Microbial Metabolite Trimethylamine N-Oxide Promotes Campylobacter jejuni Infection by Escalating Intestinal Inflammation, Epithelial Damage, and Barrier Disruption.

The interactions between Campylobacter jejuni , a critical foodborne cause of gastroenteritis, and the intestinal microbiota during infection are not completely understood. The crosstalk between C. jejuni and its host is impacted by the gut microbiota through mechanisms of competitive exclusion, microbial metabolites, or immune response. To investigate the role of gut microbiota on C. jejuni pathogenesis, we examined campylobacteriosis in the IL10KO mouse model, which was characterized by an increase in the relative abundance of intestinal proteobacteria, E. coli , and inflammatory cytokines during C. jejuni infection. We also found a significantly increased abundance of microbial metabolite Trimethylamine N-Oxide (TMAO) in the colonic lumens of IL10KO mice. We further investigated the effects of TMAO on C. jejuni pathogenesis. We determined that C. jejuni senses TMAO as a chemoattractant and the administration of TMAO promotes C. jejuni invasion into Caco-2 monolayers. TMAO also increased the transmigration of C. jejuni across polarized monolayers of Caco-2 cells, decreased TEER, and increased C. jejuni -mediated intestinal barrier damage. Interestingly, TMAO treatment and presence during C. jejuni infection of Caco-2 cells synergistically caused an increased inflammatory cytokine expression, specifically IL-1ß and IL-8. These results establish that C. jejuni utilizes microbial metabolite TMAO for increased virulence during infection.

Impact of post-procedure stenosis on outcomes of patients with severe intracranial stenosis treated with intracranial stent placement.

BACKGROUND: The optimal target post-procedure stenosis after percutaneous angioplasty and stent placement (PTAS) for intracranial stenosis is unknown. We determined the effect of post-procedure stenosis after intracranial PTAS on subsequent clinical events in patients with severe symptomatic intracranial stenosis. METHODS: We categorized the severity of post-procedure stenosis as '<30%', '30-49%', and '≥50%' among 207 patients who underwent PTAS in a multicenter randomized clinical trial. Outcomes included stroke or death within 72 hours and within 30 days, ipsilateral stroke beyond 30 days of treatment, and stroke or death within 30 days or stroke in the qualifying artery beyond 30 days (primary endpoint of the trial). Cox proportional hazards analysis was performed with adjustments for age, initial severity of stenosis, location of stenosis, and qualifying event. Kaplan-Meier curves were generated for the primary endpoint stratified by post-procedure stenosis with log-rank analysis. RESULTS: The severity of post-procedure stenosis was categorized as <30%, 30-49%, and ≥50% in 112, 73, and 22 patients, respectively. Compared with patients with post-procedure stenosis <30%, there was no difference in the risk of primary endpoint among patients with post-procedure stenoses of 30-49% (hazards ratio (HR) 0.85, 95% confidence interval (95% CI) 0.64 to 1.15) or those with ≥50% (HR 0.91, 95% CI 0.57 to 1.43). Log-rank analysis did not demonstrate a difference in rates of primary endpoint between groups stratified by post-procedure stenosis (P=0.70). CONCLUSION: In the absence of any benefit on short- and long-term outcomes, strategies to achieve a low severity of post-procedure stenosis among patients with severe intracranial stenosis may not be warranted.

Stagnant daily smoking prevalence between 2008 and 2019 among Black and Hispanic adults with serious psychological distress.

