004) well-being (Mental Health Continuum–Short Form) was observed only in the intervention group. In addition, the intervention group showed a significantly larger decline in pain intensity (Numeric Pain Rating Scale) than did the control group (U=75; P=.003). Of the available weekly modules on average 80% (12/15) was completed by patients undergoing spinal fusion and 67% (6/9) was completed by patients undergoing decompression surgery. A total of 68% (17/25) of the participants used the intervention until the final interview. Most participants (15/17, 88%) in the intervention group would recommend the intervention to future patients. ConclusionsThis pilot feasibility study showed that combining ACT and PP in a digital health intervention is promising for patients undergoing spinal surgery as the content was accepted by most of the participants and (larger) improvements in pain intensity and well-being were observed in the intervention group. A digital intervention for patients undergoing (spinal) surgery can use teachable moments, when patients are open to learning more about the surgery and rehabilitation afterward. A larger randomized controlled trial is now warranted.

Abstract Tear fluid forms a potential source for biomarker identification, and can be minimal invasively collected via Schirmer strips. The lack of knowledge on the processing of Schirmer strips however complicates the analysis and between-study comparisons. We studied two different pre-processing methods, specifically the use of punches of the strip versus elution of the strip in a buffer. Tear fluid filled Schirmer strips were collected from 5 healthy participants, and divided into two halves over the length of the strip. In either part, punches or eluates were obtained from 4 different locations, from the first part touching the eye (head) to the end, to assess the protein distribution along the strips. The levels of 92 inflammatory proteins were measured in the punches/eluates using proximity extension assays. The punch method yielded higher protein detectability compared to the elution method (76% vs 66%; p ≤ 0.001). Protein expression level was found to be slightly higher in the head of the strip, however, 3 out of 5 punches from the head failed quality control. Protein expression levels over the remaining parts of the strips were similar. Our study showed beneficial use of punches of any part of the strip except the head in future biomarker research.

Abstract In this paper, a dual-frequency wireless power transfer method is proposed, capable of achieving controllable routing and providing power through magnetic coupling resonance to various positions on a two-dimensional plane. The plane is composed of multiple power supply units with a uniform structure. Every unit has two different resonant states to switch, an activated state to power the receiver and a low-power inactive state adopted to maintain power required for state-switching. By switching and combining units in different states through wireless control circuits, directional wireless transfer of power on the plane can be realized. The circuit of power transfer through coupling is modelled and analysed. Electromagnetic simulations are conducted, followed by implementation and test of an experimental system. Both single-receiver and multiple-receiver situations are applicable in this method. The highest transmission efficiency can reach 93.3% under single receiver situation after coupling 5 units, which reveals satisfactory ability in flexibility and efficiency. Embedded in multiple application scenes, we envision further possibilities of this method such as indoor-device wireless charging and free-moving robot charging systems in factories.

Abstract Background Interprofessional education (IPE) aims to improve students’ collaborative competencies and behaviour. The effect of classroom IPE on students’ perceptions of collaboration in clinical practice, and how knowledge is possibly transferred, has yet to be investigated. The research question of this study was: How does IPE in a classroom setting influence students’ perceptions of collaboration in clinical practice? Social capital theory is used as the theoretical lens. Social capital theory describes how social relationships generate benefits for the individuals involved. Social capital can be divided into three forms of social cohesion: bonding, bridging and linking social capital. Bonding refers to connections that are close and strong, such as family. Bridging social capital occurs in more distant relationships. Linking social capital refers to relationships between individuals with different power or social status. Methods A qualitative study with semi-structured face-to-face interviews was conducted to explore students’ perceptions and experiences. Nursing and medical students who had participated in four classroom IPE-sessions were asked about the perceived influence of the IPE-sessions they had attended on their interprofessional collaboration. Thematic analysis was conducted, with sensitising concepts of ‘bonding’, ‘bridging’ and ‘linking social capital’ from the social capital theory. Results Twenty-two interviews were conducted. Students experienced: 1) exchange of discipline specific knowledge, 2) general knowledge about each other’s responsibilities, 3) reduction of hierarchy, and 4) improvement in patient care. The first two themes reflect bridging social capital, since students experience that the other student is from a different group. The third theme reflects linking social capital, since students experience a difference in (social) status. The fourth theme most explicitly reflects ‘getting ahead’ or doing better, what is referred to as an effect of increased social capital. Conclusion This study reveals new insights regarding how increased social capital of undergraduate students after IPE-sessions in a classroom setting influences the way they conceptualise and experience interprofessional collaboration in clinical practice. These insights contribute to the understanding of the effectiveness of IPE in undergraduate curricula. Further research on long-term effects is underway.

