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Introduction: To prevent extreme preterm birth, women with cervical insufficiency are eligible for transabdominal cerclage in case of prior failure or technical impossibility for transvaginal cerclage. This study aimed to identify patient characteristics that affect the success rate of transabdominal cerclage to prevent extreme preterm birth in women with cervical insufficiency., Material and Methods: Single-center retrospective cohort study in 87 women who underwent transabdominal cerclage by open laparotomy during first and early second trimester of pregnancy over a 20-year period. Participants were divided into subgroups according to indication for the intervention. Linear regression and meta-regression-analyses were performed to assess the effect of mean cervical length (before and after transabdominal cerclage placement) and gestational age of previous preterm birth, on gestational age at delivery. Kaplan-Meier analysis was performed to evaluate treatment effects on gestational age at delivery., Results: Of 87 women, 62 women underwent a history-indicated and 25 an ultrasound-indicated transabdominal cerclage. Fetal survival was 92%: 91% in the history-indicated and 96% in the ultrasound-indicated group. Median gestational age at delivery was 37.3 weeks, with a median pregnancy prolongation of 163.0 days and with 92% of deliveries ≥34 weeks. Between groups, irrespective of singleton and twin pregnancies, outcomes were comparable. Gestational age at delivery was neither affected by cervical length before transabdominal cerclage, distance between transabdominal cerclage and external os, gestational age of previous preterm birth nor additional progesterone treatment., Conclusions: The efficacy of transvaginal cerclage placement via open laparotomy during high-risk pregnancy is favorable and relates to fetal survival of 92%. Regardless of indication, pregnancy outcomes after transabdominal cerclage are similar, and independent of gestational age at previous preterm birth, cervical length before transabdominal cerclage placement, distance between transabdominal cerclage and external os, and additional progesterone administration., (© 2025 The Author(s). Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).)

Background: Bone fractures in low- and middle-income countries are commonly managed by traditional bonesetters (TBSs). Past studies emphasize the potential for improved fracture care through intersectoral cooperation. This review gauged support among stakeholders for intersectoral collaboration and the results of previous initiatives., Methods: Five medical databases were reviewed. Studies focusing on stakeholder perspectives and articles detailing collaborative initiatives were included. Data extraction and synthesis were carried out using the Cochrane Consumers and Communication Review Group's template. Additionally, all studies underwent quality assessment., Results: Of the 3821 identified articles, 16 were included after full-text screening. Twelve articles presented stakeholder perspectives, whereas four discussed collaborative initiatives. The overall article quality was low: articles on stakeholder perspectives scored on average 1.42 out of 4 points, whereas articles on collaborative initiatives scored a mean 1.25 points. In total, 62% of stakeholders (75% of TBSs, 92% of hospital staff, and 52% of patients) expressed support for intersectoral collaboration. The ratio between stakeholders expressing support versus those opposing was 4.4:1. No articles presented data on governmental perspectives. The most mentioned collaborative forms were TBS training (24% of stakeholders) and an integrative model (16% of stakeholders). Interventional studies all consisted of TBS training, reporting improved clinical outcomes and increased practice integration., Conclusion: Despite the limited and low-quality evidence on collaboration initiatives and perspectives, most stakeholders seem supportive of intersectoral collaboration, with training and integration being commonly suggested. Future research efforts exploring the feasibility of embedding TBSs into current primary care systems should ensure the involvement of local and national government., (© 2025 The Author(s). World Journal of Surgery published by John Wiley & Sons Ltd on behalf of International Society of Surgery/Société Internationale de Chirurgie (ISS/SIC).)

Background & Aims: Up to 15% of ulcerative colitis (UC) patients with an ileo-anal pouch will develop chronic or antibiotic refractory pouchitis. We aimed to evaluate the efficacy and safety of tofacitinib in these refractory patients., Methods: In this prospective single center study, adult UC patients with chronic or antibiotic refractory pouchitis (pouchitis disease activity index [PDAI] ≥ 7) were treated with tofacitinib 10 mg twice daily for 8 weeks. Clinical, biochemical, endoscopic and histologic disease activity was assessed at baseline and at week 8. The primary endpoint was the proportion of patients achieving clinical remission (PDAI < 7 and a reduction of ≥3 points from baseline) or clinical response (decrease ≥2 points from baseline)., Results: Thirteen patients were included and treated with tofacitinib. After 8 weeks, 31% achieved PDAI-defined remission (4/13) and 54% achieved response (7/13). Both the total PDAI score (11 [interquartile range 9-12.75] vs. 8 [4.5-9.75], p = 0.033) and the clinical PDAI subscore (4 [3-4] vs. 2 [0.25-3.75], p = 0.014) decreased significantly from baseline compared to week 8 or early withdrawal, respectively. We did not observe a change in endoscopic or histological PDAI subscores., Conclusion: In this pilot study, clinical remission in patients with chronic pouchitis was achieved in 31% of patients after 8 weeks of treatment with tofacitinib. Total and clinical PDAI dropped significantly compared with baseline, but we did not observe a significant change in endoscopic or histologic disease activity. Presumably, a treatment duration of 8 weeks is insufficient to induce mucosal healing in these refractory patients., (© 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.)

