An In Vitro Study of Retention and Marginal Adaptation of Endocrowns With Different Intracoronal Depths.

BACKGROUND: Marginal adaptation and retention of endocrowns are crucial for the success and survival of endocrowns. This study aimed to investigate the effect of different materials and intracoronal depth on the retention and marginal adaptation of CAD/CAM fabricated all-ceramic endocrowns. METHODS: Thirty-six mandibular premolar teeth with an average surface area of 64.49 mm² were prepared to receive CAM/CAM fabricated endocrowns. Samples were divided randomly and equally into groups of lithium disilicate with 2 mm intracoronal depth (LD2), lithium disilicate with 4 mm intracoronal depth (LD4), polymer infiltrated ceramic network with 2 mm intracoronal depth (PICN2) and polymer infiltrated ceramic network with 4 mm intracoronal depth (PICN4). All endocrowns were cemented using ParaCore resin cement with 14N pressure and cured for 20 seconds. Fifty measurements of absolute marginal discrepancy (AMD) were done using a stereomicroscope after cementation. After 24 hours, all samples were subjected to thermocycling before the retention test. This involved using a universal testing machine with a crosshead speed of 0.5 mm/min and applying a load of 500N. The maximum force to detach the crown was recorded in newtons and the mode of failure was identified. RESULTS: Two-way ANOVA revealed that the AMD for PICN was statistically significantly better than lithium disilicate (p=0.01). No statistically significant difference was detected in the AMD between the two intracoronal depths (p=0.72). PICN and endocrowns with 4 mm intracoronal depth had statistically significant better retention (p<0.05). 72.22% of the sample suffered from cohesive failures and 10 LD endocrowns suffered adhesive failures. CONCLUSIONS: Within the limitations of this study, we found that different materials and intracoronal depths can indeed influence the retention of CAD/CAM fabricated endocrowns. Based on the controlled setting findings, PICN was found to have better retention and better marginal adaptation than similar lithium disilicate premolar endocrowns.

Nile tilapia and gilthead seabream dietary self-selection of alternative feeds.

Classical assessments of new fish feeds are anthropocentric, focusing mainly on growth. Although this methodology is accurate, it does not consider the fish' perspective. This study aimed to investigate the behavioural responses and feed preferences of Nile tilapia (Oreochromis niloticus) and gilthead seabream (Sparus aurata) through a self-selection trial using self-feeders. Both species were offered three feeds: a control (PD) commercial-like feed and two diets (ORG1 and ORG2) formulated with different inclusions of alternative ingredients to address some of the current environmental concerns and/or ethical issues often associated with commercial formulations. Three groups of tilapia with an average weight of 163.0 g ± 4.3 g (mean ± SD) and four groups of seabreams with 174.7 g ± 27.0 g were tested. Tilapia exhibited a preference for ORG2 (46.5%), influenced by the sensory properties of the feed and post-ingestion signals. Seabream did not show a preference for any feed. These findings highlight the effectiveness of self-selection experiments in allowing fish to express their feeding behaviour and preferences. Therefore, this approach should be considered in the initial screening and design of new aquaculture feeds and ingredients.

Adenovirus infections after allogeneic hematopoietic cell transplantation in children and adults: a study from the Infectious Diseases Working Party of the European Society for Blood and Marrow Transplantation.

