HIV-1 Integrase T218I/S Polymorphisms Do Not Reduce HIV-1 Integrase Inhibitors' Phenotypic Susceptibility

The recently Food and Drug Administration (FDA)-approved cabotegravir (CAB) has demonstrated efficacy as an antiretroviral agent for HIV treatment and prevention, becoming an important tool to stop the epidemic in the United States of America (USA). However, the effectiveness of CAB can be compromised by the presence of specific integrase natural polymorphisms, including T97A, L74M, M50I, S119P, and E157Q, particularly when coupled with the primary drug-resistance mutations G140S and Q148H. CAB's recent approval as a pre-exposure prophylaxis (PrEP) may increase the number of individuals taking CAB, which, at the same time, could increase the number of epidemiological implications. In this context, where resistance mutations, natural polymorphisms, and the lack of drug-susceptibility studies prevail, it becomes imperative to comprehensively investigate concerns related to the use of CAB. We used molecular and cell-based assays to assess the impact of T218I and T218S in the context of major resistance mutations G140S/Q148H on infectivity, integration, and resistance to CAB. Our findings revealed that T218I and T218S, either individually or in combination with G140S/Q148H, did not significantly affect infectivity, integration, or resistance to CAB. Notably, these polymorphisms also exhibited neutrality concerning other widely used integrase inhibitors, namely raltegravir, elvitegravir, and dolutegravir. Thus, our study suggests that the T218I and T218S natural polymorphisms are unlikely to undermine the effectiveness of CAB as a treatment and PrEP strategy

Citizen satisfaction with arm's length bodies in local government:expert insights on policy and practice

Purpose: The purpose of this study is to investigate the application of citizen satisfaction (CS) as a tool for measuring performance by arm's length bodies (ALBs) in local governments across eleven countries, addressing central questions about its functionality and influencing factors. Design/methodology/approach: We employ a hybrid inductive-deductive explorative study design, characterized by an iterative interpretative approach guided by sensitizing concepts. Expert interviews are analyzed through template analysis and cover eleven countries where ALBs are present due to decentralization and outsourcing. Findings: Our study uncovers limited real-world applications of CS in evaluating public service delivery by ALBs. Expert interviews reveal insights into factors potentially influencing CS use, such as the level of autonomy of local governments, state traditions and austerity measures. A research agenda is formulated for further investigation. Originality/value: Contributing to the CS debate, our study focuses on its application in evaluating public service delivery by ALBs. The explorative design, expert opinions and theoretical foundations enhance understanding, offering insights into factors potentially shaping CS use in this context. The study proposes a research agenda, propelling further investigations into this underexplored, yet emerging, area.</p

Quality of reporting of pre-recorded music interventions in surgical patients ‐ A systematic review

Background: Perioperative music interventions are promising, with substantial beneficial effects on patients. However, adequate reporting is crucial for interpreting the outcomes and implementing the interventions. Our objective is to analyze the reporting quality of perioperative music interventions and to provide recommendations and a research agenda for future trials. Material and methods: This study utilized data from a systematic review, that was conducted as part of a separate previous analysis by Geensen, Dirven et al. For this analysis, a PROSPERO registration (CRD42023427138) was formalized. The Template for intervention Description and Replication (TiDieR) checklist was adapted and used. Nineteen intervention items were assessed, categorized in the aim, the core and the implementation. Results: Due to narrowed inclusion criteria, ten music intervention studies were included. None of the studies completely reported all intervention items. The reporting of core intervention items were poorly described. Complete description of implementation items, such as fidelity and modifications, was scarce. Conclusions: Perioperative music studies often lack the complete reporting of essential intervention items. This hinders replicability, generalization of the results and might contribute to research waste. We recommend adequate reporting in future studies to avoid these problems, by using our adapted TIDieR checklist.</p

From preferences to policy:Essays in political economy

Public spending is an essential tool of the state to improve the welfare of citizens. How public money is spent matters for the well-being of both current and future generations. The goal of this thesis is to contribute to understanding differences in spending patterns across countries, electoral systems, and economic situations. In doing so, I study three distinct cases along the path from preference formation to the implementation of public policy. First, who makes policy determines what policy is chosen. Therefore, I study the role that electoral competition plays in the selection of politicians using data from U.S. congressional elections. Second, I study the role that public attitudes have directly on policy choice. Particularly, I focus on the effect of trust in politicians for the propensity to provide public goods. I show that politicians who represent areas with less trust in politics are less likely to work on topics relating to public goods. Finally, it is vital to understand the way that preferences are formed and how external shocks can affect them. I contribute to this question with a case study on refugee influx in the Netherlands in 2015. I show that voters closely exposed to refugees are more likely to discuss religious minorities online as well as vote for anti-immigration parties

