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Serological testing for anti-acetylcholine receptor (AChR) autoantibodies is not only crucial for the diagnosing, disease monitoring, and treatment management of patients with myasthenia gravis (MG) but also for preclinical studies utilizing MG disease models. However, there are no specific guidelines on which methods to use in clinical diagnostic or research laboratories to detect or quantify any MG-specific autoantibodies. Conventional autoantibody assays, particularly those for anti-AChR antibodies, are varied and mostly laboratory-specific. Here, we report our new nonradioactive immunoprecipitation–immunoblotting method for assessing autoantibodies (anti-AChR antibodies) in a mouse model of MG. This simple, efficient, reproducible, and cost-effective assay appears superior to the enzyme-linked immunosorbent assay but comparable to the radioimmunoprecipitation or cell-based assay in specificity and sensitivity. Thus, the newly developed assay can serve as a valuable alternative to classical assays and is suitable for routine testing of AChR-specific autoantibodies in preclinical studies. The further optimization of our assay may facilitate its application in the diagnosis and therapeutic management of patients with MG.

A woman in her 70s presented with approximately 2 years of sudden-onset gait and cognitive problems. She had been diagnosed with normal pressure hydrocephalus (NPH) and underwent ventriculoperitoneal shunt (VPS) placement 1 year prior. Before VPS placement, brain imaging showed ventriculomegaly and chronic infarction of the right putamen and claustrum. A lumbar drain trial resulted in modest improvement of gait dysfunction. She underwent VPS placement for suspected NPH, but her symptoms remained unchanged. Examination revealed mild cognitive impairment, left-sided and lower body predominant parkinsonism, as well as disproportionately prominent postural instability. Gait analysis showed increased gait variability, reduced velocity and shortened step length bilaterally. Motor and gait abnormalities did not change after administration of levodopa. Her symptoms have remained stable for up to 52 months since symptom onset. We postulate that the infarction affecting the right putamen and claustrum could have led to a higher-level gait disorder mimicking NPH.

Acute confusional state (ACS) in COVID-19 is shown to be associated with poor clinical outcomes.BACKGROUNDAcute confusional state (ACS) in COVID-19 is shown to be associated with poor clinical outcomes.We assessed the impact of ACS - defined as a documented deterioration of mental status from baseline on the alertness and orientation to time, place, and person - on inpatient mortality and the need for intensive care unit (ICU) transfer in inpatient admissions with active COVID-19 infection in a single-center retrospective cohort of inpatient admissions from a designated COVID-19 tertiary care center using an electronic health record system. Furthermore, we developed and validated a neurological history and symptom-based predictive score of developing ACS.METHODSWe assessed the impact of ACS - defined as a documented deterioration of mental status from baseline on the alertness and orientation to time, place, and person - on inpatient mortality and the need for intensive care unit (ICU) transfer in inpatient admissions with active COVID-19 infection in a single-center retrospective cohort of inpatient admissions from a designated COVID-19 tertiary care center using an electronic health record system. Furthermore, we developed and validated a neurological history and symptom-based predictive score of developing ACS.Thirty seven out of 245 (15%) patients demonstrated ACS. Nineteen (51%) patients had multifactorial ACS, followed by 11 (30%) patients because of hypoxemia. ACS patients were significantly older (80 [70-85] years vs 50.5 [38-69] years, p < 0.001) and demonstrated more frequent history of dementia (43% vs 9%, p < 0.001) and epilepsy (16% vs 2%, p = 0.001). ACS patients observed significantly higher in-hospital mortality (45.9% vs 1.9%, aOR [adjusted odds ratio]: 15.7, 95% CI = 3.6-68.0, p < 0.001) and need for ICU transfer (64.9% vs 35.1%, aOR: 2.7, 95% CI = 1.2-6.1, p = 0.015). In patients who survived hospitalization, ACS was associated with longer hospital stay (6 [3.5-10.5] days vs 3 [2-7] day, p = 0.012) and numerically longer ICU stay (6 [4-10] days vs 3 [2-6] days, p = 0.078). A score to predict ACS demonstrated 75.68% sensitivity and 81.73% specificity at a cutoff of ≥3.RESULTSThirty seven out of 245 (15%) patients demonstrated ACS. Nineteen (51%) patients had multifactorial ACS, followed by 11 (30%) patients because of hypoxemia. ACS patients were significantly older (80 [70-85] years vs 50.5 [38-69] years, p < 0.001) and demonstrated more frequent history of dementia (43% vs 9%, p < 0.001) and epilepsy (16% vs 2%, p = 0.001). ACS patients observed significantly higher in-hospital mortality (45.9% vs 1.9%, aOR [adjusted odds ratio]: 15.7, 95% CI = 3.6-68.0, p < 0.001) and need for ICU transfer (64.9% vs 35.1%, aOR: 2.7, 95% CI = 1.2-6.1, p = 0.015). In patients who survived hospitalization, ACS was associated with longer hospital stay (6 [3.5-10.5] days vs 3 [2-7] day, p = 0.012) and numerically longer ICU stay (6 [4-10] days vs 3 [2-6] days, p = 0.078). A score to predict ACS demonstrated 75.68% sensitivity and 81.73% specificity at a cutoff of ≥3.A high prevalence of ACS was found in patients with COVID-19 in our study cohort. Patients with ACS demonstrated increased mortality and need for ICU care. An internally validated score to predict ACS demonstrated high sensitivity and specificity in our cohort.CONCLUSIONA high prevalence of ACS was found in patients with COVID-19 in our study cohort. Patients with ACS demonstrated increased mortality and need for ICU care. An internally validated score to predict ACS demonstrated high sensitivity and specificity in our cohort.

