Dietary sodium restriction specifically potentiates left ventricular ACE inhibition by zofenopril, and is associated with attenuated hypertrophic response in rats with myocardial infarction.

INTRODUCTION: In patients with myocardial infarction (MI)-induced heart failure, angiotensin-converting enzyme (ACE) inhibitors are proven effective therapy in inhibiting the progression towards overt heart failure. However, the prognosis in these patients is still very poor, and optimisation of therapy is warranted. The antihypertensive and renoprotective effects of ACE inhibitors (ACE-Is) can be substantially enhanced by dietary sodium restriction. In line with the latter, the aim of the present study was to explore whether dietary sodium restriction enhances the efficacy of ACE-I after MI. METHODS: Rats with MI-induced left ventricular (LV) dysfunction received ACE-I therapy with zofenopril (5.5 mg/kg/day orally), with or without dietary sodium restriction. ACE activity was measured in non-infarcted LV tissue, kidneys and plasma. Effects on cardiac hypertrophy were examined by means of organ weight/body weight ratios. After blood pressure (BP) measurements, functional consequences of therapy were evaluated as LV pressure development in isolated perfused hearts. RESULTS: Dietary sodium restriction alone had no effect on any of the measured parameters, whereas zofenopril alone significantly reduced plasma and kidney ACE activity, but not LV ACE activity, nor LV weight/body weight ratio. However, only when ACE-I therapy was combined with dietary sodium restriction was LV ACE activity significantly reduced. This effect was paralleled by inhibition of LV hypertrophy. BP was reduced after infarction, and further reduced by zofenopril, but not affected by dietary sodium. Neither treatment was associated with effects on the MI-induced reduction of LV function in vitro. CONCLUSIONS: Effects of ACE inhibition with zofenopril can be potentiated by additional dietary sodium restriction. However, these effects were tissue-specific, since LV, but not kidney or plasma, ACE activity was affected by the additional dietary sodium restriction. Effects on LV ACE activity were paralleled by reduced LV hypertrophy. Since the measured parameters did not indicate any adverse side-effects, dietary sodium restriction may provide a safe strategy to improve ACE-I efficacy in patients with infarction-induced LV dysfunction.     

Persistent Transmission of HCV among Men Who Have Sex with Men despite Widespread Screening and Treatment with Direct-Acting Antivirals

Background: In the Netherlands, unrestricted access to direct-acting antivirals (DAAs) halved the incidence of acute hepatitis C virus (HCV) infections among HIV-infected men who have sex with men (MSM). To develop strategies that can further reduce the spread of HCV, it is important to understand the transmission dynamics of HCV. We used phylogenetic analysis of a dense sample of MSM to provide insight into the impact of unrestricted access to DAAs on HCV transmission in the Netherlands and in Belgium. Methods: We included 89 MSM that were recently infected with HCV genotype 1a in ten Dutch and one Belgian HIV treatment centers. Sequences were generated using next gene sequencing and Sanger sequencing. Maximum likelihood phylogenetic analysis (general time reversible model) was performed on concatenated NS5A and NS5B sequences and a reference set of 389 highly similar control sequences selected from GenBank. A cluster was based on a minimum bootstrap support of 90% and a 3% genetic distance threshold. Results: We found that 78 (88%) of individuals were part of seven major clusters. All clusters included individuals from across the study region, however, different cities were part of different clusters. In three clusters, HIV-negative MSM clustered with sequences from HIV-positive MSM. All clusters that were observed before the introduction of DAAs persisted after unrestricted access to DAAs became available. Conclusion: Recently acquired HCV infections among MSM in the Netherlands and Belgium are strongly clustered and therefore highly suitable for targeted prevention strategies, such as contact tracing and partner notification. Importantly, despite an HCV incidence reduction after high DAA uptake and continuously monitoring, HCV transmission persisted in the same clusters.     

CST6 suppresses osteolytic bone disease in multiple myeloma by blocking osteoclast differentiation

Osteolytic bone disease is a hallmark of multiple myeloma (MM). A significant fraction (~20%) of MM patients do not develop osteolytic lesions (OLs). The molecular basis for the absence of bone disease in MM is not understood. We combined PET-CT and gene expression profiling (GEP) of purified BM CD138⁺ MM cells from 512 newly diagnosed MM patients to reveal that elevated expression of cystatin M/E (CST6) was significantly associated with the absence of OL in MM. An enzyme-linked immunosorbent assay revealed a strong correlation between CST6 levels in BM serum/plasma and CST6 mRNA expression. Both recombinant CST6 protein and BM serum from patients with high CST6 significantly inhibited the activity of the osteoclast-specific protease cathepsin K and blocked osteoclast differentiation and function. Recombinant CST6 inhibited bone destruction in ex vivo and in vivo myeloma models. Single-cell RNA-Seq showed that CST6 attenuates polarization of monocytes to osteoclast precursors. Furthermore, CST6 protein blocks osteoclast differentiation by suppressing cathepsin-mediated cleavage of NF-κB/p100 and TRAF3 following RANKL stimulation. Secretion by MM cells of CST6, an inhibitor of osteoclast differentiation and function, suppresses osteolytic bone disease in MM and probably other diseases associated with osteoclast-mediated bone loss.     

