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OBJECTIVE: Epilepsy is common in patients with PIGN diseases due to biallelic variants; however, limited epilepsy phenotyping data have been reported. We describe the epileptology of PIGN encephalopathy. METHODS: We recruited patients with epilepsy due to biallelic PIGN variants and obtained clinical data regarding age at seizure onset/offset and semiology, development, medical history, examination, electroencephalogram, neuroimaging, and treatment. Seizure and epilepsy types were classified. RESULTS: Twenty six patients (13 female) from 26 families were identified, with mean age 7 years (range = 1 month to 21 years; three deceased). Abnormal development at seizure onset was present in 25 of 26. Developmental outcome was most frequently profound (14/26) or severe (11/26). Patients presented with focal motor (12/26), unknown onset motor (5/26), focal impaired awareness (1/26), absence (2/26), myoclonic (2/26), myoclonic-atonic (1/26), and generalized tonic-clonic (2/26) seizures. Twenty of 26 were classified as developmental and epileptic encephalopathy (DEE): 55% (11/20) focal DEE, 30% (6/20) generalized DEE, and 15% (3/20) combined DEE. Six had intellectual disability and epilepsy (ID+E): two generalized and four focal epilepsy. Mean age at seizure onset was 13 months (birth to 10 years), with a lower mean onset in DEE (7 months) compared with ID+E (33 months). Patients with DEE had drug-resistant epilepsy, compared to 4/6 ID+E patients, who were seizure-free. Hyperkinetic movement disorder occurred in 13 of 26 patients. Twenty-seven of 34 variants were novel. Variants were truncating (n = 7), intronic and predicted to affect splicing (n = 7), and missense or inframe indels (n = 20, of which 11 were predicted to affect splicing). Seven variants were recurrent, including p.Leu311Trp in 10 unrelated patients, nine with generalized seizures, accounting for nine of the 11 patients in this cohort with generalized seizures. SIGNIFICANCE: PIGN encephalopathy is a complex autosomal recessive disorder associated with a wide spectrum of epilepsy phenotypes, typically with substantial profound to severe developmental impairment.

In recent years, NFTs have burst onto the global scene, quickly going from an internet meme to a multi-billion dollar digital industry. These digital assets have everyone talking, but nobody seems to know what they are or whether you actually own anything when you buy one. This article uses extensive philosophical, legal, copyright, and empirical research to explore what is actually being purchased with an NFT. With everything from the morale words of John Locke to warnings from the district office of Manhattan, this article quantifies what NFT ownership entails, which is, essentially, nothing. Although governments acknowledge the possibility of legitimate ownership for NFTs, the lack of regulations and protections, as well as the unclear copyright laws and shady ownership claims make NFTs, for our current legal system at least, essentially worthless.

Forests are currently a substantial carbon sink globally. Many climate change mitigation strategies leverage forest preservation and expansion, but rely on forests storing carbon for decades to centuries. Yet climate-driven disturbances pose critical risks to the long-term stability of forest carbon. We quantify the climate drivers that influence wildfire and climate stress-driven tree mortality, including a separate insect-driven tree mortality, for the contiguous United States for current (1984-2018) and project these future disturbance risks over the 21st century. We find that current risks are widespread and projected to increase across different emissions scenarios by a factor of >4 for fire and >1.3 for climate-stress mortality. These forest disturbance risks highlight pervasive climate-sensitive disturbance impacts on US forests and raise questions about the risk management approach taken by forest carbon offset policies. Our results provide US-wide risk maps of key climate-sensitive disturbances for improving carbon cycle modeling, conservation and climate policy.

