Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice.

Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aß plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aß deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

In vivo mapping of cellular resolution neuropathology in brain ischemia with diffusion MRI.

Noninvasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent advances in diffusion magnetic resonance imaging enabled in vivo examination of tissue microstructures well beyond the imaging resolution. Here, we proposed to use diffusion time-dependent diffusion kurtosis imaging (tDKI) to simultaneously assess cellular morphology and transmembrane permeability in hypoxic-ischemic (HI) brain injury. Through numerical simulations and organoid imaging, we demonstrated the feasibility of capturing effective size and permeability changes using tDKI. In vivo MRI of HI-injured mouse brains detected a shift of the tDKI peak to longer diffusion times, suggesting swelling of the cellular processes. Furthermore, we observed a faster decrease of the tDKI tail, reflecting increased transmembrane permeability associated with up-regulated water exchange or necrosis. Such information, unavailable from a single diffusion time, can predict salvageable tissues. Preliminary applications of tDKI in patients with ischemic stroke suggested increased transmembrane permeability in stroke regions, illustrating tDKI's potential for detecting pathological changes in the clinics.

BEDT-TTF radical-cation salts with tris(oxalato)chromate and guest additives.

The family of radical-cation salts ß''-(BEDT-TTF)4[(A)M3+(C2O4)3]·guest (M = Fe, Cr, Ga, Al, Co, Mn, Rh, Ru; A = K+, H3O+, NH4 +) has produced superconductors, metals, semiconductors, and metal-insulators through introduction of different guest molecules into the structure. We present three new additions to the family ß''-(BEDT-TTF)4[(A)Cr(C2O4)3]·guest with the guest molecules toluene, phenol, or salicylaldehyde. These new guests are liquid or solid additives within the electrocrystallisation medium. All three salts show metallic behaviour from room temperature down to <10 K and do not show a superconducting transition.

Characterising illness stages and recovery trajectories of eating disorders in young people via remote measurement technology (STORY): a multi-centre prospective cohort study protocol.

BACKGROUND: Eating disorders (EDs) are serious, often chronic, conditions associated with pronounced morbidity, mortality, and dysfunction increasingly affecting young people worldwide. Illness progression, stages and recovery trajectories of EDs are still poorly characterised. The STORY study dynamically and longitudinally assesses young people with different EDs (restricting; bingeing/bulimic presentations) and illness durations (earlier; later stages) compared to healthy controls. Remote measurement technology (RMT) with active and passive sensing is used to advance understanding of the heterogeneity of earlier and more progressed clinical presentations and predictors of recovery or relapse. METHODS: STORY follows 720 young people aged 16-25 with EDs and 120 healthy controls for 12 months. Online self-report questionnaires regularly assess ED symptoms, psychiatric comorbidities, quality of life, and socioeconomic environment. Additional ongoing monitoring using multi-parametric RMT via smartphones and wearable smart rings ('Oura ring') unobtrusively measures individuals' daily behaviour and physiology (e.g., Bluetooth connections, sleep, autonomic arousal). A subgroup of participants completes additional in-person cognitive and neuroimaging assessments at study-baseline and after 12 months. DISCUSSION: By leveraging these large-scale longitudinal data from participants across ED diagnoses and illness durations, the STORY study seeks to elucidate potential biopsychosocial predictors of outcome, their interplay with developmental and socioemotional changes, and barriers and facilitators of recovery. STORY holds the promise of providing actionable findings that can be translated into clinical practice by informing the development of both early intervention and personalised treatment that is tailored to illness stage and individual circumstances, ultimately disrupting the long-term burden of EDs on individuals and their families.

Proteasome localization and activity in pig brain and in vivo small molecule screening for activators.

