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Hamda Memon,1 Ricardo Parrondo,2 Julianna Schreurs,2 Ernesto Ayala,2 Madiha Iqbal2 1Department of Family Medicine, Geisinger Health in Wilkes Barre, Wilkes Barre, Pennsylvania, USA; 2Division of Hematology and Oncology, Mayo Clinic, Jacksonville, Florida, USACorrespondence: Madiha Iqbal, Department of Medicine,Division of Hematology-Oncology and Blood and Marrow Transplantation Program, Mayo Clinic, 4500 San Pablo road, Jacksonville, FL, 32224, USA, Email Iqbal.madiha@mayo.eduAbstract: Systemic sclerosis (SSc) is a multi-system disease characterized by a dysregulated immune system. Autologous hematopoietic cell transplantation (AHCT) is the only treatment that has been shown to confer significant benefit in controlling disease and improving survival for patients with SSc. A diagnosis of multiple myeloma (MM) after the diagnosis of SSc is rare and optimal treatment in such cases remains unclear. We here report a case of a female patient who was diagnosed with MM while she was undergoing evaluation for AHCT due to SSc. A novel conditioning regimen for AHCT, with therapeutic efficacy in SSc and MM was offered to the patient, resulting in long term remission of both diseases.Keywords: systemic sclerosis, autologous hematopoietic cell transplantation, multiple myeloma

Equity is an important topic in school context globally because international migration is rapidly diversifying schools and classrooms across the world. Teacher quality is seen strongly related to student outcomes than demographic characteristics of students, and therefore important for achieving equity. This explorative study investigates the extent to which Swedish and Dutch pre-service teachers (PSTs) understand equity and are prepared to implement equity in their practice. Qualitative method was conducted in the study. Data from semi-structured interviews with 15 PSTs from Sweden and the Netherlands was thematically analysed to examine teacher knowledge about equity in education and related dispositions. The results showed that, while Swedish pre-service teachers had more theoretical knowledge in relation to teaching for equity, Dutch pre-service teachers had more practical knowledge and were therefore more prepared to implement equity in their lessons. The study recommends that teacher professional development for both in- and pre-service teachers needs to pay more attention to how equity is taught and how teachers embody equity principles in their practice.

This study investigates how lithological changes can affect the strike-slip fault propagation patterns using analogue models. Strike-slip fault zones are long structures that may cut across pre-existing tectonic or lithological steep boundaries. How strike-slip faulting is affected by a laterally heterogeneous upper crust is crucial for understanding the evolution of regional and local fault patterns, stress reorientations, and seismic hazard. Our models undergo sinistral distributed strike-slip shear (simple shear) and have been analysed by particle image velocimetry (PIV). We use quartz sand and microbeads as brittle analogue materials over a viscous mixture to distribute the deformation through the model. The first models investigate strike-slip faulting in a homogeneous upper crust using quartz sand or microbeads only. Three further models examine how the presence of a central section which laterally differs in its properties influences strike-slip faulting. The main observations are the following: The homogeneous upper crust shows typical Mohr–Coulomb strike-slip faults, with synthetic fault strikes related to the angle of internal friction of the material used. The heterogeneous upper crust has a profound effect on synthetic fault propagation, interaction, and linkage, as well as the kinematic evolution of antithetic faults that rotate around a vertical axis. The orientation of the central section determines whether antithetic fault activity concentrates along the entire length of the central contact or not. In the first case, fault activity is segmented or the number of different faults formed is increased in distinct domains. In the second case, the properties of the central material determine fault propagation, interaction, and/or linkage across the central domain. These findings have potential implications for nature that have been seen in the NW Iberian Peninsula. In this area, the change in direction of the sinistral faults and the position of the antithetic faults can be explained due to lithological change.

