Ongeveer 12 procent van de mannen en 25 procent van de vrouwen krijgt gedurende hun leven een depressie. Onderzoekers denken dat dit verschil …
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Ongeveer 12 procent van de mannen en 25 procent van de vrouwen krijgt gedurende hun leven een depressie. Onderzoekers denken dat dit verschil …
Cardiovasc Res. 2021 Sep 22:cvab299. doi: 10.1093/cvr/cvab299. Online ahead of print.
AIMS: Research on the pathophysiology of right ventricular (RV) failure has, in spite of the associated high mortality and morbidity, lagged behind compared to the left ventricle (LV).Previous work from our lab revealed that the embryonic basic helix-loop-helix transcription factor heart and neural crest derivatives expressed-2 (Hand2) is re-expressed in the adult heart and activates a ‘fetal gene program’ contributing to pathological cardiac remodeling under conditions of LV pressure overload. As such, ablation of cardiac expression of Hand2 conferred protection to cardiac stress and abrogated the maladaptive effects that were observed upon increased expression levels. In this study, we aimed to understand the contribution of Hand2 to RV remodeling in response to pressure overload induced by pulmonary artery banding (PAB).
METHODS AND RESULTS: In the present study, Hand2F/F and MCM- Hand2F/F mice were treated with tamoxifen (control and knockout, respectively) and subjected to six weeks of RV pressure overload induced by PAB. Echocardiographic- and MRI-derived hemodynamic parameters as well as molecular remodeling were assessed for all experimental groups and compared to sham-operated controls. Six weeks after PAB, levels of Hand2 expression increased in the control banded animals but, as expected, remained absent in the knockout hearts. Despite the dramatic differences in Hand2 expression, pressure overload resulted in impaired cardiac function independently of the genotype. In fact, Hand2 depletion seems to sensitize the RV to pressure overload as these mice develop more hypertrophy and more severe cardiac dysfunction. Higher expression levels of HAND2 were also observed in RV samples of human hearts from patients with pulmonary hypertension. In turn, the LV of RV-pressure overloaded hearts was also dramatically affected as reflected by changes in shape, decreased LV mass and impaired cardiac function. RNA sequencing revealed a distinct set of genes that are dysregulated in the pressure-overloaded RV, compared to the previously described pressure-overloaded LV.
CONCLUSIONS: Cardiac-specific depletion of Hand2 is associated with severe cardiac dysfunction in conditions of RV pressure overload. While inhibiting Hand2 expression can prevent cardiac dysfunction in conditions of LV pressure overload, the same does not hold true for conditions of RV pressure overload. This study highlights the need to better understand the molecular mechanisms driving pathological remodeling of the RV in contrast to the LV, in order to better diagnose and treat patients with RV or LV failure.
TRANSLATIONAL PERSPECTIVE: RV failure associated with pulmonary hypertension reduces long-term survival rate to 55% within 3 years, suggesting that 3 years after diagnosis almost half of the patients will die. To revert these numbers an adequate RV-specific and, therefore, more efficient treatment is needed. Our work suggests that current therapies and potential mechanisms underlying LV failure may not be suitable for RV failure. While Hand2 deletion is favorable in LV response to stress, it is particularly detrimental in the RV under similar conditions, and thus, highlighting potential severe consequences of not differentiating therapeutic targets or treatment for RV or LV failure.
Braz J Microbiol. 2021 Sep 22. doi: 10.1007/s42770-021-00528-w. Online ahead of print.