Introduction Eating disorders are complex to manage, and there is limited guidance around the depth and breadth of knowledge, skills and experience required by treatment providers. The Australia & New Zealand Academy for Eating Disorders (ANZAED) convened an expert group of eating disorder researchers and clinicians to define the clinical practice and training standards recommended for mental health professionals and dietitians providing treatment for individuals with an eating disorder. General principles and clinical practice standards were first developed, after which separate mental health professional and dietitian standards were drafted and collated by the appropriate members of the expert group. The subsequent review process included four stages of consultation and document revision: (1) expert reviewers; (2) a face-to-face consultation workshop attended by approximately 100 health professionals working within the sector; (3) an extensive open access online consultation process; and (4) consultation with key professional and consumer/carer stakeholder organisations. Recommendations The resulting paper outlines and describes the following eight eating disorder treatment principles: (1) early intervention is essential; (2) co-ordination of services is fundamental to all service models; (3) services must be evidence-based; (4) involvement of significant others in service provision is highly desirable; (5) a personalised treatment approach is required for all patients; (6) education and/or psychoeducation is included in all interventions; (7) multidisciplinary care is required and (8) a skilled workforce is necessary. Seven general clinical practice standards are also discussed, including: (1) diagnosis and assessment; (2) the multidisciplinary care team; (3) a positive therapeutic alliance; (4) knowledge of evidence-based treatment; (5) knowledge of levels of care; (6) relapse prevention; and (7) professional responsibility. Conclusions These principles and standards provide guidance to professional training programs and service providers on the development of knowledge required as a foundation on which to build competent practice in the eating disorder field. Implementing these standards aims to bring treatment closer to best practice, and consequently improve treatment outcomes, reduce financial cost to patients and services and improve patient quality of life.

Diffuse intrinsic pontine glioma (DIPG), now reclassified as diffuse midline glioma (DMG), is the most common cause of mortality from paediatric central nervous system (CNS) tumours. Diagnosis is made based on characteristic clinical presentation and neuro-imaging findings. Prognosis is poor, with minimal therapeutic options, reflected in a median survival of under 12 months. We present a patient with Pendred syndrome, diagnosed with DMG at 2-years of age with characteristic presentation and neuro-imaging findings, who remains asymptomatic and well at nearly 4-years post diagnosis despite progression of the primary lesion on serial imaging.

There is international interest for consensus advice for prescribers working in the field of drug resistant epilepsy intending to trial potential therapies that are nonregistered or off-label. Cannabinoids are one such therapy. In 2017, the New South Wales State Government (Australia) set up a cannabinoid prescribing guidance service for a wide variety of indications, based on known pharmacology together with the relevant new literature as it became available. Increasing interest in cannabis medicines use outside this State over the following 5 years together with a paucity of registration-standard clinical trials, lack of information around dosing issues, drug interactions and biological plausibility meant there remained a large unmet need for such advice. To address the unmet need in epilepsy, and until medicines were registered or regulator quality data were available, it was agreed to bring together a working group comprising paediatric and adult epilepsy specialists, clinical pharmacists., clinical pharmacologists and cannabis researchers from across Australia to develop interim consensus advice for prescribers. Although interim, this consensus advice addresses much of the current practice gap by providing an informed overview of the different cannabis medicines currently available for use in the treatment of epilepsy in paediatric and adult settings, with information on dose, drug interactions, toxicity, type of seizure and frequency of symptom relief. As such it supplements the limited evidence currently available from clinical trials with experience from front-line practice. It is expected that this consensus advice will be updated as new evidence emerges and will provide guidance for a subsequent Guideline.

The majority of cortical synapses are local and excitatory. Local recurrent circuits could implement amplification, allowing for pattern completion and other computations1. Cortical circuits contain subnetworks, consisting of neurons with similar receptive fields and elevated connectivity relative to the network average2,3. Understanding the computations performed by these subnetworks during behavior has been hampered by the fact that cortical neurons encoding different types of information are spatially intermingled and distributed over large brain volumes 4,5. We used computational modeling, optical recordings and manipulations to probe the function of recurrent coupling in layer (L) 2/3 of the somatosensory cortex during tactile discrimination. A model of L2/3 dynamics revealed that recurrent excitation enhances sensory signals via amplification, but only for subnetwork with elevated connectivity. Networks with high amplification were sensitive to damage: loss of a few subnetwork members degraded stimulus encoding. We tested this prediction experimentally by mapping neuronal selectivity5 and photoablating6,7 neurons with specific selectivity. In L2/3 of the somatosensory cortex, ablating a small proportion (10-20, < 5 % of the total) of neurons representing touch dramatically reduced responses in the spared touch representation, but not other representations. Network models further predicted that degradation following ablation should be greatest among spared neurons with stimulus responses that were most similar to the ablated population. Consistent with this prediction, ablations most strongly impacted neurons with selectivity similar to the ablated population. Our data shows that recurrence among cortical neurons with similar selectivity can drive input-specific amplification during behavior.