Abstract Background Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). Methods Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. Results In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn’s disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8–59.8) of patients after the first vaccination, 61.5% (95% CI 59.2–63.7) after the second vaccination and 58% (95% CI 55.3–60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3–9.1), 7.4% (95% CI 6.2–8.7) and 6.8% (95% CI 5.4–8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (

ObjectivesScleritis represents a severe extra-articular manifestation of rheumatoid arthritis (RA). Recent clinical observations suggest a decreasing incidence of scleritis in RA, attributed to improved treatment options. Our study reports on the incidence and clinical characteristics of scleritis in RA observed in the biological era and reflects on our results in a historical perspective.MethodsWe performed a retrospective evaluation of all 1623 consecutive patients with RA diagnosed at the department of rheumatology between 2011 and 2021 at the Erasmus Medical Center to investigate the incidence of scleritis. We also reviewed clinical and laboratory data of all patients with scleritis and RA from the department of ophthalmology at our center. In addition, we reviewed the literature on this topic and discuss our results in view of changes over time.ResultsThe incidence of scleritis within recent series of patients with a diagnosis of RA in our tertiary center was 0,25% in 10 years (4 out of 1623; 2011-2021).The cumulative incidence of scleritis in RA based on literature review from the pre-biologic era varied from 0.7% per 8 years to 0,8% per 30 years. Manifestations and complications of scleritis remained unchanged over time, with scleral necrosis developing in more than 80% of cases and mortality of RA patients with scleritis remained similar to pre-biologic era (30% in 9 years after the onset of scleritis). The RA patients with scleritis often exhibited autoantibodies (rheumatoid factor and/or anti-citrullinated protein antibody) and erosive disease.ConclusionAlthough our recent series is characterized by a slightly lower incidence of scleritis in RA compared to the pre-biologic era, clinical presentation remained severe and similar to the pre-biologic era. Ophthalmologists and rheumatologists should be aware of scleritis as a severe extra-articular manifestation of RA.

Abstract The accuracy of intra-operative navigation is largely dependent on the intra-operative registration procedure. Next to accuracy, important factors to consider for the registration procedure are invasiveness, time consumption, logistical demands, user-dependency, compatibility and radiation exposure. In this study, a workflow is presented that eliminates the need for a registration procedure altogether: registration-free navigation. In the workflow, the maxillary dental model is fused to the pre-operative imaging data using commercially available virtual planning software. A virtual Dynamic Reference Frame on a splint is designed on the patient’s fused maxillary dentition: during surgery, the splint containing the reference frame is positioned on the patient’s dentition. This alleviates the need for any registration procedure, since the position of the reference frame is known from the design. The accuracy of the workflow was evaluated in a cadaver set-up, and compared to bone-anchored fiducial, virtual splint and surface-based registration. The results showed that accuracy of the workflow was greatly dependent on tracking technique used: the workflow was the most accurate with electromagnetic tracking, but the least accurate with optical tracking. Although this method offers a time-efficient, non-invasive, radiation-free automatic alternative for registration, clinical implementation is hampered by the unexplained differences in accuracy between tracking techniques.

Abstract In intra-operative navigation, a registration procedure is performed to register the patient’s position to the pre-operative imaging data. The registration process is the main factor that determines accuracy of the navigation feedback. In this study, a novel registration protocol for craniofacial surgery is presented, that utilizes a virtual splint with marker points. The accuracy of the proposed method was evaluated by two observers in five human cadaver heads, for optical and electromagnetic navigation, and compared to maxillary bone-anchored fiducial registration (optical and electromagnetic) and surface-based registration (electromagnetic). The results showed minimal differences in accuracy compared to bone-anchored fiducials at the level of the infra-orbital rim. Both point-based techniques had lower error estimates at the infraorbital rim than surface-based registration, but surface-based registration had the lowest loss of accuracy over target distance. An advantage over existing point-based registration methods (bone-anchored fiducials, existing splint techniques) is that radiological imaging does not need to be repeated, since the need for physical fiducials to be present in the image volume is eradicated. Other advantages include reduction of invasiveness compared to bone-achnored fiducials and a possible reduction of human error in the registration process.