The etiological agent for infective endocarditis (IE), a life-threatening disease, is usually gram-positive bacteria. However, gram-negative bacteria can rarely cause IE and 4% of cases are associated with morbidity and mortality. This study aimed to characterize Escherichia coli and Klebsiella pneumoniae isolates from the blood of patients with IE. The characteristics of blood isolates were compared with those of urinary isolates from patients with urinary tract infections (UTIs). The results of this study revealed that K. pneumoniae isolates from patients with IE were phylogenetically related to those from patients with UTI. Additionally, the resistance phenotype, resistance gene, virulence gene, and plasmid profiles were similar between the blood and urinary isolates. The isolates belonging to the sequence types (STs) 76, 36, 101 (K. pneumoniae), and 69 (E. coli) are reported to be associated with drug resistance. The Enterobacteriaceae isolates from patients with IE did not produce extended-spectrum β-lactamase or carbapenemase. Additionally, this study investigated the virulence phenotype, biofilm formation ability, and the ability to adhere to the epithelial cells in vitro of the isolates. The isolates from patients with IE exhibited weaker biofilm formation ability than the urinary isolates. All isolates from patients with IE could adhere to the renal epithelial cells. However, three isolates from patients with UTIs could not adhere to the epithelial cells. The closely related K. pneumoniae isolates (648, KP1, KP2, KP3, and KP4) could not form biofilms or adhere to the epithelial cells. In summary, the molecular analysis revealed that the genetic characteristics of IE-causing K. pneumoniae and E. coli were similar to those of UTI-causing isolates. These isolates belonged to the STs that are considered treatable. Genetically similar isolates did not exhibit the same virulence phenotype. Thus, these non-hypervirulent clones must be monitored as they can cause complex infections in susceptible hosts.
J Reg Sci. 2021 Aug 22. doi: 10.1111/jors.12559. Online ahead of print.
This paper examines the impact of Covid-19 lockdowns on exports by Chinese cities. We use city-level export data at a monthly frequency from January 2018 through April 2020. Differences-in-differences estimates suggest cities in lockdown experienced a ceteris paribus 34 percentage points reduction in the year-on-year growth rate of exports. The lockdown impacted the intensive and extensive margin, with higher exit and lower new entry into foreign markets. The drop in exports was smaller in (i) coastal cities; (ii) cities with better-developed ICT infrastructure; and (iii) cities with a larger share of potential teleworkers. Time-sensitive and differentiated goods experienced a more pronounced decline in export growth. Global supply chain characteristics matter, with more upstream products and industries that had accumulated larger inventories experiencing a smaller decline in export growth. Also, products that relied more on imported (domestic) intermediates experienced a sharper (flatter) slowdown in export growth. The rapid recovery in cities’ exports after lockdowns were lifted suggests the policy was cost-effective in terms of its effects on trade.
Pediatrics. 2021 Sep 21:e2021050414. doi: 10.1542/peds.2021-050414. Online ahead of print.
CONTEXT: An overview of the full range of neonatal stressors and the associated clinical, laboratory, and imaging outcomes regarding infants’ health and development may contribute to the improvement of neonatal care.
OBJECTIVE: To systematically review existing literature on the associations between all kinds of neonatal stressors and the health and development of preterm infants.
DATA SOURCES: Data sources included Embase, Medline, PsycINFO, the Cumulative Index to Nursing and Allied Health Literature, and reference lists.
STUDY SELECTION: Studies were eligible if they included a measure of neonatal stress during the NICU stay, reported clinical, laboratory, and/or imaging outcomes regarding health and/or development on discharge from the NICU or thereafter, included preterm infants, and were written in English or Dutch.
DATA EXTRACTION: Two reviewers independently screened the sources and extracted data on health and development. Study quality was assessed by using the Newcastle-Ottawa Quality Assessment Scale.
RESULTS: We identified 20 articles that reported on neonatal stress associated negatively with clinical outcomes, including cognitive, motor, and emotional development, and laboratory and imaging outcomes, including epigenetic alterations, hypothalamic-pituitary-adrenal axis functioning, and structural brain development. We found no evidence regarding associations with growth, cardiovascular health, parent-infant interaction, the neonatal immune system, and the neonatal microbiome.
LIMITATIONS: The studies were all observational and used different definitions of neonatal stress.
CONCLUSIONS: Neonatal stress has a profound impact on the health and development of preterm infants, and physicians involved in their treatment and follow-up should be aware of this fact.
Atriumfibrilleren (AF) is een veelvoorkomende hartritmestoornis waarbij het hart onregelmatig en meestal snel klopt. Vaak begint AF aanvalsgewijs, …
Het lichaamseigen verworven immuunsysteem is bij uitstek in staat tumorcellen gericht te herkennen en aan te vallen. De studies in het proefschrift …
Trends Cancer. 2021 Sep 18:S2405-8033(21)00185-0. doi: 10.1016/j.trecan.2021.09.001. Online ahead of print.
