Tuesday, April 13, 2021

Severe Referred Shoulder Pain Following Revision Fundoplication From a Stich on the Diaphragm

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Am Surg. 2021 Apr 13:31348211011110. doi: 10.1177/00031348211011110. Online ahead of print.

ABSTRACT

Complications following fundoplication surgery for hiatal hernias are rare. Herein, we present the case of a 61-year-old woman who underwent a Nissen fundoplication, complicated by dysphagia, and a revision modified Toupet fundoplication for a hiatal hernia, after which she began to experience severe prandial referred left shoulder pain that was refractory to medical management. We hypothesized that a diaphragmatic suture placed during the revision fundoplication could be the source of the pain, and we elected to remove the suture, resulting in resolution of the pain. This pain remained resolved at the most recent follow-up on postoperative week six, and the patient had no further concerns.

PMID:33847159 | DOI:10.1177/00031348211011110

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Free from Dysphagia? A Test Battery to Differentiate Between Mild and No Dysphagia

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Dysphagia. 2021 Apr 12. doi: 10.1007/s00455-021-10295-3. Online ahead of print.

ABSTRACT

Assessing mild oropharyngeal dysphagia (OD) raises the question where to draw the line between normal and pathological swallowing. There is a lack of clinical test methods appropriate in the subacute phase of recovery from dysphagia following stroke and other brain injuries. The aim of this pilot study was to investigate the diagnostic accuracy of a new test battery, called the Swallow Battery (SwaB), in relation to Fiberoptic Endoscopic Evaluation of Swallowing (FEES). SwaB consists of the validated tests Repetitive Saliva Swallowing Test (RSST), Timed Water Swallowing Test (TWST) and parts of the Test of Masticating and Swallowing Solids (ToMaSS). Nineteen adult patients with acquired brain injury who were enrolled in a rehabilitation programme underwent the SwaB and a FEES, both resulting in a pass or fail outcome. The pass or fail results were based o n RSST's and TWST's suggested cutoffs, normative values of ToMaSS and on established rating scales used for FEES. The SwaB's ability to predict FEES results was 74% according to a binary logistic regression analysis, with a 92% correct prediction of fail results and 33% correct prediction of pass results. The ToMaSS was sensitive to small changes in eating ability, failing 13 out of 19 patients using 95% CI normative values as cutoff, including patients with a passed FEES. Alternative cutoffs were therefore suggested, depending on purpose of dysphagia assessment. The results of this study indicate that the SwaB may be a useful tool when assessing mild dysphagia following brain injury. Further studies of SwaB's validity and clinical utility are suggested.

PMID:33846833 | DOI:10.1007/s00455-021-10295-3

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Comparison of Patient-Reported and Caregiver-Reported Swallowing-Related Quality of Life in Parkinson's Disease

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Dysphagia. 2021 Apr 12. doi: 10.1007/s00455-021-10301-8. Online ahead of print.

ABSTRACT

This pilot study explored agreement on swallowing-related quality-of-life scores reported by individuals with Parkinson's disease (PD) and their caregivers. Thirty-six patient-caregiver pairs completed the Swallowing Quality of Life Questionnaire (SWAL-QOL) using an online survey format. Additional background and clinical information was ascertained. A Wilcoxon signed-rank test was completed to compare the means of scores between individuals with PD and caregivers. Factors potentially influencing SWAL-QOL scores (age, employment status, sex, ethnicity, race, previous history of swallowing evaluation or treatment, caregiver concern about patient cognition, caregiver burden, and time since onset of disease) were explored using Spearman Coefficient Correlation tests. The Holm-Bonferroni method was used to adjust for multiple comparisons. Results did not reve al significant differences in SWAL-QOL scores between individuals with PD and caregiver pairs. There was a moderate degree of reliability and agreement between paired patient and caregiver scores, with the average ICC measures being 0.598 (95% CI [358, 0.748]) (F(71, 72) = 2.451, p < 0.0001). After adjusting for multiple comparisons, caregiver burden was found to be the only significant factor associated with caregivers' reported scores. No significant influential factor on reported scores by individuals with PD was found. These pilot results suggest individuals with PD and their caregivers may report similar swallowing-related quality-of-life scores. Further, caregiver burden appears to be an influential factor for caregiver-reported scores. Future studies should investigate the clinical benefits of including caregiver SWAL-QOL ratings in assessments, either as a supplement to patient scores to identify discrepancies across the dyad or in place of patient scores if needed. Furth er, caregiver burden and its influence on dysphagia identification and management should be explored, with targeted interventions to manage caregiver burden.

