Clinical findings, treatment and outcome of trapped neutrophil syndrome in Border Collies: 12 cases (2011-2022).

OBJECTIVES: This study aimed to evaluate clinical signs, diagnostic findings, treatment administered and short- (survival to 28 days) and long-term prognosis (survival >6 months) in dogs diagnosed with trapped neutrophil syndrome. MATERIALS AND METHODS: Medical records of 12 dogs (10 Border Collies and two Border Collie Crossbreeds) homozygous for VPS13B gene mutation causing trapped neutrophil syndrome from seven veterinary institutions between January 2011 and June 2022 were evaluated retrospectively. RESULTS: The most common clinical signs at the time of diagnosis were pyrexia, abnormal gait and gastrointestinal signs. Concurrent metaphyseal osteopathy and immune-mediated polyarthritis were common. Seven dogs had a segmented neutrophil count below, four dogs within and one dog above the analyser reference interval at presentation. Two dogs had a septic source identified and both were additionally identified to be homozygous mutant positive on DNA testing by polymerase chain reaction (PCR) for canine cyclic neutropenia. All dogs received at least one antimicrobial agent and 10 dogs received treatment with prednisone or prednisolone (median starting dose 1 mg/kg/day; range 0.5 to 2.5 mg/kg/day). Nine dogs were alive at 28 days and six dogs were alive at 6 months post-diagnosis. CLINICAL SIGNIFICANCE: Trapped neutrophil syndrome should be suspected in young Border Collies with pyrexia, lameness and gastrointestinal signs. Neutropenia may not always be present and long-term survival is possible. A septic focus was not commonly identified in our population; however, our results suggest that if identified, testing for concurrent canine cyclic neutropenia should be considered.

On the origin of optical rotation changes during the κ-carrageenan disorder-to-order transition.

It is well established that solutions of both polymeric and oligomeric κ-carrageenan exhibit a clear change in optical rotation (OR), in concert with gel-formation for polymeric samples, as the solution is cooled in the presence of certain ions. The canonical interpretation - that this OR change reflects a 'coil-to-helix transition' in single chains - has seemed unambiguous; the solution- or 'disordered'-state structure has ubiquitously been assumed to be a 'random coil', and the helical nature of carrageenan in the solid-state was settled in the 1970s. However, recent work has found that κ-carrageenan contains substantial helical secondary structure elements in the disordered-state, raising doubts over the validity of this interpretation. To investigate the origins of the OR, density-functional theory calculations were conducted using atomic models of κ-carrageenan oligomers. Changes were found to occur in the predicted OR owing purely to dimerization of chains, and - together with the additional effects of slight changes in conformation that occur when separated helical chains form double-helices - the predicted OR changes are qualitatively consistent with experimental results. These findings contribute to a growing body of evidence that the carrageenan 'disorder-to-order' transition is a cooperative process, and have further implications for the interpretation of OR changes demonstrated by macromolecules in general.

The impact of musculoskeletal ill health on quality of life and function after critical care: a multicentre prospective cohort study.

Physical disability is a common component of post-intensive care syndrome, but the importance of musculoskeletal health in this population is currently unknown. We aimed to determine the musculoskeletal health state of intensive care unit survivors and assess its relationship with health-related quality of life; employment; and psychological and physical function. We conducted a multicentre prospective cohort study of adults admitted to intensive care for > 48 h without musculoskeletal trauma or neurological insult. Patients were followed up 6 months after admission where musculoskeletal health state was measured using the validated Musculoskeletal Health Questionnaire score. Of the 254 participants, 150 (59%) had a musculoskeletal problem and only 60 (24%) had received physiotherapy after discharge. Functional Comorbidity Index, Clinical Frailty Scale, duration of intensive care unit stay and prone positioning were all independently associated with worse musculoskeletal health. Musculoskeletal health state moderately correlated with quality of life, rs = 0.499 (95%CI 0.392-0.589); anxiety, rs = -0.433 (95%CI -0.538 to -0.315); and depression, rs = -0.537 (95%CI -0.631 to -0.434) (all p < 0.001). Patients with a musculoskeletal problem were less physically active than those without a problem (median (IQR [range]) number of 30 min physical activity sessions per week 1 (0-3.25 [0-7]) vs. 4 (1-7 [0-7]), p < 0.001, respectively). This study found that musculoskeletal health problems were common after intensive care unit stay. However, we observed that < 25% of patients received physical rehabilitation after discharge home. Our work has identified potential high-risk groups to target in future interventional studies.