Type of D-dimer assay determines the diagnostic yield of computed tomography in patients suspected for pulmonary embolism

Background: Pulmonary embolism (PE) is a life-threatening condition with high morbidity and mortality. The diagnosis of PE is challenging due to nonspecific symptoms, making reliable diagnostic tools essential. This study addresses the clinical impact of interassay variability in D-dimer measurements on the utilization and diagnostic yield of computed tomography pulmonary angiography (CTPA). Objectives: To investigate the effect of different D-dimer assays on the decision to perform CTPA and the subsequent diagnostic yield in patients with suspected PE. Methods: This retrospective, multicenter cohort study analyzed data from 3 teaching hospitals in the southwest region of the Netherlands, covering the years 2018, 2019, 2022, and 2023. The study included data from 40,096 clinically requested D-dimer results and 11,372 CTPA records of patients with suspected PE. The D-dimer assays used were the Roche Tina-quant and Siemens INNOVANCE. Results: The study found significant differences in CTPA utilization and diagnostic yield based on the D-dimer assay used. In 2018 to 2019, hospitals using the Roche Tina-quant assay ordered 21% fewer CTPA scans and had a 9% higher positivity rate compared with those using the Siemens INNOVANCE assay. Conclusion: The findings highlight the necessity for assay-specific cutoff values or, ideally, the standardization of the D-dimer assay to optimize the accuracy and efficiency of PE diagnosis. This study demonstrates that the choice of D-dimer assay significantly influences the clinical management of suspected PE, affecting both the number of CTPA scans performed and the positivity rate of these scans. Implementing assay-specific cutoff values or standardization of the D-dimer assay could reduce unnecessary CTPA scans, minimize patient exposure to radiation, and lower healthcare costs. These results advocate enhanced collaboration between clinicians and laboratory specialists to accurately interpret D-dimer results within the context of the specific assay used. Future research should validate these findings in prospective studies and explore standardized protocols that account for interassay variability.</p

Voorbij de system-level bureaucratie:Over datastromen, algoritmes en inclusieve AI in de databureaucratie

Around the turn of the century, government digitalization mostly consisted of the automation of relatively simple bureaucratic procedures and the digitalization of organizations’ client databases. In this article, we argue that the ‘system-level bureaucracy’ has been surpassed by the emergence of information infrastructures, in which (big) data is shared among a wide variety of organizations, and the increased use of machine learning algorithms to assist administrative decision-making. We call this the ‘data-bureaucracy’. Rather than mere technical innovations developed to improve government efficiency, these developments have profound consequences for the way government organizations use public and private data, organize decision-making processes, and can be held accountable for their actions and decisions by citizens. We speak of the emergence of a ‘coding elite’ – data professionals that design concrete AI-applications and, in doing so, make (implicit) trade-offs between relevant public values beyond political and public scrutiny. In order to recover public value deliberation in algorithmic governance, we argue for the importance of inclusive design processes of AI-applications and develop a concrete framework for realizing such processes (‘inclusive AI’)

Efficacy and Safety Results With Rilzabrutinib, an Oral Bruton Tyrosine Kinase Inhibitor, in Patients With Immune Thrombocytopenia:Phase 2 Part B Study

Current treatments for persistent or chronic immune thrombocytopenia (ITP) are limited by inadequate response, toxicity, and impaired quality of life. The Bruton tyrosine kinase inhibitor rilzabrutinib was evaluated to further characterize safety and durability of platelet response. LUNA2 Part B is a multicenter, phase 1/2 study in adults with ITP (≥ 3 months duration, platelet count &lt; 30 × 109/L) who failed ≥ 1 ITP therapy (NCT03395210, EudraCT 2017–004012-19). Oral rilzabrutinib 400 mg bid was given over 24 weeks, with optional long-term extension (LTE). Primary endpoints were safety and platelet counts ≥ 50 × 109/L on ≥ 8 of the last 12 weeks of main treatment without rescue medication. From 22 March2018 to 31 January2023, 26 patients were enrolled. Patients had baseline median platelet count 13 × 109/L, ITP duration 10.3 years, and six prior ITP therapies (46% splenectomized). Nine (35%) patients achieved the primary endpoint. Platelet counts ≥ 50 × 109/L or ≥ 30 × 109/L and doubling from baseline without rescue therapy were sustained for a mean 9.3 weeks. 11 (42%) LTE-eligible patients were ongoing with median LTE platelet &gt; 80 × 109/L. Three (12%) patients received rescue medication during main treatment, none in LTE. Clinically meaningful improvements were observed in fatigue and women's health. With a median treatment duration of 167 days (main treatment), 16 (62%) patients had ≥ 1 treatment-related adverse event (AE), mainly grade 1, including diarrhea (35%), headache (23%), and nausea (15%). There was no treatment-related grade ≥ 2 bleeding/thrombotic events/infections, serious AE, or death. Rilzabrutinib continues to demonstrate durable platelet responses with favorable safety profile in previously treated ITP patients. Trial Registration: NCT03395210, EudraCT 2017-004012-19.</p