Abstract In a wind tunnel we compared the colour preference for western flower thrips to four types of colour plates (clear, white, blue and yellow) applied with two types of glue (diffuse Stikem versus clear D41). Further the results for blue and yellow preference were validated in two greenhouses. In the wind tunnel, we found a clear preference of yellow over blue when a clear glue (D41) was used. However, with a more diffuse (whitish) glue (Stikem) the preference for yellow over blue disappeared, whereby the attraction to yellow decreased (58%) while the attraction to blue increased (65%). In the greenhouses, we found similar effects as in the wind tunnel with a decrease in attraction to yellow (35%) and increase in attraction to blue (32%) for Stikem compared to D41. Light measurements showed an increase of 18% of blue, 21% of violet light, 8% of yellow and 9% of green light reflected on the yellow Stikem trap versus the yellow D41 trap. On blue plates there was only 4% increase of blue light, 8% decrease of yellow light reflected when Stikem glue was used compared to D41 glue. It is not yet clear if the change of light reflection ratio blue/yellow caused by the glue type plays a role in the change of attraction. The reflective properties of glue are so far an unknown factor in colour choice and may explain partially the different results on colour preference. A small review on thrips colour preference is discussed to determine possible other factors of influence on colour choice.

Abstract Current direct-acting antiviral therapies are highly effective in suppressing HIV-1 replication. However, mucosal inflammation undermines prophylactic treatment efficacy, and HIV-1 persists in long-lived tissue-derived dendritic cells (DCs) and CD4+ T cells of treated patients. Host-directed strategies are an emerging therapeutic approach to improve therapy outcomes in infectious diseases. Autophagy functions as an innate antiviral mechanism by degrading viruses in specialized vesicles. Here, we investigated the impact of pharmaceutically enhancing autophagy on HIV-1 acquisition and viral replication. To this end, we developed a human tissue infection model permitting concurrent analysis of HIV-1 cellular targets ex vivo. Prophylactic treatment with autophagy-enhancing drugs carbamazepine and everolimus promoted HIV-1 restriction in skin-derived CD11c+ DCs and CD4+ T cells. Everolimus also decreased HIV-1 susceptibility to lab-adapted and transmitted/founder HIV-1 strains, and in vaginal Langerhans cells. Notably, we observed cell-specific effects of therapeutic treatment. Therapeutic rapamycin treatment suppressed HIV-1 replication in tissue-derived CD11c+ DCs, while all selected drugs limited viral replication in CD4+ T cells. Strikingly, both prophylactic and therapeutic treatment with everolimus or rapamycin reduced intestinal HIV-1 productive infection. Our findings highlight host autophagy pathways as an emerging target for HIV-1 therapies, and underscore the relevancy of repurposing clinically-approved autophagy drugs to suppress mucosal HIV-1 replication.

INTRODUCTION: Self-Management Health Systems (SMHS) are envisioned to support older adults andcontribute to ageing in place. To promote the use and acceptance of SMHS, designers may resort to usingmotivational design techniques (MDT).OBJECTIVES: This paper investigates how and which older adults prefer MDT in SMHS and whether thesepreferences are mediated by either motivation for health management (MHM) or mobile device proficiency (MDP).METHODS: Based on a user evaluation with 45 older adults (mean age=84, SD=6.75), 32 MDT, MHM, andMDP were polled through questionnaires and informal interviews.RESULTS: Findings showed that most techniques were welcomed, but also that scores vary widely, reflecting heterogeneity in the population and calling for caution in its implementation. These findings are then translated into implications for design.CONCLUSION: Overall, older adults welcome MDT in SMHS. However, MDT are no panacea; tailoring MDTto users’ needs is therefore crucial.

BackgroundAlthough compression therapy is well established for patients with deep venous thrombosis (DVT) and chronic venous disease (CVD), considerable variation exists in its organization in clinical practice which may impact patient outcomes. The current study aims to deepen our understanding of the main drivers of the complex care organization for compression therapy and to identify targets for improvement.MethodsThis realist evaluation includes a mixed-method design consisting of semi-structured interviews with patients and health care professionals involved in compression therapy (n = 30), stakeholder meetings (n = 2) and surveys (n = 114). Data were collected to create the content of context-mechanism-outcome-configurations (CMOcs) important in compression therapy. Based on these CMOcs, targets for improvement to optimize the organization of compression care were identified.ResultsWe identified overarching context factors and mechanisms targeting four optimal outcomes for the organization of compression therapy: selecting initial compression therapy types that support patient's self-reliance (1), evidence based selection of elastic compression stocking type and class (2), patient-based selection of assistive devices (3), individualizing treatment duration for DVT patients (4a) and providing follow-up for CVD patients (4b). We found that increasing health care professionals' knowledge of compression therapy, the availability of unambiguous protocols and guidelines, increasing patient involvement (and if applicable their informal care giver) in the decision making process, the accessible availability of resources, and increasing interdisciplinary consultation enhanced desirable outcomes. These targets triggered mechanisms such as increased health care professionals' willingness, confidence and motivation to provide patient-based care and increased patients' self-confidence and self-efficacy.ConclusionsThis study provides a detailed insight into what needs to be in place to optimize compression care and identified five main targets for improvement.

