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Anxiety can alter an individual’s perception of their external sensory environment. Previous studies suggest that anxiety can increase the magnitude of neural responses to unexpected (or surprising) stimuli. Additionally, surprise responses are reported to be boosted during stable compared to volatile environments. Few studies, however, have examined how learning is impacted by both threat and volatility. To investigate these effects, we used threat-of-shock to transiently increase subjective anxiety in healthy adults during an auditory oddball task, in which the regularity could be stable or volatile, while undergoing functional Magnetic Resonance Imaging (fMRI) scanning. We then used Bayesian Model Selection (BMS) mapping to pinpoint the brain areas where different models of anxiety displayed the highest evidence. Behaviourally, we found that threat-of-shock eliminated the accuracy advantage conferred by environmental stability over volatility in the task at hand. Neurally, we found that threat-of-shock led to both attenuation and loss of volatility-attuning of neural activity evoked by surprising sounds across most subcortical and limbic brain regions including the thalamus, basal ganglia, claustrum, insula, anterior cingulate, hippocampal gyrus and also the superior temporal gyrus. Conversely, within two small clusters in the left medial frontal gyrus and extrastriate area, threat-of-shock boosted the neural activity (relative to the safe and volatile condition) to the levels observed during the safe and stable condition, while also inducing a loss of volatility-attuning. Taken together, our findings suggest that threat eliminates the learning advantage conferred by statistical stability compared to volatility. Thus, we propose that anxiety disrupts behavioural adaptation to environmental statistics, and that multiple subcortical and limbic regions are implicated in this process.

Objectives: In patients with chronic rhinosinusitis (CRS), olfactory dysfunction (OD) is a common complaint. The focus of this research was to evaluate the effectiveness of olfactory training (OT) in patients with CRS after sinonasal surgery. Design : Prospective controlled trial. Participants: We enrolled 111 Korean CRS patients who underwent sinonasal surgery. Main Outcome Measures: At baseline and three months after starting OT, both participants were assessed by an olfactory function test and endoscopy. The Korean version of the Sniffin’ stick II (KVSS-II) was used to perform the olfactory function test. A visual analog scale and the Mini-Mental State Examination were used to assess nasal and psychological functions. Over the course of three months, five odorants were used in OT (rose, lemon, cinnamon, orange, and peach). Results: Over a 12-week duration, OT increased olfactory activity in nearly 62 percent of subjects than in non-OT subjects. The OT group had significantly higher olfactory outcomes for the total KVSS-II and identification scores than the non-OT group between the initial and follow-up assessments. The initial score influenced the degree of olfactory improvement after OT. Conclusions: OT patients exhibited significantly higher total KVSS-II scores compared with non-OT patients after sinonasal surgery; in particular, the odor identification score was different between the two groups. The results of this study show that a 12-week period of repeated short-term exposure to various odors could be useful in enhancing olfactory activity in patients who underwent sinonasal surgery for the improvement of sensory-neural olfactory impairment.

Up to 50% of patients with systemic sclerosis (SSc) experience slow colonic transit, which may be associated with severe outcomes. Our objective, therefore, was to identify specific clinical features associated with slow colonic transit in SSc.SSc patients with gastrointestinal symptoms were prospectively enrolled and completed a scintigraphy-based whole gut transit study. Clinical features were compared between patients with and without slow colonic transit in univariate and multivariable logistic regression analyses.Forty-eight of 100 patients (48%) in our cohort had slow colonic transit. In the univariate analyses, slow colonic transit was positively associated with female sex (odds ratio [OR] 12.61 [95% confidence interval (95% CI) 1.56-101.90]), telangiectasia (OR 4.00 [95% CI 1.32-12.10]), anticentromere antibodies (OR 3.25 [95% CI 1.25-8.44]), prior or current smoking (OR 2.56 [95% CI 1.06-6.21]), and a Medsger gastrointestinal severity score of ≥3 (OR 3.94 [95% CI 1.16-13.36]). Patients were less likely to have significant restriction on pulmonary function tests (OR 0.23 [95% CI 0.09-0.63]). In our multivariable model, the association between slow colonic transit and telangiectasia (OR 3.97 [95% CI 1.20-13.20]) and less restrictive lung disease on pulmonary function tests (OR 0.28 [95% CI 0.09-0.86]) remained statistically significant, though a trend with smoking remained (OR 2.16 [95% CI 0.82-5.75]). Interestingly, there were no significant associations between slow colonic transit and delayed transit in other regions of the gastrointestinal tract.Distinct clinical features are associated with slow colonic transit in SSc. Such features may provide insight in risk stratification and the study of disease mechanism in more homogeneous subgroups.

Publisher Summary This chapter discusses the epidemiology and classification of traumatic peripheral nerve injuries, the effects of these injuries on nerve and muscle, and how electrodiagnosis is used to help classify the injury. Traumatic injury to peripheral nerves results in considerable disability across the world. In peacetime, peripheral nerve injuries result commonly from motor vehicle accident trauma and less commonly from penetrating trauma, such as falls and industrial accidents. If plexus and root injuries are also included, the incidence is about 5%. In the upper limb, the nerve injured most commonly is the radial nerve, followed by the ulnar and median nerves. Lower limb peripheral nerve injuries are less common, and the sciatic nerve is injured most frequently, followed by the peroneal and rarely the tibial or femoral nerves. Peripheral nerve injuries may be seen in isolation, but they also often accompany central nervous system (CNS) trauma. Peripheral nerve injuries have significant impact, as they impede the recovery of function and return to work. There is also a risk of secondary disability from falls, fractures, or other injuries.

BACKGROUND Chronic obstructive pulmonary disease is one of the most common clinical diagnoses among hospital inpatients. Diagnosis requires the demonstration of post-bronchodilator airflow obstruction. However, it is uncertain how often spirometry results are available at the time a diagnostic label of COPD is applied. AIM To identify how frequently spirometry results were available following an inpatient admission with a clinical diagnosis of COPD, and to determine how often the available spirometry results supported a clinical diagnosis of COPD. Inhaler prescription, at discharge, was also evaluated to determine one of the potential implications of diagnostic inaccuracy. METHODS A single centre retrospective observational study was undertaken at a 400-bed metropolitan health service between October 2016 and March 2018. RESULTS A total of 2239 inpatient separations occurred in 1469 individuals who had a clinical diagnosis of COPD during the study. Spirometry results were not available in 43.6% (n = 641) of those with a diagnosis of COPD. A further 19.7% (n = 289) had spirometry results available at the time of admission, that did not demonstrate fixed airflow obstruction. The available prescribing data (n = 443) demonstrated that inhaled medications were prescribed in a similar pattern, regardless of the availability of spirometry, or whether the results supported a clinical diagnosis of COPD. CONCLUSIONS Inpatients with a clinical diagnosis of COPD frequently did not have supportive spirometry results that confirmed the diagnosis or had results inconsistent with COPD. Misdiagnosis and inappropriate prescribing require further attention to improve the quality of care in this setting. This article is protected by copyright. All rights reserved.

Background The electroencephalogram (EEG) is a common diagnostic tool used to investigate patients for various indications including seizure disorders. In our study we investigate factors that predict the presence of epileptiform abnormalities on EEG and review the common indications for ordering an EEG. Methods We retrospectively reviewed all routine adult EEGs performed in a hospital over a six-month period. Data collated included patient demographics, clinical indication for EEG, setting in which EEG was performed, activation procedures utilised, history of epilepsy, and whether the patient was on antiepileptic medication. Our primary objective was to evaluate the factors that were predictive of an EEG with epileptiform abnormalities. Results 239 routine EEGs were included with indications including first seizure (25.9%), known epilepsy (25.1%), cognitive change (15.9%), syncope (15.0%), movement disorder (6.7%), psychogenic non-epileptic events (5.4%), unresponsiveness/ICU (4.6%), and psychiatric presentation (1.3%). Most EEGs were normal (48.1%). 8.9% of EEGs demonstrated epileptiform abnormalities. Using multivariate logistic regression, three variables proved significant in predicting an EEG with epileptiform abnormalities. Any seizure as an indication (first seizure or seizure in known epileptic), increasing patient age, and EEGs conducted in an inpatient setting and within 48 hours of seizure event were all statistically more likely to yield epileptiform abnormalities on EEG. Conclusions Our findings suggest that careful selection of patients based on appropriate indications for EEG referral would likely improve the yield of an EEG. Depending on the indication, a normal EEG result can be of similar usefulness to an abnormal EEG demonstrating epileptiform abnormalities. This article is protected by copyright. All rights reserved.

