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Sandra D Boxum,1,2,* Sabien H van Exter,3,* Jan-Jaap Reinders,1,4,5 Niek Koenders,6 Hans Drenth,1,7,8 Manon GA van den Berg,3 Michael Tieland,9,10 Sophie LW Spoorenberg,11 Evelyn J Finnema,12– 14 Philip J van der Wees,2,6 Harriët Jager-Wittenaar1,3,15 1Research Group Healthy Ageing, Allied Health Care and Nursing, Hanze University of Applied Sciences, Groningen, the Netherlands; 2Science Department IQ Health, Radboud university medical center, Nijmegen, the Netherlands; 3Department of Gastroenterology and Hepatology, Dietetics, Radboud university medical center, Nijmegen, 6500 HB, the Netherlands; 4Center for Dentistry and Dental Hygiene, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 5Research Group Interprofessional Education (IPE), Lifelong Learning, Education and Assessment Research Network (LEARN), Research Institute SHARE, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands; 6Department of Rehabilitation, Radboud university medical center, Nijmegen, the Netherlands; 7ZuidOostZorg, Organization for Elderly Care, Drachten, the Netherlands; 8Department of Primary and Long-Term Care, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 9Center of Expertise Urban Vitality, Faculty of Sports and Nutrition, Amsterdam University of Applied Sciences, Amsterdam, the Netherlands; 10School of Exercise and Nutrition Sciences, Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC, Australia; 11Primary care group ‘Dokter Drenthe’, Assen, the Netherlands; 12Health Science-Nursing Science and Education, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands; 13Research Group Living, Wellbeing and Care for Older People, NHL Stenden University of Applied Sciences, Leeuwarden, the Netherlands; 14Research Group Nursing Diagnostics, Hanze University of Applied Sciences, Groningen, the Netherlands; 15Department of Physiotherapy, Human Physiology and Anatomy, Faculty of Physical Education and Physiotherapy, Research Unit Experimental Anatomy, Vrije Universiteit Brussel, Brussels, Belgium*These authors contributed equally to this workCorrespondence: Sandra D Boxum, Hanze University of Applied Sciences, Petrus Driessenstraat 3, 9714 CA, Groningen, the Netherlands, Email s.d.boxum@pl.hanze.nlBackground: As our global population ages, malnutrition and sarcopenia are increasingly prevalent. Given the multifactorial nature of these conditions, effective management of (risk of) malnutrition and sarcopenia necessitates interprofessional collaboration (IPC). This study aimed to understand primary and social care professionals’ barriers, facilitators, preferences, and needs regarding interprofessional management of (risk of) malnutrition and sarcopenia in community-dwelling older adults.Methods: We conducted a qualitative, Straussian, grounded theory study. We collected data using online semi-structured focus group interviews. A grounded theory data analysis was performed using open, axial, and selective coding, followed by developing a conceptual model.Results: We conducted five online focus groups with 28 professionals from the primary and social care setting. We identified five selective codes: 1) Information exchange between professionals must be smooth, 2) Regular consultation on the tasks, responsibilities, and extent of IPC is needed; 3) Thorough involvement of older adults in IPC is preferred; 4) Coordination of interprofessional care around the older adult is needed; and 5) IPC must move beyond healthcare systems. Our conceptual model illustrates three interconnected dimensions in interprofessional collaboration: professionals, infrastructure, and older adults.Conclusion: Based on insights from professionals, interprofessional collaboration requires synergy between professionals, infrastructure, and older adults. Professionals need both infrastructure elements and the engagement of older adults for successful interprofessional collaboration.Keywords: malnutrition, sarcopenia, interprofessional, older adults

Background and aimsENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).Approach and resultsPatients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response [alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN] at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) ( p < 0.0001). ALP normalization occurred in 5.4% ( p =0.08) and 27.3% ( p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo [10 mg: -3.14 ( p =0.02); placebo: -1.55]. Alanine aminotransferase decreased significantly with seladelpar versus placebo [5 mg: 23.4% ( p =0.0008); 10 mg: 16.7% ( p =0.03); placebo: 4%]. There were no serious treatment-related adverse events.ConclusionsPatients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.

