Search

Abstract Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease with a fatal outcome. There is accumulating evidence of a prominent role of glia in the pathology of HD, and we investigated this by conducting single nuclear RNA sequencing (snRNAseq) of human post mortem brain in four differentially affected regions; caudate nucleus, frontal cortex, hippocampus and cerebellum. Across 127,205 nuclei from donors with HD and age/sex matched controls, we found heterogeneity of glia which is altered in HD. We describe prominent changes in the abundance of certain subtypes of astrocytes, microglia, oligodendrocyte precursor cells and oligodendrocytes between HD and control samples, and these differences are widespread across brain regions. Furthermore, we highlight possible mechanisms that characterise the glial contribution to HD pathology including depletion of myelinating oligodendrocytes, an oligodendrocyte-specific upregulation of the calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1 A (PDE1A) and an upregulation of molecular chaperones as a cross-glial signature and a potential adaptive response to the accumulation of mutant huntingtin (mHTT). Our results support the hypothesis that glia have an important role in the pathology of HD, and show that all types of glia are affected in the disease.

Abstract Background The physical and the social environment are important predictors of healthy weight, especially in low socioeconomic position (SEP) neighborhoods. Many Dutch municipalities have implemented a healthy weight approach (HWA). Yet, there is room for improvement. This system science study examined what influences the utilization of HWA facilities and activities, and what aspects can help to achieve a desired systems change (also called leverage point themes (LPTs)) in the HWA system as perceived by citizens living in low SEP neighborhoods. Method All research phases were performed with four citizens co-researchers. Forty-seven citizens living in low SEP neighborhoods were semi-structurally interviewed about the neighborhood HWA facilities and municipal HWA activities. A rapid coding qualitative analysis approach was applied per topic. The topics were citizens’ healthy living description, personal circumstances, and satisfaction with foot and cycle paths, sports facilities, playgrounds, green spaces, museums and theaters, community centers, churches, healthcare, school, food supplies, contact with neighborhood, unfamiliar and/or unused activities, familiar and used activities, unavailable but desired (lacking) activities, and reaching citizens. Results The utilization of HWA facilities and activities was influenced by the overarching themes of social cohesion, familiarity, reaching citizens, maintenance, safety, physical accessibility, financial accessibility, social accessibility, fit with personal context, and fit with the neighborhood’s specific needs. Different overarching themes stood out across different facilities and activities. LPTs indicated the overarching themes needed in combination with one another for a specific activity or facility to increase utilization. For example, the LPT regarding foot and cycle paths was “accessible, safe, and maintained foot and cycle paths”. The LPTs regarding familiar and used activities were “customized activities; information provision (e.g., about possibilities to join without paying); social contact, meeting others, and everyone feels included”. Conclusion Conducting inclusive qualitative research from a systems perspective among citizens living in low SEP neighborhoods has contributed valuable insights into their needs. This enables practical implementation of HWAs by providing a deeper understanding of the LPTs within the HWA system. LPTs can help HWA stakeholders to further develop current HWAs toward systems approaches. Future research could study the leverage points that may contribute to LPT implementation.

Background: To improve (patient-tailored) instructions for intranasal corticosteroid (INC) administration, we need to gain insight into specific characteristics of INC users and comedication use. Objective: We examined INC prescriptions obtained from the Dutch InterAction Database to gain insight into the prevalence and incidence rates, INC use in previous years, and comedication. Methods: We retrospectively examined INC prescriptions written between January 1, 2015, and December 31, 2019. Prevalence and incidence rates were stratified by age and sex. The use of INCs in previous years and comedication were analyzed. Results: In 2019, a total of 172,563 INC prescriptions were written and dispensed to 75,048 individuals. Also in 2019, the prevalence and incidence of INC users were 68.9 and 25.6 per 1000 individuals, respectively. INCs were used by all age groups. More than half of INC users in 2019 did not receive a prescription in 2018, almost a quarter received a prescription in 5 consecutive years, 28% used an INC in combination with an inhaler, 29% used an INC together with a systemic antihistamine, 9% used an INC along with ocular medication, and 1% used an INC with an intranasal antihistamine. Several corticosteroid-containing drugs were being used in combination with INCs by 2% to 16% of those studied. Conclusion: This study gives insights into opportunities for patient-tailored instructions. INCs are used by various age groups and by new or intermittent users as well as by continuous users. On the bases of these results, patient-tailored instructions can be developed and subsequently studied to determine whether the instructions affect treatment adherence and efficacy. The insights gained about comedication provide opportunities for improved evaluation of the INC administration technique. Taken together, these suggestions might lead to a more patient-tailored approach, which might in turn lead to improved treatment with INCs.