The inability to unequivocally identify senescent cancer cells is hindering the development of novel anticancer therapies using senolytic compounds. In a recent study in Cell Reports, Jochems et al. used a machine-learning approach to generate a classifier for senescent cancer cells based on transcriptional signatures.
Veel mensen krijgen tijdens hun leven last van depressieve symptomen. Hoewel deze symptomen niet bij iedereen voldoen aan de criteria voor een …
Elife. 2021 Sep 21;10:e70452. doi: 10.7554/eLife.70452. Online ahead of print.
Human herpesviruses 6A and 6B (HHV-6A/6B) are ubiquitous pathogens that persist lifelong in latent form and can cause severe conditions upon reactivation. They are spread by community-acquired infection of free virus (acqHHV6A/6B) and by germline transmission of inherited chromosomally-integrated HHV-6A/6B (iciHHV-6A/6B) in telomeres. We exploited a hypervariable region of the HHV-6B genome to investigate the relationship between acquired and inherited virus and revealed predominantly maternal transmission of acqHHV-6B in families. Remarkably, we demonstrate that some copies of acqHHV-6B in saliva from healthy adults gained a telomere, indicative of integration and latency, and that the frequency of viral genome excision from telomeres in iciHHV-6B carriers is surprisingly high and varies between tissues. In addition, newly formed short telomeres generated by partial viral genome release are frequently lengthened, particularly in telomerase-expressing pluripotent cells. Consequently, iciHHV-6B carriers are mosaic for different iciHHV-6B structures, including circular extra-chromosomal forms that have the potential to reactivate. Finally, we show transmission of an HHV-6B strain from an iciHHV-6B mother to her non-iciHHV-6B son. Altogether we demonstrate that iciHHV-6B can readily transition between telomere-integrated and free virus forms.
Br J Clin Pharmacol. 2021 Sep 20. doi: 10.1111/bcp.15088. Online ahead of print.
Brigatinib was recently approved for the treatment of anaplastic lymphoma kinase-positive non-small cell lung cancer and is dosed according to a one-dose-fits-all paradigm. We aimed to identify a pharmacokinetically-guided precision dosing strategy to improve treatment response with brigatinib through simulations using a previously published pharmacokinetic-pharmacodynamic model. Dosing strategies explored were the approved 180mg QD, the highest tolerable dose tested in clinical trials: 240mg QD, and two precision dosing strategies targeting the median trough concentrations following 180mg QD, and 240mg QD. We investigated the impact of alternative dosing regimens on progression-free survival (PFS), overall survival (OS), and the probability of developing a grade ≥2 rash or grade ≥2 amylase increase. Median PFS and OS increased by 1.6 and 7.8 months, respectively between the currently approved dosing strategy and precision dosing to the median trough concentration of the 240mg dosing strategy, with only a minor increase in the probability of developing toxicity.
Leukemia. 2021 Sep 20. doi: 10.1038/s41375-021-01406-y. Online ahead of print.
In the current classification of the World Health Organization (WHO), bone marrow mastocytosis (BMM) is a provisional variant of indolent systemic mastocytosis (ISM) defined by bone marrow involvement and absence of skin lesions. However, no additional diagnostic criteria for BMM have been proposed. Within the registry dataset of the European Competence Network on Mastocytosis, we compared characteristics and outcomes of 390 patients with BMM and 1175 patients with typical ISM. BMM patients were significantly older, predominantly male, had lower tryptase and lower burden of neoplastic mast cells, and displayed a higher frequency of allergic reactions, mainly triggered by Hymenoptera, than patients with typical ISM. The estimated 10-year progression-free survival of BMM and typical ISM was 95.9% and 92.6%, respectively. In BMM patients defined by WHO-based criteria, the presence of one B-Finding and tryptase level ≥125 ng/mL were identified as risk factors for progression in multivariate analyses. BMM patients without any of these risk factors were found to have better progression-free survival (p < 0.05) and better overall survival (p < 0.05) than other ISM patients. These data support the proposal to define BMM as a separate SM variant characterized by SM criteria, absence of skin lesions, absence of B-Findings, and tryptase levels <125 ng/mL.
