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The industrial sector is a significant energy consumer, primarily reliant on fossil fuels. Nevertheless, the potential of Concentrated Solar Power (CSP) technologies for decarbonizing the industry is promising and the challenges posed by variability in weather and seasons can be effectively addressed through the use of seasonal storage methods, such as Thermochemical Energy Storage (TCES). This study presents a dynamic lumped-capacitance model, implemented in Dymola, designed to simulate a continuous suspension reactor employing salt hydrates like calcium oxalate monohydrate/anhydrous. The model mainly comprised (i) heat balances, (ii) reaction kinetics for the dehydration process and (iii) a heat transfer model. Furthermore, the study delves into a comprehensive case study involving the integration of CSP and TCES into a dairy processing facility located in Spain, addressing both daily operational requirements and seasonal energy storage demands. The solar field, heating demand, and storage tanks are described in detail. The transient simulation results for July showcase the efficacy of the solar installation and sensible energy storage for day-to-day operations, resulting in a total solar contribution of 47.3%. Notably, the thermochemical energy stored during this period can cover 22.1% of the low-temperature energy demand in January. The study underscores the importance of TCES in sustainable energy systems and paves the way for further optimization, economic assessment, and expanded applications. Future work will focus on enhancing the model and incorporating additional thermochemical materials, supported by additional experimental data.

The CAPTure Open Volumetric Air Receiver (OVAR) design is based on ceramic stackable “free floating” absorber modules that form the receiver structure and avoid a complex metallic double membrane design. The novel receiver design has been validated at small-scale (15 kWth) at a solar simulator, as well as on the top of an experimental tower at 300 kWth, up to absorber module outlet temperatures above 900ºC. The novel OVAR concept is attractive for both the concentrated solar power (CSP) sector, as well as for high-temperature process heat supply. The thermal efficiency of the receiver concept is expected to be above 80% at outlet temperatures of 900ºC.

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS), and congenital myasthenic syndromes (CMS) represent an etiologically heterogeneous group of (very) rare chronic diseases. MG and LEMS have an autoimmune-mediated etiology, while CMS are genetic disorders. A (strain dependent) muscle weakness due to neuromuscular transmission disorder is a common feature. Generalized MG requires increasingly differentiated therapeutic strategies that consider the enormous therapeutic developments of recent years. To include the newest therapy recommendations, a comprehensive update of the available German-language guideline ‘Diagnostics and therapy of myasthenic syndromes’ has been published by the German Neurological society with the aid of an interdisciplinary expert panel. This paper is an adapted translation of the updated and partly newly developed treatment guideline. It defines the rapid achievement of complete disease control in myasthenic patients as a central treatment goal. The use of standard therapies, as well as modern immunotherapeutics, is subject to a staged regimen that takes into account autoantibody status and disease activity. With the advent of modern, fast-acting immunomodulators, disease activity assessment has become pivotal and requires evaluation of the clinical course, including severity and required therapies. Applying MG-specific scores and classifications such as Myasthenia Gravis Activities of Daily Living, Quantitative Myasthenia Gravis, and Myasthenia Gravis Foundation of America allows differentiation between mild/moderate and (highly) active (including refractory) disease. Therapy decisions must consider age, thymic pathology, antibody status, and disease activity. Glucocorticosteroids and the classical immunosuppressants (primarily azathioprine) are the basic immunotherapeutics to treat mild/moderate to (highly) active generalized MG/young MG and ocular MG. Thymectomy is indicated as a treatment for thymoma-associated MG and generalized MG with acetylcholine receptor antibody (AChR-Ab)-positive status. In (highly) active generalized MG, complement inhibitors (currently eculizumab and ravulizumab) or neonatal Fc receptor modulators (currently efgartigimod) are recommended for AChR-Ab-positive status and rituximab for muscle-specific receptor tyrosine kinase (MuSK)-Ab-positive status. Specific treatment for myasthenic crises requires plasmapheresis, immunoadsorption, or IVIG. Specific aspects of ocular, juvenile, and congenital myasthenia are highlighted. The guideline will be further developed based on new study results for other immunomodulators and biomarkers that aid the accurate measurement of disease activity.

