Supra- and infra-tentorial degeneration patterns in primary lateral sclerosis: a multimodal longitudinal neuroradiology study.

BACKGROUND: Primary lateral sclerosis (PLS) is traditionally solely associated with progressive upper motor neuron dysfunction manifesting in limb spasticity, gait impairment, bulbar symptoms and pseudobulbar affect. Recent studies have described frontotemporal dysfunction in some patients resulting in cognitive manifestations. Cerebellar pathology is much less well characterised despite sporadic reports of cerebellar disease. METHODS: A multi-timepoint, longitudinal neuroimaging study was conducted to characterise the evolution of both intra-cerebellar disease burden and cerebro-cerebellar connectivity. The volumes of deep cerebellar nuclei, cerebellar cortical volumes, cerebro-cerebellar structural and functional connectivity were assessed longitudinally in a cohort of 43 individuals with PLS. RESULTS: Cerebello-frontal, -temporal, -parietal, -occipital and cerebello-thalamic structural disconnection was detected at baseline based on radial diffusivity (RD) and cerebello-frontal decoupling was also evident based on fractional anisotropy (FA) alterations. Functional connectivity changes were also detected in cerebello-frontal, parietal and occipital projections. Volume reductions were identified in the vermis, anterior lobe, posterior lobe, and crura. Among the deep cerebellar nuclei, the dorsal dentate was atrophic. Longitudinal follow-up did not capture statistically significant progressive changes. Significant primary motor cortex atrophy and inter-hemispheric transcallosal degeneration were also captured. CONCLUSIONS: PLS is not only associated with upper motor neuron dysfunction, but cerebellar cortical volume loss and deep cerebellar nuclear atrophy can also be readily detected. In addition to intra-cerebellar disease burden, cerebro-cerebellar connectivity alterations also take place. Our data add to the evolving evidence of widespread neurodegeneration in PLS beyond the primary motor regions. Cerebellar dysfunction in PLS is likely to exacerbate bulbar, gait and dexterity impairment and contribute to pseudobulbar affect.

Language deficits in primary lateral sclerosis: cortical atrophy, white matter degeneration and functional disconnection between cerebral regions.

BACKGROUND: Primary lateral sclerosis (PLS) is traditionally regarded as a pure upper motor neuron disorder, but recent cases series have highlighted cognitive deficits in executive and language domains. METHODS: A single-centre, prospective neuroimaging study was conducted with comprehensive clinical and genetic profiling. The structural and functional integrity of language-associated brain regions and networks were systematically evaluated in 40 patients with PLS in comparison to 111 healthy controls. The structural integrity of the arcuate fascicle, frontal aslant tract, inferior occipito-frontal fascicle, inferior longitudinal fascicle, superior longitudinal fascicle and uncinate fascicle was evaluated. Functional connectivity between the supplementary motor region and the inferior frontal gyrus and connectivity between Wernicke's and Broca's areas was also assessed. RESULTS: Cortical thickness reductions were observed in both Wernicke's and Broca's areas. Fractional anisotropy reduction was noted in the aslant tract and increased radical diffusivity (RD) identified in the aslant tract, arcuate fascicle and superior longitudinal fascicle in the left hemisphere. Functional connectivity was reduced along the aslant track, i.e. between the supplementary motor region and the inferior frontal gyrus, but unaffected between Wernicke's and Broca's areas. Cortical thickness alterations, structural and functional connectivity changes were also noted in the right hemisphere. CONCLUSIONS: Disease-burden in PLS is not confined to motor regions, but there is also a marked involvement of language-associated tracts, networks and cortical regions. Given the considerably longer survival in PLS compared to ALS, the impact of language impairment on the management of PLS needs to be carefully considered.

The clinical impact of early detection of ESBL-producing Enterobacterales with PCR-based blood culture assays.

