Non-selective dampening of the host immune response after hepatitis C clearance and its association with circulating chemokine and endotoxin levels.

BACKGROUND & AIMS: Direct-acting antiviral (DAA) therapy has revolutionized treatment for the hepatitis C virus (HCV). While DAA therapy is common, little is known about the intrahepatic immunological changes after sustained virologic response (SVR). We aim to describe transcriptional alterations of the gut microbiome and the liver after SVR. METHODS: Twenty-two HCV patients were evaluated before and 9 months after 12 weeks of sofosbuvir/velpatasvir treatment. All achieved SVR. A liver biopsy, portal blood (direct portal vein cannulation), peripheral blood and stool samples were obtained. RNA-seq and immunofluorescent staining were performed on liver biopsies. RNA-seq and 16S rRNA metagenomics were performed on stool. RESULTS: Differential expression within liver transcription showed 514 downregulated genes (FDR q < .05; foldchange > 2) enriched in inflammatory pathways; of note, GO:0060337, type 1 IFN signalling (p = 8e-23) and GO:0042742, defence response to bacterium (p = 8e-3). Interestingly, microbial products increased in the portal blood and liver after SVR. Due to the increase in microbial products, the gut microbiome was investigated. There was no dysbiosis by Shannon diversity index or Bacteroides/Firmicutes ratio. There was a differential increase in genes responsible for bacterial lipopolysaccharide production after SVR. CONCLUSIONS: The decrease in the antiviral interferon pathway expression was expected after SVR; however, there was an unanticipated decrease in the transcription of genes involved in recognition and response to bacteria, which was associated with increased levels of microbial products. Finally, the alterations in the function of the gut microbiome are a promising avenue for further investigation of the gut-liver axis, especially in the context of the significant immunological changes noted after SVR.

Clinical consensus guideline on the management of phaeochromocytoma and paraganglioma in patients harbouring germline SDHD pathogenic variants.

Patients with germline SDHD pathogenic variants (encoding succinate dehydrogenase subunit D; ie, paraganglioma 1 syndrome) are predominantly affected by head and neck paragangliomas, which, in almost 20% of patients, might coexist with paragangliomas arising from other locations (eg, adrenal medulla, para-aortic, cardiac or thoracic, and pelvic). Given the higher risk of tumour multifocality and bilaterality for phaeochromocytomas and paragangliomas (PPGLs) because of SDHD pathogenic variants than for their sporadic and other genotypic counterparts, the management of patients with SDHD PPGLs is clinically complex in terms of imaging, treatment, and management options. Furthermore, locally aggressive disease can be discovered at a young age or late in the disease course, which presents challenges in balancing surgical intervention with various medical and radiotherapeutic approaches. The axiom-first, do no harm-should always be considered and an initial period of observation (ie, watchful waiting) is often appropriate to characterise tumour behaviour in patients with these pathogenic variants. These patients should be referred to specialised high-volume medical centres. This consensus guideline aims to help physicians with the clinical decision-making process when caring for patients with SDHD PPGLs.

Synchronous glioblastoma and brain metastases: illustrative case.

BACKGROUND: Radiosurgical treatment of brain metastases is usually performed without brain tissue confirmation. While it is extremely rare for glioblastoma to develop concurrently in patients with brain metastases, they can look radiographically similar, and recognition is important because it alters management and prognosis. The synchronous presence of brain metastases and glioblastoma has not been published to date in the literature, making this a rare illustrative case. OBSERVATIONS: A 70-year-old female had lung biopsy-proven metastatic lung adenocarcinoma and multiple brain metastases. Her treatment course included initial carboplatin, pemetrexed, and bevacizumab followed by maintenance nivolumab, and she underwent stereotactic radiosurgery to the multiple brain metastases. During interval radiological surveillance, one lesion in the right temporal lobe was noted to slowly progress associated with development of significant perilesional edema causing midline shift despite repeated stereotactic radiosurgical treatments. Biopsy of this lesion revealed glioblastoma, IDH wildtype. LESSONS: Glioblastomas and brain metastases have similar radiological features, so the possibility of incorrect diagnosis needs to be considered for all lesions with interval growth poststereotactic radiosurgery. Biopsy and/or resection/laser ablation should be considered prior to reirradiation.

Multidisciplinary Programed Learning Simulation to Improve Visual Blood Loss Estimation for Obstetric Trauma Scenarios.