Introduction Poverty has far-reaching and detrimental effects on children’s physical and mental health, across all geographies. Financial advice and income-maximisation services can provide a promising opportunity for shifting the physical and mental health burdens that commonly occur with financial hardship, yet awareness of these services is limited, and referrals are not systematically integrated into existing healthcare service platforms. We aim to map and synthesise evidence on the impact of healthcare-income maximisation models of care for families of children aged 0–5 years in high-income countries on family finances, parent/caregiver(s) or children’s health and well-being.Methods and analysis To be included in the review, studies must be families (expectant mothers or parents/caregivers) of children who are aged between 0 and 5 years, accessing a healthcare service, include a referral from healthcare to an income-maximisation service (ie, financial counselling), and examine impacts on child and family health and well-being. A comprehensive electronic search strategy will be used to identify studies written in English, published from inception to January 2021, and indexed in MEDLINE, EMBase, PsycINFO, CINAHL, Proquest, Family & Society Studies Worldwide, Cochrane Library, and Informit Online. Search strategies will include terms for: families, financial hardship and healthcare, in various combinations. Bibliographies of primary studies and review articles meeting the inclusion criteria will be searched manually to identify further eligible studies, and grey literature will also be searched. Data on objective and self-reported outcomes and study quality will be independently extracted by two review authors; any disagreements will be resolved through a third reviewer. The protocol follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols.Ethics and dissemination Ethical approval is not required. The results will be disseminated widely via peer-reviewed publication and presentations at conferences related to this field.PROSPERO registration number CRD42020195985.

BackgroundThe digital transformation in health care has been accelerated by the COVID-19 pandemic. Video consultation has become the alternative for hospital consultation. It remains unknown how to select patients suitable for video consultation. ObjectiveThis study aimed to develop a tool based on patient-reported outcomes (PROs) to triage total hip arthroplasty (THA) patients to hospital or video consultation. MethodsA pilot study with expert panels and a retrospective cohort with prospectively collected data from 1228 THA patients was executed. The primary outcome was a PRO triage tool to allocate THA patients to hospital or video consultation 6 weeks postoperatively. Expert panels defined the criteria and selected the patient-reported outcome measure (PROM) questions including thresholds. Data were divided into training and test cohorts. Distribution, floor effect, correlation, responsiveness, PRO patient journey, and homogeneity of the selected questions were investigated in the training cohort. The test cohort was used to provide an unbiased evaluation of the final triage tool. ResultsThe expert panels selected moderate or severe pain and using 2 crutches as the triage tool criteria. PROM questions included in the final triage tool were numeric rating scale (NRS) pain during activity, 3-level version of the EuroQol 5 dimensions (EQ-5D-3L) questions 1 and 4, and Oxford Hip Score (OHS) questions 6, 8, and 12. Of the training cohort, 201 (201/703, 28.6%) patients needed a hospital consultation, which was statistically equal to the 150 (150/463, 32.4%) patients in the test cohort who needed a hospital consultation (P=.19). ConclusionsA PRO triage tool based on moderate or severe pain and using 2 crutches was developed. Around 70% of THA patients could safely have a video consultation, and 30% needed a hospital consultation 6 weeks postoperatively. This tool is promising for selecting patients for video consultation while using an existing PROM infrastructure.

