Potential application of [18F]AlF-PSMA-11 PET/CT in radioiodine refractory thyroid carcinoma.

BACKGROUND: Patients diagnosed with radioiodine refractory (RAI-R) thyroid carcinoma (TC) have a significantly worse prognosis than patients with radiosensitive TC. These refractory malignancies are often dedifferentiated, hindering the effectiveness of iodine-based imaging. Additionally, the role of metabolic imaging using [18F]FDG PET/CT is also limited in these cases, making adequate staging of RAI-R TC challenging. Recent case series have shown promising results regarding the role of the prostate-specific membrane antigen (PSMA) in TC. In this study we explored the value of [18F]AlF-PSMA-11 PET/CT in RAI-R TC. METHODS: In this phase II study, lesions detected on [18F]AlF-PSMA-11 PET were compared to findings from [18F]FDG PET/CT. Additionally, the serologic soluble prostate-specific membrane antigen (sPSMA) was measured using ELISA. PSMA-expression on tumor tissue in any available resection specimens was analysed with an immunostainer. RESULTS: Eight patients were included, with a total of 39 identified lesions based on PET imaging. [18F]AlF-PSMA-11 PET identified 30 of 39 lesions, and [18F]FDG PET identified 33 lesions, leading to a detection rate of 76.9% and 84.6%, respectively. Interestingly, while nine lesions were solely visualized on [18F]FDG, six were uniquely seen on [18F]AlF-PSMA-11 PET. While sPSMA was immeasurable in all female patients, no correlation was found between sPSMA in male patients and disease-related factors. In five out of eight patients immunohistology showed PSMA expression on the primary tumor. CONCLUSIONS: Although not all lesions could be visualized, [18F]PSMA-11 PET identified multiple lesions imperceptible on [18F]FDG PET. These results display the potential additional diagnostic role of PSMA-targeted imaging in patients with RAI-R TC. Trial registration number No. EudraCT 2021-000456-19.

Efficacy and safety of once-weekly semaglutide 2·4 mg versus placebo in people with obesity and prediabetes (STEP 10): a randomised, double-blind, placebo-controlled, multicentre phase 3 trial.

BACKGROUND: There are currently limited data regarding the effect of semaglutide 2·4 mg in individuals with obesity and prediabetes in clinical trials. We aimed to assess the efficacy and safety of semaglutide 2·4 mg for weight management and glycaemic control in participants with obesity and prediabetes. METHODS: STEP 10 was a randomised, double-blind, parallel-group, phase 3 trial done across 30 trial sites in Canada, Denmark, Finland, Spain, and the UK and included participants aged 18 years or older with a BMI of 30 kg/m2 or higher and prediabetes according to UK National Institute for Health and Care Excellence criteria (defined as having at least one of the following at screening: HbA1c of 6·0-6·4% [42-47 mmol/mol] or fasting plasma glucose [FPG] of 5·5-6·9 mmol/L). Participants were randomly assigned (2:1) to once-weekly subcutaneous semaglutide 2·4 mg or placebo with diet and physical activity counselling for 52 weeks, followed by a 28-week off-treatment period. Primary endpoints were percentage change in bodyweight and proportion of participants reverting to normoglycaemia (HbA1c <6·0% [<42 mmol/mol] and FPG <5·5 mmol/L) at week 52 (assessed in all randomly assigned participants by intention to treat). Selective safety data were collected for participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT05040971, and is complete. FINDINGS: Between Sept 16 and Dec 29, 2021, 138 participants were randomly assigned to semaglutide 2·4 mg and 69 to placebo. 147 (71%) were female and 60 (29%) were male; 183 (88%) were White. All randomly assigned participants received at least one dose of study drug. Baseline mean age was 53 years (SD 11), bodyweight 111·6 kg (22·2), BMI 40·1 kg/m2 (6·9), waist circumference 120·1 cm (14·7), HbA1c 5·9% (0·3; 41·3 mmol/mol [3·0]), and FPG 5·9 mmol/L (0·6). There was a significantly greater reduction in bodyweight with semaglutide 2·4 mg than with placebo at week 52 (-13·9% [SD 0·7] vs -2·7% [0·6]; estimated treatment difference -11·2% [95% CI -13·0 to -9·4]; p<0·0001). Greater proportions of participants reverted to normoglycaemia at week 52 with semaglutide 2·4 mg than with placebo (103 [81%] of 127 vs nine [14%] of 64; odds ratio 19·8 [95% CI 8·7 to 45·2]; p<0·0001). Serious adverse events occurred in 12 (9%) participants receiving semaglutide 2·4 mg versus six (9%) receiving placebo. Adverse events leading to treatment discontinuation occurred in eight (6%) participants in the semaglutide 2·4 mg group versus one (1%) participant in the placebo group. No new safety signals were reported. INTERPRETATION: Semaglutide 2·4 mg provided superior reduction in bodyweight and reversion to normoglycaemia versus placebo in participants with obesity and prediabetes. The safety and tolerability profile was consistent with previous studies and with the GLP-1 receptor agonist class. These findings support the potential use of semaglutide 2·4 mg as a treatment option for individuals with obesity and prediabetes to achieve reversion to normoglycaemia. FUNDING: Novo Nordisk. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