Microgravity exposure induces a cephalad fluid shift and an overall reduction in physical activity levels which can lead to cardiovascular deconditioning in the absence of countermeasures. Future spaceflight missions will expose crew to extended periods of microgravity among other stressors, the effects of which on cardiovascular health are not fully known. In this study, we determined cardiac responses to extended microgravity exposure using the rat hindlimb unloading (HU) model. We hypothesized that exposure to prolonged simulated microgravity and subsequent recovery would lead to increased oxidative damage and altered expression of genes involved in the oxidative response. To test this hypothesis, we examined hearts of male (three and nine months of age) and female (3 months of age) Long-Evans rats that underwent HU for various durations up to 90 days and reambulated up to 90 days post-HU. Results indicate sex-dependent changes in oxidative damage marker 8-hydroxydeoxyguanosine (8-OHdG) and antioxidant gene expression in left ventricular tissue. Three-month-old females displayed elevated 8-OHdG levels after 14 days of HU while age-matched males did not. In nine-month-old males, there were no differences in 8-OHdG levels between HU and normally loaded control males at any of the timepoints tested following HU. RNAseq analysis of left ventricular tissue from nine-month-old males after 14 days of HU revealed upregulation of pathways involved in pro-inflammatory signaling, immune cell activation and differential expression of genes associated with cardiovascular disease progression. Taken together, these findings provide a rationale for targeting antioxidant and immune pathways and that sex differences should be taken into account in the development of countermeasures to maintain cardiovascular health in space.

Providing students with feedback on their performance is a critical part of enhancing student learning in chemistry and is often integrated into homework assignments, quizzes, and exams. However, not all feedback is created equal, and the type of feedback the student receives can dramatically alter the utility of the feedback to reinforce correct processes and assist in correcting incorrect processes. This work seeks to establish a ranking of how eleven different types of testing feedback affected student retention or growth in performance on multiple-choice general chemistry questions. These feedback methods ranged from simple noncorrective feedback to more complex and engaging elaborative feedback. A test-retest model was used with a one-week gap between the initial test and following test in general chemistry I. Data collection took place at multiple institutions over multiple years. Data analysis used four distinct grading schemes to estimate student performance. These grading schemes included dichotomous scoring, two polytomous scoring techniques, and the use of item response theory to estimate students' true score. Data were modeled using hierarchical linear modeling which was set up to control for any differences in initial abilities and to determine the growth in performance associated with each treatment. Results indicated that when delayed elaborative feedback was paired with students being asked to recall/rework the problem, the largest student growth was observed. To dive deeper into student growth, both the differences in specific content-area improvement and the ability levels of students who improved the most were analyzed.

With the already widespread nature of multiple-choice assessments and the increasing popularity of answer-until-correct, it is important to have methods available for exploring the validity of these types of assessments as they are developed. This work analyzes a 20-question multiple choice assessment covering introductory undergraduate chemistry topics which was given to students in an answer-until-correct manner. Response process validity was investigated through one-on-one think-aloud interviews with undergraduate chemistry students. Answer-until-correct validity was also explored using an analysis of partial credit assignments. Results indicated the convenience of the quantitative partial credit method came at great cost to the precision of validity issue detection and is therefore not a valid shortcut to more rich qualitative approaches. The repeated attempt processing issue detection (RAPID) method is a novel method developed as a combination of response process and answer-until-correct validity. Results from this new method revealed validity issues that were undetected from the use of either approach individually or in concert.

BackgroundBreast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers.AimTo assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS.MethodsAnalyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death.ResultsThere was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55-0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09-1.56)].ConclusionSystemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk.

Background and Aims: Refractory celiac disease type II (RCDII) is characterized by a clonally expanded aberrant cell population in the small intestine. The role of other tissue-resident immune subsets in RCDII is unknown. Here, we characterized CD8 and CD4 T cells in RCDII duodenum at the single-cell level and in situ. Methods: We applied mass cytometry on CD45+ duodenal cells derived from intestinal biopsies (n = 23) and blood samples (n = 20) from RCDII patients and controls. Additionally, we analyzed intestinal biopsies from celiac disease (n = 11) and RCDI (n = 2) patients. We performed single-cell RNA-sequencing on CD45+ duodenal cells derived from a RCDII patient, immunofluorescence staining for in situ analysis and flow cytometry for phenotyping of RCDII aberrant and CD8 T cells. Results: Compared to healthy controls, we observed that CD27+PD-1+ memory CD8αβ cells and CD4 T regulatories (Tregs) were more abundant in RCDII duodenum (CD8 ∗∗0.0029; CD4 ∗∗∗0.0001). The CD27+PD-1+ memory CD8αβ cells expressed the tissue-resident marker CD69, immunoregulatory markers (TIGIT, HAVCR2, TNFRSF9), NKG2A, were enriched for activated pathways and displayed cytotoxic gene signatures (NKG7, PRF1, GZMA). The absence of CD103 accords with their localization in the lamina propria as determined by in situ analysis. The CD25+FoxP3+CD27+CD127dim/- CD4 Tregs expressed IL1R2 and IL32 and costimulatory molecules (TNFSRS4, ICOS and TNFRSF18) and resided in the lamina propria as well. Flow cytometry confirmed the presence of the inhibitory receptor NKG2A on expanded duodenal CD8 T cells and HLA-E, the ligand for NKG2A, on expanded aberrant cells. Conclusion: RCDII is characterized by the simultaneous presence of an activated CD27+PD-1+ memory CD8αβ T cell subset and CD4 Tregs, suggesting that checkpoint blockade with anti-NKG2A/PD-1 and/or anticytotoxic T lymphocyte antigen 4 may be an attractive treatment option.