Abstract Background Blood–brain barrier (BBB) dysfunction and immune cell migration into the central nervous system (CNS) are pathogenic drivers of multiple sclerosis (MS). Ways to reinstate BBB function and subsequently limit neuroinflammation present promising strategies to restrict disease progression. However, to date, the molecular players directing BBB impairment in MS remain poorly understood. One suggested candidate to impact BBB function is the transient receptor potential vanilloid-type 4 ion channel (TRPV4), but its specific role in MS pathogenesis remains unclear. Here, we investigated the role of TRPV4 in BBB dysfunction in MS. Main text In human post-mortem MS brain tissue, we observed a region-specific increase in endothelial TRPV4 expression around mixed active/inactive lesions, which coincided with perivascular microglia enrichment in the same area. Using in vitro models, we identified that microglia-derived tumor necrosis factor-α (TNFα) induced brain endothelial TRPV4 expression. Also, we found that TRPV4 levels influenced brain endothelial barrier formation via expression of the brain endothelial tight junction molecule claudin-5. In contrast, during an inflammatory insult, TRPV4 promoted a pathological endothelial molecular signature, as evidenced by enhanced expression of inflammatory mediators and cell adhesion molecules. Moreover, TRPV4 activity mediated T cell extravasation across the brain endothelium. Conclusion Collectively, our findings suggest a novel role for endothelial TRPV4 in MS, in which enhanced expression contributes to MS pathogenesis by driving BBB dysfunction and immune cell migration.

Spinocerebellar Ataxia Type 7 (SCA7) is an autosomal dominantly inherited disorder, primarily characterized by cerebellar ataxia and visual loss. SCA7 is caused by a CAG repeat expansion in exon 3 of the ATXN7 gene. We generated human induced pluripotent stem cells (hiPSCs) from peripheral blood-derived erythroblasts from two SCA7 patients (LUMCi051-A,B and LUMCi052-A,B,C) using integration-free episomal vectors. All hiPSC clones express pluripotency factors, show a normal karyotype, and can differentiate into the three germ layers. These lines can be used for in vitro disease modeling and therapy testing.

The Parkin (PRKN) gene mutation is prevalent in young-onset Parkinson's disease (PD), typically emerging before age 30, accompanied by early motor symptoms. Induced pluripotent stem cells (iPSCs) were derived from peripheral blood mononuclear cells of a PD patient with an exon 3 deletion in PRKN using Sendai-virus reprogramming. PD diagnosis was confirmed via the Unified Parkinson's Disease Rating Scale (UPDRS). Characterization of the iPSC line ensured self-renewal and pluripotency. This resource serves as a valuable platform for drug screening and elucidating the pathophysiology of this mutation, facilitating advancements in PD research.

Abstract Antisense oligonucleotides (ASOs) are incredibly versatile molecules that can be designed to specifically target and modify RNA transcripts to slow down or halt rare genetic disease progression. They offer the potential to target groups of patients or can be tailored for individual cases. Nonetheless, not all genetic variants and disorders are amenable to ASO-based treatments, and hence, it is important to consider several factors before embarking on the drug development journey. Here, we discuss which genetic disorders have the potential to benefit from a specific type of ASO approach, based on the pathophysiology of the disease and pathogenic variant type, as well as those disorders that might not be suitable for ASO therapies. We further explore additional aspects, such as the target tissues, intervention time points, and potential clinical benefits, which need to be considered before developing a compound. Overall, we provide an overview of the current potentials and limitations of ASO-based therapeutics for the treatment of monogenic disorders.