BACKGROUND: Starting January 4, 2021, our health system core microbiology laboratory changed blood culture identification (BCID) platforms to ePlex BCID from BioFire BCID1 with the additional capability to detect the blaCTX-M-Type gene of ESBL-producing organisms. Clinical outcomes of ESBL bloodstream infections (BSI) after implementing ePlex BCID were unknown. METHODS: Patients with ESBL BSI were compared pre and postimplementation of ePlex BCID in this 11-hospital retrospective analysis (BioFire BCID1 in 2019 vs ePlex BCID in 2021). The primary outcome was time from the Gram stain result to escalation to a carbapenem. Secondary outcomes included in-hospital mortality, 30-day readmission rate, length of stay (LOS), and the duration of antimicrobial therapy. RESULTS: A total of 275 patients were analyzed. The median time of Gram stain result to escalation to carbapenem was reduced from 44.5 hours with BioFire BCID1 to 7.9 hours with ePlex BCID (P < .001). There were no significant differences in mortality, 30-day readmission, or LOS. The duration of antimicrobial therapy for ESBL BSI was lower in the ePlex BCID group (from 14.4 days to 12.7 days, P = .014). CONCLUSIONS: Timely detection of the blaCTX-M-Type gene by BCID provides valuable information for the early initiation of appropriate and effective antimicrobial therapy. Although it was not associated with lower mortality, 30-day readmission, or LOS, it may have benefits such as decreasing antimicrobial exposure to patients.

Andrographolide Relieves Post-Operative Wound Pain but Affects Local Angiogenesis.

Andrographolide (Andro), the major constituent of Andrographis paniculata Nees (Acanthaceae), is was known to reduces inflammatory reaction. In the current study, the ability of Andro to reduce pain sensation in a rat post-operative wound model was explored. The hind paws of 18 Sprague-Dawley rats (SD) bearing post-operative wounds received the following three treatments: Saline, Andro via direct injection into the paw (Andro-injected) and Tablet containing Andro + poly (lactic-co-glycolic acid) (PLGA) (Andro-tablet). Von Frey tests assessed mechanical allodynia at 1, 3, 5 h and 1-, 2-, 3-, 4-, and 5-days post-operation. Behavioral analyses were performed to measure reaction threshold and reaction frequencies. Immunoreactivity of p-ERK and GluR1 was examined in the dorsal horn of the spinal cord. Histopathological and immunostaining studies were conducted on paw epidermis to observe the gross morphology and angiogenesis. The threshold for inducing allodynia increased and the reaction frequency reduced in the Andro-injected group compared to the saline-group, at 3 h post-surgery and the effect lasted between 3-4 days. The threshold for inducing pain and reaction frequency for the Andro-tablet group did not differ from the saline-treated group. The levels of p-ERK and GluR1 in the dorsal horn were reduced after Andro treatment. No significant difference in wound healing index was observed between saline and Andro-injected groups, but CD-31 staining showed less angiogenesis in the Andro-injected group. Andro significantly reduced mechanical allodynia compared to saline treatment, both in shorter and longer time frames. Furthermore, Andro influenced the expression of p-ERK and GluR1 in the dorsal horn, and the angiogenesis process in the wound healing area.

Interactions between Obstructive Sleep Apnea Syndrome Severity, Obesity, Sex Difference and Attention-Deficit/Hyperactivity Disorder on Health-Related Quality of Life: A Non-Interventional Prospective Observational Study.

Obstructive sleep apnea syndrome (OSAS) severity, obesity, sex difference, and attention-deficit/hyperactivity disorder (ADHD) had a complex impact on health-related quality of life (HRQoL). However, the interactive effects among these features on HRQoL remained to be clarified. This study aimed to investigate the individual and interactive associations between the four characteristics of interest and HRQoL as determined by 36-Item Short Form Health Survey, Pittsburgh Sleep Quality Index (PSQI), and Epworth Sleepiness Scale (ESS). This non-interventional, prospective, observational study enrolled a total of 132 patients with suspected OSAS for analysis. While OSAS severity and ADHD detected by adult ADHD Self-Report Scale, termed as screened ADHD, interact with each other, all the four studied features were individually associated with HRQoL. After adjusting for potential physiological and polysomnographic confounders, screened ADHD was independently correlated with PSQI > 5 (OR = 4.126, 95% CI, 1.490−11.424), mental component score < 50 (OR = 5.873, 95% CI, 2.262−15.251) and ESS > 10 (OR = 3.648, 95% CI, 1.738−7.657). Our results show that ADHD detection is necessary and should be incorporated into clinical practice for OSAS management.

Aspergillus pleural empyema in a chronic smoker - A case report and review of literature.