The gastrointestinal tract is a prominent portal of entry for HIV-1 during sexual or perinatal transmission, as well as a major site of HIV-1 persistence and replication. Elucidation of underlying mechanisms of intestinal HIV-1 infection are thus needed for the advancement of HIV-1 curative therapies. Here, we present a human 2D intestinal immuno-organoid system to model HIV-1 disease that recapitulates tissue compartmentalization and epithelial-immune cellular interactions. Our data demonstrate that apical exposure of intestinal epithelium to HIV-1 results in viral internalization, with subsequent basolateral shedding of replication-competent viruses, in a manner that is impervious to antiretroviral treatment. Incorporation of subepithelial dendritic cells resulted in HIV-1 luminal sampling and amplification of residual viral replication of lab-adapted and transmitted-founder (T/F) HIV-1 variants. Markedly, intraepithelial viral capture ensued an altered distribution of specialized endosomal pathways alongside durable sequestration of infectious HIV-1 within lysobisphosphatidic acid (LPBA)-rich vesicles. Therapeutic neutralization of LBPA-dependent trafficking limited productive HIV-1 infection, and thereby demonstrated the pivotal role of intraepithelial multivesicular endosomes as niches for virulent HIV-1 within the intestinal mucosa. Our study showcases the application of primary human 2D immune-competent organoid cultures in uncovering mechanisms of intestinal HIV-1 disease as well as a platform for preclinical antiviral drug discovery.

Toll-like receptor (TLR) agonists are being developed as anti-cancer therapeutics due to their potent immunostimulatory properties. However, clinical trials testing TLR agonists as monotherapy have often failed to demonstrate significant improvement over standard of care. We hypothesized that the anti-cancer efficacy of TLR agonist immunotherapy could be improved by combinatorial approaches. To prevent increased toxicity, often seen with systemic combination therapies, we developed a hydrogel to deliver TLR agonist combinations at low doses, locally, during cancer debulking surgery. Using tumor models of WEHI 164 and bilateral M3–9-M sarcoma and CT26 colon carcinoma, we assessed the efficacy of pairwise combinations of poly(I:C), R848, and CpG in controlling local and distant tumor growth. We show that combination of the TLR3 agonist poly(I:C) and TLR7/8 agonist R848 drives anti-tumor immunity against local and distant tumors. In addition, combination of local poly(I:C) and R848 sensitized tumors to systemic immune checkpoint blockade, improving tumor control. Mechanistically, we demonstrate that local therapy with poly(I:C) and R848 recruits inflammatory monocytes to the tumor draining lymph nodes early in the anti-tumor response. Finally, we provide proof of concept for intraoperative delivery of poly(I:C) and R848 together via a surgically applicable biodegradable hydrogel.

In industrialized societies characterized by ubiquitous connectivity, many individuals disconnect from their phones or social media to break patterns of habitual use, reduce information overload, alleviate stress, and avoid distractions. Although research has predominantly focused on (young) adults, information on digital disconnection among adolescents remains limited. In response, in the present study, we analyzed survey data from 956 Flemish adolescents in Belgium (Mage = 15.10, SD = 1.61, and 64.8% girls) and, using latent class analysis, identified two subgroups: Class 1 labeled as “low adoption of social media apps and disconnection tools,” and Class 2 labeled as “high adoption of social media apps and disconnection tools.” Adolescents in Class 2 were more likely to use social media, specifically social networking, instant messaging, and entertainment apps, and to adopt disconnection tools (e.g., iOS Screentime or the Forest app). Next, drawing on the media practice model, we investigated how sociodemographic and sociopsychological factors contribute to those usage patterns and found that girls, older adolescents, and adolescents with higher scores for depressive symptoms and flourishing were more likely to belong to Class 2. Those findings offer new insights into adolescents’ social media connection and disconnection that can inform interventions to promote healthier smartphone use among adolescents.