The complex polyploid genome architecture of sugarcane.

Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

Prevention of respiratory virus transmission by resident memory CD8+ T cells.

An ideal vaccine both attenuates virus growth and disease in infected individuals and reduces the spread of infections in the population, thereby generating herd immunity. Although this strategy has proved successful by generating humoral immunity to measles, yellow fever and polio, many respiratory viruses evolve to evade pre-existing antibodies1. One approach for improving the breadth of antiviral immunity against escape variants is through the generation of memory T cells in the respiratory tract, which are positioned to respond rapidly to respiratory virus infections2-6. However, it is unknown whether memory T cells alone can effectively surveil the respiratory tract to the extent that they eliminate or greatly reduce viral transmission following exposure of an individual to infection. Here we use a mouse model of natural parainfluenza virus transmission to quantify the extent to which memory CD8+ T cells resident in the respiratory tract can provide herd immunity by reducing both the susceptibility of acquiring infection and the extent of transmission, even in the absence of virus-specific antibodies. We demonstrate that protection by resident memory CD8+ T cells requires the antiviral cytokine interferon-γ (IFNγ) and leads to altered transcriptional programming of epithelial cells within the respiratory tract. These results suggest that tissue-resident CD8+ T cells in the respiratory tract can have important roles in protecting the host against viral disease and limiting viral spread throughout the population.

The menstrual cycle regulates migratory CD4 T-cell surveillance in the female reproductive tract via CCR5 signaling.

Despite their importance for immunity against sexually transmitted infections, the composition of female reproductive tract (FRT) memory T-cell populations in response to changes within the local tissue environment under the regulation of the menstrual cycle remains poorly defined. Here, we show that in humans and pig-tailed macaques, the cycle determines distinct clusters of differentiation 4 T-cell surveillance behaviors by subsets corresponding to migratory memory (TMM) and resident memory T cells. TMM displays tissue-itinerant trafficking characteristics, restricted distribution within the FRT microenvironment, and distinct effector responses to infection. Gene pathway analysis by RNA sequencing identified TMM-specific enrichment of genes involved in hormonal regulation and inflammatory responses. FRT T-cell subset fluctuations were discovered that synchronized to cycle-driven CCR5 signaling. Notably, oral administration of a CCR5 antagonist drug blocked TMM trafficking. Taken together, this study provides novel insights into the dynamic nature of FRT memory CD4 T cells and identifies the menstrual cycle as a key regulator of immune surveillance at the site of STI pathogen exposure.

Cholestenoic acid as endogenous epigenetic regulator decreases hepatocyte lipid accumulation in vitro and in vivo.