A comprehensive overview of barriers and strategies for AI implementation in healthcare: Mixed-method design.

Implementation of artificial intelligence systems for healthcare is challenging. Understanding the barriers and implementation strategies can impact their adoption and allows for better anticipation and planning. This study's objective was to create a detailed inventory of barriers to and strategies for AI implementation in healthcare to support advancements in methods and implementation processes in healthcare. A sequential explanatory mixed method design was used. Firstly, scoping reviews and systematic literature reviews were identified using PubMed. Selected studies included empirical cases of AI implementation and use in clinical practice. As the reviews were deemed insufficient to fulfil the aim of the study, data collection shifted to the primary studies included in those reviews. The primary studies were screened by title and abstract, and thereafter read in full text. Then, data on barriers to and strategies for AI implementation were extracted from the included articles, thematically coded by inductive analysis, and summarized. Subsequently, a direct qualitative content analysis of 69 interviews with healthcare leaders and healthcare professionals confirmed and added results from the literature review. Thirty-eight empirical cases from the six identified scoping and literature reviews met the inclusion and exclusion criteria. Barriers to and strategies for AI implementation were grouped under three phases of implementation (planning, implementing, and sustaining the use) and were categorized into eleven concepts; Leadership, Buy-in, Change management, Engagement, Workflow, Finance and human resources, Legal, Training, Data, Evaluation and monitoring, Maintenance. Ethics emerged as a twelfth concept through qualitative analysis of the interviews. This study illustrates the inherent challenges and useful strategies in implementing AI in healthcare practice. Future research should explore various aspects of leadership, collaboration and contracts among key stakeholders, legal strategies surrounding clinicians' liability, solutions to ethical dilemmas, infrastructure for efficient integration of AI in workflows, and define decision points in the implementation process.

Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers.

Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug-drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Charting Health Challenges for Digital Preventive Interventions Among Adult Survivors of Childhood Acute Lymphoblastic Leukemia: National Long-Term Follow-Up Survey of Self-Rated Health Outcomes.

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood, but the prognosis has remarkably improved over the last 50 years in high-income countries, and thus, there is a focus on long-term health outcomes following survival and how to best provide health care support to adult long-term survivors of childhood ALL to prevent and handle potential health problems. Digital health interventions are promising to deliver feasible health promotion and prevention programs. This is particularly relevant for ensuring long-term follow-up in cases where continuous contact with oncology care may be disrupted. Moreover, these interventions are beneficial in reaching geographically dispersed target groups and overcoming the time constraints of everyday life that often hinder participation in such programs. OBJECTIVE: This study aimed to fill the gaps in existing research on adult long-term survivors of childhood ALL and provide formative data that can inform the development of formalized follow-up services designed to meet the needs of these survivors in ways that align with their preferences for digital health interventions. METHODS: In this cross-sectional national study, adult survivors (aged ≥18 years) of childhood ALL for over 10 years after diagnosis were compared to their siblings in terms of mental and physical health-related factors, including sleep, stress, anxiety, and depression (Depression Anxiety and Stress Scale 21 [DASS-21]); several dimensions of fatigue (Multidimensional Fatigue Inventory 20 [MFI-20]); work ability (Work Ability Index); chronic pain; and prevalences of diabetes, cardiovascular disease, headache or migraine, and rheumatic disease. RESULTS: Overall, 426 of 855 eligible ALL survivors responded (mean age 30.9, SD 7.7 years), and they participated at an average of 24 (SD 6.9) years after ALL diagnosis. Siblings (n=135; mean age 31.5, SD 7.7 years) acted as controls. Sleep quality, sleep quantity, and mean work ability scores were significantly lower, and physical fatigue, reduced motivation, and reduced activity scores were higher in ALL survivors than in siblings. There were no significant differences between the groups in terms of BMI and prevalence of chronic pain, depression, anxiety, or stress. Physical and psychological complications were more frequent among adult ALL survivors who had received hematopoietic stem cell transplantation (HSCT) than among those who had not received HSCT. CONCLUSIONS: Our nationwide cross-sectional study addressed the scarcity of knowledge regarding the self-reported health outcomes of adult long-term survivors of childhood ALL. We highlighted significant disparities within this population and emphasized the potential of comprehensive digital interventions that target vitality, sleep quality, fatigue, and psychosocial well-being to enhance well-being and bolster the capacity for managing chronic health conditions in this target group. Such an intervention would align with the needs of this target group, which is a prerequisite for successfully incorporating technology into the daily lives of survivors of childhood ALL.