Introduction: Loss of proteasome function, proteinopathy, and proteotoxicity may cause neurodegeneration across the human lifespan in several forms of brain injury and disease. Drugs that activate brain proteasomes in vivo could thus have a broad therapeutic impact in neurology. Methods: Using pigs, a clinically relevant large animal with a functionally compartmental gyrencephalic cerebral cortex, we evaluated the localization and biochemical activity of brain proteasomes and tested the ability of small molecules to activate brain proteasomes. Results: By Western blotting, proteasome protein subunit PSMB5 and PSMA3 levels were similar in different pig brain regions. Immunohistochemistry for PSMB5 showed localization in the cytoplasm (diffuse and particulate) and nucleus (cytoplasm < nucleus). Some PSMB5 immunoreactivity was colocalized with mitochondrial (voltage-gated anion channel and cyclophilin D) and cell death (Aven) proteins in the neuronal soma and neuropil in the neocortex of pig and human brains. In the nucleus, PSMB5 immunoreactivity was diffuse, particulate, and clustered, including perinucleolar decorations. By fluorogenic assay, proteasome chymotrypsin-like activities (CTL) in crude tissue soluble fractions were generally similar within eight different pig brain regions. Proteasome CTL activity in the hippocampus was correlated with activity in nasal mucosa biopsies. In pilot analyses of subcellular fractions of pig cerebral cortex, proteasome CTL activity was highest in the cytosol and then ~50% lower in nuclear fractions; ~15-20% of total CTL activity was in pure mitochondrial fractions. With in-gel activity assay, 26S-singly and -doubly capped proteasomes were the dominant forms in the pig cerebral cortex. With a novel in situ histochemical activity assay, MG132-inhibitable proteasome CTL activity was localized to the neuropil, as a mosaic, and to cell bodies, nuclei, and centrosome-like perinuclear satellites. In piglets treated intravenously with pyrazolone derivative and chlorpromazine over 24 h, brain proteasome CTL activity was modestly increased. Discussion: This study shows that the proteasome in the pig brain has relative regional uniformity, prominent nuclear and perinuclear presence with catalytic activity, a mitochondrial association with activity, 26S-single cap dominance, and indications from small molecule systemic administration of pyrazolone derivative and chlorpromazine that brain proteasome function appears safely activable.

The quality of teaching behaviors in learning environments of DHH students.

Classrooms are complex learning environments, with instruction, climate, and teacher-student interactions playing important roles in students' academic progress. To investigate the learning environments of deaf and hard-of-hearing (DHH) students, we developed a new observational tool called the Quality of the Learning Environment-DHH rating scale (QLE-DHH) and rated 98 teachers of DHH students being educated in a range of classroom environments. The present study sought to (1) determine if the items on the QLE-DHH are good indicators of theoretically meaningful dimensions of classroom quality; (2) determine to what extent these dimensions predicted language and reading outcomes of DHH students; and (3) examine how teachers of DHH students were rated on the indicators of classroom quality. The findings suggested that the QLE-DHH has excellent structural validity. Ratings predicted student reading outcomes. Finally, the QLE-DHH was able to capture teachers' strengths and skills in need of improvement. The QLE-DHH appears to hold promise for use in both research and teacher preparation programs.

Hypothermic Protection in Neocortex Is Topographic and Laminar, Seizure Unmitigating, and Partially Rescues Neurons Depleted of RNA Splicing Protein Rbfox3/NeuN in Neonatal Hypoxic-Ischemic Male Piglets.

