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Kerstin Kutsche and colleagues report that mutations in GRIN2A and GRIN2B cause variable neurodevelopmental phenotypes including mental retardation and epilepsy. GRIN2A and GRIN2B encode regulatory subunits of N-methyl-D-aspartate (NMDA) receptors, which mediate excitatory neurotransmission in the brain. N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca 2+ -permeable cation channels which are blocked by extracellular Mg 2+ in a voltage-dependent manner 1 . Either GRIN2B or GRIN2A , encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A N615K (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg 2+ block and a decrease in Ca 2+ permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.

ObjectivesTreat-to-target recommendations have identified ‘remission’ as a target in systemic lupus erythematosus (SLE), but recognise that there is no universally accepted definition for this. Therefore, we initiated a process to achieve consensus on potential definitions for remission in SLE.MethodsAn international task force of 60 specialists and patient representatives participated in preparatory exercises, a face-to-face meeting and follow-up electronic voting. The level for agreement was set at 90%.ResultsThe task force agreed on eight key statements regarding remission in SLE and three principles to guide the further development of remission definitions:1. Definitions of remission will be worded as follows: remission in SLE is a durable state characterised by …………………. (reference to symptoms, signs, routine labs).2. For defining remission, a validated index must be used, for example, clinical systemic lupus erythematosus disease activity index (SLEDAI)=0, British Isles lupus assessment group (BILAG) 2004 D/E only, clinical European consensus lupus outcome measure (ECLAM)=0; with routine laboratory assessments included, and supplemented with physician's global assessment.3. Distinction is made between remission off and on therapy: remission off therapy requires the patient to be on no other treatment for SLE than maintenance antimalarials; and remission on therapy allows patients to be on stable maintenance antimalarials, low-dose corticosteroids (prednisone ≤5 mg/day), maintenance immunosuppressives and/or maintenance biologics.The task force also agreed that the most appropriate outcomes (dependent variables) for testing the prognostic value (construct validity) of potential remission definitions are: death, damage, flares and measures of health-related quality of life.ConclusionsThe work of this international task force provides a framework for testing different definitions of remission against long-term outcomes.

ObjectiveTo achieve consensus on a definition of remission in SLE (DORIS).BackgroundRemission is the stated goal for both patient and caregiver, but consensus on a definition of remission has been lacking. Previously, an international task force consisting of patient representatives and medical specialists published a framework for such a definition, without reaching a final recommendation.MethodsSeveral systematic literature reviews were performed and specific research questions examined in suitably chosen data sets. The findings were discussed, reformulated as recommendations and voted on.ResultsBased on data from the literature and several SLE-specific data sets, a set of recommendations was endorsed. Ultimately, the DORIS Task Force recommended a single definition of remission in SLE, based on clinical systemic lupus erythematosus disease activitiy index (SLEDAI)=0, Evaluator’s Global Assessment <0.5 (0–3), prednisolone 5 mg/day or less, and stable antimalarials, immunosuppressives, and biologics.ConclusionThe 2021 DORIS definition of remission in SLE is recommended for use in clinical care, education, and research including clinical trials and observational studies.

BackgroundElevated pre-treatment baseline inflammation has been associated with cancer therapy-related cardiac dysfunction (CTRCD) in patients with breast cancer. Monocyte-to-lymphocyte ratio (MLR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio and systemic immune-inflammation index (NLR × platelets) have emerged in clinical context as markers of disease-related inflammation. ObjectivesTo evaluate development of CTRCD according to pre-treatment blood inflammatory biomarkers in patients with breast cancer. MethodsPilot cohort study including consecutive female patients ≥ 18 years with HER2-positive early breast cancer who consulted at the institution's breast oncology outpatient clinic between march/2019 and march/2022. CTRCD: absolute reduction in LVEF > 10% to below 53% (2D-echocardiogram). Survival analysis was performed using Kaplan–Meier curves, compared by the log-rank test, and discrimination ability was evaluated through AUC-ROC.ResultsForty-nine patients (53.3 ± 13.3 y) were included and followed-up for a median of 13.2 months. CTRCD was observed in 6 (12.2%) patients. Patients with high blood inflammatory biomarkers had lower CTRCD-free survival (P < 0.050 for all). MLR showed statistically significant AUC (0.802; P = 0.017). CTRCD was observed in 27.8% of patients with high MLR versus 3.2% with low MLR (P = 0.020); negative predictive value was 96.8% (95%CI 83.3–99.4%).ConclusionIn patients with breast cancer, elevated pre-treatment inflammatory markers were associated with increased risk of cardiotoxicity. Among these markers, MLR had good discriminatory performance and high negative predictive value. The incorporation of MLR might improve risk evaluation and selection of patients for follow-up during cancer therapy.