Abstract Telomerase is a ribonucleoprotein (RNP) enzyme that extends telomeric repeats at eukaryotic chromosome ends to counterbalance telomere loss caused by incomplete genome replication. Human telomerase is comprised of two distinct functional lobes tethered by telomerase RNA (hTR): a catalytic core, responsible for DNA extension; and a Hinge and ACA (H/ACA) box RNP, responsible for telomerase biogenesis. H/ACA RNPs also have a general role in pseudouridylation of spliceosomal and ribosomal RNAs, which is critical for the biogenesis of the spliceosome and ribosome. Much of our structural understanding of eukaryotic H/ACA RNPs comes from structures of the human telomerase H/ACA RNP. Here we report a 2.7 Å cryo-electron microscopy structure of the telomerase H/ACA RNP. The significant improvement in resolution over previous 3.3 Å to 8.2 Å structures allows us to uncover new molecular interactions within the H/ACA RNP. Many disease mutations are mapped to these interaction sites. The structure also reveals unprecedented insights into a region critical for pseudouridylation in canonical H/ACA RNPs. Together, our work advances understanding of telomerase-related disease mutations and the mechanism of pseudouridylation by eukaryotic H/ACA RNPs.

Most psycholinguistic models of reading aloud and of speech production do not include linguistic representations more fine-grained than the phoneme, despite the fact that the available empirical evidence suggests that feature-level representations are activated during reading aloud and speech production. In a series of masked-priming experiments that employed the reading aloud task, we investigated effects of phonological features, such as voicing, place of articulation, and constriction location, on response latencies in English and Russian. We propose a hypothesis that predicts greater likelihood of obtaining feature-priming effects when the onsets of the prime and the target share more feature values than when they share fewer. We found that prime-target pairs whose onsets differed only in voicing (e.g., /p/-/b/) primed each other consistently in Russian, as has already been found in English. Response latencies for prime-target pairs whose onsets differed in place of articulation (e.g., /b/-/d/) patterned differently in English and Russian. Prime-target pairs whose onsets differed in constriction location only (e.g., /s/ and /[voiceless retroflex fricative]/) did not yield a priming effect in Russian. We conclude that feature-priming effects are modulated not only by the phonological similarity between the onsets of primes and targets but also by the dynamics of feature activation and by the language-specific relationship between orthography and phonology. Our findings suggest that feature-level representations need to be included in models of reading aloud and of speech production if we are to move forward with theorizing in these research domains.

Abstract Low heart rate variability (HRV) has been widely reported as a predictor for increased mortality. However, the molecular mechanisms are poorly understood. Therefore, this study aimed to identify novel genetic loci associated with HRV and assess the association of phenotypic HRV and genetically predicted HRV with mortality. In a GWAS of 46,075 European ancestry individuals from UK biobank, we identified 17 independent genome-wide significant genetic variants in 16 loci associated with HRV traits. Notably, eight of these loci (RNF220, GNB4, LINCR-002, KLHL3/HNRNPA0, CHRM2, KCNJ5, MED13L, and C160rf72) have not been reported previously. In a prospective phenotypic relationship between HRV and mortality during a median follow-up of seven years, individuals with lower HRV had higher risk of dying from any cause. Genetically predicted HRV, as determined by the genetic risk scores, was not associated with mortality. To the best of our knowledge, the findings provide novel biological insights into the mechanisms underlying HRV. These results also underline the role of the cardiac autonomic nervous system, as indexed by HRV, in predicting mortality.

Antisense technology demonstrates significant potential for addressing inherited brain diseases, with over a dozen products already available and numerous others in the development pipeline. The versatility of differentiating induced pluripotent stem cells (iPSCs) into nearly all neural cell types proves invaluable for comprehending the mechanisms behind neurological diseases, replicating cellular phenotypes, and advancing the testing and development of new therapies, including antisense oligonucleotide therapeutics. While delivering antisense oligonucleotides (ASOs) to human iPSC-based neuronal models has posed challenges, this study explores various delivery methods, including lipid-based transfection, gymnotic uptake, Ca(2+)-enhanced medium (CEM)-based delivery, and electroporation, in 2D and 3D hiPSC-derived neuronal models. This study reveals that CEM-based delivery exhibits efficiency and low toxicity in both 2D neuronal cultures and 3D brain organoids. Furthermore, the findings indicate that CEM is slightly more effective in neurons than in astrocytes, suggesting promising avenues for further exploration and optimization of preclinical ASO strategies in the treatment of neurological disorders.