The objective of the study was the analysis of clinical types, outcomes, and risk factors associated with the outcome of adenovirus (ADV) infection, in children and adults after allo-HCT. A total number of 2529 patients (43.9% children; 56.1% adults) transplanted between 2000 and 2022 reported to the EBMT database with diagnosis of ADV infection were analyzed. ADV infection manifested mainly as viremia (62.6%) or gastrointestinal infection (17.9%). The risk of 1-year mortality was higher in adults (p = 0.0001), and in patients with ADV infection developing before day +100 (p < 0.0001). The 100-day overall survival after diagnosis of ADV infections was 79.2% in children and 71.9% in adults (p < 0.0001). Factors contributing to increased risk of death by day +100 in multivariate analysis, in children: CMV seropositivity of donor and/or recipient (p = 0.02), and Lansky/Karnofsky score <90 (p < 0.0001), while in adults: type of ADV infection (viremia or pneumonia vs gastrointestinal infection) (p = 0.0004), second or higher HCT (p = 0.0003), and shorter time from allo-HCT to ADV infection (p = 0.003). In conclusion, we have shown that in patients infected with ADV, short-term survival is better in children than adults. Factors directly related to ADV infection (time, clinical type) contribute to mortality in adults, while pre-transplant factors (CMV serostatus, Lansky/Karnofsky score) contribute to mortality in children.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Shared effects of electroconvulsive shocks and ketamine on neuroplasticity: A Systematic Review of Animal Models of Depression.

Electroconvulsive shocks (ECS) and ketamine are antidepressant treatments with a relatively fast onset of therapeutic effects compared to conventional medication and psychotherapy. While the exact neurobiological mechanisms underlying the antidepressant response of ECS and ketamine are unknown, both interventions are associated with neuroplasticity. Restoration of neuroplasticity may be a shared mechanism underlying the antidepressant efficacy of these interventions. In this systematic review, literature of animal models of depression is summarized to examine the possible role of neuroplasticity in ECS and ketamine on a molecular, neuronal, synaptic and functional level, and specifically to what extent these mechanisms are shared between both interventions. The results highlight that hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF) levels are consistently increased after ECS and ketamine. Moreover, both interventions positively affect glutamatergic neurotransmission, astrocyte and neuronal morphology, synaptic density, vasculature and functional plasticity. However, a small number of studies investigated these processes after ECS. Understanding the shared fundamental mechanisms of fast-acting antidepressants can contribute to the development of novel therapeutic approaches for patients with severe depression.

Relation between the internal anal sphincter and defecation disorders in patients with anorectal malformations.

OBJECTIVES: To investigate associations between the rectoanal inhibitory reflex (RAIR), type of congenital anorectal malformations (ARMs), type of operation that patients with ARM had undergone, and objectively measured fecal incontinence and defecation problems. METHODS: We retrospectively included 69 pediatric patients with ARM. All underwent anorectal function tests at the University Medical Center of Groningen during the last 10 years. We assessed anorectal physiology using the Rome IV criteria and anorectal function tests. RESULTS: We found the reflex in 67% of patients and all types of ARMs. All patients who had not been operated on, and those who had undergone less extensive surgery possessed the reflex. In contrast, patients who underwent posterior sagittal anorectoplasty, 44% possessed it. We found no difference between mean rectal volumes in patients with and without the reflex (251 mL vs. 325 mL, respectively, p = 0.266). We found that over time, patients without the reflex seemed to develop significantly higher rectal volumes than patients who had it. We did not find a significant difference between the reflex and fecal incontinence; however, it seems that the absence of the reflex, resting anal sphincter pressure, and fecal incontinence are related. CONCLUSION: The RAIR seems present in patients with ARM irrespective of their malformation type. Corrective surgery, however, may impair this reflex. Seemingly, its absence results in constipation with enlarged rectal volumes and fecal incontinence. Every effort should be made to preserve this reflex during surgery and to use extensive surgical procedures as sparingly as possible.

Burden re-analysis of neurodevelopmental disorder cohorts for prioritization of candidate genes.

