Search Results (26)

Pathological USH2A mutations cause Usher syndrome type II, characterized by progressive retinitis pigmentosa and hearing and balance impairment. This study aims to investigate the cellular mechanisms underlying USH2A-related retinal degeneration using human induced pluripotent stem cell (hiPSC)-derived retinal organoids. The introduction of a homozygous nonsense mutation in the USH2A hotspot exon-13 resulted in normal photoreceptor development but loss of ciliary localization of usherin long form B and its interacting proteins, ADGRV1 and whirlin. Notably, single-cell RNA sequencing revealed unexpected significant transcriptional changes in Müller glial cells (MGCs), suggestive of disruptions in the translation, innate immune response, and endolysosomal system. These findings suggest that, while photoreceptor cells are mildly affected by the exon-13 USH2A mutation, MGCs exhibit major transcriptional changes, potentially contributing to the disease progression and therefore shedding light on potential alternative therapeutic targets. Full article

Background/Objectives: In the Netherlands, selective ultrasound (US) screening for developmental dysplasia of the hip (DDH) typically occurs at 3 months of age. During the COVID-19 pandemic, US screening was temporarily halted in Dutch hospitals, with consequent delay in DDH screening and possibly inferior outcomes in DDH patients. Methods: We analyzed 1849 infants screened for DDH during the COVID-19 pandemic (March–August 2020) and 1663 infants screened before the pandemic (March–August 2019). We compared mean age and timing of screening (standard vs. delayed (delayed defined as ≥15 weeks)). For secondary outcomes, we compared DDH patients with delayed screening to standard screening, assessing severity at diagnosis, treatment method and duration, and outcomes at the age of one year, including acetabular index (AI) on radiographs. Results: Mean age at screening was 17.3 weeks during the COVID-19 crisis (2020) vs. 15.8 weeks in the 2019 cohort (mean difference 1.5, 95% CI 1.1–1.8, p < 0.001). Delayed screening occurred in 57.6% of infants in 2020 vs. 36.7% in 2019 (p < 0.001). Patients with DDH with delayed screening (n = 284), compared to standard screening (n = 284), did not differ in mean alpha angle at diagnosis (55.0° vs. 54.4°, mean difference 0.6, 95% CI −0.06–1.25, p = 0.08) and AI at one year (24.0° vs. 24.5°, mean difference −0.5, 95% CI −1.05–0.14, p = 0.13). Conclusions: This study revealed that disruption of healthcare caused by the COVID-19 pandemic resulted in a delay in the Dutch DDH-screening program. However, in this study, delayed screening was not associated with inferior outcomes at the age of one year. Full article

Simple and low-cost flame curtain (“Kon-Tiki”) kilns are currently the preferred biochar technology for smallholder farmers in the tropics. While gas and aerosol emissions have been documented for woody feedstocks (twigs and leaves) with varying moisture contents, there is a lack of data on emissions from other types of feedstocks. This study aims to document the gas and aerosol emissions for common non-woody feedstocks and to compare emissions from finely grained, high-lignin feedstock (coffee husk) with those from coarser, low-lignin feedstocks (maize cobs, grass, sesame stems). Throughout each pyrolysis cycle, all carbon-containing gases and NO_x were monitored using hand-held sensitive instruments equipped with internal pumps. Carbon balances were used to establish emission factors in grams per kilogram of biochar. The resulting methane emissions were nearly zero (<5.5 g/kg biochar) for the pyrolysis of three dry (~10% moisture) maize cobs, grass, and a 1:1 mixture of grass and woody twigs. For sesame stems, methane was detected in only two distinct spikes during the pyrolysis cycle. Carbon monoxide (CO) and aerosol (Total Suspended Particles, TSP) emissions were recorded at levels similar to earlier data for dry twigs, while nitrogen oxide (NO_x) emissions were negligible. In contrast, the pyrolysis of finely grained coffee husks generated significant methane and aerosol emissions, indicating that technologies other than flame curtain kilns are more suitable for finely grained feedstocks. The emission results from this study suggest that certification of biochar made from dry maize, sesame, and grass biomass using low-tech pyrolysis should be encouraged. Meanwhile, more advanced systems with syngas combustion are needed to sufficiently reduce CO, CH₄, and aerosol emissions for the pyrolysis of finely grained biomasses such as rice, coffee, and nut husks. The reported data should aid overarching life-cycle analyses of the integration of biochar practice in climate-smart agriculture and facilitate carbon credit certification for tropical smallholders. Full article