Abstract Background In biomedicine, machine learning (ML) has proven beneficial for the prognosis and diagnosis of different diseases, including cancer and neurodegenerative disorders. For rare diseases, however, the requirement for large datasets often prevents this approach. Huntington’s disease (HD) is a rare neurodegenerative disorder caused by a CAG repeat expansion in the coding region of the huntingtin gene. The world’s largest observational study for HD, Enroll-HD, describes over 21,000 participants. As such, Enroll-HD is amenable to ML methods. In this study, we pre-processed and imputed Enroll-HD with ML methods to maximise the inclusion of participants and variables. With this dataset we developed models to improve the prediction of the age at onset (AAO) and compared it to the well-established Langbehn formula. In addition, we used recurrent neural networks (RNNs) to demonstrate the utility of ML methods for longitudinal datasets, assessing driving capabilities by learning from previous participant assessments. Results Simple pre-processing imputed around 42% of missing values in Enroll-HD. Also, 167 variables were retained as a result of imputing with ML. We found that multiple ML models were able to outperform the Langbehn formula. The best ML model (light gradient boosting machine) improved the prognosis of AAO compared to the Langbehn formula by 9.2%, based on root mean squared error in the test set. In addition, our ML model provides more accurate prognosis for a wider CAG repeat range compared to the Langbehn formula. Driving capability was predicted with an accuracy of 85.2%. The resulting pre-processing workflow and code to train the ML models are available to be used for related HD predictions at: https://github.com/JasperO98/hdml/tree/main . Conclusions Our pre-processing workflow made it possible to resolve the missing values and include most participants and variables in Enroll-HD. We show the added value of a ML approach, which improved AAO predictions and allowed for the development of an advisory model that can assist clinicians and participants in estimating future driving capability.

In Huntington disease, cellular toxicity is particularly caused by toxic protein fragments generated from the mutant huntingtin (HTT) protein. By modifying the HTT protein, we aim to reduce proteolytic cleavage and ameliorate the consequences of mutant HTT without lowering total HTT levels. To that end, we use an antisense oligonucleotide (AON) that targets HTT pre-mRNA and induces partial skipping of exon 12, which contains the critical caspase-6 cleavage site. Here, we show that AON-treatment can partially restore the phenotype of YAC128 mice, a mouse model expressing the full-length human HTT gene including 128 CAG-repeats. Wild-type and YAC128 mice were treated intracerebroventricularly with AON12.1, scrambled AON or vehicle starting at 6 months of age and followed up to 12 months of age, when MRI was performed and mice were sacrificed. AON12.1 treatment induced around 40% exon skip and protein modification. The phenotype on body weight and activity, but not rotarod, was restored by AON treatment. Genes differentially expressed in YAC128 striatum changed toward wild-type levels and striatal volume was preserved upon AON12.1 treatment. However, scrambled AON also showed a restorative effect on gene expression and appeared to generally increase brain volume.

Ovarian cancer (OC) belongs to the most common malignancies in women and remains the leading cause of mortality among gynecological cancers. Poly (ADP-ribose) polymerase (PARP) inhibitors have shown significant promise in the treatment of OC. Drawing on the latest insights from the American Society of Clinical Oncology (ASCO 2023) annual congress, this review summarizes the data of the recent trials evaluating PARP inhibitors, as well as discusses remaining therapeutic challenges such as drug resistance and the quest for novel predictive biomarkers in OC. The ongoing research presented at the 2023 ASCO annual meeting heralds a hopeful future for OC patients, with PARP inhibitors at the forefront of this paradigm shift. PEER REVIEWED ARTICLE Peer reviewers: Dr David König (University Hospital Basel, Basel, Switzerland); Dr Priska Bützberger (Cantonal Hospital Baden, Baden, Switzerland) Submitted: July 20, 2023 CEST; Accepted: November 28, 2023 CEST

