Innate Immune Dysfunction and Neuroinflammation in Autism Spectrum Disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation. Appeared originally in Brain Behav Immun 2023; 108:245-254.

Towards a farmer-feasible soil health assessment that is globally applicable.

Globally, agriculture has had a significant and often detrimental impact on soil. The continued capacity of soil to function as a living ecosystem that sustains microbes, plants, and animals (including humans), its metaphorical health, is of vital importance across geographic scales. Healthy soil underpins food production and ecosystem resilience against a changing climate. This paper focuses on assessing soil health, an area of increasing interest for farming communities, researchers, industry and policy-makers. Without accessible and reliable soil assessment, any management and interventions to improve soil health are likely to be sub-optimal. Here we explore available soil health assessments (SHAs) that may be feasible for farmers of varying income levels and suitable for broad geographic application. Whilst there is a range of existing approaches to SHA, we find that no one framework currently meets these broad aims. Firstly, reliance on expensive and logistically complex laboratory methods reduces viability and accessibility for many farmers. Secondly, lack of defined indicator baselines and associated thresholds or gradients for soil health prevents the assessment of soil measurements against achieving optima for a given set of local soil-climate conditions. Since soils vary greatly, these baselines and thresholds must be defined considering the local biogeographic context; it is inappropriate to simply transfer calibrated information between contexts. These shortcomings demand progress towards a feasible, globally applicable and context-relevant SHA framework. The most feasible SHAs we identified were developed locally in conjunction with farmers, who have been repeatedly found to assess the health of their soils accurately, often using relatively simple, observable indications. To progress, we propose assessment of which indicators add information to a SHA in local contexts, with a focus on sufficiency, to reduce data burden. Provision of a standardised protocol for measurement and sampling that considers the reliability and accuracy of different methods would also be extremely valuable. For greatest impact, future work should be taken forward through a cross-industry collaborative approach involving researchers, businesses, policy makers, and, above all, farmers, who are both experts and users.

The top 100 most cited articles on artificial intelligence in radiology: a bibliometric analysis.

AIM: To identify the most influential publications relating to artificial intelligence (AI) in radiology in order to identify current trends in the literature and to highlight areas requiring further research. MATERIALS AND METHODS: A retrospective bibliometric analysis was performed of the top 100 most cited articles on this topic. Data pertaining to year of publication, publishing journal, journal impact factor, authorship, article title, institution, country, type of article, article subject, and keywords were collected. RESULTS: The number of citations per article for the top 100 list ranged from 254 to 3,576 (median 353). The number of citations per year, per article ranged from 10.4 to 894 (median 65.6). The majority of articles (n=62) were published within the last 10 years. The USA was the most common country of origin (n=44). The journal with the greatest number of articles was IEEE Transactions On Medical Imaging (n=38). University Medical Center Utrecht contributed the greatest number of articles (n=6). There were 92 original research articles, 52 of which were clinical studies. The most common clinical subjects were neuroimaging (n=25) and oncology (n=16). The most common keyword used was "deep learning" (n=34). CONCLUSION: This study provides an in-depth analysis of the top 100 most-cited papers on the use of AI in radiology. It also provides researchers with detailed insight into the current influential papers in this field, the characteristics of those studies, as well as potential future trends in this fast-developing area of radiology.

Integrated intracellular organization and its variations in human iPS cells.

Understanding how a subset of expressed genes dictates cellular phenotype is a considerable challenge owing to the large numbers of molecules involved, their combinatorics and the plethora of cellular behaviours that they determine1,2. Here we reduced this complexity by focusing on cellular organization-a key readout and driver of cell behaviour3,4-at the level of major cellular structures that represent distinct organelles and functional machines, and generated the WTC-11 hiPSC Single-Cell Image Dataset v1, which contains more than 200,000 live cells in 3D, spanning 25 key cellular structures. The scale and quality of this dataset permitted the creation of a generalizable analysis framework to convert raw image data of cells and their structures into dimensionally reduced, quantitative measurements that can be interpreted by humans, and to facilitate data exploration. This framework embraces the vast cell-to-cell variability that is observed within a normal population, facilitates the integration of cell-by-cell structural data and allows quantitative analyses of distinct, separable aspects of organization within and across different cell populations. We found that the integrated intracellular organization of interphase cells was robust to the wide range of variation in cell shape in the population; that the average locations of some structures became polarized in cells at the edges of colonies while maintaining the 'wiring' of their interactions with other structures; and that, by contrast, changes in the location of structures during early mitotic reorganization were accompanied by changes in their wiring.

Detailed analysis of in-hospital transmission of SARS-CoV-2 using whole genome sequencing.