Gut microbial and functional alterations lead to metagenomic signatures for midgut neuroendocrine tumor patients and for carcinoid syndrome

Midgut neuroendocrine tumors (NET) derive from enterochromaffin cells, which have a close interrelationship with intestinal microbiota. Recently, we have utilized 16S rRNA sequencing to uncover that midgut NET patients have a depleted gut microbiome and a specific fecal microbial signature. This study aims to validate these findings and to further characterize the role of microbes and microbial metabolic pathways in midgut NET patients with and without carcinoid syndrome (CS). Fecal samples from 60 midgut NET patients and 20 household-matched controls were subjected to whole metagenome sequencing. The gut microbial community composition of midgut NET patients differed from that of controls, with 2 genera, 17 species and 9 microbial pathways showing differential abundance (P &lt; 0.001). No differences in the microbial composition were observed between midgut NET patients with and without CS (P &gt; 0.05). However, we did observe changes in inter-genus correlations of Bacteroides, Odoribacter, Parasutterella, Klebsiella, Ruminococcus and Proteobacteria when comparing these two patient groups. A signature of 16 microbial species (area under the receiver operating characteristics (AUROC) curve 0.892) or 18 microbial pathways (AUROC 0.909) accurately predicted the presence of a midgut NET. Furthermore, a microbial signature consisting of 14 functional microbial pathways distinguished CS patients from non-CS patients (AUROC 0.807). Thus, this study confirms that the gut microbiome of midgut NET patients is altered at the metagenomic level, which is not related to the presence of CS. A fecal microbial signature could constitute a novel biomarker for the diagnosis of midgut NET or CS.</p

Longitudinal health-related quality of life in patients with pancreatic cancer stratified by treatment:a nationwide cohort study

Background: Pancreatic adenocarcinoma (PAC) has a poor prognosis and substantially impairs health-related quality of life (HRQoL). Large studies on longitudinal HRQoL in patients with PAC, taking patient treatment into account, are lacking. This study aimed to investigate HRQoL over time in patients with PAC undergoing various treatments. Methods: This nationwide cohort study included patients diagnosed with PAC between 2015 and 2020. Data were collected from the Dutch Pancreatic Cancer Project (PACAP) and the Netherlands Cancer Registry. Patients were categorized into four groups based on treatment modality: resection (R-PAC), chemotherapy for localized disease (C-PAC), chemotherapy for metastatic disease (M1-C-PAC), and best supportive care (BSC). HRQoL was assessed using the EORTC QLQ-C30 and -PAN26 questionnaires at baseline, during treatment, and at 0–3 months and 3–6 months after treatment. Linear mixed models were used to analyze changes in HRQoL over time, with clinically relevant changes defined as a minimal mean difference of 10 points in absolute scores and reported with 95% confidence intervals.Findings: Overall, 1496 patients were included (673 [45.0%] female), of whom 675 (45.1%) in R-PAC, 319 (21.3%) in C-PAC, 340 patients (22.7%) in M1-C-PAC, and 162 (10.8%) in BSC group. In R-PAC, hepatic symptoms and health care satisfaction improved while role and social functioning deteriorated and eating related problems, side effects and fear of future health increased during treatment. In C-PAC, insomnia, pancreatic pain, hepatic symptoms decreased while diarrhea, side effects and fear of future health increased. In M1-C-PAC, pain, insomnia, pancreatic pain, hepatic symptoms, ascites and constipation decreased, sexuality improved while fear of future health and side effects increased. In BSC, hepatic symptoms decreased and flatulence increased. Interpretation: This nationwide study identified specific improvements and deteriorations in various HRQoL domains during 6 months follow-up. This information may be valuable in the clinical setting to inform patients on potential outcomes of the course of HRQoL during various treatment strategies. </p