BACKGROUND Patients with chronic obstructive pulmonary disease (COPD) can develop left ventricular (LV) systolic dysfunction and geometric changes due to several reasons. We investigated subclinical LV systolic dysfunction and structural features in patients with COPD, and its correlation with the severity of airway obstruction, identified by GOLD classification. METHODS We studied 52 patients with COPD and 29 age and sex-matched controls, without any cardiac disease. In addition to conventional echocardiographic evaluation speckle tracking echocardiography (STE) based strain imaging were performed to analyze sub-clinical LV systolic dysfunction. Also LV volumes were measured by using three dimensional real time echocardiography (3DRTE). All patients underwent spirometry. RESULTS Conventional echocardiographic parameters (LV wall thickness and diameters, LV EF) and LV volume measurements were similar between the groups. LV global longitudinal peak systolic strain (-14.76 ± 2.69% to -20.27 ± 1.41%, p

Previous research established that rhythmic sensory stimulation can affect subsequent stimulus perception, possibly through 'entrainment' of oscillations in the brain. Alpha frequency is a natural target for visual entrainment, because fluctuations in posterior alpha oscillations have been linked to visual target detection or discrimination. On the other hand, alpha oscillations also relate to attentional mechanisms, such as attentional orienting or selection. Previous visual alpha entrainment studies focused on differential processing of targets presented in-phase with the preceding rhythmic stimulation relative to out-of-phase targets (an 'SOA effect'), putatively related to the phase of entrained neuronal alpha oscillations. Fewer studies probed the consequences of rhythmic alpha stimulation for attention mechanisms related to alpha power. Here, we asked whether alpha stimulation of one hemifield has similar effects on reaction times as we see for increased alpha synchronization in magneto/electroencephalography (M/EEG) studies (i.e., more alpha means impaired processing and functional inhibition). We implemented a task inspired by attention studies, assessing reaction times to ipsilateral vs. contralateral visual targets, with and without concurrent presentation of distractors. Yet, in place of any attention cues, we presented a rhythmic, vs. arrhythmic, alpha-frequency train of visual flashes to one hemifield, in a large sample size (N = 115) in an online experiment. We found clear evidence that flash train rhythmicity did not impact task performance. We also found that the spatial congruence between the unilateral flash train and the subsequent visual target did impact response times but only in the presence of contralateral distractor stimuli. We discuss implications, limitations and future directions.

BACKGROUND: The mythical effect of the lunar cycle on seizures has been debated over time. Previously healthy individuals presenting with first-ever seizures in whom investigations are negative often invoke questions about potential reasons including a full moon. AIMS: To determine whether there is a temporal relationship between the occurrence of the first-ever unprovoked seizure and the lunar cycle. METHODS: We studied adults who presented with a first-ever unprovoked seizure to two tertiary centres in Australia. Seizure onset time was obtained from the emergency department and ambulance documentations. We used Poisson regression modelling and incidence rate ratios (IRR) to determine whether seizures have a preponderance for a particular lunar phase. We performed further analysis on "first seizure epilepsy" and "first seizure not epilepsy" subgroups based on the International League Against Epilepsy criteria for a diagnosis of epilepsy after a single unprovoked seizure. RESULTS: We analysed 1710 patients (38% females; median 39 yr), of whom 18% had epileptiform abnormalities on EEG and potentially epileptogenic lesions were detected on neuroimaging in 28%. Based on the EEG and imaging findings, 684 (40%) patients were categorized as "first seizure epilepsy" and 1026 (60%) "first seizure not epilepsy". The whole cohort and subgroup analysis demonstrated no significant difference in the seizure occurrence among the four lunar quarters. CONCLUSIONS: First unprovoked seizures are not influenced by the lunar cycle. Patients pondering the cause of their first-ever unprovoked seizure can be reassured that the full moon was not responsible. This article is protected by copyright. All rights reserved.

Background Less invasive inflammatory bowel disease (IBD) tests are increasingly being incorporated into clinical practice as adjuncts to endoscopy to monitor disease activity and guide optimal care. Little is known about patient perspectives of these tests. Aims To assess patient perspectives of the current IBD tests and potential future tests, such as saliva, urine or breath. Methods New Zealand adults with IBD were invited to complete an anonymous online survey. Experiences relating to blood or faecal tests, medical imaging (abdominal ultrasound, abdominal computerised tomography and magnetic resonance enterography) and colonoscopy were collected. Results Of the 117 completed surveys, 112 respondents provided background details. The majority (85%) of participants were female and 88% were under 55 years of age with a mean disease duration of 8.98 years. General blood tests were reported as the most prescribed, completed, comfortable test and the least worrying test results. Imaging tests were reported as the least ordered and the most refused tests. Colonoscopy was rated as the least comfortable and generated the most worry. Test explanations by a referring clinician significantly impacted on respondents' levels of understanding across all tests, but did not affect the level of worry when receiving test results. Saliva, blood and breath tests were chosen as the most preferred disease monitoring tests. Conclusion Patients with IBD preferred any tests less invasive than colonoscopy. An explanation by referring doctor enhanced patients' understanding, but did not necessarily influence their level of comfort or worry. This article is protected by copyright. All rights reserved.

Objective To determine the incidence of tuberculous lymphadenitis (TBL) and other pathologies in cervical lymphadenopathies in Somalia and accompanying radiological findings. Methods In this hospital-based retrospective study, the demographic characteristics, pathology results and radiological findings of 263 patients who underwent ultrasound (US)-guided cervical lymph node biopsy between January 2016 and February 2020 were analyzed. Results Of 241 patients 118 men and 123 women (mean age 27.9 ± 18.1 years) included in the study, 46.1% (n = 111) were diagnosed as necrotizing granulomatous lymphadenitis (caseified, consistent with TBL) and 21.6% (n = 12, atypical lymphoid cells and n = 40, metastases) as malignancy. The most common type of metastasis was squamous cell cancer (n = 31), and the primary source of most of them was esophageal cancer (16/31, 51.6%). The age of patients with TBL was significantly lower than that of non-TBL (21.9 ± 14.6 vs. 41.9 ± 24.6, P = 0.003) and the incidence of TBL in pediatric patients was statistically higher (58.0% vs. 21.5%, P = 0.019). The rate of patients with TBL being localized at level 4 and level 5 was significantly more than non-TBL patients (18.0% vs. 10.0% and 23.4% vs. 10.8%, respectively, P = 0.01). Half of patients with TBL who have chest radiography had pathological findings; consolidation and bronchopneumonia were present in 52.6% of them. There were 2 patients with paravertebral abscess and one patient with gastrointestinal tuberculosis. Conclusion In Somalia, in the presence of cervical lymphadenopathy, after diagnosis by using US-guided biopsy; primarily considering of TBL and malignancy, thoracic involvement should be investigated, and esophageal carcinoma must be excluded in terms of metastatic lymph node.