BACKGROUND: Racial/ethnic minority status and mental illness independently drive inequity in cigarette smoking and related morbidity. Racial/ethnic minority groups suffer a disproportionate burden of tobacco-related diseases. People with serious mental illness (SMI) smoke at up to 7 times the rate of the general population. There is a need to quantify smoking prevalence and trends among people at the intersection of both groups. METHODS: This study analyzes 2008-2019 data from the National Survey on Drug Use and Health. Linear time trends of daily smoking prevalence were assessed among people with serious psychological distress (SPD; marker for SMI) and people without SPD reporting White, Black, Hispanic, and Other race/ethnicity using logistic regression, with survey year as the predictor. Models with year-by-smoking status interaction terms and F-tests assessed differential time trends. RESULTS: The prevalence of daily smoking among people without SPD decreased over time among people reporting White (aOR=0.96, p<0.001), Black (aOR=0.96, p<0.001), Hispanic (aOR=0.95, p<0.001), and Other (aOR=0.97, p=0.002) race/ethnicity. Among people with SPD, the smoking prevalence decreased among people with White race/ethnicity (aOR=0.95, p<0.001), with no significant changes among people of Black, Hispanic, and Other race/ethnicity. CONCLUSIONS: Smoking among people with SPD who report Black and Hispanic race/ethnicity has not changed significantly in the past 11 years, despite decreasing among non-SPD and White groups. People who are Black/Hispanic and people with SPD struggle to quit smoking, which is amplified intersectionally. Tailored interventions may be a better mechanism to reduce barriers to smoking cessation in this population.

Neonatal Spontaneous Bilateral Posterior Fossa Chronic Subdural Hematoma and Obstructive Hydrocephalus with a Successful Outcome: A Case Report.

Background: Chronic supratentorial subdural hematoma is uncommon in neonates but accounts for most neurosurgical procedures in neonatal age. However, its occurrence in the posterior fossa is extremely rare. It can be caused by instrumental delivery, coagulation abnormality, hypoxic insult, and various structural abnormalities. Furthermore, spontaneous onset has been reported only in a few case reports. Case Presentation: A twenty-nine-day-old male neonate presented with failure to suck for three days duration associated with vomiting. Imaging showed bilateral posterior fossa chronic subdural hematoma and obstructive hydrocephalus. Bilateral burrhole craniostomy and hematoma evacuation was done which resulted in an excellent outcome. Conclusion: Posterior fossa chronic subdural hematoma is extremely rare in the neonatal period. It can be caused by various possible etiologic agents; however, rarely it can occur spontaneously. Management with suboccipital burrhole craniostomy and hematoma evacuation can result in a good outcome. Intraoperative monitoring and management with an experienced anesthesiology team are indispensable for a good outcome. Study Setting: Pediatrics neurosurgery ward, St Peter's Comprehensive Specialized Hospital, Addis Ababa, Ethiopia.

Lymph node targeted multi-epitope subunit vaccine promotes effective immunity to EBV in HLA-expressing mice.

The recent emergence of a causal link between Epstein-Barr virus (EBV) and multiple sclerosis has generated considerable interest in the development of an effective vaccine against EBV. Here we describe a vaccine formulation based on a lymph node targeting Amphiphile vaccine adjuvant, Amphiphile-CpG, admixed with EBV gp350 glycoprotein and an engineered EBV polyepitope protein that includes 20 CD8+ T cell epitopes from EBV latent and lytic antigens. Potent gp350-specific IgG responses are induced in mice with titers >100,000 in Amphiphile-CpG vaccinated mice. Immunization including Amphiphile-CpG also induces high frequencies of polyfunctional gp350-specific CD4+ T cells and EBV-specific CD8+ T cells that are 2-fold greater than soluble CpG and are maintained for >7 months post immunization. This combination of broad humoral and cellular immunity against multiple viral determinants is likely to provide better protection against primary infection and control of latently infected B cells leading to protection against the development of EBV-associated diseases.

Chronic Heel Pain Found to Be Diffuse Large B-cell Lymphoma of the Calcaneus.

Primary non-Hodgkin lymphoma of the bone is quite rare, accounting for less than 2% of all lymphomas in adults. We present a unique case of chronic left heel pain in a 34-year-old pregnant woman with a remote history of lower extremity trauma. Unresponsive to conservative treatment, advanced imaging showed an infiltrative soft tissue mass involving the calcaneus and surrounding soft tissues. Biopsy of the area confirmed the diagnosis of Stage I-AE diffuse large B-cell lymphoma. The patient underwent 20 localized radiation treatments to the left heel. Nine years after the diagnosis, the patient remains in remission without signs of disease recurrence. This case report demonstrates that atypical and less common causes of chronic heel pain should be considered in certain clinical scenarios, especially in those unresponsive to conservative treatment.

A Comparison of Thoracolumbar Injury Classification in Spine Trauma Patients Among Neurosurgeons in East Africa Versus North America.