Pada era sekarang, ditengah pesatnya perkembangan teknologi, ada banyak orang yang menyalahgunakan teknologi untuk melakukan tindakkan kurang menyenangkan terhadap orang lain, salah satunya bullying yang dilakukan menggunakan media sosial yang disebut sebagai cyberbullying. Maka peneliti melakukan pengklasifikasian data komentar pada media sosial apakah termasuk bullying atau tidak. Tujuan dari penelitian ini untuk melakukan pengklasifikasian data komentar pada sosial media termasuk cyberbullying atau tidak dengan membandingkan terlebih dahulu kinerja antara algoritma Naive Bayes Multinomial dan Bernoulli dalam mengklasifikasikan data komentar tersebut. Peneliti membandingkan algoritma Naive Bayes Classifier model Multinomial dan Bernoulli untuk mendapatkan model terbaik. Peneliti juga membandingkan penggunaan metode feature extraction Bag of Words dan TF-IDF untuk meningkatkan akurasi dari algoritma yang digunakan. Hasil dari penelitian yang dilakukan adalah algoritma Naive Bayes model Multinomial memperoleh akurasi lebih tinggi dan memperoleh rata - rata waktu pemrosesan yang lebih cepat dibandingkan model Bernoulli. Penggunaan metode feture extraction Bag of Words juga dapat meningkatkan akurasi lebih signifikasi dibanding TF-IDF.

Abstract Repetitive nerve stimulation (RNS) is a standard test for the diagnosis of myasthenia gravis (MG), where decrement of compound muscle action potentials (CMAP) corresponds to clinical muscle fatigability. Our aim was to ascertain the diagnostic and prognostic utility of RNS in MG patients. This study included MG patients treated between 01/2000 and 12/2016, with an observational period of at least one year and a minimum of two neurological examinations. Clinical and electrophysiological data were retrospectively gathered from patient records, and CMAP decrement was correlated with autoantibody titers and clinical disease severity at different time points. Ninety-four patients were included, with 88.3% of the cohort testing positive for acetylcholine receptor autoantibodies (AChR-Abs). RNS sensitivity was higher in patients with generalized disease (71.6%) than in purely ocular MG (38.5%). CMAP decrement did not significantly correlate with AChR-Ab titers, nor with clinical symptom severity at the time of testing or last follow up. However, there was a significant correlation between CMAP decrement and the worst recorded clinical status on a group level. RNS testing is more sensitive in generalized disease and AChR-Ab positive patients, but our data do not support RNS as a tool for long-term outcome prediction. Future studies with a prospective study design could help to overcome a number of limiting factors discussed in our study.

BackgroundThe anti-seizure medication vigabatrin (VGB) is effective for controlling seizures, especially infantile spasms. However, use is limited by VGB-associated visual field loss (VAVFL). The mechanisms by which VGB causes VAVFL remains unknown. Average peripapillary retinal nerve fibre layer (ppRNFL) thickness correlates with the degree of visual field loss (measured by mean radial degrees). Duration of VGB exposure, maximum daily VGB dose, and male sex are associated with ppRNFL thinning. Here we test the hypothesis that common genetic variation is a predictor of ppRNFL thinning in VGB exposed individuals. Identifying pharmacogenomic predictors of ppRNFL thinning in VGB exposed individuals could potentially enable safe prescribing of VGB and broader use of a highly effective drug.MethodsOptical coherence topography (OCT) and GWAS data were processed from VGB-exposed individuals (n = 71) recruited through the EpiPGX Consortium. We conducted quantitative GWAS analyses for the following OCT measurements: (1) average ppRNFL, (2) inferior quadrant, (3) nasal quadrant, (4) superior quadrant, (5) temporal quadrant, (6) inferior nasal sector, (7) nasal inferior sector, (8) superior nasal sector, and (9) nasal superior sector. Using the summary statistics from the GWAS analyses we conducted gene-based testing using VEGAS2. We conducted nine different PRS analyses using the OCT measurements. To determine if VGB-exposed individuals were predisposed to having a thinner RNFL, we calculated their polygenic burden for retinal thickness. PRS alleles for retinal thickness were calculated using published summary statistics from a large-scale GWAS of inner retinal morphology using the OCT images of UK Biobank participants.ResultsThe GWAS analyses did not identify a significant association after correction for multiple testing. Similarly, the gene-based and PRS analyses did not reveal a significant association that survived multiple testing.ConclusionWe set out to identify common genetic predictors for VGB induced ppRNFL thinning. Results suggest that large-effect common genetic predictors are unlikely to exist for ppRNFL thinning (as a marker of VAVFL). Sample size was a limitation of this study. However, further recruitment is a challenge as VGB is rarely used today because of this adverse reaction. Rare variants may be predictors of this adverse drug reaction and were not studied here.