The purpose of this study was to produce metabolite-specific T 2 and concentration maps in a clinically compatible time frame. A multi-TE 2D MR spectroscopic imaging (MRSI) experiment (multi-echo single-shot MRSI [MESS-MRSI]) deployed truncated and partially sampled multi-echo trains from single scans and was combined with simultaneous multiparametric model fitting. It was tested in vivo for the brain in five healthy subjects. Cramér-Rao lower bounds (CRLB) were used as the measure of performance. The novel method was compared with (1) traditional multi-echo multi-shot (MEMS) MRSI and, as proof of concept, with (2) a truncated version of MEMS, which mimics the MESS acquisition (MESS-mocked) on the original fully sampled MEMS dataset. MESS-MRSI simultaneously yields concentration and T 2 maps with a nominal voxel size of ~2 cm 3 with a 16 × 16 FOV matrix in 7 min scan time. The estimated values not only align well with the equivalent mocked experiment but are also in good agreement with the traditional threefold longer MEMS acquisition. The MESS-MRSI scheme extends former findings for single-voxel MESS, with improvements in CRLB ranging from 17% to 45% for concentrations and 10% to 23% for T 2 s when compared to traditional MEMS. This finding suggests that concentrations and T 2 times can be reliably estimated in a multi-echo spectroscopic imaging exam by trading off spectral resolution (for some of the acquired TEs) with a significant reduction in scan time, as long as (1) an appropriate bidimensional frequency-TE model is deployed and (2) one TE is sampled in full. Thus, high spectral resolution information can be injected to the partially sampled TEs during fitting by prior knowledge from the one fully sampled TE. Tissue-type and regional distributions of 16 metabolite concentrations align well with the literature, and T 2 distributions for five major metabolites are described by region and tissue. The novel MRSI acquisition strategy, based on partially sampled single-shot multi-echo trains twinned to multiparametric fitting, is optimally suited to provide simultaneous 2D concentration and T 2 maps in clinic-compatible scan times. MESS principles allow embedding advanced MRSI techniques to further improve speed, coverage, or resolution. Preliminary findings from a cohort of five subjects reveal correlations between T 2 relaxation times and the relative fraction of gray/white matter, suggesting tissue-type-dependent microstructural changes., (© 2025 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: Persons with Parkinson's disease (PD) experience progressive motor and non-motor symptoms which may influence their ability to drive a car. This is experienced as a massive challenge by many affected individuals, for whom being able to drive a car is vital to maintain functional independence., Objectives: We assessed how the diagnosis of PD affected the possession of a driving license, how people with PD had adapted their driving style, and to what extent they had communicated about their driving ability with their healthcare professionals. We also evaluated their knowledge on insurance- and Driver and Vehicle Licensing Agency (DVLA)-related implications., Method: A cross-sectional 10-item survey was completed by 540 participants of a population-based cohort of persons with PD in the Netherlands (PRIME-NL study)., Results: Participants had a mean age of 70 years and disease duration of 7.3 years. 84% possessed a valid driving license. Of those who gave up their license, this was done mostly (78%) on a voluntarily basis. Forty percent of those with a driving license adjusted their driving style. Over 50% of respondents had not discussed the impact of PD on their driving ability with their healthcare professionals. Although not compulsory by Dutch law, 52% of the respondents had informed the DVLA about their diagnosis., Conclusion: This study highlights the need for information and support from healthcare professionals to proactively address driving in their clinical practice. This will help persons with PD in their efforts to maintain their driving license for as long as possible., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Purpose: The purpose of this study was to develop a multidisciplinary guideline for patellofemoral pain (PFP) and patellar tendinopathy (PT) to facilitate clinical decision-making in primary and secondary care., Methods: A multidisciplinary expert panel identified questions in clinical decision-making. Based on a systematic literature search, the strength of the scientific evidence was determined according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) method and the weight assigned to the considerations by the expert panel together determined the strength of the recommendations., Results: After confirming PFP or PT as a clinical diagnosis, patients should start with exercise therapy. Additional conservative treatments are indicated only when exercise therapy does not result in clinically relevant changes after six (PFP) or 12 (PT) weeks. Pain medications should be reserved for cases of severe pain. The additional value of imaging assessments for PT is limited. Open surgery is reserved for very specific cases of nonresponders to exercise therapy and those requiring additional conservative treatments. Although the certainty of evidence regarding exercise therapy for PFP and PT had to be downgraded ('very low GRADE' and 'low GRADE'), the expert panel advocates its use as the primary treatment strategy. The panel further formulated weaker recommendations regarding additional conservative treatments, pain medications, imaging assessments and open surgery ('very low GRADE' to 'low GRADE' assessment or absence of scientific evidence)., Conclusion: This guideline recommends starting with exercise therapy for PFP and PT. The recommendations facilitate clinical decision-making, and thereby optimizing treatment and preventing unnecessary burdens, risks and costs to patients and society., Level of Evidence: Level V, clinical practice guideline., (© 2024 The Author(s). Knee Surgery, Sports Traumatology, Arthroscopy published by John Wiley & Sons Ltd on behalf of European Society of Sports Traumatology, Knee Surgery and Arthroscopy.)

Background: In recent years, delayed elective care and growing waiting lists increasingly resulted in postponed surgeries for patients with chronic back and leg pain., Objective: To develop, implement, and evaluate the feasibility of a triage tool for patients with chronic back and/or leg pain to identify those eligible for referral to spinal cord stimulation (SCS) consultation., Methods: A triage tool was developed, based on Dutch SCS guidelines, literature review and expert panel consultation. The triage process was detected and implemented in collaboration with a multidisciplinary team, prior to first orthopaedic consultation. Feasibility, reliability and predictive accuracy were analysed as part of the evaluation of the triage tool., Results: The triage indicators included: Pain location (leg/mixed), DN4 > 3, pain duration ≥ 3 months, leg pain ≥ back pain and NPRS leg pain ≥ 5. The triage tool was applied on patients on the orthopaedic waiting list, followed by a full orthopaedic review if they were not excluded. A total of 1025 orthopaedic patients with chronic back and leg pain were assessed with the triage tool. The triage tool was evaluated as feasible (mean System Usability Score 74.2 [SD 11.5]), reliable (inter-rater reliability [Fleiss' Kappa 0.79], intra-rater reliability [Cohen's Kappa 0.89]) and accurate (sensitivity [100%], specificity [98.8%], positive predictive value [40%] and negative predictive value [100%])., Conclusion: Early triage of potential SCS candidates potentially supports rapid and appropriate care allocation, shortens waiting list time and improves clinical outcomes. Future research should explore strategies to optimise the tool's performance in identifying patients most likely to benefit from SCS therapy., Significance: A novel triage tool was developed to identify patients with chronic back and leg pain for an early referral to SCS. This tool, evaluated for feasibility, reliability, and predictive accuracy, shows promise in reducing waiting times and improving patient selection. It can be a prelude to the further development of decision support for SCS and an acceleration in the care process for SCS candidates., (© 2025 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Objectives: This survey was conducted to describe current European postnatal prophylaxis (PNP) and infant feeding policies with the aim of informing future harmonized guidelines., Methods: A total of 32 senior clinicians with relevant expertise, working in 20 countries within the European Region, were invited to complete a REDCap questionnaire between July and September 2023., Results: Twenty-three of the 32 invited paediatricians responded, representing 16/20 countries. There were multiple respondents from the same country for Italy (n = 5), the UK (n = 2), Germany (n = 2) and France (n = 2). All countries use risk stratification to guide PNP regimen selection. Nine out of 16 countries reported three risk categories, six out of 16 reported two, and one country reported differences in categorization. Criteria used to stratify risk varied between and within countries. For the lowest risk category, the PNP regimen reported ranged from no PNP to up to four weeks of one drug; the drug of choice reported was zidovudine, apart from one country which reported nevirapine. For the highest risk category, the most common regimen was zidovudine/lamivudine/nevirapine (20/23 respondents); regimen duration varied from two to six weeks with variation in recommended dosing. Guidelines support breastfeeding for infants born to people living with HIV in eight out of 16 countries; in the other eight, guidelines do not support/specify., Conclusions: Guidelines and practice for PNP and infant feeding vary substantially across Europe and within some countries, reflecting the lack of robust evidence. Effort is needed to align policies and practice to reflect up-to-date knowledge to ensure the vertical transmission risk is minimized and unnecessary infant HIV testing and PNP avoided, while simultaneously supporting families to make informed decisions on infant feeding choice., (© 2024 The Author(s). HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association.)

