Head and neck squamous cell carcinoma (HNSCC) is linked to significant morbidity, adversely affecting survival and functional capacity. Post-treatment challenges such as pain, dysphonia, and ...dysphagia are common, prompting increased attention in survivorship research. Quality of Life (QoL) questionnaires, especially the MD Anderson Dysphagia Inventory (MDADI), are prevalent outcome measures in clinical studies but often lack parallel objective swallowing function evaluations, leading to potential outcome discrepancies. This study aimed to illuminate the relationship between subjective QoL (EQ-5D-5L and MDADI) measures and objective swallowing function (evaluated via Fiberoptic Endoscopic Evaluation of Swallowing, FEES) in patients with HNSCC. The analysis revealed a notable discordance between objective measures of swallowing function, such as the Penetration-Aspiration Scale (PAS) and residue ratings in the vallecula or piriform sinus, and patients' subjective QoL assessments (
= 0.21). Despite the lack of correlation, swallowing-related QoL, as measured by the MDADI, was more indicative of disease severity than generic QoL assessments. Generic QoL scores did not demonstrate substantial variation between patients. In contrast, MDADI scores significantly declined with advancing tumor stage, multimodal therapy, and reliance on feeding tubes. However, the clinical significance of this finding was tempered by the less than 10-point difference in MDADI scores. The findings of this study underline the limitations of QoL measures as standalone assessments in patients with HNSCC, given their reliance on patient-perceived impairment. While subjective QoL is a crucial aspect of evaluating therapeutic success and patient-centric outcomes, it may fail to capture critical clinical details such as silent aspirations. Consequently, QoL assessments should be augmented by objective evaluations of swallowing function in clinical research and practice to ensure a holistic understanding of patient well-being and treatment impact.
Acquired von Willebrand syndrome (aVWS) has been reported in patients with congenital heart diseases associated with shear stress caused by significant blood flow gradients. Its etiology and impact ...on intraoperative bleeding during pediatric cardiac surgery have not been systematically studied. This single-center, prospective, observational study investigated appropriate diagnostic tools of aVWS compared with multimer analysis as diagnostic criterion standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0 to 12 months scheduled for cardiac surgery at our tertiary referral center from March 2018 to July 2019 were included in the analysis. The glycoprotein Ib M assay (GPIbM)/von Willebrand factor antigen (VWF:Ag) ratio provided the best predictability of aVWS (area under the receiver operating characteristic curve AUC, 0.81 95% CI, 0.75-0.86), followed by VWF collagen binding assay/VWF:Ag ratio (AUC, 0.70 0.63-0.77) and peak systolic echocardiographic gradients (AUC, 0.69 0.62-0.76). A cutoff value of 0.83 was proposed for the GPIbM/VWF:Ag ratio. Intraoperative high-molecular-weight multimer ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r = -0.57) and aortic cross-clamp time (r = -0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (P = .016) and fibrinogen concentrate (P = .011) than those without. The amounts of other administered blood components and chest closure times did not differ significantly. CPB appears to trigger aVWS in pediatric cardiac surgery. The GPIbM/VWF:Ag ratio is a reliable test that can be included in routine intraoperative laboratory workup. Our data provide the basis for further studies in larger patient cohorts to achieve definitive clarification of the effects of aVWS and its potential treatment on intraoperative bleeding.
The efficacy of Internet- and mobile-based interventions (IMIs) for depression in adults is well established. Yet, comprehensive knowledge on the mediators responsible for therapeutic change in these ...interventions is pending. Therefore, we conducted the first systematic review on mediators in IMIs for depression, investigating mechanisms of change in interventions with different theoretical backgrounds and delivery modes (PROSPERO CRD42019130301). Two independent reviewers screened references from five databases (i.e., Cochrane Library, Embase, MEDLINE/PubMed, PsycINFO and ICTRP), selected studies for inclusion and extracted data from eligible studies. We included 26 RCTs on mediators in IMIs for depression (6820 participants), rated their risk of bias and adherence to methodological quality criteria for psychotherapy process research. Primary studies examined 64 mediators, with cognitive variables (e.g., perceived control, rumination or interpretation bias) being the largest group of both examined (m = 28) and significant mediators (m = 22); followed by a range of other mediators, including mindfulness, acceptance and behavioral activation. Our findings might contribute to the empirically-informed advancement of interventions and mental health care practices, enabling optimized treatment outcomes for patients with depression. Furthermore, we discuss implications for future research and provide methodological recommendations for forthcoming mediation studies with more pertinent designs, allowing for inferences with higher causal specificity.
•Internet- and mobile-based interventions (IMIs) are efficacious in treating depression.•We conducted the first systematic review on mediators in various IMIs for depression.•Twenty-six RCTs evaluating 64 mediator variables were included in this review.•Cognitive factors are the largest group of both examined and significant mediators.•Implications and methodological recommendations for future process research are discussed.