Langmuir. 2021 Sep 21. doi: 10.1021/acs.langmuir.1c01542. Online ahead of print.
This paper describes the fabrication of microfluidic devices with a focus on controlling the orientation of photosystem I (PSI) complexes, which directly affects the performance of biophotovoltaic devices by maximizing the efficiency of the extraction of electron/hole pairs from the complexes. The surface chemistry of the electrode on which the complexes assemble plays a critical role in their orientation. We compared the degree of orientation on self-assembled monolayers of phenyl-C61-butyric acid and a custom peptide on nanostructured gold electrodes. Biophotovoltaic devices fabricated with the C61 fulleroid exhibit significantly improved performance and reproducibility compared to those utilizing the peptide, yielding a 1.6-fold increase in efficiency. In addition, the C61-based devices were more stable under continuous illumination. Our findings show that fulleroids, which are well-known acceptor materials in organic photovoltaic devices, facilitate the extraction of electrons from PSI complexes without sacrificing control over the orientation of the complexes, highlighting this combination of traditional organic semiconductors with biomolecules as a viable approach to coopting natural photosynthetic systems for use in solar cells.
Parkinsonism Relat Disord. 2021 Sep 15;91:96-101. doi: 10.1016/j.parkreldis.2021.09.011. Online ahead of print.
BACKGROUND: The supplementary motor area (SMA) is implicated in stereotypic multi-limb movements such as walking with arm swing. Gait difficulties in Parkinson’s Disease (PD) include reduced arm swing, which is associated with reduced SMA activity.
OBJECTIVE: To test whether enhanced arm swing improves Parkinsonian gait and explore the role of the SMA in such an improvement.
METHODS: Cortical activity and gait characteristics were assessed by ambulant EEG, accelerometers and video recordings in 27 PD patients with self-reported gait difficulties and 35 healthy participants when walking normally. Within these two groups, 19 PD patients additionally walked with enhanced arm swing and 30 healthy participants walked without arm swing. Power changes across the EEG frequency spectrum were assessed by Event Related Spectral Perturbation analysis of recordings from Fz over the putative SMA and gait analysis was performed.
RESULTS: Baseline PD gait, characterized by reduced arm swing among other features, exhibited reduced within-step Event Related Desynchronization (ERD)/Synchronization (ERS) alternation (Fz; 20-50Hz), accompanied by a reduced step length and walking speed. All became similar to normal gait when patients walked with enhanced arm swing. When healthy controls walked without arm swing, their alternating ERD-ERS pattern decreased, mimicking baseline PD gait.
CONCLUSION: Enhanced arm swing may serve as a driving force to overcome impaired gait control in PD patients by restoring reduced ERD-ERS alternation over the putative SMA. Accompanied by increased step length and walking speed, this provides a neural underpinning of arm swing as an effective rehabilitation concept for improving Parkinsonian gait.
Phys Chem Chem Phys. 2021 Sep 21. doi: 10.1039/d1cp03328j. Online ahead of print.
Single-material organic solar cells have recently attracted research attention due to their simplicity, morphological robustness and high yield of exciton dissociation. Using α-sexithiophene as a model system, we show that the single-event probability of the exciton dissociation at the boundaries of polycrystalline domains with different molecular orientation is extremely low (∼0.5%), while a high efficiency of charge generation is gained via hundred-fold crossings of the domain boundaries due to the long exciton diffusion length (∼45 nm).
J Pers Assess. 2021 Sep 21:1-14. doi: 10.1080/00223891.2021.1975726. Online ahead of print.