The effects of hypothermia on neonatal encephalopathy may vary topographically and cytopathologically in the neocortex with manifestations potentially influenced by seizures that alter the severity, distribution, and type of neuropathology. We developed a neonatal piglet survival model of hypoxic-ischemic (HI) encephalopathy and hypothermia (HT) with continuous electroencephalography (cEEG) for seizures. Neonatal male piglets received HI-normothermia (NT), HI-HT, sham-NT, or sham-HT treatments. Randomized unmedicated sham and HI piglets underwent cEEG during recovery. Survival was 2-7 days. Normal and pathological neurons were counted in different neocortical areas, identified by cytoarchitecture and connectomics, using hematoxylin and eosin staining and immunohistochemistry for RNA-binding FOX-1 homolog 3 (Rbfox3/NeuN). Seizure burden was determined. HI-NT piglets had a reduced normal/total neuron ratio and increased ischemic-necrotic/total neuron ratio relative to sham-NT and sham-HT piglets with differing severities in the anterior and posterior motor, somatosensory, and frontal cortices. Neocortical neuropathology was attenuated by HT. HT protection was prominent in layer III of the inferior parietal cortex. Rbfox3 immunoreactivity distinguished cortical neurons as: Rbfox3-positive/normal, Rbfox3-positive/ischemic-necrotic, and Rbfox3-depleted. HI piglets had an increased Rbfox3-depleted/total neuron ratio in layers II and III compared to sham-NT piglets. Neuronal Rbfox3 depletion was partly rescued by HT. Seizure burdens in HI-NT and HI-HT piglets were similar. We conclude that the neonatal HI piglet neocortex has: (1) suprasylvian vulnerability to HI and seizures; (2) a limited neuronal cytopathological repertoire in functionally different regions that engages protective mechanisms with HT; (3) higher seizure burden, insensitive to HT, that is correlated with more panlaminar ischemic-necrotic neurons in the somatosensory cortex; and (4) pathological RNA splicing protein nuclear depletion that is sensitive to HT. This work demonstrates that HT protection of the neocortex in neonatal HI is topographic and laminar, seizure unmitigating, and restores neuronal depletion of RNA splicing factor.

In vivo Mapping of Cellular Resolution Neuropathology in Brain Ischemia by Diffusion MRI.

Non-invasive mapping of cellular pathology can provide critical diagnostic and prognostic information. Recent developments in diffusion MRI have produced new tools for examining tissue microstructure at a level well below the imaging resolution. Here, we report the use of diffusion time ( t )-dependent diffusion kurtosis imaging ( t DKI) to simultaneously assess the morphology and transmembrane permeability of cells and their processes in the context of pathological changes in hypoxic-ischemic brain (HI) injury. Through Monte Carlo simulations and cell culture organoid imaging, we demonstrate feasibility in measuring effective size and permeability changes based on the peak and tail of t DKI curves. In a mouse model of HI, in vivo imaging at 11.7T detects a marked shift of the t DKI peak to longer t in brain edema, suggesting swelling and beading associated with the astrocytic processes and neuronal neurites. Furthermore, we observed a faster decrease of the t DKI tail in injured brain regions, reflecting increased membrane permeability that was associated with upregulated water exchange upon astrocyte activation at acute stage as well as necrosis with disrupted membrane integrity at subacute stage. Such information, unavailable with conventional diffusion MRI at a single t, can predict salvageable tissues. For a proof-of-concept, t DKI at 3T on an ischemic stroke patient suggested increased membrane permeability in the stroke region. This work therefore demonstrates the potential of t DKI for in vivo detection of the pathological changes in microstructural morphology and transmembrane permeability after ischemic injury using a clinically translatable protocol.

Writing knowledge, practices, efficacy, interests, attitudes, and beliefs of deaf education teachers: a randomized controlled trial.

Writing teachers play an extraordinarily important role in their students' writing development. Teachers' motivational beliefs, such as attitudes toward writing, perceptions of their efficacy to teach writing, or preparation to use evidence-based instructional practices, impact their writing instruction, which directly affects the advancement of students' writing skills. Deaf writers are a subpopulation of writers who may face discriminatory beliefs toward their writing development stemming from ableism, audism, or linguicism. Deaf education teachers may doubt their abilities to teach bilingual/multilingual students or teach deaf students experiencing language deprivation. The current study investigates whether deaf education teachers' beliefs can be fostered through an intensive one-year professional development (PD) program designed specifically for deaf education teachers. In this randomized controlled trial, we examine the extent to which the participation of deaf education teachers in specialized PD and subsequent writing instruction implementation (n = 26) impacts their pedagogical content knowledge, use of evidence-based practices for teaching writing, interest, attitudes, efficacy in teaching writing, and epistemological beliefs about writing compared to teachers in a business as usual condition (n = 24). Pre-post regression analyses indicate statistically significant group differences (with the treatment group scoring higher) on all variables except attitude and some epistemological beliefs. We speculate that specialized, sustained PD paired with supported implementation of writing instruction and ongoing teacher reflection are contributing factors to changes in teachers' motivational beliefs.