Clinician perspectives on clinical decision support systems in lung cancer: Implications for shared decision‐making

BackgroundLung cancer treatment decisions are typically made among clinical experts in a multidisciplinary tumour board (MTB) based on clinical data and guidelines. The rise of artificial intelligence and cultural shifts towards patient autonomy are changing the nature of clinical decision‐making towards personalized treatments. This can be supported by clinical decision support systems (CDSSs) that generate personalized treatment information as a basis for shared decision‐making (SDM). Little is known about lung cancer patients'' treatment decisions and the potential for SDM supported by CDSSs. The aim of this study is to understand to what extent SDM is done in current practice and what clinicians need to improve it.ObjectiveTo explore (1) the extent to which patient preferences are taken into consideration in non‐small‐cell lung cancer (NSCLC) treatment decisions; (2) clinician perspectives on using CDSSs to support SDM.DesignMixed methods study consisting of a retrospective cohort study on patient deviation from MTB advice and reasons for deviation, qualitative interviews with lung cancer specialists and observations of MTB discussions and patient consultations.Setting and ParticipantsNSCLC patients (N = 257) treated at a single radiotherapy clinic and nine lung cancer specialists from six Dutch clinics.ResultsWe found a 10.9% (n = 28) deviation rate from MTB advice; 50% (n = 14) were due to patient preference, of which 85.7% (n = 12) chose a less intensive treatment than MTB advice. Current MTB recommendations are based on clinician experience, guidelines and patients'' performance status. Most specialists (n = 7) were receptive towards CDSSs but cited barriers, such as lack of trust, lack of validation studies and time. CDSSs were considered valuable during MTB discussions rather than in consultations.ConclusionLung cancer decisions are heavily influenced by clinical guidelines and experience, yet many patients prefer less intensive treatments. CDSSs can support SDM by presenting the harms and benefits of different treatment options rather than giving single treatment advice. External validation of CDSSs should be prioritized.Patient or Public ContributionThis study did not involve patients or the public explicitly; however, the study design was informed by prior interviews with volunteers of a cancer patient advocacy group. The study objectives and data collection were supported by Dutch health care insurer CZ for a project titled ‘My Best Treatment’ that improves patient‐centeredness and the lung cancer patient pathway in the Netherlands.     

Histological and magnetic resonance imaging assessment of Liqoseal in a spinal in vivo pig model

BackgroundLiqoseal (Polyganics, B.V.) is a dural sealant patch for preventing postoperative cerebrospinal fluid (CSF) leakage. It has been extensively tested preclinically and CE (Conformité Européenne) approved for human use after a first cranial in‐human study. However, the safety of Liqoseal for spinal application is still unknown. The aim of this study was to assess the safety of spinal Liqoseal application compared with cranial application using histology and magnetic resonance imaging characteristics.MethodsEight female Dutch Landrace pigs underwent laminectomy, durotomy with standard suturing and Liqoseal application. Three control animals underwent the same procedure without sealant application. The histological characteristics and imaging characteristics of animals with similar survival times were compared to data from a previous cranial porcine model.ResultsSimilar foreign body reactions were observed in spinal and cranial dura. The foreign body reaction consisted of neutrophils and reactive fibroblasts in the first 3 days, changing to a chronic granulomatous inflammatory reaction with an increasing number of macrophages and lymphocytes and the formation of a fibroblast layer on the dura by day 7. Mean Liqoseal plus dura thickness reached a maximum of 1.2 mm (range 0.7–2.0 mm) at day 7.ConclusionThe spinal dural histological reaction to Liqoseal during the first 7 days was similar to the cranial dural reaction. Liqoseal did not swell significantly in both application areas over time. Given the current lack of a safe and effective dural sealant for spinal application, we propose that an in‐human safety study of Liqoseal is the logical next step.

Liqoseal is a dural sealant patch to prevent postoperative cerebrospinal fluid (CSF) leakage. Eight female Dutch Landrace pigs underwent laminectomy, durotomy with standard suturing and Liqoseal application. The aim of this study was to assess safety of spinal Liqoseal application using histology and magnetic resonance imaging characteristics in comparison to cranial application.