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Abstract Originally described as a risk factor for autism, CHD8 loss‐of‐function variants have recently been associated with a wider spectrum of neurodevelopmental abnormalities. We further expand the CHD8‐related phenotype with the description of two unrelated patients who presented with childhood‐onset progressive dystonia. Whole‐exome sequencing conducted in two independent laboratories revealed a CHD8 nonsense variant in one patient and a frameshift variant in the second. The patients had strongly overlapping phenotypes characterized by generalized dystonia with mild‐to‐moderate neurodevelopmental comorbidity. Deep brain stimulation led to clinical improvement in both cases. We suggest that CHD8 should be added to the growing list of neurodevelopmental disorder‐associated genes whose mutations can also result in dystonia‐dominant phenotypes.

Abstract This study investigated treatment characteristics of Guillain-Barré syndrome (GBS) in a real-world setting between 2000 and 2019. We analyzed clinical improvement between nadir and last follow-up in patients with severe GBS (defined as having a GBS disability scale > 2 at nadir) and aimed to detect clinical factors associated with multiple treatments. We included 121 patients (74 male; median age 48 [IQR 35–60]) with sensorimotor (63%), pure motor (15%), pure sensory (10%) and localized GBS (6%) as well as Miller Fisher syndrome (6%). 44% of patients were severely affected. All but one patient received at least one immunomodulatory treatment with initially either intravenous immunoglobulins (88%), plasma exchange (10%) or corticosteroids (1%), and 25% of patients received more than one treatment. Severe GBS but not age, sex, GBS subtype or date of diagnosis was associated with higher odds to receive more than one treatment (OR 4.22; 95%CI 1.36–13.10; p = 0.01). Receiving multiple treatments had no adjusted effect (OR 1.30, 95%CI 0.31–5.40, p = 0.72) on clinical improvement between nadir and last follow-up in patients with severe GBS. This treatment practice did not change over the last 20 years.

Abstract Objective Resistance to antiseizure medications (ASMs) is one of the major concerns in the treatment of epilepsy. Despite the increasing number of ASMs available, the proportion of individuals with drug‐resistant epilepsy remains unchanged. In this study, we aimed to investigate the role of rare genetic variants in ASM resistance. Methods We performed exome sequencing of 1,128 individuals with non‐familial non‐acquired focal epilepsy (NAFE) (762 non‐responders, 366 responders) and were provided with 1,734 healthy controls. We undertook replication in a cohort of 350 individuals with NAFE (165 non‐responders, 185 responders). We performed gene‐based and gene‐set‐based kernel association tests to investigate potential enrichment of rare variants in relation to drug response status and to risk for NAFE. Results We found no gene or gene set that reached genome‐wide significance. Yet, we identified several prospective candidate genes – among them DEPDC5, which showed a potential association with resistance to ASMs. We found some evidence for an enrichment of truncating variants in dominant familial NAFE genes in our cohort of non‐familial NAFE and in association with drug‐resistant NAFE. Interpretation Our study identifies potential candidate genes for ASM resistance. Our results corroborate the role of rare variants for non‐familial NAFE and imply their involvement in drug‐resistant epilepsy. Future large‐scale genetic research studies are needed to substantiate these findings.

