Federated Learning Survival Model and Potential Radiotherapy Decision Support Impact Assessment for Non-small Cell Lung Cancer Using Real-World Data.

AIMS: The objective of this study was to develop a two-year overall survival model for inoperable stage I-III non-small cell lung cancer (NSCLC) patients using routine radiation oncology data over a federated (distributed) learning network and evaluate the potential of decision support for curative versus palliative radiotherapy. METHODS: A federated infrastructure of data extraction, de-identification, standardisation, image analysis, and modelling was installed for seven clinics to obtain clinical and imaging features and survival information for patients treated in 2011-2019. A logistic regression model was trained for the 2011-2016 curative patient cohort and validated for the 2017-2019 cohort. Features were selected with univariate and model-based analysis and optimised using bootstrapping. System performance was assessed by the receiver operating characteristic (ROC) and corresponding area under curve (AUC), C-index, calibration metrics and Kaplan-Meier survival curves, with risk groups defined by model probability quartiles. Decision support was evaluated using a case-control analysis using propensity matching between treatment groups. RESULTS: 1655 patient datasets were included. The overall model AUC was 0.68. Fifty-eight percent of patients treated with palliative radiotherapy had a low-to-moderate risk prediction according to the model, with survival times not significantly different (p = 0.87 and 0.061) from patients treated with curative radiotherapy classified as high-risk by the model. When survival was simulated by risk group and model-indicated treatment, there was an estimated 11% increase in survival rate at two years (p < 0.01). CONCLUSION: Federated learning over multiple institution data can be used to develop and validate decision support systems for lung cancer while quantifying the potential impact of their use in practice. This paves the way for personalised medicine, where decisions can be based more closely on individual patient details from routine care.

Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects.

SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).

Automated detection, delineation and quantification of whole-body bone metastasis using FDG-PET/CT images.

Non-small cell lung cancer (NSCLC) patients with the metastatic spread of disease to the bone have high morbidity and mortality. Stereotactic ablative body radiotherapy increases the progression free survival and overall survival of these patients with oligometastases. FDG-PET/CT, a functional imaging technique combining positron emission tomography (PET) with 18 F-fluorodeoxyglucose (FDG) and computer tomography (CT) provides improved staging and identification of treatment response. It is also associated with reduction in size of the radiotherapy tumour volume delineation compared with CT based contouring in radiotherapy, thus allowing for dose escalation to the target volume with lower doses to the surrounding organs at risk. FDG-PET/CT is increasingly being used for the clinical management of NSCLC patients undergoing radiotherapy and has shown high sensitivity and specificity for the detection of bone metastases in these patients. Here, we present a software tool for detection, delineation and quantification of bone metastases using FDG-PET/CT images. The tool extracts standardised uptake values (SUV) from FDG-PET images for auto-segmentation of bone lesions and calculates volume of each lesion and associated mean and maximum SUV. The tool also allows automatic statistical validation of the auto-segmented bone lesions against the manual contours of a radiation oncologist. A retrospective review of FDG-PET/CT scans of more than 30 candidate NSCLC patients was performed and nine patients with one or more metastatic bone lesions were selected for the present study. The SUV threshold prediction model was designed by splitting the cohort of patients into a subset of 'development' and 'validation' cohorts. The development cohort yielded an optimum SUV threshold of 3.0 for automatic detection of bone metastases using FDG-PET/CT images. The validity of the derived optimum SUV threshold on the validation cohort demonstrated that auto-segmented and manually contoured bone lesions showed strong concordance for volume of bone lesion (r = 0.993) and number of detected lesions (r = 0.996). The tool has various applications in radiotherapy, including but not limited to studies determining optimum SUV threshold for accurate and standardised delineation of bone lesions and in scientific studies utilising large patient populations for instance for investigation of the number of metastatic lesions that can be treated safety with an ablative dose of radiotherapy without exceeding the normal tissue toxicity.

What is the evidence that advertising policies could have an impact on gambling-related harms? A systematic umbrella review of the literature.

