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Optimal nutrition during infancy is critical given its influence on lifelong health and wellbeing. Two novel methods of infant complementary feeding, commercial baby food pouch use and baby-led weaning (BLW), are becoming increasingly popular worldwide. Household food insecurity may influence complementary feeding practices adopted by families, but no studies have investigated the use of BLW and baby food pouches in families experiencing food insecurity. The First Foods New Zealand study was a multicentre, observational study in infants 7.0-9.9 months of age. Households (n = 604) were classified into one of three categories of food insecurity (severely food insecure, moderately food insecure, and food secure). The use of complementary feeding practices was assessed via a self-administered questionnaire, both at the current age (mean 8.4 months) and retrospectively at 6 months. Mothers experiencing severe food insecurity had 5.70 times the odds of currently using commercial baby food pouches frequently (≥5 times/week) compared to food secure mothers (95% CI [1.54, 21.01]), reporting that pouches were 'easy to use' (89%) and made it 'easy to get fruits and vegetables in' (64%). In contrast, no evidence of a difference in the prevalence of current BLW was observed among mothers experiencing moderate food insecurity (adjusted OR; 1.28, 95% CI [0.73, 2.24]) or severe food insecurity (adjusted OR; 1.03, 95% CI [0.44, 2.43]) compared to food secure mothers. The high prevalence of frequent commercial baby food pouch use in food insecure households underscores the need for research to determine whether frequent pouch use impacts infant health., (© 2024 The Author(s). Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background: Research in the developmental origins of health and disease provides compelling evidence that adverse events during the first 1000 days of life from conception can impact life course health. Despite many decades of research, we still lack a complete understanding of the mechanisms underlying some of these associations. The Newcastle 1000 Study (NEW1000) is a comprehensive, prospective population-based pregnancy cohort study based in Newcastle, New South Wales, Australia, that will recruit pregnant women and their partners at 11-14 weeks' gestation, with assessments at 20, 28, and 36 weeks; birth; 6 weeks; and 6 months, in order to provide detailed data about the first 1000 days of life to investigate the developmental origins of noncommunicable diseases., Objective: The study aims to provide a longitudinal multisystem approach to phenotyping, supported by robust clinical data and collection of biological samples in NEW1000., Methods: This manuscript describes in detail the large variety of samples collected in the study and the method of collection, storage, and utility of the samples in the biobank, with a particular focus on incorporation of the samples into emerging and novel large-scale "-omics" platforms, including the genome, microbiome, epigenome, transcriptome, fragmentome, metabolome, proteome, exposome, and cell-free DNA and RNA. Specifically, this manuscript details the methods used to collect, process, and store biological samples, including maternal, paternal, and fetal blood, microbiome (stool, skin, vaginal, oral), urine, saliva, hair, toenail, placenta, colostrum, and breastmilk., Results: Recruitment for the study began in March 2021. As of July 2024, 1040 women and 684 partners were enrolled, with 922 infants born. The NEW1000 biobank contains 24,357 plasma aliquots from ethylenediaminetetraacetic acid (EDTA) tubes, 5284 buffy coat aliquots, 4000 plasma aliquots from lithium heparin tubes, 15,884 blood serum aliquots, 2977 PAX RNA tubes, 26,595 urine sample aliquots, 2280 fecal swabs, 17,687 microbiome swabs, 2356 saliva sample aliquots, 1195 breastmilk sample aliquots, 4007 placental tissue aliquots, 2680 hair samples, and 2193 nail samples., Conclusions: NEW1000 will generate a multigenerational, deeply phenotyped cohort with a comprehensive biobank of samples relevant to a large variety of analyses, including multiple -omics platforms., International Registered Report Identifier (irrid): DERR1-10.2196/63562., (©Joshua J Fisher, Tegan Grace, Nathan A Castles, Elizabeth A Jones, Sarah J Delforce, Alexandra E Peters, Gabrielle K Crombie, Emily C Hoedt, Kirby E Warren, Richard GS Kahl, Jonathan J Hirst, Kirsty G Pringle, Craig E Pennell. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 15.11.2024.)

Participants in the 100,000 Genomes Project (100kGP) could consent to receive additional finding (AF) results, individual variants relating to genes associated with susceptibility to cancer and familial hypercholesterolemia (FH). In the study reported here, qualitative interviews were used to explore the experiences of National Health Service (NHS) professionals from across England who were tasked with returning over 80,000 "no AF" results and 700 positive AF results to 100kGP participants. Interviews were conducted with 45 professionals from a range of backgrounds, including Genetic Counsellors, Clinical Geneticists, FH Clinical Nurse Specialists and Clinical Scientists. Interviews were analysed using a codebook thematic analysis approach. Returning AF results has been a significant endeavour, with challenges for pathways, administrative processes and clinical and laboratory time when the capacity of NHS services is already stretched. Professionals discussed going "above and beyond" to prioritise patient care through pathway design, additional clinics, overtime, longer appointments and provision of follow-up appointments. Professionals also described facing practical and emotional challenges when returning AFs. Benefits for patients from receiving AFs in the 100kGP were highlighted and professionals were generally positive about offering clinically actionable AFs within routine NHS clinical care. Professionals were, however, cautious around the implementation of AFs into routine care and felt more research and discussion was needed to determine which AFs to offer, approaches to consent and communication of results, costs and the potential strain on NHS capacity and resources. Further consultation is required with careful review of pathways and resources before offering AFs in clinical practice., (© 2024. The Author(s).)