There are two borderline left-heart phenotypes in the fetus: (1) severe aortic stenosis (AS), which is associated with a 'short, fat', globular left ventricle (LV), LV systolic dysfunction and LV growth arrest; and (2) severe left-heart hypoplasia (LHH), which is associated with a 'long, skinny' LV, laminar flow across hypoplastic mitral and aortic valves and arch hypoplasia. Both phenotypes may be counseled for possible single-ventricle palliation. We aimed to compare the rates of left-sided cardiac structure growth and Z-score change over gestation and to describe the postnatal outcomes associated with these two phenotypes. We hypothesized that the left-sided structures would grow faster in fetuses with LHH compared to those with AS, and that those with LHH would be more likely to achieve biventricular circulation.This was a retrospective cohort study using data collected in an institutional cardiology database between April 2001 and April 2018. We included fetuses with severe AS or severe LHH, and with at least two fetal echocardiograms. Inclusion criteria for the AS group included: aortic-annulus Z-score -2.0, severe AS, depressed LV function, retrograde systolic flow in the aortic arch and endocardial fibroelastosis. Inclusion criteria for the LHH group included: aortic-annulus Z-score -2.0, hypoplastic but apex-forming LV, normal LV function and retrograde systolic flow in the aortic arch. Exclusion criteria were: abnormal cardiac connections, other forms of structural congenital heart disease, cardiomyopathy, history of fetal aortic valvuloplasty and participation in a maternal hyperoxygenation study. Measurements and respective Z-scores for the aortic-valve annulus, mitral-valve annulus, LV long- and short-axis dimensions, along with aortic-arch measurements, were collected longitudinally for each fetus and plotted over time for both cohorts. Mean slopes of change in dimension and Z-scores over gestation were calculated and compared between the two groups using mixed generalized linear regression accounting for repeated measures. A subanalysis was performed, matching six fetuses from each group for initial aortic-annulus Z-score and gestational age, due to the significant differences in these two variables between the original cohorts.In total, 53 fetuses with 158 echocardiograms were included. In the AS cohort, there were 20 (38%) fetuses with 65 echocardiograms, and in the LHH cohort there were 33 (62%) fetuses with 93 echocardiograms. On the first echocardiogram, LHH fetuses had a later gestational age and a larger aortic-annulus diameter. The rate of aortic-annulus growth was greater in the LHH group compared with the AS group (mean ± SD, 0.15 ± 0.01 mm/week for LHH vs 0.07 ± 0.01 mm/week for AS (P 0.001)). While the LHH group had a decrease in aortic-annulus Z-score over time, this was at a slower rate than the decrease in the AS group (mean ± SD, -0.04 ± 0.02/week for LHH vs -0.13 ± 0.02/week for AS (P 0.001)). A similar pattern was seen for the mitral-valve and LV short-axis-dimension Z-scores. Subanalysis of six fetuses from each group matched for initial aortic-annulus Z-score and gestational age demonstrated similar findings, with the LHH group Z-scores decreasing at a slower rate than those in the AS group. Fifty-two of the 53 fetuses were liveborn, one LHH fetus dying in utero. Of the 20 liveborn in the AS cohort, 15 (75%) infants underwent single-ventricle palliation, two (10%) underwent biventricular repair and three (15%) died prior to intervention. Of the 32 liveborn in the LHH cohort, three (9.4%) underwent single-ventricle palliation, 28 (87.5%) achieved biventricular circulation, of which six required no surgery, and one (3.1%) died prior to intervention.The left-sided cardiac structures grow at a faster rate in fetuses with severe LHH than they do in fetuses with severe AS, and the Z-scores decrease at a slower rate in fetuses with severe LHH than they do in those with severe AS. The majority of infants in the LHH group did not undergo single-ventricle palliation. This information can be useful in counseling families on the expected growth potential of the fetus's aortic valve, mitral valve and LV, depending on the cardiac phenotype. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

The diagnosis of polyneuropathy usually requires neurophysiological investigation, necessitating specialised testing and interpretation thereby increasing the time to final diagnosis. We investigated the predictive value of the clinical examination in patients with potential neuropathies. Patients were recruited based on their referral requesting neurophysiological testing. Two examiners tested ankle jerk reflexes and gradient to temperature sensation prior to the patient undergoing neurophysiology investigations, blinded to subsequent testing results. The neurophysiology investigations were either standard nerve conduction study (NCS) or thermal threshold testing (TTT) or both. These data were then analysed to determine the Kappa between examiners as well as sensitivity, specificity, and positive and negative likelihood ratios. There was a modest level of agreement between examiners for ankle jerk testing (Kappa=0.6) but poor agreement for gradient temperature testing (Kappa=0.3). Bilateral absence of ankle jerk reflexes was moderately associated with abnormal NCS, with the following characteristics: sensitivity 72%, specificity 91%, positive likelihood ratio 7.6, and negative likelihood ratio 0.3. The presence of a temperature gradient was poorly diagnostic for abnormal TTT: sensitivity 87%, specificity 14%, with positive and negative likelihood ratios close to 1. In conclusion, the absence of ankle jerks performed moderately well in identifying patients likely to have large fibre neuropathy and could potentially be used to help decide who should be sent for NCS. Gradient temperature testing was much more subjective and did not change the likelihood of abnormal TTT. This article is protected by copyright. All rights reserved.

Objectives Current treatments are effective only in 30% of lupus nephritis patients emphasizing the need for novel therapeutic strategies. To develop mechanistic hypotheses and explore novel biomarkers, we analyzed the longitudinal urinary proteomic profiles in patients with lupus nephritis undergoing treatment. Methods We quantified 1,000 urinary proteins in 30 patients with lupus nephritis at the time of the diagnostic renal biopsy and after 3, 6, and 12 months. The proteins and molecular pathways detected in the urine proteome were then analyzed with respect to baseline clinical features and longitudinal trajectories. The intrarenal expression of candidate biomarkers was evaluated using single cell transcriptomics of renal biopsies from lupus nephritis patients. Results Our analysis revealed multiple biological pathways including chemotaxis, neutrophil activation, platelet degranulation, and extracellular matrix organization that could be noninvasively quantified and monitored in the urine. We identified 237 urinary biomarkers associated with lupus nephritis as compared to controls without SLE. IL-16, CD163, and TGF-β mirrored intrarenal nephritis activity. Response to treatment was paralleled by a reduction of urinary IL-16, a CD4 ligand with proinflammatory and chemotactic properties. Single cell RNA sequencing independently demonstrated that IL16 is the second most expressed cytokine by most infiltrating immune cells in lupus nephritis kidneys. IL-16 producing cells were found at key sites of kidney injury. Conclusion Urine proteomics may profoundly change the diagnosis and management of lupus nephritis by noninvasively monitor active intrarenal biological pathways. These findings implicate IL-16 in lupus nephritis pathogenesis designating it as a potentially treatable target and biomarker.

To compare T1ρ relaxation times of the medial and lateral regions of the patella and femoral trochlea at 6 and 12 months following anterior cruciate ligament reconstruction (ACLR) on the ACLR and contralateral extremity. Greater T1ρ relaxation times are associated with a lower proteoglycan density of articular cartilage.This study involved 20 individuals (11 males, 9 females; mean ± SD age 22 ± 3.9 years, weight 76.11 ± 13.48 kg, and height 178.32 ± 12.32 cm) who underwent a previous unilateral ACLR using a patellar tendon autograft. Magnetic resonance images from both extremities were acquired at 6 and 12 months post-ACLR. Voxel by voxel T1ρ relaxation times were calculated using a 5-image sequence. The medial and lateral regions of the femoral trochlea and patellar articular cartilage were manually segmented on both extremities. Separate extremity (ACLR and contralateral extremity) by time (6 months and 12 months) analysis of variance tests were performed for each region (P 0.05).For the medial patella and lateral trochlea, T1ρ relaxation times increased in both extremities between 6 and 12 months post-ACLR (medial patella P = 0.012; lateral trochlea P = 0.043). For the lateral patella, T1ρ relaxation times were significantly greater on the contralateral extremity compared to the ACLR extremity (P = 0.001). The T1ρ relaxation times of the medial trochlea on the ACLR extremity were significantly greater at 6 (P = 0.005) and 12 months (P 0.001) compared to the contralateral extremity. T1ρ relaxation times of the medial trochlea significantly increased from 6 to 12 months on the ACLR extremity (P = 0.003).Changes in T1ρ relaxation times occur within the first 12 months following ACLR in specific regions of the patellofemoral joint on the ACLR and contralateral extremity.

Background Barrett's oesophagus (BO) is known precursor of oesophageal adenocarcinoma (EAC). Early EAC includes T1a (invasion into mucosa) and T1b (invasion into submucosa but not muscularis propria). Endoscopic mucosal resection (EMR) provides accurate histological staging and definitive treatment for early EAC. Post EMR, the remaining Barrett's is eradicated with radiofrequency ablation (RFA). However, there is a paucity of long-term Australian data. Aims To investigate the efficacy and long-term outcomes of EMR and RFA in management of early EAC. Methods Retrospective analysis of patients early EAC treated endoscopically at three Western Australian tertiary centres, with at least 12-months follow-up, over last 10-years. Results Sixty-seven patients with early EAC (61 T1a and 6 T1b) were treated with EMR. Complete Barrett's eradication was done by EMR in 31/67 patients whereas 36/67 patients underwent RFA for residual Barrett's. EMR changed pinch biopsy histology from HGD (n=33), HGD suspicious for IMC (n=5) and LGD (n=1) to early EAC in 58.2% (n=39) patients. During a mean follow-up of 37.2 months (IQR 20, 56), complete remission of dysplasia (CRD) and intestinal metaplasia (CRIM) was seen in 97% (n=65) and 89.5% (n=60) patients. One patient with T1b EAC underwent oesophagectomy. No cases developed metachronous EAC, progression to invasive adenocarcinoma or development of nodal/distant metastasis. Complications were endoscopically treated haematemesis (n=1) and strictures (n=16) requiring dilatations. 3 patients died due to causes unrelated to IMC. Conclusion EMR in conjunction with RFA is an effective and safe management for early EAC. EMR provides accurate staging and has low complication rates. This article is protected by copyright. All rights reserved.

