Radboud University Medical Centre (Radboudumc)

Background: Patients experience long-lasting health problems defined as post-intensive care syndrome (PICS) after Intensive Care Unit (ICU) admission. Little is known about PICS in primary care. Objectives: To investigate whether ICU survivors encounter more new International Classification of Primary Care-2 (ICPC-2) diagnoses and general practitioner (GP) contact compared to patients with similar comorbidity without ICU admission. Methods: Prospective multicentre cohort study in three Dutch general practices. Numbers of disease-episodes and GP contacts of ICU survivors ≥ 16 years admitted between 2008 and 2017 were extracted from GPs' information systems. A non-ICU reference cohort was matched 1:1 for age, sex, follow-up period and comorbidity groups from patients' medical history. Negative binominal regression analysis was used to compare both cohorts 0-3, 3-6, 6-12 months, 1-2 and 2-5 years after ICU admission and 1 year prior to admission. Results: ICU survivors (n = 199) encountered more new disease-episodes 1 year before (mean 3.97 (95% confidence interval [CI] 3.50-4.52]]; reference 2.36 [1.28-3.17]) to 2-5 years after ICU admission (3.65 [3.15-4.26]; reference 2.86 [2.52-3.22]). ICU survivors also had more GP contacts 1 year before (mean 19.61 [17.31-22.17]; reference 10.02 [7.81-12.38]) to 2-5 years after ICU admission (18.53 [15.58-21.85]; reference 12.03 [10.33-13.91]). Patients with prior ICU admission did not encounter patterns in specific ICPC-2 chapters compared to non-ICU patients. Conclusion: Patients admitted to the ICU encounter more new primary care disease-episodes and GP contacts. As patients present their symptoms to their GP first, it is therefore up to the GP to recognise these critical illness-related symptoms.

Considerable geographical variation in the uptake of euthanasia has been reported: some municipalities in the Netherlands have a 25 times higher euthanasia rate than other municipalities. Current ‘geomedical’ frameworks for interpreting practice variation in health care utilization seem inadequately tailored to understand regional variation in morally controversial procedures such as euthanasia. The aim of this conceptual article is threefold: i) to add relevant medical ethical principles to current frameworks; ii) to provide a four-step ethical-geomedical model for the interpretation of geographical differences in the utilization of health care in general and for ethically controversial treatments in specific; iii) to gain better understanding of the existing geographical variation in the incidence of euthanasia by using this framework in our analysis.

Treatment of skin and soft tissue infections with nontuberculous mycobacteria sometimes fails despite repeated debridements and long-term systemic antibiotic therapy. These treatment-refractory infections can cause significant morbidity and pose a treatment challenge. Following surgery, we treated three patients with negative pressure wound therapy with the instillation and dwell time of topical antibiotics, in addition to systemic antibiotic treatment. Treatment was successful and well tolerated, except for some local irritation.

Purpose Growing recognition of the gut microbiome as an influential modulator of cancer treatment efficacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to enhance cancer and health outcomes. The highly modifiable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid effects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population. Methods A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically effective supportive care strategy used by cancer survivors. Results Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists. Conclusions Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various influences of exercise modalities, intensities, frequencies, durations, and volumes to explore dose-response relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.

Objectives This paper evaluates 16 year results of the Allergy EQA program shared by EQA organisers in Belgium, Finland, Portugal, and The Netherlands. Methods The performance of Thermo Fisher and Siemens user groups (in terms of concordance between both groups, between laboratory CV, prevalence of clinically significant errors) and suitability of samples (stability and validity of dilution of patient samples) are evaluated using data of 192 samples in the EQA programs from 2007 to 2022. Measurands covered are total IgE, screens and mixes, specific IgE extracts and allergen components. Results There is perfect (53 %), acceptable (40 %) and poor (6 %) concordance between both method groups. In case of poor concordance the best fit with clinical data is seen for Thermo Fisher (56 %) and Siemens (26 %) respectively. The between laboratory CV evolves from 7.8 to 6.6 % (Thermo Fisher) and 7.3 to 7.7 % (Siemens). The prevalence of blunders by individual laboratories is stable for Siemens (0.4 %) and drops from 0.4 to 0.2 % for Thermo Fisher users. For IgE, the between year CV of the mean of both user groups is 1 %, and a fifteen-fold dilution of a patient sample has an impact of 2 and 4 % on the recovery of Thermo Fisher and Siemens user groups. Conclusions The analytical performance of Thermo Fisher is slightly better than that of Siemens users but the clinical impact of this difference is limited. Stability of the sample and the low impact of dilution on the recovery of measurands demonstrates the suitability for purpose of the EQA program.