Animals must navigate changing environments to find food, shelter or mates. In mammals, grid cells in the medial entorhinal cortex construct a neural spatial map of the external environment 1-5 . However, how grid cell firing patterns rapidly adapt to novel or changing environmental features on a timescale relevant to behaviour remains unknown. Here, by recording over 15,000 grid cells in mice navigating virtual environments, we tracked the real-time state of the grid cell network. This allowed us to observe and predict how altering environmental features influenced grid cell firing patterns on a nearly instantaneous timescale. We found evidence that visual landmarks provide inputs to fixed points in the grid cell network. This resulted in stable grid cell firing patterns in novel and altered environments after a single exposure. Fixed visual landmark inputs also influenced the grid cell network such that altering landmarks induced distortions in grid cell firing patterns. Such distortions could be predicted by a computational model with a fixed landmark to grid cell network architecture. Finally, a medial entorhinal cortex-dependent task revealed that although grid cell firing patterns are distorted by landmark changes, behaviour can adapt via a downstream region implementing behavioural timescale synaptic plasticity 6 . Overall, our findings reveal how the navigational system of the brain constructs spatial maps that balance rapidity and accuracy. Fixed connections between landmarks and grid cells enable the brain to quickly generate stable spatial maps, essential for navigation in novel or changing environments. Conversely, plasticity in regions downstream from grid cells allows the spatial maps of the brain to more accurately mirror the external spatial environment. More generally, these findings raise the possibility of a broader neural principle: by allocating fixed and plastic connectivity across different networks, the brain can solve problems requiring both rapidity and representational accuracy., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objective: Most wet commercial infant foods are now sold in squeezable 'pouches'. While multiple expert groups have expressed concern about their use, it is not known how commonly they are consumed and whether they impact energy intake or body mass index (BMI). The objectives were to describe pouch use, and determine associations with energy intake and BMI, in infants and young children., Methods: In this observational cross-sectional study of 933 young New Zealand children (6.0 months-3.9 years), pouch use was assessed by a questionnaire ('frequent' use was consuming food from a baby food pouch ≥5 times/week in the past month), usual energy intake using two 24-h recalls, and BMI z-score calculated using World Health Organization standards., Results: The sample broadly represented the wider population (27.1% high socioeconomic deprivation, 22.5% Māori). Frequent pouch use declined with age (infants 27%, toddlers 16%, preschoolers 8%). Few children were both frequent pouch users and regularly used the nozzle (infants 5%, toddlers 13%, preschoolers 8%). Preschoolers who were frequent pouch users consumed significantly less energy than non-users (-580 kJ [-1094, -67]), but infants (115 [-35, 265]) and toddlers (-206 [-789, 378]) did not appear to have a different energy intake than non-users. There were no statistically significant differences in the BMI z-score by pouch use., Conclusions: These results do not support the strong concerns expressed about their use, particularly given the lack of evidence for higher energy intake or BMI.

Trithorax-related H3K4 methyltransferases, KMT2C and KMT2D, are critical epigenetic modifiers. Haploinsufficiency of KMT2C was only recently recognized as a cause of neurodevelopmental disorder (NDD), so the clinical and molecular spectrums of the KMT2C-related NDD (now designated as Kleefstra syndrome 2) are largely unknown. We ascertained 98 individuals with rare KMT2C variants, including 75 with protein-truncating variants (PTVs). Notably, ∼15% of KMT2C PTVs were inherited. Although the most highly expressed KMT2C transcript consists of only the last four exons, pathogenic PTVs were found in almost all the exons of this large gene. KMT2C variant interpretation can be challenging due to segmental duplications and clonal hematopoesis-induced artifacts. Using samples from 27 affected individuals, divided into discovery and validation cohorts, we generated a moderate strength disorder-specific KMT2C DNA methylation (DNAm) signature and demonstrate its utility in classifying non-truncating variants. Based on 81 individuals with pathogenic/likely pathogenic variants, we demonstrate that the KMT2C-related NDD is characterized by developmental delay, intellectual disability, behavioral and psychiatric problems, hypotonia, seizures, short stature, and other comorbidities. The facial module of PhenoScore, applied to photographs of 34 affected individuals, reveals that the KMT2C-related facial gestalt is significantly different from the general NDD population. Finally, using PhenoScore and DNAm signatures, we demonstrate that the KMT2C-related NDD is clinically and epigenetically distinct from Kleefstra and Kabuki syndromes. Overall, we define the clinical features, molecular spectrum, and DNAm signature of the KMT2C-related NDD and demonstrate they are distinct from Kleefstra and Kabuki syndromes highlighting the need to rename this condition., Competing Interests: Declaration of interests R.W. is a consultant (equity) for Alamya Health., (Copyright © 2024 American Society of Human Genetics. All rights reserved.)

Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases., (© 2024. The Author(s).)

The full impact of apolipoprotein E4 (APOE4), the strongest genetic risk factor for Alzheimer's disease (AD), on neuronal and network function remains unclear. We found hippocampal region-specific network hyperexcitability in young APOE4 knock-in (E4-KI) mice which predicted cognitive deficits at old age. Network hyperexcitability in young E4-KI mice was mediated by hippocampal region-specific subpopulations of smaller and hyperexcitable neurons that were eliminated by selective removal of neuronal APOE4. Aged E4-KI mice exhibited hyperexcitable granule cells, a progressive inhibitory deficit, and E/I imbalance in the dentate gyrus, exacerbating hippocampal hyperexcitability. Single-nucleus RNA-sequencing revealed neuronal cell type-specific and age-dependent transcriptomic changes, including Nell2 overexpression in E4-KI mice. Reducing Nell2 expression in specific neuronal types of E4-KI mice with CRISPRi rescued their abnormal excitability phenotypes, implicating Nell2 overexpression as a cause of APOE4-induced hyperexcitability. These findings highlight the early transcriptomic and electrophysiological alterations underlying APOE4-induced hippocampal network dysfunction and its contribution to AD pathogenesis with aging.

Fibromyalgia, a chronic pain condition marked by abnormal pain processing, impacts a significant part of the population, leading to reduced quality of life and function. Hallmark symptoms include widespread persistent pain, sleep disturbances, fatigue, cognitive dysfunction, and mood changes. Through this updated review, we aim to contribute to the evolving understanding and management of fibromyalgia, offering insights into the diverse tools available to improve the lives of those affected by this challenging condition. Management begins with educating patients to ultimately relieve them of unnecessary testing and provide reassurance. Treatment emphasizes a comprehensive approach, combining nonpharmacological interventions such as aforementioned education, exercise, and psychotherapy, alongside pharmacologic management-namely duloxetine, milnacipran, pregabalin, and amitriptyline-which have consistent benefits for a range of symptoms across the spectrum of fibromyalgia. Notably, drugs like nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are generally not recommended due to limited efficacy and associated risks. Lastly, a variety of other medications have shown promise, including NMDA-receptor antagonists, naltrexone, and cannabinoids; however, they should be used with caution due to a small amount of evidence and potential for adverse effects.

Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)-a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis., (© 2024. The Author(s).)

Iron deficiency in infants can impact development, and there are concerns that the use of baby food pouches and baby-led weaning may impair iron status. First Foods New Zealand (FFNZ) was an observational study of 625 New Zealand infants aged 6.9 to 10.1 months. Feeding methods were defined based on parental reports of infant feeding at "around 6 months of age": "frequent" baby food pouch use (five+ times per week) and "full baby-led weaning" (the infant primarily self-feeds). Iron status was assessed using a venepuncture blood sample. The estimated prevalence of suboptimal iron status was 23%, but neither feeding method significantly predicted body iron concentrations nor the odds of iron sufficiency after controlling for potential confounding factors including infant formula intake. Adjusted ORs for iron sufficiency were 1.50 (95% CI: 0.67-3.39) for frequent pouch users compared to non-pouch users and 0.91 (95% CI: 0.45-1.87) for baby-led weaning compared to traditional spoon-feeding. Contrary to concerns, there was no evidence that baby food pouch use or baby-led weaning, as currently practiced in New Zealand, were associated with poorer iron status in this age group. However, notable levels of suboptimal iron status, regardless of the feeding method, emphasise the ongoing need for paying attention to infant iron nutrition.

Background: Children with Down syndrome often engage in contextually inappropriate social behavior, which researchers suggest may function to escape from difficult activities to preferred social interactions. Caregivers may reinforce the behavior, perceiving it only as evidence of the child's social strength, when, in fact, the pattern may also prevent or slow the development of critical skills. Unlike overt forms of challenging behavior, contextually inappropriate social behavior had never been subjected to experimental analysis., Aims: The purpose of the current study was to identify and demonstrate functional control of contextually inappropriate social behavior to caregiver-informed contingencies., Method and Procedures: We interviewed caregivers and subjected contextually inappropriate social behavior to functional analyses for nine young children with Down syndrome., Outcomes and Results: We found sensitivity to the caregiver-informed contingencies for all nine participants with strong functional control and large effect sizes for most., Conclusions and Implications: Caregivers may not perceive contextually inappropriate social behavior as problematic, yet patterns of contextually inappropriate and other problem behaviors suggest decreased engagement and poor task persistence. Assessments that lead to intervention decisions may be more informative when they include questions about social topographies of behavior not typically considered as problematic. Once caregivers are aware of the pattern, they may be better prepared to intervene., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

While the detection of single-nucleotide variants (SNVs) is important for evaluating human health and disease, most genotyping methods require a nucleic acid extraction step and lengthy analytical times. Here, we present a protocol which utilizes the integration of locked nucleic acids (LNAs) into self-annealing loop primers for the allelic discrimination of five isocitrate dehydrogenase 1 R132 ( IDH1 -R132) variants using loop-mediated isothermal amplification (LAMP). This genotyping panel was initially evaluated using purified synthetic DNA to show proof of specific SNV discrimination. Additional evaluation using glioma tumor lysates with known IDH1 -R132 mutational status demonstrated specificity in approximately 35 min without the need for a nucleic acid extraction purification step. This LNA-LAMP-based genotyping assay can detect single base differences in purified nucleic acids or tissue homogenates, including instances where the variant of interest is present in an excess of background wild-type DNA. The pH-based colorimetric indicator of LNA-LAMP facilitates convenient visual interpretation of reactions, and we demonstrate successful translation to an end-point format using absorbance ratio, allowing for an alternative and objective approach for differentiating between positive and negative reactions. Importantly, the LNA-LAMP genotyping panel is highly reproducible, with no false-positive or false-negative results observed., (© The Author(s) 2024. Published by Oxford University Press.)