Objective The objective of this study was to characterize the independent risk factors for seizures in critically ill patients monitored with continuous EEG (cEEG). Methods We retrospectively investigated variables associated with cEEG seizures, first in the entire cohort of 156 patients and, subsequently, in the subgroup without seizures in the first 30 minutes of monitoring. Results Seizures were observed in 19.2% of recordings, and in 50% of these, seizures occurred in the first 30 minutes. In the entire cohort, epilepsy, acute seizures prior to cEEG, interictal epileptiform discharges (IEDs), lateralized periodic discharges (LPDs), and brief potentially ictal rhythmic discharges (BIRDs) were associated with a higher incidence of cEEG seizures, whereas coma, intravenous anaesthetic drugs, and generalized periodic discharges (GPDs) were associated with a lower incidence of seizures. On multivariate analysis, this association was maintained for acute seizures before cEEG (OR: 5.92) and IEDs (OR: 6.81). Excluding patients with seizures at the beginning of monitoring, acute seizures before cEEG, IEDs, LPDs, and BIRDs were associated with an increased risk of seizures. The presence of IEDs or LPDs in the first 30 minutes was associated with a 4.14-fold greater chance of seizures on cEEG. On multivariate analysis, acute seizures prior to recording (OR 7.29) and LPDs (OR: 5.38) remained associated with seizures on cEEG. Due to the sample size, BIRDs were not included in multivariate models. Significance Acute seizures prior to monitoring, IEDs, LPDs and BIRDs are important risk factors for cEEG seizures in critically ill patients.

ObjectiveThe Accelerator Program for Discovery in Brain Disorders using Stem Cells (ADBS) is a longitudinal study focused on collecting and analysing clinical, neuropsychological, neurophysiological, and multimodal neuroimaging data from five cohorts of patients with major psychiatric disorders from genetically high-risk families, their unaffected first-degree relatives, and healthy subjects. Here, we present a complete description of the acquisition of multimodal MRI data along with the quality assurance (QA) and quality check (QC) procedures that we are following in this study.MethodsThe QA procedure consists of monitoring of different quantitative measurements using an agar gel and a geometrical phantom. For the already acquired data from human subjects, we describe QC steps for each imaging modality. To quantify reliability of outcome measurements, we perform test-retest reliability on human volunteers.ResultsWe have presented results from analysis of phantom data and test-retest reliability on a human volunteer. Results show consistency in data acquisition and reliable quantification of different outcome measurements.ConclusionThe acquisition protocol and QA-QC procedures described here can yield consistent and reliable outcome measures. We hope to acquire and eventually release high quality longitudinal neuroimaging dataset that will serve the scientific community and pave the way for interesting discoveries.

Mitochondrial transcription factor A (TFAM) controls the transcription of core proteins required for mitochondrial homeostasis. This study was undertaken to investigate changes in TFAM expression in systemic sclerosis (SSc), to analyze mitochondrial function, and to evaluate the consequences for fibroblast activation.TFAM expression was analyzed by immunofluorescence and Western blotting. The effects of TFAM knockout were investigated in cultured fibroblasts and in murine models of bleomycin-induced skin fibrosis, bleomycin-induced lung fibrosis, and skin fibrosis induced by overexpression of constitutively active transforming growth factor β type I receptor (TGFβRΙ).TFAM expression was down-regulated in fibroblasts in SSc skin and in cultured SSc fibroblasts. The down-regulation of TFAM was associated with decreased mitochondrial number and accumulation of damaged mitochondria with release of mitochondrial DNA (mtDNA), accumulation of deletions in mtDNA, metabolic alterations with impaired oxidative phosphorylation, and release of the mitokine GDF15. Normal fibroblasts subjected to long-term, but not acute, exposure to TGFβ mimicked SSc fibroblasts, with down-regulation of TFAM and accumulation of mitochondrial damage. Down-regulation of TFAM promoted fibroblast activation with up-regulation of fibrosis-relevant Gene Ontology terms in RNA-Seq, partially in a reactive oxygen species-dependent manner. Mice with fibroblast-specific knockout of Tfam were prone to fibrotic tissue remodeling, with fibrotic responses even to NaCl instillation and enhanced sensitivity to bleomycin injection and overexpression of constitutively active TGFβRI. TFAM knockout fostered Smad3 signaling to promote fibroblast activation.Alterations in the key mitochondrial transcription factor TFAM in response to prolonged activation of TGFβ and associated mitochondrial damage induce transcriptional programs that promote fibroblast-to-myofibroblast transition and drive tissue fibrosis.

Objective To investigate differences in EMG muscle activity and scapular kinematics during elevation in the scapular plane between healthy controls, participants with multidirectional shoulder laxity (MDL), and patients with multidirectional shoulder instability (MDI) who are diagnosed with hypermobile Ehlers-Danlos syndrome (hEDS) or Hypermobility Spectrum Disorder (HSD). Methods Twenty-seven women with hEDS/HSD and MDI, 27 female healthy control subjects, and 28 female subjects with MDL participated in this study. Scapular 3D kinematic data were obtained using 8 Oqus Qualisys cameras. Simultaneously, surface electromyography (EMG) was used to measure muscle activity of the upper, middle, and lower trapezius, infraspinatus, latissimus dorsi, serratus anterior, posterior deltoid, and pectoralis major during arm elevation in the scapular plane. Group differences were assessed using statistical parametric mapping. Results Regarding scapular kinematics, significantly less upward rotation was observed in hEDS/HSD patients with MDI compared to both healthy controls and MDL subjects. Significantly less posterior tilt was seen in hEDS/HSD patients compared to MDL subjects. Furthermore, significantly higher EMG activity of the infraspinatus, middle trapezius, and posterior deltoid was found in hEDS/HSD patients with MDI. Conclusion hEDS/HSD patients with MDI demonstrate altered scapular kinematics and increased EMG muscle activity compared to subjects without MDI. These findings could serve as stepping stone for future research regarding treatment strategies in patients belonging to the hypermobility spectrum.

Recently, functional homotopy (FH) architecture, defined as robust functional connectivity (FC) between homotopic regions, has been frequently reported to be altered in MDD patients (MDDs) but with divergent locations.In this study, we obtained resting-state functional magnetic resonance imaging (R-fMRI) data from 1004 MDDs (mean age, 33.88 years; age range, 18-60 years) and 898 matched healthy controls (HCs) from an aggregated dataset from 20 centers in China. We focused on interhemispheric function integration in MDDs and its correlation with clinical characteristics using voxel-mirrored homotopic connectivity (VMHC) devised to inquire about FH patterns.As compared with HCs, MDDs showed decreased VMHC in visual, motor, somatosensory, limbic, angular gyrus, and cerebellum, particularly in posterior cingulate gyrus/precuneus (PCC/PCu) (false discovery rate [FDR] q 0.002, z = -7.07). Further analysis observed that the reduction in SMG and insula was more prominent with age, of which SMG reflected such age-related change in males instead of females. Besides, the reduction in MTG was found to be a male-special abnormal pattern in MDDs. VMHC alterations were markedly related to episode type and illness severity. The higher Hamilton Depression Rating Scale score, the more apparent VMHC reduction in the primary visual cortex. First-episode MDDs revealed stronger VMHC reduction in PCu relative to recurrent MDDs.We confirmed a significant VMHC reduction in MDDs in broad areas, especially in PCC/PCu. This reduction was affected by gender, age, episode type, and illness severity. These findings suggest that the depressive brain tends to disconnect information exchange across hemispheres.