OBJECTIVE: To summarise the evidence on the impacts of gambling-related advertising that could lead to gambling-related harm, including impacts on vulnerable individuals and inequalities in the distribution of harms. STUDY DESIGN: An umbrella review of studies investigating the impact of gambling advertising. METHODS: A review was undertaken of systematic reviews of qualitative, quantitative and mixed method studies reporting outcomes associated with gambling advertising and marketing. The search strategy included database searches (Web of Science, PsycInfo) and website searches. The quality of the included reviews was determined using A MeaSurement Tool to Assess systematic Reviews 2. RESULTS: 1024 papers were identified by database searches. Eight systematic reviews, including 74 unique studies, met inclusion criteria. Included studies, using quantitative and qualitative methods, consistently support the existence of a causal relationship between exposure to advertising of gambling products/brands and more positive attitudes to gambling, greater intentions to gamble and increased gambling activity at both individual and population level. There is evidence of a 'dose-response' effect; greater advertising exposure increases participation which leads to a greater risk of harm. There was more evidence for the impact on children and young people and for those already at risk from current gambling activity with those most vulnerable more likely to be influenced. CONCLUSION: Gambling advertising restrictions could reduce overall harm and mitigate the impact of advertising on gambling-related inequalities. Public health harm prevention strategies should include policies which limit exposure to advertising, particularly among children and vulnerable groups.

Unclassified white matter disorders: A diagnostic journey requiring close collaboration between clinical and laboratory services.

BACKGROUND: Next generation sequencing studies have revealed an ever-increasing number of causes for genetic disorders of central nervous system white matter. A substantial number of disorders are identifiable from their specific pattern of biochemical and/or imaging findings for which single gene testing may be indicated. Beyond this group, the causes of genetic white matter disorders are unclear and a broader approach to genomic testing is recommended. AIM: This study aimed to identify the genetic causes for a group of individuals with unclassified white matter disorders with suspected genetic aetiology and highlight the investigations required when the initial testing is non-diagnostic. METHODS: Twenty-six individuals from 22 families with unclassified white matter disorders underwent deep phenotyping and genome sequencing performed on trio, or larger, family groups. Functional studies and transcriptomics were used to resolve variants of uncertain significance with potential clinical relevance. RESULTS: Causative or candidate variants were identified in 15/22 (68.2%) families. Six of the 15 implicated genes had been previously associated with white matter disease (COL4A1, NDUFV1, SLC17A5, TUBB4A, BOLA3, DARS2). Patients with variants in the latter two presented with an atypical phenotype. The other nine genes had not been specifically associated with white matter disease at the time of diagnosis and included genes associated with monogenic syndromes, developmental disorders, and developmental and epileptic encephalopathies (STAG2, LSS, FIG4, GLS, PMPCA, SPTBN1, AGO2, SCN2A, SCN8A). Consequently, only 46% of the diagnoses would have been made via a current leukodystrophy gene panel test. DISCUSSION: These results confirm the importance of broad genomic testing for patients with white matter disorders. The high diagnostic yield reflects the integration of deep phenotyping, whole genome sequencing, trio analysis, functional studies, and transcriptomic analyses. CONCLUSIONS: Genetic white matter disorders are genetically and phenotypically heterogeneous. Deep phenotyping together with a range of genomic technologies underpin the identification of causes of unclassified white matter disease. A molecular diagnosis is essential for prognostication, appropriate management, and accurate reproductive counseling.

Nutrition and stem cell integrity in aging.

Adult stem cells (SCs) represent the regenerative capacity of organisms throughout their lifespan. The maintenance of robust SC populations capable of renewing organs and physiological systems is one hallmark of healthy aging. The local environment of SCs, referred to as the niche, includes the nutritional milieu, which is essential to maintain the quantity and quality of SCs available for renewal and regeneration. There is increased recognition that SCs have unique metabolism and conditional nutrient needs compared to fully differentiated cells. However, the contribution of SC nutrition to overall human nutritional requirements is an understudied and underappreciated area of investigation. Nutrient needs vary across the lifespan and are modified by many factors including individual health, disease, physiological states including pregnancy, age, sex, and during recovery from injury. Although current nutrition guidance is generally derived for apparently healthy populations and to prevent nutritional deficiency diseases, there are increased efforts to establish nutrient-based and food-based recommendations based on reducing chronic disease. Understanding the dynamics of SC nutritional needs throughout the life span, including the role of nutrition in extending biological age by blunting biological systems decay, is fundamental to establishing food and nutrient guidance for chronic disease reduction and health maintenance. This review summarizes a 3-day symposium of the Marabou Foundation (www.marabousymposium.org) held to examine the metabolic properties and unique nutritional needs of adult SCs and their role in healthy aging and age-related chronic disease.

Assessing adherence and exploring barriers to provision of prescribed texture modifications for dysphagia in a residential aged care facility in rural Australia.