Prostaglandin D2 receptor 2 downstream signaling and modulation of type 2 innate lymphoid cells from patients with asthma.

Increased production of Prostaglandin D2 (PGD2) is linked to development and progression of asthma and allergy. PGD2 is rapidly degraded to its metabolites, which initiate type 2 innate lymphoid cells (ILC2) migration and IL-5/IL-13 cytokine secretion in a PGD2 receptor 2 (DP2)-dependent manner. Blockade of DP2 has shown therapeutic benefit in subsets of asthma patients. Cellular mechanisms of ILC2 activity in response to PGD2 and its metabolites are still unclear. We hypothesized that ILC2 respond non-uniformly to PGD2 metabolites. ILC2s were isolated from peripheral blood of patients with atopic asthma. ILC2s were stimulated with PGD2 and four PGD2 metabolites (Δ12-PGJ2, Δ12-PGD2, 15-deoxyΔ12,14-PGD2, 9α,11ß-PGF2) with or without the selective DP2 antagonist fevipiprant. Total RNA was sequenced, and differentially expressed genes (DEG) were identified by DeSeq2. Differential gene expression analysis revealed an upregulation of pro-inflammatory DEGs in ILC2s stimulated with PGD2 (14 DEGs), Δ12-PGD2 (27 DEGs), 15-deoxyΔ12,14-PGD2 (56 DEGs) and Δ12-PGJ2 (136 DEGs), but not with 9α,11ß-PGF2. Common upregulated DEGs were i.e. ARG2, SLC43A2, LAYN, IGFLR1, or EPHX2. Inhibition of DP2 via fevipiprant mainly resulted in downregulation of pro-inflammatory genes such as DUSP4, SPRED2, DUSP6, ETV1, ASB2, CD38, ADGRG1, DDIT4, TRPM2, or CD69. DEGs were related to migration and various immune response-relevant pathways such as "chemokine (C-C motif) ligand 4 production", "cell migration", "interleukin-13 production", "regulation of receptor signaling pathway via JAK-STAT", or "lymphocyte apoptotic process", underlining the pro-inflammatory effects of PGD2 metabolite-induced immune responses in ILC2s as well as the anti-inflammatory effects of DP2 inhibition via fevipiprant. Furthermore, PGD2 and metabolites showed distinct profiles in ILC2 activation. Overall, these results expand our understanding of DP2 initiated ILC2 activity.

Multi-Task ADME/PK prediction at industrial scale: leveraging large and diverse experimentaldatasets.

ADME (Absorption, Distribution, Metabolism, Excretion) properties are key parameters to judge whether a drug candidate exhibits a desired pharmacokinetic (PK) profile. In this study, we tested multi-task machine learning (ML) models to predict ADME and animal PK endpoints trained on in-house data generated at Boehringer Ingelheim. Models were evaluated both at the design stage of a compound (i. e., no experimental data of test compounds available) and at testing stage when a particular assay would be conducted (i. e., experimental data of earlier conducted assays may be available). Using realistic time-splits, we found a clear benefit in performance of multi-task graph-based neural network models over single-task model, which was even stronger when experimental data of earlier assays is available. In an attempt to explain the success of multi-task models, we found that especially endpoints with the largest numbers of data points (physicochemical endpoints, clearance in microsomes) are responsible for increased predictivity in more complex ADME and PK endpoints. In summary, our study provides insight into how data for multiple ADME/PK endpoints in a pharmaceutical company can be best leveraged to optimize predictivity of ML models.

Hepatitis E virus infection in immunosuppressed patients and its clinical manifestations.