Objectives Elastic compression stocking (ECS) therapy is an important treatment for patients with deep venous thrombosis (DVT) and chronic venous insufficiency (CVI). This study aimed to provide insight into the structure and variability of the ECS therapy process, its effects on outcomes, and to elicit improvement themes from a multiple stakeholder perspective.Design Thirty semi-structured interviews with professionals and patients were performed. The essential functions for the process of ECS therapy were extracted to create two work-as-done models using the Functional Resonance Analysis Method (FRAM). These findings were used to guide discussion between stakeholders to identify improvement themes.Setting Two regions in the Netherlands, region Limburg and region North-Holland, including an academic hospital and a general hospital and their catchment region.Participants The interviewees were purposely recruited and included 25 healthcare professionals (ie, general practitioners, internists, dermatologists, nurses, doctor’s assistants, occupational therapists, home care nurses and medical stocking suppliers) and 5 patients with DVT or CVI.Results Two FRAM models were created (one for each region). The variability of the functions and their effect on outcomes, as well as interdependencies between functions, were identified. These were presented in stakeholder meetings to identify the structure of the process and designated variable and uniform parts of the process and its outcomes. Ultimately, six improvement themes were identified: dissemination of knowledge of the entire process; optimising and standardising initial compression therapy; optimising timing to contact the medical stocking supplier (when oedema has disappeared); improving the implementation of assistive devices; harmonising follow-up duration for patients with CVI; personalising follow-up and treatment duration in patients with DVT.Conclusions This study provided a detailed understanding of how ECS therapy is delivered in daily practice by describing major functions and variability in performances and elicited six improvement themes from a multistakeholder perspective.

Objectives Guidelines advise to test for anti–Sjögren's-syndrome-related antigen A (anti-SSA) and anti–Sjögren's-syndrome-related antigen B (anti-SSB) antibodies in all patients with rheumatoid arthritis (RA) who wish to conceive. Our objective was to determine the prevalence and titres of anti-SSA and anti-SSB autoantibodies in patients with RA with a wish to conceive or pregnant.Methods Patients were derived from two large cohorts on RA and pregnancy (PARA cohort and PreCARA cohort). In addition, to determine the clinical relevance of searching for anti-SSA and anti-SSB in patients with RA, we studied the prevalence of the maternal diagnosis of RA in the French national registry of neonatal lupus syndrome (NLS) and congenital heart block (CHB).Results 26 out of 647 patients with RA had detectable anti-SSA and/or anti-SSB. Anti-SSA was detected in 25 out of 647 patients (3.9%) (Ro-52, n=17; Ro-60, n=19), anti-SSB in 7 out of 647 (1.1%). Thirteen women had a titre of >240 units/mL of anti-SSA antibodies. The prevalence of anti-SSA and/or anti-SSB was higher in rheumatoid factor (RF)-positive patients compared with RF-negative patients (5.1% vs 1.6%, p=0.04). No cases of CHB and/or NLS in the offspring were observed. In the French national register, the prevalence of RA in mothers with SSA related CHB was 1.5%.Conclusion Anti-SSA and anti-SSB have a low prevalence in patients with RA who wish to conceive. Especially for RF-negative patients, the current advise to test for anti-SSA and anti-SSB should be reconsidered.

Introduction Poverty and deprivation can harm children’s future health, learning, economic productivity and societal participation. The Australian Healthier Wealthier Families project seeks to reduce the childhood inequities caused by poverty and deprivation by creating a systematic referral pathway between two free, community-based services: universal, well-child nursing services, which provide health and development support to families with children from birth to school entry, and financial counselling. By adapting the successful Scottish ‘Healthier Wealthier Children’ model, the objectives of this Australian pilot are to test the (1) feasibility of systematising the referral pathway, and (2) short-term impacts on household finances, caregiver health, parenting efficacy and financial service use.Methods and analysis This pilot randomised controlled trial will run in three sites across two Australian states (Victoria and New South Wales), recruiting a total of 180 participants. Nurses identify eligible caregivers with a 6-item, study-designed screening survey for financial hardship. Caregivers who report one or more risk factors and consent are randomised. The intervention is financial counselling. The comparator is usual care plus information from a government money advice website. Feasibility will be evaluated using the number/proportion of caregivers who complete screening, consent and research measures, and access financial counselling. Though powered to assess feasibility, impacts will be measured 6 months post-enrolment with qualitative interviews and questionnaires about caregiver-reported income, loans and costs (adapted from national surveys, for example, the Household, Income and Labour Dynamics in Australia Survey); health (General Health Questionnaire 1, EuroQol five-dimensional questionnaire, Depression, Anxiety, Stress Scale short-form); efficacy (from the Longitudinal Study of Australian Children); and financial service use (study-designed) compared between arms.Ethics and dissemination Ethics committees of the Royal Children’s Hospital (HREC/57372/RCHM-2019) and South West Sydney Local Health District (2019/ETH13455) have approved the study. Participants and stakeholders will receive results through regular communication channels comprising meetings, presentations and publications.Trial registration number ACTRN12620000154909; prospectively registered. Pre-results.