Cholestenoic acid (CA) has been reported as an important biomarker of many severe diseases, but its physiological and pathological roles remain unclear. This study aimed to investigate the potential role of CA in hepatic lipid homeostasis. Enzyme kinetic studies revealed that CA specifically activates DNA methyltransferases 1 (DNMT1) at low concentration with EC50 = 1.99 × 10-6 M and inhibits the activity at higher concentration with IC50 = 9.13 × 10-6 M, and specifically inhibits DNMT3a, and DNMT3b activities with IC50= 8.41 × 10-6 M and IC50= 4.89 × 10-6 M, respectively. In a human hepatocyte in vitro model of high glucose (HG)-induced lipid accumulation, CA significantly increased demethylation of 5mCpG in the promoter regions of over 7,000 genes, particularly those involved in master signaling pathways such as calcium-AMPK and 0.0027 at 6 h. RNA sequencing analysis showed that the downregulated genes are affected by CA encoding key enzymes, such as PCSK9, MVK, and HMGCR, which are involved in cholesterol metabolism and steroid biosynthesis pathways. In addition, untargeted lipidomic analysis showed that CA significantly reduced neutral lipid levels by 60% in the cells cultured in high-glucose media. Administration of CA in mouse metabolic dysfunction-associated steatotic liver disease (MASLD) models significantly decreases lipid accumulation, suppresses the gene expression involved in lipid biosynthesis in liver tissues, and alleviates liver function. This study shows that CA as an endogenous epigenetic regulator decreases lipid accumulation via epigenetic regulation. The results indicate that CA can be considered a potential therapeutic target for the treatment of metabolic disorders.NEW & NOTEWORTHY To our knowledge, this study is the first to identify the mitochondrial monohydroxy bile acid cholestenoic acid (CA) as an endogenous epigenetic regulator that regulates lipid metabolism through epigenome modification in human hepatocytes. The methods used in this study are all big data analysis, and the results of each part show the global regulation of CA on human hepatocytes rather than narrow point effects.

Pretreatment characteristics associated with symptom reduction during group cognitive processing therapy versus exposure therapy for PTSD: an exploratory study of Veterans.

Exposure and cognitive-based therapies are both effective for PTSD, but knowledge of which intervention is best for which patient is lacking. This lack of knowledge is particularly noticeable for group treatments, as no study has examined whether responses to different group therapies are associated with different pretreatment characteristics. Here, we explored whether pretreatment levels of three types of psychological characteristics-PTSD symptom clusters, posttraumatic cognitions, and emotion regulation difficulties-were associated with symptom reduction during group-delivered cognitive versus exposure-based PTSD treatment. Participants were Veterans with PTSD drawn from two previous clinical trials: one of group CPT (GCPT; n = 32) and the other of group-based exposure therapy (GBET; n = 21). Growth curve modeling was used to identify pretreatment variables that predicted weekly PTSD symptom changes during each therapy. Higher posttraumatic cognitions at pretreatment predicted steeper PTSD symptom reduction during GCPT but not GBET. Additionally, symptom reduction during each therapy was associated with different pretreatment emotion regulation difficulties: difficulties with goal-directed behavior for GBET and lack of emotional clarity and limited access to emotion regulation strategies for GCPT. These findings suggest that assigning Veterans to a group PTSD therapy that better matches their pretreatment psychological profile might facilitate a better therapeutic response.

Framework for Accurate Classification of Self-Reported Stress From Multisession Functional MRI Data of Veterans With Posttraumatic Stress.

Background: Posttraumatic stress disorder (PTSD) is a significant burden among combat Veterans returning from the wars in Iraq and Afghanistan. While empirically supported treatments have demonstrated reductions in PTSD symptomatology, there remains a need to improve treatment effectiveness. Functional magnetic resonance imaging (fMRI) neurofeedback has emerged as a possible treatment to ameliorate PTSD symptom severity. Virtual reality (VR) approaches have also shown promise in increasing treatment compliance and outcomes. To facilitate fMRI neurofeedback-associated therapies, it would be advantageous to accurately classify internal brain stress levels while Veterans are exposed to trauma-associated VR imagery. Methods: Across 2 sessions, we used fMRI to collect neural responses to trauma-associated VR-like stimuli among male combat Veterans with PTSD symptoms (N = 8). Veterans reported their self-perceived stress level on a scale from 1 to 8 every 15 s throughout the fMRI sessions. In our proposed framework, we precisely sample the fMRI data on cortical gray matter, blurring the data along the gray-matter manifold to reduce noise and dimensionality while preserving maximum neural information. Then, we independently applied 3 machine learning (ML) algorithms to this fMRI data collected across 2 sessions, separately for each Veteran, to build individualized ML models that predicted their internal brain states (self-reported stress responses). Results: We accurately classified the 8-class self-reported stress responses with a mean (± standard error) root mean square error of 0.6 (± 0.1) across all Veterans using the best ML approach. Conclusions: The findings demonstrate the predictive ability of ML algorithms applied to whole-brain cortical fMRI data collected during individual Veteran sessions. The framework we have developed to preprocess whole-brain cortical fMRI data and train ML models across sessions would provide a valuable tool to enable individualized real-time fMRI neurofeedback during VR-like exposure therapy for PTSD.