Aspergillus species are ubiquitous saprophytic fungi that are present in the air, water, soil, and decaying vegetables. Clinical features of Aspergillus infection largely depend on the interplay between the fungi and the host immune status. We present a case of a chronic smoker with shortness of breath who was found to have diffuse bronchiectatic changes and empyema of the right lung. Emphysema was also noticed in the left lung. Rare Aspergillus fumigatus was identified in the pleural fluid, while the acid-fast stain and bacterial cultures were negative. The patient's serum Aspergillus fumigatus IgG antibody and galactomannan antigen were negative; however, the pleural galactomannan antigen was elevated. He was treated with video-assisted thoracoscopic surgery (VATS) and partial decortication of the right lung, along with intravenous voriconazole. Despite aggressive therapeutic measures, he died after a prolonged hospital stay. Aspergillus pleural empyema is rare but can be fatal; however, it is not included in the classification for pulmonary aspergillosis. Clinicians should be vigilant to evaluate for fungal empyema in patients with chronic obstructive pulmonary diseases, even without profound immunosuppression.

Clusters of anatomical disease-burden patterns in ALS: a data-driven approach confirms radiological subtypes.

Amyotrophic lateral sclerosis (ALS) is associated with considerable clinical heterogeneity spanning from diverse disability profiles, differences in UMN/LMN involvement, divergent progression rates, to variability in frontotemporal dysfunction. A multitude of classification frameworks and staging systems have been proposed based on clinical and neuropsychological characteristics, but disease subtypes are seldom defined based on anatomical patterns of disease burden without a prior clinical stratification. A prospective research study was conducted with a uniform imaging protocol to ascertain disease subtypes based on preferential cerebral involvement. Fifteen brain regions were systematically evaluated in each participant based on a comprehensive panel of cortical, subcortical and white matter integrity metrics. Using min-max scaled composite regional integrity scores, a two-step cluster analysis was conducted. Two radiological clusters were identified; 35.5% of patients belonging to 'Cluster 1' and 64.5% of patients segregating to 'Cluster 2'. Subjects in Cluster 1 exhibited marked frontotemporal change. Predictor ranking revealed the following hierarchy of anatomical regions in decreasing importance: superior lateral temporal, inferior frontal, superior frontal, parietal, limbic, mesial inferior temporal, peri-Sylvian, subcortical, long association fibres, commissural, occipital, 'sensory', 'motor', cerebellum, and brainstem. While the majority of imaging studies first stratify patients based on clinical criteria or genetic profiles to describe phenotype- and genotype-associated imaging signatures, a data-driven approach may identify distinct disease subtypes without a priori patient categorisation. Our study illustrates that large radiology datasets may be potentially utilised to uncover disease subtypes associated with unique genetic, clinical or prognostic profiles.

A Fuzzy Neural Network Model for Rapid Prediction of Optimal Positive Airway Pressures in OSAS Patients.

Manual titration of positive airway pressure (PAP) is a gold standard to provide an optimal pressure for the treatment of obstructive sleep apnea-hypopnea syndrome (OSAS). Since manual titration studies were costly and time-consuming, many statistical models for predicting effective PAPs were reported. However, the prediction accuracies of the models associated with nocturnal parameters still remain low. This study proposes a fuzzy neural prediction network (FNPN) with input candidate variables, selected among easily available measurements (e.g., body mass index (BMI), waist circumstance (WC), and body composition) and OSAS related questionnaires, to rapidly predict an optimal PAP. The FNPN comprises fuzzy rules and is characterized with the ability of automatic rule growing and pruning from training data. A total of 147 participants from April 2018 to April 2019 were enrolled in Taichung Veterans General Hospital, Taiwan. After two selection processes for feature extraction, WC and BMI were the significant variables for entering the FNPN to predict optimal PAP. Experimental results showed that the average successful prediction rate of the proposed method was 71.8%. This study also found that Epworth sleepiness scales (ESS) and body composition, such as visceral fat area and percent body fat, were excluded in the final prediction model. Compared with existing models, the proposed prediction approach provided a rapid prediction of optimal PAP with higher accuracy.

Phenotypic categorisation of individual subjects with motor neuron disease based on radiological disease burden patterns: A machine-learning approach.