Competing Interests: Dr Silverberg has received honoraria as a consultant and/or advisory board member for AbbVie, Alamar, Aldena, Amgen, AOBiome, Arcutis, Arena, Asana, Aslan, BiomX, Biosion, Bodewell, Boehringer Ingelheim, Bristol Myers Squibb, Cara, Castle Biosciences, Celgene, Connect BioPharma, Dermavant, Dermira, DermTech, Eli Lilly, Galderma, GlaxoSmithKline, Incyte, Kiniksa, Leo Pharma, Menlo, Novartis, Optum, Pfizer, RAPT, Recludix, Regeneron, Sanofi-Genzyme, Shaperon, Union, and UpToDate; has served as a speaker for AbbVie, Eli Lilly, Leo Pharma, Pfizer, Regeneron, and Sanofi-Genzyme; and has received grants (paid to the institution) from Galderma, 10.13039/100017655Incyte, and 10.13039/100004319Pfizer. Author Cronin and Drs Jones and Dave were employees of CorEvitas, LLC at the time of this work. Dr McLean is an employee of CorEvitas, LLC. Dr Greenberg is an employee of CorEvitas, LLC. Dr Strober has received honoraria as a consultant for AbbVie, Almirall, Amgen, Arcutis, Arena, Aristea, Asana, Boehringer Ingelheim, Bristol Myers Squibb, Connect BioPharma, Dermavant, Eli Lilly, Equillium, GlaxoSmithKline, Immunic Therapeutics, Janssen, Leo Pharma, Maruho, Meiji Seika Pharma, Mindera Health, Novartis, Ortho Dermatologics, Pfizer, Regeneron, Sanofi-Genzyme, Sun Pharma, UCB, Ventyxbio, and vTv Therapeutics; has served as a speaker for AbbVie, Eli Lilly, Janssen, and Sanofi-Genzyme; coscientific director (consulting fee) for CorEvitas’ (Corrona) Psoriasis Registry; and investigator for AbbVie, Cara, CorEvitas’ (Corrona) Psoriasis Registry, Dermavant, Dermira, and Novartis. Dr Bieber has served as a speaker and/or consultant, and/or investigator for AbbVie, Affibody, Almirall, Amagma, AnaptysBio, AOBiome, Arena, Aristea, Asana Biosciences, ASLAN pharma, Bayer Health, BioVersys, Boehringer Ingelheim, Bristol Myers Squibb, Connect Pharma, Daiichi Sankyo, Dermavant, DICE Therapeutics, Domain Therapeutics, DS Pharma, EQRx, Galderma, Galapagos, Glenmark, GSK, Incyte, Innovaderm, IQVIA, Janssen, Kirin, Kymab, LEO, LG Chem, Lilly, L’Oréal, MSD, Medac, Novartis, Numab, OM-Pharma, Pfizer, Pierre Fabre, Q32 Bio, RAPT, Sanofi/Regeneron, UCB, and Union Therapeutics; and is the founder and chairman of the board of the nonprofit biotech “Davos Biosciences.” Dr Gooderham has served as an investigator, speaker, and/or adviser for AbbVie, Amgen, Akros, Arcutis, Aristea, AnaptysBio, Apogee, Bausch Health, BMS, Boehringer Ingelheim, Celgene, Dermira, Dermavant, Eli Lilly, Galderma, GSK, Incyte, Janssen, Kyowa Kirin, LEO Pharma, MedImmune, Meiji, Merck, MoonLake, Nimbus, Novartis, Pfizer, Regeneron, Roche, Sanofi-Genzyme, Sun Pharma, Tarsus, Takeda, UCB, Union, and Ventyx. Dr Paller has served as an investigator for AbbVie, Dermavant, Eli Lilly, Incyte, Janssen, Krystal, and UCB; has served as a consultant for Aegerion Pharma, Azitra, BioCryst, Boehringer Ingelheim, Bristol Myers Squibb, Castle Creek, Eli Lilly, Janssen, Krystal, LEO Pharma, Novartis, Regeneron, Sanofi/Genzyme, Seanergy, TWI Biotechnology, and UCB; and as a data safety monitoring board member for AbbVie, Abeona, Catawba, Galderma, and InMed. Dr Simpson has received consulting fees from AbbVie, Amgen, Arena Pharmaceuticals, Aslan Pharma, Benevolent AI Bio Limited “BAI,” BiomX Ltd, Bluefin Biomedicine Inc, Boehringer Ingelheim, Boston Consulting Group, Collective Acumen, LLC (CA), Coronado, Dermira, Eli Lilly, Evidera, Excerpta Medica, Galderma, GlaxoSmithKline, Forte Bio RX, Incyte Dermatologics, Janssen, Kyowa Kirin Pharmaceutical Development, Leo Pharm, Medscape LLC, Merck, Novartis, Ortho Galderma, Pfizer, Physicians World LLC, Pierre Fabre Dermo Cosmetique, Regeneron, Roivant, Sanofi-Genzyme, SPARC India, Trevi Therapeutics, WebMD, and Valeant; has served as a speaker for AbbVie, Leo, Eli Lilly, Medscape, Pfizer, Regeneron, Sanofi-Genzyme; has received advisory or steering committee fee from Arena Pharmaceuticals, Eli Lilly, GlaxoSmithKline, Incyte, Janssen, Kyowa Kirin Pharmaceutical Development, Leo, Pfizer, Regeneron and Sanofi-Genzyme; has received grants or contracts from AbbVie, Amgen, Arcutis, Aslan, Celgene, CorEvitas, Dermavant, Dermira, Eli Lilly, Galderma, Incyte, Kymab, Kyowa Hakko Kirin, Leo Pharmaceuticals, Merck, Novartis, Pfizer, Regeneron, Sanofi, and TARGET-DERM; and has been a PI for CorEvitas (paid to the institution).

Synchronous excitatory discharges from the entorhinal cortex (EC) to the dentate gyrus (DG) generate fast and prominent patterns in the hilar local field potential (LFP), called dentate spikes (DSs). As sharp-wave ripples in CA1, DSs are more likely to occur in quiet behavioral states, when memory consolidation is thought to take place. However, their functions in mnemonic processes are yet to be elucidated. The classification of DSs into types 1 or 2 is determined by their origin in the lateral or medial EC, as revealed by current source density (CSD) analysis, which requires recordings from linear probes with multiple electrodes spanning the DG layers. To allow the investigation of the functional role of each DS type in recordings obtained from single electrodes and tetrodes, which are abundant in the field, we developed an unsupervised method using Gaussian mixture models to classify such events based on their waveforms. Our classification approach achieved high accuracies (> 80%) when validated in 8 mice with DG laminar profiles. The average CSDs, waveforms, rates, and widths of the DS types obtained through our method closely resembled those derived from the CSD-based classification. As an example of application, we used the technique to analyze single-electrode LFPs from apolipoprotein (apo) E3 and apoE4 knock-in mice. We observed that the latter group, which is a model for Alzheimer's disease, exhibited wider DSs of both types from a young age, with a larger effect size for DS type 2, likely reflecting early pathophysiological alterations in the EC-DG network, such as hyperactivity. In addition to the applicability of the method in expanding the study of DS types, our results show that their waveforms carry information about their origins, suggesting different underlying network dynamics and roles in memory processing., (© 2024. The Author(s).)