Background/Objectives: The literature reports high complication rates in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who undergo balloon pulmonary angioplasty (BPA), especially in patients with poor pulmonary hemodynamics. Here, we describe the complications of BPA based on the new definitions. Methods: All patients with CTEPH who completed BPA treatment before 15 September 2023 were selected from the CTEPH database. Peri-procedural complications were collected and classified according to the 2023 consensus paper on BPA treatment. Complications were analyzed in subgroups of patients with pulmonary vascular resistance (PVR), ≤ or >6.6 WU, and mean pulmonary artery pressure (mPAP), ≤ or >45 mmHg, at first BPA. Results: In this analysis, 87 patients (63% women; mean age 61.1 ± 14.0 years; 62% on dual PH targeted medical therapy) underwent 426 (mean 4.9 ± 1.6 per patient) BPAs. Only non-severe complications occurred in 14% of BPA treatments and in 47% of the patients; 31% patients had a thoracic complication. The thoracic complications were mild (71%) or moderate (29%). Patients with a PVR > 6.6 WU (n = 8) underwent more BPA treatments (6.6 ± 1.5 versus 4.6 ± 1.5, p = 0.002), had more complications (88% versus 41% of patients, p = 0.020), and had more thoracic complications (17% vs. 7% of BPAs, p = 0.013) than patients with PVR ≤ 6.6 WU. Patients with mPAP > 45 mmHg (n = 13) also had more BPA treatments (6.5 ± 1.7 versus 4.6 ± 1.4, p < 0.001), more complications (77% versus 44% of patients, p = 0.027) and more thoracic complications (14% versus 8% of BPAs, p = 0.039) than patients with mPAP ≤ 45 mmHg. Conclusions: Complications occurred in 14% of BPAs and were mostly mild. Patients with severe pulmonary hemodynamics suffered more (thoracic) complications. Full article

Soils on many smallholder farms in Southern Africa are severely depleted in plant nutrients, in particular phosphorus (P), following years of maize monocropping with little or no fertilizer input. Past studies suggest that pigeon pea (Cajanus cajan (L.) Millsp.) may increase plant-available P. Pigeon pea is not a common crop in much of Southern Africa, and the effect of locally grown pigeon pea varieties on plant-available P is unknown. We assessed the changes in plant-available P after growing pigeon pea varieties MPPV-2, MPPV-3, and Babati White in Zambia, viz. Lixisols of Choma and Mkushi, Acrisols of Chipata and Kasama, and Arenosols of Kaoma. The selected soils were not fertilized. Baseline soils (0–20 cm), sampled after long-term maize monocropping and soils from the same fields after growing pigeon pea were collected from field trials in Kaoma, Chipata, Choma, and Mkushi and analyzed for plant-available P. Further, a greenhouse study was conducted with soils from Kasama, Choma, Kaoma, and Chipata, under which soil P was determined before and after growing pigeon pea, soybean (Dina), and maize (SC 419) without fertilizer addition. Pigeon pea under field studies had no significant (p > 0.05) effect on plant-available P in Choma, Kaoma, and Chipata. In Mkushi, pigeon pea cropping resulted in a 47.5% significant decline (p ≤ 0.05) in plant-available P, amounting to a loss of 11.2 kg ha⁻¹. The greenhouse study showed a significant decline (p ≤ 0.001) in plant-available P after seven weeks of maize growth, while there was no significant (p > 0.05) effect on plant-available P after soybean and pigeon pea cropping. The latter was primarily due to the significantly higher P uptake associated with larger biomass production of maize after seven weeks in the greenhouse. During the initial seven weeks, pigeon pea biomass had significantly higher P concentrations than maize. Thus, P deficiency symptoms were exhibited in maize, while pigeon pea appeared healthy. However, mobilized P, calculated as the sum of plant P and soil P after cropping minus soil P before planting, was significantly lower (p ≤ 0.01) in pigeon pea compared to soybean and maize. Synthesizing field and greenhouse experiments suggests that there is a low net decline of plant-available P from soils after pigeon pea cropping. Therefore, rotation with these pigeon pea varieties could be beneficial to resource-poor farmers due to low P removal and its ability to grow in P-deficient soil. Full article