Smartphone sensors are used increasingly in the assessment of ataxias. To date, there is no specific consensus guidance regarding a priority set of smartphone sensor measurements, or standard assessment criteria that are appropriate for clinical trials. As part of the Ataxia Global Initiative Digital-Motor Biomarkers Working Group (AGI WG4), aimed at evaluating key ataxia clinical domains (gait/posture, upper limb, speech and oculomotor assessments), we provide consensus guidance for use of internal smartphone sensors to assess key domains. Guidance was developed by means of a literature review and a two stage Delphi study conducted by an Expert panel, which surveyed members of AGI WG4, representing clinical, research, industry and patient-led experts, and consensus meetings by the Expert panel to agree on standard criteria and map current literature to these criteria. Seven publications were identified that investigated ataxias using internal smartphone sensors. The Delphi 1 survey ascertained current practice, and systems in use or under development. Wide variations in smartphones sensor use for assessing ataxia were identified. The Delphi 2 survey identified seven measures that were strongly endorsed as priorities in assessing 3/4 domains, namely gait/posture, upper limb, and speech performance. The Expert panel recommended 15 standard criteria to be fulfilled in studies. Evaluation of current literature revealed that none of the studies met all criteria, with most being early-phase validation studies. Our guidance highlights the importance of consensus, identifies priority measures and standard criteria, and will encourage further research into the use of internal smartphone sensors to measure ataxia digital-motor biomarkers.

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to treat the genetic defect in cystinosis using synthetic mRNA in cell models and ctns−/− zebrafish embryos. Cystinosis is a prototype lysosomal storage disorder caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and the most severely affected organs, presenting glomerular and proximal tubular dysfunction, progressing to end-stage kidney failure. The current therapeutic standard cysteamine, reduces cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA can restore lysosomal cystinosin expression following lipofection into CTNS−/− kidney cells and injection into ctns−/− zebrafish. A single CTNS mRNA administration decreases cellular cystine accumulation for up to 14 days in vitro. In the ctns−/− zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. Therefore, this proof-of-principle study takes the first steps in establishing an mRNA-based therapy to restore cystinosin expression, resulting in cystine reduction in vitro and in the ctns−/− larvae, and restoration of the zebrafish pronephros function.

Background As mortality of invasive mould infections (IMI) remains high, there is a need for improved biomarkers for timely diagnosis and patient stratification. Various moulds have been shown to induce T-helper cell (Th) 1, Th2, Th9 and Th17 subsets resulting not in potent anti-Aspergillus T-cells effector mechanisms, and in elevated serum levels of cytokines such as IFN-γ and IL-6, IL-8, IL-15 and IL-17. The ECMM study “Immunologic Markers for Treatment Monitoring and Diagnosis in Invasive Mold Infection” aimed to identify circulating immunological markers that could be useful for an early diagnosis of IMI. Methods We collected longitudinal serum samples from 33 cases with probable/proven IMI and two matched control cohorts without IMI, and from an independent validation cohort with 20 cases and 20 matched controls (Figure 1, Table 1). None of the patients received mold active prophylaxis. A panel of 92 circulating proteins involved in inflammation was measured using a targeted proteomics platform (Olink Proteomics AB (Uppsala, Sweden)) and protein concentrations were compared. Correction for multiple testing was performed by Benjamini-Hochberg method. Figure 1 Overview of sample collection Table 1 An overview of the main characteristics of and differences between the derivation cohort and the validation cohort, including characteristics of all cases and all controls. Results Abundance analysis on the day of diagnosis revealed 30 differentially regulated proteins. Nine were replicated in an independent cohort: MMP-10, IL-18, IL-18-R1, IL10, CDCP1 and IL-17C. In the analysis of serum samples collected more than 10 days before diagnosis, six proteins showed higher concentrations in the cases compared to the controls (CCL20, IL-6, IL-17C, CCL23, CXCL5, CXCL1 and CX3CL1), while nine proteins had lower concentrations (Figure 2). The higher IL-17C concentration could be replicated in the independent validation cohort (Figure 3). When comparing cases only to infected controls this difference in expression was not significant anymore after correcting for multiple testing. Figure 2 Figure 3 Conclusion We found a consistent higher expression of IL-17C in cases with IMI versus non-infected controls, both at the time of diagnosis and in samples 10 days before the diagnosis of IMI. IL-17C, known for its pro-inflammatory function at the epithelial sites, activates expression of other proinflammatory cytokines and of chemokines such as CXCL1/2/3 and CCL20, and could present an early biomarker for IMI. Abundance analysis of the primary cohort (a) at time of diagnosis, and (b) at more than 10 days before diagnosis, comparing cases with non infected controls. Abundance analysis of the validation cohort (a) at time of diagnosis, and (b) at more than 10 days before diagnosis, comparing cases with non infected controls. Table 2-1 Table 2 Clinical and microbiological information of the 33 cases included in the primary cohort and the 20 cases included in the validation cohort PART 1. Disclosures Martin Hoenigl, n/a, Astellas: Grant/Research Support|Euroimmun: Grant/Research Support|F2G: Grant/Research Support|Gilead: Grant/Research Support|Immy: Grant/Research Support|MSD: Grant/Research Support|Mundipharma: Grant/Research Support|Pfizer: Grant/Research Support|Pulmocide: Grant/Research Support|Scynexis: Grant/Research Support