BACKGROUND: Hospital transmission of SARS-CoV-2 has proved difficult to control, with healthcare-associated infections troublesome throughout. AIM: To understand factors contributing to hospital transmission of infections, which is necessary for containing spread. METHODS: An outbreak of 56 staff and patient cases of COVID-19 over a 31-day period in a tertiary referral unit is presented, with at least a further 29 cases identified outside of the unit and the hospital by whole genome sequencing (WGS). FINDINGS: Transmission is documented from staff to staff, staff to patients, and patients to staff, showing disruption of a tertiary referral service, despite implementation of nationally recommended control measures, superior ventilation, and use of personal protective equipment. There was extensive spread from the index case, despite this patient spending only 10 h bed bound on the ward in strict cubicle isolation and with an initial single target low level (CT = 32) polymerase chain reaction test. CONCLUSION: This investigation highlights how effectively and rapidly SARS-CoV-2 can spread in certain circumstances. It raises questions about infection control measures in place at the time and calls into question the premise that transmissibility can be reliably detected by using lower sensitivity rapid antigen lateral flow tests. We also highlight the value of early intervention in reducing impact as well as the value of WGS in understanding outbreaks.

Innate immune dysfunction and neuroinflammation in autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by communication and social behavior deficits. The presence of restricted and repetitive behaviors often accompanies these deficits, and these characteristics can range from mild to severe. The past several decades have seen a significant rise in the prevalence of ASD. The etiology of ASD remains unknown; however, genetic and environmental risk factors play a role. Multiple hypotheses converge to suggest that neuroinflammation, or at least the interaction between immune and neural systems, may be involved in the etiology of some ASD cases or groups. Repeated evidence of innate immune dysfunction has been seen in ASD, often associated with worsening behaviors. This evidence includes data from circulating myeloid cells and brain resident macrophages/microglia in both human and animal models. This comprehensive review presents recent findings of innate immune dysfunction in ASD, including aberrant innate cellular function, evidence of neuroinflammation, and microglia activation.

Experimental evaluation of biological regeneration of arable soil: The effects of grass-clover leys and arbuscular mycorrhizal inoculants on wheat growth, yield, and shoot pathology.

Wheat yields have plateaued in the UK over the last 25 years, during which time most arable land has been annually cropped continuously with short rotations dominated by cereals. Arable intensification has depleted soil organic matter and biology, including mycorrhizas, which are affected by tillage, herbicides, and crop genotype. Here, we test whether winter wheat yields, mycorrhization, and shoot health can be improved simply by adopting less intensive tillage and adding commercial mycorrhizal inoculum to long-term arable fields, or if 3-year grass-clover leys followed direct drilling is more effective for biological regeneration of soil with reduced N fertiliser. We report a trial of mycorrhization, ear pathology, and yield performance of the parents and four double haploid lines from the Avalon x Cadenza winter wheat population in a long-term arable field that is divided into replicated treatment plots. These plots comprised wheat lines grown using ploughing or disc cultivation for 3 years, half of which received annual additions of commercial arbuscular mycorrhizal (AM) inoculum, compared to 3-year mown grass-clover ley plots treated with glyphosate and direct-drilled. All plots annually received 35 kg of N ha-1 fertiliser without fungicides. The wheat lines did not differ in mycorrhization, which averaged only 34% and 40% of root length colonised (RLC) in the ploughed and disc-cultivated plots, respectively, and decreased with inoculation. In the ley, RLC increased to 52%. Two wheat lines were very susceptible to a sooty ear mould, which was lowest in the ley, and highest with disc cultivation. AM inoculation reduced ear infections by >50% in the susceptible lines. In the ley, yields ranged from 7.2 to 8.3 t ha-1, achieving 92 to 106% of UK average wheat yield in 2018 (7.8 t ha-1) but using only 25% of average N fertiliser. Yields with ploughing and disc cultivation averaged only 3.9 and 3.4 t ha-1, respectively, with AM inoculum reducing yields from 4.3 to 3.5 t ha-1 in ploughed plots, with no effect of disc cultivation. The findings reveal multiple benefits of reintegrating legume-rich leys into arable rotations as part of a strategy to regenerate soil quality and wheat crop health, reduce dependence on nitrogen fertilisers, enhance mycorrhization, and achieve good yields.

Clinical characteristics, attendance outcomes and deaths of homeless persons in the emergency department: implications for primary health care and community prevention programmes.