Orthognathic surgery is a widely performed procedure to correct dentofacial deformities. Virtual treatment planning is an important preparation step. One advantage of the use of virtual treatment planning is the possibility to assess the accuracy of orthognathic surgery. In this study, a tool (OrthoGnathicAnalyser 2.0), which allows for quantification of the accuracy of orthognathic surgery, is presented and validated. In the OrthoGnathicAnalyser 2.0 the accuracy of the osseous chin can now be assessed which was not possible in the earlier version of the OrthoGnathicAnalyser. 30 patients who underwent bimaxillary surgery in combination with a genioplasty were selected from three different centers in the Netherlands. A pre-operative (CB)CT scan, virtual treatment planning and postoperative (CB)CT scan were required for assessing the accuracy of bimaxillary surgery. The preoperative and postoperative (CB)CT scans were aligned using voxel-based matching. Furthermore, voxel-based matching was used to align the pre-operative maxilla, mandible and rami towards their postoperative position whereas surface-based matching was used for aligning the pre-operative chin towards the postoperative position. The alignment resulted in a transformation matrix which contained the achieved translations and rotations. The achieved translations and rotations can be compared to planning values of the virtual treatment plan. To study the reproducibility, two independent observers processed all 30 patients to assess the inter-observer variability. One observer processed the patients twice to assess the intra-observer variability. Both the intra- and inter-observer variability showed high ICC values (> 0.92) and low measurement variations (< 0.673±0.684mm and < 0.654±0.824°). The results of this study show that the OrthoGnathicAnalyser 2.0 has an excellent reproducibility for quantification of skeletal movements between two (CB)CT scans.

The aims of this study were (1) to quantify the intra-individual variation in the upper airway measurements on supine computed tomography (CT) scans at two different time points; and (2) to identify the most stable parameters of the upper airway measurements over time. Ten subjects with paired CT datasets (3–6 months interval) were studied, using computer software to segment and measure the upper airway. The minimum cross-sectional area of the total airway and all its segments (velopharynx, oropharynx, tongue base, and epiglottis) generally had the largest variation, while the length of the total airway had the lowest variation. Sphericity was the only parameter that was stable over time (relative difference

BackgroundChronic pain can be complex and taxing to live with, and treatment and support require a multicomponent approach, which may not always be offered or available. Smartphones, tablets, and personal computers are already incorporated into patients’ daily lives, and therefore, they can be used to communicate, educate, and support self-management. Although some web-based self-management interventions exist, research examining the evidence and effect of digital solutions supporting self-management for patients living with chronic pain is limited, findings are inconclusive, and new innovative ideas and solutions are needed. ObjectiveThis feasibility pilot study aimed to explore the system use, perceived usefulness, ease of use, and preliminary effects of EPIO, an app-based cognitive-behavioral pain self-management intervention program for patients living with chronic pain. MethodsThe EPIO intervention was delivered in a blended-care model containing (1) one face-to-face introduction session, (2) nine cognitive behavior–based pain self-management modules, delivered in an app-based format for smartphones or tablets, and (3) one follow-up phone call at 2 to 3 weeks after the introduction session. Patients living with chronic pain (N=50) completed pre-post outcome measures at baseline and 3 months after the introduction session, with registration of system use (ie, log data) until 6 months. The use, perceived usefulness, and ease of use of the EPIO program were examined through system use data, as well as a study-specific use/usability questionnaire and the System Usability Scale (SUS). Outcome measures to test feasibility of use and estimate preliminary effects included the Brief Pain Inventory, health-related quality of life (HRQoL) scale, Hospital Anxiety and Depression Scale, Self-Regulatory Fatigue scale, Pain Catastrophizing Scale, and Chronic Pain Acceptance Questionnaire. ResultsParticipants (N=50) had a median age of 52 years (range 29-74 years) at inclusion and were mainly female (40/50, 80%). Thirty-one participants completed at least six of the nine modules within the 3-month study period (62% completion rate). Forty-five participants completed outcome measures at 3 months, and the EPIO program was rated as useful (ie, “totally agree” or “agree”; 39/45, 87%) and easy to use (42/45, 93%), and as having easily understandable exercises (44/45, 98%). The average overall system usability (SUS) score was 85.7, indicating grade A and excellent system usability. Preliminary psychosocial outcome measure estimates showed primarily nonsignificant pre-post intervention improvements at 3 months, but with significant positive effects related to some aspects of HRQoL (bodily pain, P=.02 and change, P=.049). Conclusions Digital self-management intervention programs may be of use and support for patients living with chronic pain. In this feasibility study, EPIO showed an acceptable program completion rate and was rated as useful and easy to use, with excellent user satisfaction. Program optimization and efficacy testing in a large-scale randomized controlled trial are warranted and in progress. Trial RegistrationClinicalTrials.gov NCT03705104; https://clinicaltrials.gov/ct2/show/NCT03705104