The vast and ever-growing amount of agricultural and food wastes has become a major concern throughout the whole world. Therefore, strategies for their processing and value-added reuse are needed to enable a sustainable utilization of feedstocks and reduce the environmental burden. By-products of potato, tomato, cereals and olive arise in significant amounts in European countries and are consequently of high relevance. Due to their composition with various beneficial ingredients, the waste products can be valorized by different techniques leading to economic and environmental advantages. This paper focuses on the waste generation during industrial processing of potato, tomato, cereals and olives within the European Union and reviews state-of-the-art technologies for their valorization. Furthermore, current applications, future perspectives and challenges are discussed.

Recent data revealed the importance of immune reconstitution (IR) for the evaluation of possible biomarkers in National Institutes of Health (NIH)-defined chronic graft-vs.-host disease (cGVHD) and its clinical aspects. In this large pediatric study ( = 146), we have analyzed whether cellular and humoral parameters of IR in the long-term follow-up (FU) with a special emphasis on B-cell reconstitution correlate with NIH-defined cGVHD criteria. HYPOTHESIS: we were especially interested in whether meaningful cGVHD biomarkers could be defined in a large pediatric cohort. We here demonstrate for the first time in a highly homogenous pediatric patient cohort that both cGVHD ( = 38) and its activity were associated with the perturbation of the B-cell compartment, including low frequencies of CD19 CD27 memory B-cells and increased frequencies of circulating CD19 CD21 B-cells, a well-known hyperactivated B-cell subset frequently found elevated in chronic infection and autoimmunity. Notably, resolution of cGVHD correlated with expansion of CD19 CD27 memory B-cells and normalization of CD19 CD21 B-cell frequencies. Moreover, we found that the severity of cGVHD had an impact on parameters of IR and that severe cGVHD was associated with increased CD19 CD21 B-cell frequencies. When comparing the clinical characteristics of the active and non-active cGVHD patients (in detail at time of analyses), we found a correlation between activity and a higher overall severity of cGVHD, which means that in the active cGVHD patient group were more patients with a higher disease burden of cGVHD-despite similar risk profiles for cGVHD. Our data also provide solid evidence that the time point of analysis regarding both hematopoietic stem cell transplantation (HSCT) FU and cGVHD disease activity may be of critical importance for the detailed investigation of pediatric cohorts. Finally, we have proven that the differences in risk factors and patterns of IR, with cGVHD as its main confounding factor, between malignant and non-malignant diseases, are important to be considered in future studies aiming at identification of novel biomarkers for cGVHD.

When the patient leaflet and the clinical guidelines say different things on the use of antirheumatic medications during pregnancy and breastfeeding: global health care providers say that conflicting information can cause confusion and tension in the patient-clinician relationship Background: When pregnant or breastfeeding, women with rheumatic musculoskeletal diseases (RMDs) face challenges in managing their condition due to conflicting information about medication safety. Healthcare providers (HCPs) often struggle with discrepancies between clinical guidelines and the safety information provided with medications, such as the Summary of Product Characteristics and Patient Information Leaflets. This discrepancy can lead to difficulties in advising patients about safe medication use during pregnancy and breastfeeding. HCPs might feel uncertain or uncomfortable discussing medication safety, which can affect the patient-doctor relationship and even lead to stopping necessary treatments. The PRAISE study: To understand these challenges better, the PRAISE study conducted an online survey among 414 HCPs worldwide. We aimed to assess how HCPs prescribe medications, their comfort levels in advising patients, and the challenges they face due to conflicting information. Our key findings include: Confidence in prescribing : HCPs who prescribe medications were more comfortable discussing medication safety during pregnancy than those who do not prescribe. Usefulness of guidelines : Most prescribers found clinical guidelines very useful in managing patient care. Conflicting information : Over half of the HCPs reported feeling confused or tense when dealing with conflicting information between guidelines and medication safety documents. This confusion can lead to discontinuing treatments, which might negatively impact disease control. Communication strategies : HCPs often use clear communication and shared decision-making to address patient concerns. In conclusion, PRAISE highlights the need for better alignment between clinical guidelines and medication safety information to improve patient care and reduce confusion. This could help ensure that pregnant and breastfeeding women with RMDs receive the best possible.