This study aimed to uncover novel genes associated with neurodevelopmental disorders (NDD) by leveraging recent large-scale de novo burden analysis studies to enhance a virtual gene panel used in a diagnostic setting. We re-analyzed historical trio-exome sequencing data from 745 individuals with NDD according to the most recent diagnostic standards, resulting in a cohort of 567 unsolved individuals. Next, we designed a virtual gene panel containing candidate genes from three large de novo burden analysis studies in NDD and prioritized candidate genes by stringent filtering for ultra-rare de novo variants with high pathogenicity scores. Our analysis revealed an increased burden of de novo variants in our selected candidate genes within the unsolved NDD cohort and identified qualifying de novo variants in seven candidate genes: RIF1, CAMK2D, RAB11FIP4, AGO3, PCBP2, LEO1, and VCP. Clinical data were collected from six new individuals with de novo or inherited LEO1 variants and three new individuals with de novo PCBP2 variants. Our findings add additional evidence for LEO1 as a risk gene for autism and intellectual disability. Furthermore, we prioritize PCBP2 as a candidate gene for NDD associated with motor and language delay. In summary, by leveraging de novo burden analysis studies, employing a stringent variant filtering pipeline, and engaging in targeted patient recruitment, our study contributes to the identification of novel genes implicated in NDDs.

Diagnostic criteria and long-term outcomes in AIH-PBC variant syndrome under combination therapy.

Background & Aims: Autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) can co-exist in AIH-PBC, requiring combined treatment with immunosuppression and ursodeoxycholic acid (UDCA). The Paris criteria are commonly used to identify these patients; however, the optimal diagnostic criteria are unknown. We aimed to evaluate the use and clinical relevance of both Paris and Zhang criteria. Methods: Eighty-three patients with a clinical suspicion of AIH-PBC who were treated with combination therapy were included. Histology was re-evaluated. Characteristics and long-term outcomes were retrospectively compared to patients with AIH and PBC. Results: Seventeen (24%) patients treated with combination therapy fulfilled the Paris criteria. Fifty-two patients (70%) fulfilled the Zhang criteria. Patients who met Paris and Zhang criteria more often had inflammation and fibrosis on histology compared to patients only meeting the Zhang criteria. Ten-year liver transplant (LT)-free survival was 87.3% (95% CI 78.9-95.7%) in patients with AIH-PBC. This did not differ in patients in or outside the Paris or Zhang criteria (p = 0.46 and p = 0.40, respectively) or from AIH (p = 0.086). LT-free survival was significantly lower in patients with PBC and severe hepatic inflammation - not receiving immunosuppression - compared to those with AIH-PBC (65%; 95% CI 52.2-77.8% vs. 87%; 95% CI 83.2-90.8%; hazard ratio 0.52; p = 0.043). Conclusions: In this study, patients with AIH-PBC outside Paris or Zhang criteria were frequently labeled as having AIH-PBC and were successfully treated with combination therapy with similar outcomes. LT-free survival was worse in patients with PBC and hepatic inflammation than in those treated as having AIH-PBC. More patients may benefit from combination therapy. Impact and implications: This study demonstrated that patients with AIH-PBC variant syndrome treated with combined therapy consisting of immunosuppressants and ursodeoxycholic acid often do not fulfill the Paris criteria. They do however have comparable response to therapy and long-term outcomes as patients who do fulfill the diagnostic criteria. Additionally, patients with PBC and additional signs of hepatic inflammation have poorer long-term outcomes compared to patients treated as having AIH-PBC. These results implicate that a larger group of patients with features of both AIH and PBC may benefit from combined treatment. With our results, we call for improved consensus among experts in the field on the diagnosis and management of AIH-PBC variant syndrome.

Advice after urgent suspected cancer referral when cancer is not found in England: Survey of patients' preferences and perceived acceptability.

Objective: No standardised approach exists to provide advice after urgent suspected cancer (USC) referral when cancer is not found. This study aimed to assess preferences and acceptability of receiving advice after USC referral related to: 1) managing ongoing symptoms, 2) responding to early symptoms of other cancers, 3) cancer screening, 4) reducing risks of future cancer. Methods: 2,541 patients from two English NHS Trusts were mailed a survey 1-3 months after having no cancer found following urgent suspected gastrointestinal or head and neck cancer referral. Participants were asked about: willingness to receive advice; prospective acceptability; preferences related to mode, timing and who should provide advice; and previous advice receipt. Results: 406 patients responded (16.0%) with 397 in the final analyses. Few participants had previously received advice, yet most were willing to. Willingness varied by type of advice: fewer were willing to receive advice about early symptoms of other cancers (88.9%) than advice related to ongoing symptoms (94.3%). Acceptability was relatively high for all advice types. Reducing the risk of future cancer advice was more acceptable. Acceptability was lower in those from ethnic minority groups, and with lower levels of education. Most participants preferred to receive advice from a doctor; with results or soon after; either face to face or via the telephone. Conclusions: There is a potential unmet need for advice after USC referral when no cancer is found. Equitable intervention design should focus on increasing acceptability for people from ethnic minority groups and those with lower levels of education.