Motor neuron disease is an umbrella term encompassing a multitude of clinically heterogeneous phenotypes. The early and accurate categorisation of patients is hugely important, as MND phenotypes are associated with markedly different prognoses, progression rates, care needs and benefit from divergent management strategies. The categorisation of patients shortly after symptom onset is challenging, and often lengthy clinical monitoring is needed to assign patients to the appropriate phenotypic subgroup. In this study, a multi-class machine-learning strategy was implemented to classify 300 patients based on their radiological profile into diagnostic labels along the UMN-LMN spectrum. A comprehensive panel of cortical thickness measures, subcortical grey matter variables, and white matter integrity metrics were evaluated in a multilayer perceptron (MLP) model. Additional exploratory analyses were also carried out using discriminant function analyses (DFA). Excellent classification accuracy was achieved for amyotrophic lateral sclerosis in the testing cohort (93.7%) using the MLP model, but poor diagnostic accuracy was detected for primary lateral sclerosis (43.8%) and poliomyelitis survivors (60%). Feature importance analyses highlighted the relevance of white matter diffusivity metrics and the evaluation of cerebellar indices, cingulate measures and thalamic radiation variables to discriminate MND phenotypes. Our data suggest that radiological data from single patients may be meaningfully interpreted if large training data sets are available and the provision of diagnostic probability outcomes may be clinically useful in patients with short symptom duration. The computational interpretation of multimodal radiology datasets herald viable diagnostic, prognostic and clinical trial applications.

Explainable fuzzy neural network with easy-to-obtain physiological features for screening obstructive sleep apnea-hypopnea syndrome.

OBJECTIVE/BACKGROUND: Recently, several tools for screening obstructive sleep apnea-hypopnea syndrome (OSAHS) have been devised with varied shortcomings. To overcome these drawbacks, we aimed to propose a self-estimation method using an explainable prediction model with easy-to-obtain variables and evaluate its performance for predicting OSAHS. PATIENTS/METHODS: This retrospective, cross-sectional study selected significant easy-to-obtain variables from patients, suspected of having OSAHS by regression analysis, and fed these variables into the proposed explainable fuzzy neural network (EFNN), a back propagation neural network (BPNN) and a stepwise regression model to compare the screening performance for OSAHS. RESULTS: Of the 300 participants, three easily available features, such as waist circumference, mean blood pressure (BP) at the end of polysomnography and the difference in systolic BP between the end and start of polysomnography, were obtained from regression analysis with a five-fold cross-validation scheme. Feeding these three variables into the prediction models showed that the average prediction differences for apnea-hypopnea index (AHI) when using the EFNN, BPNN, and regression model were respectively 1.5 ± 18.2, 3.5 ± 19.1 and 0.1 ± 19.3, indicating none of the tested methods had good efficacy to predict the AHI values. The performance as determined by the sensitivity + specificity-1 value for screening moderate-to-severe OSAHS of the EFNN, BPNN and regression model were respectively 0.440, 0.414 and 0.380. CONCLUSIONS: When fed with easy-to-obtain physiological features, the understandable EFNN should be the preferred method to predict moderate-to-severe OSAHS.

Effects of Water Extract of Cynanchum paniculatum (Bge.) Kitag. on Different Breast Cancer Cell Lines.

Cynanchum paniculatum (Bge.) Kitag. (CP) is an important medicinal herb used in Chinese herbal medicine, with a variety of biological activities including anticancer property. In this study, we explored the water extract of CP, for its anticancer effects against breast cancer cells with different mutation types. Cells were grouped as untreated (Control); CP direct treatment (dir-CP); Conditioned medium from CP treated (sup-CP), and untreated cells (sup-Control). Effects of dir-CP and sup-CP were compared to corresponding untreated cells on cytotoxicity, cell migration, and protein expression (cleaved caspase-3, caspase-9, and MMP-2 and 9). CP treatment showed time-dependent decrease in cell number of MDA-MB-231 and SK-Br-3 (both ER(-) PR(-)), while the decrease in cell number was not as significant in MCF-7 and ZR-75-1 cells (both ER(+) PR(+)). sup-CP treatment inhibited the cell migration of MDA-MB-231 and MCF-7 (Her2(-)) in a 24 h scratch assay. Our data suggested that ER(-) PR(-) cells are more sensitive to the CP in terms of direct cytotoxicity, which is not regulated by caspase-3. CP inhibited the migration of the two Her2(-) cells, and this correlated with MMP-2 regulation. The migration of ER(-) PR(-) cells was more sensitive to conditioned medium with CP treatment than to direct CP, and this is not regulated by MMP-2. Our data suggested that CP has anticancer potential on various breast cancer cells through different mechanisms and is specifically effective in inhibiting the migration of the triple negative MDA-MB-231. Our data provide insight into the mechanism of CP against breast cancer progression and would benefit the medical practitioners in better management with CP usage.