AbstractBackground Cardiac sympathetic hyperinnervation after myocardial infarction (MI) is associated with arrhythmogenesis and sudden cardiac death. The characteristics of cardiac sympathetic hyperinnervation remain underexposed.Objective To provide a systematic review on cardiac sympathetic hyperinnervation after MI, taking into account: (1) definition, experimental model and quantification method and (2) location, amount and timing, in order to obtain an overview of current knowledge and to expose gaps in literature.Methods References on cardiac sympathetic hyperinnervation were screened for inclusion. The included studies received a full-text review and quality appraisal. Relevant data on hyperinnervation were collected and qualitatively analysed.Results Our literature search identified 60 eligible studies performed between 2000 and 2022. Cardiac hyperinnervation is generally defined as an increased sympathetic nerve density or increased number of nerves compared to another control group (100%). Studies were performed in a multitude of experimental models, but most commonly in male rats with permanent left anterior descending (LAD) artery ligation (male: 63%, rat: 68%, permanent ligation: 93%, LAD: 97%). Hyperinnervation seems to occur mainly in the borderzone. Quantification after MI was performed in regions of interest in µm2/mm2 (41%) or in percentage of nerve fibres (46%) and the reported amount showed a great variation ranging from 439 to 126,718 µm2/mm2. Hyperinnervation seems to start from three days onwards to >3 months without an evident peak, although studies on structural evaluation over time and in the chronic phase were scarce.Conclusions Cardiac sympathetic hyperinnervation after MI occurs mainly in the borderzone from three days onwards and remains present at later timepoints, for at least 3 months. It is most commonly studied in male rats with permanent LAD ligation. The amount of hyperinnervation differs greatly between studies, possibly due to differential quantification methods. Further studies are required that evaluate cardiac sympathetic hyperinnervation over time and in the chronic phase, in transmural sections, in the female sex, and in MI with reperfusion.

Telomerase adds telomeric repeats at chromosome ends to compensate for the telomere loss that is caused by incomplete genome end replication1. In humans, telomerase is upregulated during embryogenesis and in cancers, and mutations that compromise the function of telomerase result in disease2. A previous structure of human telomerase at a resolution of 8 Å revealed a vertebrate-specific composition and architecture3, comprising a catalytic core that is flexibly tethered to an H and ACA (hereafter, H/ACA) box ribonucleoprotein (RNP) lobe by telomerase RNA. High-resolution structural information is necessary to develop treatments that can effectively modulate telomerase activity as a therapeutic approach against cancers and disease. Here we used cryo-electron microscopy to determine the structure of human telomerase holoenzyme bound to telomeric DNA at sub-4 Å resolution, which reveals crucial DNA- and RNA-binding interfaces in the active site of telomerase as well as the locations of mutations that alter telomerase activity. We identified a histone H2A-H2B dimer within the holoenzyme that was bound to an essential telomerase RNA motif, which suggests a role for histones in the folding and function of telomerase RNA. Furthermore, this structure of a eukaryotic H/ACA RNP reveals the molecular recognition of conserved RNA and protein motifs, as well as interactions that are crucial for understanding the molecular pathology of many mutations that cause disease. Our findings provide the structural details of the assembly and active site of human telomerase, which paves the way for the development of therapeutic agents that target this enzyme.

Abstract It is currently unknown whether the complexity and variability of cardiac dynamics predicts future depression and whether within-subject change herein precedes the recurrence of depression. We tested this in an innovative repeated single-subject study in individuals who had a history of depression and were tapering their antidepressants. In 50 individuals, electrocardiogram (ECG) derived Interbeat-interval (IBI) time-series data were collected for 5 min every morning and evening, for 4 months. Usable data were obtained from 14 participants who experienced a transition (i.e., a clinically significant increase in depressive symptoms) and 14 who did not. The mean, standard deviation, Higuchi dimension and multiscale entropy, calculated from IBIs, were examined for time trends. These quantifiers were also averaged over a baseline period and compared between the groups. No consistent trends were observed in any quantifier before increases in depressive symptoms within individuals. The entropy baseline levels significantly differed between the two groups (morning: P value

The purpose of this study was to establish the normal renal artery parameters in German Shepherd dogs. Consequently, the acquired values can be applied to the subsequent clinical research and the interpretation of the findings. Doppler ultrasound was used in this study to assess 24 healthy German shepherd dogs, including 11 female dogs (45.8%) and 13 male dogs (54.2%). The mean age of the dogs was 2.7 years (minimum age of 9 months and maximum age of 15 years) with a standard deviation of 1.07. The Doppler parameters in the renal arteries were evaluated in each case together with their normal values. The mean PSV and EDV in the major renal arteries were 84.07 cm/s and 44.46 cm/s, respectively. Mean PSV, EDV, RI, and AT for intrarenal arteries were 64.81 cm/s, 33.03 cm/s, 0.54 cm/s, and 36.53 m/s, respectively. The findings of the current study represent the typical renal artery parameters in healthy German Shepherd dogs that can be applied to clinical examinations and the interpretation of test results.