Background: After lumbar spine surgery, a Core Outcome Set (COS) for acute pain is essential to ensure that the most meaningful outcomes are monitored consistently in the perioperative period. The aim of the present study was to consent on a COS for assessing the efficacy of acute pain management for patients undergoing lumbar spinal surgery., Method: A modified Delphi procedure was conducted among a national (Dutch) expert panel. External endorsement of the final COS was conducted among an international panel of anaesthesiologists and the Dutch chronic pain patient association., Results: A panel of 35 experts representing 10 stakeholder groups, including orthopaedic surgeons, anaesthesiologists, patient representatives, physician assistants, researchers, a neurosurgeon, nurses, and a psychologist, took part in the Delphi procedure. Five outcome domains reached consensus for inclusion in this COS. This COS contains the following domains: pain intensity, analgesic use, early mobilisation, length of stay, and adverse events. Of an international panel of 27 key opinion leaders, 77% agreed on the final COS. The patient association also consented to the final COS., Conclusions: A COS to evaluate acute pain treatment after lumbar surgery is proposed after national Delphi consensus rounds and (international) external endorsement. Future research should focus on determining suitable measurement instruments, assessing feasibility, validation, and implementation of the COS in daily clinical practice and research., Significance: This research proposes a clinically relevant spine-specific core outcome set (COS) of domains focusing on the acute postoperative phase (until 30 days). This is the first COS for evaluation of acute pain after lumbar spine surgery., (© 2025 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

This systematic review aims at presenting the ethical debate on the artificial placenta (AP) by identifying, distinguishing, and organizing the different ethical arguments described in the literature. Articles were selected based on predefined inclusion criteria: discussing ethical arguments, on AP, written in English. QUAGOL methodology was used for analysis. Forty-five articles were included. We identified three themes. First, foundational-ethical issues. There is disagreement on whether the AP subject should be considered an infant or a new moral entity. While physiologically it stays in the fetus, it sits outside the womb. Second, reproductive ethics issues. Few authors believed that the AP would increase reproductive choices. The majority warned that the AP could limit reproductive choices by creating pressure to use it in healthy pregnancies or as an alternative to abortion. Third, research ethics issues. Publications mostly focused on the selection of the in-human trial participants. We concluded that AP ethical literature focuses mostly on the potential use of AP as an alternative to abortion or healthy pregnancies rather than on its intended use as a treatment after extremely premature birth. Therefore, we conclude that the current ethical literature on AP is imbalanced: it leans more toward science fiction than actual clinical and technological reality., (© 2024 John Wiley & Sons Ltd.)

Drug development is a lengthy process with considerable uncertainty at each milestone. Several trials are needed to progress to confirmatory evaluation and establish a positive benefit-risk balance. One of the critical milestones is the decision to progress to phase III based on phase II trial results. Use of probability of success is becoming standard in pharmaceutical companies to support this decision. However, the lack of consistency in terminology makes it difficult to assess the comparative value of different approaches. By leveraging the availability of high-quality external data (e.g., real-world data, historical clinical trial data, etc.), probability of success-based procedures may further improve decision-making. We performed a scoping review of approaches to calculate the probability of success of a phase III trial depending on the available data sources and the availability of specific endpoints. Calculation of probability of success is relatively straightforward if data for the primary endpoint of the phase III trial are also available in phase II trials. Often, phase II trials are based on biomarker or surrogate outcomes, due to challenges associated with study duration and required sample size. Probability of success-based procedures as reviewed can incorporate external data sources, for example, from clinical trials testing the same or similar drug or real-world data on the targeted population-optimizing the calculation of probability of trial success and the projected drug candidate value. We conclude the paper by reflecting on alternative approaches and ideas for uses within pharmaceutical companies and academia., (© 2025 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lower risk (LR) myelodysplastic syndromes (MDS) are heterogeneous hematopoietic stem and progenitor disorders caused by the accumulation of somatic mutations in various genes including epigenetic regulators that may produce convergent DNA methylation patterns driving specific gene expression profiles. The integration of genomic, epigenomic, and transcriptomic profiling has the potential to spotlight distinct LR-MDS categories on the basis of pathophysiological mechanisms. We performed a comprehensive study of somatic mutations and DNA methylation in a large and clinically well-annotated cohort of treatment-naive patients with LR-MDS at diagnosis from the EUMDS registry (ClinicalTrials.gov.NCT00600860). Unsupervised clustering analyses identified six clusters based on genetic profiling that concentrate into four clusters on the basis of genome-wide methylation profiling with significant overlap between the two clustering modes. The four methylation clusters showed distinct clinical and genetic features and distinct methylation landscape. All clusters shared hypermethylated enhancers enriched in binding motifs for ETS and bZIP (C/EBP) transcription factor families, involved in the regulation of myeloid cell differentiation. By contrast, one cluster gathering patients with early leukemic evolution exhibited a specific pattern of hypermethylated promoters and, distinctly from other clusters, the upregulation of AP-1 complex members FOS/FOSL2 together with the absence of hypermethylation of their binding motif at target gene enhancers, which is of relevance for leukemic initiation. Among MDS patients with lower-risk IPSS-M, this cluster displayed a significantly inferior overall survival ( p  < 0.0001). Our study showed that genetic and DNA methylation features of LR-MDS at early stages may refine risk stratification, therefore offering the frame for a precocious therapeutic intervention., Competing Interests: The authors declare no conflict of interest., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Familial Platelet Disorder with associated Myeloid Malignancy (FPDMM, FPD/AML, RUNX1 -FPD), caused by monoallelic deleterious germline RUNX1 variants, is characterized by bleeding diathesis and predisposition for hematologic malignancies, particularly myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Clinical data on FPDMM-associated AML (FPDMM-AML) are limited, complicating evidence-based clinical decision-making. Here, we present retrospective genetic and clinical data of the largest cohort of FPDMM patients reported to date. We describe 159 European patients (from 94 families) of whom 134 were evaluable for the development of malignant disease. Sixty developed a hematologic malignancy (44.8%), most frequently AML (36/134, 26.9%) or MDS (18/134, 13.4%). Somatic alterations of RUNX1 by gene mutation (48%) and chromosome 21 aberrations (14.3%) were the most common somatic genetic aberrations in FPDMM-AML, followed by FLT3-ITD mutations (24.1%). Somatic RUNX1 and FLT3-ITD mutations were not detected in FPDMM-associated MDS, suggesting important contributions to leukemic transformation. Remission-induction chemotherapy resulted in complete remission in 80% of FPDMM-AML patients with a 5-year overall survival (OS) of 50.4%. Survival outcome was non-inferior compared to a large cohort of newly diagnosed adult RUNX1 -mutated AML (5-year OS 36.6%, p  = 0.5), with relatively infrequent concurrent adverse risk somatic aberrations ( ASXL1 mutation, monosomal karyotype, monosomy 5/del 5q) in FPDMM-AML. Collectively, data support the notion that step-wise leukemic evolution in FPDMM is associated with distinct genetic events and indicate that a substantial subset of FPDMM-AML patients achieves prolonged survival with conventional AML treatment, including allogeneic stem cell transplant. These findings are anticipated to inform personalized clinical decision-making in this rare disorder., Competing Interests: The authors declare no conflict of interest., (© 2025 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)