Hematopoietic stem cell transplantation for DLBCL: a report from the European Society for Blood and Marrow Transplantation on more than 40,000 patients over 32 years.

Autologous(auto-) and allogeneic(allo-) hematopoietic stem cell transplantation (HSCT) are key treatments for relapsed/refractory diffuse large B-cell lymphoma (DLBCL), although their roles are challenged by CAR-T-cells and other immunotherapies. We examined the transplantation trends and outcomes for DLBCL patients undergoing auto-/allo-HSCT between 1990 and 2021 reported to EBMT. Over this period, 41,148 patients underwent auto-HSCT, peaking at 1911 cases in 2016, while allo-HSCT saw a maximum of 294 cases in 2018. The recent decline in transplants corresponds to increased CAR-T treatments (1117 cases in 2021). Median age for auto-HSCT rose from 42 (1990-1994) to 58 years (2015-2021), with peripheral blood becoming the primary stem cell source post-1994. Allo-HSCT median age increased from 36 (1990-1994) to 54 (2015-2021) years, with mobilized blood as the primary source post-1998 and reduced intensity conditioning post-2000. Unrelated and mismatched allo-HSCT accounted for 50% and 19% of allo-HSCT in 2015-2021. Three-year overall survival (OS) after auto-HSCT improved from 56% (1990-1994) to 70% (2015-2021), p < 0.001, with a decrease in relapse incidence (RI) from 49% to 38%, while non-relapse mortality (NRM) remained unchanged (4%). After allo-HSCT, 3-year-OS increased from 33% (1990-1999) to 46% (2015-2021) (p < 0.001); 3-year RI remained at 39% and 1-year-NRM decreased to 19% (p < 0.001). Our data reflect advancements over 32 years and >40,000 transplants, providing insights for evaluating emerging DLBCL therapies.

Neuroimaging and fluid biomarkers in Parkinson's disease in an era of targeted interventions.

A major challenge in Parkinson's disease is the variability in symptoms and rates of progression, underpinned by heterogeneity of pathological processes. Biomarkers are urgently needed for accurate diagnosis, patient stratification, monitoring disease progression and precise treatment. These were previously lacking, but recently, novel imaging and fluid biomarkers have been developed. Here, we consider new imaging approaches showing sensitivity to brain tissue composition, and examine novel fluid biomarkers showing specificity for pathological processes, including seed amplification assays and extracellular vesicles. We reflect on these biomarkers in the context of new biological staging systems, and on emerging techniques currently in development.

Assessment of the chemical composition of buriti (Mauritia flexuosa Liliopsida) and cassava (Manihot esculenta Crantz) residues and their possible application in the bioproduction of coconut aroma (6 pentyl-α-pyrone).