PURPOSE: Purpose: Between 55-65% of residents living in residential aged care facilities (RACFs) experience dysphagia and are prescribed texture-modified diets by a speech-language pathologist (SLP). The aim of this study was to assess current adherence to prescribed texture modification for people with dysphagia; and explore barriers to implementation in a rural aged care setting. METHOD: Method: Meal texture audits (N = 42) were completed with residents with dysphagia in a rural RACF who were prescribed texture-modified diets or fluids by a SLP. Semi-structured focus groups were conducted with nursing and food preparation staff (N = 11) to identify barriers to implementation. RESULT: Result: Mealtime texture audits identified that 54.8% (n = 23) of residents' food modification requirements were incorrectly documented in the manual entry database (kitchen form) and 64.3% (n = 27) of meal trays contained foods that did not meet residents' dysphagia management plans. Focus group data revealed seven main themes impacting on the ability of staff to implement prescribed texture-modified diets. Complicated processes and communication between nursing, food services and SLP staff were identified as major barriers. These were complicated further by time pressures experienced by staff as well as staffing issues, resourcing of the kitchen, accommodating individual dietary preferences and the variety/presentation of dietary options at the aged care facility.Conclusion: There was low adherence to SLP prescribed texture-modified diets and fluids in the participating rural RACF. This study identified major barriers to implementing SLP prescribed texture-modified diets including complicated processes, communication breakdowns, time pressures and limited staffing. Implementation of an online menu management system and regular dysphagia-specific training may address barriers to communication and complicated paper-based menu systems and should be a priority for health services to ensure adequate dysphagia management.

The prevalence of hazardous and harmful drinking in the UK Police Service, and their co-occurrence with job strain and mental health problems.

AIMS: Due to the stressful nature of policing, police employees are at risk of mental health problems and problematic alcohol use. We aim to determine the prevalence of hazardous and harmful alcohol use in the UK Police Service, and to explore the associations with job strain and mental health problems. METHODS: Cross-sectional data from the Airwave Health Monitoring Study (N = 40 986) included measures of alcohol consumption (total units in past week), mental health (depression, anxiety and post-traumatic stress disorder [PTSD]) and job strain. The associations between mental health and job strain with alcohol consumption (i.e. abstinence, low-risk [<14 units per week, reference group], hazardous [>14 to 35 units for women, >14 to 50 units for men], harmful [>35 units for women, >50 units for men]), were analysed using multinomial logistic regressions, adjusting for potential confounders (i.e. age, gender, ethnicity, marital status, children under 18, income and smoking status). RESULTS: A total of 32.6% of police employees reported hazardous drinking, with 3.0% drinking at harmful levels. Compared to those without a mental health problem, police employees with depression, anxiety or PTSD were twice as likely to be harmful drinkers and were also 1.3 times more likely to report abstinence. Those reporting low strain (reference group) were more likely to drink hazardously compared to those reporting high strain, which was statistically moderated by mental health. When the sample was stratified by mental health status, the association between low strain (compared to all other categories) and hazardous drinking, was significant only in those without a mental health problem. CONCLUSIONS: These findings indicate that police employees may be an occupational group at risk of alcohol harm, with one-third drinking hazardously. The J-shaped relationship between mental health and alcohol use highlights a need for an integration of mental health and alcohol services, tailored for the UK Police Service.

LC-ICP-MS method for the determination of "extractable copper" in serum.

Copper is an essential element for biological functions within humans and animals. There are several known diseases associated with Cu deficiency or overload, such as Menkes disease and Wilson disease, respectively. A common clinical method for determining extractable Cu levels in serum, which is thought to be potentially dangerous if in excess, is to subtract the value of tightly incorporated Cu in ceruloplasmin from total serum Cu. In this work, an automated sample preparation and liquid chromatography (LC) system was combined with inductively coupled plasma-mass spectrometry (ICP-MS) to determine bound Cu and extractable Cu in serum. This LC-ICP-MS method took 250 s for sample preparation and analysis, followed by a column recondition/system reset, thus, a 6 minute sample-to-sample time including sample preparation. The method was validated using serum collected from either control (Atp7b+/-) or Wilson disease rats (Atp7b-/-). The extractable Cu was found to be 4.0 ± 2.3 µM Cu in healthy control rats, but 2.1 ± 0.6 µM Cu in healthy Wilson rats, and 27 ± 16 µM Cu in diseased Wilson rats, respectively. In addition, the extractable Cu/bound Cu ratio was found to be 6.4 ± 3.5%, 38 ± 29%, and 34 ± 22%, respectively. These results suggest that the developed method could be of diagnostic value for Wilson disease, and possibly other copper related diseases.