Background and purpose: External validation is a crucial step after prediction model development. Despite increasing interest in prediction models, external validation is frequently overlooked. We aimed to evaluate whether joint registries can be utilized for external validation of prediction models, and whether published prediction models are valid for the Dutch population with a total hip arthroplasty. Methods: We identified prediction models developed in patients undergoing arthroplasty through a systematic literature search. Model variables were evaluated for availability in the Dutch Arthroplasty Registry (LROI). We assessed the model performance in terms of calibration and discrimination (area under the curve [AUC]). Furthermore, the models were updated and evaluated through intercept recalibration and logistic recalibration. Results: After assessing 54 papers, 19 were excluded for not describing a prediction model (n = 16) or focusing on non-TJA populations (n = 3), leaving 35 papers describing 44 prediction models. 90% (40/44) of the prediction models used outcomes or predictors missing in the LROI, such as diabetes, opioid use, and depression. 4 models could be externally validated on LROI data. The models’ discrimination ranged between poor and acceptable and was similar to that in the development cohort. The calibration of the models was insufficient. The model performance improved slightly after updating. Conclusion: External validation of the 4 models resulted in suboptimal predictive performance in the Dutch population, highlighting the importance of external validation studies.

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.

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.

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.

Background With a growing population of older people in all Western countries, interprofessional education (IPE) can help to prepare students for the complex care for these patients. Which aspects of this complex care could benefit from IPE? In this study we evaluated the differences in content of health care plans made by students who participated in IPE. Methods Undergraduate nursing and medical students were included and attended four sessions in which they wrote a health care plan for a paper-based geriatric patient case. Approximately half of the students were included in the IPE-group. To evaluate the content of interprofessional collaboration between the students, the other half of the students were included in a ‘uniprofessional education’ (UPE) group. UPE-students made the health care plan alone. In the IPE-group a medical and a nursing students compiled the health care plan together. All health care plans were assessed by comparing them with a validated health care plan. We zoomed into the differences in the content of the health care plans, and calculated a score ratio, proportion of correct items. Results The health care plans made by IPE-students had an average score ratio of 0.31. The health care plans made by UPE-students had an average score ratio of 0.22. Most differences were found in the subcategories medication, nursing actions and aftercare. Specific items within these categories were more frequently thought of in the IPE-group than in the UPE-group, for example delirium interventions and consultation with a transfer nurse. Conclusion This study gives insights into which health care actions are more often considered by interprofessional couples in IPE than by students in UPE. Awareness of these items in clinical practice could make a difference in the care for older patients.

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. Introduction:. Chronic pain affects a wide range of physical and psychological aspects of life for those impacted. Psychosocial treatment approaches may be of support, but outreach is still limited. Objectives:. To evaluate the efficacy of EPIO, an evidence-informed, user-centered digital self-management intervention for people with chronic pain, in a 12-month randomized controlled trial. Methods:. People living with chronic pain (N = 266) were randomized to the EPIO intervention (n = 132) or a usual-care control group (n = 134). The intervention was delivered in a simple blended care model, and outcome measures collected at baseline, 6 months, and 12 months. Generalized linear models for repeated measures were fitted to compare groups over time. Results:. Participants were primarily female (81%), median age 49 years (range 22–78), with heterogeneous pain conditions, and had lived with pain >5 years (77.6%). A mixed linear model with all timepoints included revealed no statistically significant group differences for the primary outcome of pain interference. Significant psychological benefits in favor of the intervention group were however detected for depression (P = 0.022), self-regulatory fatigue (P = 0.024), vitality (P = 0.016), and mental health (P = 0.047). Baseline to 12-month changes showed additional favorable effects for anxiety (between-group mean differences [MDs] = 0.79, P = 0.047), depression (MD = 1.08, P = 0.004), self-regulatory fatigue (MD = 2.42, P = 0.021), pain catastrophizing (MD = 2.62, P = 0.009), and health-related quality of life. Conclusions:. The EPIO program aims to improve outreach of evidence-based pain self-management interventions. Findings demonstrate how using EPIO can lead to sustainable psychological change, enhancing mental health and health-related quality of life for people suffering from pain, providing a chance to live well with the pain.