INTRODUCTION: We designed and implemented a Programmed Learning Simulation (PLS) exercise depicting obstetric scenarios of hemorrhage to train anesthesiologists, ancillary staff, and surgeons to accurately estimate blood loss visually. We then measured the efficacy of this exercise in a clinical setting. METHODS: We conducted a prospective study to assess the effect of implementing a PLS exercise on quantification of blood loss in an operative setting. The PLS exercise consisted of 13 simulation stations of varying quantities of simulated blood loss paired with standardized objects of known volume. Eighty-eight individuals participated including attending physicians, residents, medical students, and ancillary staff participated in this study. The PLS was part of regularly scheduled continuing medical education activities; thus, the sampling used was non-randomized convenience method. The percent error was calculated for each of the 13 stations. A subgroup analysis was performed to assess the effect of the years of experience, size of hemorrhage, and occupation on accuracy. Univariate analyses for continuous variables were compared using a one-way ANOVA test. For the comparison of the three groups (years of experience and size of hemorrhage), a p-value of <0.02 was considered statistically significant and for 5-way comparison (professional grouping) a p <0.01 was considered significant after application of the Bonferroni correction (α=0.05). (Part A). To determine the effect of PLS in a clinical setting, the percent error of blood loss estimation for cesarean deliveries during the two-month period after the PLS exercise was compared to the two-month period immediately prior to using the student's t-test with p<0.05 as significant (Part B). Statistical analysis was performed using International Business Machine, Statistical Package for the Social Sciences, Version 26.0 (IBM SPSS). RESULTS: During Part A, the baseline performance of the participants was evaluated during the PLS activity. The PLS data showed no significant difference in absolute value of mean percent error estimation (standard deviation) across professions: student 63.61% (69.74), ob/gyn 56.91% (47.72), ancillary 62.15% (77.90), general/trauma surgeon 66.70% (65.06), anesthesia 61.51% (63.12). (p = 0.681), or levels of experience 0-5: 62.21% (60.06), 6-10 years: 56.22% (52.66), greater than 10 years: 61.89% (71.89) (p = 0.831). However, mean percent error of estimation was higher when participants estimated smaller samples 77.7% (104.73) compared to either medium 56.8% (49.06) or large 57.9% (46.19) samples (p<0.001). For Part B, 179 cesarean deliveries occurred during the pre-intervention period and 193 occurred during the post-intervention period. Mean error in provider estimation of blood loss significantly improved from 47% (68.51) pre-intervention to 31% (32.70) post-intervention (p=0.009). CONCLUSION: We believe our described PLS activity was effective in teaching techniques for visual blood loss estimation. This was reflected by improved competency in a clinical setting, demonstrated by more accurate visually estimated blood loss during the period immediately following simulation activity compared to a prior time frame. Further research is needed to assess the impact of simulation activities on patient outcomes, such as utilization of blood products and patient morbidity.

Post-COVID Care Center to Address Rehabilitation Needs in COVID-19 Survivors: A Model of Care.

The severe acute respiratory syndrome coronavirus 2019 pandemic surge left a large cohort of patients vulnerable to cardiopulmonary, neurological, and psychiatric complications. This post-COVID Care center was established to identify patients with disease sequalae and deliver early multidisciplinary rehabilitation services. The evaluation included comprehensive history and physicals, screening tests, labs, and imaging to determine appropriate specialist referrals. After a 6-month period, 278 unique referrals were made to address symptoms reported by 114 patients in specialities including pulmonology, cardiology, and psychiatry. This framework allowed for individualized patient treatment and monitoring of disease after the acute phase of infection. This study highlights the substantial physical and psychosocial impact a coronavirus disease 2019 infection has on patients' long-term trajectory and emphasizes the need for early targeted rehabilitation Post-COVID Care centers. As the world transitions into the chronic phase of this pandemic, this model of care will provide a framework to improve the quality of health care delivery.

Chronic Atypical Depression as an Early Feature of Pituitary Adenoma: A Case Report and Literature Review.

Pituitary adenomas are often diagnosed as incidental findings on brain imaging. We present the case of a 52-year-old African American female patient with long standing depressed mood prior to the incidental finding of a pituitary adenoma. We explore the possibility of certain mood symptoms prompting an early diagnosis of pituitary adenoma.

On Neuropsychiatric Manifestations of Basal Ganglia Injury: A Report of Three Cases and Literature Review.

The basal ganglia have been considered to primarily play a role in motor processing. A growing body of theoretical and clinical evidence shows that in addition to the motor functions the basal ganglia play a key role in perceptual and visual disturbances. This role may be evident in patients with basal ganglia pathology and subsequent manifestation of symptoms that include cognitive, perceptual, and affective disturbances. We present three cases with basal ganglia pathology that demonstrate affective and psychotic symptoms. Two of the cases presented with late onset psychotic disturbances suggesting likely neurological etiologies. The third case presented with treatment refractory psychosis and symptoms that are rare for a diagnosis of schizophrenia. The role of incidental bilateral basal ganglia calcifications in all the cases is discussed. A review of current literature highlighting various neuropsychiatric manifestations of basal ganglia pathologies in various patients with psychiatric symptoms is presented.