BACKGROUND & AIMS: Hepatitis E virus (HEV) is a main cause of acute hepatitis globally. However, immunosuppressed patients regularly develop chronic courses. The aim of this study was to analyse the current status of HEV diagnostics, characterize clinical manifestations and identify risk factors for complicated HEV infections. METHODS: In this retrospective study at two large hospitals, 512 patients with borderline and positive anti-HEV-IgM and 94 patients with positive HEV-PCR between January 1999 and May 2023 were included. RESULTS: Detection by anti-HEV-IgM-ELISA led to a positive HEV-PCR in only 17.9 %. Amongst patients with positive HEV-PCR, 61 had underlying immunosuppression and 23 were patients after solid organ transplantation (SOT). All 13 patients with chronic HEV infections were immunosuppressed. Generally, immunosuppression led to higher HEV-RNA concentrations and a higher probability of receiving immediate treatment. However, all fulminant courses with liver failure happened in patients without immunosuppression. Immunocompetent patients showed symptoms more frequently and primarily had higher bilirubin levels indicating more severe liver damage. A risk factor for delayed or failed viral clearance after SOT was the administration of mTOR inhibitors. CONCLUSIONS: Fulminant HEV infections happen primarily in immunocompetent patients. Nevertheless, immunosuppressed patients bear the risk of undetected, prolonged HEV infections, reflected by the rare occurrence of symptoms.

Free-breathing 3D phase-resolved functional lung MRI vs breath-hold hyperpolarized 129Xe ventilation MRI in patients with chronic obstructive pulmonary disease and healthy volunteers.

OBJECTIVES: 3D phase-resolved functional lung (PREFUL) MRI offers evaluation of pulmonary ventilation without inhalation of contrast agent. This study seeks to compare ventilation maps obtained from 3D PREFUL MRI with a direct ventilation measurement derived from 129Xe MRI in both patients with chronic obstructive pulmonary disease (COPD) and healthy volunteers. METHODS: Thirty-one patients with COPD and 12 healthy controls underwent free-breathing 3D PREFUL MRI and breath-hold 129Xe MRI at 1.5 T. For both MRI techniques, ventilation defect (VD) maps were determined and respective ventilation defect percentage (VDP) values were computed. All parameters of both techniques were compared by Spearman correlation coefficient (r) and the differences between VDP values were quantified by Bland-Altman analysis and tested for significance using Wilcoxon signed-rank test. In a regional comparison of VD maps, spatial overlap and Sørensen-Dice coefficients of healthy and defect areas were computed. RESULTS: On a global level, all 3D PREFUL VDP values correlated significantly to VDP measure derived by 129Xe ventilation imaging (all r > 0.65; all p < 0.0001). 129Xe VDP was significantly greater than 3D PREFUL derived VDPRVent (mean bias = 10.5%, p < 0.001) and VDPFVL-CM (mean bias = 11.3%, p < 0.0001) but not for VDPCombined (mean bias = 1.7%, p = 0.70). The total regional agreement of 129Xe and 3D PREFUL VD maps ranged between 60% and 63%. CONCLUSIONS: Free-breathing 3D PREFUL MRI showed a strong correlation with breath-hold hyperpolarized 129Xe MRI regarding the VDP values and modest differences in the detection of VDs on a regional level. CLINICAL RELEVANCE STATEMENT: 3D PREFUL MRI correlated with 129Xe MRI, unveiling regional differences in COPD defect identification. This proposes 3D PREFUL MRI as a ventilation mapping surrogate, eliminating the need for extra hardware or inhaled gases. KEY POINTS: Current non-invasive evaluation techniques for lung diseases have drawbacks; 129Xe MRI is limited by cost and availability. 3D PREFUL MRI correlated with 129Xe MRI, with regional differences in identifying COPD defects. 3D PREFUL MRI can provide ventilation mapping without the need for additional hardware or inhaled gases.

SoCap YMH - youth mental health, social capital and help-seeking: a study protocol.