Background In January 2021, we published findings evaluating the validity of thoracolumbar injury classification and biomechanical approach in the clinical outcome of operative and non-operative treatments. A notable result in our study was patients with unstable burst fractures received an Arbeitsgemeinschaft für Osteosynthesefragen System (AO) score that recommended conservative treatment compared to a Thoracolumbar Injury Classification and Severity Scale (TLICS) score that recommended surgical intervention. We designed a survey to determine reported differences in thoracolumbar injury classification, including the percentage of thoracolumbar spine fractures, type of classification system(s) used, use of classification system by board-certified neurosurgeons and neurosurgical residents, reliance on classification system to guide management, use of MRI in the evaluation of the posterior ligamentous complex, and readmission rate < 90 days at treating facilities. This study aims to determine which areas of neurosurgical practice in spine trauma patients differ among surgeons in North America and East Africa, including Ethiopia, Kenya, and Sudan. Multiple classification systems have been proposed to describe thoracolumbar spine injuries. We hypothesized that there would be marked variability in the classification systems used to evaluate thoracolumbar spine injury among neurosurgeons in North America and East Africa. Methods The survey consisted of seven questions and was sent to 440 neurosurgeons practicing on the continents of North America and East Africa. Results A total of 67 surgeons responded, 50 from North America and 17 from East Africa, including Ethiopia, Kenya, and Sudan. A significant percentage of African respondents reported a higher thoracolumbar spine fracture rate than respondents in North America (53% and 30%, respectively). Regarding the classification system used, 65% of surgeons in East Africa reported using TLICS, whereas 62% of surgeons in North America reported using Denis 3-column classification. For patients with spine trauma, surgeons in East Africa and North America reported a similar percentage of readmission <90 days (47% and 52%, respectively). Conclusion Our findings vary in spine trauma classification for American and East African patients and still highlight crucial areas for improvement due to patient load, education, and resource accessibility.

Atypical pulmonary presentation of Strongyloides stercoralis hyperinfection in a patient with philadelphia chromosome-positive acute lymphoblastic leukemia: Case report.

Strongyloides stercoralis is a soil-transmitted helminth endemic to tropical and subtropical regions and can be acquired due to parasite penetration through the skin. It can remain dormant in the gastrointestinal system for decades after the primary infection. In immunocompromised patients, this parasite can cause autoinfection with progression to hyperinfection syndrome. Here we report a unique case of pulmonary strongyloidiasis in a 32-year-old female, originally from Guatemala, with a significant clinical history of Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia diagnosed in 2019. The patient is status post chemotherapy with tyrosine kinase inhibitor plus hyper-CVAD regimen (Cyclophosphamide, Vincristine sulfate, Doxorubicin hydrochloride (Adriamycin), and Dexamethasone). History of drug-induced hyperglycemia and obesity was also noted. Her current chief complaint included dyspnea, tachycardia, and chest pain. Chest computerized tomography (CT) scan showed diffuse interstitial pulmonary edema with septal thickening, scattered ground-glass opacities, and small pericardial effusion. Due to normal ejection fraction, the differential diagnosis included non-cardiogenic pulmonary edema, pneumonitis secondary to chemotoxicity, and infection. She rapidly progressed to acute hypoxic respiratory failure, and a bronchoalveolar lavage study revealed numerous larvae consistent with Strongyloides hyperinfection. Further workup revealed eosinophilia with negative Strongyloides IgG antibody. Given the rarity of this infection in the United States and the patient's place of birth, acquired latent Strongyloides infection is favored as the initial source of infection. The reactivation of the infection process was most likely secondary to her chemotherapy treatment. Strongyloides hyperinfection diagnosis can be challenging to establish and entails a high level of suspicion. Cytology evaluation is an essential factor for diagnosis.

A Conservative Approach to the Treatment of a Rare Case of Cervical Spine Double Expressor Diffuse Large B-cell Lymphoma: A Case Report.