There is international interest for consensus advice for prescribers working in the field of drug resistant epilepsy intending to trial potential therapies which are non-registered or off-label. Cannabinoids are one such therapy. In Australia in 2017, the New South Wales State Government set up a cannabinoid prescribing guidance service for a wide variety of indications, based on known pharmacology together with the relevant new literature as it became available. Increasing interest in cannabis medicines outside NSW over the following last five years together with a paucity of registration-standard clinical trials and lack of information around dosing issues, drug interactions and biological plausibility means there remains a large unmet need for such advice. To address the unmet need, and until medicines were registered or regulator quality data was available, it was agreed to bring together a working group comprising paediatric and adult epilepsy specialists, clinical pharmacists. pharmacologists and cannabis researchers from across Australia, to develop interim ‘Consensus Advice’ for prescribers. Although interim, this consensus advice addresses much of the current practice gap by providing an informed overview of the different cannabis medicines currently available for use in the treatment of epilepsy in paediatric and adult settings, with information on dose, drug interactions, toxicity and type and frequency of symptom and seizure relief. As such it supplements the limited evidence currently available from clinical trials with experience from front-line practice. It is expected that this consensus advice will be updated as new evidence emerges and will provide guidance for a subsequent Guideline.

Advances are needed to ensure safe and effective treatment is available for people with eating disorders. Recently developed clinical practice and training standards for mental health professionals and dietitians represent a significant step in this direction by providing a consensus statement on eating disorder treatment as a foundation on which to build competent practice. This commentary argues that a credentialing system could promote implementation of these practice standards through formal recognition of qualifications, knowledge, training and professional activities to meet minimum standards for delivery of safe and effective eating disorder treatment. Drivers for credentialing include the imperative to provide safe and effective care, promotion of workforce development in eating disorder practice and, importantly, readily available and transparent information for referrers, consumers, and carers to identify health professionals credentialed to provide eating disorder treatment. However, a number of factors must be considered to ensure that credentialing does not restrict access to care, such as prohibitively narrow criteria to become credentialed, absence of pathways for education, training, or professional development opportunities, and lack of consultation with or endorsement by stakeholders of the credentialing criteria, application and approval processes, and ways of identifying credentialed practitioners. Further work, including development of credentialing criteria and aligned training opportunities, currently being undertaken by the Australia & New Zealand Academy for Eating Disorders and the National Eating Disorders Collaboration in consultation with stakeholders in the eating disorders sector and health professions will advance understanding of the feasibility of a system of credentialing for eating disorders within Australia and New Zealand. The availability of clinical practice and training standards, supported by implementation pathways, including credentialing of eating disorders practitioners, aim to improve quality of life, reduce financial burden, and close the treatment gap.