BackgroundPatients with occupational injuries often receive multidisciplinary rehabilitation for a rapid return to work. Rehabilitation aftercare programs give patients the opportunity to help patients apply the progress they have made during the rehabilitation to their everyday activities. Telerehabilitation aftercare programs can help reduce barriers, such as lack of time due to other commitments, because they can be used regardless of time or location. Careful identification of barriers, facilitators, and design requirements with key stakeholders is a critical step in developing a telerehabilitation aftercare program. ObjectiveThis study aims to identify barriers, facilitators, and design requirements for a future telerehabilitation aftercare program for patients with occupational injuries from the perspective of the key stakeholders. MethodsWe used a literature review and expert recommendations to identify key stakeholders. We conducted semistructured interviews in person and via real-time video calls with 27 key stakeholders to collect data. Interviews were transcribed verbatim, and thematic analysis was applied. We selected key stakeholder statements about facilitators and barriers and categorized them as individual, technical, environmental, and organizational facilitators and barriers. We identified expressions that captured aspects that the telerehabilitation aftercare program should fulfill and clustered them into attributes and overarching values. We translated the attributes into one or more requirements and grouped them into content, functional, service, user experience, and work context requirements. ResultsThe key stakeholders identified can be grouped into the following categories: patients, health care professionals, administrative personnel, and members of the telerehabilitation program design and development team. The most frequently reported facilitators of a future telerehabilitation aftercare program were time savings for patients, high motivation of the patients to participate in telerehabilitation aftercare program, high usability of the program, and regular in-person therapy meetings during the telerehabilitation aftercare program. The most frequently reported barriers were low digital affinity and skills of the patients and personnel, patients’ lack of trust and acceptance of the telerehabilitation aftercare program, slow internet speed, program functionality problems (eg, application crashes or freezes), and inability of telerehabilitation to deliver certain elements of in-person rehabilitation aftercare such as monitoring exercise performance. In our study, the most common design requirements were reducing barriers and implementing facilitators. The 2 most frequently discussed overarching values were tailoring of telerehabilitation, such as a tailored exercise plan and tailored injury-related information, and social interaction, such as real-time psychotherapy and digital and in-person rehabilitation aftercare in a blended care approach. ConclusionsKey stakeholders reported on facilitators, barriers, and design requirements that should be considered throughout the development process. Tailoring telerehabilitation content was the key value for stakeholders to ensure the program could meet the needs of patients with different types of occupational injuries.

Introduction and Objectives: Autoimmune liver diseases (AILD) are rare causes hepatocellular carcinoma (HCC), and data on the efficacy and tolerability of anti-tumor therapies are scarce. This pan-European study aimed to assess outcomes in AILD-HCC patients treated with tyrosine kinase inhibitors (TKIs) or transarterial chemoembolization (TACE) compared with patients with more common HCC etiologies, including viral, alcoholic or non-alcoholic fatty liver disease. Materials and Methods: 107 patients with HCC-AILD (AIH:55; PBC:52) treated at 13 European centres between 1996 and 2020 were included. 65 received TACE and 28 received TKI therapy. 43 (66 %) were female (median age 73 years) with HCC tumor stage BCLC A (34 %), B (46 %), C (9 %) or D (11 %). For each treatment type, propensity score matching was used to match AILD to non-AILD-HCC on a 1:1 basis, yielding in a final cohort of 130 TACE and 56 TKI patients for comparative analyses of median overall survival (mOS) and treatment tolerability. Results: HCC-AILD patients showed comparable mOS to controls for both TACE (19.5 vs. 22.1 months, p = 0.9) and TKI (15.4 vs. 15.1 months, p = 0.5). Adverse events were less frequent in AILD-HCC patients than controls (33 % % vs. 62 %, p = 0.003). For TKIs, there were no significant differences in adverse events (73% vs. 86%, p = 0.2) or interruption rates (44% vs. 36 %, p = 0.7). Conclusions: In summary, this study demonstrates comparable mOS for AILD-HCC patients undergoing local and systemic treatments, with better tolerability than HCC of other causes. TKIs remain important therapeutic options for AILD-HCC patients, particularly given their exclusion from recent immunotherapy trials.

Background & Aims: Although primary biliary cholangitis (PBC) is considered a rare disorder, accurate determination of its incidence and prevalence remains challenging due to limited comprehensive population-based registries. We aimed to assess the incidence and prevalence of PBC in the Netherlands over time through the nationwide Dutch PBC Cohort Study (DPCS). Methods: DPCS retrospectively included every identifiable patient with PBC in the Netherlands from 1990 onwards in all 71 Dutch hospitals. Incidence and prevalence were assessed between 2008-2018 by Poisson regression between sex and age groups over time. Results: On the 1st of January 2008, there were 1,458 patients with PBC in the Netherlands. Between 2008-2018, 2,187 individuals were newly diagnosed, 46 were transplanted and 468 died. The yearly incidence of PBC in 2008 was 1.38, increasing to 1.74 per 100,000 persons in 2018. When compared to those aged