Neuropsychiatric Manifestations of Partial Agenesis of the Corpus Callosum: A Case Report and Literature Review.

Agenesis of the corpus callosum is a rare congenital defect that has been linked to psychiatric disorders, cognitive deficits, learning disabilities, and developmental delays. We present the case of a patient with partial agenesis of the corpus callosum who exhibits depressed mood, transient loss of memory, and history of cognitive, social, and behavioral disturbances that developed during his childhood. Recent and pertinent literature was reviewed and the agenesis of the corpus callosum and its associated neuropsychiatric manifestations are discussed.

Inflammatory pathways in alcoholic steatohepatitis.

Inflammatory processes are primary contributors to the development and progression of alcoholic steatohepatitis (ASH), with severe alcoholic hepatitis characterised by non-resolving inflammation. Inflammation in the progression of ASH is a complex response to microbial dysbiosis, loss of barrier integrity in the intestine, hepatocellular stress and death, as well as inter-organ crosstalk. Herein, we review the roles of multiple cell types that are involved in inflammation in ASH, including resident macrophages and infiltrating monocytes, as well as other cell types in the innate and adaptive immune system. In response to chronic, heavy alcohol exposure, hepatocytes themselves also contribute to the inflammatory process; hepatocytes express a large number of chemokines and inflammatory mediators and can also release damage-associated molecular patterns during injury and death. These cellular responses are mediated and accompanied by changes in the expression of pro- and anti-inflammatory cytokines and chemokines, as well as by signals which orchestrate the recruitment of immune cells and activation of the inflammatory process. Additional mechanisms for cell-cell and inter-organ communication in ASH are also reviewed, including the roles of extracellular vesicles and microRNAs, as well as inter-organ crosstalk. We highlight the concept that inflammation also plays an important role in promoting liver repair and controlling bacterial infection. Understanding the complex regulatory processes that are disrupted during the progression of ASH will likely lead to better targeted strategies for therapeutic interventions.

Perivascular Adipocytes Store Norepinephrine by Vesicular Transport.

Objective- Perivascular adipose tissue (PVAT) contains an independent adrenergic system that can take up, metabolize, release, and potentially synthesize the vasoactive catecholamine norepinephrine. Norepinephrine has been detected in PVAT, but the mechanism of its protection within this tissue is unknown. Here, we investigate whether PVAT adipocytes can store norepinephrine using VMAT (vesicular monoamine transporter). Approach and Results- High-performance liquid chromatography identified norepinephrine in normal male Sprague Dawley rat aortic, superior mesenteric artery, and mesenteric resistance vessel PVATs, and retroperitoneal fat. Real-time polymerase chain reaction revealed VMAT1 and VMAT2 mRNA expression in the adipocytes and stromal vascular fraction of mesenteric resistance vessel PVAT. Immunofluorescence demonstrated the presence of VMAT1 and VMAT2, and the colocalization of VMAT2 with norepinephrine, in the cytoplasm of adipocytes in mesenteric resistance vessel PVAT. A protocol was developed to capture real-time uptake of Mini 202-a functional and fluorescent VMAT probe-in live rat PVAT adipocytes. Mini 202 was taken up by freshly isolated and differentiated adipocytes from mesenteric resistance vessel PVAT and adipocytes from thoracic aortic and superior mesenteric artery PVATs. In adipocytes freshly isolated from mesenteric resistance vessel PVAT, addition of rose bengal (VMAT inhibitor), nisoxetine (norepinephrine transporter inhibitor), or corticosterone (organic cation 3 transporter inhibitor) significantly reduced Mini 202 signal. Immunofluorescence supports that neither VMAT1 nor VMAT2 is present in retroperitoneal adipocytes, suggesting that PVAT adipocytes may be unique in storing norepinephrine. Conclusions- This study supports a novel function of PVAT adipocytes in storing amines in a VMAT-dependent manner. It provides a foundation for future studies exploring the purpose and mechanisms of norepinephrine storage by PVAT in normal physiology and obesity-related hypertension.

Cladophialophora Bantiana : A Rare Intracerebral Fungal Abscess-Case Series and Review of Literature.

Background Intracerebral Cladophialophora bantiana may carry up to a 70% mortality rate despite advances in surgical resection capabilities and the use of both systemic and intrathecal antifungal treatments. Objectives The authors examined a retrospective case series of two patients with intracerebral infection from the rare, neurotropic fungus Cladophialophora bantiana and conducted a literature review to evaluate optimal therapies. Patients/Methods At our institution, the patients' cases presented with raised intracranial features of headache, visual field cut, and/or memory loss, with a correspondingly wide variety of radiological differential diagnoses. It was the microbiological, histopathological, and genomic identification of C. bantiana that ensured targeted, individualized patient therapies. Results and Conclusions Successful treatment depends on obtaining a complete surgical resection, an accurate microbiological diagnoses for mold identification, and an effective long-term, personalized antifungal treatment. Close radiographic surveillance is necessary to ensure complete eradication of pheoid fungi.