Bile acids (BAs) and their signaling pathways have been identified as therapeutic targets for liver and metabolic diseases. We generated Cyp2c70^−/− (KO) mice that were not able to convert chenodeoxycholic acid into rodent-specific muricholic acids (MCAs) and, hence, possessed a more hydrophobic, human-like BA pool. Recently, we have shown that KO mice display cholangiopathic features with the development of liver fibrosis. The aim of this study was to determine whether BA sequestration modulates liver pathology in Western type-diet (WTD)-fed KO mice. The BA sequestrant colesevelam was mixed into the WTD (2% w/w) of male Cyp2c70^+/+ (WT) and KO mice and the effects were evaluated after 3 weeks of treatment. Colesevelam increased fecal BA excretion in WT and KO mice and reduced the hydrophobicity of biliary BAs in KO mice. Colesevelam ameliorated diet-induced hepatic steatosis in WT mice, whereas KO mice were resistant to diet-induced steatosis and BA sequestration had no additional effects on liver fat content. Total cholesterol concentrations in livers of colesevelam-treated WT and KO mice were significantly lower than those of untreated controls. Of particular note, colesevelam treatment normalized plasma levels of liver damage markers in KO mice and markedly decreased hepatic mRNA levels of fibrogenesis-related genes in KO mice. Lastly, colesevelam did not affect glucose excursions and insulin sensitivity in WT or KO mice. Our data show that BA sequestration ameliorates liver pathology in Cyp2c70^−/− mice with a human-like bile acid composition without affecting insulin sensitivity. Full article

Thermal propagation events of the traction batteries in electric vehicles are rare. However, their impact on the passengers in form of fire, smoke and heat can be severe. Current data on the dependencies and the reproducibility of thermal propagation is limited despite these major implications. Therefore, a thermal propagation test bench was developed for custom multi pouch experiments. This setup includes a multitude of temperature sensors throughout the module, voltage monitoring and a mass flow sensor. Two distinct experiments were initiated by nail penetration. These show a high degree of reproducibility thus allowing for future experiments regarding the dependencies of initial module temperatures and State of Charge (SoC) variations. Full article

Introduction: Nailfolds of patients with systemic sclerosis (SSc) provide an opportunity to directly visualize microvascular remodeling in SSc. Nailfold video capillaroscopy (NVC) remains the gold standard for assessing nailfold capillaroscopy (NFC). However, access to NVC is limited by expense and expertise. This review aims to synthesize current research on other NFC devices compared to NVC. Methods: The literature search included the primary research of adult patients with SSc as defined by the 2013 ACR/EULAR criteria. Methods of assessing NFC included stereomicroscopy/wide-field microscopy, ophthalmoscopy, dermatoscopy, smartphone devices, and digital USB microscopy. Primary outcomes included both qualitative (normal vs. abnormal nailfolds, overall pattern recognition, presence/absence of giant capillaries, hemorrhages, and abnormal morphology) and quantitative (capillary density and dimension) measures. Results: The search yielded 471 studies, of which 9 were included. Five studies compared NVC to dermatoscopy, two compared it to widefield/stereomicroscopy, one to smartphone attachments, and one to USB microscopy. In dermatoscopy studies, NVC had a higher percentage of images that were interpretable (63–77% vs. 100%), classifiable (70% vs. 84%), or gradable (70% vs. 79.3%) across three studies. Dermatoscopy had a lower sensitivity (60.2% vs. 81.6%) and higher specificity (92.5% vs. 84.6%) compared to NVC. One stereomicroscopy study found a significant difference between methods in capillary density in limited cutaneous SSc, while another found correlations in all parameters between stereomicroscopy and NVC. One smartphone lens had good agreement with NVC on abnormal capillary morphology and density. USB microscopy was able to differentiate between SSc and healthy controls using mean capillary width but not by capillary density. Discussion: A dermatoscope may serve as a more portable and affordable screening tool to identify a normal “scleroderma pattern”, and images that need further corroboration by NVC. NFC parameters reported are heterogenous and the standardization of these parameters is important, especially in non-gold-standard devices. Full article