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9–95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation – not receiving immunosuppression – compared to those with AIH-PBC (65%; 95% CI 52.2–77.8% vs. 87%; 95% CI 83.2–90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Abstract Background Nowadays, large benign lateral spreading lesions (LSLs) and sessile polyps in the colorectum are mostly resected by endoscopic mucosal resection (EMR). A major drawback of EMR is the polyp recurrence rate of up to 20%. Snare tip soft coagulation (STSC) is considered an effective technique to reduce recurrence rates. However, clinical trials on STSC have mainly been conducted in expert referral centers. In these studies, polyp recurrence was assessed optically, and additional adjunctive techniques were excluded. In the current trial, we will evaluate the efficacy and safety of STSC in daily practice, by allowing adjunctive techniques during EMR and the use of both optical and histological polyp recurrence to assess recurrences during follow-up. Methods The RESPECT study is a multicenter, parallel-group, international single blinded randomized controlled superiority trial performed in the Netherlands and Germany. A total of 306 patients undergoing piecemeal EMR for LSLs or sessile colorectal polyps sized 20–60 mm will be randomized during the procedure after endoscopic complete polyp resection to the intervention or control group. Post-EMR defects allocated to the intervention group will be treated with thermal ablation with STSC of the entire resection margin. Primary outcome will be polyp recurrence by optical and histological confirmation at the first surveillance colonoscopy after 6 months. Secondary outcomes include technical success and complication rates. Discussion The RESPECT study will evaluate if STSC is effective in reducing recurrence rates after piecemeal EMR of large colorectal lesions in daily clinical practice performed by expert and non-expert endoscopists. Moreover, endoscopists will be allowed to use adjunctive techniques to remove remaining adenomatous tissue during the procedure. Finally, adenomatous polyp recurrence during follow-up will be defined by histologic identification. Trial registration ClinicalTrials.gov NCT05121805. Registered on 16 November 2021. Start recruitment: 17 March 2022. Planned completion of recruitment: 31 April 2025.

Abstract Background Autoimmune hepatitis (AIH) is a rare, chronic inflammatory disease of the liver. The treatment goal is reaching complete biochemical response (CR), defined as the normalisation of aspartate and alanine aminotransferases and immunoglobulin gamma. Ongoing AIH activity can lead to fibrosis and (decompensated) cirrhosis. Incomplete biochemical response is the most important risk factor for liver transplantation or liver-related mortality. First-line treatment consists of a combination of azathioprine and prednisolone. If CR is not reached, tacrolimus (TAC) or mycophenolate mofetil (MMF) can be used as second-line therapy. Both products are registered for the prevention of graft rejection in solid organ transplant recipients. The aim of this study is to compare the effectiveness and safety of TAC and MMF as second-line treatment for AIH. Methods The TAILOR study is a phase IIIB, multicentre, open-label, parallel-group, randomised (1:1) controlled trial performed in large teaching and university hospitals in the Netherlands. We will enrol 86 patients with AIH who have not reached CR after at least 6 months of treatment with first-line therapy. Patients are randomised to TAC (0.07 mg/kg/day initially and adjusted by trough levels) or MMF (max 2000 mg/day), stratified by the presence of cirrhosis at inclusion. The primary endpoint is the difference in the proportion of patients reaching CR after 12 months. Secondary endpoints include the difference in the proportion of patients reaching CR after 6 months, adverse effects, difference in fibrogenesis, quality of life and cost-effectiveness. Discussion This is the first randomised controlled trial comparing two second-line therapies for AIH. Currently, second-line treatment is based on retrospective cohort studies. The rarity of AIH is the main issue in clinical research for alternative treatment options. The results of this trial can be implemented in existing international clinical guidelines. Trial registration ClinicalTrials.gov NCT05221411 . Retrospectively registered on 3 February 2022; EudraCT number 2021–003420-33. Prospectively registered on 16 June 2021.