Abstract Background Medical schools must select students from a large pool of well-qualified applicants. A challenging issue set forward in the broader literature is that of which cognitive and (inter)personal qualities should be measured to predict diverse later performance. To address this gap, we designed a ‘backward chaining’ approach to selection, based on the competences of a ‘good doctor’. Our aim was to examine if this outcome-based selection procedure was predictive of study success in a medical bachelor program. Methods We designed a multi-tool selection procedure, blueprinted to the CanMEDS competency framework. The relationship between performance at selection and later study success across a three-year bachelor program was examined in three cohorts. Study results were compared between selection-positive and selection-negative (i.e. primarily rejected) students. Results Selection-positive students outperformed their selection-negative counterparts throughout the entire bachelor program on assessments measuring cognitive (e.g. written exams), (inter)personal and combined outcomes (i.e. OSCEs). Of the 30 outcome variables, selection-positive students scored significantly higher in 11 cases. Fifteen other, non-significant between-group differences were also in favor of the selection-positives. An overall comparison using a sign test indicated a significant difference between both groups (p

Abstract The hippocampus is important for spatial navigation, episodic memory and affective behaviour. Increasing evidence suggests that these multiple functions are accomplished by different segments along the dorsal-ventral (septal-temporal) axis. Long-term potentiation (LTP), the best-investigated cellular correlate of learning and memory, has distinct properties along this axis in the CA1 region, but so far, little is known about longitudinal differences in dentate gyrus (DG). Therefore, here we examined potential dorsoventral differences in DG-LTP using in vitro multi-electrode array recordings. In young mice, we found higher basal synaptic transmission in the dorsal DG, while the LTP magnitude markedly increased towards the ventral pole. Strikingly, these differences were greatly reduced in slices from middle-aged mice. Short-term plasticity, evaluated by paired-pulse ratios, was similar across groups. Recordings in the presence and absence of GABAA-receptor blocker picrotoxin suggested a higher inhibitory tone in the ventral DG of young mice, confirmed by an increased frequency of miniature inhibitory postsynaptic currents. Our findings support the view that the hippocampus contains discrete functional domains along its dorsoventral axis and demonstrate that these are subject to age-dependent changes. Since these characteristics are presumably conserved in the human hippocampus, our findings have important clinical implications for hippocampus- and age-related disorders.

A round-trip human mission to Mars is anticipated to last roughly three years. Spaceflight conditions are known to cause loss of bone mineral density (BMD) in astronauts, increasing bone fracture risk. There is an urgent need to understand BMD progression as a function of spaceflight time to minimize associated health implications and ensure mission success. Here we introduce a nonlinear mathematical model of BMD loss for candidate human missions to Mars: (i) Opposition class trajectory (400-600 days), and (ii) Conjunction class trajectory (1000-1200 days). Using femoral neck BMD data (N = 69) from astronauts after 132-day and 228-day spaceflight and the World Health Organization's fracture risk recommendation, we predicted post-mission risk and associated osteopathology. Our model predicts 62% opposition class astronauts and 100% conjunction class astronauts will develop osteopenia, with 33% being at risk for osteoporosis. This model can help in implementing countermeasure strategies and inform space agencies' choice of crew candidates.

ObjectiveTo explore experiences among pregnant women diagnosed with a small-for-gestational age (SGA) fetus, and monitored by frequent ultrasounds.MethodsWe performed a qualitative study at the outpatient clinic of the Gynecology and Obstetrics department of a large academic hospital in Amsterdam. Semi-structured interviews were conducted with fifteen women, diagnosed with an SGA fetus during their pregnancy and having had at least two monitoring ultrasounds since. Themes were identified following analysis of the interview transcripts.ResultsMost women experienced the frequent ultrasounds as a source of support providing comfort and a feeling of safety. It was considered necessary, in the best interest of the baby, which outweighed the discomfort caused by having to come to the hospital frequently. Women described anxiety building up prior to each ultrasound, but feeling reassured and relieved afterwards. During the ultrasound a continuous explanation was preferred, which provided confirmation and a feeling of security. Women identified the uncertainty of SGA's cause and prognosis as one of the biggest challenges to cope with, for which they used different strategies. Many women expressed a need for more detailed information and counselling, including non-medical aspects of pregnancy and delivery as well. Lastly, many women reported that seeing different doctors negatively influenced the perceived quality of care.ConclusionsIn general, women in this study were satisfied with the ultrasounds for their small-for-gestational age pregnancies. However, women expressed a need for additional information to help cope with a feeling of uncertainty regarding cause and prognosis. Their medical team should preferably provide this in a consistent and continuous manner.