Background: A large proportion of people who sustain a whiplash injury will have persistent pain, disability, and participation problems. Several prognostic factors for functional recovery have been reported in the literature but these factors are often evaluated based on differing implementations in clinical practice. Additionally, physiotherapists also rely on their clinical intuition to estimate the functional prognosis of their patients, but this is seldom measured in experimental research. Furthermore, no study to date has explored the associations between clinical intuition, clinically estimated factors, and objectively measured factors for functional recovery of patients with Whiplash-Associated Disorders (WAD). Aim: The aim of this exploratory study is to evaluate associations between prognostic factors for functional recovery, based on routinely collected data in a specialized primary care physiotherapy practice in a consecutive sample of patients (n = 523) with WAD. Methods: Three sources of prognostic factors were selected: (1) physiotherapists’ synthesis of clinical intuition in terms of high-risk, inconclusive risk, or low-risk for functional recovery, (2) patient-registered factors from history taking, and (3) patient-reported prognostic factors derived from questionnaires. Prognostic factors were selected based on the literature, recommendations in Dutch clinical practice guidelines, and consensus between experts. Spearman’s rank correlation coefficients were calculated to explore the associations between sources of prognostic factors, using a cutoff ≥0.25 for acceptable association. Results: Associations between physiotherapists’ intuitive synthesis and patient-registered variables were substantial (r_s = 0.86), between patient-registered variables and patient-reported variables fair (ranging from 0.30 to 0.41) to substantial (ranging from 0.69 to 0.73), and between physiotherapists intuitive synthesis and patient-reported variables fair (ranging from 0.30 to 0.37). Conclusion: When estimating prognosis for functional recovery using clinical reasoning, physiotherapists should integrate patients’ registered experience of their course of recovery, as well as the timeline after an accident, with their own synthesis of clinical intuition regarding prognostic factors in patients with WAD. Full article

Elevated nitrogen (N) deposition may further acidify soils in tropical forests. Yet, we have limited evidence on this prediction and it remained unclear how this would affect fine root growth therein. Here, we report responses of fine root biomass, vitality, and chemistry, as well as related soil parameters to eight years of N additions in three tropical forests different in initial soil N status, with one primary forest being N-saturated, and another two younger forests (one secondary forest and one planted forest) less N-rich. Results showed that in the primary forest, fine root biomass decreased and fine root necromass increased following N addition, resulting in lower live fine root proportion (fine root vitality). Declining fine root vitality was associated with fine root Fe accumulation and soil acidification indicated by regression analysis. These alterations of fine root growth and chemistry co-occurred with soil pH decline, soil exchangeable Fe³⁺ mobilization, exchangeable Ca²⁺, and Mg²⁺ depletion after N treatments in the primary forest. In contrast, N addition only elevated fine root K, Al, and Fe content in the secondary forest. In the planted forest, moderate but significant decreases in soil pH, soil exchangeable K⁺, and Mg²⁺ were found after N treatment, with fine root biomass negatively correlated with soil exchangeable Al³⁺ and Al³⁺/(Ca²⁺ + Mg²⁺) ratio. Our results suggested that long-term N fertilization may negatively affect fine root growth, via severed soil acidification, Fe mobilization, and base cation depletion in highly acidified, N-saturated primary tropical forests. Initial forest N status, influenced by different land-use history, mediates N deposition effects on fine root growth. Full article

Acid forest soils in South China experience a chronically elevated input of atmospheric nitrogen (N), turning them into hot spots for gaseous N emissions. Soil moisture is known to be a major controller for the partitioning of gaseous N loss to nitric (NO) and nitrous oxide (N₂O), which may be of particular relevance in the monsoonal climate of South China. To study this partitioning in more detail, we determined gas phase kinetics of NO and N₂O release during laboratory dry-out of acidic surface soils from the headwater catchment TieShanPing (TSP), situated close to Chongqing, SW China. Soils were sampled from two hydrologically distinct environments, a well-drained hill slope (HS), and a periodically flooded groundwater discharge zone (GDZ). Production and consumption of NO were studied in an automated flow-through system purged with NO-free or NO-spiked air. Production rates peaked at 21% and 18% water filled pore space (WFPS) in HS and GDZ soils, respectively, suggesting nitrification as the dominant process of NO formation in both landscape units. In HS soils, maximum production and consumption occurred at the same WFPS, whereas GDZ soils displayed maximum NO consumption at higher WFPS than maximum production, suggesting that denitrification is an important NO sink in GDZ soils. Net N₂O release was largest at 100% WFPS and declined steadily during drying. Integrated over the entire range of soil moisture, potential NO-N loss outweighed potential N₂O-N loss, suggesting that N-saturated, acid forest soil is an important NO source. Full article