The Ralstonia solanacearum species complex is a group of globally important plant pathogens. Bacteria in this very large and genetically diverse group all colonize the xylem elements of angiosperm plants and cause high-impact wilting diseases of many crops. Because they threaten economic and food security, several R. solanacearum species complex subgroups are strictly regulated as quarantine pests. Biologically meaningful and consistent nomenclature is essential for organisms that have major economic and regulatory importance, such as plant-pathogenic Ralstonia. There are currently three species of Ralstonia wilt pathogens: R. pseudosolanacearum (corresponding to two phylogenetic groups that are described in the literature as phylotypes I and III), R. solanacearum (phylotypes IIA, IIB, and IIC), and R. syzygii (phylotype IV, containing three subspecies: subsp. syzygii, subsp. celebensis, and subsp. indonesiensis). A recent paper proposed reclassifying phylotype I as a new species named “Ralstonia nicotianae.” The purpose of this commentary is to register our objection to the taxon “Ralstonia nicotianae.” [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Abstract Background Frailty and multimorbidity are common among patients in geriatric rehabilitation care (GRC). Proper care of these patients involves multiple professionals which requires optimal interprofessional collaboration to provide the best possible support. Interprofessional collaboration (IPC) goes beyond multi-professional collaboration. It requires professionals to think beyond the expertise of their own discipline and work on joint outcomes in which the patient is actively involved. This study describes the development of the GRC teams of an elderly care organization towards the IPC. Methods Mixed method pre-post study of 15 months. The interprofessional training program comprised team trainings, webinars, and online team sessions. Data was aggregated by administering the Extended Professional Identity Scale (EPIS) and QuickScan Interprofessional Collaboration (QS) measurements to GRC staff and by observations of the multi-professional team consultation (MPC) meetings of six GRC teams of an organization for elderly care in Drachten and Dokkum in the Netherlands. ADL independence (Barthel Index) and number of inpatient days were analyzed before and after the project. Results Pretest healthcare professional response was 106, patients for analyses was 181; posttest response was 84, patients was 170. The EPIS shows improvement on “interprofessional belonging” (P = .001, 95%CI: 0.57–2.21), “interprofessional commitment” (P = .027, 95%CI: 0.12–1.90), and overall “interprofessional identity” (P = .013, 95%CI: 0.62 − 5.20). On the QS, all domains improved; “shared values” (P = .009, 95%CI: 0.07 − 0.47), “context” (P = .005, 95%CI: 0.08 − 0.44), “structure & organization” (P = .001, 95%CI: 0.14 − 0.56), “group dynamics & interaction” (P

Background: Palliative care patients desire more symptom management interventions that are complementary to their medical treatment. Within the multi-professional team, nurses could help support pain management with non-pharmacological interventions feasible for their practice and adaptable to palliative care patients’ needs. Objectives: The objective was to identify non-pharmacological interventions feasible in the nursing scope of practice affecting pain in palliative care patients. Design: A systematic review. Data sources and methods: A defined search strategy was used in PubMed, CINAHL, PsycINFO, and Embase. Search results were screened double-blinded. Methodological quality was double-appraised with the Joanna Briggs Institute Critical Appraisal Tools. Data were extracted from selected studies and the findings were summarized. The methodological quality, quantity of studies evaluating the same intervention, and consistency in the findings were synthesized in a best-evidence synthesis to rank evidence as strong, moderate, limited, mixed, or insufficient. Results: Out of 2385 articles, 22 studies highlighted non-pharmacological interventions in the nursing scope of practice. Interventions using massage therapy and virtual reality demonstrated most evidentiary support for pain management, while art therapy lacked sufficient evidence. Mindful breathing intervention showed no significant reduction in pain. Hypnosis, progressive muscle-relaxation-interactive-guided imagery, cognitive-behavioral audiotapes, wrapped warm footbath, reflexology, and music therapy exhibited promising results in pain reduction, whereas mindfulness-based stress reduction program, aromatherapy, and aroma-massage therapy did not. Conclusion: Despite not all studies reaching significant changes in pain scores, non-pharmacological interventions can be clinically relevant to palliative care patients. Its use should be discussed for its potential value and nurses to be trained for safe practice. Methodologically rigorous research for non-pharmacological interventions in nursing scope of practice for pain relief in palliative care patients is necessary. Trial registration: The protocol for this study is registered in the International Prospective Register of Systematic Review (PROSPERO registration number: CRD42020196781).

Background: People with dementia have a yearly risk of falling of 60 to 80 percent. Therefore, a walker is often recommended. However, the use of a walker in people with dementia is associated with a threefold increased odds of falls compared to their healthy peers. Better advice and training could reduce fall risk. Therefore, a tool to assess functional walking skills with a walker is needed. The SUMAC was developed to fill this gap. So far, there is no Dutch instrument available that can assess functional walking skills with a walker in people with dementia. Methods: Reliability was evaluated by scoring videos of people with dementia (n = 9) using a walker performing the SUMAC-NL. ICC was used to assess inter-rater and test-retest reliability. An expert panel (n = 8) evaluated the content validity using the content validity index (CVI) and the content validity ratio (CVR). Results: Inter-rater reliability of the SUMAC-NL was statistically significant for the PF domain (ICC = 0.94, 95%CI (0.84, 0.98, p < 0.001) and for the EQ domain (ICC = 0.79, 95%CI (0.49 – 0.95), p < 0.001). Test-retest reliability was statistically significant for both the PF domain (ICC = 0.95, 95%CI (0.89, 0.99), p < 0.001) and EQ domain (ICC = 0.92, 95%CI (0.82, 0.98), p < 0.001). The SUMAC-NL shows content validity with a CVI >0.79 for both domains and a CVR of 0.53 on the PF domain and 0.78 on the EQ domain. Conclusions: The SUMAC-NL shows good to excellent reliability and content validity for both the PF and the EQ domain. The SUMAC-NL seems to be a promising tool to assess walking with a walker in people with dementia in the Netherlands.