Automation of boron chromatographic purification for δ11 B analysis of coral aragonite.

RATIONALE: To detect the small changes in past pH, the boron isotope ratio of coral carbonates, expressed as the δ11 B value, needs to be both precise and accurate (2sd <<1‰). Boron measurements by Multi-Collector Inductively Coupled Plasma Mass Spectrometry (MC-ICPMS) require the boron to be carefully purified before analysis, which is time consuming, and requires specialist training. Here, we use the prepFAST-MC method that enables the automatic extraction of B (up to 25 ng load) from a CaCO3 matrix. METHODS: Samples were purified using the prepFAST-MC automated system with a ~25-µL column of Amberlite IRA743 resin. Boron isotope measurements were performed by MC-ICPMS. The effects of matrix load, speed of sample loading onto the column, and blank contamination were tested to evaluate the effects on the purification process. The optimised protocol was tested on various standards and samples of aragonite corals. RESULTS: The blank contribution for the approach is ~60 pg and is negligible given our sample size (<0.2% sample size). Efficiency of matrix removal is demonstrated with the addition of up to 1.6 mg of dissolved low-B calcium carbonate to NIST SRM 951 with no impact on the accuracy of δ11 B values. The Japanese Geological Survey Porites reference material JCp-1, boric acid standard NIST SRM 951, and seawater, all processed on the prepFAST-MC system, give δ11 B values within error of literature values (δ11 BJCp-1 = 24.31 ± 0.20‰ (2sd, n = 20); δ11 BNIST 951 = -0.02 ± 0.15‰ (2sd, n = 13) and δ11 BSeawater = 39.50 ± 0.06‰ (2sd, n = 2)). Results obtained from the coral Siderastrea siderea purified with the prepFAST-MC system show an average offset from the manual ion-exchange protocols of Δδ11 B = 0.01 ± 0.28‰ (2sd, n = 12). CONCLUSIONS: Our study demonstrates the capacity of the prepFAST-MC method to generate accurate and reproducible δ11 B values for a range of materials, without fractionation, with efficient matrix removal and with negligible blank contribution.

The vascular access questionnaire: a single centre UK experience.

BACKGROUND: Haemodialysis is capable of prolonging life in patients with end stage renal disease, however this therapy comes with significant negative impact on quality of life. For patients requiring haemodialysis, the need for an adequately functioning vascular access (VA) is an everyday concern. The Vascular Access Questionnaire (VAQ) provides a mechanism for identifying and scoring factors in haemodialysis that impact on patients' quality of life and perception of their therapy. METHODS: Between April 2017-18 the VAQ was administered to prevalent haemodialysis patients at 10 units in the West Midlands via structured interviews. RESULTS: 749 of 920 potentially eligible patients completed the survey. The mean VAQ score was seen to improve significantly with age (7.7 in < 55 vs. 3.8 in 75+) and the duration of access (8.9 if less than 1 month old vs. 5.0 at a year). Better average scores were demonstrated for Arteriovenous fistulas (AVF) than other modalities (AVF 5.1 vs. AVG (arteriovenous grafts) 7.2 vs. CVC (central venous catheter) 6.6). There was no significant difference in scores between fistulas on non-dominant or dominant arms, with both having a mean of 5.2 (p = 0.341). CONCLUSIONS: Overall, better satisfaction scores were seen in AVF. The presence of an AVF on the non-dominant arm was not a concern for the majority of patients and did not affect the VAQ score. A number of factors were identified that can influence VAQ satisfaction score.

Activity of oxygen-versus sulfur-containing analogs of the Flex-Het anticancer agent SHetA2.