Carbon offsets are widely used by individuals, corporations, and governments to mitigate their greenhouse gas emissions on the assumption that offsets reflect equivalent climate benefits achieved elsewhere. These climate-equivalence claims depend on offsets providing real and additional climate benefits beyond what would have happened, counterfactually, without the offsets project. Here, we evaluate the design of California's prominent forest carbon offsets program and demonstrate that its climate-equivalence claims fall far short on the basis of directly observable evidence. By design, California's program awards large volumes of offset credits to forest projects with carbon stocks that exceed regional averages. This paradigm allows for adverse selection, which could occur if project developers preferentially select forests that are ecologically distinct from unrepresentative regional averages. By digitizing and analyzing comprehensive offset project records alongside detailed forest inventory data, we provide direct evidence that comparing projects against coarse regional carbon averages has led to systematic over-crediting of 30.0 million tCO2 e (90% CI: 20.5-38.6 million tCO2 e) or 29.4% of the credits we analyzed (90% CI: 20.1%-37.8%). These excess credits are worth an estimated $410 million (90% CI: $280-$528 million) at recent market prices. Rather than improve forest management to store additional carbon, California's forest offsets program creates incentives to generate offset credits that do not reflect real climate benefits.

Forests are currently a substantial carbon sink globally. Many climate change mitigation strategies rely on forest preservation and expansion, but the effectiveness of these approaches hinges on forests sequestering carbon for centuries despite anthropogenic climate change. Yet climate-driven disturbances pose critical risks to the long-term stability of forest carbon. We quantify the key climate drivers that fuel wildfire, drought, and insects, for the United States over 1984-2018 and project future disturbance risks over the 21st century. We find that current risks are widespread and projected to increase across different emission scenarios by a factor of 4-14 for fire and 1.3-1.8 for drought and insects. Our results provide insights for carbon cycle modeling, conservation, and climate policy, underscoring the escalating climate risks facing forests and the need for emissions reductions to mitigate climate change.

Carbon offsets are widely used by individuals, corporations, and governments to mitigate their greenhouse gas emissions on the assumption that offsets reflect equivalent climate benefits achieved elsewhere. These climate-equivalence claims depend on offsets providing “additional” climate benefits beyond what would have happened, counterfactually, without the offsets project. Here, we evaluate the design of California’s prominent forest carbon offsets program and demonstrate that its climate-equivalence claims fall far short on the basis of directly observable evidence. By design, California’s program awards large volumes of offset credits to forest projects with carbon stocks that exceed regional averages. This paradigm allows for adverse selection, which could occur if project developers preferentially select forests that are ecologically distinct from unrepresentative regional averages. By digitizing and analyzing comprehensive offset project records alongside detailed forest inventory data, we provide direct evidence that comparing projects against coarse regional carbon averages has led to systematic over-crediting of 30.0 million tCO2e (90% CI: 20.5 to 38.6 million tCO2e) or 29.4% of the credits we analyzed (90% CI: 20.1 to 37.8%). These excess credits are worth an estimated $410 million (90% CI: $280 to $528 million) at recent market prices. Rather than improve forest management to store additional carbon, California’s offsets program creates incentives to generate offset credits that do not reflect real climate benefits.Significance StatementForest carbon offsets are increasingly prominent in corporate and government “net zero” emission strategies, but face growing criticism about their efficacy. California’s forest offsets program is frequently promoted as a high-quality approach that improves on the failures of earlier efforts. Our analysis demonstrates, however, that substantial ecological and statistical shortcomings in the design of California’s forest offset protocol generate offset credits that do not reflect real climate benefits. Looking globally, our results illustrate how protocol designs with easily exploitable rules can undermine policy objectives and highlight the need for stronger governance in carbon offset markets.

Quickly and flexibly exploring high-dimensional datasets, such as scRNAseq data, is underserved but critical for hypothesis generation, dataset annotation, publication, sharing, and community reuse. cellxgene is a highly generalizable, web-based interface for exploring high dimensional datasets along categorical, continuous and spatial dimensions, as well as feature annotation. cellxgene is differentiated by its ability to performantly handle millions of observations, and bridges a critical gap by enabling computational and experimental biologists to iteratively ask questions of private and public datasets. In doing so, cellxgene increases the utility and reusability of datasets across the single-cell ecosystem.The codebase can be accessed at https://github.com/chanzuckerberg/cellxgene. For questions and inquiries, please contact cellxgene@chanzuckerberg.com.