Climate change in northern latitudes is increasing the vulnerability of peatlands and the riparian transition zones between peatlands and upland forests (referred to as ecotones) to greater frequency of wildland fires. We examined early post-fire vegetation regeneration following the 2011 Utikuma complex fire (central Alberta, Canada). This study examined 779 peatlands and adjacent ecotones, covering an area of ~182 km 2 . Based on the known regional fire history, peatlands that burned in 2011 were stratified into either long return interval (LRI) fire regimes of >80 years (i.e., no recorded prior fire history) or short fire return interval (SRI) of 55 years (i.e., within the boundary of a documented severe fire in 1956). Data from six multitemporal airborne lidar surveys were used to quantify trajectories of vegetation change for 8 years prior to and 8 years following the 2011 fire. To date, no studies have quantified the impacts of post-fire regeneration following short versus long return interval fires across this broad range of peatlands with variable environmental and post-fire successional trajectories. We found that SRI peatlands demonstrated more rapid vascular and shrub growth rates, especially in peatland centers, than LRI peatlands. Bogs and fens burned in 1956, and with little vascular vegetation (classified as "open peatlands") prior to the 2011 fire, experienced the greatest changes. These peatlands tended to transition to vascular/shrub forms following the SRI fire, while open LRI peatlands were not significantly different from pre-fire conditions. The results of this study suggest the emergence of a positive feedback, where areas experiencing SRI fires in southern boreal peatlands are expected to transition to forested vegetation forms. Along fen edges and within bog centers, SRI fires are expected to reduce local peatland groundwater moisture-holding capacity and promote favorable conditions for increased fire frequency and severity in the future., (© 2024 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Multiphoton intravital microscopy (MP-IVM) is an imaging technique used for the observation of living organisms at a microscopic resolution. The tissue of interest is exposed through a window allowing imaging of cells in real time. Using MP-IVM, the temporospatial kinetics of leukocyte transendothelial migration can be visualized and quantitated using reporter mice and cell-specific fluorophore-conjugated monoclonal antibodies to track the leukocytes within and outside of vascular beds. Here we describe a method used to study neutrophil transendothelial migration and blood-brain barrier permeability in a mouse model of herpes simplex virus I (HSV) encephalitis., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

Although concern is frequently expressed regarding the potential impact of baby food pouch use and Baby-Led Weaning (BLW) on infant health, research is scarce. Data on pouch use, BLW, energy intake, eating behaviour and body mass index (BMI) were obtained for 625 infants aged 7-10 months in the First Foods New Zealand study. Frequent pouch use was defined as ≥5 times/week during the past month. Traditional spoon-feeding (TSF), "partial" BLW and "full" BLW referred to the relative proportions of spoon-feeding versus infant self-feeding, assessed at 6 months (retrospectively) and current age. Daily energy intake was determined using two 24-h dietary recalls, and caregivers reported on a variety of eating behaviours. Researchers measured infant length and weight, and BMI z-scores were calculated (World Health Organization Child Growth Standards). In total, 28% of infants consumed food from pouches frequently. Frequent pouch use was not significantly related to BMI z-score (mean difference, 0.09; 95% CI -0.09, 0.27) or energy intake (92 kJ/day; -19, 202), but was associated with greater food responsiveness (standardised mean difference, 0.3; 95% CI 0.1, 0.4), food fussiness (0.3; 0.1, 0.4) and selective/restrictive eating (0.3; 0.2, 0.5). Compared to TSF, full BLW was associated with greater daily energy intake (BLW at 6 months: mean difference 150 kJ/day; 95% CI 4, 297; BLW at current age: 180 kJ/day; 62, 299) and with a range of eating behaviours, including greater satiety responsiveness, but not BMI z-score (6 months: 0.06 (-0.18, 0.30); current age: 0.06 (-0.13, 0.26)). In conclusion, neither feeding approach was associated with weight in infants, despite BLW being associated with greater energy intake compared with TSF. However, infants who consumed pouches frequently displayed higher food fussiness and more selective eating., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Real-world data on the effectiveness of systemic therapy in atopic dermatitis (AD) are limited., Methods: Adult patients with AD in the CorEvitas AD registry (2020-2021) who received systemic therapies for 4-12 months prior to enrollment were included based on disease severity: body surface area (BSA) 0%-9% and BSA ≥10%. Demographics, clinical characteristics, and outcomes were assessed using descriptive statistics. Pairwise effect sizes (ES) were used to compare BSA groups., Results: The study included 308 patients (BSA 0%-9%: 246 [80%]; BSA ≥10%: 62 [20%]). Despite systemic therapy, both BSA groups reported the use of additional topical therapy and the presence of lesions at difficult locations. Moderate-to-severe AD (vIGA-AD ® ) was reported by 11% (BSA 0%-9%) and 66% (BSA ≥10%; ES = 0.56) of patients. Mean disease severity scores: total BSA (2% and 22%; ES = 3.59), EASI (1.1 and 11.1; ES = 2.60), and SCORAD (12.1 and 38.0; ES = 1.99). Mean scores for PROs: DLQI (3.7 and 7.5; ES = 0.75), and peak pruritus (2.2 and 4.5; ES = 0.81). Inadequate control of AD was seen in 27% and 53% of patients (ES = 0.23)., Conclusions: Patients with AD experience a high disease burden despite systemic treatment for 4-12 months. This study provides potential evidence of suboptimal treatment and the need for additional effective treatment options for AD.

Concurrently performing septal perforation repair and rhinoplasty is challenging. Successful management of patients who require or desire these procedures performed simultaneously can be achieved with appropriate preoperative workup and optimization, thoughtful surgical planning, masterful execution, and diligent postoperative care. Consideration of perforation etiology and status of the perforation along with overall nasal health are the foundation upon which surgery may be planned. Preoperative evaluation to determine locations of obstruction, aesthetic goals, and feasibility of procedure is required. Rhinoplasty techniques and perforation closure techniques may share common maneuvers making concurrent surgery possible. Surgical techniques to achieve perforation closure often influence rhinoplasty considerations, and vice versa. Care must be taken to account and possibly even to capitalize on these influences. Perforation closure techniques that may be readily combined with rhinoplasty include interposition grafting and intranasal mucosal rotational advancement flaps, which may exert forces upon the nose with aesthetic or functional consequences. Rhinoplasty techniques targeting any third of the nose also can impact tension or available mucosa for perforation closure techniques. Combining these procedures can be very rewarding for the patient and provider but should be considered responsibly and thoughtfully., Competing Interests: None declared., (Thieme. All rights reserved.)