Five series of chromans with urea and thiourea linkers connecting a chroman unit (ring A) and a 4-substituted benzene unit (ring B) have been prepared and evaluated relative to SHetA2 (NSC 721689) for activity against the human A2780 ovarian cancer cell line. The lead compound SHetA2 had a sulfur in place of the oxygen in ring A and a thiourea linker to ring B. The 2-Me-4-Me series (two sets of geminal dimethyl groups at C2 and at C4 on the ring A unit) permitted direct comparison with SHetA2. Ring B in this series was evaluated with specific functional groups at C4 on the ring, including NO2, CO2Et, CF3, OCF3, CN and SO2NH2. The 2-H-4-Me series (only one geminal dimethyl group at the C4 position on ring A) permitted structure-activity relationship analysis to assess the importance of the hydrophobic geminal dimethyl groups on ring A to the activity of SHetA2. The remaining three series 2-Et-4-Me, 2-Me-4-Et and 2-Et-4-Et (ring A methyl groups replaced with ethyls at C2, at C4 and at both C2 and C4, respectively) offered the opportunity to modulate the hydrophobicity of the chroman moiety. Additionally, in all these series, the influence of a urea versus a thiourea linker was also investigated. The results of these modifications are summarized below. The exact analog of SHetA2 with oxygen substituted for sulfur in ring A (2a) showed comparable efficacy but a significantly lower IC50 against the ovarian cancer cell line. The urea linked analogs bearing CN, CF3 and OCF3 at C4 of ring B (3c,d and f) showed greater efficacy than SHetA2, but also had lower IC50 values. Removing the geminal dimethyl group at C2 (4a-c, 5a-c) caused a significant lowering of the efficacy and percent growth inhibition, indicating that the hydrophobic geminal dimethyl group at C2 in ring A is crucial for activity. Finally, replacing the geminal dimethyl groups with geminal diethyls on ring A in the urea derivatives gave 6b-c, 7c-d and 8b, all of which outperformed SHetA2 with respect to efficacy and IC50. The results for compounds 4-8 are in concurrence with modeling studies, which predicted that greater hydrophobicity in ring A would be beneficial. Binding energies were determined for compounds docked in silico to mortalin, the protein identified as a receptor of SHetA2. The urea linker promoted activity comparable to or, in some cases, greater than compounds with a thiourea linker. Several compounds achieved 94% efficacy and an IC50 of 2 µM, which were better than SHetA2 (84%, 3 µM).

State and trait influences on attentional bias to food-cues: The role of hunger, expectancy, and self-perceived food addiction.

Food-related attentional bias (AB) varies both between individuals (i.e. trait differences) and within individuals (i.e. state differences), as a function of a food's momentary incentive value. People with self-perceived food addiction (SPFA) find food particularly rewarding and may therefore demonstrate increased AB to food-related cues, relative to those who do not perceive themselves as food addicts. However, these trait differences may interact with state factors, such as hunger and the perceived availability of food, to differentially affect AB to food-cues. In the current study, female participants (N = 120) completed an eye-tracking task to assess AB to chocolate pictures in which the expectancy of receiving chocolate was manipulated on a trial-by-trial basis (0%, 50%, 100%). Participants were randomly allocated such that half completed the task when hungry (hungry condition), and half completed the task following a lunch meal (satiated condition). Participants also indicated the extent to which they perceived themselves to be 'food addicts' (SPFAs: n = 37; Non-addicts: n = 53; Undecided: n = 28). Consistent with previous findings, there was a significant main effect of chocolate expectancy; food-related AB was greater on 100% and 50% trials, compared to 0% trials. However, there was no effect of hunger condition (hungry vs. satiated) on AB. Contrary to our hypotheses, SPFAs did not show increased AB to food-cues, and this was not moderated by hunger condition or the expectancy information. Exploratory analyses revealed that higher desire-to-eat (DtE) chocolate was associated with increased AB to chocolate pictures. These findings partially support contemporary theoretical models of AB by indicating a key role for state factors (reward expectancy, DtE) in determining AB to food-cues, while a trait factor (SPFA) was not a significant determinant of food AB.

Graphitization of Glassy Carbon after Compression at Room Temperature.

Glassy carbon is a technologically important material with isotropic properties that is nongraphitizing up to ∼3000 °C and displays complete or "superelastic" recovery from large compression. The pressure limit of these properties is not yet known. Here we use experiments and modeling to show permanent densification, and preferred orientation occurs in glassy carbon loaded to 45 GPa and above, where 45 GPa represents the limit to the superelastic and nongraphitizing properties of the material. The changes are explained by a transformation from its sp^{2} rich starting structure to a sp^{3} rich phase that reverts to fully sp^{2} bonded oriented graphite during pressure release.

MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Evolution of 2D tin oxides on the surface of molten tin.

The exfoliation of two dimensional (2D) oxides, established on the surface of specific liquid metals, has recently been introduced. One such liquid metal is molten tin, which forms a variety of surface 2D oxides. However, the development behaviour of these surface tin oxides is still unknown. Here the evolution of stoichiometry and thickness from single-layer SnO to highly oxidised multi-layer SnO2 in ambient oxygen is explored.