Summary: Background: Paediatric Huntington disease with highly expanded mutations (HE-PHD; >80 CAG repeats) presents atypically, compared to adult-onset Huntington disease (AOHD), with neurodevelopmental delay, epilepsy, abnormal brain glucose metabolism, early striatal damage, and reduced lifespan. Since genetic GLUT-1 deficiency syndrome shows a symptom spectrum similar to HE-PHD, we investigated the potential role of the two main glucose transporters, GLUT-1 and GLUT-3, in HE-PHD. Methods: We compared GLUT-1 and GLUT-3 protein expression in HE-PHD, juvenile-onset (JOHD), and AOHD brains (n = 2; n = 3; n = 6) and periphery (n = 3; n = 2; n = 2) versus healthy adult controls (n = 6; n = 6). We also investigated mitochondrial complexes and hexokinase-II protein expression. Findings: GLUT-1 and GLUT-3 expression were significantly lower in HE-PHD frontal cortex (p = 0.009, 95% [CI 13.4, 14.7]; p = 0.017, 95% [CI 14.2, 14.5]) versus controls. In fibroblasts, GLUT-1 and GLUT-3 expression were lower compared to controls (p

Dit artikel, dat gebaseerd is op een analyse van een zeventigtal vragenlijsten uitgezet onder businessunitmanagers gedurende de eerste zogenoemde ‘intelligente’ corona-lockdown in Nederland, zoomt in op het zogenoemde ‘Threat-rigidity effect’. Bij dit effect staat het idee centraal dat in tijden van crisis organisaties de spreekwoordelijke teugels aanhalen, minder vrijheden geven aan hun managers en meer gecentraliseerd beslissingen gaan nemen. Dit effect treedt ook op in Nederland. Daar waar acuut genomen controlmaatregelen echter vaak leiden tot meer stress bij betrokkenen, leiden zij blijkens dit onderzoek daarnaast tot meer rolduidelijkheid, en daarmee tot minder stress. Dit artikel reflecteert op dit fenomeen.

Objectives To assess to what extent leflunomide (LEF) and hydroxychloroquine (HCQ) therapy in patients with primary Sjögren’s syndrome (RepurpSS-I) targets type I IFN-associated responses and to study the potential of several interferon associated RNA-based and protein-based biomarkers to predict and monitor treatment.Methods In 21 patients treated with LEF/HCQ and 8 patients treated with placebo, blood was drawn at baseline, 8, 16 and 24 weeks. IFN-signatures based on RNA expression of five IFN-associated genes were quantified in circulating mononuclear cells and in whole blood. MxA protein levels were measured in whole blood, and protein levels of CXCL10 and Galectin-9 were quantified in serum. Differences between responders and non-responders were assessed and receiver operating characteristic analysis was used to determine the capacity of baseline expression and early changes (after 8 weeks of treatment) in biomarkers to predict treatment response at the clinical endpoint.Results IFN-signatures in peripheral blood mononuclear cell and whole blood decreased after 24 weeks of LEF/HCQ treatment, however, changes in IFN signatures only poorly correlated with changes in disease activity. In contrast to baseline IFN signatures, baseline protein concentrations of galectin-9 and decreases in circulating MxA and Galectin-9 were robustly associated with clinical response. Early changes in serum Galectin-9 best predicted clinical response at 24 weeks (area under the curve 0.90).Conclusions LEF/HCQ combination therapy targets type-I IFN-associated proteins that are associated with strongly decreased B cell hyperactivity and disease activity. IFN-associated Galectin-9 is a promising biomarker for treatment prediction and monitoring in pSS patients treated with LEF/HCQ.