Endometriosis is an estrogen-dependent chronic disease characterized by the presence of endometriumlike tissue outside the uterus and is often associated with symptoms, such as dysmenorrhea, dysuria, dyschezia, chronic pelvic pain, and infertility. Moreover, women diagnosed with endometriosis can report gastrointestinal symptoms, including bloating, constipation or diarrhea, and abdominal cramping, which can be associated with irritable bowel syndrome and can result in the misdiagnosis of endometriosis as irritable bowel syndrome at first. Treatment usually involves hormonal therapy, pain management, surgery, and/or assisted reproductive techniques in case of infertility. Nonetheless, these treatment methods can be insufficient for alleviating symptoms or can have unacceptable side effects, leading to noncompliance. Therefore, women often apply self-management strategies, including dietary interventions.One of the diets frequently suggested as a tool to manage endometriosis-related symptoms on social media and patient forums is a gluten-free diet. Although a gluten-free diet has been proven effective in managing nonceliac wheat sensitivity or celiac disease, its effectiveness in endometriosis remains uncertain. The Nurses’ Health Study II found it unlikely that gluten intake was a strong factor in endometriosis etiology and symptomatology. To the best of our knowledge, the most frequently cited and sole published intervention study on the efficacy of a gluten-free diet for endometriosis has several important limiting factors, including the absence of a control group. In addition, gluten consumption is highly susceptible to a placebo effect and a nocebo effect, where women might experience symptom relief after eliminating gluten and return of symptoms after they consume gluten again, solely because they believe that gluten is bad for them. Despite the inverse association between body mass index and endometriosis and between a gluten-free diet and increased body mass index, this is an association, and no causality was proven. In addition, other factors should be taken into consideration.Of note, a gluten-free diet is expensive, has limited availability, and has a significant effect on quality of life. Moreover, without proper dietary guidance, it may adversely affect the gastrointestinal microbiome. Therefore, scientifically substantiated advice regarding the use of a gluten-free diet for endometriosis-related symptoms is currently not available, and a gluten-free diet should be discouraged unless there is an additional diagnosis of nonceliac wheat sensitivity or celiac disease.

Background/Objectives: The redirection or reshaping of the acetabulum might be warranted to attain a concentric and stable hip in children with developmental dysplasia of the hip (DDH). The aim of this study is to assess the late clinical and radiological results, and to determine the number of patients requiring secondary surgery or a total hip arthroplasty at a long-term follow-up. Methods: Our institution performed 99 Salter osteotomies on 76 patients without underlying neuromuscular conditions over a 21-year period, from 1981 to 2002. These procedures were carried out by three different surgeons. Patients underwent a comprehensive evaluation at the review visit, including a physical examination, clinical assessments using the Harris hip score (HHS), Oxford score (OHS) and Visual Analogue Scale (VAS) pain score, as well as pelvic radiographs. Results: At a median follow-up of 22 years, total hip arthroplasty was performed in 6 out of 77 hips (8%). Patients who underwent a Salter osteotomy with an open reduction had a higher rate of avascular necrosis (AVN) of the femoral head compared to those who only underwent a Salter pelvic osteotomy (p < 0.001). There were statistically significant differences in the group with and without AVN in terms of HHS (p = 0.006, 95%CI 0.003 to 0.006), OHS (p = 0.016, 95%CI 0.012 to 0.017), a modified OHS (p = 0.018, 95% CI 0.012 to 0.016), a VAS score in activity (p = 0.046, 95%CI 0.042 to 0.050) and VAS score satisfaction (p = 0.005, 95%CI 0.003 to 0.006). Conclusions: The rate of THA was 8% at a mean of follow-up of 22 years. Secondary results suggest that AVN occurs more frequently when a Salter osteotomy is combined with an open reduction. The occurrence of AVN is associated with significantly lower clinical outcome scores and patient satisfaction, as well as significantly higher pain scores. In the absence of AVN, good clinical results can be expected at long-term follow-up.