Whole-brain imaging allows for comprehensive functional mapping of distributed neural pathways, but neuronal perturbation experiments are usually limited to targeting predefined regions or genetically identifiable cell types. To complement whole-brain measures of activity with brain-wide manipulations for testing causal interactions, we introduce a system that uses measured activity patterns to guide optical perturbations of any subset of neurons in the same fictively behaving larval zebrafish. First, a light-sheet microscope collects whole-brain data that are rapidly analyzed by a distributed computing system to generate functional brain maps. On the basis of these maps, the experimenter can then optically ablate neurons and image activity changes across the brain. We applied this method to characterize contributions of behaviorally tuned populations to the optomotor response. We extended the system to optogenetically stimulate arbitrary subsets of neurons during whole-brain imaging. These open-source methods enable delineating the contributions of neurons to brain-wide circuit dynamics and behavior in individual animals.

Introduction The Australia & New Zealand Academy for Eating Disorders (ANZAED) recently developed general principles and clinical practice standards recommended for mental health clinicians and dietitians providing treatment for people with eating disorders. Separate mental health practice and training standards were then devised as a foundation for strengthening the workforce and providing guidance to professional training programs and service providers on the minimal standards required for practice in the eating disorder field. Recommendations The present recommendations for mental health professionals providing eating disorder treatment describe the following practice and training standards: eating disorder treatment foundations (including co-ordination of services, establishing a positive therapeutic alliance, professional responsibility and knowledge of levels of care), assessment, diagnosis, intervention (including evidence-based intervention, managing psychiatric risk and managing co-morbid mental health problems), and monitoring and evaluation. Conclusions Further work is required to disseminate these standards to clinicians providing services across Australia to people with eating disorders, and to support adherence in the clinic room where they can translate to improved outcomes for clients. Pathways to supporting adherence include expert supervision of practice, incorporation in training and supervised practice in university settings, and support with checklists that can be used by consumers and referring professionals.

Risks to mitigation potential of forests Much recent attention has focused on the potential of trees and forests to mitigate ongoing climate change by acting as sinks for carbon. Anderegg et al. review the growing evidence that forests' climate mitigation potential is increasingly at risk from a range of adversities that limit forest growth and health. These include physical factors such as drought and fire and biotic factors, including the depredations of insect herbivores and fungal pathogens. Full assessment and quantification of these risks, which themselves are influenced by climate, is key to achieving science-based policy outcomes for effective land and forest management. Science , this issue p. eaaz7005

The stimulus selectivity of neurons in V1 is well known, as is the finding that their responses can be affected by visual input to areas outside of the classical receptive field. Less well understood are the ways selectivity is modified as signals propagate to visual areas beyond V1, such as V2. We recently proposed a role for V2 neurons in representing the higher order statistical dependencies found in images of naturally occurring visual texture. V2 neurons, but not V1 neurons, respond more vigorously to “naturalistic” images that contain these dependencies than to “noise” images that lack them. In this work, we examine the dependency of these effects on stimulus size. For most V2 neurons, the preference for naturalistic over noise stimuli was modest when presented in small patches and gradually strengthened with increasing size, suggesting that the mechanisms responsible for this enhanced sensitivity operate over regions of the visual field that are larger than the classical receptive field. Indeed, we found that surround suppression was stronger for noise than for naturalistic stimuli and that the preference for large naturalistic stimuli developed over a delayed time course consistent with lateral or feedback connections. These findings are compatible with a spatially broad facilitatory mechanism that is absent in V1 and suggest that a distinct role for the receptive field surround emerges in V2 along with sensitivity for more complex image structure. NEW & NOTEWORTHY The responses of neurons in visual cortex are often affected by visual input delivered to regions of the visual field outside of the conventionally defined receptive field, but the significance of such contextual modulations are not well understood outside of area V1. We studied the importance of regions beyond the receptive field in establishing a novel form of selectivity for the statistical dependencies contained in natural visual textures that first emerges in area V2.