Examining the effects of prenatal alcohol exposure on performance of the sustained attention to response task in children with an FASD.

Prenatal alcohol exposure (PAE), the leading known cause of childhood developmental disability, has long-lasting effects extending throughout the lifespan. It is well documented that children prenatally exposed to alcohol have difficulties inhibiting behavior and sustaining attention. Thus, the Sustained Attention to Response Task (SART), a Go/No-go paradigm, is especially well suited to assess the behavioral and neural functioning characteristics of children with PAE. In this study, we utilized neuropsychological assessment, parent/guardian questionnaires, and magnetoencephalography during SART random and fixed orders to assess characteristics of children 8-12 years old prenatally exposed to alcohol compared to typically developing children. Compared to neurotypical control children, children with a Fetal Alcohol Spectrum Disorder (FASD) diagnosis had significantly decreased performance on neuropsychological measures, had deficiencies in task-based performance, were rated as having increased Attention-Deficit/Hyperactivity Disorder (ADHD) behaviors and as having lower cognitive functioning by their caretakers, and had decreased peak amplitudes in Broadmann's Area 44 (BA44) during SART. Further, MEG peak amplitude in BA44 was found to be significantly associated with neuropsychological test results, parent/guardian questionnaires, and task-based performance such that decreased amplitude was associated with poorer performance. In exploratory analyses, we also found significant correlations between total cortical volume and MEG peak amplitude indicating that the reduced amplitude is likely related in part to reduced overall brain volume often reported in children with PAE. These findings show that children 8-12 years old with an FASD diagnosis have decreased amplitudes in BA44 during SART random order, and that these deficits are associated with multiple behavioral measures.

Outcomes After Hybrid Palliation for Infants With Critical Left Heart Obstruction.

BACKGROUND: Hybrid palliation (bilateral pulmonary artery banding with or without ductal stenting) is an initial management strategy for infants with critical left heart obstruction and serves as palliation until subsequent operations are pursued. OBJECTIVES: This study sought to determine patient characteristics and factors associated with subsequent outcomes for infants who underwent hybrid palliation. METHODS: From 2005 to 2019, 214 of 1,236 prospectively enrolled infants within the Congenital Heart Surgeons' Society's critical left heart obstruction cohort underwent hybrid palliation across 24 institutions. Multivariable hazard modeling with competing risk methodology was performed to determine risk and factors associated with outcomes of biventricular repair, Fontan procedure, transplantation, or death. RESULTS: Preoperative comorbidities (eg, prematurity, low birth weight, genetic syndrome) were identified in 70% of infants (150 of 214). Median follow-up was 7 years, ranging up to 17 years. Overall 12-year survival was 55%. At 5 years after hybrid palliation, 9% had biventricular repair, 36% had Fontan procedure, 12% had transplantation, 35% died without surgical endpoints, and 8% were alive without an endpoint. Factors associated with transplantation were absence of ductal stent, older age, absent interatrial communication, smaller aortic root size, larger tricuspid valve area z-score, and larger left ventricular volume. Factors associated with death were low birth weight, concomitant genetic syndrome, cardiopulmonary bypass use during hybrid palliation, moderate to severe tricuspid valve regurgitation, and smaller ascending aortic size. CONCLUSIONS: Mortality remains high after hybrid palliation for infants with critical left heart obstruction. Nonetheless, hybrid palliation may facilitate biventricular repair for some infants and for others may serve as stabilization for intended functional univentricular palliation or primary transplantation.