Door middel van een gestructureerde medicatie-analyse door klinisch geriater en ziekenhuisapotheker-klinisch farmacoloog zijn (potentiële) geneesmiddelgerelateerde problemen in kaart gebracht. Patiënten die werden opgenomen op de afdeling geriatrie en waar de klinisch geriater en/of de ziekenhuisapotheker problemen zagen of voorzagen werden beoordeeld volgens een vast model. De voorgestelde interventies werden plenair besproken en de uitgevoerde (of overgenomen) interventies werden vervolgd. In een periode van 30 maanden werden de medicatiegegevens van 184 patiënten aan een medicatie-analyse onderworpen. Van de voorgestelde interventies door de ziekenhuisapotheker werd 65% overgenomen door de klinisch geriater. Het stoppen van medicatie, doseerwijzigingen of vervangen van een bestaand middel werden het meest uitgevoerd. Interventievoorstellen die niet werden overgenomen betroffen vooral onwil van de patiënt of diens begeleider of logistieke problemen.

BackgroundIt is unclear how cardiac autonomic function, as indicated by heart rate (HR), heart rate variability (HRV), HR increase during exercise, and HR recovery after exercise, is related to blood pressure (BP). We aimed to examine the observational and genetic evidence for a potential causal effect of these HR(V) traits on BP.MethodsWe performed multivariable adjusted linear regression using Lifelines and UK Biobank cohorts to investigate the relationship between HR(V) traits and BP. Linkage disequilibrium score regression was conducted to examine genetic correlations. We used two-sample Mendelian randomization (2SMR) to examine potential causal relations between HR(V) traits and BP.ResultsObservational analyses showed negative associations of all HR(V) traits with BP, except for HR, which was positively associated. Genetic correlations were directionally consistent with the observational associations, but most significant genetic correlations between HR(V) traits and BP were limited to diastolic blood pressure (DBP). 2SMR analyses suggested a potentially causal relationship between HR(V) traits and DBP but not systolic blood pressure (SBP). No reverse effect of BP on HR(V) traits was found. One standard deviation (SD) unit increase in HR was associated with a 1.82 mmHg elevation of DBP. In contrast, one ln(ms) unit increase of the root mean square of the successive differences (RMSSD) and corrected RMSSD (RMSSDc), decreased DBP by 1.79 and 1.83 mmHg, respectively. For HR increase and HR recovery at 50 s, every additional SD increase was associated with a lower DBP by 2.05 and 1.47 mmHg, respectively. Results of secondary analyses with pulse pressure as outcome were inconsistent between observational and 2SMR analyses, as well as between HR(V) traits, and therefore inconclusive.ConclusionBoth observational and genetic evidence show strong associations between indices of cardiac autonomic function and DBP, suggesting that a larger relative contribution of the sympathetic versus the parasympathetic nervous system to cardiac function may cause elevated DBP.

Background Benralizumab is highly effective in many, but not all, patients with severe asthma. Baseline characteristics alone are insufficient to predict an individual's probability of long-term benralizumab response. The objectives of the present study were to: 1) study whether parameters at 3 months, in addition to baseline characteristics, contribute to the prediction of benralizumab response at 1 year; and 2) develop an easy-to-use prediction tool to assess an individual's probability of long-term response. Methods We assessed the effect of benralizumab treatment in 192 patients from the Dutch severe asthma registry (RAPSODI). To investigate predictors of long-term benralizumab response (≥50% reduction in maintenance oral corticosteroid (OCS) dose or annual exacerbation frequency) we used logistic regression, including baseline characteristics and 3-month Asthma Control Questionnaire (ACQ-6) score and maintenance OCS dose. Results Benralizumab treatment significantly improved several clinical outcomes, and 144 (75%) patients were classified as long-term responders. Response prediction improved significantly when 3-month outcomes were added to a predictive model with baseline characteristics only (area under the receiver-operating characteristic (AUROC) 0.85 versus 0.72, p=0.001). Based on this model, a prediction tool using sex, prior biologic use, baseline blood eosinophils, forced expiratory volume in 1 s, and at 3 months OCS dose and ACQ-6 was developed which classified patients into three categories with increasing probability of long-term response (95% CI): 25% (3–65%), 67% (57–77%) and 97% (91–99%), respectively. Conclusion In addition to baseline characteristics, treatment outcomes at 3 months contribute to the prediction of benralizumab response at 1 year in patients with severe eosinophilic asthma. Prediction tools as proposed in this study may help physicians optimise the use of costly biologics.