Abstract The use of proton pump inhibitors (PPIs) has been proposed as a potential risk factor for neurodegenerative diseases, but little is known regarding its role in amyotrophic lateral sclerosis (ALS). We therefore aimed to assess the association of PPI use with the subsequent risk of ALS, and performed a register-based nationwide nested case–control study, including 2,484 ALS cases diagnosed during July 2006–December 2013 in Sweden and 10 population controls per case that were individually matched to the case by sex, age, and area of residence. Dispenses and cumulative defined daily doses (cDDDs) of PPIs were extracted from the Swedish Prescribed Drug Register. The association of PPI use with the risk of ALS was assessed using conditional logistic regression, after applying different lag windows to avoid reverse causation. ALS patients were more likely to be dispensed with PPIs before diagnosis than controls. However, previous PPI use was not associated with an increased risk of ALS (OR = 1.08, 95% CI 0.97–1.19), and there was no dose–response relationship between cDDDs of PPIs and ALS risk (p = 0.0874), after excluding dispenses during the year before ALS diagnosis. The results were similar after excluding dispenses during the 2 or 3 years before ALS diagnosis.

Abstract Background Guillain-Barré syndrome (GBS) is an autoimmune disease that results in demyelination and axonal damage. Five percent of patients die and 20% remain significantly disabled on recovery. Recovery is slow in most cases and eventual disability is difficult to predict, especially early in the disease. Blood or cerebrospinal fluid (CSF) biomarkers that could help identify patients at risk of poor outcome are required. We measured serum neurofilament light chain (sNfL) concentrations from blood taken upon admission and investigated a correlation between sNfL and clinical outcome. Methods Baseline sNfL levels in 27 GBS patients were compared with a control group of 22 patients with diagnoses not suggestive of any axonal damage. Clinical outcome parameters for GBS patients included (i) the Hughes Functional Score (HFS) at admission, nadir, and discharge; (ii) the number of days hospitalised; and (iii) whether intensive care was necessary. Results The median sNfL concentration in our GBS sample on admission was 85.5 pg/ml versus 9.1 pg/ml in controls. A twofold increase in sNfL concentration at baseline was associated with an HFS increase of 0.6 at nadir and reduced the likelihood of discharge with favourable outcome by a factor of almost three. Higher sNfL levels upon admission correlated well with hospitalisation time (r s = 0.69, p

Abstract Variants in GABRA1 have been associated with different epilepsies ranging from mild generalized forms to epileptic encephalopathies. Despite the broad clinical spectrum, phenotypes were found to be largely concordant within families. Contrary to this observation, we report monozygotic twin sisters with generalized epilepsy due to the c.541C>T; p.(Pro181Ser) de novo variant in GABRA1. One experienced juvenile absence seizures promptly responding to first‐line medication, whereas the second developed severe treatment‐refractory epilepsy with febrile, absence, atonic, and tonic‐clonic seizures indicating marked intrafamilial variability in GABRA1‐related epilepsy. Moreover, we provide a molecular characterization of the novel variant based on recently published structural data.

We report the rapid development of a myasthenic crisis as the first-time manifestation of myasthenia gravis. The symptoms developed in the course of acute leptospirosis associated with a new sequence type of Leptospira interrogans. Antibiotic treatment led to rapid amelioration of myasthenia.