Background: The increase in adolescents reporting mental health problems presents a major public health challenge. The complex association between mental health and social capital motivates further investigation of social capital as a crucial aspect in shaping adolescents' help-seeking knowledge, attitudes, and behaviours. Aim: This protocol presents a project that aims to investigate social capital in relation to help-seeking and mental health in close collaboration with adolescents and key stakeholders in the school setting, in the southern part of Sweden. Methods: A mixed-method design with three interconnected work packages (WP) will be undertaken with an emphasis on co-production where adolescents are involved throughout the process. WP1 is a development and validation of two questionnaire instruments for assessing social capital and help-seeking in adolescence. WP2 is a longitudinal quantitative study involving 1,500 adolescents from two regions representing rural and suburban/urban settings. Adolescents aged 15 will be asked to complete questionnaires concerning social capital, mental health, and help-seeking in a baseline and one-year follow-up, allowing for investigation of the role of social capital for help-seeking. WP3 is designed to elucidate experiences and knowledge of adolescents and key stakeholders via collaborative World Café workshops. These will be held along the project to evolve the generated knowledge and maximize it's applicability during and after the project is finalized. Conclusion: The results are expected to further the understanding of the relationship between adolescents' social capital, mental health, and help-seeking, to contribute to a deeper understanding of the mechanisms behind the paradoxical help-seeking patterns among adolescents today and to narrow the gap between research and practice to produce sustainable and efficient strategies, which may facilitate help-seeking and improve the mental health of adolescents within existing organizational structures.

Sex Differences in Children with Uncomplicated Attention Deficit/Hyperactivity Disorder and Sleep Problems.

BACKGROUND: Approximately 7.6% of children are diagnosed with attention deficit/hyperactivity disorder (ADHD), and sleep impairments affect 25-85%. There is a noticeable lack of research on girls and sex differences. The aim of this study was to examine sex differences in children with uncomplicated ADHD and sleep problems. METHODS: Cross-sectional baseline data were retrieved from a randomized controlled trial with weighted blankets (55 boys and 41 girls, 6-14 years) on a cohort recently diagnosed with uncomplicated ADHD and sleep problems. Differences between boys and girls in ADHD symptoms, objectively and subjectively measured sleep, anxiety, and functioning were examined via parent- or self-reported validated instruments. RESULTS: Girls reported significantly lower (worse) satisfaction with well-being, life overall, and school, but not for family. Parents reported more sleep anxiety and night-time wakings among boys, but no sex differences in other measures and also not in self-reported measures or objective sleep measures. Children who reported worry, sadness, or unhappiness had more sleep problems. CONCLUSIONS: Boys with ADHD and sleep problems may need support with sleep-related anxiety and night-time wakings, while girls may require support with overall functioning. Additionally, children who express feelings of worry, sadness, or unhappiness alongside their ADHD symptoms should have attention given to their sleep.

Aquaponics in schools: Hands-on learning about healthy eating and a healthy planet.

Our food system is giving rise to a growing social, health and environmental crisis. Much of the food consumed in the United Kingdom is cheap, nutrient-poor and highly processed, leading to under-consumption of essential foods such as grains, beans, vegetables and fruit. This has contributed to a rise in diet-related diseases, with approximately 22% of primary school leavers being overweight or obese. Food production is unsustainable with agriculture responsible for 10% of the UK's greenhouse gas emissions and intensive farming practices have led to a significant loss of soil carbon and a decline in biodiversity. COVID-19 increased inequalities in our food system. Therefore, there is an urgent need for interventions to counteract these adverse social, health and environmental impacts. Education can play a crucial role as an intervention to address challenges in the food system. We tested an innovative school initiative using portable aquaponic pods and aligned to the national curriculum, to engage pupils in food production and foster learning about sustainability, climate change and healthy eating. The evaluation, based on teacher surveys, aquapod chart data, student blogs and postcards and feedback from the development team, revealed positive impacts on students' environmental awareness, as well as sustainability and practical food production knowledge. However, the programme encountered logistical challenges and we therefore highlight future improvements to produce a curriculum programme that can be delivered at scale to enhance food education and empower pupils to drive the agenda on tackling food sustainability and climate change.

Effects of basic carbohydrate counting versus standard dietary care for glycaemic control in type 2 diabetes (The BCC Study): a randomised, controlled trial.