De novo and inherited mutations in the X-linked gene CLCN4 are associated with syndromic intellectual disability and behavior and seizure disorders in males and females.

Variants in CLCN4, which encodes the chloride/hydrogen ion exchanger CIC-4 prominently expressed in brain, were recently described to cause X-linked intellectual disability and epilepsy. We present detailed phenotypic information on 52 individuals from 16 families with CLCN4-related disorder: 5 affected females and 2 affected males with a de novo variant in CLCN4 (6 individuals previously unreported) and 27 affected males, 3 affected females and 15 asymptomatic female carriers from 9 families with inherited CLCN4 variants (4 families previously unreported). Intellectual disability ranged from borderline to profound. Behavioral and psychiatric disorders were common in both child- and adulthood, and included autistic features, mood disorders, obsessive-compulsive behaviors and hetero- and autoaggression. Epilepsy was common, with severity ranging from epileptic encephalopathy to well-controlled seizures. Several affected individuals showed white matter changes on cerebral neuroimaging and progressive neurological symptoms, including movement disorders and spasticity. Heterozygous females can be as severely affected as males. The variability of symptoms in females is not correlated with the X inactivation pattern studied in their blood. The mutation spectrum includes frameshift, missense and splice site variants and one single-exon deletion. All missense variants were predicted to affect CLCN4's function based on in silico tools and either segregated with the phenotype in the family or were de novo. Pathogenicity of all previously unreported missense variants was further supported by electrophysiological studies in Xenopus laevis oocytes. We compare CLCN4-related disorder with conditions related to dysfunction of other members of the CLC family.

Incorrect dosage of IQSEC2, a known intellectual disability and epilepsy gene, disrupts dendritic spine morphogenesis.

There is considerable genetic and phenotypic heterogeneity associated with intellectual disability (ID), specific learning disabilities, attention-deficit hyperactivity disorder, autism and epilepsy. The intelligence quotient (IQ) motif and SEC7 domain containing protein 2 gene (IQSEC2) is located on the X-chromosome and harbors mutations that contribute to non-syndromic ID with and without early-onset seizure phenotypes in both sexes. Although IQ and Sec7 domain mutations lead to partial loss of IQSEC2 enzymatic activity, the in vivo pathogenesis resulting from these mutations is not known. Here we reveal that IQSEC2 has a key role in dendritic spine morphology. Partial loss-of-function mutations were modeled using a lentiviral short hairpin RNA (shRNA) approach, which achieved a 57% knockdown of Iqsec2 expression in primary hippocampal cell cultures from mice. Investigating gross morphological parameters after 8 days of in vitro culture (8DIV) identified a 32% reduction in primary axon length, in contrast to a 27% and 31% increase in the number and complexity of dendrites protruding from the cell body, respectively. This increase in dendritic complexity and spread was carried through dendritic spine development, with a 34% increase in the number of protrusions per dendritic segment compared with controls at 15DIV. Although the number of dendritic spines had normalized by 21DIV, a reduction was noted in the number of immature spines. In contrast, when modeling increased dosage, overexpression of wild-type IQSEC2 led to neurons with shorter axons that were more compact and displayed simpler dendritic branching. Disturbances to dendritic morphology due to knockdown of Iqsec2 were recapitulated in neurons from Iqsec2 knockout mice generated in our laboratory using CRISPR/Cas9 technology. These observations provide evidence of dosage sensitivity for IQSEC2, which normally escapes X-inactivation in females, and links these disturbances in expression to alterations in the morphology of developing neurons.

Bright and photostable nitrogen-vacancy fluorescence from unprocessed detonation nanodiamond.

Bright and photostable fluorescence from nitrogen-vacancy (NV) centers is demonstrated in unprocessed detonation nanodiamond particle aggregates. The optical properties of these particles is analyzed using confocal fluorescence microscopy and spectroscopy, time resolved fluorescence decay measurements, and optically detected magnetic resonance experiments. Two particle populations with distinct optical properties are identified and compared to high-pressure high-temperature (HPHT) fluorescent nanodiamonds. We find that the brightness of one detonation nanodiamond particle population is on the same order as that of highly processed fluorescent 100 nm HPHT nanodiamonds. Our results may open the path to a simple and up-scalable route for the production of fluorescent NV nanodiamonds for use in bioimaging applications.