Background: In patients with chronic intestinal failure, the content and type of parenteral nutrition are individually determined based on various factors, including body composition. In clinical practice, bioelectrical impedance analysis is used to assess body composition using standardized protocols. However, these protocols lack specific recommendations for patients receiving parenteral nutrition. Therefore, this study described the effect of parenteral nutrition infusion on fat-free mass as evaluated by single-frequency bioelectrical impedance analysis., Methods: We performed a descriptive cohort study using bioelectrical impedance analysis to assess adult patients with chronic intestinal failure receiving parenteral nutrition. Measurements were performed at baseline (before parenteral nutrition infusion) and 0, 1, 2, and 4 h after (usually) 18-h parenteral nutrition infusion using hand-to-foot single-frequency bioelectrical impedance analysis (Bodystat 500). The primary outcome of fat-free mass was calculated using the Kyle equation. A linear mixed model was used to compare baseline values with other time points. A difference of >1 kg in fat-free mass compared with baseline was considered clinically relevant., Results: Twenty patients (70% female) with a mean age of 58 (SD, 14) years and a median body mass index of 22.3 (IQR, 21.2-24.8) kg/m 2 were included in the analysis. No significant change in fat-free mass after parenteral nutrition infusion was observed, and 90% (69/77 measurements) of all fat-free mass outcomes after parenteral nutrition infusion remained within the ≤1-kg clinically relevant range., Conclusion: This study found that parenteral nutrition infusion does not affect fat-free mass estimation as assessed by hand-to-foot single-frequency bioelectrical impedance analysis., (© 2025 The Author(s). Journal of Parenteral and Enteral Nutrition published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Competing Interests: The authors declare no conflict of interest.

Background and Purpose: Cognitive impairment (CI) in multiple sclerosis (MS) is associated with bidirectional changes in resting-state centrality measures. However, practicable functional magnetic resonance imaging (fMRI) biomarkers of CI are still lacking. The aim of this study was to assess the graph-theory-based degree rank order disruption index (k D ) and its association with cognitive processing speed as a marker of CI in patients with MS (PwMS) in a secondary cross-sectional fMRI analysis., Methods: Differentiation between PwMS and healthy controls (HCs) using k D and its correlation with CI (Symbol Digit Modalities Test) was compared to established imaging biomarkers (regional degree, volumetry, diffusion-weighted imaging, lesion mapping). Additional associations were assessed for fatigue (Fatigue Scale for Motor and Cognitive Functions), gait and global disability., Results: Analysis in 56 PwMS and 58 HCs (35/27 women, median age 45.1/40.5 years) showed lower k D in PwMS than in HCs (median -0.30/-0.06, interquartile range 0.55/0.54; p = 0.009, Mann-Whitney U test), yielding acceptable yet non-superior differentiation (area under curve 0.64). k D and degree in medial prefrontal cortex (MPFC) correlated with CI (k D /MPFC Spearman's ρ = 0.32/-0.45, p = 0.019/0.001, n = 55). k D also explained fatigue (ρ = -0.34, p = 0.010, n = 56) but neither gait nor disability., Conclusions: k D is a potential biomarker of CI and fatigue warranting further validation., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Acid sphingomyelinase deficiency (ASMD) is an ultra-rare lysosomal storage disease with a broad spectrum of manifestations ranging from severe neuropathic forms to attenuated, chronic visceral forms. Manifestations of the chronic visceral subtype are variable and encompass different degrees of hepatosplenomegaly, pulmonary disease and dyslipidemia. The aim of this study was to provide insights into the natural course of adult patients with the chronic visceral subtype. Based on these insights, we proposed tentative criteria for initiation and follow-up of enzyme replacement therapy (ERT). The data of 23 adult patients were collected in a prospective study. Clinical, genetic and demographic data, plasma measurements, abdominal imaging, pulmonary imaging, pulmonary function tests and quality of life questionnaires were collected. Stability of disease based on several clinical, biochemical and radiological markers (i.e., spleen volume, platelet levels, liver volume, alanine aminotransferase [ALT] levels, diffusion capacity of the lungs for carbon monoxide [DLCO] chitotriosidase activity and lysosphingomyelin [LSM]) was assessed. Cardiovascular risk was estimated based on sex, age, smoking, systolic blood pressure and lipid profile. Quality of life was evaluated with the 36-Item Short Form Health Survey and the Health Assessment Questionnaire. Median follow-up was 6.1 years (range 1.3-19.5 years). The most common manifestations were splenomegaly (100%), decreased high-density lipoprotein cholesterol (HDL-C) plasma levels (83%), (signs of) steatosis measured with transient elastography (82%), thrombocytopenia (64%), hepatomegaly (52%) and decreased diffusion capacity (45%). The majority of markers remained stable during follow-up. Twelve patients showed progression of disease: four for spleen volume, two for liver volume, three for DLCO, seven for chitotriosidase activity and three for LSM. One patient showed progression of disease based on four markers, although this patient did not report any problems at the last visit. Cardiovascular risk was estimated and was increased in half of the patients older than 40 years. Patient-reported quality of life did not differ from the general population, but differences in median 36-Item Short Form Health Survey (SF-36) scores of patients with severe pulmonary involvement and those of patients without pulmonary involvement were observed. Tentative criteria for initiation and effect of therapy were proposed. In conclusion, the chronic visceral subtype of ASMD showed a predominantly stable disease course in this cohort. We propose that ERT should be initiated on an individual basis and only in case of progression or symptomatic disease. Collection and analysis of real world data are necessary to refine start, stop and follow-up criteria in the future., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