BACKGROUND: Clinical guidelines recommend basic carbohydrate counting (BCC), or similar methods to improve carbohydrate estimation skills and to strive for higher consistency in carbohydrate intake potentially improving glycaemic control. However, evidence for this approach in type 2 diabetes (T2D) is limited. OBJECTIVE: To examine the efficacy of a structured education program in BCC as add-on to standard dietary care on glycaemic control in individuals with T2D. METHODS: The BCC Study was a randomized, controlled, open-label, parallel-group trial. Individuals with T2D aged 18-75 years with glycated haemoglobin A1c (HbA1c) 53-97 mmol/mol (7.0-11.0%) were randomly assigned (1:1) to BCC or standard dietary care. The primary outcomes were differences in changes in HbA1c or glycaemic variability (calculated as mean amplitude of glycaemic excursions [MAGE]) between groups after six months of intervention. RESULTS: Between September 2018 and July 2021, 48 participants were randomly assigned, 23 to BCC and 25 to standard dietary care. Seven participants did not receive the allocated intervention. From a baseline-adjusted mean of 65 mmol/mol (95% CI 62-68 [8.1%, 7.8-8.4]), HbA1c changed by -5 mmol/mol (-8 to -1 [-0.5%, -0.7 to -0.1]) in BCC and -3 mmol/mol (-7 to 1 [-0.3%, -0.6 to 0.1]) in standard care with an estimated treatment effect of -2 mmol/mol (-7 to 4 [-0.2%, -0.6 to 0.4]); p = 0.554. From a baseline-adjusted mean of 4.2 mmol/l (3.7 to 4.8), MAGE changed by -16% (-33 to 5) in BCC and by -3% (-21 to 20) in standard care with an estimated treatment effect of -14% (-36 to 16); p = 0.319. Only median carbohydrate estimation error in favour of BCC (estimated treatment difference -55% (-70 to -32); p < 0.001) remained significant after multiple testing adjustment. CONCLUSIONS: No glycaemic effects were found but incorporating BCC as a supplementary component to standard dietary care led to improved skills in estimating carbohydrate intake among individuals with T2D.

Soluble CD46 as a diagnostic marker of hepatic steatosis.

BACKGROUND: The increasing prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) incurs substantial morbidity, mortality and healthcare costs. Detection and clinical intervention at early stages of disease improves prognosis; however, we are currently limited by a lack of reliable diagnostic tests for population screening and monitoring responses to therapy. To address this unmet need, we investigated human invariant Natural Killer T cell (iNKT) activation by fat-loaded hepatocytes, leading to the discovery that circulating soluble CD46 (sCD46) levels accurately predict hepatic steatosis. METHODS: sCD46 in plasma was measured using a newly developed immuno-competition assay in two independent cohorts: Prospective living liver donors (n = 156; male = 66, female = 90) and patients with liver tumours (n = 91; male = 58, female = 33). sCD46 levels were statistically evaluated as a predictor of hepatic steatosis. FINDINGS: Interleukin-4-secreting (IL-4+) iNKT cells were over-represented amongst intrahepatic lymphocytes isolated from resected human liver samples. IL-4+ iNKT cells preferentially developed in cocultures with a fat-loaded, hepatocyte-like cell line, HepaRG. This was attributed to induction of matrix metalloproteases (MMP) in fat-loaded HepaRG cells and primary human liver organoids, which led to indiscriminate cleavage of immune receptors. Loss of cell-surface CD46 resulted in unrepressed differentiation of IL-4+ iNKT cells. sCD46 levels were elevated in patients with hepatic steatosis. Discriminatory cut-off values for plasma sCD46 were found that accurately classified patients according to histological steatosis grade. INTERPRETATION: sCD46 is a reliable clinical marker of hepatic steatosis, which can be conveniently and non-invasively measured in serum and plasma samples, raising the possibility of using sCD46 levels as a diagnostic method for detecting or grading hepatic steatosis. FUNDING: F.B. was supported by the Else Kröner Foundation (Award 2016_kolleg.14). G.G. was supported by the Bristol Myers Squibb Foundation for Immuno-Oncology (Award FA-19-009). N.S. was supported by a Wellcome Trust Fellowship (211113/A/18/Z). J.A.H. received funding from the European Union's Horizon 2020 research and innovation programme (Award 860003). J.M.W. received funding from the Else Kröner Foundation (Award 2015_A10).

Prevalence and prognostic relevance of invasive fungal disease during veno-arterial ECMO: A retrospective single-center study.

PURPOSE: To assess the prevalence and relevance of invasive fungal disease (IFD) during veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO). METHODS: Retrospective analysis from January 2013 to November 2023 of adult V-A ECMO cases at a German University Hospital. Parameters relating to IFD, demographics, length of stay (LoS), days on ECMO and mechanical ventilation, prognostic scores and survival were assessed. Multivariable logistic regression analyses with IFD and death as dependent variables were performed. Outcome was assessed after propensity score matching IFD-patients to non-IFD-controls. RESULTS: 421 patients received V-A ECMO. 392 patients with full electronic datasets were included. The prevalence of IFD, invasive candidiasis and probable invasive pulmonary aspergillosis was 4.6%, 3.8% and 1.0%. Severity of acute disease, pre-existing moderate-to-severe renal disease and continuous kidney replacement therapy were predictive of IFD. In-hospital mortality (94% (17/18) compared to 67% (252/374) in non-IFD patients (p = 0.0156)) was predicted by female sex, SOFA score at admission, SAVE score and IFD (for IFD: OR: 8.31; CI: 1.60-153.18; p: 0.044). There was no difference in outcome after matching IFD-cases to non-IFD-controls. CONCLUSIONS: IFD are detected in about one in 20 patients on V-A ECMO, indicating mortality >90%. However, IFD do not contribute to prognosis in this population.