Summary: Pre-clinical studies developing novel therapies to prevent cancer recurrence require appropriate surgical models. Here, we present a protocol for surgical debulking of subcutaneous tumors in mice, which allows for intraoperative application of immunotherapy-loaded biomaterials. We describe steps for inoculating tumor cells, anesthetizing mice, and performing surgery. We then detail procedures for applying biomaterial, bandaging mice, and data collection and analysis. The optimized bandaging regimen resolves the issue of wound dehiscence after surgery, for C57BL/6 mice, which interfere with surgical sites.For complete details on the use and execution of this protocol, please refer to Rwandamuriye et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

To determine the changes in surveillance category by adding a polygenic risk score based on 311 breast cancer (BC)-associated variants (PRS311), questionnaire-based risk factors and breast density on personalized BC risk in unaffected women from Dutch CHEK2 c.1100delC families.In total, 117 unaffected women (58 heterozygotes and 59 non-carriers) from CHEK2 families were included. Blood-derived DNA samples were genotyped with the GSAMDv3-array to determine PRS311. Lifetime BC risk was calculated in CanRisk, which uses data from the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA). Women, were categorized into three surveillance groups.The surveillance advice was reclassified in 20 (34.5%) heterozygotes and 21 (35.6%) non-carriers after adding PRS311. Including questionnaire-based risk factors resulted in an additional change in 11 (20.0%) heterozygotes and 8 (15.1%) non-carriers; and a sub-analysis showed that adding breast density on top shifted another 9 (23.1%) heterozygotes and 5 (27.8%) non-carriers. Overall, the majority of heterozygotes were reclassified to a less intensive surveillance, while non-carriers would require intensified surveillance.The addition of PRS311, questionnaire-based risk factors and breast density to family history resulted in a more personalized BC surveillance advice in CHEK2-families, which may lead to more efficient use of surveillance.

Background and purpose: This study aims to assess time trends in case-mix and to evaluate the risk of revision and causes following primary THA, TKA, and UKA in private and public hospitals in the Netherlands. Methods: We retrospectively analyzed 476,312 primary arthroplasties (public: n = 413,560 and private n = 62,752) implanted between 2014 and 2023 using Dutch Arthroplasty Register data. We explored patient demographics, procedure details, trends over time, and revisions per hospital type. Adjusted revision risk was calculated for comparable subgroups (ASA I/II, age ≤ 75, BMI ≤ 30, osteoarthritis diagnosis, and moderate–high socioeconomic status (SES). Results: The volume of THAs and TKAs in private hospitals increased from 4% and 9% in 2014, to 18% and 21% in 2022. Patients in private hospitals were younger, had lower ASA classification, lower BMI, and higher SES compared with public hospital patients. In private hospitals, age and ASA II proportion increased over time. Multivariable Cox regression demonstrated a lower revision risk for primary THA (HR 0.7, CI 0.7–0.8), TKA (HR 0.8, CI 0.7–0.9), and UKA (HR 0.8, CI 0.7–0.9) in private hospitals. After initial arthroplasty in private hospitals, 49% of THA and 37% of TKA revisions were performed in public hospitals. Conclusion: Patients in private hospitals were younger, had lower ASA classification, lower BMI, and higher SES com­pared with public hospital patients. The number of arthroplasties increased in private hospitals, with a lower revision risk compared with public hospitals.