Background Up to 3% of methotrexate (MTX)-treated rheumatoid arthritis (RA) patients may develop liver fibrosis or cirrhosis, requiring effective screening algorithms. Aims To assess the utility of non-invasive liver fibrosis assessment in RA patients on MTX. Methods 56 patients were recruited from rheumatology outpatient clinics in a public tertiary centre from July 2017 to October 2018. Clinical data was collected. Screening for hepatic fibrosis was performed utilising transient elastography (TE), aminoaspartate transaminase to platelet ratio index (APRI), Hepascore, and Fibrosis-4 index (FIB-4). Those with suspected significant liver fibrosis based on these screening tests were assessed by a hepatologist. Results 27 patients were suspected to have liver fibrosis on screening, including 10/56 (18%) by TE, 20/56 (36%) by Hepascore, 2/56 by APRI (4%) and 1/56 by FIB-4 (2%). Of these 27 patients, 11 were reviewed by a hepatologist and 1 diagnosed with significant liver fibrosis. TE, but not APRI, Hepascore or FIB-4, was found to have 100% sensitivity and 84% specificity (p=0.029) for hepatologist-diagnosed liver fibrosis. Conclusion Liver fibrosis develops in a minority of MTX-treated RA patients. This study suggests that TE is a more sensitive screening test than APRI, FIB-4 or Hepascore in the identification of people with RA at risk of hepatic fibrosis. This article is protected by copyright. All rights reserved.

We developed and validated a set of composite scores that combine quantitative magnetic resonance imaging (MRI)-based measurements of hyaline cartilage damage, bone marrow lesions (BMLs), and effusion-synovitis into composite scores.We selected 300 participants (n = 100 for development cohort; n = 200 for validation cohort) from the Osteoarthritis Initiative with complete clinical, radiographic, and MRI data at baseline and 24 months. We used semiautomated programs to quantify tibiofemoral and patellar cartilage damage, BML volume, and whole-knee effusion-synovitis volume. The candidate composite scores were formed by summing changes from baseline to 24 months based on prespecified methods. We evaluated the candidate composite scores for 1) the ability to differentiate groups with and without knee osteoarthritis progression (17 radiographic and patient-reported definitions), 2) sensitivity to change (standardized response means), and 3) relative performance relating to legacy outcome measures of knee osteoarthritis progression.Three of 13 developed composite scores qualified for testing in the validation cohort (ranked by sensitivity to change): whole-knee cumulative cartilage damage, unweighted total knee score, and BML plus effusion-synovitis volume. Change in cumulative cartilage damage associated with radiographic progression (Kellgren/Lawrence grade: odds ratio [OR] 1.84; joint space width progression: OR 2.11). Changes in the unweighted total knee score (OR 1.97) and BML plus effusion-synovitis score (OR 1.92) associated with Western Ontario and McMaster Universities Osteoarthritis Index knee pain progression.Two composite scores emerged, reflecting discrete domains of knee osteoarthritis progression. First, cumulative damage, which is measured by a whole-knee cartilage damage score, reflects the damage accrued over time. Second, dynamic disease activity, which is measured by a BML plus effusion-synovitis score, relates to changes in a patient's state of disease and symptoms.

Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease.

Key points Synchronized TMS pulses with pre-defined brain oscillatory phases allows to evaluate the impact of brain states on TMS effects. TMS pulses over M1 at the negative peak of μ-frequency band induces higher phase-lock synchronization with interconnected contralateral homologous regions. Cortico-cortical synchronization changes are linearly predicted by the fiber density and cross-section of the white matter tract that connect the two brain regions. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase magnitude and reliability of within-network synchronization. Abstract Recent studies have synchronized transcranial magnetic stimulation (TMS) application with pre-defined brain oscillatory phases showing how the effect of a perturbation depends on the brain state. However, none have investigated if phase-dependent TMS can possibly modulate connectivity with homologous distant brain regions belonging to the same network. In the framework of network-targeted TMS, we investigated whether stimulation delivered at a specific phase of ongoing brain oscillations might favor stronger cortico-cortical (c-c) synchronization of distant network nodes connected to the stimulation target. Neuronavigated TMS pulses were delivered over the primary motor cortex (M1) during ongoing electroencephalography recording in twenty-four healthy individuals over two repeated sessions 1-month apart. Stimulation effects were analyzed considering whether the TMS pulse was delivered at the time of a positive (peak) or negative (trough) phase of μ-frequency oscillation, which determines c-c synchrony within homologous areas of the sensorimotor network. Diffusion Weighted Imaging was used to study c-c connectivity within the sensorimotor network and identify contralateral regions connected with the stimulation spot. Depending on when during the μ-activity the TMS-pulse was applied (peak or trough), its impact on inter-hemispheric network synchrony varied significantly. Higher M1-M1 phase-lock synchronization with after the TMS-pulse (0-200ms) in the μ-frequency band was found for trough compared to peak stimulation trials in both study visits. Phase-dependent TMS delivery might be crucial not only to amplify local effects but also to increase magnitude and the reliability of the response to the external perturbation, with implications for interventions aimed at engaging more distributed functional brain networks. This article is protected by copyright. All rights reserved.

OBJECTIVE Elevated interleukin 10 (IL10) in SLE patients has B-cell promoting effects, contributing to autoantibody production and tissue damage. We aimed to characterize upregulated IL10+ B-cell subsets and dysregulated IL10 expression in SLE B cells for new therapeutic options. METHODS Proportions of Th10 and IL10+ B-cell subsets in PBMCs were assessed using flow cytometry. The IL10-3'UTR dual-luciferase vector was constructed and co-transfected with siRNA, miRNA mimics or inhibitors into RAJI cell line. Transcript levels were quantified using Taqman assays. RESULTS Culture conditions that induced IL10+ Breg in healthy controls (HC) resulted in expansion of IL10+ DN2 (IgD- CD27- CD21- CD11c+ ) B-cells in SLE PBMCs. Proportions of IL10+ DN2, but not those of IL10- DN2, correlated with disease activity, levels of antibodies to dsDNA, and associated with high levels or seropositivity of anti-Smith and anti-cardiolipin IgG in SLE patients from two cohorts of mainly African Americans and Asians, respectively. Proportions of Th10 (CD45RA- CXCR5- CXCR3+ PD1hi CD4+ ) cells correlated with IL10+ DN2 frequencies, ANA titers and proteinuria levels in SLE patients. Screening predicted IL10 3'UTR-targeting miRNAs in SLE B cells identified miR-17-5p and miR-20a-5p with their levels inversely correlated with IL10 and transcription factor E2F2. In RAJI cells, knockdown of E2F2 expression resulted in increased levels of miR-17-5p and miR-20a-5p and decreased IL10 mRNA and protein levels, and overexpression and inhibition of miR-17-5p down-regulated and up-regulated IL10 mRNA levels respectively; suggesting regulation of IL10 expression by E2F2-miR-17-5p loop. CONCLUSION IL10 promotes extrafollicular autoimmune responses in active SLE patients, which might be dampened by targeting the E2F2-miR-17-5p circuitry.

BACKGROUND AND PURPOSE Small molecule BGP-15 has been reported to alleviate signs of heart failure and improve muscle function in murine models. Here, we investigated the acute and chronic effects of BGP-15 in a rabbit model of atherosclerotic cardiomyopathy. EXPERIMENTAL APPROACH Rabbits were maintained on standard chow (Control) or atherogenic diet (HC) for 16 weeks. BGP-15 was administered intravenously (once) or orally (for 16 weeks), to assess acute and chronic effects. Cardiac function was evaluated by echocardiography, endothelium-dependent vasorelaxation was assessed, and key molecules of the protein kinase G (PKG) axis were examined by ELISA and Western blot. Passive force generation was investigated in skinned cardiomyocytes. KEY RESULTS Both acute and chronic BGP-15 treatment improved the diastolic performance of the diseased heart, however, vasorelaxation and serum lipid markers were unaffected. Myocardial cGMP levels were elevated in the BGP-15-treated group, along with preserved PKG activity and increased phospholamban Ser16-phosphorylation. PDE5 expression decreased in the BGP-15-treated group, and the substance inhibited PDE1 enzyme. Cardiomyocyte passive tension reduced in BGP-15-treated rabbits, the ratio of titin N2BA/N2B isoforms increased, and PKG-dependent N2B-titin phosphorylation elevated in the BGP-15-treated group. CONCLUSIONS AND IMPLICATIONS Here we report that BGP-15-treatment improves diastolic function, reduces cardiomyocyte stiffness, and restores titin compliance in a rabbit model of atherosclerotic cardiomyopathy by increasing the activity of the cGMP-PKG axis. As BGP-15 is proven to be safe, it may have clinical value in the treatment of diastolic dysfunction.