The conventional gradient-echo steady-state signal model is the basis of various spoiled gradient-echo (SPGR) based quantitative MRI models, including variable flip angle (VFA) MRI and dynamic contrast-enhanced MRI (DCE). However, including preparation pulses, such as fat suppression or saturation bands, disrupts the steady-state and leads to a bias in T 1 and DCE parameter estimates. This work introduces a signal model that improves the accuracy of VFA T 1 -mapping and DCE for interrupted spoiled gradient-echo (I-SPGR) acquisitions. The proposed model was applied to a VFA T 1 -mapping I-SPGR sequence in the Gold Standard T 1 -phantom (3 T), in the brain of four healthy volunteers (3 T), and to an abdominal DCE examination (1.5 T). T 1 -values obtained with the proposed and conventional model were compared to reference T 1 -values. Bland-Altman analysis (phantom) and analysis of variance (in vivo) were used to test whether bias from both methods was significantly different (p = 0.05). The proposed model outperformed the conventional model by decreasing the bias in the phantom with respect to the phantom reference values (mean bias -2 vs. -35% at 3 T) and in vivo with respect to the conventional SPGR (-6 vs. -37% bias in T 1 , p < 0.01). The proposed signal model estimated approximately 48% (depending on baseline T 1 ) higher contrast concentrations in vivo, which resulted in decreased DCE pharmacokinetic parameter estimates of up to 35%. The proposed signal model improves the accuracy of quantitative parameter estimation from disrupted steady-state I-SPGR sequences. It therefore provides a flexible method for applying fat suppression, saturation bands, and other preparation pulses in VFA T 1 -mapping and DCE., (© 2024 The Author(s). NMR in Biomedicine published by John Wiley & Sons Ltd.)

Background: myotilinopathy is a very rare inherited muscle disease that belongs to the group of myofibrillar myopathies. These diseases share a common alteration of the sarcomere organization at the level of the Z disk resulting in pathological protein aggregation, autophagic abnormalities, and ultimately muscle degeneration. Most reported cases are due to dominant missense mutations in the MYOT gene, two of which are largely recurrent., Methods: We describe the clinical, radiological, pathological, and molecular analysis including long-read sequencing of a family affected by late-onset dominant proximodistal myopathy and muscle hypertrophy., Results: We identified a duplication of the entire MYOT gene as the molecular cause of late-onset-myotilinopapthy with typical clinical and pathological features., Conclusions: This study expands the molecular spectrum of myotilinopathy and highlights the use of long-read sequencing in the diagnosis of genetic neurological diseases caused by duplications and genomic structural variants. Myotilinopathy as well as other myofibrillar and distal myopathies should be considered in the differential diagnosis of patients affected by distal muscle weakness, even when presenting at an old age., (© 2025 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The duration of response (DoR) is defined as the time from the onset of response to treatment up to progression of disease or death due to any reason, whichever occurs earlier. The expected DoR could be a suitable estimand to measure the efficacy of a treatment but is in practice difficult to estimate, since patients' follow-up times are often right-censored. Instead, the restricted mean duration of response (RMDoR) is often used. The RMDoR in a time τ $$ \tau $$ is equal to the expected DoR restricted to the interval 0 τ $$ \left[0,\tau \right] $$ . In this paper, we consider the behaviour of the RMDoR as a function of τ $$ \tau $$ and its suitability as a measure to quantify the efficacy of a treatment. Besides, we focus on the estimation of the RMDoR. In oncology, the events response to treatment and progression of disease are typically detected through time-scheduled scans and are therefore interval-censored. We describe multiple estimators for the RMDoR that deal with the interval censoring in different ways and study the performance of these estimators in single arm trials and randomised controlled trials., (© 2025 The Author(s). Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Cardiac involvement (CI) in phosphomannomutase 2-congenital disorders of glycosylation (PMM2-CDG) is part of the multisystemic presentation contributing to high mortality rates. The most common cardiac manifestations are pericardial effusion, cardiomyopathy, and structural heart defects. A genotype-phenotype correlation with organ involvement has not yet been described. We analyzed clinical, biochemical, and molecular genetic data of 222 patients from eight European centers and characterized the natural course of patients with CI. Fifty-seven patients (45 children) presented with CI, of whom 24 died (median age 21 months, standard deviation 49.8). Pericardial effusion was the most frequent manifestation (55.4%), occurring mostly within the first 6 months of life. The most common pathogenic variants in patients with CI were p.(Arg141His) in 74%, followed by p.(Val231Met) in 36%, which is 3.5 times higher than in PMM2-CDG patients without CI (p < 0.0001). Twenty-one out of 36 patients with p.(Val231Met) had CI; among them, 15 died, compared to 33 out of 166 patients without p.(Val231Met) who had CI (p < 0.0001). Nine out of 33 patients died (p = 0.0015), indicating greater clinical severity. Furthermore, the p.(Val231Met) variant is predominant in Eastern Europe, suggesting a founder effect. Cardiac complications in PMM2-CDG patients are common and serious. The variant p.(Val231Met) profoundly influences the extent of CI and mortality rates. Therefore, we recommend cardiac surveillance be included in the follow-up protocols for PMM2-CDG., (© 2024 SSIEM.)

Shared governance in hospitals promotes the inclusion of nurses' expertise, knowledge and skills in organisational processes, and nurses increasingly fulfil positions in organisational hierarchies. However, incorporating nursing expertise in strategic governance structures might be complicated, as these structures are primarily linked to managerial and biomedical expertise. Drawing on a Foucauldian perspective on knowledge and power, intertwined and embedded in everyday (inter)actions, we study how newly appointed directors of nursing challenge these dominant 'modes of knowing'. By focusing on a (Dutch) healthcare organisation, a large academic medical centre, we gained insight into how the history of director of nursing roles relates to how nursing expertise is valued. We gathered qualitative data (from multiple sources) to get close to the daily practices of these directors. In this way, we were able to highlight three tactics that enable directors to relate to new 'knowledge-power knots': (1) positioning, by creating more unity; (2) profiling, by showing significance and (3) powering, by being alert and intervening. With these tactics, the directors of nursing try to embed themselves and their expertise in hospital governance. This study contributes to an everyday understanding of power and the tactics that directors of nursing employ as an ongoing practice. This provides practical starting points for embedding nursing in governance and decision-making., (© 2025 The Author(s). Nursing Inquiry published by John Wiley & Sons Ltd.)