Phytophthora root rot (PRR) of chickpea (Cicer arietinum) caused by Phytophthora medicaginis is an important disease. Partial resistance to PRR is sourced from Cicer echinospermum. In this study, we evaluated if lines with low levels of PRR foliage symptoms in two contrasting recombinant inbred line (RIL) populations parented by chickpea cultivars (Yorker and Rupali) and 04067-81-2-1-1 (C. echinospermum, interspecific breeding line) had a significant drag on yield parameters. For the Yorker × 04067-81-2-1-1 population with the highest level of PRR resistance, in the absence of PRR, low foliage symptom RIL had significantly later flowering and podding, lower grain yields, and lighter seed and shorter plant phenotypes than high foliage symptom RIL. A quantitative trait locus analysis identified significant QTL for flowering, height, 100-seed weight, and yield, and there was a significantly higher frequency of alleles for the negative agronomic traits (i.e., drag) from the 04067-81-2-1-1 parent in low foliage symptom RIL than in high foliage symptom RIL. For the Rupali × 04067-81-2-1-1 population with lower levels of PRR resistance, in the absence of PRR, low foliage symptom RIL had significantly lighter seed and shorter plants than high foliage symptom RIL. Significant QTL were detected, the majority were for the timing of flowering and podding (n = 18), others were for plant height, yield, and 100-seed weight. For this second population, the frequency of alleles for the negative agronomic traits from the 04067-81-2-1-1 parent did not differ between low and high foliage symptom RIL. The 100 seed weight of RIL under moderate PRR disease pressure showed some promise as a yield component trait to identify phenotypes with both high levels of PRR resistance and grain yield potential for further seed number evaluations. We identified that large population sizes are required to enable selection among chickpea × C. echinospermum crosses for high levels of PRR resistance without a significant drag on yield.

The origin of cancer-associated fibroblasts (CAFs) in cancer remains to be identified. Here, single-cell transcriptomics, in vivo and in vitro studies suggest that CD26+ and CD26- normal fibroblasts transform into distinct CAF subpopulations in mouse models of breast cancer.

Abstract Background Currently, the standard therapy for autoimmune hepatitis (AIH) consists of a combination of prednisolone and azathioprine. However, 15% of patients are intolerant to azathioprine which necessitates cessation of azathioprine or changes in therapy. In addition, not all patients achieve complete biochemical response (CR). Uncontrolled data indicate that mycophenolate mofetil (MMF) can induce CR in a majority of patients. Better understanding of first-line treatment and robust evidence from randomised clinical trials are needed. The aim of this study was to explore the potential benefits of MMF as compared to azathioprine, both combined with prednisolone, as induction therapy in a randomised controlled trial in patients with treatment-naive AIH. Methods CAMARO is a randomised (1:1), open-label, parallel-group, multicentre superiority trial. All patients with AIH are screened for eligibility. Seventy adult patients with AIH from fourteen centres in the Netherlands and Belgium will be randomised to receive MMF or azathioprine. Both treatment arms will start with prednisolone as induction therapy. The primary outcome is biochemical remission, defined as serum levels of alanine aminotransferase and immunoglobulin G below the upper limit of normal. Secondary outcomes include safety and tolerability of MMF and azathioprine, time to remission, changes in Model For End-Stage Liver Disease (MELD)-score, adverse events, and aspects of quality of life. The study period will last for 24 weeks. Discussion The CAMARO trial investigates whether treatment with MMF and prednisolone increases the proportion of patients in remission compared with azathioprine and prednisolone as the current standard treatment strategy. In addition, we reflect on the challenges of conducting a randomized trial in rare diseases. Trial registration EudraCT 2016-001038-91 . Prospectively registered on 18 April 2016. Graphical Abstract