Vesicle fusion is executed via formation of an Ω-shaped structure (Ω-profile), followed by closure (kiss-and-run) or merging of the Ω-profile into the plasma membrane (full fusion). Although ...Ω-profile closure limits release but recycles vesicles economically, Ω-profile merging facilitates release but couples to classical endocytosis for recycling. Despite its crucial role in determining exocytosis/endocytosis modes, how Ω-profile merging is mediated is poorly understood in endocrine cells and neurons containing small ∼30-300 nm vesicles. Here, using confocal and super-resolution STED imaging, force measurements, pharmacology and gene knockout, we show that dynamic assembly of filamentous actin, involving ATP hydrolysis, N-WASP and formin, mediates Ω-profile merging by providing sufficient plasma membrane tension to shrink the Ω-profile in neuroendocrine chromaffin cells containing ∼300 nm vesicles. Actin-directed compounds also induce Ω-profile accumulation at lamprey synaptic active zones, suggesting that actin may mediate Ω-profile merging at synapses. These results uncover molecular and biophysical mechanisms underlying Ω-profile merging.
Hematopoietic stem cells give rise to all blood cells in a differentiation process that involves widespread epigenome remodeling. Here we present genome-wide reference maps of the associated DNA ...methylation dynamics. We used a meta-epigenomic approach that combines DNA methylation profiles across many small pools of cells and performed single-cell methylome sequencing to assess cell-to-cell heterogeneity. The resulting dataset identified characteristic differences between HSCs derived from fetal liver, cord blood, bone marrow, and peripheral blood. We also observed lineage-specific DNA methylation between myeloid and lymphoid progenitors, characterized immature multi-lymphoid progenitors, and detected progressive DNA methylation differences in maturing megakaryocytes. We linked these patterns to gene expression, histone modifications, and chromatin accessibility, and we used machine learning to derive a model of human hematopoietic differentiation directly from DNA methylation data. Our results contribute to a better understanding of human hematopoietic stem cell differentiation and provide a framework for studying blood-linked diseases.
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•Sequencing provides DNA methylation maps of hematopoietic stem and progenitor cells•Methylation differs in HSCs from fetal liver, bone marrow, cord, and peripheral blood•Myeloid and lymphoid progenitors are distinguished by enhancer-linked DNA methylation•Machine learning enables data-driven reconstruction of the hematopoietic lineage
As part of the IHEC consortium, Bock and colleagues present genome-wide reference maps of DNA methylation dynamics during human blood development. The characteristic DNA methylation patterns they see in the different cell types allow data-driven inference of an epigenome-based model of hematopoietic differentiation. Explore the IHEC web portal at http://www.cell.com/consortium/IHEC.
Mesenchymal cells contribute to the 'stroma' of most normal and malignant tissues, with specific mesenchymal cells participating in the regulatory niches of stem cells. By examining how mesenchymal ...osteolineage cells modulate haematopoiesis, here we show that deletion of Dicer1 specifically in mouse osteoprogenitors, but not in mature osteoblasts, disrupts the integrity of haematopoiesis. Myelodysplasia resulted and acute myelogenous leukaemia emerged that had acquired several genetic abnormalities while having intact Dicer1. Examining gene expression altered in osteoprogenitors as a result of Dicer1 deletion showed reduced expression of Sbds, the gene mutated in Schwachman-Bodian-Diamond syndrome-a human bone marrow failure and leukaemia pre-disposition condition. Deletion of Sbds in mouse osteoprogenitors induced bone marrow dysfunction with myelodysplasia. Therefore, perturbation of specific mesenchymal subsets of stromal cells can disorder differentiation, proliferation and apoptosis of heterologous cells, and disrupt tissue homeostasis. Furthermore, primary stromal dysfunction can result in secondary neoplastic disease, supporting the concept of niche-induced oncogenesis.
Experimental studies suggest involvement of trimethylamine N-oxide (TMAO) in the aetiology of cardiometabolic diseases and chronic kidney disease (CKD), in part via metabolism of ingested food. Using ...a comparative biomimetic approach, we have investigated circulating levels of the gut metabolites betaine, choline, and TMAO in human CKD, across animal species as well as during hibernation in two animal species. Betaine, choline, and TMAO levels were associated with renal function in humans and differed significantly across animal species. Free-ranging brown bears showed a distinct regulation pattern with an increase in betaine (422%) and choline (18%) levels during hibernation, but exhibited undetectable levels of TMAO. Free-ranging brown bears had higher betaine, lower choline, and undetectable TMAO levels compared to captive brown bears. Endogenously produced betaine may protect bears and garden dormice during the vulnerable hibernating period. Carnivorous eating habits are linked to TMAO levels in the animal kingdom. Captivity may alter the microbiota and cause a subsequent increase of TMAO production. Since free-ranging bears seems to turn on a metabolic switch that shunts choline to generate betaine instead of TMAO, characterisation and understanding of such an adaptive switch could hold clues for novel treatment options in burden of lifestyle diseases, such as CKD.