Background: Vaccination is a key measure in influenza control, yet global coverage rates remain low, although previous research reported an increase in influenza vaccination coverage rates (VCR) after the onset of the COVID-19 pandemic. This study aims to assess whether these changes were sustained over time by analyzing VCR trends from 2012 to 2023 in the countries included in the FluCov project., Methods: Data on influenza VCR from 2012 to 2023 for different age and risk groups were extracted from national health organizations and international sources for countries included in the FluCov project. For coverage rates in the older adults, segmented regression models were used to test if 2020 marked a significant change in VCR trends. Moreover, polynomial regression models were fitted for each country with VCR in the period 2012 to 2020 to predict coverage rates for 2021 to 2023 and to compare these to the actual coverage rates for 2021 to 2023., Results: For the elderly, we retrieved influenza VCR data for 12 countries. In 2020, VCR among elderly increased in 10 countries, but the increase was statistically significant in Spain and England only. Moreover, all countries except Spain reverted to levels within the confidence intervals of trends modeled using pre-2020 data., Conclusions: Although influenza VCR increased in 2020, these changes were statistically significant in only two out of 12 countries, and no consistent, sustained increase was observed afterward, except in Spain. The findings suggest the need for continuous monitoring of VCR and the implementation of strategies to promote and maintain high vaccination coverage rates., (© 2025 The Author(s). Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)

Hereditary fructose intolerance (HFI) is characterized by liver damage and a secondary defect in N-linked glycosylation due to impairment of mannose phosphate isomerase (MPI). Mannose treatment has been shown to be an effective treatment in a primary defect in MPI (i.e., MPI-CDG), which is also characterized by liver damage. Therefore, the aims of this study were to determine: (1) hepatic nucleotide sugar levels, and (2), the effect of mannose supplementation on hepatic nucleotide sugar levels and liver fat, in a mouse model for HFI. Aldolase B deficient mice (Aldob -/- ) were treated for four weeks with 5% mannose via the drinking water and compared to Aldob -/- mice and wildtype mice treated with regular drinking water. We found that hepatic GDP-mannose and hepatic GDP-fucose were lower in water-treated Aldob -/- mice when compared to water-treated wildtype mice (p = 0.002 and p = 0.002, respectively), consistent with impaired N-linked glycosylation. Of interest, multiple other hepatic nucleotide sugars not involved in N-linked glycosylation, such as hepatic UDP-glucuronic acid, UDP-xylose, CMP-N-acetyl-beta-neuraminic acid, and CDP-ribitol (p = 0.002, p = 0.003, p = 0.002, p = 0.002), were found to have altered levels as well. However, mannose treatment did not correct the reduction in hepatic GDP-mannose levels, nor was liver fat affected. Aldob -/- mice are characterized by hepatic nucleotide sugar abnormalities, but these were not abrogated by mannose treatment. Future studies are needed to identify the underlying mechanisms responsible for the abnormal hepatic nucleotide sugar pattern and intrahepatic lipid accumulation in HFI. Trial Registration: PCT ID: PCTE0000340, this animal experiment is registered at (https://preclinicaltrials.eu/)., (© 2024 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Introduction: Children's early language and communication skills are efficiently measured using parent report, for example, communicative development inventories (CDIs). These have scalable potential to determine risk of later language delay, and associations between delay and risk factors such as prematurity and poverty. However, there may be measurement difficulties in parent reports, including anomalous directions of association between child age/socioeconomic status and reported language. Findings vary on whether parents may report older infants as having smaller vocabularies than younger infants, for example., Methods: We analysed data from the UK Communicative Development Inventory (Words and Gestures); UK-CDI (W&G) to determine whether anomalous associations would be replicated in this population, and/or with gesture. In total 1204 families of children aged 8-18 months (598 girls, matched to UK population for income, parental education and ethnicity as far as possible) completed Vocabulary and Gesture scales of the UK-CDI (W&G)., Results: Overall scores on the Gesture scale showed more significant relationships with biological risk factors including prematurity than did Vocabulary scores. Gesture also showed more straightforward relationships with social risk factors including income. Relationships between vocabulary and social risk factors were less straightforward; some at-risk groups reported higher vocabulary scores than other groups., Discussion: We conclude that vocabulary report may be less accurate than gesture for this age. Parents have greater knowledge of language than gesture milestones, hence may report expectations for vocabulary, not observed vocabulary. We also conclude that gesture should be included in early language scales partly because of its greater, more straightforward association with many risk factors for language delay., What This Paper Adds: What is already known on the subject We already know that it is possible to measure children's early communicative skills using parent-completed inventories (Communicative Development Inventories, CDIs) and that some aspects of early communication can predict which children are likely to go on to have long-lasting communicative development difficulties. We also know that most uses of CDIs include only vocabulary, not early gesture. In addition, child-related and family-related variables such as prematurity, family history of language disorder and socioeconomic status may be related to communication development. What this paper adds to existing knowledge We looked at a large sample (N = approx. 1200) of families representative of the UK population with an infant aged 8 through 18 months and asked them about their infant's comprehension and production vocabulary as well as their early gesture skills. Gesture was more closely related to possible risk factors for communication development difficulties, for example, family history of communication difficulties, prematurity and multiple birth status. Vocabulary was only related in a straightforward way to family history and had complex relationships to socioeconomic differences. Families with different economic backgrounds may approach questions about their child's development in different ways. What are the potential or actual clinical implications of this work? We suggest that clinicians need to ensure that not only vocabulary but also gesture ability is assessed when looking at very early communication skills. We also suggest that gesture may be more predictive of later communicative development difficulties, and that clinicians need to be sure that parents are clear on how vocabulary questions are asked and what exactly is required of them in answering these types of questions., (© 2025 The Author(s). International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)

Objectives: To describe incidence, clinical course, diagnostic and therapeutic management and long-term follow-up of paediatric intestinal pseudo-obstruction (PIPO) in the Netherlands between 2000 and 2020., Methods: Multicenter, national, retrospective, observational study including patients aged <18 years diagnosed with PIPO and treated between 2000 and 2020 in Dutch academic medical centres. Outcomes included demographics, incidence, symptoms, diagnostic- and treatment methods used during follow-up, number of hospital admissions and mortality., Results: Between 2000 and 2020, 43 children (median age 120 months, range 13-301, 54% female) were diagnosed with PIPO in the Netherlands. Mean incidence was 0.008/100,000/years (range 0/100 000-0.029/100 000). Twenty-six patients developed PIPO in the neonatal period. Initial symptoms were vomiting (n = 21/35, 60%) and abdominal distension (n = 14/35, 40%). Diagnostic strategies included imaging, manometry, histopathology, metabolic- and genetic screening, endoscopy and exploratory surgery. Treatment was divided in nutritional support, pharmacotherapy, colonic irrigation and surgical interventions, of which nutrition and surgery were the cornerstones for care. During the observed study period, the median number of hospital admissions was 22.5 (range 1-176) with a median of 157.5 days (range 3-840) during 20-year follow-up. Two patients (6%) died: one from sepsis and one due to a severe underlying neurological disease. Heterogeneity in diagnostic- en treatment methods existed between patients., Conclusions: PIPO is a rare, long-lasting complex disease requiring a high number of diagnostic and therapeutic interventions and hospital admissions. However, mortality rate is relatively low. Based on our results, we recommend centralization and standardization of care for this complex rare disease., (© 2024 The Author(s). Journal of Pediatric Gastroenterology and Nutrition published by Wiley Periodicals LLC on behalf of European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition.)