Non-Hodgkin's lymphomas are a group of lymphoid neoplasms, with diffuse large B-cell lymphoma (DLBCL) being the most common subtype. Genetic alterations involving c-MYC, BCL-2, and BCL-6 have been implicated in the pathogenesis of subtypes of DLBCL with poor prognostic implications. This case report demonstrates a retropharyngeal mass with extension through the bilateral neuroforamina into the epidural space and posterior elements of the cervical spine (C2-C3), for which biopsy revealed diffuse large B-cell lymphoma. Here we present a unique case as it provides a solution for the dilemma on how to treat a patient with a known prior malignancy (gastrointestinal [GI] melanoma) with a retropharyngeal mass with epidural extension (dumbbell-shaped tumor) with an inconclusive initial CT-guided needle-core biopsy. A CT-guided biopsy only yielded that the mass was neoplasm; we had a choice between attempting gross total resection of the mass or open biopsy. Attempting gross total resection would have entailed an anterior approach (transoral with possible odontoidectomy or endoscopic endonasal with possible odontoidectomy) along with posterior instrumentation and fusion from occiput to C3, which is a rather morbid procedure that would subject the patient to a decreased quality of life as well as risks of vascular injury, dysphagia, and infection. We elected to perform an open biopsy of the epidural component of the mass through a decompressive laminectomy, which allowed for decompression of the spinal cord as well as a sampling of the mass. This provided treatment for possible increasing epidural compression from the mass, as well as diagnostic tissue. A multidisciplinary team discussed the case and developed a treatment plan for the patient with systemic and intrathecal chemotherapy in combination with radiotherapy.

Tumor microenvironment in pancreatic ductal adenocarcinoma: Implications in immunotherapy.

Pancreatic ductal adenocarcinoma is one of the most aggressive and lethal cancers. Surgical resection is the only curable treatment option, but it is available for only a small fraction of patients at the time of diagnosis. With current therapeutic regimens, the average 5-year survival rate is less than 10% in pancreatic cancer patients. Immunotherapy has emerged as one of the most promising treatment options for multiple solid tumors of advanced stage. However, its clinical efficacy is suboptimal in most clinical trials on pancreatic cancer. Current studies have suggested that the tumor microenvironment is likely the underlying barrier affecting immunotherapy drug efficacy in pancreatic cancer. In this review, we discuss the role of the tumor microenvironment in pancreatic cancer and the latest advances in immunotherapy on pancreatic cancer.

B-cell lymphoma-associated hemophagocytic lymphohistiocytosis: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by an exaggerated but dysregulated immune response resulting in hyperinflammation, with a potential for progression to multiple organ dysfunction and failure. Infectious diseases, inflammatory disorders, malignancies and immunodeficiency syndromes are known triggers of HLH in adults. The present study reported the case of a middle-aged man with HLH triggered by B-cell lymphoma who was successfully treated with dexamethasone; etoposide, prednisone, vincristine, cyclophosphamide, hydroxy-doxorubicin and rituximab chemotherapy; and multiple intrathecal methotrexate with a good outcome.

The Effect of Thoracolumbar Injury Classification in the Clinical Outcome of Operative and Non-Operative Treatments.

This review assesses the validity of a biomechanical approach using finite element analysis in the Thoracolumbar Injury Classification and Severity Score System (TLICS) by addressing the "gray zone" decision discrepancy of thoracolumbar spinal injuries. A systematic review was performed using the keywords "Thoracolumbar Injury Classification" AND "finite element analysis of the spinal column" to evaluate the validity of the TLICS and finite element analysis of the thoracolumbar spinal column. Results were classified according to the main conclusions and level of evidence. Thirteen articles are included. Four of the articles evaluated the TLICS in comparison to other classification systems of thoracolumbar spinal injuries. A notable finding is that the TLICS had inconsistencies with other classification systems in the treatment of burst fractures without neurological deficits. One article evaluated the TLICS with the inclusion of magnetic resonance imaging (MRI) in the evaluation, which decreased the agreement between the suggested and actual treatment. Among the three finite element analysis studies, limited data have been published on the posterior ligamentous complex (PLC) status when an injury is suspected or indeterminate. The TLICS has been a reliable classification system in the management of single-column fractures and three-column injuries treated with surgical stabilization. Special attention to enhancing the TLICS classification system by eliminating the "gray zone" of a TLICS score of 4 is essential. Biomedical computational modeling evaluating the PLC status of indeterminate or injury suspected is needed to enhance the current TLICS system and to clarify the decision discrepancy in the "gray zone."