OBJECTIVES: Persons experiencing homelessness (PEH) are known to be often excluded from primary health care and community prevention programmes leading to high use of hospital emergency departments (EDs). This study aimed to identify demographic features, clinical characteristics and attendance outcomes of PEH presenting to ED. STUDY DESIGN: Analysis of routinely collected data set. METHODS: Clinical presentations and drug prescription data of PEH who presented a major ED in the West Midlands region of England from 2014 to 2019 were extracted and analysed using descriptive and inferential statistics. RESULTS: During the study period, 3271 of 596,198 presentations were made by PEH; 74% PEH attendees were male. Drug- and alcohol-related conditions, as well as pain and injury constituted the most frequent reasons for presentation, contributing to over half of all presentations. A significantly higher proportion of males (n = 481, 20.3%) presented with drug and alcohol problems than females (n = 93, 11.2%) (P ≤ 0.001). However, pain was the primary reason for presentation for twice as many female patients (n = 189, 22.8%) compared with males (n = 305, 12.9%) (P < 0.001). Nearly one in five left the ED before being assessed and a total of 39 patients (1.2%) died in the ED and 785 (24.0%) required in-patient admissions to the same hospital. CONCLUSIONS: Drug, alcohol and pain including the need of opioid analgesics constituted the majority of presentations made by PEH in ED. The observed rate of death of PEH in ED is 12 times higher than the general population. A very high proportion of PEH also leave the ED before being treated. Future research should focus on strengthening community interventions, particularly to improve access to those at risk of dual diagnoses of substance misuse and mental health problems. Interventions involving multisector collaborations are needed to improve seamless discharge from ED and minimise repeat attendance. Gender differences in the nature of presentations and ED outcomes needs to be investigated further.

The varus cemented femoral stem in total hip arthroplasty: Predictors, implications and The Femoral Access Ratio.

INTRODUCTION: We describe a novel morphological ratio, the Femoral Access Ratio, in the preoperative femur to investigate the predictors of femoral stem malalignment. METHODS: We reviewed 70 cemented femoral stems. Preoperative 'FAR' score was measured. Postoperative coronal stem alignment was measured and ten year survivorship and functional outcomes investigated. RESULTS: There were three predictors of varus stem malalignment-BMI, GT-height and 'FAR' score. Increasing BMI led to higher rates of malalignment (p = 0.048). 'FAR' score <1 lead to 68.4% of varus stems. GT height contributed most to the prediction of varus stem malalignment (p = 0.013). CONCLUSION: FAR score is a simple preoperative radiographic measurement that can predict the likelihood of femoral stem varus malalignment in cemented femoral stems.

Diagnostic Limitations in Congenital Zika Virus Infection.

This is the first documented case of an infant with congenital Zika virus infection (ZVI) born in Ireland. A term infant was delivered with an antenatal diagnosis of severe microcephaly. First trimester bloods confirmed maternal ZVI and although the infant did not have Zika virus RNA or Zika-specific IgM in her blood or urine, she had multiple clinical features of congenital ZVI and Zika virus RNA was present in the placenta.

Proteomic comparison of osteoarthritic and reference human menisci using data-independent acquisition mass spectrometry.

OBJECTIVE: Recent research in knee osteoarthritis (OA) highlights the role of the meniscus in OA pathology. Our aim was to compare the proteomes of medial and lateral menisci from end-stage medial compartment knee OA patients, with reference menisci from knee-healthy deceased donors, using mass spectrometry. DESIGN: Tissue plugs of Ø3 mm were obtained from the posterior horns of the lateral and medial menisci from one knee of 10 knee-healthy deceased donors and 10 patients undergoing knee replacement. Proteins were extracted and prepared for mass spectrometric analysis. Statistical analysis was conducted on abundance data that was log2-transformed, using a linear mixed effects model and evaluated using pathway analysis. RESULTS: We identified a total of 835 proteins in all samples, of which 331 were included in the statistical analysis. The largest differences could be seen between the medial menisci from OA patients and references, with most proteins showing higher intensities in the medial menisci from OA patients. Several matrix proteins, e.g., matrix metalloproteinase 3 (MMP3) (4.3 times higher values [95%CI 1.8, 10.6]), TIMP1 (3.5 [1.4, 8.5]), asporin (4.1 [1.7, 10.0]) and versican (4.4 [1.8, 10.9]), all showed higher abundance in medial menisci from OA patients compared to medial reference menisci. OA medial menisci also showed increased activation of several pathways involved in inflammation. CONCLUSION: An increase in protein abundance for proteins such as MMP and TIMP1 in the medial menisci from OA patients suggests simultaneous activation of both catabolic and anabolic processes that warrants further attention.

Relating MR relaxation times of ex vivo meniscus to tissue degeneration through comparison with histopathology.