Abstract Background People who use drugs (PWUD) are at high risk for hepatitis C virus (HCV) infection and its complications. Given the high prevalence rate of HCV in PWUD, the World Health Organization (WHO) emphasizes PWUD as a target population for HCV elimination. The introduction of pangenotypic direct acting antivirals (DAAs) greatly simplifies HCV treatment, which encourages integration of HCV treatment in primary care. Facilitating low threshold HCV care for PWUD by implementing decentralized models is crucial for HCV elimination. Aims With this study we aim to (1) eliminate 90% of identified HCV infections in Dutch addiction care, using a decentralized PWUD-HCV care model, and (2) identify facilitators and barriers for successful implementation of the model using interviews. Methods We will perform a multicenter mixed-method study on HCV treatment in addiction care. In a prospective observational study we will examine HCV-related outcomes in PWUD receiving HCV treatment as part of addiction care. The primary outcome is viral elimination, defined as percentage of identified HCV positive patients cured with DAAs. In parallel, we will perform a qualitative study to explore facilitators and barriers for implementation of fully decentralized HCV-PWUD care. We will interview addiction care professionals and board members about their experience with HCV-care as part of addiction care. Discussion This study will show effectiveness of integration of HCV care within addiction care, and provide insight in facilitators and barriers to implement integrated HCV-addiction care. The results will provide recommendations for implementation and maintenance of the decentralized HCV pathway, which can facilitate scaling-up to contribute to reaching WHO HCV elimination goals. Trial registration NCT05401136.

Tripe-negative breast cancers poorly respond to immune checkpoint inhibition therapy, due to their immune-hostile tumour microenvironment. Authors here show that the oncogene MYC plays a pivotal role in suppressing anti-tumour immunity via directly regulating the transcription of interferon signalling genes.

Background & Aims: Non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) affect 17–46% of Western countries, making coexistence with other liver diseases inevitable. We investigated the prevalence and clinical significance of NAFLD/NASH or the components of metabolic syndrome (MetS) in a large multicentric cohort of patients with autoimmune hepatitis (AIH). Methods: Data from six academic centres (Greece, Canada, Japan, Germany, The Netherlands, and Spain) were evaluated. The presence of NAFLD/NASH in liver biopsy, MetS components, and clinical and laboratory parameters were recorded. Results: A total of 640 patients (474 females, age 49 [4–87] years; follow-up 78 [1–521] months) were included. NAFLD was present in 146 (22.8%) patients (AIH/non-alcoholic fatty liver [NAFL] 115 [18%], AIH/NASH 31 [4.8%]). AIH/NAFL patients were older (p = 0.017), more frequently overweight or obese (p = 0.002), had hypertension (p = 0.001), and had diabetes (p = 0.016), whereas they less frequently had acute presentation (p = 0.002) and soluble liver antigen/liver pancreas positivity (p

BackgroundGiven the increasing number of cancer survivors and their rising survival rates, rehabilitation plays an increasingly important role. Social support among patients is an essential element of inpatient and day care rehabilitation. The internet can empower patients with cancer to become more active health care consumers and facilitate information and supportive care needs. By contrast, therapists suspect that high internet use during rehabilitation may severely limit social interactions between patients, thus interfering with the patients’ rehabilitation program and jeopardizing treatment success. ObjectiveWe hypothesized that the extent of internet use would be negatively related to social support among patients with cancer during their clinical stay as well as fewer improvements in patient-reported treatment outcomes from the first to the last day of their clinical stay. MethodsPatients with cancer participated during their inpatient rehabilitation. Cross-sectional data, such as the extent of participants’ internet use and perceived social support among patients, were collected during the last week of their clinic stay. The treatment outcomes, that is, participants’ levels of distress, fatigue, and pain, were collected on the first and last day of the clinic stay. We used multiple linear regression analysis to study the association between the extent of internet use and social support among patients with cancer. We used linear mixed model analyses to study the association between the extent of internet use by patients with cancer and the change in patient-reported treatment outcomes. ResultsOf the 323 participants, 279 (86.4%) participants reported that they used the internet. The extent of the internet use (t315=0.78; P=.43) was not significantly associated with the perceived social support among the participants during their clinical stay. In addition, the extent of participants’ internet use during their clinical stay was not associated with changes in participants’ levels of distress (F1,299=0.12; P=.73), fatigue (F1,299=0.19; P=.67), and pain (F1,303=0.92; P=.34) from the first to the last day of their clinical stay. ConclusionsThe extent of internet use does not seem to be negatively associated with the perceived social support among patients with cancer or with the change in patients’ levels of distress, fatigue, or pain from the first to the last day of their clinical stay.