Sensory features are part of the diagnostic criteria for autism and include sensory hypo/hyper reactivity and unusual sensory interest; however, additional sensory differences, namely differences in sensory integration, have not been routinely explored. This study characterized sensory integration differences in a cohort of children (n = 93) with a confirmed diagnosis of autism (5-9 years) using a standardized, norm-referenced battery. Mean z scores, autism diagnostic scores, and IQ are reported. Participants showed substantial deficits in tactile perception, praxis, balance, visual perception, and visual-motor skills. Relationship with autism diagnostic test scores were weak or absent. Findings suggest additional sensory difficulties that are not typically assessed or considered when characterizing sensory features in autism. These data have implications for a greater understanding of the sensory features in the autism phenotype and the development of personalized treatments., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Near-complete skin clearance has become a rapidly achievable treatment goal for patients with psoriasis receiving systemic biologic therapies. However, real-world evidence for durability of near-complete skin clearance and risk factors associated with loss of near-complete skin clearance is limited., Methods: This study described durability of near-complete skin clearance (≥ 90% improvement in Psoriasis Area and Severity Index from initiation; PASI90) and identified clinical factors or patient characteristics associated with loss of PASI90 among patients with psoriasis from the CorEvitas Psoriasis Registry (April 2015-August 2021). Included patients had PASI > 5 at biologic initiation and achieved PASI90 at approximately 6 months from initiation (index). A Kaplan-Meier estimate described time to loss of treatment response over 24 months follow-up from index. Proportional hazards regression was used to identify independent predictors of loss of treatment response., Results: This study included 687 patient initiations (instances of patients initiating a biologic). Following achievement of PASI90, treatment response was maintained in more than half of patient initiations (54%). Treatment response was maintained at 6, 12, and 18 months from index in an estimated 73% (95% [confidence interval] CI 70-77%), 60% (95% CI 56-63%), and 50% (95% CI 47-54%) of patient initiations, respectively. Adjusted hazards regression suggested non-White race, full-time employment, greater body weight, concomitant psoriatic arthritis, prior use of biologics, and clinically meaningful skin symptoms were associated with loss of treatment response., Conclusions: Among real-world patients with psoriasis who achieved PASI90 with biologic therapy, about one-quarter lost response at 6 months, and half lost response at 18 months. Prior use of a biologic therapy and clinically meaningful skin symptoms at index, including itch and skin pain, were associated with loss of treatment response. Therefore, dermatologists may consider focusing on patient-reported symptoms as part of any intervention designed to reduce the likelihood of loss of response to biologic therapies., Trial Registration: ClinicalTrials.gov identifier, NCT02707341., (© 2023. The Author(s).)

Ketamine, a rapid-acting anesthetic and acute antidepressant, carries undesirable spatial cognition side effects including out-of-body experiences and spatial memory impairments. The neural substrates that underlie these alterations in spatial cognition however, remain incompletely understood. Here, we used electrophysiology and calcium imaging to examine ketamine's impacts on the medial entorhinal cortex and hippocampus, which contain neurons that encode an animal's spatial position, as mice navigated virtual reality and real world environments. Ketamine acutely increased firing rates, degraded cell-pair temporal firing-rate relationships, and altered oscillations, leading to longer-term remapping of spatial representations. In the reciprocally connected hippocampus, the activity of neurons that encode the position of the animal was suppressed after ketamine administration. Together, these findings demonstrate ketamine-induced dysfunction of the MEC-hippocampal circuit at the single cell, local-circuit population, and network levels, connecting previously demonstrated physiological effects of ketamine on spatial cognition to alterations in the spatial navigation circuit., (© 2023. Springer Nature Limited.)

Methods to identify carelessness in survey research can be valuable tools in reducing bias during survey development, validation, and use. Because carelessness may take multiple forms, researchers typically use multiple indices when identifying carelessness. In the current study, we extend the literature on careless response identification by examining the usefulness of three item-response theory-based person-fit indices for both random and overconsistent careless response identification: infit MSE outfit MSE , and the polytomous l z statistic. We compared these statistics with traditional careless response indices using both empirical data and simulated data. The empirical data included 2,049 high school student surveys of teaching effectiveness from the Network for Educator Effectiveness. In the simulated data, we manipulated type of carelessness (random response or overconsistency) and percent of carelessness present (0%, 5%, 10%, 20%). Results suggest that infit and outfit MSE and the l z statistic may provide complementary information to traditional indices such as LongString, Mahalanobis Distance, Validity Items, and Completion Time. Receiver operating characteristic curves suggested that the person-fit indices showed good sensitivity and specificity for classifying both over-consistent and under-consistent careless patterns, thus functioning in a bidirectional manner. Carelessness classifications based on low fit values correlated with carelessness classifications from LongString and completion time, and classifications based on high fit values correlated with classifications from Mahalanobis Distance. We consider implications for research and practice., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Virtual surgical planning is a revolutionary tool for the head and neck reconstructive surgeon. As with any tool, there are strengths and weaknesses. The strengths include shorter operative time, shorter ischemic time, streamlined dental rehabilitation, facilitation of complex reconstruction, non-inferior and possibly superior accuracy, and increased durability. The weaknesses are increased up-front costs, potential delays to operative management, limited flexibility on the day of surgery, and loss of familiarity with conventionally planned surgery., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Telehealth behavioral interventions are increasingly necessary when in-person services are not accessible (e.g., due to geographic location, time, cost, and health and safety restrictions). There is a growing evidence-base for the effectiveness of telehealth interventions but few demonstrations of telehealth interventions for pediatric feeding disorders. The purpose of this study was to evaluate a telehealth caregiver training package to teach caregivers to implement a feeding intervention, in their home as primary interventionists, to treat their children's food selectivity. To address some previously documented caregiver concerns regarding some intervention procedures (e.g., nonremoval of the spoon or escape extinction) and ensure caregivers could safely/feasibility implement intervention, the intervention included differential reinforcement of bites consumed within a 3-minute opportunity. All three caregivers demonstrated high levels of correct performance following training and all children demonstrated increases in the number of bites consumed and decreases in disruptive behaviors. Findings suggest training caregivers via telehealth may be a viable option to treat some children's food selectivity without first requiring in-person services.