PMID:33846834 | DOI:10.1007/s00455-021-10301-8

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Scientometric Analysis of Dental Implant Research over the Past 10 Years and Future Research Trends

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Background. We conducted a bibliometrics analysis to explore the recent trends in dental implant research which could help researchers have a clear grasp of the relevant research hotspots and prospects. Material and Methods. Altogether, 15,770 articles on dental implants, from January 1, 2010, to October 31, 2019, were selected from the Web of Science Core Collection. We used BICOMB software to extract the high-frequency MeSH terms and construct binary and coword matrices. gCLUTO software was used for biclustering and visual analysis, Ucinet 6 software for social network analysis, SCIMAT software for strategic diagram building, Citespace 5.5 software to form timeline visualization, and VOSviewer software, eventually, for bibliometrics cocitation network. Results. Altogether, 72 high-frequency keywords were extracted from the selected articles and 4 clusters and 7 subcategories were identified through biclustering analysis in the dental implant research field. The use of the strategic diagram also enabled us to find the research hotspot and development trends. Conclusions. The survival rate of dental implants and subsequent restoration have always been the core focus of research. Sinus floor elevation and guided bone regeneration are worthy of constant exploration owing to their reliability. With continuous improvement in technology, immediate loading could become a future research hot spot.
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Fisetin Attenuates Lipopolysaccharide-Induced Inflammatory Responses in Macrophage

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Several studies have reported the efficacy and safety of polyphenols in human health; however, the verification of their efficacy remains insufficient. The aim of this study was to examine whether fisetin, one of flavonoids prevalently present in fruits and vegetables, could suppress lipopolysaccharide- (LPS-) induced inflammatory responses in macrophages. LPS increased proinflammatory mRNA abundance (MCP 1, IL-1β, and iNOS) but were suppressed by fisetin. The increment of nitric oxide by LPS, an oxidative stress factor, was attenuated by fisetin. In addition, LPS-enhanced phosphorylation of mitogen-activated protein kinase (ERK and JNK) was reduced. Finally, fisetin attenuated the expression or activity of uPA, uPAR, MMP-2, and MMP-9, which are known as associated factors of macrophage recru itment or infiltration. In conclusion, fisetin is a promising therapeutic agent for macrophage-related inflammation diseases, like sepsis and atherosclerosis.
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Disulfiram inhibits inflammation and fibrosis in a rat unilateral ureteral obstruction model by inhibiting gasdermin D cleavage and pyroptosis

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Abstract

Background

As an inhibitor of GSDMD, Disulfiram (DSL) can significantly inhibit cell pyroptosis. Cell pyroptosis plays an important role in renal fibrosis.

Methods

HK-2 cells were induced by Lps and ATP to form a pyroptosis model, and the cells were treated by DSL. CCK-8 detected the cell activity. Immunofluorescence (IF) detected the GSDMD. ELISA detected the expression of inflammatory cytokines. Flow cytometry and Western blot detected cell apoptosis and pyroptosis. Collagen type I kit detected collagen secretion, and western blot detected fibrosis marker protein expression. Then, a rat model of unilateral ureteral obstruction (UUO) was established. HE staining detected the degree of renal tissue injury, and Masson staining detected the degree of fibrosis. What's more, the apoptosis level of tissue cells was detected by TUNEL. And the inflammatory factors in peripheral blood and renal tissue were detected by ELISA. Furthermore, the expression of GSDMD was detected by immunohistochemistry (IHC), and Western blot was used to detect the expression levels of apoptosis and pyroptosis-related proteins in tissues.

Results

It was found that DSL can inhibit the cell membrane perforation of GSDMD-N by inhibiting the cleavage of GSDMD, hence, it inhibited the occurrence of inflammation, cell pyroptosis, and the fibrosis of HK-2 cells. But if the cell has already undergone pyroptosis, DSL does not provide significant prevention. In vivo experiment, it further verified that pretreated DSL had inhibited renal fibrosis injury.

Conclusion

Disulfiram can inhibit inflammation and fibrosis in renal fibrosis rats by inhibiting GSDMD.

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Uncovering the prevalence and neural substrates of anhedonia in frontotemporal dementia

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Abstract
Much of human behaviour is motivated by the drive to experience pleasure. The capacity to envisage pleasurable outcomes and to engage in goal-directed behaviour to secure these outcomes depends upon the integrity of frontostriatal circuits in the brain. Anhedonia refers to the diminished ability to experience, and to pursue, pleasurable outcomes, and represents a prominent motivational disturbance in neuropsychiatric disorders. Despite increasing evidence of motivational disturbances in frontotemporal dementia (FTD), no study to date has explored the hedonic experience in these syndromes. Here, we present the first study to document the prevalence and neural correlates of anhedonia in FTD in comparison with Alzheimer's disease, and its potential overlap with related motivational symptoms including apathy and depression. A total of 172 participants were recruited, including 87 FTD, 34 Alzheimer's disease, and 51 healthy older control participa nts. Within the FTD group, 55 cases were diagnosed with clinically probable behavioural variant FTD, 24 presented with semantic dementia, and eight cases had progressive non-fluent aphasia (PNFA). Premorbid and current anhedonia was measured using the Snaith-Hamilton Pleasure Scale, while apathy was assessed using the Dimensional Apathy Scale, and depression was indexed via the Depression, Anxiety and Stress Scale. Whole-brain voxel-based morphometry analysis was used to examine associations between grey matter atrophy and levels of anhedonia, apathy, and depression in patients. Relative to controls, behavioural variant FTD and semantic dementia, but not PNFA or Alzheimer's disease, patients showed clinically significant anhedonia, representing a clear departure from pre-morbid levels. Voxel-based morphometry analyses revealed that anhedonia was associated with atrophy in an extended frontostriatal network including orbitofrontal and medial prefrontal, paracingulate and insular co rtices, as well as the putamen. Although correlated on the behavioural level, the neural correlates of anhedonia were largely dissociable from that of apathy, with only a small region of overlap detected in the right orbitofrontal cortices whilst no overlapping regions were found between anhedonia and depression. This is the first study, to our knowledge, to demonstrate profound anhedonia in FTD syndromes, reflecting atrophy of predominantly frontostriatal brain regions specialized for hedonic tone. Our findings point to the importance of considering anhedonia as a primary presenting feature of behavioural variant FTD and semantic dementia, with distinct neural drivers to that of apathy or depression. Future studies will be essential to address the impact of anhedonia on everyday activities, and to inform the development of targeted interventions to improve quality of life in patients and their families.
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Classification of neurological diseases using multi-dimensional cerebrospinal fluid analysis