Background: Vagus nerve stimulation (VNS) functions through neuromodulatory mechanisms to provide quality of life improvements to those with drug-resistant epilepsy. Responsive VNS (rVNS) generators are designed to further reduce seizure burden by detecting ictal tachycardia and aborting seizures soon after their onset. Methods: Electronic medical records were accessed from January 2015 to December 2018 to identify patients with epilepsy managed with rVNS generators. Data were collected on seizure burden before and after rVNS implantation. Seizure burden was compared using t-tests, and monthly seizure reductions were gauged with the McHugh scale. Twenty-seven individuals met inclusion criteria; 10 were eliminated due to prior VNS implantation or undocumented seizure frequencies.Results: The average seizure burden prior to rVNS implantation was 24.78 seizures/month. Following generator placement, the mean seizure frequencies at three months, six months, 12 months, and 18 months were 6.81, 16.57, 5.65, and 5.78 seizures/month, respectively. However, despite documented reductions in the average monthly seizure frequency, we found no statistically significant differences in seizure frequency relative to baseline.Conclusion: While many participants showed individual reductions in seizure burden, this study was unable to definitively conclude that rVNS therapy leads to statistically significant reduction in seizure burden.

Aging and neurodegeneration impact structural brain integrity and can result in changes to behavior and cognition. Personality, a relatively stable trait in adults as compared to behavior, in part relies on normative individual differences in cellular organization of the cerebral cortex, but links between brain structure and personality expression have been mixed. One key finding is that personality has been shown to be a risk factor in the development of Alzheimer's disease, highlighting a structure–trait relationship. Magnetic resonance elastography (MRE) has been used to noninvasively study age‐related changes in tissue mechanical properties because of its high sensitivity to both the microstructural health and the structure–function relationship of the tissue. Recent advancements in MRE methodology have allowed for reliable property recovery of cortical subregions, which had previously presented challenges due to the complex geometry and overall thin structure. This study aimed to quantify age‐related changes in cortical mechanical properties and the relationship of these properties to measures of personality in an older adult population (N = 57; age 60–85 years) for the first time. Mechanical properties including shear stiffness and damping ratio were calculated for 30 bilateral regions of the cortex across all four lobes, and the NEO Personality Inventory (NEO‐PI) was used to measure neuroticism and conscientiousness in all participants. Shear stiffness and damping ratio were found to vary widely across regions of the cortex, upward of 1 kPa in stiffness and by 0.3 in damping ratio. Shear stiffness changed regionally with age, with some regions experiencing accelerated degradation compared to neighboring regions. Greater neuroticism (i.e., the tendency to experience negative emotions and vulnerability to stress) was associated with high damping ratio, indicative of poorer tissue integrity, in the rostral middle frontal cortex and the precentral gyrus. This study provides evidence of structure–trait correlates between physical mechanical properties and measures of personality in older adults and adds to the supporting literature that neurotic traits may impact brain health in cognitively normal aging. Shear stiffness and damping ratio were found to vary widely across the cortex. Shear stiffness changed regionally with age, with some regions experiencing accelerated degradation compared to neighboring regions. Greater neuroticism was associated with high damping ratio in the regions of the frontal lobe.