Introduction Narsoplimab (OMS721) is a fully human monoclonal antibody that binds to and inhibits mannan-binding lectin-associated serine protease 2 (MASP-2). MASP-2 is the key enzyme responsible for activation of the lectin pathway of the complement system. The lectin pathway is activated when plasma is exposed to molecular patterns present on microbes and injured host cell surfaces, initiating a proteolytic cascade that results in the activation of complement components C4, C2, C3 and C5 to yield multiple biologically active products. Inhibiting MASP-2 activity prevents lectin-mediated generation of complement activation products, thereby reducing inflammation and tissue injury. Narsoplimab is the first lectin pathway-specific complement inhibitor in clinical development. In published clinical studies and case reports, improvement has been observed in narsoplimab-treated patients with hematopoietic stem cell transplant-associated thrombotic microangiopathy, immunoglobulin A (IgA) nephropathy and atypical hemolytic uremic syndrome. Here we describe the development of pharmacodynamic (PD) assays to quantify MASP-2 inhibition ex vivo and their use to study duration of action and to establish the pharmacokinetic (PK)/PD relationship of narsoplimab in monkeys and humans. Methods PD assays to measure lectin pathway activity, a measure of MASP-2 activity, in minimally diluted (90%) serum from human and monkey were developed using immobilized mannan as a lectin pathway-specific complement activator with C4b as the activation endpoint. ELISA and flow cytometry assay platforms were employed to assess the PD response of monkeys or normal healthy human volunteers administered narsoplimab, respectively. The PD response was used to characterize the time-course and dose-response of lectin pathway inhibition by narsoplimab. Drug concentration data obtained from matched serum samples were used to estimate the ex vivo EC50 of lectin pathway inhibition in monkeys and humans. Lectin pathway-specific complement activation assays applicable to minimally diluted serum samples were developed by evaluating the time-course of lectin-induced complement activation response under varying reaction temperatures and selecting optimized test conditions within the dynamic range of the assay platform. The test methods were used to characterize monkey and human lectin pathway inhibition profiles of narsoplimab in vitro, and the flow cytometric method was validated for analysis of human serum samples. Results The PD assays were used to characterize the PD response of monkeys administered a single intravenous (IV) bolus injection of narsoplimab at 0.05, 0.15, 0.5, 1.5 or 5 mg/kg, and of normal human healthy volunteers administered a single IV infusion of the drug at 0.25, 0.625 or 2 mg/kg, or 6 weekly IV infusions at 2 or 4 mg/kg. A clear, dose-dependent initial PD response was observed in monkeys in the dose range of 0.5 mg/kg to 5 mg/kg, which subsequently declined over time. In humans, a minimal PD response was observed at 0.025 mg/kg. A near maximal initial PD response was seen at 0.675 mg/kg or higher, followed by a decline over time. In the 6-week repeat-dose study, once-weekly dosing of narsoplimab at 2 mg/kg resulted in a mean trough PD response of ~55% lectin pathway inhibition, which increased to an ~80% mean trough response with once-weekly dosing of 4 mg/kg. PK sample analysis revealed a clear PK/PD relationship in monkeys and humans. Modeling of the PK/PD relationship in monkeys indicated an EC50 value of ~7 µg/mL (~ 46 nM), which is comparable to the IC50 value of lectin pathway inhibition in vitro (33 nM). In humans, modeling of the PK/PD relationship data indicated an EC50 value of ~500 ng/mL (3.3 nM), again very similar to the IC50 value of lectin pathway inhibition in vitro (3.4 nM). Conclusion We successfully developed PD assays to monitor blockade of lectin pathway activation in monkeys and humans administered narsoplimab. Using a validated PD assay, we demonstrate that a high level of lectin pathway blockade can be maintained in normal human healthy volunteers by once-weekly administration of narsoplimab at 4 mg/kg IV. We also demonstrate a consistent PK/PD relationship across the study population, indicating that narsoplimab concentration ranges can be used to target the desired level of lectin pathway inhibition. Figure 1 Disclosures Freeman: Omeros Corporation: Current Employment. Cummings:Omeros Corporation: Current Employment. Chuidian:Omeros Corporation: Current Employment. Dudler:Omeros Corporation: Current Employment.