Gyrate atrophy of the choroid and retina (GACR, OMIM #258870) is a rare inherited metabolic disorder characterized by progressive chorioretinal degeneration and hyperornithinemia. Current therapeutic modalities potentially slow disease progression but are not successful in preventing blindness. To allow for trial development, increased knowledge of the clinical phenotype and current therapeutic outcomes is required. In this study, we analyzed 27 patients with GACR. The median age at inclusion was 24 years (range 8-58), with a median age at diagnosis of 14 years (range 0-42). Symptoms began at a mean age of 9 years (range 0-21). Mixed-models analysis showed a significant association between dietary natural protein intake and plasma ornithine levels. Ornithine increased significantly with age, independent of dietary natural protein intake. We found no statistically significant association between ornithine levels and best-corrected visual acuity over time. Patients who started a natural protein-restricted diet below 10 years of age had better VF outcomes compared to patients that started at a later age. MR spectroscopy was used to asses cerebral creatine deficiency, which was present in 15/20 patients, of whom 10 were supplemented with creatine at the time. Finally, using the Michigan Retinal Degeneration Questionnaire, we provided a first insight into the vision-related disability reported by patients with GACR and showed that higher foveal sensitivity was associated with less perceived disability. To conclude, this study provides insights into the phenotype, genotype, biochemistry, and treatment effects of GACR, which can be used for care pathways and clinical trial design., (© 2025 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.)