Root reinforcement and extracellular products reduce streambank fluvial erosion.

A detailed understanding of the factors that impact bank erodibility is necessary to effectively model changes in channel form. This study evaluated the combined contributions of roots and soil microorganisms to soil resistance against fluvial erosion. To do this, three flume walls were constructed to simulate unvegetated and rooted streambanks. Unamended and organic material (OM) amended soil treatments with either no-roots (bare soil), synthetic (inert) roots, or living roots (Panicum virgatum) were created and tested with the corresponding flume wall treatment. OM stimulated the production of extracellular polymeric substances (EPS) and appeared to increase the applied stress required to initiate soil erosion. Synthetic fibers alone provided a base reduction in soil erosion, regardless of the flow rate used. When used in combination, synthetic roots and OM-amendments reduced erosion rates by 86 % or more compared to bare soil; this reduction was identical to the live rooted treatments (95 % to 100 %). In summary, a synergistic relationship between roots and organic carbon inputs can significantly reduce soil erosion rates due to fiber reinforcement and EPS production. These results indicate that root-biochemical interactions, like root physical mechanisms, play an important role in influencing channel migration rates due to reductions in streambank erodibility.

Histological examination of choroid plexus epithelia changes in schizophrenia.

BACKGROUND: The choroid plexus (CP) produces and secretes most of the cerebrospinal fluid (CSF) of the central nervous system. The CP is suggested to be regulated by descending neurons and by circulating factors and is involved in the interaction between central and peripheral inflammation. Quantitative imaging has demonstrated volumetric CP changes in psychosis, schizophrenia and depression. This study histologically examines CP epithelial cell morphology in these illnesses to identify the biological source of such volumetric changes. METHODS: Formalin-fixed paraffin-embedded (FFPE) blocks were obtained bilaterally from the lateral ventricles of 13 cases of sex- and age-matched brains from each of schizophrenia (SZ) with psychosis, major depressive disorder (MDD) and matched controls (NPD). FFPE blocks were sectioned at 7 µm and routinely stained for H&E. Morphological analysis of 180 CP epithelia/case was conducted blindly on digital images collected at x600 magnification. Calcification was assessed in all CP regions manually. RESULTS: Analysis with a General Linear Model demonstrated a significant effect of diagnosis on somal width (p = 0.006, R2 = 0.33 R2(adj) = 0.25) demonstrating increased somal width in SZ without psychotic medication versus controls (p = 0.032), but not in medicated SZ cases. No effects were observed in calcification. DISCUSSION: The epithelial cells that were examined were attached to the CP fibrous surface, so width expansion describes the primary methods for these cells to expand with adherence to this surface in SZ. The interaction of antipsychotic medication and diagnosis demonstrates that this is an illness-specific change mediated through the DA-system with likely neuronal origin. CP alterations were not found in MDD where they are instead generally associated with heightened allostatic load that was unknown in this cohort.

PFAS contaminated asphalt and concrete - Knowledge gaps for future research and management.

Per- and polyfluoroalkyl substances (PFAS) are now widespread in the environment. Globally, airfields and paved firefighting training surfaces are particularly affected due to extensive use of aqueous film forming foams (AFFF). This PFAS contamination in exposed concrete and asphalt has not been widely addressed. This review focusses on PFAS interaction with concrete and asphalt, traversing extraction, analytical identification/quantification, PFAS fractionation via differential adsorption on organic and inorganic substrates, and reuse options for contaminated concrete and asphalt. A total of 24 knowledge gaps and management challenges for concrete and asphalt characterisation and management have been identified.

Evaluation of in silico pathogenicity prediction tools for the classification of small in-frame indels.