Polynitroxylated PEGylated hemoglobin protects pig brain neocortical gray and white matter after traumatic brain injury and hemorrhagic shock.

Polynitroxylated PEGylated hemoglobin (PNPH, aka SanFlow) possesses superoxide dismutase/catalase mimetic activities that may directly protect the brain from oxidative stress. Stabilization of PNPH with bound carbon monoxide prevents methemoglobin formation during storage and permits it to serve as an anti-inflammatory carbon monoxide donor. We determined whether small volume transfusion of hyperoncotic PNPH is neuroprotective in a porcine model of traumatic brain injury (TBI) with and without accompanying hemorrhagic shock (HS). TBI was produced by controlled cortical impact over the frontal lobe of anesthetized juvenile pigs. Hemorrhagic shock was induced starting 5 min after TBI by 30 ml/kg blood withdrawal. At 120 min after TBI, pigs were resuscitated with 60 ml/kg lactated Ringer's (LR) or 10 or 20 ml/kg PNPH. Mean arterial pressure recovered to approximately 100 mmHg in all groups. A significant amount of PNPH was retained in the plasma over the first day of recovery. At 4 days of recovery in the LR-resuscitated group, the volume of frontal lobe subcortical white matter ipsilateral to the injury was 26.2 ± 7.6% smaller than homotypic contralateral volume, whereas this white matter loss was only 8.6 ± 12.0% with 20-ml/kg PNPH resuscitation. Amyloid precursor protein punctate accumulation, a marker of axonopathy, increased in ipsilateral subcortical white matter by 132 ± 71% after LR resuscitation, whereas the changes after 10 ml/kg (36 ± 41%) and 20 ml/kg (26 ± 15%) PNPH resuscitation were not significantly different from controls. The number of cortical neuron long dendrites enriched in microtubules (length >50 microns) decreased in neocortex by 41 ± 24% after LR resuscitation but was not significantly changed after PNPH resuscitation. The perilesion microglia density increased by 45 ± 24% after LR resuscitation but was unchanged after 20 ml/kg PNPH resuscitation (4 ± 18%). Furthermore, the number with an activated morphology was attenuated by 30 ± 10%. In TBI pigs without HS followed 2 h later by infusion of 10 ml/kg LR or PNPH, PNPH remained neuroprotective. These results in a gyrencephalic brain show that resuscitation from TBI + HS with PNPH protects neocortical gray matter, including dendritic microstructure, and white matter axons and myelin. This neuroprotective effect persists with TBI alone, indicating brain-targeting benefits independent of blood pressure restoration.

Pandemic effects on the reading trajectories of deaf and hard of hearing students: a pilot analysis.

It is important to understand the nature of the effect that the COVID-19 pandemic had upon student learning, especially those at risk such as deaf students. The limited communication that many deaf students have at home may mean less support is available for learning remotely. Reading may be one of the areas where progress was diminished. We collected Measures of Academic Progress (MAP) scores in reading from deaf students in a residential school for the deaf in grades 3 to 12 every fall and spring from 2016 to 2021. A cohort-sequential approach yielded growth data (2570 observations), with 546 students measured up to 10 times each. As is typical of MAP reading achievement in grades 3 to 12, growth was steep in early grades, slowing in later grades. Students in the Alternative Curriculum performed lower and grew slower. Cohorts differed, with more recent cohorts typically having higher performance than older cohorts. Tenure had a substantial effect, suggesting that students who had been in the school for the deaf longer had higher performance compared to students who joined the school as older students. The pandemic appeared to have a strong, but diminishing effect in each semester, but this effect differed widely across demographic groups. This suggests that effects of the pandemic are neither clear nor simple for deaf students even within the same school. These findings have implications for understanding how the impact of pandemic may vary as a function of deaf students' educational experiences and other demographic factors.