BACKGROUND: Quantitative magnetic resonance imaging (MRI), e.g. relaxation parameter mapping, may be sensitive to structural and compositional tissue changes, and could potentially be used to non-invasively detect and monitor early meniscus degeneration related to knee osteoarthritis. OBJECTIVE: To investigate MR relaxation times as potential biomarkers for meniscus degeneration through comparisons with histopathology. METHODS: We measured MR relaxation parameters in the posterior horn of 40 menisci (medial and lateral) at a wide range of degenerative stages. T1, T2 and T2* were mapped using standard and ultrashort echo time sequences at 9.4 T and compared to gold standard histology using Pauli's histopathological scoring system, including assessment of surface integrity, collagen organization, cellularity and Safranin-O staining. RESULTS: All three relaxation times increased with total Pauli score (mean difference per score (95% CI) for T2*: 0.62 (0.37, 0.86), T2: 0.83 (0.53, 1.1) and T1: 24.7 (16.5, 32.8) ms/score). Clear associations were seen with scores of surface integrity (mean difference per score for T2*: 3.0 (1.8, 4.2), T2: 4.0 (2.5, 5.5) and T1: 116 (75.6, 156) ms/score) and collagen organization (mean difference between highest and lowest score for T2*: 5.3 (1.6, 8.9), T2: 6.1 (1.7, 11) and T1: 204 (75.9, 332) ms). The results were less clear for the remaining histopathological measures. CONCLUSIONS: MR relaxation times T1, T2 and T2* of ex vivo human menisci are associated with histologically verified degenerative processes, in particular related to surface integrity and collagen organization. If confirmed in vivo, MR relaxation times may thus be potential biomarkers for meniscus degeneration.

Overlapping evidence of innate immune dysfunction in psychotic and affective disorders.

Disturbances of the immune system and immune responses after activation are a common finding in neuropsychiatric disorders. Psychotic and affective disorders such as major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BD) also share high rates of comorbidity with inflammatory and metabolic disorders. Evidence of elevated circulating inflammatory cytokines, altered numbers and function of immune cells, and evidence of neuroinflammation including activation of microglia in the brain have been found in patients with SCZ, BD and MDD. Often these findings correlate to psychological state at the time of measurement. However, significant variation exists across these studies in many aspects, creating challenges in identifying a specific signature of immune dysfunction in these disorders. Innate immune dysfunction, and alterations in monocytes, the critical sentinel cells of the innate immune system, have been seen repeatedly in all three of these disorders, with frequent overlap in findings. In this review, dysfunction specific to the innate arm of the immune system is compared for overlapping evidence across three major psychotic and affective disorders.

Ultra-high field magnetic resonance imaging parameter mapping in the posterior horn of ex vivo human menisci.

OBJECTIVE: To investigate the relationship between meniscus magnetic resonance (MR) relaxation parameters and meniscus degradation through quantitative imaging of ex vivo posterior horns of menisci from subjects with and without knee osteoarthritis (OA). DESIGN: We sampled medial and lateral menisci from ten medial compartment knee OA patients (mean age 63 years) undergoing total knee replacement and from ten deceased donors (references, mean age 51 years). MR relaxation parameters T2*, T2 and T1 of the posterior horn were measured at a 9.4 T scanner. Comparisons were made between OA patients and references (with adjustment for age) as well as between medial and lateral menisci from the same knees. RESULTS: Mean values (standard deviation) of mean T2* were 13 (3.8), 6.9 (2.3), 7.2 (1.9) and 7.2 (1.7) ms for the medial and lateral patient menisci and the medial and lateral reference menisci, respectively. Corresponding values were 17 (3.7), 9.0 (2.2), 12 (4) and 9.0 (1.3) ms for T2 and 1810 (150), 1630 (30), 1580 (90) and 1560 (50) ms for T1. All three relaxation times were significantly longer in medial OA menisci compared to the other groups. Among medial reference menisci, relaxation times (mainly T1) tended to increase with age. CONCLUSIONS: MR relaxation times T2*, T2 and T1 in the posterior horn are longer in the medial menisci of patients with end-stage medial compartment knee OA compared to the corresponding lateral menisci and to reference menisci. The meniscus seems to undergo intrasubstance alterations related to both OA and ageing.

A Life-Saving Palsy: Hereditary Neuropathy with Liability to Pressure Palsies (HNPP) Presenting As Hand Weakness during Cardiopulmonary Resuscitation (CPR) Training

Aim To describe a case of acute and transient hand weakness that developed during cardiopulmonary resuscitation (CPR) training. Hereditary neuropathy with liability to pressure palsies (HNPP) should be considered in patients with recurrent, painless motor or sensory neuropathies at sites of peripheral nerve compression. Methods Nerve conduction studies confirmed neuropraxia of the distal ulnar nerve with a mild background demyelinating peripheral neuropathy. Results A positive family history emerged and HNPP was confirmed by genetic testing. HNPP is most reliably diagnosed by molecular testing for peripheral myelin protein 22 (PMP22) gene deletion or point mutation on chromosome 17p11.2. Conclusion CPR, a procedure carried out by medical professionals on a daily basis, is a high-energy manual task and provides multiple opportunities for nerve compression. This case demonstrates the importance of having a high index of clinical suspicion of this disorder in patients. Recognising a diagnosis of HNPP may prevent unnecessary surgical decompression.