Relatively few empirical studies of pediatric chewing interventions have been published in the psychology literature. The purpose of this paper was to systematically review chewing interventions within the applied behavior analysis literature. We identified a small, but growing, behavior analytic literature demonstrating the effectiveness of various multicomponent treatment packages to teach and improve chewing skills. Future researchers should consider a range of participant characteristics, including results of oral motor assessments, explore a more extensive definition of chewing to target the complex nature of chewing as well as component skills, and examine the necessary and sufficient components of chewing interventions along with the potential benefits of multidisciplinary interventions.

Building on studies of preferences for social interaction in children with autism spectrum disorder (ASD) we sought to provide a way for siblings with ASD to express their perspective about the quality of their sibling relationships. We developed a behavioral assessment of sibling relationship preference (Sibling Relationship Assessment [SRA]) and examined the psychometric properties of test-retest reliability, inter-rater reliability, and convergent validity. The SRA was feasible to administer and revealed expected differences between sibling dyads with one sibling with ASD compared to typically-developing sibling dyads. We found strong positive correlations for inter-rater reliability and test-retest reliability and convergent validity. The SRA provides a way to assess the perspective of the sibling with ASD that taps one characteristic, preference for spending time with one's sibling, of the quality of sibling relationships.

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A -related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca , an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara -/- ; tspearb -/- double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

The brain can represent behaviorally relevant information through the firing of individual neurons as well as the coordinated firing of ensembles of neurons. Neurons in the hippocampus and associated cortical regions participate in a variety of types of ensembles to support navigation. These ensemble types include single cell codes, population codes, time-compressed sequences, behavioral sequences, and engrams. We present the physiological basis and behavioral relevance of ensemble firing. We discuss how these traditional definitions of ensembles can constrain or expand potential analyses due to the underlying assumptions and abstractions made. We highlight how coding can change at the ensemble level while underlying single cell codes remain intact. Finally, we present how ensemble definitions could be broadened to better understand the full complexity of the brain., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Caregivers' substance use is associated with child maltreatment., Objective: Examine trends from 2005 to 2018 in percentages of three outcomes with caregivers' drug or alcohol use: child protective services (CPS) referrals, substantiated maltreatment reports, and foster care placements., Participants and Setting: 22 U.S. states that contributed child-level maltreatment outcomes and caregivers' substance use data to the National Child Abuse and Neglect Data System from 2005 to 2018., Methods: Joinpoint regression was used to examine the average annual percent change (AAPC) in outcomes with caregivers' drug or alcohol use and to identify temporal changes., Results: From 2005 to 2018, CPS referrals with caregivers' drug use increased (AAPC 2.33, p < .001), while referrals with alcohol use remained unchanged (AAPC -0.11, p = .92) (trend difference p = .04). Substantiated reports with caregivers' drug and alcohol use increased (AAPC drug use 3.63, p < .001, AAPC alcohol use 1.28, p = .03), with a greater increase observed with drug use (difference p = .03). Foster care placements with caregivers' drug use increased (AAPC 2.54, p < .001), while placements with alcohol use did not change (AAPC -1.22, p = .29), (difference p = .005). Within the study period, changes in trends with caregivers' drug use included increased substantiated reports from 2010 to 2018 (p < .001) and increased foster care placements from 2009 to 2018 (p < .001). With caregivers' alcohol use, CPS referrals and foster care placements decreased from 2007 to 2018 (all p < .001)., Conclusions: Trends differed for outcomes with caregivers' drug versus alcohol use. Findings can inform policies to improve care for families affected by substance use., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Recurrent respiratory syncytial virus (RSV) infection requiring hospitalization is rare and the underlying mechanism is unknown. We aimed to determine the role of CD14-mediated immunity in the pathogenesis of recurrent RSV infection., Methods: We performed genotyping and longitudinal immunophenotyping of the first patient with a genetic CD14 deficiency who developed recurrent RSV infection. We analyzed gene expression profiles and interleukin (IL)-6 production by patient peripheral blood mononuclear cells in response to RSV pre- and post-fusion (F) protein. We generated CD14-deficient human nasal epithelial cells cultured at air-liquid interface (HNEC-ALI) of patient-derived cells and after CRISPR-based gene editing of control cells. We analyzed viral replication upon RSV infection., Results: Sanger sequencing revealed a homozygous single-nucleotide deletion in CD14, resulting in absence of the CD14 protein in the index patient. In vitro, viral replication was similar in wild-type and CD14-/- HNEC-ALI. Loss of immune cell CD14 led to impaired cytokine and chemokine responses to RSV pre- and post-F protein, characterized by absence of IL-6 production., Conclusions: We report an association of recurrent RSV bronchiolitis with a loss of CD14 function in immune cells. Lack of CD14 function led to defective immune responses to RSV pre- and post-F protein without a change in viral replication., (© The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Interleukin-1 receptor-associated kinases (IRAKs) -4, -2, and -1 are involved in transducing signals from Toll-like receptors (TLRs) via the adaptor myeloid differentiation primary-response protein 88 (MYD88). How MYD88/IRAK4/2/1 complexes are formed, their redundancies, and potential non-enzymatic roles are subjects of debate. Here, we examine the hierarchical requirements for IRAK proteins in the context of TLR4 activation and confirmed that the kinase activity of IRAK4 is essential for MYD88 signaling. Surprisingly, the IRAK4 scaffold is required for activation of the E3 ubiquitin ligase TNF receptor-associated factor 6 (TRAF6) by both MYD88 and TIR domain-containing adaptor protein inducing IFN-β (TRIF), a unique adaptation in the TLR4 response. IRAK4 scaffold is, therefore, essential in integrating MYD88 and TRIF in TLR4 signaling., Competing Interests: Declaration of interests The authors declare no competing financial interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The objective of this article is to explore minimally invasive techniques to treat a poorly functioning nasal valve. It reviews the literature to introduce anatomy and examination, detail efficacy, instruct procedural protocols, and summarize utility. The article was composed based upon literature review and expert opinion. Nasal obstruction is a frequent problem managed by the facial plastic surgeon. It can occur at multiple sites, but commonly problematic regions are the nasal valves. A comprehensive nasal exam can elucidate the source of obstruction and validated obstruction measurements, such as the Nasal Obstruction Symptom Evaluation Instrument or the Standardized Cosmesis and Health Nasal Outcomes Survey for Functional and Cosmetic Rhinoplasty, can classify severity. Cartilage grafting and open septorhinoplasty techniques are invaluable for correcting nasal valve obstruction; however, the traditional methods may be neither possible nor optimal for all patients. Minimally invasive treatment modalities have emerged to offer an alternative to classical treatment algorithms. Minimally invasive techniques aimed at improving the nasal valve function include nasal dilators, suture suspension, lateral nasal wall bioresorbable implants, and cartilaginous radio frequency remodeling. Benefits of these methods include clinic-based intervention, avoidance of general anesthesia, use in previously operated noses, and minimally invasive nature. Publications with ranging levels of evidence support the efficacy of these interventions when patients with isolated nasal valve obstruction are examined. Limitations in the data, such as study power, source of funding, duration of follow-up, and longevity of response, warrant the need for further investigation; however, the efficacy of these techniques justifies implementation in proper patient populations into current practice. Minimally invasive nasal valve correction is a valuable tool in the armamentarium of the facial plastic surgeon. It cannot and should not replace traditional septorhinoplasty; however, the techniques are a valuable consideration for the appropriate patient population., Competing Interests: None declared., (Thieme. All rights reserved.)