A Digital Health Solution for Child Growth Monitoring at Home: Testing the Accuracy of a Novel "GrowthMonitor" Smartphone Application to Detect Abnormal Height and Body Mass Indices.

Objective: To develop and evaluate a smartphone application that accurately measures height and provides notifications when abnormalities are detected. Patients and Methods: A total of 145 (75 boys) participants with a mean age ± SD of 8.7±4.5 years (range, 1.0-17.0 years), from the Children's Hospital at Barts Health Trust, London, United Kingdom, were enrolled in the study. "GrowthMonitor" (UCL Creatives) iPhone application (GMA) measures height using augmented reality. Using population-based (UK-WHO) references, algorithms calculated height SD score (HSDS), distance from target height (THSDSDEV), and HSDS change over time (ΔHSDS). Pre-established thresholds discriminated normal/abnormal growth. The GMA and a stadiometer (Harpenden; gold standard) measured standing heights of children at routine clinic visits. A subset of parents used GMA to measure their child's height at home. Outcome targets were 95% of GMA measurements within ±0.5 SDS of the stadiometer and the correct identification of abnormal HSDS, THSDSDEV, and ΔHSDS. Results: Bland-Altman plots revealed no appreciable bias in differences between paired study team GMA and stadiometer height measurements, with a mean of the differences of 0.11 cm with 95% limits of agreement of -2.21 to 2.42 cm. There was no evidence of greater bias occurring for either shorter/younger children or taller/older children. The 2 methods of measurements were highly correlated (R=0.999). GrowthMonitor iPhone application measurements performed by parents in clinic and at home were slightly less accurate. The κ coefficient indicated reliable and consistent agreement of flag alerts for HSDS (κ=0.74) and THSDSDEV (κ=0.88) between 83 paired GMA and stadiometer measurements. GrowthMonitor iPhone application yielded a detection rate of 96% and 97% for HSDS-based and THSDSDEV-based red flags, respectively. Forty-two (18 boys) participants had GMA calculated ΔHSDS using an additional height measurement 6-16 months later, and no abnormal flag alerts were triggered for ΔHSDS values. Conclusion: GrowthMonitor iPhone application provides the potential for parents/carers and health care professionals to capture serial height measurements at home and without specialized equipment. Reliable interpretation and flagging of abnormal measurements indicate the potential of this technology to transform childhood growth monitoring.

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic.

Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.

Evaluating the sensitivity and specificity of the UK and Dutch growth referral criteria in predicting the diagnosis of pathological short stature.

OBJECTIVE: The aim of this observational study was to evaluate the UK and Dutch referral criteria for short stature to determine their sensitivity and specificity in predicting pathological short stature. Adherence to the recommended panel of investigations was also assessed. STUDY DESIGN: Retrospective review of medical records to examine the auxological parameters, investigations and diagnosis of subjects referred to two paediatric endocrine clinics at the Royal London Children's Hospital between 2016 and 2021. We analysed: height SD score (HtSDS), height SDS minus target height SDS (Ht-THSDS) and height deflection SDS (HtDefSDS). The UK referral criteria were HtSDS <-2.7, Ht-THSDS >2.0 and HtDefSDS >1.3. The Dutch referral criteria were HtSDS <-2.0, Ht-THSDS >1.6 and HtDefSDS >1.0. RESULTS: Data were available for 143 subjects (72% males) with mean (range) age 8.7 years (0.5-19.9). HtSDS and Ht-THSDS were significantly lower in the pathological stature (n=66) versus the non-pathological stature (n=77) subjects (-2.67±0.82 vs -1.97±0.70; p<0.001 and -2.07±1.02 vs -1.06±0.99; p<0.001, respectively). The sensitivity and specificity to detect pathology was 41% and 83% for the UK criteria (HtSDS <-2.7) compared with 59% and 79% for the Dutch criteria (HtSDS <-2.0), 48% and 83% for UK criteria (Ht-THSDS <-2.0) compared with 74% and 72% for Dutch criteria (Ht-THSDS <-1.6) and 33% and 68% for UK criteria (HtDefSDS >1.3) compared with 44% and 63% for the Dutch criteria (HtDefSDS >1.0). On average, each patient had 88% of the recommended investigations, and 53% had all the recommended testing. New pathology was identified in 36% of subjects. CONCLUSIONS: In isolation, the UK auxological referral thresholds have limited sensitivity and specificity for pathological short stature. The combination of HtSDS and Ht-THSDS improved the sensitivity of UK criteria to detect pathology from 41% to 68%. Attention to the child's genetic height potential prior to referral can prevent unnecessary assessments.