Myasthenic syndromes are typically characterized by muscle weakness and increased fatigability due to an impaired transmission at the neuromuscular junction (NMJ). Most cases are caused by acquired autoimmune conditions such as myasthenia gravis (MG), typically with antibodies against the acetylcholine receptor (AChR). Different drugs are among the major factors that may complicate pre-existing autoimmune myasthenic conditions by further impairing transmission at the NMJ. Some clinical observations are substantiated by experimental data, indicating that presynaptic, postsynaptic or more complex pathomechanisms at the NMJ may be involved, depending on the individual compound. Most robust data exist for the risks associated with some antibiotics (e.g., aminoglycosides, ketolides, fluoroquinolones) and cardiovascular medications (e.g., class Ia antiarrhythmics, beta blockers). Apart from primarily autoimmune-mediated disorders of the NMJ, de novo myasthenic manifestations may also be triggered by medical treatments that induce an autoimmune reaction. Most notably, there is growing evidence that the immune checkpoint inhibitors (ICI), a modern class of drugs to treat various malignancies, represent a relevant risk factor to develop severe and progressive medication-induced myasthenia via an immune-mediated mechanism. From a clinical perspective, it is of utmost importance for the treating physicians to be aware of such adverse treatment effects and their consequences. In this article, we aim to summarize existing evidence regarding the key molecular and immunological mechanisms as well as the clinical implications of medication-aggravated and medication-induced myasthenic syndromes.

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

Introduction: When a doctor is informed of a patient’s future care preferences if they were to lose capacity, there is an ethical and legal obligation to share this information with the treating medical team. In frail older patients, conversations about treatment preferences often occur during hospital admission. We sought to assess the communication of these preferences to the patient’s GP. Methods: Retrospective chart review of consecutive discharges from acute geriatric wards across seven hospitals. Records were excluded if the patient was admitted for less than 48 hours, was under orthogeriatric care, or died in hospital. Results: 339 notes were included, 41-50 from each hospital. GPs were informed of the resuscitation status of 28% of all patients. 52% of patients had an inpatient DNACPR, the GP was informed of 54% of these. 36% of patients had an inpatient ceiling of treatment documented, of which GPs were informed of 19%. 53% of hospital DNACPRs were converted into community DNACPRs on discharge: GPs were informed of only 24% of new community DNACRPs. 47% of patients discharged with a new communityDNACPR lacked capacity to be involved in that decision; for just 6% of these was the GP asked to review the DNACPR order in the community. Inpatient Advance Care Planning (ACP) discussions were held for 9% of patients, of which the GP was informed in 59% of cases. 49% of ACP conversations involved the next-of-kin but not the patient. Among patients who had a new DNACPR decision made during their admission (n=124), there was documentary evidence in only 25% that the patient or next-of-kin was informed whether this was time-limited or indefinite. Conclusions: Communication from hospitals to GPs about resuscitation, ceiling of care and ACP discussions is very limited. For patients who have expressed ongoing future care preferences, there is a legal obligation to share this information with the treating medical team, which on discharge is the GP. There is poor documentary evidence of discussions with patients about whether DNACPR decisions are time-limited or indefinite. Furthermore, many hospitalised frail patients lack capacity to make DNACPR decisions but they may subsequently regain capacity, particularly those with delirium. Despite this, GPs are rarely asked to review new community DNACPRs, including those made for patients without capacity. [ABSTRACT FROM AUTHOR]

ObjectiveThe SCN1A gene, coding for the voltage-gated Na+ channel alpha subunit NaV1.1, is the clinically most relevant epilepsy gene. With the advent of high-throughput next-generation sequencing, clinical laboratories are generating an ever-increasing catalogue of SCN1A variants. Variants are more likely to be classified as pathogenic if they have already been identified previously in a patient with epilepsy. Here, we critically re-evaluate the pathogenicity of this class of variants in a cohort of patients with common epilepsy syndromes and subsequently ask whether a significant fraction of benign variants have been misclassified as pathogenic.MethodsWe screened a discovery cohort of 448 patients with a broad range of common genetic epilepsies and 734 controls for previously reported SCN1A mutations that were assumed to be disease causing. We re-evaluated the evidence for pathogenicity of the identified variants using in silico predictions, segregation, original reports, available functional data and assessment of allele frequencies in healthy individuals as well as in a follow up cohort of 777 patients.Results and interpretationWe identified 8 known missense mutations, previously reported as pathogenic, in a total of 17 unrelated epilepsy patients (17/448; 3.80%). Our re-evaluation indicates that 7 out of these 8 variants (p.R27T; p.R28C; p.R542Q; p.R604H; p.T1250M; p.E1308D; p.R1928G; NP_001159435.1) are not pathogenic. Only the p.T1174S mutation may be considered as a genetic risk factor for epilepsy of small effect size based on the enrichment in patients (P = 6.60 x 10-4; OR = 0.32, fishers exact test), previous functional studies but incomplete penetrance. Thus, incorporation of previous studies in genetic counseling of SCN1A sequencing results is challenging and may produce incorrect conclusions.