Dengue virus (DENV), transmitted by infected mosquitoes, is a major public health concern, with approximately half the world’s population at risk for infection. Recent decades have increasing incidence of dengue-associated disease alongside growing frequency of outbreaks. Although promising progress has been made in anti-DENV immunizations, post-infection treatment remains limited to non-specific supportive treatments. Development of antiviral therapeutics is thus required to limit DENV dissemination in humans and to help control the severity of outbreaks. Dendritic cells (DCs) are amongst the first cells to encounter DENV upon injection into the human skin mucosa, and thereafter promote systemic viral dissemination to additional human target cells. Autophagy is a vesicle trafficking pathway involving the formation of cytosolic autophagosomes, and recent reports have highlighted the extensive manipulation of autophagy by flaviviruses, including DENV, for viral replication. However, the temporal profiling and function of autophagy activity in DENV infection and transmission by human primary DCs remains poorly understood. Herein, we demonstrate that mechanisms of autophagosome formation and extracellular vesicle (EV) release have a pro-viral role in DC-mediated DENV transmission. We show that DENV exploits early-stage canonical autophagy to establish infection in primary human DCs. DENV replication enhanced autophagosome formation in primary human DCs, and intrinsically-heightened autophagosome biogenesis correlated with relatively higher rates of DC susceptibility to DENV. Furthermore, our data suggest that viral replication intermediates co-localize with autophagosomes, while productive DENV infection introduces a block at the late degradative stages of autophagy in infected DCs but not in uninfected bystander cells. Notably, we identify for the first time that approximately one-fourth of DC-derived CD9/CD81/CD63+ EVs co-express canonical autophagy marker LC3, and demonstrate that DC-derived EV populations are an alternative, cell-free mechanism by which DCs promote DENV transmission to additional target sites. Taken together, our study highlights intersections between autophagy and secretory pathways during viral infection, and puts forward autophagosome accumulation and viral RNA-laden EVs as host determinants of DC-mediated DENV infection in humans. Host-directed therapeutics targeting autophagy and exocytosis pathways thus have potential to enhance DC-driven resistance to DENV acquisition and thereby limit viral dissemination by initial human target cells following mosquito-to-human transmission of DENV.

Future Internet of Things (IoT) networks are expected to realize far-field wireless power transfer (WPT) to mitigate the sensors’ dependence on batteries. Recently, simultaneous wireless information and power transfer (SWIPT) has gained attention by utilizing RF signals for both information as well as power transfer. In this paper, a novel N-tone multitone quadrature-amplitude-modulation (QAM) transmission waveform carrying $(N-1)$ information symbols, is proposed for an integrated information-energy receiver with a lower power consumption compared to conventional separated information-energy receiver architectures. The multitone QAM signal is designed by exploiting the non-linearity of the receiver-rectifier, and both amplitudes and phases are used for information transfer offering an advantage of a higher degree of freedom to optimize WPT and wireless information transfer (WIT) performances. It is shown that the power performance of the designed waveform varies with the orientation of the symbol constellation. Two asymmetric QAM constellation designs, expanded symbol constellation and compressed symbol constellation, are proposed to enhance WPT performance according to the application-specific requirement, such as whether a higher level of minimum continuous power transfer is critical or if a high-power transfer in short bursts is preferred for the SWIPT’s operation. It has been shown that WPT and WIT performances can be enhanced according to the IoT node’s requirements by varying the transmission probabilities of inner symbols and outer symbols of the QAM constellation.

In the era of Internet of Things (IoT) networks, far-field wireless power transfer using radio frequency (RF) waves has attracted attention as a solution to remove the need for batteries at the sensors. However, RF communication signals can be used for energy as well as information for better resource management. Therefore, recently, simultaneous wireless information and power transfer (SWIPT) technology has gained significance for charging these low-power IoT devices wirelessly. In this paper, a novel N-tone multitone amplitude shift keying (ASK) transmission signal scheme is proposed by utilizing the non-linearity of integrated information-energy rectifier receiver architecture. The data rate is increased by transmitting $(N-1)$ symbols over a single N-tone Multitone ASK signal stream. Wireless power transfer (WPT) and wireless information transfer (WIT) performances of the proposed transmission scheme are analyzed, and a trade-off between WPT and WIT performances is discussed. WPT performance of the designed transmitted signal has been shown to improve with increasing the minimum level of the symbols approaching the maximum possible power efficiency of the rectifier. Logarithmically distributed symbols have been shown to improve WPT compared to linearly distributed symbols due to the non-linearity of the rectifier circuitry, whereas linearly distributed symbols result in better WIT performance. It is possible to attain a good WIT performance with a low transmitted signal power.