Enantiopure and racemic radical-cation salts of B(mandelate)2- and B(2-chloromandelate)2- anions with BEDT-TTF.

We report the first examples of radical-cation salts of BEDT-TTF with spiroborate anions [B(mandelate)2]- and [B(2-chloromandelate)2]-, synthesized from either enantiopure or racemic bidentate mandelate or chloromandelate ligands. In the salts prepared using enantiopure ligands only one of two diastereoisomers of the spiroborate anion is incorporated, with the boron centre having the same stereochemistry as the enantiopure ligand. For the racemic salts one racemic pair of spiroborate anions containing an R and an S mandelate ligand is incorporated. In certain solvents helical crystals were obtained when using spiroborate anions with enantiopure ligands. Electrical and magnetic properties, and band structure calculations are reported.

Long-term personalized low FODMAP diet improves symptoms and maintains luminal Bifidobacteria abundance in irritable bowel syndrome.

BACKGROUND: Short-term trials demonstrate the low FODMAP diet improves symptoms of irritable bowel syndrome (IBS) but impacts nutrient intake and the gastrointestinal microbiota. The aim of this study was to investigate clinical symptoms, nutrient intake, and microbiota of patients with IBS 12 months after starting a low FODMAP diet. METHODS: Participants enrolled in a previous short-term clinical trial and who had been through structured FODMAP restriction, reintroduction, and personalization were invited to participate in a follow-up study at one time point at 12 months. Gastrointestinal symptoms, stool output, dietary intake, and quality of life were recorded. Stool samples were collected and analyzed for microbiota (qPCR) and short-chain fatty acids (SCFA). Data were compared with baseline (prior to any intervention in the original clinical trial) using non-parametric statistics. KEY RESULTS: Eighteen participants were included in the study. Adequate relief of symptoms occurred in 5/18 (28%) at baseline and increased to 12/18 (67%) following long-term personalized low FODMAP diet (p = 0.039). There was a reduction in IBS-SSS total score between baseline (median 227, IQR 99) and long term (154, 89; p < 0.001). Bifidobacteria abundance was not different between baseline (median 9.29 log10 rRNA genes/g, IQR 1.45) and long term (9.20 log10 rRNA genes/g, 1.41; p = 0.766, q = 0.906); however, there were lower concentrations of total SCFA, acetate, propionate, and butyrate. CONCLUSIONS: In this long-term analysis, two thirds of patients reported adequate relief of symptoms after 12 months of personalized low FODMAP diet that did not result in differences from baseline in Bifidobacteria. FODMAP reintroduction and personalization may normalize some of the effects of short-term FODMAP restriction.

Group education on the low FODMAP diet improves gastrointestinal symptoms but neither anxiety or depression in irritable bowel syndrome.