BACKGROUND: The use of in silico pathogenicity predictions as evidence when interpreting genetic variants is widely accepted as part of standard variant classification guidelines. Although numerous algorithms have been developed and evaluated for classifying missense variants, in-frame insertions/deletions (indels) have been much less well studied. METHODS: We created a dataset of 3964 small (< 100 bp) indels predicted to result in in-frame amino acid insertions or deletions using data from gnomAD v3.1 (minor allele frequency of 1-5%), ClinVar and the Deciphering Developmental Disorders (DDD) study. We used this dataset to evaluate the performance of nine pathogenicity predictor tools: CADD, CAPICE, FATHMM-indel, MutPred-Indel, MutationTaster2021, PROVEAN, SIFT-indel, VEST-indel and VVP. RESULTS: Our dataset consisted of 2224 benign/likely benign and 1740 pathogenic/likely pathogenic variants from gnomAD (n = 809), ClinVar (n = 2882) and, DDD (n = 273). We were able to generate scores across all tools for 91% of the variants, with areas under the ROC curve (AUC) of 0.81-0.96 based on the published recommended thresholds. To avoid biases caused by inclusion of our dataset in the tools' training data, we also evaluated just DDD variants not present in either gnomAD or ClinVar (70 pathogenic and 81 benign). Using this subset, the AUC of all tools decreased substantially to 0.64-0.87. Several of the tools performed similarly however, VEST-indel had the highest AUCs of 0.93 (full dataset) and 0.87 (DDD subset). CONCLUSIONS: Algorithms designed for predicting the pathogenicity of in-frame indels perform well enough to aid clinical variant classification in a similar manner to missense prediction tools.

Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program.

PURPOSE: The CD20 antigen is expressed on more than 90% of B-cell lymphomas. It is appealing for targeted therapy, because it does not shed or modulate. A chimeric monoclonal antibody more effectively mediates host effector functions and is itself less immunogenic than are murine antibodies. PATIENTS AND METHODS: This was a multiinstitutional trial of the chimeric anti-CD20 antibody, IDEC-C2B8. Patients with relapsed low grade or follicular lymphoma received an outpatient treatment course of IDEC-C2B8 375 mg/m2 intravenously weekly for four doses. RESULTS: From 31 centers, 166 patients were entered. Of this intent-to-treat group, 48% responded. With a median follow-up duration of 11.8 months, the projected median time to progression for responders is 13.0 months. Serum antibody levels were sustained longer after the fourth infusion than after the first, and were higher in responders and in patients with lower tumor burden. The majority of adverse events occurred during the first infusion and were grade 1 or 2; fever and chills were the most common events. Only 12% of patients had grade 3 and 3% grade 4 toxicities. A human antichimeric antibody was detected in only one patient. CONCLUSION: The response rate of 48% with IDEC-C2B8 is comparable to results with single-agent cytotoxic chemotherapy. Toxicity was mild. Attention needs to be paid to the rate of antibody infusion, with titration according to toxicity. Further investigation of this agent is warranted, including its use in conjunction with standard chemotherapy.

Molecular dynamics simulations and X-ray scattering show the κ-carrageenan disorder-to-order transition to be the formation of double-helices.

Recent molecular dynamics simulations, verified experimentally by solution-state x-ray scattering experiments, have found that κ-carrageenan chains contain helical secondary structure, akin to that found in the solid-state, even in aqueous solution. Furthermore, upon the addition of ions to single chains the simulations found no evidence that any conformational transitions take place. These findings challenge the long-held assumption that the so-called disorder-to-order transition in carrageenan systems involves a uni-molecular 'coil-to-helix transition'. Herein, the results of further molecular dynamics simulations undertaken using pairs of κ-carrageenan chains in 0.1 M NaI solutions are reported, and are validated experimentally using state-of-the-art solution-state WAXS experiments. From initially separated chains double-helices are shown to form, leading the authors to propose 'two single helices-to-stabilized double-helix' as a description of the molecular events taking place during the disorder-to-order transition.