Abstract Background Patients undergoing radical prostatectomy for localised prostate cancer generally have good long‐term survival rates. However, late recurrences can occur and require lifelong follow‐up. Objective This research aims to investigate different stakeholders' perceptions on the use of mobile health (mHealth) applications for prostate cancer follow‐up after radical prostatectomy. Methods A cross‐sectional qualitative study was conducted to explore stakeholders' perceptions of an mHealth application for follow‐up after radical prostatectomy. Urologists, nurses, and patients treated with radical prostatectomy were interviewed, and data were transcribed and analysed using thematic analysis according to Qualitative Analysis Guide of Leuven. Recommended features for an ideal mHealth application were grouped according to the Persuasive Systems Design model. Results and Limitations A total of 30 stakeholders, consisting of nurse specialists (n = 7), urologists (n = 8), and patients (n = 15), were interviewed. Expected benefits and barriers were mentioned and grouped in five overarching themes: healthcare optimisation, disease management, app compliance, legal and organisational requirements, and patient–mHealth interaction. Stakeholders provided a multitude of suggestions for an ideal mHealth app. Yet, not all types of stakeholders were interviewed, and patient selection limited generalisability of findings. Conclusions Stakeholders indicate that an mHealth app in the care for post‐prostatectomy patients can improve patient care and promote disease management but consider app compliance as a major challenge. Patient Summary We interviewed patients, nurses, and urologists about using an mHealth application for follow‐up after radical prostatectomy. The participants agreed that an mHealth app could improve care optimisation and disease management, but some concerns and barriers were expressed. This resulted in a list of recommended features for an ideal app.

Lowering the dependency of receivers and sensors on energy supplies is a requirement for a realistic Internet of Things. This is certainly achieved when sensor nodes are powered wirelessly. Local oscillators (LOs), required to receive and transmit modern radio frequency (RF) waveforms, consume a considerable amount of the power budget. We propose a Wireless Local Oscillator (WiLO) concept to move the LO from the sensor to an external location and transmit it wirelessly to the sensor. This WiLO is modeled as a constant tone transmission. As is well known, the sensor can backscatter the constant tone, which enables uplink transmission. Our system approach allows the downconversion of any RF waveform without LO and mixer while simultaneously utilizing the same signal for power transfer. In this work, we demonstrate our approach to different types of OFDM signals, which can be considered as a general complex RF signal example to be received. Our WiLO-based technique to receive any modern communication signal without LO, in combination with harvesting energy from the tone and backscattering on that tone, results in a promising energy-efficient IoT solution. We present the performance model with design requirements for WiLO tone and amplitudes of OFDM tones for feasible reception of WiLO-OFDM. Simultaneous Wireless Information and Power Transfer (SWIPT) applications typically operate in a high SNR regime, and both energy harvesting and information transfer are equally important. The cost of 12 dB performance with an AWGN noisy channel can be acceptable by saving a significant amount of power by removing the LO.

Basin inversion is a process that takes place when a sedimentary basin is subjected to compressional stresses resulting in the reactivation of pre-existing faults and/or the localization of deformation along new reverse faults. The Araripe Basin (NE Brazil) is an example of a Cretaceous intracontinental aborted rift, with its sedimentary infill found at ca. 1000 m altitude, 500 m above the host basement. Post-rift basin inversion has been proposed by previous authors as the cause of this topographic high, but how inversion affected this basin remains a matter of debate, with the following two end-member scenarios: reactivation of pre-existing normal faults leading to local uplift or regional uplift and differential erosion. Neither end-member fully explains the observations from seismic and field data. In this study, we, therefore, conducted analogue models to explore how basin inversion in the Araripe Basin could have taken place. We present two series of crustal-scale brittle–viscous experiments: (i) extension followed by compression without sedimentation, with a variation in divergence and convergence directions (orthogonal or 45∘ oblique); and (ii) extension with syn-rift sedimentation followed by compression, with the same variation in rifting and inversion directions. We found that orthogonal rifting without sedimentation forms throughgoing graben boundary faults, whereas oblique rifting initially creates en échelon faults that eventually link up, creating large graben boundary faults. Rift basins with syn-rift sedimentation evolved in a similar fashion; however, sedimentary loading resulted in increased subsidence. During both oblique and orthogonal inversion, most shortening was accommodated along new low-angle reverse faults. Significant intra-graben fault reactivation occurred in all models without syn-rift sedimentation. By contrast, orthogonal inversion of models with syn-rift sedimentation did not reactivate rift faults, whereas only a minor reactivation of rift faults took place during oblique inversion since the sediments strengthened the otherwise weakened basin, thus acting as a buffer during convergence. Based on our modelling results, we propose an alternative scenario for the evolution of the Araripe Basin, involving oblique inversion and the development of low-angle reverse faults, which better fits observations from seismic lines and field data from the region.