BACKGROUND: Human mesial temporal lobe epilepsies (MTLE) represent the most frequent form of partial epilepsies and are frequently preceded by febrile seizures (FS) in infancy and early childhood. Genetic associations of several complement genes including its central component C3 with disorders of the central nervous system, and the existence of C3 dysregulation in the epilepsies and in the MTLE particularly, make it the C3 gene a good candidate for human MTLE. METHODOLOGY/PRINCIPAL FINDINGS: A case-control association study of the C3 gene was performed in a first series of 122 patients with MTLE and 196 controls. Four haplotypes (HAP1 to 4) comprising GF100472, a newly discovered dinucleotide repeat polymorphism [(CA)8 to (CA)15] in the C3 promoter region showed significant association after Bonferroni correction, in the subgroup of MTLE patients having a personal history of FS (MTLE-FS+). Replication analysis in independent patients and controls confirmed that the rare HAP4 haplotype comprising the minimal length allele of GF100472 [(CA)8], protected against MTLE-FS+. A fifth haplotype (HAP5) with medium-size (CA)11 allele of GF100472 displayed four times higher frequency in controls than in the first cohort of MTLE-FS+ and showed a protective effect against FS through a high statistical significance in an independent population of 97 pure FS. Consistently, (CA)11 allele by its own protected against pure FS in a second group of 148 FS patients. Reporter gene assays showed that GF100472 significantly influenced C3 promoter activity (the higher the number of repeats, the lower the transcriptional activity). Taken together, the consistent genetic data and the functional analysis presented here indicate that a newly-identified and functional polymorphism in the promoter of the complement C3 gene might participate in the genetic susceptibility to human MTLE with a history of FS, and to pure FS. CONCLUSIONS/SIGNIFICANCE: The present study provides important data suggesting for the first time the involvement of the complement system in the genetic susceptibility to epileptic seizures and to epilepsy.

Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.

The dynorphin/κ-opioid receptor (KOP-R) system has been shown to play a role in different types of behavior regulation, including reward-related behavior and drug craving. It has been shown that alleles with 3 or 4 repeats (HH genotype) of the variable nucleotide tandem repeat (68-bp VNTR) functional polymorphism of the prodynorphin (PDYN) gene are associated with higher levels of dynorphin peptides than alleles with 1 or 2 repeats (LL genotype). We used fMRI on N = 71 prescreened healthy participants to investigate the effect of this polymorphism on cerebral activation in the limbic-corticostriatal loop during reward anticipation. Individuals with the HH genotype showed higher activation than those with the LL genotype in the medial orbitofrontal cortex (mOFC) when anticipating a possible monetary reward. In addition, the HH genotype showed stronger functional coupling (as assessed by effective connectivity analyses) of mOFC with VMPFC, subgenual anterior cingulate cortex, and ventral striatum during reward anticipation. This hints at a larger sensitivity for upcoming rewards in individuals with the HH genotype, resulting in a higher motivation to attain these rewards. These findings provide first evidence in humans that the PDYN polymorphism modulates neural processes associated with the anticipation of rewards, which ultimately may help to explain differences between genotypes with respect to addiction and drug abuse.

Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365 kb deletion affecting two untranslated 5'-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.