BACKGROUND: The low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet is an effective dietitian-led treatment for irritable bowel syndrome (IBS). An increasing demand of IBS patient referrals has warranted group FODMAP education led by specialist dietitians. Psychological co-morbidities are common in IBS, although how the low FODMAP diet influences psychological outcomes is not understood. The present study aimed to evaluate symptom related outcomes of the diet following group education and assess its effect on psychological profiles. METHODS: An observational, prospective study was conducted in 55 IBS patients who attended FODMAP Restriction and FODMAP Reintroduction group sessions. Data were collected at baseline and follow-up after FODMAP Restriction and analysed using descriptive and McNemar's tests. Primary outcome was evaluated by IBS Symptom Severity Score (IBS-SSS). Secondary psychological outcomes included anxiety and depression using the Hospital Anxiety and Depression Scale (HADS) and risk of eating disorder questionnaire (SCOFF). RESULTS: After FODMAP Restriction, 27 of 55 (54%) patients reported clinically relevant symptom improvement, as defined by a reduction in the IBS-SSS ≥50 points, whereas no differences were recorded in the proportion of patients identified with clinical anxiety (p = 1.000) or clinical depression (p = 0.375). Positively, no increased risk of an eating disorder was observed. CONCLUSIONS: The present study provides data supporting the efficacy of the low FODMAP diet in IBS patients who attended dietitian led group education settings in tertiary care. Clinically significant improvements in gastrointestinal symptoms were observed, although with no impact on clinical levels of anxiety, depression or the risk of an eating disorder.

Basal forebrain magnocellular cholinergic systems are damaged in mice following neonatal hypoxia-ischemia.

Neonatal hypoxic-ischemic encephalopathy (HIE) causes lifelong neurologic disability. Despite the use of therapeutic hypothermia, memory deficits and executive functions remain severely affected. Cholinergic neurotransmission from the basal forebrain to neocortex and hippocampus is central to higher cortical functions. We examined the basal forebrain by light microscopy and reported loss of choline acetyltransferase-positive (ChAT)+ neurons, at postnatal day (P) 40, in the ipsilateral medial septal nucleus (MSN) after neonatal hypoxia-ischemia (HI) in mice. There was no loss of ChAT+ neurons in the ipsilateral nucleus basalis of Meynert (nbM) and striatum. Ipsilateral striatal and nbM ChAT+ neurons were abnormal with altered immunoreactivity for ChAT, shrunken and crenated somas, and dysmorphic appearing dendrites. Using confocal images with 3D reconstruction, nbM ChAT+ dendrites in HI mice were shorter than sham (p = .0001). Loss of ChAT+ neurons in the MSN directly correlated with loss of ipsilateral hippocampal area. In the nbM and striatum, percentage of abnormal ChAT+ neurons correlated with loss of ipsilateral cerebral cortical and striatal area, respectively. Acetylcholinesterase (AChE) activity increased in adjacent ipsilateral cerebral cortex and hippocampus and the increase was linearly related to loss of cortical and hippocampal area. Numbers and size of cathepsin D+ lysosomes increased in large neurons in the ipsilateral nbM. After neonatal HI, abnormalities were found throughout the major cholinergic systems in relationship to amount of forebrain area loss. There was also an upregulation of cathepsin D+ particles within the nbM. Cholinergic neuropathology may underlie the permanent dysfunction in learning, memory, and executive function after neonatal brain injury.

Sex differences in social communication behaviors in toddlers with suspected autism spectrum disorder as assessed by the ADOS-2 toddler module.

LAY ABSTRACT: When toddlers are suspected of autism spectrum disorder (ASD), the gold-standard assessment technique is with the Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) Toddler Module, a behavioral observation system. ASD is a neurodevelopmental condition more frequently diagnosed in toddler boys than in toddler girls. There is some evidence that the ADOS-2 assesses behaviors that are more characteristic of boys with ASD than girls. Thus, it is possible that focusing on these behaviors contributes at least in part to why more boys are diagnosed than girls. Specifically, girls may show more social skills than boys during the ADOS-2 assessment due to their socialization histories, which may lead to missed diagnoses of ASD in toddler girls. The current study examined eight social behaviors assessed by the ADOS-2 in a sample of toddlers with suspected ASD to see if they contributed differently to the total score of those items. Examination of those items suggested that those social communication behaviors work the same for boys and girls with suspected ASD, which was inconsistent with hypotheses. However, examination of particular items raises the possibility of examining creative/imaginative play as an area for future research.