Untreated unilateral developmental dysplasia of the hip (DDH) results in asymmetry of gait and hip strength and may lead to early osteoarthritis, which is commonly treated with a total hip arthroplasty (THA). There is limited knowledge about the obtained symmetry of gait and hip strength after the THA. The objectives of this cross-sectional study were to: a) identify asymmetries between the operated and non-operated side in kinematics, kinetics and hip strength, b) analyze if increased walking speed changed the level of asymmetry in patients c) compare these results with those of healthy subjects.Women (18-70 year) with unilateral DDH who had undergone unilateral THA were eligible for inclusion. Vicon gait analysis system was used to collect frontal and sagittal plane kinematic and kinetic parameters of the hip joint, pelvis and trunk during walking at comfortable walking speed and increased walking speed. Furthermore, hip abductor and extensor muscle strength was measured.Six patients and eight healthy subjects were included. In the patients, modest asymmetries in lower limb kinematics and kinetics were present during gait, but trunk lateral flexion asymmetry was evident. Patients' trunk lateral flexion also differed compared to healthy subjects. Walking speed did not significantly influence the level of asymmetry. The hip abduction strength asymmetry of 23% was not statistically significant, but the muscle strength of both sides were significantly weaker than those of healthy subjects.In patients with a DDH treated with an IBG THA modest asymmetries in gait kinematics and kinetics were present, with the exception of a substantial asymmetry of the trunk lateral flexion. Increased walking speed did not result in increased asymmetries in gait kinematics and kinetics. Hip muscle strength was symmetrical in patients, but significantly weaker than in healthy subjects. Trunk kinematics should be included as an outcome measure to assess the biomechanical benefits of the THA surgery after DDH.

Mindfulness based stress reduction (MBSR) training has been proposed to improve attentional skills by modulating thalamo-cortical loops that affect the sensitivity of relevant cortical areas like the somatosensory cortex. This modulation may be reflected in the electroencephalographic (EEG) alpha rhythm, and could affect the processing of subsequently applied intracutaneous electrical stimuli. Participants took part in an MBSR training and participated in two EEG sessions. EEG was measured in variants of an endogenous orienting paradigm in which attention had to be directed to the left or right forearm. After the orienting interval, the electrical stimulus was applied, equally likely on the attended or the unattended forearm. One group of participants took part in the EEG session before and after the training, while the other group took part after the training, and another time, eight weeks later. The influence of the MBSR training and spatial attention were examined with behavioral measures, lateralized alpha power within the orienting interval, and with event-related potentials (ERPs) evoked by the electrical stimuli. Self-reported mindfulness was clearly affected by the training, but no influence was found on other behavioral measures. Alpha power was clearly lateralized due to spatial attention and several ERP components (N130, N180, P340) were modulated by spatial attention but no support was found for an influence of the MBSR training. Finally, analyses revealed that individual differences in training time modulated some of the observed effects, but no support was found for an influence on attentional orienting.

Selection is the first assessment of medical education and training. Medical schools must select from a pool of academically successful applicants and ensure that the way in which they choose future clinicians is robust, defensible, fair to all who apply and cost-effective. However, there is no comprehensive and evidence-informed guide to help those tasked with setting up or rejuvenating their local selection process. To address this gap, our guide draws on the latest research, international case studies and consideration of common dilemmas to provide practical guidance for designing, implementing and evaluating an effective medical school selection system. We draw on a model from the field of instructional design to frame the many different activities involved in doing so: the ADDIE model. ADDIE provides a systematic framework of Analysis (of the outcomes to be achieved by the selection process, and the barriers and facilitators to achieving these), Design (what tools and content are needed so the goals of selection are achieved), Development (what materials and resources are needed and available), Implementation (plan [including piloting], do study and adjust) and Evaluation (quality assurance is embedded throughout but the last step involves extensive evaluation of the entire process and its outcomes). Robust, defensible and fair selection into medical school is essential. This guide systematically covers the processes required to achieve this, from needs analysis through design, development and implementation, to evaluation of the success of a selection process. [ABSTRACT FROM AUTHOR]