The derivation of rhythm‐specific spatial patterns of electroencephalographic (EEG) signals for covert speech EEG classification task is dealt in this work. This study has been performed on a publicly accessible multi‐channel covert speech EEG database consisting of multi‐syllabic words. With the motivation of deriving more discriminative features, each channel data has been decomposed into distinct bands focussing on the five basic EEG rhythms using the discrete wavelet transform (DWT)‐based signal decomposition algorithm. Following that, for each band, the multi‐class common spatial pattern (CSP) features are computed using joint approximate diagonalisation. The final feature vector is formed by retaining a few significant CSP components from all five bands. Radial basis function kernel‐based support vector machines are used for covert speech classification. After 5‐fold cross‐validation, the proposed DWT‐based bandwise‐CSP features are noted to yield an average classification accuracy of 94%. In contrast with the existing (non‐decomposed) CSP feature, a relative improvement of about 24% is achieved. For generalisation purposes, the proposed approach has also been evaluated for another covert speech database comprising more classes and subjects. The study highlights the discovery of more discriminative patterns with rhythm‐specific processing in the context of covert speech classification. The proposed approach has the potential to be useful in other brain‐computer interface paradigms that employ EEG signals.

Background Dysregulation of BZRAP1‐AS1 was associated with immune statuses of cancer or Alzheimer's disease patients, yet little is known about its role in rheumatoid arthritis. Methods RT‐qPCR and western blot were applied to assess the expression of indicated expression. CCK‐8 and BrdU proliferation assays were used to measure the proliferation of RA‐HFLS. Apoptosis in RA‐HFLS was evidenced by the alteration of caspase‐3 activity and apoptosis‐related factors. ELISA was performed to detect IL‐6, IL‐1β, and TNF‐α level. Luciferase reporter, RIP, and pull‐down assays were used to confirm the BZRAP1‐AS1/miR‐1286/COL5A2 cascade predicted by bioinformatics analysis. Results BZRAP1‐AS1 and COL5A2 were downregulated in RA tissues and RA‐HFLS while miR‐1286 was amplified. Overexpression of BZRAP1‐AS1 reduced the RA‐HFLS proliferation, IL‐6, IL‐1β, and TNF‐α level and induced cell apoptosis while BZRAP1‐AS1 silence produced an opposite effect. Overexpression of BZRAP1‐AS1 reduced the miR‐1286 expression which in turn increased the COL5A2 expression, thereby relieving the excessive proliferation and limited apoptosis in RA‐HFLS. Conclusion Our findings suggested that BZRAP1‐AS1 sequestered miR‐1286 and reshaped the COL5A2 expression, thereby suppressed RA‐HFLS proliferation and inflammation, and triggered cell apoptosis, resulting in the attenuation of RA progression.

Transthyretin amyloid cardiomyopathy (ATTR‐CM) is caused by the cardiac deposition of insoluble amyloid fibrils formed by misfolded transthyretin proteins and is associated with various cardiac symptoms, such as progressive heart failure, conduction disturbance, and arrhythmia. The implementation of 99mtechnetium (99mTc)‐labelled bone radiotracer scintigraphy for diagnosing ATTR‐CM has enabled accurate diagnosis of the disease with high sensitivity and specificity and positioned this diagnostic modality as an integral part of disease diagnostic algorithms. In 2020, 99mTc‐pyrophosphate scintigraphy received exceptional approval for Japanese national health insurance reimbursement as a diagnostic method of ATTR‐CM. Nevertheless, the utility of 99mTc‐labelled bone radiotracer scintigraphy and the importance of an early diagnosis of suspected ATTR‐CM using this technique have yet to be internalized as common practice by general cardiologists, and guidance on daily clinical scenarios to consider this technique for a diagnosis of suspected ATTR‐CM is warranted. In this review, we discuss the utility of 99mTc‐labelled bone radiotracer scintigraphy for the early diagnosis of ATTR‐CM based on published literature and the outcomes of an advisory board meeting. This review also discusses clinical scenarios that could support early diagnosis of suspected ATTR‐CM as well as common pitfalls, correct implementation, and future perspectives of 99mTc‐labelled bone radiotracer scintigraphy in daily clinical practice. The clinical scenarios to consider 99mTc‐labelled bone radiotracer scintigraphy in daily practice may include, but are not limited to, patients with a family history of the hereditary type of disease; elderly patients (aged ≥60 years) with unexplained cardiac findings (e.g. cardiac hypertrophy associated with abnormalities on an electrocardiogram, heart failure with preserved ejection fraction associated with unexplained left ventricular hypertrophy, and heart failure with reduced ejection fraction associated with atrial fibrillation and left ventricular hypertrophy); and patients with cardiac hypertrophy associated with diastolic dysfunction, right ventricular/interatrial septum/valve thickness, left ventricular sparkling, or apical sparing. Cardiac hypertrophy and persistent elevation in cardiac troponin in elderly patients are also suggestive of ATTR‐CM. 99mTc‐labelled bone radiotracer scintigraphy is also recommended in patients with characteristic cardiac magnetic resonance findings (e.g. diffuse subendocardial late gadolinium enhancement patterns, native T1 increase, and increase in extracellular volume) or patients with cardiac hypertrophy and bilateral carpal tunnel syndrome.

Aims Therapeutic drug monitoring (TDM) of gentamicin in neonates is recommended for safe and effective dosing and is currently performed by plasma sampling, which is an invasive and painful procedure. In this study, feasibility of a non-invasive gentamicin TDM strategy using saliva was investigated. Methods This was a multicentre, prospective, observational cohort study including 54 neonates. Any neonate treated with intravenous gentamicin was eligible for the study. Up to eight saliva samples were collected per patient at different time-points. Gentamicin levels in saliva were determined with liquid chromatography tandem mass-spectrometry (LC-MS/MS). A population pharmacokinetic (PK) model was developed using nonlinear mixed-effects modelling (NONMEM) to describe the relation between gentamicin concentrations in saliva and plasma. Monte Carlo simulations with a representative virtual cohort (n = 3000) were performed to evaluate the probability of target attainment with saliva versus plasma TDM. Results Plasma PK was adequately described with an earlier published model. An additional saliva compartment describing the salivary gentamicin concentrations was appended to the model with first-order input (k(13) 0.023 h(-1)) and first-order elimination (k(30) 0.169 h(-1)). Inter-individual variability of k(30) was 38%. Postmenstrual age (PMA) correlated negatively with both k(13) and k(30). Simulations demonstrated that TDM with four saliva samples was accurate in 81% of the simulated cases versus 94% when performed with two plasma samples and 87% when performed with one plasma sample. Conclusion TDM of gentamicin using saliva is feasible and the difference in precision between saliva and plasma TDM may not be clinically relevant, especially for premature neonates.

Longstanding epilepsy can lead to modulation of cortical networks over time and unexpected seizure onset zones. Frontal lobe seizures, in particular, can have diverse semiologies and evolution patterns. We present a male patient with drug-resistant epilepsy secondary to severe traumatic brain injury who underwent bilateral stereo electroencephalography (SEEG) for surgical planning. SEEG localized an ictal circular head roll to the right anterior prefrontal region. This was followed by spread to the left orbitofrontal region and later the left amygdala and hippocampus, at which point a different semiology with behavioral arrest, lip smacking and oral automatisms began. This case, in which an ictal circular head roll was localized to the anterior prefrontal region, demonstrates the complexity of broad seizure networks that develop over time, leading to remote seizure spread.

Reflex seizures are consistently evoked by a specific afferent stimulus or by patient activity. Patients experiencing reflex seizures when playing a game on a mobile phone are rarely reported. We describe a boy with reflex seizures after prolonged exposure to the game, Cut the rope, on his mobile phone. The video-EEG documented electroclinical events characterized by distal myoclonic jerks of the upper limbs, in combination with irregular, diffuse spike-and-wave and polyspike-and-wave discharges on EEG, followed by a tonic-clonic seizure. Playing video games on mobile phones may potentially induce reflex seizures, similar to other commonly used platforms such as docking stations connected to video screens.