The DSM-5 presents two competing diagnostic frameworks for personality disorders: the standard categorical model and the Alternative Model of Personality Disorders (AMPD). The AMPD was initially criticized for being too complex and theory laden for clinical implementation. Though inter-rater reliability studies have contested initial claims of the model’s complexity, little attention has been paid to how clinicians experience the usability and learnability of either model. We interviewed twenty Norwegian clinicians about their experiences with either the SCID-II/5-PD (n = 9), SCID-5-AMPD-I (n = 8), or both (n = 3). Separate thematic analyses were conducted for SCID-II/5-PD and SCID-5-AMPD-I groups, and group themes were compared. We identified four themes for each group, relating to required skills, training, challenges and information gained through the interview. We found that training and clinical experience were considered to be important for both interviews. Moreover, the SCID-5-AMPD-I was considered to rely more explicitly on theory specific to the development and content of the AMPD model in general and the LPFS specifically We also identified shared and unique challenges and shortcomings of each interview. We comment on how our findings relate to the debate surrounding the AMPD, and recommend development of clear training guidelines for both interviews.
J Neurotrauma. 2021 Sep 19. doi: 10.1089/neu.2021.0037. Online ahead of print.
Magnetic resonance imaging (MRI) is rarely used in the acute evaluation of traumatic brain injury (TBI), but may identify findings of clinical importance not detected by computed tomography (CT). We aimed to characterize the association of cytotoxic edema and hemorrhage, including traumatic microbleeds, on MRI obtained within hours of acute head trauma and investigated the relationship to clinical outcomes. Patients prospectively enrolled in the Traumatic Head Injury Neuroimaging Classification study (NCT01132937) with evidence of diffusion-related findings or hemorrhage on neuroimaging were included. Blinded interpretation of MRI for diffusion-weighted imaging and hemorrhage was conducted, with subsequent quantification of apparent diffusion coefficient (ADC) values. Of 161 who met criteria, 82 patients had conspicuous hyperintense lesions on diffusion-weighted imaging (DWI) with corresponding regions of hypointense ADC in proximity to hemorrhage. Median time from injury to MRI was 21 (10-30) hours. Median ADC values per patient grouped by time from injury to MRI were lowest within 24 hours after injury. ADC values associated with hemorrhagic lesions are lowest early after injury, with an increase in diffusion during the subacute period, suggesting transformation from cytotoxic to vasogenic edema during the subacute post-injury period. Of 118 patients with outcome data, 60 had Glasgow Outcome Scale Extended <6 at 30/90 days post-injury. Cytotoxic edema on MRI (OR 2.91 [1.32-6.37], P=0.008) and TBI severity (OR 2.51 [1.32-4.74], P=0.005) were independent predictors of outcome. These findings suggest that in TBI patients with findings of hemorrhage on CT, patients with DWI/ADC lesions on MRI are more likely to do worse.
Front Cardiovasc Med. 2021 Sep 3;8:730316. doi: 10.3389/fcvm.2021.730316. eCollection 2021.
Myocardial strain analysis from cinematic magnetic resonance imaging (cine-MRI) data provides a more thorough characterization of cardiac mechanics than volumetric parameters such as left-ventricular ejection fraction, but sources of variation including segmentation and motion estimation have limited its wider clinical use. We designed and validated a fast, fully-automatic deep learning (DL) workflow to generate both volumetric parameters and strain measures from cine-MRI data consisting of segmentation and motion estimation convolutional neural networks. The final motion network design, loss function, and associated hyperparameters are the result of a thorough ad hoc implementation that we carefully planned specific for strain quantification, tested, and compared to other potential alternatives. The optimal configuration was trained using healthy and cardiovascular disease (CVD) subjects (n = 150). DL-based volumetric parameters were correlated (>0.98) and without significant bias relative to parameters derived from manual segmentations in 50 healthy and CVD test subjects. Compared to landmarks manually-tracked on tagging-MRI images from 15 healthy subjects, landmark deformation using DL-based motion estimates from paired cine-MRI data resulted in an end-point-error of 2.9 ± 1.5 mm. Measures of end-systolic global strain from these cine-MRI data showed no significant biases relative to a tagging-MRI reference method. On 10 healthy subjects, intraclass correlation coefficient for intra-scanner repeatability was good to excellent (>0.75) for all global measures and most polar map segments. In conclusion, we developed and evaluated the first end-to-end learning-based workflow for automated strain analysis from cine-MRI data to quantitatively characterize cardiac mechanics of healthy and CVD subjects.