Abstract Background Australian guidelines recommend trimethoprim or nitrofurantoin as first-line agents for uncomplicated urinary tract infections (UTIs). Laboratory surveillance indicates high rates of trimethoprim resistance among urinary bacterial isolates, but there are scant local clinical data about risk factors and impact of trimethoprim resistance. Objectives To determine the prevalence, risk factors, mechanism and impact of resistance to first-line antibiotic therapy for uncomplicated UTIs in the community setting. Methods A prospective observational study from October 2019 to November 2021 in four general practices in Melbourne, Australia. Female adult patients prescribed an antibiotic for suspected or confirmed uncomplicated acute cystitis were eligible. Primary outcome was urine isolates with resistance to trimethoprim and/or nitrofurantoin. Results We recruited 87 participants across 102 UTI episodes with median (IQR) age of 63 (47–76) years. Escherichia coli was the most common uropathogen cultured (48/62; 77%); 27% (13/48) were resistant to trimethoprim (mediated by a dfrA gene) and none were resistant to nitrofurantoin. Isolates with resistance to a first-line therapy were more common among patients reporting a history of recurrent UTIs [risk ratio (RR): 2.08 (95% CI: 1.24–3.51)] and antibiotic use in the previous 6 months [RR: 1.89 (95% CI: 1.36–2.62)]. Uropathogen resistance to empirical therapy was not associated with worse clinical outcomes. Conclusions Resistance to trimethoprim is common in uncomplicated UTIs in Australia but may not impact clinical outcomes. Further research is warranted on the appropriateness of trimethoprim as empirical therapy, particularly for patients with antimicrobial resistance risk factors.

Background Magnetic resonance elastography (MRE) is an MRI technique that uses mild, externally applied vibrations to quantify the mechanical properties of tissues in vivo. MRE measures, such as stiffness, have been shown to be sensitive to changes in brain health with aging and neurodegeneration. Here we used MRE to characterize differences in brain mechanical properties between individuals with amnestic mild cognitive impairment (aMCI) and cognitively unimpaired subjects (CU). Method A cohort of 67 cognitively unimpaired subjects (21M/46F; 60‐82y) and a cohort of 34 subjects with aMCI (11M/23F; 60‐89y) completed an MRE scan to assess their brain mechanical properties. From this, we quantified basal ganglia (BG) stiffness in each subject including the caudate, pallidum, putamen, and nucleus accumbens. Subjects also completed the NIH toolbox cognition battery from which we examined fluid cognition composite score, which reflects logic and reasoning skills. Result We found a significant group difference in stiffness of the basal ganglia (BG). Interestingly, aMCI subjects had significantly higher BG stiffness than CUs (2.99 vs. 2.89 kPa, p<0.05; Figure 1). Within the aMCI group, BG stiffness was positively correlated with fluid cognitive score (r = 0.48, p<0.01; Figure 2), where higher scores were associated with greater stiffness; the same relationship in the CU group was not statistically significant. Conclusion Higher BG stiffness found in the aMCI group may reflect aspects of aMCI pathology and progression that MRE can sensitively detect. Most MRE studies report that healthy brains are associated with higher stiffness than those with neurodegenerative pathology, with our previous work showing that aMCI participants had softer hippocampi than age‐matched CUs (Delgorio, 2023). Our findings in the BG are surprising in this context but may indicate a compensatory mechanism that occurs during early progression of aMCI and results in increased stiffness, which was previously suggested by Murphy (2016). Here we also provide the first evidence that higher BG stiffness in aMCI is associated with better cognitive function, which further points to higher stiffness being compensatory rather than pathological. The neurobiological basis of this compensatory increase in BG stiffness of aMCI subjects requires further study but could be influenced by acute neuroinflammatory processes.