This paper reports on a literary corpus study of four grammatical tenses across four European languages. The corpus consists of a selection of eight chapters from Javier Marías’s Spanish novel Así empieza lo malo ‘Thus bad begins’, and its translations to English, Dutch, and French. We annotated 1579 verb forms in the Spanish source text for tense, and, subsequently, their translations in the other languages, distinguishing between two registers within the novel, i.e., dialogue and narration. We found that the vast majority of the Spanish tenses are translated one-to-one to their counterparts in the three languages, especially in narration. In dialogue, we found several deviations, which we could partially account for within an Optimality Theoretic approach by appealing to the notion of markedness along two different typological dimensions, namely, tense (present versus past) and aspect (imperfective versus perfective). Full article

Background: Gestational diabetes mellitus (GDM) is a pregnancy complication characterized by second trimester hyperglycemia. Untreated, GDM is related to an increased risk for adverse pregnancy outcomes. Both beta cell dysfunction and insulin resistance underlie impaired glucose tolerance. Understanding the dominant mechanism predisposing to GDM may be important to provide effective treatment in order to improve perinatal outcomes. We hypothesize that insulin resistance rather that beta cell dysfunction predisposes to GDM. Methods: A 75g oral glucose tolerance test (OGTT) was performed on 2112 second-trimester pregnant women to determine the relationship between insulin resistance (HOMA-IR), beta cell function (HOMA-β), and the prevalence of abnormal glucose handling. Results: High insulin resistance raised the risk of GDM (relative risk (RR) 6.1, 95% confidence interval (CI) (4.4–8.5)), as did beta cell dysfunction (RR 3.8, 95% CI (2.7–5.4)). High insulin resistance, but not beta cell function, enhances the necessity for additional glucose lowering medication on top of a low carbohydrate diet in women diagnosed with GDM. Conclusions: Both high insulin resistance and beta cell dysfunction increase the risk of GDM. As increased insulin resistance, rather than beta cell function, is related to an insufficient response to a low carbohydrate diet, we speculate that insulin sensitizers rather than insulin therapy may be the most targeted therapeutic modality in diet-insensitive GDM. Full article

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I–II melanoma) is watchful waiting, while >40% of patients with stage IB–IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I–II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I–II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4–96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3–84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41–6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a ‘low risk’ of recurrence (96.8% 5-year RFS (95%CI 91.6–98.8), n = 130), 49% as ‘intermediate risk’ (88.4% 5-year RFS (95%CI 83.6–91.8), n = 261), and 26% as ‘high risk’ (61.1% 5-year RFS (95%CI 51.9–69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I–II melanoma into two groups differentiated by RFS. Full article

Acute myeloid leukemia (AML) is a hematological malignancy caused by clonal expansion of myeloid progenitor cells. Most patients with AML respond to chemotherapy, but relapses often occur and infer a very poor prognosis. Thirty to thirty-five percent of AMLs carry a four base pair insertion in the nucleophosmin 1 gene (NPM1) with a C-terminal alternative reading frame of 11 amino acids. We previously identified various neopeptides from the alternative reading frame of mutant NPM1 (dNPM1) on primary AML and isolated an HLA-A*02:01-restricted T-cell receptor (TCR) that enables human T-cells to kill AML cells upon retroviral gene transfer. Here, we isolated T-cells recognizing the dNPM1 peptide AVEEVSLRK presented in HLA-A*11:01. The TCR cloned from a T-cell clone recognizing HLA-A*11:01+ primary AML cells conferred in vitro recognition and lysis of AML upon transfer to CD8 cells, but failed to induce an anti-tumor effect in immunodeficient NSG mice engrafted with dNPM1 OCI-AML3 cells. In conclusion, our data show that AVEEVSLRK is a dNPM1 neoantigen on HLA-A*11:01+ primary AMLs. CD8 cells transduced with an HLA-A*11:01-restricted TCR for dNPM1 were reactive against AML in vitro. The absence of reactivity in a preclinical mouse model requires further preclinical testing to predict the potential efficacy of this TCR in clinical development. Full article