Despite growing knowledge of pregnancy-induced changes in physiology that may alter maternal and fetal pharmacokinetics, evidence-based antenatal doses are lacking for most drugs. Pharmacokinetic modeling and expanding clinical data in pregnancy may support antenatal doses. We aimed to develop and pilot a comprehensive and user-driven Framework for Dose Selection in Pregnancy to support the clinical implementation of a best-evidence antenatal dose for sertraline. After initial development and evaluation by experts, the framework prototype was piloted to formulate an antenatal dosing strategy for sertraline in depression and anxiety disorders. Next, the framework was reviewed and assessed for usability by a multidisciplinary working committee of end-users comprising healthcare practitioners, experts from other disciplines including pharmacometrics, reproductive toxicology and medical ethics, alongside pregnant women and a partner. The resulting framework encompasses the following: rationale for drug selection, a comprehensive analysis of pharmacokinetic and dose-related efficacy and safety data, and implementation aspects including feasibility and desirability of the recommended antenatal dose based on a structured maternal and fetal benefit-risk assessment. An antenatal dose recommendation for sertraline, as a case study, was formulated using this approach and endorsed for clinical use by the working committee. Future applications of the framework for other drugs can further demonstrate its suitability for developing best evidence, acceptable and clinically feasible antenatal doses., (© 2024 The Author(s). Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Accurately predicting individual antidepressant treatment response could expedite the lengthy trial-and-error process of finding an effective treatment for major depressive disorder (MDD). We tested and compared machine learning-based methods that predict individual-level pharmacotherapeutic treatment response using cortical morphometry from multisite longitudinal cohorts. We conducted an international analysis of pooled data from six sites of the ENIGMA-MDD consortium (n = 262 MDD patients; age = 36.5 ± 15.3 years; 154 (59%) female; mean response rate = 57%). Treatment response was defined as a ≥ 50% reduction in symptom severity score after 4-12 weeks post-initiation of antidepressant treatment. Structural MRI was acquired before, or < 14 days after, treatment initiation. The cortex was parcellated using FreeSurfer, from which cortical thickness and surface area were measured. We tested several machine learning pipeline configurations, which varied in (i) the way we presented the cortical data (i.e., average values per region of interest, as a vector containing voxel-wise cortical thickness and surface area measures, and as cortical thickness and surface area projections), (ii) whether we included clinical data, and the (iii) machine learning model (i.e., gradient boosting, support vector machine, and neural network classifiers) and (iv) cross-validation methods (i.e., k-fold and leave-one-site-out) we used. First, we tested if the overall predictive performance of the pipelines was better than chance, with a corrected 10-fold cross-validation permutation test. Second, we compared if some machine learning pipeline configurations outperformed others. In an exploratory analysis, we repeated our first analysis in three subpopulations, namely patients (i) from a single site, (ii) with comparable response rates, and (iii) showing the least (first quartile) and the most (fourth quartile) treatment response, which we call the extreme (non-)responders subpopulation. Finally, we explored the effect of including subcortical volumetric data on model performance. Overall, performance predicting antidepressant treatment response was not significantly better than chance (balanced accuracy = 50.5%; p = 0.66) and did not vary with alternative pipeline configurations. Exploratory analyses revealed that performance across models was only significantly better than chance in the extreme (non-)responders subpopulation (balanced accuracy = 63.9%, p = 0.001). Including subcortical data did not alter the observed model performance. Cortical structural MRI alone could not reliably predict individual pharmacotherapeutic treatment response in MDD. None of the used machine learning pipeline configurations outperformed the others. In exploratory analyses, we found that predicting response in the extreme (non-)responders subpopulation was feasible on both cortical data alone and combined with subcortical data, which suggests that specific MDD subpopulations may exhibit response-related patterns in structural data. Future work may use multimodal data to predict treatment response in MDD., (© 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Because the occurrence of metabolic syndrome (MetS) might contribute to childhood cancer survivor's excess risk of cardiovascular disease, the authors assessed the prevalence and determinants of MetS in the Dutch Childhood Cancer Survivor Study (DCCSS-LATER2) cohort., Methods: In total, 2338 adult childhood cancer survivors (CCS) were cross-sectionally assessed for the prevalence of MetS, using the Lifelines cohort (N = 132,226 adults without a history of cancer) as references. The prevalence of MetS was clinically assessed using existing classifications, as well as an alternative method using dual-energy x-ray absorptiometry fat% instead of waist circumference to define abdominal adiposity. Logistic regression models, adjusted for age and sex, were used to investigate the association between the presence of MetS and both cohorts. Demographic, lifestyle, and treatment determinants of MetS were identified through multivariable logistic regression., Results: The survivor cohort (median age, 34.7 years, median follow-up time, 27.1 years) showed increased adjusted odds ratio (aOR) for MetS (modified National Cholesterol Education Program Adult Treatment Panel III criteria), as compared to the reference cohort (aOR, 2.07; 95% confidence interval [CI], 1.85-2.32). Compared to these criteria, the alternative method identified 57 additional survivors with MetS (395 of 2070 [19.1%] vs. 452 of 1960 [23.1%], respectively). Age (odds ratio [OR], 1.07; 95% CI, 1.04-1.10, per year increase), smoking (OR, 1.46; 95% CI, 1.04-2.04), low physical activity (OR, 1.48; 95% CI, 1.05-2.09), abdominal radiotherapy (OR, 2.13; 95% CI, 1.01-4.31; >30 Gy), cranial radiotherapy (OR, 2.89; 95% CI, 1.67-4.96; 1-25 Gy; and OR, 2.44; 95% CI, 1.30-4.47; >25 Gy), total body irradiation (OR, 6.17; 95% CI, 3.20-11.76), and underlying central nervous system tumor (OR, 1.78; 95% CI, 1.21-2.60) were associated with MetS., Conclusion: The high risk of MetS in CCS, combined with several potential modifiable factors, underscores the need for timely identification and intervention strategies to mitigate the long-term cardiovascular risks in CCS., (© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Inborn errors of metabolism (IEMs) are rare genetic conditions with significant morbidity and mortality. Technological advances have increased therapeutic options, making it challenging to remain up to date. A centralized therapy knowledgebase is needed for early diagnosis and targeted treatment. This study aimed to identify all treatable IEMs through a scoping literature review, followed by data extraction and analysis according to the Treatabolome principles. Knowledge of treatable IEMs, therapeutic categories, efficacy, and evidence was integrated into the Inborn Errors of Metabolism Knowledgebase (IEMbase), an online database encompassing all IEMs. The study identified 275 treatable IEMs, 18% of all currently known 1564 IEMs, according to the International Classification of Inherited Metabolic Disorders. Disorders of fatty acid and ketone body metabolism had the highest treatability (67%), followed by disorders of vitamin and cofactor metabolism (60%), and disorders of lipoprotein metabolism (42%). The most common treatment strategies were pharmacological therapy (34%), nutritional therapy (34%), and vitamin and trace element supplementation (12%). Treatment effects were most commonly observed in nervous system abnormalities (34%), metabolism/homeostasis abnormalities (33%), and growth (7%). Predominant evidence sources included case reports with evidence levels 4 (48%) and 5 (12%), and individual cohort studies with evidence level 2b (12%). Our study generated the Metabolic Treatabolome 2024. IEMs are the largest group of monogenic disorders amenable to disease-modifying therapy. With drug repurposing efforts and advancements in gene therapies, this number will expand. IEMbase now provides up-to-date, comprehensive information on clinical and biochemical symptoms and therapeutic options, empowering patients, families, healthcare professionals, and researchers in improving patient outcomes., (© 2025 The Author(s). Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Goal setting is an essential step in the clinical reasoning process of speech and language therapists (SLTs) who provide care for children, adolescents and adults with communication disorders. In the light of person-centred care, shared or collaborative goal setting between the SLT and client is advised in (inter)national guidelines. SLTs face challenges in implementing (shared) goal setting as theoretical frameworks and practical interventions are scarce and less applicable to use with a wide range of communication vulnerable populations., Aims: A first step in developing theory and practical interventions is to explore first-hand experiences of SLTs and clients about day-to-day goal-setting practice. This study was guided by the following research question: What are the perspectives and needs of SLTs and persons with communication disorders regarding (shared) goal setting in routine SLT services?, Methods & Procedures: The qualitative study was carried out in the setting of routine speech-language therapy services in community practices, primary education and neurological rehabilitation in the Netherlands. Data collection followed the principles of video-reflexive ethnography, using video footage of goal-setting conversations to facilitate semi-structured, reflexive interviews. Data analysis was based on reflexive thematic analysis. A total of 12 interviews were conducted with client-SLT dyads, covering perspectives from children, parents and adults with a range of communication difficulties and their SLTs., Outcomes & Results: Data analysis resulted in four themes, of which two contain subthemes. Each theme represents a central organizing concept found in SLT and client interviews. The themes were identified as: (1) goal setting is a complex process; (2) goal talk needs to be communication accessible; (3) communicative participation goals are hard to grasp; and (4) the importance of relationships. Topics such as power imbalance, communication vulnerability, effective communication strategies, and motivation and trust are explored under these themes., Conclusions & Implications: SLTs are encouraged to view shared goal setting as a process that needs to be explicitly planned and communicated with clients regardless of their age or communication vulnerability. SLTs have expert knowledge and skills when it comes to supporting communication and applying these skills during goal talks might strengthen shared goal setting and foster a therapeutic relationship. There is a need to concretely conceptualize and embed shared goal setting in policy and clinical guidelines. The themes reported have tentative clinical implications for developing such policy, and shared goal-setting interventions for SLT practice, under the condition that SLTs and people with communication disorders are continuously involved., What This Paper Adds: What is already known on the subject SLTs want to set meaningful goals together with their patients but lack theory and resources to effectively shape the goal-setting process. Few studies have directly reported on the perspectives and needs of SLTs and patients regarding goal setting. Patients generally perceive goal setting as a vague activity in which they minimally participate. SLTs want to involve patients in the goal-setting process and describe the potential benefits, but they also want to report barriers on the systemic and professional competence level. What this paper adds to the existing knowledge SLTs and patients perceive shared goal setting as a multifaceted process, rather than a one-off conversation. This process holds potential vulnerabilities for SLTs and patients alike, and the themes in this study propose potentially helpful ingredients to mediate this vulnerability and shape the goal-setting process. What are the potential or clinical implications of this work? To take the first steps towards effective shared goal setting, SLTs should embrace the element of discovery in goal setting and apply their expert knowledge in supporting communication. To develop practical interventions for SLTs, shared goal setting needs to be further conceptualized and embedded in policy and clinical guidelines., (© 2024 The Author(s). International Journal of Language & Communication Disorders published by John Wiley & Sons Ltd on behalf of Royal College of Speech and Language Therapists.)