Lay Abstract: The sibling relationship can be negatively impacted when one child has autism spectrum disorder. One way to improve the quality of that relationship is through typically developing sibling participation in a support group in which they learn about autism spectrum disorder and coping skills, develop a peer network, and discuss their feelings. Compared to participating in a similar group without a focus on autism spectrum disorder, siblings in the support group showed improvements in the quality of the sibling relationship. Findings suggest that sibling support groups can be a valuable resource to improve sibling relationship quality when one sibling has autism spectrum disorder.

New variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to emerge, causing surges, breakthrough infections, and devastating losses-underscoring the importance of identifying SARS-CoV-2 antivirals. A simple, accessible human cell culture model permissive to SARS-CoV-2 variants is critical for identifying and assessing antivirals in a high-throughput manner. Although human alveolar A549 cells are a valuable model for studying respiratory virus infections, they lack two essential host factors for SARS-CoV-2 infection: angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). SARS-CoV-2 uses the ACE2 receptor for viral entry and TMPRSS2 to prime the SARS-CoV-2 spike protein, both of which are negligibly expressed in A549 cells. Here, we report the generation of a suitable human cell line for SARS-CoV-2 studies by transducing human ACE2 and TMPRSS2 into A549 cells. We show that subclones highly expressing ACE2 and TMPRSS2 ("ACE2plus" and the subclone "ACE2plusC3") are susceptible to infection with SARS-CoV-2, including the delta and omicron variants. These subclones express more ACE2 and TMPRSS2 transcripts than existing commercial A549 cells engineered to express ACE2 and TMPRSS2. Additionally, the antiviral drugs EIDD-1931, remdesivir, nirmatrelvir, and nelfinavir strongly inhibit SARS-CoV-2 variants in our infection model. Our data show that ACE2plusC3 cells are highly permissive to SARS-CoV-2 infection and can be used to identify anti-SARS-CoV-2 drugs.

Plasmodium falciparum (P. falciparum) induces trained innate immune responses in vitro, where initial stimulation of adherent PBMCs with P. falciparum-infected RBCs (iRBCs) results in hyperresponsiveness to subsequent ligation of TLR2. This response correlates with the presence of T and B lymphocytes in adherent PBMCs, suggesting that innate immune training is partially due to adaptive immunity. We found that T cell-depleted PBMCs and purified monocytes alone did not elicit hyperproduction of IL-6 and TNF-α under training conditions. Analysis of P. falciparum-trained PBMCs showed that DCs did not develop under control conditions, and IL-6 and TNF-α were primarily produced by monocytes and DCs. Transwell experiments isolating purified monocytes from either PBMCs or purified CD4+ T cells, but allowing diffusion of secreted proteins, enabled monocytes trained with iRBCs to hyperproduce IL-6 and TNF-α after TLR restimulation. Purified monocytes stimulated with IFN-γ hyperproduced IL-6 and TNF-α, whereas blockade of IFN-γ in P. falciparum-trained PBMCs inhibited trained responses. Assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-Seq) on monocytes from patients with malaria showed persistently open chromatin at genes that appeared to be trained in vitro. Together, these findings indicate that the trained immune response of monocytes to P. falciparum is not completely cell intrinsic but depends on soluble signals from lymphocytes.

Cerebral microvascular rarefaction, the reduction in number of functional or structural small blood vessels in the brain, is thought to play an important role in the early stages of microvascular related brain disorders. A better understanding of its underlying pathophysiological mechanisms, and methods to measure microvascular density in the human brain are needed to develop biomarkers for early diagnosis and to identify targets for disease modifying treatments. Therefore, we provide an overview of the assumed main pathophysiological processes underlying cerebral microvascular rarefaction and the evidence for rarefaction in several microvascular related brain disorders. A number of advanced physiological MRI techniques can be used to measure the pathological alterations associated with microvascular rarefaction. Although more research is needed to explore and validate these MRI techniques in microvascular rarefaction in brain disorders, they provide a set of promising future tools to assess various features relevant for rarefaction, such as cerebral blood flow and volume, vessel density and radius and blood-brain barrier leakage.

Purpose: The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution., Methods: Retrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods., Results: Abnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%., Conclusions: Our results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)