To assess the clinical utility of prenatal chromosomal microarray analysis (CMA) in fetuses with abnormal renal sonographic findings, and to evaluate the association of pathogenic or likely pathogenic copy number variants (P/LP CNVs) with different types of renal abnormality.This was a retrospective study of fetuses at 14-36 weeks screened routinely for renal and other structural abnormalities at the Maternal and Child Health Hospital of Guangxi Zhuang Autonomous Region. We retrieved and analyzed data from fetuses with abnormal renal sonographic findings, examined between January 2013 and November 2019, which underwent CMA analysis using tissue obtained from chorionic villus sampling (CVS), amniocentesis or cordocentesis. We evaluated the CMA findings according to type of renal ultrasound anomaly and according to whether renal anomalies were isolated or non-isolated.Ten types of renal anomaly were reported on prenatal ultrasound screening, at a mean ± SD gestational age of 24.9 ± 4.8 weeks. The anomalies were diagnosed relatively late in this series, as 64% of cases with an isolated renal anomaly underwent cordocentesis rather than CVS. Fetal pyelectasis was the most common renal ultrasound finding, affecting around one-third (34.32%, 301/877) of fetuses with a renal anomaly, but only 3.65% (n = 11) of these harbored a P/LP CNV (comprising: isolated cases, 2.37% (4/169); non-isolated cases, 5.30% (7/132)). Hyperechogenic kidney was found in 5.47% (n = 48) of fetuses with a renal anomaly, of which 39.58% (n = 19) had a P/LP CNV finding (comprising: isolated cases, 44.44% (16/36); non-isolated cases, 25.00% (3/12)), the highest diagnostic yield among the different types of renal anomaly. Renal agenesis, which accounted for 9.92% (n = 87) of all abnormal renal cases, had a CMA diagnostic yield of 12.64% (n = 11) (comprising: isolated cases, 11.54% (9/78); non-isolated cases, 22.22% (2/9); unilateral cases, 11.39% (9/79); bilateral cases, 25.00% (2/8)), while multicystic dysplastic kidney (n = 110), renal cyst (n = 34), renal dysplasia (n = 27), crossed fused renal ectopia (n = 31), hydronephrosis (n = 98), renal duplication (n = 42) and ectopic kidney (n = 99) had overall diagnostic rates of 11.82%, 11.76%, 7.41%, 6.45%, 6.12%, 4.76% and 3.03%, respectively. Compared with the combined group of CMA-negative fetuses with any other type of renal anomaly, the rate of infant being alive and well at birth was significantly higher in CMA-negative fetuses with isolated fetal pyelectasis or ectopic kidney, whereas the rate was significantly lower in fetuses with isolated renal agenesis, multicystic dysplastic kidney or severe hydronephrosis. The most common pathogenic CNV was 17q12 deletion, which accounted for 30.14% (22/73) of all positive CMA findings, with a rate of 2.51% (22/877) among fetuses with an abnormal renal finding. Fetuses with 17q12 deletion exhibited a wide range of renal phenotypes. Other P/LP CNVs in the recurrent region that were associated with prenatal renal ultrasound abnormalities included 22q11.2, Xp21.1, Xp22.3, 2q13, 16p11.2 and 1q21, which, collectively, accounted for 2.17% (19/877) of the fetuses with prenatal renal anomalies.In this retrospective review of CMA findings in a large cohort of fetuses with different types of renal ultrasound abnormality, the P/LP CNV detection rate varied significantly (3.03-39.58%) among the different types of kidney anomaly. Our data may help in the decision regarding whether to perform prenatal genetic testing in fetuses with renal ultrasound findings. Specifically, prenatal CMA testing should be performed in cases of hyperechogenic kidney, regardless of whether or not the anomaly is isolated, while it should be performed postnatally rather than prenatally in cases of fetal pyelectasis. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

To compare the performance of transvaginal and transabdominal ultrasound with that of the first-line staging method (contrast-enhanced computed tomography (CT)) and a novel technique, whole-body magnetic resonance imaging with diffusion-weighted sequence (WB-DWI/MRI), in the assessment of peritoneal involvement (carcinomatosis), lymph-node staging and prediction of non-resectability in patients with suspected ovarian cancer.Between March 2016 and October 2017, all consecutive patients with suspicion of ovarian cancer and surgery planned at a gynecological oncology center underwent preoperative staging and prediction of non-resectability with ultrasound, CT and WB-DWI/MRI. The evaluation followed a single, predefined protocol, assessing peritoneal spread at 19 sites and lymph-node metastasis at eight sites. The prediction of non-resectability was based on abdominal markers. Findings were compared to the reference standard (surgical findings and outcome and histopathological evaluation).Sixty-seven patients with confirmed ovarian cancer were analyzed. Among them, 51 (76%) had advanced-stage and 16 (24%) had early-stage ovarian cancer. Diagnostic laparoscopy only was performed in 16% (11/67) of the cases and laparotomy in 84% (56/67), with no residual disease at the end of surgery in 68% (38/56), residual disease ≤ 1 cm in 16% (9/56) and residual disease 1 cm in 16% (9/56). Ultrasound and WB-DWI/MRI performed better than did CT in the assessment of overall peritoneal carcinomatosis (area under the receiver-operating-characteristics curve (AUC), 0.87, 0.86 and 0.77, respectively). Ultrasound was not inferior to CT (P = 0.002). For assessment of retroperitoneal lymph-node staging (AUC, 0.72-0.76) and prediction of non-resectability in the abdomen (AUC, 0.74-0.80), all three methods performed similarly. In general, ultrasound had higher or identical specificity to WB-DWI/MRI and CT at each of the 19 peritoneal sites evaluated, but lower or equal sensitivity in the abdomen. Compared with WB-DWI/MRI and CT, transvaginal ultrasound had higher accuracy (94% vs 91% and 85%, respectively) and sensitivity (94% vs 91% and 89%, respectively) in the detection of carcinomatosis in the pelvis. Better accuracy and sensitivity of ultrasound (93% and 100%) than WB-DWI/MRI (83% and 75%) and CT (84% and 88%) in the evaluation of deep rectosigmoid wall infiltration, in particular, supports the potential role of ultrasound in planning rectosigmoid resection. In contrast, for the bowel serosal and mesenterial assessment, abdominal ultrasound had the lowest accuracy (70%, 78% and 79%, respectively) and sensitivity (42%, 65% and 65%, respectively).This is the first prospective study to document that, in experienced hands, ultrasound may be an alternative to WB-DWI/MRI and CT in ovarian cancer staging, including peritoneal and lymph-node evaluation and prediction of non-resectability based on abdominal markers of non-resectability. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

OBJECTIVE The postictal state after bilateral tonic-clonic seizures is often prolonged and can have significant impact on a patient's quality of life. Considerable variability exists in the magnitude of postictal agitation and in the speed of recovery, the determinants of which are not well understood. We studied postictal behavior after tonic-clonic seizures in various epilepsy localizations, focusing on postictal agitation and time to responsiveness. METHODS We retrospectively identified 15 adult patients each with idiopathic generalized, left temporal lobe, right temporal lobe and frontal lobe epilepsy. Localization in focal epilepsy was validated by good outcome after resective surgery at one-year of follow-up. The first tonic-clonic seizure with reliable video and EEG for each patient was analyzed by two reviewers, one of whom was blinded to clinical data. Clinical, ictal and postictal variables were collected for each patient and analyzed. Postictal agitation was classified as mild and marked. RESULTS We reviewed 60 tonic-clonic seizures, 15 in each of four patient groups. Postictal agitation was observed in 14 patients (23.3%; marked in one and mild in 13). Postictal agitation was most common in patients with left temporal (seven patients) and least common in idiopathic generalized epilepsy (one patient) groups (p=0.035). Based on subgroup analysis (n=28), time to responsiveness was 6.6 minutes for frontal, 7.2 minutes for generalized, 10 minutes for right temporal and 15.7 minutes for the left temporal groups (p

Milvexian (BMS‐986177/JNJ‐70033093) is a small molecule, active‐site inhibitor of factor XIa (FXIa) being developed to prevent and treat thrombotic events. The safety, tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of milvexian were assessed in a two‐part, double‐blind, placebo‐controlled, sequential single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy adults. Participants in SAD panels (6 panels of 8 participants; n = 48) were randomized (3:1) to receive milvexian (4, 20, 60, 200, 300, or 500 mg) or placebo. The 200‐ and 500‐mg panels investigated the pharmacokinetic impact of a high‐fat meal. Participants in MAD panels (7 panels of 8 participants; n = 56) were randomized (3:1) to receive milvexian (once‐ or twice‐daily) or placebo for 14 days. All milvexian dosing regimens were safe and well‐tolerated, with only mild treatment‐emergent adverse events and no clinically significant bleeding events. In SAD panels, maximum milvexian plasma concentration occurred 3 h postdose in all fasted panels. The terminal half‐life (T1/2) ranged from 8.3 to 13.8 h. In fasted panels from 20 to 200 mg, absorption was dose‐proportional; results at higher doses (300 and 500 mg) were consistent with saturable absorption. Food increased milvexian bioavailability in a dose‐dependent fashion. In MAD panels, steady‐state milvexian plasma concentration was reached within 3 and 6 dosing days with once‐ and twice‐daily dosing, respectively. Renal excretion was less than 20% in all panels. Prolongation of activated partial thromboplastin time was observed and was directly related to drug exposure. These results suggest that the safety, tolerability, PK, and PD properties of milvexian are suitable for further clinical development.