Dynamic Contrast Enhanced MRI and Intravoxel Incoherent Motion to Identify Molecular Subtypes of Breast Cancer with Different Vascular Normalization Gene Expression.

OBJECTIVE: To assess the expression of vascular normalization genes in different molecular subtypes of breast cancer and to determine whether molecular subtypes with a higher vascular normalization gene expression can be identified using dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI). MATERIALS AND METHODS: This prospective study evaluated 306 female (mean age ± standard deviation, 50 ± 10 years), recruited between January 2014 and August 2017, who had de novo breast cancer larger than 1 cm in diameter (308 tumors). DCE MRI followed by IVIM DWI studies using 11 different b-values (0 to 1200 s/mm²) were performed on a 1.5T MRI system. The Tofts model and segmented biexponential IVIM analysis were used. For each tumor, the molecular subtype (according to six [I-VI] subtypes and PAM50 subtypes), expression profile of genes for vascular normalization, pericytes, and normal vascular signatures were determined using freshly frozen tissue. Statistical associations between imaging parameters and molecular subtypes were examined using logistic regression or linear regression with a significance level of p = 0.05. RESULTS: Breast cancer subtypes III and VI and PAM50 subtypes luminal A and normal-like exhibited a higher expression of genes for vascular normalization, pericyte markers, and normal vessel function signature (p < 0.001 for all) compared to other subtypes. Subtypes III and VI and PAM50 subtypes luminal A and normal-like, versus the remaining subtypes, showed significant associations with Ktrans, kep, vp, and IAUGCBN90 on DEC MRI, with relatively smaller values in the former. The subtype grouping was significantly associated with D, with relatively less restricted diffusion in subtypes III and VI and PAM50 subtypes luminal A and normal-like. CONCLUSION: DCE MRI and IVIM parameters may identify molecular subtypes of breast cancers with a different vascular normalization gene expression.

Mucormycosis after Coronavirus disease 2019 infection in a heart transplant recipient - Case report and review of literature.

Mucormycosis is an invasive fungal infection (IFI) due to several species of saprophytic fungi, occurring in patients with underlying co-morbidities (including organ transplantation). During the ongoing Coronavirus disease 2019 (COVID-19) pandemic, there have been increasing reports of bacterial and fungal co-infections occurring in COVID-19 patients, including COVID-19 associated pulmonary aspergillosis (CAPA). We describe a case of mucormycosis occurring after COVID-19, in an individual who received a recent heart transplant for severe heart failure. Two months after heart transplant, our patient developed upper respiratory and systemic symptoms and was diagnosed with COVID-19. He was managed with convalescent plasma therapy and supportive care. Approximately three months after COVID-19 diagnosis, he developed cutaneous mucormycosis at an old intravascular device site. He underwent extensive surgical interventions, combined with broad-spectrum antifungal therapy. Despite the aggressive therapeutic measures, he died after a prolonged hospital stay. In this case report, we also review the prior well-reported cases of mucormycosis occurring in COVID-19 patients and discuss potential mechanisms by which COVID-19 may predispose to IFIs. Similar to CAPA, mucormycosis with COVID-19 may need to be evaluated as an emerging disease association. Clinicians should be vigilant to evaluate for invasive fungal infections such as mucormycosis in patients with COVID-19 infection.

An Unusual Case of Streptococcus anginosus Endocarditis in a Healthy Host With Bicuspid Aortic Valve.

Streptococcus anginosus group (SAG) is a subgroup of viridans streptococci and can be found ubiquitously in normal human flora. SAG is known to form invasive pyogenic infection when it becomes pathogenic. Yet, SAG is a very rare cause of endocarditis, and there is a dearth of case reports on this topic. We present a rare case of native bicuspid aortic valve endocarditis secondary to S. anginosus that caused aortic insufficiency and ascending aortic aneurysm. To our knowledge, this is the first well-documented case report of community-acquired S. anginosus endocarditis on a bicuspid aortic valve in an immunocompetent patient. The patient first presented with cough that was likely due to bronchus irritation from a 5.5 x 5.2 cm ascending aortic aneurysm. He underwent aortic valve replacement with bovine bioprosthesis and ascending aortic aneurysm repairment and was treated with a two-week regimen of IV ceftriaxone and gentamicin followed by another four weeks of IV ceftriaxone. He was eventually discharged to a rehabilitation facility. SAG is usually susceptible to beta-lactam antibiotics. The prognosis of SAG infection is usually good, but progression to bacteremia carries a poor outcome.