Changes in Symptoms and General Well-being After Reversal of Roux-en-Y Gastric Bypass: A Questionnaire Survey.

PURPOSE: After Roux-en-Y gastric bypass (RYGB), few patients develop severe complications, which ultimately may require reversal of RYGB. We aimed to examine the effect of reversal of RYGB on symptoms and well-being. MATERIALS AND METHODS: Via contact to medical and surgical departments treating patients with RYGB, we identified 18 patients, who had undergone reversal, 2009-2019. We conducted a Danish, nationwide questionnaire survey concerning symptoms before and after reversal of the RYGB including the patients' own perceptions of their well-being. RESULTS: Fourteen patients responded to the questionnaire (86% female; median age at RYGB, 36.2 years [IQR, 30.9-38.6 years]). The median time from RYGB to reversal was 5.8 years (IQR, 5.1-7.5 years). After RYGB, 13 patients (93%) reported abdominal pain, while 12 patients still had abdominal pain after reversal. Six out of 11 patients (45%) reported complete remission of dumping/post-bariatric hypoglycemia (PBH) after reversal. Malabsorption disappeared in 10 out of 11 patients (90%). Reversal had minor effect on neuropathy. The median weight loss from RYGB was 61 kg (IQR, 56-75 kg), while the median weight regain after reversal was 30 kg (IQR, 13-46 kg). Regarding the well-being, 72 of the patients felt better or much better after reversal. CONCLUSION: In total, 72% of the patients felt better or much better after reversal of RYGB, though some still had RYGB-related symptoms. The reversal relieved dumping/PBH and malabsorption, but not abdominal pain and neuropathy. Finally, half of the weight loss was regained after reversal. Reversal of RYGB may be an option in highly selected cases.

Validity and reliability of the Swedish version of the Children's Sleep Habits Questionnaire (CSHQ-SWE).

BACKGROUND: To translate and culturally adapt the Children's Sleep Habits Questionnaire (CSHQ) to a Swedish version, CSHQ-SWE, and to assess its validity and reliability for use with children with attention deficit hyperactivity disorder (ADHD). METHODS: A total of 84 children with ADHD (51 boys and 33 girls; 6-12 years) and parents (7 men and 77 women; 28-51 years) were included in the study. CSHQ was translated and culturally adapted to Swedish, and assessed for concurrent validity with sleep actigraphy (analyzed by Kendall's Tau) and for reliability by internal consistency (analyzed by McDonald's Omega H). Face and content validity was evaluated by parents (n = 4) and healthcare professionals (n = 6) qualitatively (comprehensiveness, relevance, and comprehensibility assessed by interviews and analyzed by thematic analysis) and quantitatively (analyzed by content validity ratio and content validity index for 33 items and four non-scored inquiries). RESULTS: Parent-reported sleep problems (CSHQ-SWE total score) were moderately correlated with less "Sleep Efficiency" (Tau = -0.305; p < 0.001) measured by sleep actigraphy. Parent-reported problems with "Sleep Onset Delay" was moderately correlated with measured time for "Sleep Onset Latency" (Tau = 0.433; p < 0.001). Parent-reported problems with "Night Wakings" were weakly correlated with measured time for "Wake After Sleep Onset" (Tau = 0.282; p < 0.001). Parents estimation of "Total daily sleep duration" was moderately correlated with measured "Total Sleep Time" (Tau = 0.386; p < 0.001). Five of the seven subscales reached an acceptable level for internal consistency (McDonald's Omega H > 0.700). Comprehensiveness, relevance, and comprehensibility of CSHQ-SWE were satisfactory overall. Content validity ratio was 0.80 to 1.00 for six items, 0.00 to 0.60 for 22 items, and < 0.00 for nine items. Content validity index was 0.22. CONCLUSIONS: CSHQ-SWE demonstrated acceptable concurrent validity with objectively measured sleep and internal consistency, whereas the overall results of face and content validity assessment varied. The instrument needs to be further evaluated regarding construct validity, responsiveness, test-retest reliability, and its generalization to other populations.