BACKGROUND: Infantile spasms constitute a severe form of epileptic encephalopathy. In the International Collaborative Infantile Spasms Study (ICISS), we showed that combining vigabatrin with hormonal therapy was more effective than hormonal therapy alone at stopping spasms between days 14 and 42 of treatment. In this planned follow-up, we aimed to assess whether combination therapy was associated with improved developmental and epilepsy outcomes at 18 months of age.METHODS: In ICISS, a multicentre, open-label, randomised controlled trial, infants were enrolled from 102 hospitals (three in Australia, 11 in Germany, two in New Zealand, three in Switzerland, and 83 in the UK). Eligible infants had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) electroencephalogram (EEG) no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing epilepsy and developmental outcomes at 18 months were masked to treatment allocation. Minimum doses were oral prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without oral vigabatrin 100 mg/kg per day. The primary outcome at 18 months was development as assessed by the Vineland Adaptive Behaviour Scales (VABS) composite score. Secondary outcomes were the presence or absence of epileptic seizures or infantile spasms in the previous 28 days, as recorded by parents and carers, and the use of any anti-epileptic treatment (including ketogenic diet) in the previous 28 days. Analysis was by intention to treat. The trial is registered with the ISRCTN registry, number 54363174, and EudraCT, number 2006-000788-27.FINDINGS: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (n=186) or hormonal therapy alone (n=191). 362 infants were assessed for developmental and epilepsy outcomes at 18 months, 181 in each treatment group. Mean VABS scores did not differ significantly between the combination therapy group and the hormonal therapy alone group (73·9 [SE 1·3] vs 72·7 [1·4], difference -1·2 [95% CI -4·9 to 2·6], p=0·55). Presence of epilepsy at the assessment at age 18 months was similar in both treatment groups (54 [30·0%] of 180 infants who received combination therapy vs 52 [29·2%] of 178 who received hormonal therapy alone; difference 0·8% [95% CI -8·8 to 10·4], p=0·90). Presence of spasms was also similar in both treatment groups (27 [15·0%] of 180 infants on combination therapy vs 28 [15·7%] of 178 on hormonal therapy alone; difference 0·7% [95% CI -6·9 to 8·3], p=0·85). At the 18-month assessment, 158 (44·1%) of 358 infants were on some form of anti-epileptic treatment. Initial control of spasms between days 14 and 42 of treatment was associated with higher mean VABS scores at 18 months (79·1 [SE 1·2] vs 63·2 [1·1], difference 15·9 [95% CI 12·4 to 19·5], pINTERPRETATION: Combination therapy did not result in improved developmental or epilepsy outcomes at 18 months. However, early clinical response to treatment was associated with improved developmental and epilepsy outcomes at 18 months. Longer lead-time to treatment was associated with poorer outcomes. Rapid diagnosis and effective treatment of infantile spasms could therefore improve outcomes.FUNDING: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, BRONNER-BENDER Stiftung/Gernsbach, University Children's Hospital Zurich.

Understanding how the brain operates requires understanding how large sets of neurons function together. Modern recording technology makes it possible to simultaneously record the activity of hundreds of neurons, and technological developments will soon allow recording of thousands or tens of thousands. As with all experimental techniques, these methods are subject to confounds that complicate the interpretation of such recordings, and could lead to erroneous scientific conclusions. Here, we discuss methods for assessing and improving the quality of data from these techniques, and outline likely future directions in this field.

Neural circuitry has evolved to form distributed networks that act dynamically across large volumes. Collecting data from individual planes, conventional microscopy cannot sample circuitry across large volumes at the temporal resolution relevant to neural circuit function and behaviors. Here, we review emerging technologies for rapid volume imaging of neural circuitry. We focus on two critical challenges: the inertia of optical systems, which limits image speed, and aberrations, which restrict the image volume. Optical sampling time must be long enough to ensure high-fidelity measurements, but optimized sampling strategies and point spread function engineering can facilitate rapid volume imaging of neural activity within this constraint. We also discuss new computational strategies for the processing and analysis of volume imaging data of increasing size and complexity. Together, optical and computational advances are providing a broader view of neural circuit dynamics, and help elucidate how brain regions work in concert to support behavior.