Using principal component (PC) analysis, we studied the genetic constitution of 3,112 individuals from Europe as portrayed by more than 270,000 single nucleotide polymorphisms (SNPs) genotyped with the Illumina Infinium platform. In cohorts where the sample size was >100, one hundred randomly chosen samples were used for analysis to minimize the sample size effect, resulting in a total of 1,564 samples. This analysis revealed that the genetic structure of the European population correlates closely with geography. The first two PCs highlight the genetic diversity corresponding to the northwest to southeast gradient and position the populations according to their approximate geographic origin. The resulting genetic map forms a triangular structure with a) Finland, b) the Baltic region, Poland and Western Russia, and c) Italy as its vertexes, and with d) Central- and Western Europe in its centre. Inter- and intra- population genetic differences were quantified by the inflation factor lambda (lambda) (ranging from 1.00 to 4.21), fixation index (F(st)) (ranging from 0.000 to 0.023), and by the number of markers exhibiting significant allele frequency differences in pair-wise population comparisons. The estimated lambda was used to assess the real diminishing impact to association statistics when two distinct populations are merged directly in an analysis. When the PC analysis was confined to the 1,019 Estonian individuals (0.1% of the Estonian population), a fine structure emerged that correlated with the geography of individual counties. With at least two cohorts available from several countries, genetic substructures were investigated in Czech, Finnish, German, Estonian and Italian populations. Together with previously published data, our results allow the creation of a comprehensive European genetic map that will greatly facilitate inter-population genetic studies including genome wide association studies (GWAS).

Changes in the cis-regulation of neural genes likely contributed to the evolution of our species' unique attributes, but evidence of a role for natural selection has been lacking. We found that positive natural selection altered the cis-regulation of human prodynorphin, the precursor molecule for a suite of endogenous opioids and neuropeptides with critical roles in regulating perception, behavior, and memory. Independent lines of phylogenetic and population genetic evidence support a history of selective sweeps driving the evolution of the human prodynorphin promoter. In experimental assays of chimpanzee-human hybrid promoters, the selected sequence increases transcriptional inducibility. The evidence for a change in the response of the brain's natural opioids to inductive stimuli points to potential human-specific characteristics favored during evolution. In addition, the pattern of linked nucleotide and microsatellite variation among and within modern human populations suggests that recent selection, subsequent to the fixation of the human-specific mutations and the peopling of the globe, has favored different prodynorphin cis-regulatory alleles in different parts of the world.