Persoonsgerichte zorg is bij geriatrische revalidatie (GR) het resultaat van gezamenlijke goal setting en het volgen van de voortgang tijdens de revalidatie. Het impliceert een actieve betrokkenheid van de patiënt. Samenwerking tussen zorgprofessionals en patiënten is waardevol bij goal setting en draagt bij aan persoonsgerichte zorg. Met deze studie onderzoeken we hoe in de praktijk invulling wordt gegeven aan actieve participatie, welke wensen GR-patiënten hebben en welke handvatten hiervoor nodig zijn. Hiervoor werden cross-sectioneel semigestructureerde interviews afgenomen bij 23 GR-patiënten gedurende 1 jaar. Het onderzoek laat zien dat patiënten actief benaderd en ondersteund willen worden door zorgprofessionals voor actieve patiëntparticipatie. De mate waarin en de manier waarop is verschillend, waardoor een flexibele aanpak nodig is die rekening houdt met de behoeften en mogelijkheden van de patiënt en diens omgeving. Vanuit dit onderzoek zijn aanbevelingen voor de praktijk geformuleerd.

Abstract Background In patients with severe polycystic liver disease (PLD), there is a need for new treatments. Estrogens and possibly other female sex hormones stimulate growth in PLD. In some patients, liver volume decreases after menopause. Female sex hormones could therefore be a target for therapy. The AGAINST-PLD study will examine the efficacy of the GnRH agonist leuprorelin, which blocks the production of estrogen and other sex hormones, to reduce liver growth in PLD. Methods The AGAINST-PLD study is an investigator-driven, multicenter, randomized controlled trial. Institutional review board (IRB) approval was received at the University Medical Center of Groningen and will be collected in other sites before opening these sites. Thirty-six female, pre-menopausal patients, with a very large liver volume for age (upper 10% of the PLD population) and ongoing liver growth despite current treatment options will be randomized to direct start of leuprorelin or to 18 months standard of care and delayed start of leuprorelin. Leuprorelin is given as 3.75 mg subcutaneously (s.c.) monthly for the first 3 months followed by 3-monthly depots of 11.25 mg s.c. The trial duration is 36 months. MRI scans to measure liver volume will be performed at screening, 6 months, 18 months, 24 months and 36 months. In addition, blood will be drawn, DEXA-scans will be performed and questionnaires will be collected. This design enables comparison between patients on study treatment and standard of care (first 18 months) and within patients before and during treatment (whole trial). Main outcome is annualized liver growth rate compared between standard of care and study treatment. Secondary outcomes are PLD disease severity, change in liver growth within individuals and (serious) adverse events. The study is designed as a prospective open-label study with blinded endpoint assessment (PROBE). Discussion In this trial, we combined the expertise of hepatologist, nephrologists and gynecologists to study the effect of leuprorelin on liver growth in PLD. In this way, we hope to stop liver growth, reduce symptoms and reduce the need for liver transplantation in severe PLD. Trial registration Eudra CT number 2020-005949-16, registered at 15 Dec 2020. https://www.clinicaltrialsregister.eu/ctr-search/search?query=2020-005949-16 .

Background & Aims: Recently, novel inborn errors of metabolism were identified because of mutations in V-ATPase assembly factors TMEM199 and CCDC115. Patients are characterized by generalized protein glycosylation defects, hypercholesterolemia, and fatty liver disease. Here, we set out to characterize the lipid and fatty liver phenotype in human plasma, cell models, and a mouse model. Methods and Results: Patients with TMEM199 and CCDC115 mutations displayed hyperlipidemia, characterized by increased levels of lipoproteins in the very low density lipoprotein range. HepG2 hepatoma cells, in which the expression of TMEM199 and CCDC115 was silenced, and induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells from patients with TMEM199 mutations showed markedly increased secretion of apolipoprotein B (apoB) compared with controls. A mouse model for TMEM199 deficiency with a CRISPR/Cas9-mediated knock-in of the human A7E mutation had marked hepatic steatosis on chow diet. Plasma N-glycans were hypogalactosylated, consistent with the patient phenotype, but no clear plasma lipid abnormalities were observed in the mouse model. In the siTMEM199 and siCCDC115 HepG2 hepatocyte models, increased numbers and size of lipid droplets were observed, including abnormally large lipid droplets, which colocalized with lysosomes. Excessive de novo lipogenesis, failing oxidative capacity, and elevated lipid uptake were not observed. Further investigation of lysosomal function revealed impaired acidification combined with impaired autophagic capacity. Conclusions: Our data suggest that the hypercholesterolemia in TMEM199 and CCDC115 deficiency is due to increased secretion of apoB-containing particles. This may in turn be secondary to the hepatic steatosis observed in these patients as well as in the mouse model. Mechanistically, we observed impaired lysosomal function characterized by reduced acidification, autophagy, and increased lysosomal lipid accumulation. These findings could explain the hepatic steatosis seen in patients and highlight the importance of lipophagy in fatty liver disease. Because this pathway remains understudied and its regulation is largely untargeted, further exploration of this pathway may offer novel strategies for therapeutic interventions to reduce lipotoxicity in fatty liver disease.