Injecting anti-tumor necrosis factor (TNF)α antibodies into patient joints at the site of inflammation, inter-articular (IA) delivery, has demonstrated modest success for treatment of Spondyloarthritis (SpA), Rheumatoid Arthritis (RA), and osteoarthritis. However, IA delivery is not the treatment route of choice due to rapid clearance from the site of administration. Elastin-like polypeptides (ELPs) are reported to undergo phase transition; forming reversible aggregates above their transition temperature, which when injected into IA space have a 25-fold longer half-life compared to the soluble form. Here, we fused an ELP repeat to the C-terminus of each heavy chain of an anti-TNFα monoclonal antibody (mAb) and provide detailed characterization of the fusion IgG molecule. Expression and purification yielded homogenous protein confirmed by gels, hydrophobic-interaction chromatography, Capilary Electrophoresis (CE), Mass Spectrometry (MS), and analytical ultracentrifugation. The ELPs altered hydrophobicity and pI of the parent mAb and new elastic properties were imparted to the molecule; forming large stable complexes with a hydrodynamic radius of 40 nm above 39°C that dissociated into soluble, active monomer below 37°C. The fusion mAb retained its affinity and ability to neutralize TNFα as determined by surface plasmon resonance and cell-based assay, respectively, with equal potency to unmodified anti-TNFα mAb. Differential-scanning calorimetry studies show stabilization of adjacent CH2 and CH3 domains in the fusion molecule and the aggregated molecule was found to be fully functional after 7 days at 37°C. For the first time, we reveal architecture of an ELP-fusion mAb and binding to antigen using single-particle-transmission-electron microscopy. Unstructured ELP was visualized at the C-terminus and binding to antigen was shown at the N-terminus. Collectively, these studies indicate that it is possible to impart elastic properties to a monoclonal antibody while retaining purity, stability, and ability to effectively bind and neutralize antigen.

Direct observation of multiple reactive sites in the zeolite HZSM-5, a member of the MFI family of zeolite structures, contradicts the traditional view of only one type of active protonic species in industrially important zeolites. In addition to the well-known Bronsted acid site proton, two other protonic species undergo room-temperature hydrogen–deuterium exchange with an alkane hydrocarbon reagent, including one zeolite moiety characterized by a broad 1H chemical shift at ca. 12–15 ppm that is reported here for the first time. Although the ca. 13 ppm chemical shift value is consistent with computational predictions from the literature for a surface-stabilized hydroxonium ion in a zeolite, data suggest that the signal does not arise from hydroxonium species but rather from hydroxyls on extra-lattice aluminol species proximate to Bronsted lattice sites, i.e., a small population of highly deshielded acid sites. Double-resonance experiments show that this species is proximate to Al atoms, similar to the Br...

Summary Comprehensive measurement of neural activity remains challenging due to the large numbers of neurons in each brain area. We used volumetric two-photon imaging in mice expressing GCaMP6s and nuclear red fluorescent proteins to sample activity in 75% of superficial barrel cortex neurons across the relevant cortical columns, approximately 12,000 neurons per animal, during performance of a single whisker object localization task. Task-related activity peaked during object palpation. An encoding model related activity to behavioral variables. In the column corresponding to the spared whisker, 300 layer (L) 2/3 pyramidal neurons (17%) each encoded touch and whisker movements. Touch representation declined by half in surrounding columns; whisker movement representation was unchanged. Following the emergence of stereotyped task-related movement, sensory representations showed no measurable plasticity. Touch direction was topographically organized, with distinct organization for passive and active touch. Our work reveals sparse and spatially intermingled representations of multiple tactile features. Video Abstract