This work aimed to define strategies to increase the bioproduction of 6 pentyl-α-pyrone (bioaroma). As first strategy, fermentations were carried out in the solid state, with agro-industrial residues: Mauritia flexuosa Liliopsida. and Manihot esculenta Crantz in isolation, conducting them with different nutrient solutions having Trichoderma harzianum as a fermenting fungus. Physicochemical characterizations, centesimal composition, lignocellulosic and mineral content and antimicrobial activity were required. Fermentations were conducted under different humidification conditions (water, nutrient solution without additives and nutrient solutions with glucose or sucrose) for 9 days. Bioaroma was quantified by gas chromatography, assisted by solid-phase microextraction. The results showed the low production of this compound in fermentations conducted with sweet cassava (around 6 ppm (w/w)). The low bioproduction with sweet cassava residues can probably be related to its starch-rich composition, homogeneous substrate, and low concentration of nutrients. Already using buriti, the absence of aroma production was detected. Probably the presence of silicon and high lignin content in buriti minimized the fungal activity, making it difficult to obtain the aroma of interest. Given the characteristics presented by the waste, a new strategy was chosen: mixing waste in a 1:1 ratio. This fermentation resulted in the production of 156.24 ppm (w/w) of aroma using the nutrient solution added with glucose. This combination, therefore, promoted more favorable environment for the process, possibly due to the presence of fermentable sugars from sweet cassava and fatty acids from the buriti peel, thus proving the possibility of an increase of around 2500% in the bioproduction of coconut aroma.

The effect of hydrostatic pressure on lipid membrane lateral structure.

High pressure is both an environmental challenge to which deep sea biology has to adapt, and a highly sensitive thermodynamic tool that can be used to trigger structural changes in biological molecules and assemblies. Lipid membranes are amongst the most pressure sensitive biological assemblies and pressure can have a large influence on their structure and properties. In this chapter, we will explore the use of high pressure small angle X-ray diffraction and high pressure microscopy to measure and quantify changes in the lateral structure of lipid membranes under both equilibrium high pressure conditions and in response to pressure jumps.

The impact of saline and water stress on the agronomic performance of beet crops.

Excessive salts in irrigation water and water stress have a negative impact on the productive yield of agricultural crops. In this regard, the objective was to evaluate the effect of combined saline and water stress on the agronomic performance of the beet crop. The experiment was conducted in a greenhouse located at the Universidade da Integração Internacional da Lusofonia Afro-Brasileira, in Redenção, Ceará. The experimental design used was completely randomized with split-plots arrangement. The main plots were formed by the electrical conductivities of the irrigation water (0.8, 1.5, 3.0, 4.5, and 6.0 dS m-1), while the irrigation depths of 50 and 100% of the crop evapotranspiration (ETc) were the subplots, with 6 replications. Saline stress negatively affected growth, biomass, tuber root length, and productivity, while increasing the soluble solids of the beet crop. Excessive salts in the irrigation water caused reductions in physiological indices of the beet crop, although with less severity under the 100% ETc.

Calcineurin and CK2 reciprocally regulate synaptic AMPA receptor phenotypes via α2δ-1 in spinal excitatory neurons.