Rapid-eye-movement sleep-predominant central sleep apnea relieved by positive airway pressure: a case report.

Central Sleep Apnea (CSA) is characterized by intermittent apneas and hypopneas during sleep that result from absent central respiratory drive. CSA occurs almost exclusively during non-rapid-eye-movement (NREM) sleep due to enhanced neuronal ventilatory drive during REM sleep that makes central apneas highly unlikely to form. A 45-year-old obese African American female presented with co-existing Obstructive Sleep Apnea (OSA) and CSA, not in the form of mixed or complex sleep apnea. Peculiarly, her CSA occurred only during rapid-eye-movement (REM) sleep, which is exceedingly rare. The patient's CSA was resolved when appropriate positive airway pressure (PAP) was prescribed. Our patient remains stable and has reported significant benefit from PAP usage. We offer possible neuro-physiological mechanisms herein, including enhanced loop gain and/or malfunction or malformation of the pre-Botzinger nucleus or other neurological process, that could explain the unique findings of this case.

3T3-L1 cells and perivascular adipocytes are not equivalent in amine transporter expression.

Rat perivascular adipose tissue (PVAT) stores, takes up, and releases norepinephrine (NE; Ayala-Lopez et al. (2014) Pharmacol Res Perspect 2, e00041). We hypothesized that 3T3-L1 adipocytes would exhibit similar behaviors and, thus, could serve as a model for PVAT adipocytes. However, basal levels of NE were not detected in 3T3-L1 adipocytes. While incubation of 3T3-L1 adipocytes with exogenous NE increased their cellular NE content, the mRNA expression of several NE transporters [e.g., norepinephrine transporter (NET)] were not detected in these cells. Similarly, we observed expression of the vesicular monoamine transporter 1 (VMAT1) in 3T3-L1 adipocytes by qRT-PCR and immunostaining, but stimulation of the cells with tyramine (100 µm) did not cause a significant release of NE. These studies support that 3T3-L1 adipocytes are not an adequate model of perivascular adipocytes for studying NE handling.

Atypical teratoid rhabdoid tumour of the spine: report of a case and literature review.

Atypical teratoid rhabdoid tumour (ATRT) is a rare and highly aggressive malignant neoplasm of the central nervous system (CNS), which occurs predominantly in children less than 2 years of age. There are less than 50 cases described in adult. We report a case of primary spinal ATRT in a 65-year-old male who presented to us with cauda equina syndrome. To the best of our knowledge, our patient is the (1) second oldest patient to be diagnosed with ATRT and only the third case of adult spinal ATRT report in the literature; (2) first reported case of CNS ATRT occurring in a patient with non-rhabdoid renal cancer; (3) first adult patient of ATRT to present with cauda equina syndrome.

The unique case of foot drop secondary to a large ovarian cyst.

We describe the unique case of a 58-year-old woman who presented with right leg radiculopathy caused by an ovarian cyst mimicking lumbar pathology. A review of the literature shows that this is a rare case where a histologically confirmed benign ovarian cystadenoma (of indeterminate type) is shown to cause foot drop and radiculopathy.

The Isadora syndrome: a case report of cervical, oesophageal and tracheal transection in a go-karting accident.

We report a case of cervical spine, tracheal and oesophageal trauma from a go-karting injury caused by the patient's scarf catching in the vehicle's wheel. We discuss the significance of the pre-hospital and operative management of this potentially life-threatening injury by a multi-specialty surgical team. The importance of health and safety issues in recreational sports is highlighted in view of the increasing incidence of cervical spine trauma over past two decades.

A comparison of the outcome of aneurysmal subarachnoid haemorrhage before and after the introduction of an endovascular service.

There has been a rapid change from predominantly surgical to endovascular treatment of ruptured intracranial aneurysms giving the opportunity to assess change in patient outcome during this transition. We identified and followed 139 patients with subarachnoid haemorrhage (SAH) treated in the year prior to (group 1) and following (group 2) the introduction of an endovascular service in a retrospective, cross-sectional study. A total of 78.7% of patients in group 1 underwent surgical treatment, 10.7% underwent endovascular treatment and 10.7% received no treatment, whereas patients in group 2 received 29.7%, 65.7% and 4.7%, respectively. MRS scores were obtained in 91% of patients in group 1 and in 89% of patients in group 2. A total of 30.7% and 24.0% of patients had a poor outcome in groups 1 and 2 respectively (p=0.34). The overall change in the management of ruptured cerebral aneurysms in the post-International Subarachnoid Aneurysm Trial (ISAT) era has not significantly changed cross-sectional outcome, although absolute differences appear to reflect difference in outcome noted in the ISAT.