The members of tribe Microlicieae in the flowering plant family Melastomataceae are nearly all endemic to the cerrado biome of Brazil. Traditional classifications of the Melastomataceae have attributed between 15 and 17 genera to the Microlicieae, but subsequent revisions have circumscribed the tribe more narrowly. The monophyly and intergeneric relationships of the Microlicieae were evaluated through phylogenetic analyses with molecular and morphological data sets. Incorporation of DNA sequences from the intron of the chloroplast gene rpl16 into a previously generated family-wide data set yielded a clade comprising Chaetostoma, Lavoisiera, Microlicia, Rhynchanthera, Stenodon, and Trembleya (\"core Microlicieae\"), with Rhynchanthera as the first-diverging lineage. The other four genera of Microlicieae sampled are placed in other clades: Eriocnema with Miconieae; Siphanthera with Aciotis, Nepsera, and Acisanthera of Melastomeae; Castratella as sister to Monochaetum of Melastomeae; and Cambessedesia as part of an unresolved polytomy in a large clade that includes most Melastomataceae. Analyses of the chloroplast genes rbcL and ndhF that included three core genera produced similar results, as did the combined analysis of all three data sets. Combined parsimony analyses of DNA sequences from rpl16 and the nuclear ribosomal intercistronic transcribed spacer (ITS) region of 22 species of core Microlicieae yielded generally low internal support values. Lavoisiera, recently redefined on the basis of several morphological characters, was strongly supported as monophyletic. A morphological phylogenetic analysis of the Microlicieae based on 10 parsimony-informative characters recovered a monophyletic core Microlicieae but provided no further resolution among genera. Penalized likelihood analysis with two calibration time windows produced an age estimate of 3.7 million years for the time of initial divergence of strictly Brazilian core Microlicieae. This date is in general agreement with the estimated age of the most active stage of development of cerrado vegetation and implies an adaptive shift from hydric to seasonally dry habitats during the early evolution of this group.

Background Airway management remains one of the most important responsibilities of anesthesiologists. Prediction of difficult airway allows time for proper selection of equipment, technique, and personnel experienced in managing patients with difficult airway. Face to face preoperative anesthesia interviews are difficult to conduct as they necessitate patients traveling to the clinics, and, in practice, are usually conducted in the morning of the procedure by the anesthesiologist, when identification of predictors of difficult intubation may lead to schedule delays or case cancelations. We hypothesized that an airway assessment tool could be used by patients or physician assistants to accurately assess their airways. Methods We administered an airway assessment tool, which had been constructed in consultation with a psychometrician and revised after non-medical layperson feedback, to 215 patients presenting to the preoperative clinic for evaluation. Separately, patients had the airway exam performed by a physician assistant and an anesthesiologist. Agreement was compared using kappa. Results We found good agreement between observers only on “can you put three fingers in your mouth?” (three-way kappa = .733, p  < 0.001) and poor agreement on Mallampati classification (three-way kappa = .195, p  < 0.001) and “Can you fit three fingers between your chin and your Adam’s Apple?” (three-way kappa = .216, p  < 0.001). The agreements for the other questions were mostly fair. Agreements between patients and anesthesiologists were similar to those between physician assistants and anesthesiologists. Conclusions Neither the patients’ self-assessments nor the physician assistants’ assessments were adequate to substitute for the anesthesiologists’ airway assessments.

Spinal cord injury (SCI) remains a devastating condition with poor prognosis and very limited treatment options. Affected patients are severely restricted in their daily activities. Shock wave therapy (SWT) has shown potent regenerative properties in bone fractures, wounds, and ischemic myocardium via activation of the innate immune receptor TLR3. Here, we report on the efficacy of SWT for regeneration of SCI. SWT improved motor function and decreased lesion size in WT but not Tlr3-/- mice via inhibition of neuronal degeneration and IL6-dependent recruitment and differentiation of neuronal progenitor cells. Both SWT and TLR3 stimulation enhanced neuronal sprouting and improved neuronal survival, even in human spinal cord cultures. We identified tlr3 as crucial enhancer of spinal cord regeneration in zebrafish. Our findings indicate that TLR3 signaling is involved in neuroprotection and spinal cord repair and suggest that TLR3 stimulation via SWT could become a potent regenerative treatment option.