Calcineurin inhibitors, such as cyclosporine and tacrolimus (FK506), are commonly used immunosuppressants for preserving transplanted organs and tissues. However, these drugs can cause severe and persistent pain. GluA2-lacking, calcium-permeable AMPA receptors (CP-AMPARs) are implicated in various neurological disorders, including neuropathic pain. It is unclear whether and how constitutive calcineurin, a Ca2+/calmodulin protein phosphatase, controls synaptic CP-AMPARs. In this study, we found that blocking CP-AMPARs with IEM-1460 markedly reduced the amplitude of AMPAR-EPSCs in excitatory neurons expressing vesicular glutamate transporter-2 (VGluT2), but not in inhibitory neurons expressing vesicular GABA transporter, in the spinal cord of FK506-treated male and female mice. FK506 treatment also caused an inward rectification in the current-voltage relationship of AMPAR-EPSCs specifically in VGluT2 neurons. Intrathecal injection of IEM-1460 rapidly alleviated pain hypersensitivity in FK506-treated mice. Furthermore, FK506 treatment substantially increased physical interaction of α2δ-1 with GluA1 and GluA2 in the spinal cord and reduced GluA1/GluA2 heteromers in endoplasmic reticulum-enriched fractions of spinal cords. Correspondingly, inhibiting α2δ-1 with pregabalin, Cacna2d1 genetic knockout, or disrupting α2δ-1-AMPAR interactions with an α2δ-1 C-terminus peptide reversed inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons caused by FK506 treatment. In addition, CK2 inhibition reversed FK506 treatment-induced pain hypersensitivity, α2δ-1 interactions with GluA1 and GluA2, and inward rectification of AMPAR-EPSCs in spinal VGluT2 neurons. Thus, the increased prevalence of synaptic CP-AMPARs in spinal excitatory neurons plays a major role in calcineurin inhibitor-induced pain hypersensitivity. Calcineurin and CK2 antagonistically regulate postsynaptic CP-AMPARs through α2δ-1-mediated GluA1/GluA2 heteromeric assembly in the spinal dorsal horn.Significance Statement Clinically used calcineurin inhibitors can cause severe pain, known as calcineurin inhibitor-induced pain syndrome (CIPS). However, its underlying mechanisms remain elusive. This study shows for the first time that calcineurin inhibition caused cell type-specific expression of synaptic Ca2+-permeable AMPARs in spinal cord excitatory neurons. Blocking spinal Ca2+-permeable AMPARs reduced CIPS. Calcineurin inhibition potentiated the α2δ-1 (previously known as a calcium channel subunit) interaction with GluA1 and GluA2 subunits, disrupting their intracellular assembly in the spinal cord. Additionally, inhibiting spinal CK2 diminished α2δ-1-AMPAR interactions and synaptic Ca2+-permeable AMPARs augmented by calcineurin inhibitors. Thus, calcineurin and CK2 dynamically control AMPAR phenotypes in spinal excitatory neurons through α2δ-1-mediated GluA1/GluA2 assembly. Targeting α2δ-1 and CK2 are effective strategies for treating CIPS.

Primary central nervous system lymphomas: EHA-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.

This EHA-ESMO Clinical Practice Guideline provides key recommendations for managing primary DLBCL of the CNS.The guideline covers clinical, imaging and pathological diagnosis, staging and risk assessment, treatment and follow-up.Algorithms for first-line and salvage treatments are provided.The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.Recommendations are based on available scientific data and the authors' collective expert opinion.

Exploring the role of clinical and demographic characteristics on the effects of virtual reality cognitive behavioral therapy for psychosis: A moderator analysis.

BACKGROUND: Virtual Reality cognitive behavioral therapy (VR-CBT) has proven to be an effective treatment method for paranoia and anxiety in psychosis. However, it is unknown, which individuals benefit most from VR-CBT. Previous studies examined factors affecting the treatment effect of regular CBTp, including illness duration, paranoia, depression, and pre-therapy avoidance behaviors, but results are inconsistent. The study aims to investigate the factors that influence the effectiveness of VR-CBT. METHODS: A total of 95 participants with a psychotic disorder and at least moderate paranoia (GTPS >40) were included in this explorative study. Data were collected as part of a multicenter randomized controlled trial in which participants were assigned to VR-CBT or treatment as usual (TAU). The VR-CBT group received 16 sessions of individual treatment. A moderator analysis was conducted to examine the influence of baseline demographic (age, gender, and education level) and clinical characteristics (duration of illness, paranoia, anxiety, depression, safety behavior, self-esteem, and social functioning) on treatment effects of paranoia and anxiety as measured with questionnaires and the experience sampling method (ESM) directly after treatment (12 weeks after baseline). RESULTS: More use of safety behavior at baseline resulted in greater benefits of VR-CBT on paranoid ideation and ESM paranoia. A higher age was associated with greater benefits of VR-CBT on social anxiety but not paranoia outcomes. There was no consistent evidence of moderation by any of the other sociodemographic or clinical variables for paranoid ideation and social anxiety. CONCLUSIONS: Our findings suggest that a diverse spectrum of patients, with different backgrounds and symptom severity may be able to benefit from VR-CBT. VR-CBT can be recommended to a broad spectrum of patients with psychotic disorders, and particularly those with high levels of safety behaviors, including severe avoidance, seem to benefit more.