Ultra high frequency ultrasound enables real-time visualization of blood supply from chorioallantoic membrane to human autosomal dominant polycystic kidney tissue.

Ultra high frequency (UHF) ultrasound enables the visualization of very small structures that cannot be detected by conventional ultrasound. The utilization of UHF imaging as a new imaging technique for the 3D-in-vivo chorioallantoic membrane (CAM) model can facilitate new insights into tissue perfusion and survival. Therefore, human renal cystic tissue was grafted onto the CAM and examined using UHF ultrasound imaging. Due to the unprecedented resolution of UHF ultrasound, it was possible to visualize microvessels, their development, and the formation of anastomoses. This enabled the observation of anastomoses between human and chicken vessels only 12 h after transplantation. These observations were validated by 3D reconstructions from a light sheet microscopy image stack, indocyanine green angiography, and histological analysis. Contrary to the assumption that the nutrient supply of the human cystic tissue and the gas exchange happens through diffusion from CAM vessels, this study shows that the vasculature of the human cystic tissue is directly connected to the blood vessels of the CAM and perfusion is established within a short period. Therefore, this in-vivo model combined with UHF imaging appears to be the ideal platform for studying the effects of intravenously applied therapeutics to inhibit renal cyst growth.

Cytokine Response of Natural Killer Cells to Hepatitis B Virus Infection Depends on Monocyte Co-Stimulation.

Hepatitis B virus (HBV) is a major driver of chronic hepatic inflammation, which regularly leads to liver cirrhosis or hepatocellular carcinoma. Immediate innate immune cell response is crucial for the rapid clearance of the infection. Here, natural killer (NK) cells play a pivotal role in direct cytotoxicity and the secretion of antiviral cytokines as well as regulatory function. The aim of this study was to further elucidate NK cell responses triggered by an HBV infection. Therefore, we optimized HBV in vitro models that reliably stimulate NK cells using hepatocyte-like HepG2 cells expressing the Na+-taurocholate co-transporting polypeptide (NTCP) and HepaRG cells. Immune cells were acquired from healthy platelet donors. Initially, HepG2-NTCP cells demonstrated higher viral replication compared to HepaRG cells. Co-cultures with immune cells revealed increased production of interferon-γ and tumor necrosis factor-α by NK cells, which was no longer evident in isolated NK cells. Likewise, the depletion of monocytes and spatial separation from target cells led to the absence of the antiviral cytokine production of NK cells. Eventually, the combined co-culture of isolated NK cells and monocytes led to a sufficient cytokine response of NK cells, which was also apparent when communication between the two immune cell subpopulations was restricted to soluble factors. In summary, our study demonstrates antiviral cytokine production by NK cells in response to HBV+ HepG2-NTCP cells, which is dependent on monocyte bystander activation.

Effect of a higher protein diet and lifestyle camp intervention on childhood obesity (The COPE study): results from a nonrandomized controlled trail with 52-weeks follow-up.

PURPOSE: In adults, diets rich in protein seem beneficial in relation to satiety, weight loss, and weight management; however, studies investigating dietary protein and weight development in children are scarce and inconsistent. This nonrandomized controlled trial aimed to investigate the effect of a higher protein diet during lifestyle intervention on anthropometry and metabolic biomarkers in children with overweight and obesity. METHODS: Children (n:208) were recruited from two multicomponent lifestyle camps. One camp was assigned as the intervention group. In the intervention group, carbohydrates-rich foods at breakfast and two in-between-meals were replaced with protein-containing foods to increase the amount of protein from ~ 10-15 energy percent (E%) per day to ~ 25E% per day. Other components were similar between groups. Anthropometry and biochemical measurements were collected at baseline, 10 weeks (after camp) and 52 weeks. RESULTS: The intervention group had a non-significant improvement in BMI-SDS (- 0.07 SD (- 0.19; 0.05), p = 0.24) compared to the control group, but in general, there was no effect of a higher protein diet on anthropometry and metabolic biomarkers. Overall, 10 weeks at camp resulted in a more favorable body composition [- 6.50 kg (p < 0.00), - 0.58 BMI-SDS (p < 0.00), and - 5.92% body fat (p < 0.00)], and improved metabolic health, with most changes maintained at 52 weeks. CONCLUSION: A higher protein diet had no significant effect on body composition and metabolic health; however, these lifestyle camps are an efficiatious treatment strategy for childhood obesity. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov with ID: NCT04522921. Preregistered August 21st 2020.