The bladder exstrophy-epispadias complex (BEEC) represents the severe end of the uro-rectal malformation spectrum, and is thought to result from aberrant embryonic morphogenesis of the cloacal ...membrane and the urorectal septum. The most common form of BEEC is isolated classic bladder exstrophy (CBE). To identify susceptibility loci for CBE, we performed a genome-wide association study (GWAS) of 110 CBE patients and 1,177 controls of European origin. Here, an association was found with a region of approximately 220kb on chromosome 5q11.1. This region harbors the ISL1 (ISL LIM homeobox 1) gene. Multiple markers in this region showed evidence for association with CBE, including 84 markers with genome-wide significance. We then performed a meta-analysis using data from a previous GWAS by our group of 98 CBE patients and 526 controls of European origin. This meta-analysis also implicated the 5q11.1 locus in CBE risk. A total of 138 markers at this locus reached genome-wide significance in the meta-analysis, and the most significant marker (rs9291768) achieved a P value of 2.13 × 10-12. No other locus in the meta-analysis achieved genome-wide significance. We then performed murine expression analyses to follow up this finding. Here, Isl1 expression was detected in the genital region within the critical time frame for human CBE development. Genital regions with Isl1 expression included the peri-cloacal mesenchyme and the urorectal septum. The present study identified the first genome-wide significant locus for CBE at chromosomal region 5q11.1, and provides strong evidence for the hypothesis that ISL1 is the responsible candidate gene in this region.
Background
There is limited evidence on the cost effectiveness of Internet‐based treatments for depression. The aim was to evaluate the cost effectiveness of guided Internet‐based interventions for ...depression compared to controls.
Methods
Individual–participant data from five randomized controlled trials (RCT), including 1,426 participants, were combined. Cost‐effectiveness analyses were conducted at 8 weeks, 6 months, and 12 months follow‐up.
Results
The guided Internet‐based interventions were more costly than the controls, but not statistically significant (12 months mean difference = €406, 95% CI: − 611 to 1,444). The mean differences in clinical effects were not statistically significant (12 months mean difference = 1.75, 95% CI: − .09 to 3.60 in Center for Epidemiologic Studies Depression Scale CES‐D score, .06, 95% CI: − .02 to .13 in response rate, and .00, 95% CI: − .03 to .03 in quality‐adjusted life‐years QALYs). Cost‐effectiveness acceptability curves indicated that high investments are needed to reach an acceptable probability that the intervention is cost effective compared to control for CES‐D and response to treatment (e.g., at 12‐month follow‐up the probability of being cost effective was .95 at a ceiling ratio of 2,000 €/point of improvement in CES‐D score). For QALYs, the intervention's probability of being cost effective compared to control was low at the commonly accepted willingness‐to‐pay threshold (e.g., at 12‐month follow‐up the probability was .29 and. 31 at a ceiling ratio of 24,000 and 35,000 €/QALY, respectively).
Conclusions
Based on the present findings, guided Internet‐based interventions for depression are not considered cost effective compared to controls. However, only a minority of RCTs investigating the clinical effectiveness of guided Internet‐based interventions also assessed cost effectiveness and were included in this individual–participant data meta‐analysis.
Psoriasis is a stigmatized skin disease. This randomized controlled trial aimed to evaluate an Instagram based stigma-reduction intervention targeting daily Instagram users aged 18 to 49 years ...without psoriasis. After stratification for baseline characteristics (t0), stigmatization of psoriasis was assessed using a questionnaire and a photo-rating task immediately before (t1) and after (t2) the intervention and two weeks post-intervention (t3). Data from 54 participants, recruited in a university setting and via Instagram, were analysed. For 10 min between t1 and t2, the intervention group (n = 26) and the control group (n = 28) scrolled through two different Instagram accounts. Psoriasis-sensitizing content was displayed to the intervention group while beauty-glorifying posts were shown to the control group. Results indicated significantly less Disease-related Misconceptions in the intervention group in comparison to the control group at t2 (U = 145.50, Z = -3.79, p < 0.001) and at t3 (U = 177.00, Z = -3.25, p = 0.003). Moreover, the intervention group showed a significant reduction over time in Stereotype Endorsement (F(2, 50) = 13.40, p < 0.001, partial η² = 0.35) and Disease-related Misconceptions (χ2(2) = 12.64, p = 0.002). These findings suggest that addressing psoriasis on Instagram has the potential to effectively reduce the related stigmatization. Further studies are necessary to assess the impact of social media on stigmatization concerning psoriasis in more depth.
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