Background: Safety-netting is intended to protect against harm from uncertainty in diagnosis/disease trajectory. Despite recommendations to communicate diagnostic uncertainty when safety-netting, this is not always done., Aims: To explore how and why doctors safety-netted in response to several clinical scenarios, within the broader context of exploring how doctors communicate diagnostic uncertainty., Methods: Doctors working in internal medical specialties (n=36) from five hospitals were given vignettes in a randomised order (all depicting different clinical scenarios involving diagnostic uncertainty). After reading each, they told an interviewer what they would tell a 'typical patient' in this situation. A follow-up semistructured interview explored reasons for their communication. Interviews were recorded, transcribed and coded. We examined how participants safety-netted using a content analysis approach, and why they safety-netting with thematic analysis of the semistructured follow-up interviews using thematic analysis., Results: We observed n=78 instances of safety-netting (across 108 vignette encounters). We found significant variation in how participants safety-netted. Safety-netting was common (although not universal), but clinicians differed in the detail provided about symptoms to be alert for, and the action advised. Although many viewed safety-netting as an important tool for managing diagnostic uncertainty, diagnostic uncertainty was infrequently explicitly discussed; most advised patients to return if symptoms worsened or new 'red flag' symptoms developed, but they rarely linked this directly to the possibility of diagnostic error. Some participants expressed concerns that communicating diagnostic uncertainty when safety-netting may cause anxiety for patients or could drive inappropriate reattendance/over-investigation., Conclusions: Participants safety-netted variously, even when presented with identical clinical information. Although safety-netting was seen as important in avoiding diagnostic error, concerns about worrying patients may have limited discussion about diagnostic uncertainty. Research is needed to determine whether communicating diagnostic uncertainty makes safety-netting more effective at preventing harm associated with diagnostic error, and whether it causes significant patient anxiety., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Aims: Communication is important in determining how patients understand the diagnostic process. Empirical studies involving direct observation of communication within diagnostic processes are relatively limited. This ethnographic study aimed to identify communicative practices facilitating or inhibiting shared understanding between patients and doctors in UK acute secondary care settings., Methods: Data were collected in acute medical sectors of three English hospitals. Researchers observed doctors as they assessed patients; semistructured interviews were undertaken with doctors and patients directly afterwards. Patients were also interviewed 2-4 weeks later. Case studies of individual encounters (consisting of these interviews and observational notes) were created, and were cross-examined by an interdisciplinary team to identify divergence and convergence between doctors' and patients' narratives. These data were analysed thematically., Results: We conducted 228 h of observation, 24 doctor interviews, 32 patient interviews and 15 patient follow-up interviews. Doctors varied in their communication. Patient diagnostic understanding was sometimes misaligned with that of their doctors; interviews revealed that they often made incorrect assumptions to make sense of the fragmented information received. Thematic analysis identified communicative practices that seemed to facilitate, or inhibit, shared diagnostic understanding between patient and doctor, revealing three themes: (1) communicating what has been understood from the medical record, (2) sharing the thought process and diagnostic reasoning and (3) closing the loop and discharge communication. Shared understanding was best fostered by clear communication about the diagnostic process, what had already been done and what was achievable in acute settings. Written information presents an underutilised tool in such communication., Conclusions: In UK acute secondary settings, the provision of more information about the diagnostic process often fostered shared understanding between doctor and patient, helping to minimise the confusion and dissatisfaction that can result from misaligned expectations or conclusions about the diagnosis, and the uncertainty therein., Patient/public Contribution: A patient and public involvement group (of a range of ages and backgrounds) was consulted. They contributed to the design of the protocol, including the timing of interviews, the acceptability of a follow-up telephone interview, the development of the interview guides and the participant information sheets., (© 2024 The Author(s). Health Expectations published by John Wiley & Sons Ltd.)

Background: Despite the availability of guidance for the provision of good end-of-life care, there are significant variations across the UK in its delivery. This study sought to identify the influences on end-of-life treatment and care planning across several areas where deficiencies in evidence-based practice have been identified, and to develop consensus among healthcare providers and users for recommendations on how to address these deficits., Methods: An online survey (106 responses), qualitative interviews (55 participants) and a consensus-building exercise (475 participants in the initial round) were undertaken. Participants included people approaching the end of life, people important to them, and health and care practitioners who help people plan for the end of life or provide end-of-life care. Recruitment was via online methods, including social media and online newsletters of relevant charities and professional organisations. Thematic analysis using the framework method was used to analyse qualitative data. Synthesis of qualitative and quantitative data led to the development of statements regarding recommendations for advancing implementation of good practice. A two-stage consensus-building exercise asked respondents first to rate these statements and then to rate and rank further sub-recommendations in three areas., Results: Results from the consensus building exercise confirmed that end-of-life care planning conversations are to be welcomed and encouraged, and that the priority should be to have the conversation (which could be initiated by a range of professionals, or people planning end-of-life care themselves), rather than to wait for an ideal time to have it. Further rounds identified specific components of a standardised record of end-of-life treatment and care preferences that should be prioritised, specific health and care staff that should be empowered through training in advanced communication, and aspects of communication most important to include in training for healthcare professionals., Conclusions: Our study has identified opportunities for action to improve end-of-life treatment and care by combining multiple stakeholder perspectives and building consensus among them: the resulting recommendations have sufficient granularity to be implemented and evaluated. They are of relevance to policy makers, those who train healthcare professionals, and those looking after patients approaching the end of life., (© 2024. The Author(s).)

Competing Interests: Competing interests: The BMJ has judged that the authors have no disqualifying financial ties to commercial companies that are relevant to this paper. ZF declares that she chairs the ReSPECT subcommittee for Resuscitation council UK. Provenance and peer review: Commissioned, based on an idea from the author; externally peer reviewed.