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Abstract
Although cerebrospinal fluid (CSF) analysis routinely enables diagnosis of neurological diseases, it is mainly used for gross distinction between infectious, autoimmune inflammatory, and degenerative central nervous system (CNS) disorders. To investigate, whether a multi-dimensional cellular blood and CSF characterization can support the diagnosis of clinically similar neurological diseases, we analyzed 546 patients with autoimmune neuro-inflammatory, degenerative, or vascular conditions in a cross-sectional retrospective study. By combining feature selection with dimensionality reduction and machine learning approaches we identified pan-disease parameters altered across all autoimmune neuro-inflammatory CNS-diseases and differentiating them from other neurological conditions and inter-autoimmunity classifiers sub-differentiating variants of CNS-directed autoimmunity. Pan-disease as well as diseases-specific changes formed a continuum, reflecting clinical disease evolution. A validation cohort of 231 independent patients confirmed that combining multiple parameters into composite scores can assist classification of neurological patients. Overall, we show that an integrated analysis of blood and CSF parameters improves differential diagnosis of neurological diseases, thereby facilitating early treatment decisions.
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Photo-oxygenation by a biocompatible catalyst reduces amyloid-β levels in Alzheimer’s disease mice

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Abstract
Amyloid formation and the deposition of the amyloid-β peptide are hallmarks of Alzheimer's disease pathogenesis. Immunotherapies using anti-amyloid-β antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer's disease by enhancing microglial clearance of amyloid-β peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-β via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-β from the brains of living Alzheimer's disease model mice, and enhances the microglial degradation of amyloid-β peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-β strategy in Alzheimer's disease, which is compatible with immunotherapy.
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Phase 2 multicenter study of enzalutamide in metastatic castration resistant prostate cancer to identify mechanisms driving resistance

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Purpose: Enzalutamide is a second-generation androgen receptor (AR) inhibitor which has improved overall survival (OS) in metastatic castration resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase 2 multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. Results: 65 patients initiated treatment, of whom 22 (33.8%) had receiv ed prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53) which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression versus 53.9% at baseline) and BRCA2 alterations (64.7% at progression versus 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR regulated-genes, and neuroendocrine markers at progression. Conclusions: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide highlighting importance of serial tumor sampling in CRPC.

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Targeted deep sequencing of bladder tumors reveals novel associations between cancer gene mutations and mutational signatures with major risk factors

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Purpose: Exome and whole-genome sequencing of muscle-invasive bladder cancer (BC) has revealed important insights into the molecular landscape; however, there are few studies of non-muscle invasive BC with detailed risk factor information. Experimental Design: We examined the relationship between smoking and other BC risk factors and somatic mutations and mutational signatures in bladder tumors. Targeted sequencing of frequently mutated genes in BC was conducted in 322 formalin-fixed paraffin-embedded bladder tumors from a population-based case-control study. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), evaluating mutations and risk factors. We used SignatureEstimation to extract four known single base substitution mutational signatures and Poisson regression to calculate risk ratios (RRs) and 95%CIs, evaluating signatures and risk factors. Results:Non-silent KDM6A mutations were more common in females than males (OR=1.83,95%CI:1.05-3.19). There was striking heterogeneity in the relationship between smoking status and established single base substitution signatures: current smoking status was associated with greater ERCC2-Signature mutations compared to former (p-value=0.024) and never smoking (RR=1.40, 95% CI: 1.09-1.80, p-value=0.008); former smoking was associated with greater APOBEC-Signature13 mutations (p-value=0.05); and never smoking was associated with greater APOBEC-Signature2 mutations (RR=1.54, 95% CI: 1.17-2.01, p-value=0.002). There was evidence that smoking duration (the component most strongly associated with BC risk) was associated with ERCC2-Signature mutations and APOBEC-Signature13 mutations among current (p-trend=0.005) and former smokers (p=0.0004), respectively. Conclusions: These data quantify the contribution of BC risk factors to mutational burden and suggest different signature enrichments among never, former, and current smokers.< /p>

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