Phytophthora root rot caused by Phytophthora medicaginis is an important disease of chickpeas (Cicer arietinum) in Australia with limited management options, increasing reliance on breeding for improved levels of genetic resistance. Resistance based on chickpea–Cicer echinospermum crosses is partial with a quantitative genetic basis provided by C. echinospermum and some disease tolerance traits originating from C. arietinum germplasm. Partial resistance is hypothesised to reduce pathogen proliferation, while tolerant germplasm may contribute some fitness traits, such as an ability to maintain yield despite pathogen proliferation. To test these hypotheses, we used P. medicaginis DNA concentrations in the soil as a parameter for pathogen proliferation and disease assessments on lines of two recombinant inbred populations of chickpea–C. echinospermum crosses to compare the reactions of selected recombinant inbred lines and parents. Our results showed reduced inoculum production in a C. echinospermum backcross parent relative to the C. arietinum variety Yorker. Recombinant inbred lines with consistently low levels of foliage symptoms had significantly lower levels of soil inoculum compared to lines with high levels of visible foliage symptoms. In a separate experiment, a set of superior recombinant inbred lines with consistently low levels of foliage symptoms was tested for soil inoculum reactions relative to control normalised yield loss. The in-crop P. medicaginis soil inoculum concentrations across genotypes were significantly and positively related to yield loss, indicating a partial resistance-tolerance spectrum. Disease incidence and the rankings for in-crop soil inoculum were correlated strongly to yield loss. These results indicate that soil inoculum reactions may be useful to identify genotypes with high levels of partial resistance.

Abstract Rivaroxaban has been investigated in the EINSTEIN‐Jr program for the treatment of acute venous thromboembolism (VTE) in children aged 0 to 18 years and in the UNIVERSE program for thromboprophylaxis in children aged 2 to 8 years with congenital heart disease after Fontan‐procedure. Physiologically‐based pharmacokinetic (PBPK) and population pharmacokinetic (PopPK) modeling were used throughout the pediatric development of rivaroxaban according to the learn‐and‐confirm paradigm. The development strategy was to match pediatric drug exposures to adult exposure proven to be safe and efficacious. In this analysis, a refined pediatric PopPK model for rivaroxaban based on integrated EINSTEIN‐Jr data and interim PK data from part A of the UNIVERSE phase III study was developed and the influence of potential covariates and intrinsic factors on rivaroxaban exposure was assessed. The model adequately described the observed pediatric PK data. PK parameters and exposure metrics estimated by the PopPK model were compared to the predictions from a previously published pediatric PBPK model for rivaroxaban. Ninety‐one percent of the individual post hoc clearance estimates were found within the 5th to 95th percentile of the PBPK model predictions. In patients below 2 years of age, however, clearance was underpredicted by the PBPK model. The iterative and integrative use of PBPK and PopPK modeling and simulation played a major role in the establishment of the bodyweight‐adjusted rivaroxaban dosing regimen that was ultimately confirmed to be a safe and efficacious dosing regimen for children aged 0 to 18 years with acute VTE in the EINSTEIN‐Jr phase III study.

Background Reducing the overuse of care that is proven to be of low value increases the quality and safety of care. We aimed to identify lessons for reducing low-value care by looking at: (1) The effects of eight de-implementation projects. (2) The barriers and facilitators that emerged. (3) The experiences with the different components of the projects.Methods We performed a process evaluation of eight multicentre projects aimed at reducing low-value care. We reported the quantitative outcomes of the eight projects on the volume of low-value care and performed a qualitative analysis of the project teams’ experiences and evaluations. A total of 40 hospitals and 198 general practitioners participated.Results Five out of eight projects resulted in a reduction of low-value care, ranging from 11.4% to 61.3%. The remaining three projects showed no effect. Six projects monitored balancing measures and observed no negative consequences of their strategy. The most important barriers were a lack of time, an inability to reassure the patient, a desire to meet the patient’s wishes, financial considerations and a discomfort with uncertainty. The most important facilitators were support among clinicians, knowledge of the harms of low-value care and a growing consciousness that more is not always better. Repeated education and feedback for clinicians, patient information material and organisational changes were valued components of the strategy.Conclusions Successfully reducing low-value care is possible in spite of the powerful barriers that oppose it. The projects managed to recruit many hospitals and general practices, with five of them achieving significant results without measuring negative consequences. Based on our findings, we offer practical recommendations for successfully reducing low-value care.