The complex symbiotic relationship between the mammalian body and gut microbiome plays a critical role in the health outcomes of offspring later in life. The gut microbiome modulates virtually all physiological functions through direct or indirect interactions to maintain physiological homeostasis. Previous studies indicate a link between maternal/early-life gut microbiome, brain development, and behavioral outcomes relating to social cognition. Here we present direct evidence of the role of the gut microbiome in brain development. Through magnetic resonance imaging (MRI), we investigated the impact of the gut microbiome on brain organization and structure using germ-free (GF) mice and conventionalized mice, with the gut microbiome reintroduced after weaning. We found broad changes in brain volume in GF mice that persist despite the reintroduction of gut microbes at weaning. These data suggest a direct link between the maternal gut or early-postnatal microbe and their impact on brain developmental programming.

Background Anhedonia and other deficits in reward- and motivation-related processing in psychiatric patients, including patients with major depressive disorder (MDD), represent a high unmet medical need. Neurobiologically, these deficits in MDD patients are mainly associated with low dopamine function in a frontostriatal network. In this study, alterations in brain activation changes during reward processing and at rest in MDD patients compared with healthy subjects are explored and the effects of a single low dose of the dopamine D2 receptor antagonist amisulpride are investigated. Methods This is a randomized, controlled, double-blind, single-dose, single-center parallel-group clinical trial to assess the effects of a single dose of amisulpride (100 mg) on blood-oxygenation-level-dependent (BOLD) responses during reward- and motivation-related processing in healthy subjects (n = 60) and MDD patients (n = 60). Using functional magnetic resonance imaging (fMRI), BOLD responses are assessed during the monetary incentive delay (MID) task (primary outcome). Exploratory outcomes include BOLD responses and behavioral measures during the MID task, instrumental learning task, effort-based decision-making task, social incentive delay task, and probabilistic reward task as well as changes in resting state functional connectivity and cerebral blood flow. Discussion This study broadly covers all aspects of reward- and motivation-related processing as categorized by the National Institute of Mental Health Research Domain Criteria and is thereby an important step towards precision psychiatry. Results regarding the immediate effects of a dopaminergic drug on deficits in reward- and motivation-related processing not only have the potential to significantly broaden our understanding of underlying neurobiological processes but might eventually also pave the way for new treatment options. Trial registration ClinicalTrials.gov NCT05347199. April 12, 2022.

Purpose To explore whether a patient's prior knowledge of the symptoms associated with rhegmatogenous retinal detachment (RRD) relates to the visual outcome after treatment. Methods We performed a prospective survey study on 126 patients receiving treatment for primary RRD between March and July 2021. Results Thirty‐seven per cent ( n = 47) of patients responded that they were aware of the RRD symptoms prior to the detachment. A history of RRD in the fellow eye or knowledge of family members treated for RRD was frequently reported as a reason for the patient's awareness of RRD symptoms. Patients aware of RRD symptoms presented significantly more often with an attached macula ( χ ² , p = 0.002) and a better visual outcome following surgery (Mann–Whitney U, p = 0.028) compared to patients who were not aware of RRD‐related symptoms. Among 76 patients with a myopic refractive error, only 15% ( n = 11) indicated that they had been warned about the increased RRD risk related to myopia, suggesting that three‐quarters of patients were not actively informed by their eye care professionals. Conclusion RRD symptom awareness is significantly related to a higher rate of macula‐on RRDs and better visual outcomes after treatment. There is limited awareness of increased RRD risk in myopic RRD patients. These findings suggest that counselling individuals at high risk of RRD about related symptoms is inadequate and better counselling may improve visual outcomes following RRD treatment.

Mitochondria play a key role in kidney physiology and pathology. They produce ATP to fuel energy-demanding water and solute reabsorption processes along the nephron. Moreover, mitochondria contribute to cellular health by the regulation of autophagy, (oxidative) stress responses, and apoptosis. Mitochondrial abundance is particularly high in cortical segments, including proximal and distal convoluted tubules. Dysfunction of the mitochondria has been described for tubulopathies such as Fanconi, Gitelman, and Bartter-like syndromes and renal tubular acidosis. In addition, mitochondrial cytopathies often affect renal (tubular) tissues, such as in Kearns-Sayre and Leigh syndromes. Nevertheless, the mechanisms by which mitochondrial dysfunction results in renal tubular diseases are only scarcely being explored. This review provides an overview of mitochondrial dysfunction in the development and progression of kidney tubulopathies. Furthermore, it emphasizes the need for further mechanistic investigations to identify links between mitochondrial function and renal electrolyte reabsorption. Expected final online publication date for the Annual Review of Physiology, Volume 86 is February 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.