Background Magnetic resonance elastography (MRE) is an MRI technique that uses mild, externally applied vibrations to quantify the mechanical properties of tissues in vivo. MRE measures, such as stiffness, have been shown to be sensitive to changes in brain health with aging and neurodegeneration. Here we used MRE to characterize differences in brain mechanical properties between individuals with amnestic mild cognitive impairment (aMCI) and cognitively unimpaired subjects (CU). Method A cohort of 67 cognitively unimpaired subjects (21M/46F; 60‐82y) and a cohort of 34 subjects with aMCI (11M/23F; 60‐89y) completed an MRE scan to assess their brain mechanical properties. From this, we quantified basal ganglia (BG) stiffness in each subject including the caudate, pallidum, putamen, and nucleus accumbens. Subjects also completed the NIH toolbox cognition battery from which we examined fluid cognition composite score, which reflects logic and reasoning skills. Result We found a significant group difference in stiffness of the basal ganglia (BG). Interestingly, aMCI subjects had significantly higher BG stiffness than CUs (2.99 vs. 2.89 kPa, p<0.05; Figure 1). Within the aMCI group, BG stiffness was positively correlated with fluid cognitive score (r=0.48, p<0.01; Figure 2), where higher scores were associated with greater stiffness; the same relationship in the CU group was not statistically significant. Conclusion Higher BG stiffness found in the aMCI group may reflect aspects of aMCI pathology and progression that MRE can sensitively detect. Most MRE studies report that healthy brains are associated with higher stiffness than those with neurodegenerative pathology, with our previous work showing that aMCI participants had softer hippocampi than age‐matched CUs (Delgorio, 2023). Our findings in the BG are surprising in this context but may indicate a compensatory mechanism that occurs during early progression of aMCI and results in increased stiffness, which was previously suggested by Murphy (2016). Here we also provide the first evidence that higher BG stiffness in aMCI is associated with better cognitive function, which further points to higher stiffness being compensatory rather than pathological. The neurobiological basis of this compensatory increase in BG stiffness of aMCI subjects requires further study but could be influenced by acute neuroinflammatory processes.

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung–Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung–Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White–Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson–Forssman–Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung–Jansen, Börjeson–Forssman–Lehmann and White–Kernohan syndromes.

Background Large colon impactions are a common cause of colic in the horse. There are no scientific reports on the clinical presentation, diagnostic tests and treatments used in first opinion practice for large colon impaction cases. The aim of this study was to describe the presentation, diagnostic approach and treatment at the primary assessment of horses with large colon impactions. Methods Data were collected prospectively from veterinary practitioners on the primary assessment of equine colic cases over a 12 month period. Inclusion criteria were a diagnosis of primary large colon impaction and positive findings on rectal examination. Data recorded for each case included history, signalment, clinical and diagnostic findings, treatment on primary assessment and final case outcome. Case outcomes were categorised into three groups: simple medical (resolved with single treatment), complicated medical (resolved with multiple medical treatments) and critical (required surgery, were euthanased or died). Univariable analysis using one-way ANOVA and Tukey’s post-hoc test, Kruskal Wallis with Dunn’s post-hoc test and Chi squared analysis were used to compare between different outcome categories. Results 1032 colic cases were submitted by veterinary practitioners: 120 cases met the inclusion criteria for large colon impaction. Fifty three percent of cases were categorised as simple medical, 36.6% as complicated medical, and 9.2% as critical. Most cases (42.1%) occurred during the winter. Fifty nine percent of horses had had a recent change in management, 43% of horses were not ridden, and 12.5% had a recent / current musculoskeletal injury. Mean heart rate was 43bpm (range 26-88) and most cases showed mild signs of pain (67.5%) and reduced gut sounds (76%). Heart rate was significantly increased and gut sounds significantly decreased in critical compared to simple medical cases (p<0.05). Fifty different treatment combinations were used, with NSAIDs (93%) and oral fluids (71%) being administered most often. Conclusions Large colon impactions typically presented with mild signs of colic; heart rate and gut sounds were the most useful parameters to distinguish between simple and critical cases at the primary assessment. The findings of seasonal incidence and associated management factors are consistent with other studies. Veterinary practitioners currently use a wide range of different treatment combinations for large colon impactions.