Lung adenocarcinoma (LUAD) accounts for almost 40% of lung cancers, leading to significant associated morbidity and mortality rates. However, the mechanism of LUAD tumorigenesis remains far from clear. Here, we scanned downregulated genes involved in LUAD sourced from Cancer Genome Atlas and Gene Expression Omnibus data and focused on G protein-coupled receptor 133 (GPR133). We offer compelling evidence that GPR133 was expressed at low levels in the setting of LUAD and higher expression was positively related with a better prognosis among LUAD patients. Functionally, GPR133 inhibited cell proliferation and tumor growth in vitro and in vivo. Regarding the mechanism, flow cytometry assays and western blot assays showed that GPR133 enhanced p21 and decreased cyclin B1 expression, thus triggered LUAD cells at G2/M-phase arrest. Consistent with this, we evaluated the expression levels of cell-cycle biomarkers and found that Bioinformatics analysis combined with N6 -methyladenosine (m6 A; methylation at the N6 position in adenosine) RNA immunoprecipitation-qPCR (MeRIP-qPCR) assay indicated that GPR133 expression was downregulated by this modification. Moreover, we observed that methyltransferase-like 3 was impaired in LUAD and that it is able to significantly increase levels of GPR133 by enhancing its RNA stability. In conclusion, we found that GPR133 expression was downregulated in LUAD via m6 A modification. Increasing GPR133 levels could suppress LUAD cell proliferation and tumor growth.

Systemic sclerosis (SSc)-associated gastrointestinal (GI) complications are attributed to a variety of factors, including diet, microbiota dysbiosis, or GI transit abnormalities. Our objective was to examine the contribution of abnormal GI transit to SSc Medsger GI severity scores and/or University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract (UCLA GIT) 2.0 symptoms.Patients with SSc and GI symptoms (n = 71) and healthy controls (n = 18) underwent whole gut transit (WGT) scintigraphy to assess transit from the esophagus to the colon. The presence of delayed transit and percent emptying in each GI region were measured. We compared the WGT measurements between categories of the Medsger GI severity score (0-4) and across UCLA GIT 2.0 domains and total score (0-3).A total of 88% of patients had1 abnormal region of the gut on WGT scintigraphy. All patients requiring total parenteral nutrition had delayed small bowel transit, compared to only approximately 11% of patients in other Medsger GI severity groups (P ≤ 0.01). Severe colonic transit delays were more likely in patients with Medsger GI scores of 3 (pseudo-obstruction and/or malabsorption) compared to other Medsger GI groups (P = 0.02). Seventy-percent of these patients had ≤30% colonic emptying at 72 hours. Modest associations were noted between gastroesophageal reflux disease symptoms and delayed esophageal (r = -0.31, P = 0.05) and gastric emptying (r = -0.32, P = 0.05).These data are important in providing evidence that SSc bowel disease affects transit of GI content and that delay in transit accounts in part for both bowel symptoms and Medsger GI severity. Prospective studies examining the benefit of early therapeutic intervention targeting GI transit abnormalities in patients at high risk for severe GI complications are needed.

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy according to real-world data. Therefore, robust predictive biomarkers for selecting adjuvant chemotherapy (ADJ) or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by fluorescence in situ hybridization (FISH). Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were performed. Formalin-fixed, paraffin-embedded (FFPE) samples from 1,136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients ≥ 65 years, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (HR: 0.084, 95% CI: 0.009, 0.806; P = 0.032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages, HR: 1.214, 95% CI: 0.848, 1.738; P = 0.289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative adjuvant chemotherapy for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side effects of adjuvant chemotherapy, and saving medical costs.

Background Identifying the factors affecting osteoblast differentiation ofperiodontal ligamentcells (PDLCs) can help enhance the regeneration of periodontal tissue.LncRNAplasmacytoma variant translocation 1 (lncPVT1) is an important regulatory factor involved in many biological processes, but its role in osteogenesisremains unclear. Methods Expressionsof osteogenic markers were detected by quantitative reverse transcription polymerase chain reaction and Western blot analysis. Alkaline phosphatase staining was conducted for early osteoblast differentiation and alizarin red S staining was used for mineral deposition. RNA sequencing was used to identify the miRNAs regulated by lncPVT1 during osteogenesis. Cell transfection was used to overexpress or knockdown lncPVT1 and miR-10a-5p. Dual luciferase reporter assayswere conducted to analyze the binding of miR-10a-5p to brain-derived neurotrophic factor (BDNF). Results LncPVT1 was significantly increased during osteogenic induction of PDLCs. Overexpression of lncPVT1 promoted osteogenesis, whereas lncPVT1 knockdown inhibited this process. RNA sequencing showed that miR-10a-5p expression was significantly increased after lncPVT1 knockdown.RNA immunoprecipitation assay further demonstrated the binding potential of lncPVT1 and miR-10a-5p. MiR-10a-5p inhibited the osteogenesis of PDLCs, and partially reversed the stimulatory effects of lncPVT1.Subsequently, we identified a predicted binding site for miR-10a-5p on BDNF and confirmed it using dual luciferase reporter assays. Moreover, lncPVT1 upregulated the expression of BDNF, while miR-10a-5p downregulated BDNF expression. BDNF promoted osteogenesis and partially rescued the si-lncPVT1-mediated inhibition of PDLCs osteogenic differentiation. Conclusion LncPVT1 positively regulated the osteogenic differentiation of PDLCs via miR-10a-5p and BDNF.Our resultsprovide a promising target for enhancing the osteogenic potential of PDLCs. This article is protected by copyright. All rights reserved.

To examine the association between inferior vena cava (IVC) diameter and postpartum blood loss and assess whether IVC diameter is a useful marker in the evaluation of intravascular volume status in women with postpartum hemorrhage (PPH).This was a prospective case-control study conducted in a university medical teaching center in Afula, Israel, between November 2018 and March 2020. The study cohort consisted of women with a singleton pregnancy who delivered vaginally at term. The PPH group included women diagnosed with PPH based on visually estimated blood loss of 1000 mL or more at the time of enrolment. Hemodynamically unstable women or women with major bleeding at the time of diagnosis were not included. The control group consisted of women with an uneventful fourth stage of labor. IVC diameter was measured using transabdominal ultrasonography during inspiration (IVCi diameter) and expiration (IVCe diameter), and the collapsibility index was calculated ((IVCe - IVCi)/IVCe × 100). The primary outcome was the percentage difference in IVC diameter and collapsibility index between the PPH group and controls. The performance of the IVC collapsibility index in the prediction of the need for blood transfusion in women with PPH was assessed. In order to demonstrate a difference of 20% with a power of 80% and alpha of 0.05, 108 women, at a ratio of 1:2 in the study and control groups, respectively, were needed.Overall, 36 and 72 women were included in the final analysis in the PPH and control groups, respectively. IVCi and IVCe diameters were significantly smaller in the PPH group (0.93 ± 0.30 cm and 1.26 ± 0.32 cm, respectively) than in controls (1.42 ± 0.31 cm and 1.75 ± 0.28 cm, respectively) (P = 0.001 for both). The percentage reductions in IVCi and IVCe diameters in the PPH group compared with controls were 35.0% and 28.0%, respectively. IVC collapsibility index was increased significantly, by 42.9% (26.04 ± 8.67% vs 18.15 ± 5.07%; P = 0.001) in the PPH group compared with controls. IVC collapsibility index was a significant predictor of the need for blood transfusion and correctly predicted 81% of cases. Logistic regression analysis demonstrated that IVC collapsibility index was also a significant predictor of a drop in hemoglobin level of ≥ 2 g/dL (P = 0.001).IVC diameter changes in response to postpartum blood loss. Measurement of IVC diameter using transabdominal ultrasonography is an objective and useful non-invasive method for the early evaluation of intravascular volume status in women with PPH and for the prediction of cases that might require blood transfusion. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.