Rapid whole-blood assay to detect SARS-CoV-2-specific memory T-cell immunity following a single dose of AstraZeneca ChAdOx1-S COVID-19 vaccine.

OBJECTIVES: With the ongoing emergence of SARS-CoV-2 variants and potential to evade vaccine-induced neutralisation, understanding the magnitude and breadth of vaccine-induced T-cell immunity will be critical for the ongoing optimisation of vaccine approaches. Strategies that provide a rapid and easily translatable means of assessing virus-specific T-cell responses provide an opportunity to monitor the impact of vaccine rollouts in the community. In this study, we assessed whether our recently developed SARS-CoV-2 whole-blood assay could be used effectively to analyse T-cell responses following vaccination. METHODS: Following a median of 15 days after the first dose of the ChAdOx1-S (AstraZeneca®) vaccine, peripheral blood was isolated from 58 participants. Blood was incubated overnight with an overlapping set of spike protein peptides and assessed for cytokine production using a cytometric bead array. RESULTS: The majority of vaccine recipients (51/58) generated a T helper 1 response (IFN-γ and/or IL-2) following a single dose of ChAdOx1-S. The magnitude of the IFN-γ and IL-2 response strongly correlated in vaccine recipients. While the production of other cytokines was evident in individuals who did not generate IFN-γ and IL-2, they showed no correlation in magnitude, nor did we see a correlation between sex or age and the magnitude of the response. CONCLUSIONS: The whole-blood cytokine assay provides a rapid approach to assessing T-cell immunity against SARS-CoV-2 in vaccine recipients. While the majority of participants generated a robust SARS-CoV-2-specific T-cell response following their first dose, some did not, demonstrating the likely importance of the booster dose in improving T-cell immunity.

Kinase domain mutants of Bcr-Abl exhibit altered transformation potency, kinase activity, and substrate utilization, irrespective of sensitivity to imatinib.

Kinase domain (KD) mutations of Bcr-Abl interfering with imatinib binding are the major mechanism of acquired imatinib resistance in patients with Philadelphia chromosome-positive leukemia. Mutations of the ATP binding loop (p-loop) have been associated with a poor prognosis. We compared the transformation potency of five common KD mutants in various biological assays. Relative to unmutated (native) Bcr-Abl, the ATP binding loop mutants Y253F and E255K exhibited increased transformation potency, M351T and H396P were less potent, and the performance of T315I was assay dependent. The transformation potency of Y253F and M351T correlated with intrinsic Bcr-Abl kinase activity, whereas the kinase activity of E255K, H396P, and T315I did not correlate with transforming capabilities, suggesting that additional factors influence transformation potency. Analysis of the phosphotyrosine proteome by mass spectroscopy showed differential phosphorylation among the mutants, a finding consistent with altered substrate specificity and pathway activation. Mutations in the KD of Bcr-Abl influence kinase activity and signaling in a complex fashion, leading to gain- or loss-of-function variants. The drug resistance and transformation potency of mutants may determine the outcome of patients on therapy with Abl kinase inhibitors.

A Race for survival: can Bromus tectorum seeds escape Pyrenophora semeniperda-caused mortality by germinating quickly?

BACKGROUND AND AIMS: Pathogen-seed interactions may involve a race for seed resources, so that seeds that germinate more quickly, mobilizing reserves, will be more likely to escape seed death than slow-germinating seeds. This race-for-survival hypothesis was tested for the North American seed pathogen Pyrenophora semeniperda on seeds of the annual grass Bromus tectorum, an invasive plant in North America. In this species, the seed germination rate varies as a function of dormancy status; dormant seeds germinate slowly if at all, whereas non-dormant seeds germinate quickly. METHODS: Three experimental approaches were utilized: (a) artificial inoculations of mature seeds that varied in primary dormancy status and wounding treatment; (b) naturally inoculated undispersed seeds that varied in primary dormancy status; and (c) naturally inoculated seeds from the carry-over seed bank that varied in degree of secondary dormancy, habitat of origin and seed age. KEY RESULTS: In all three approaches, seeds that germinated slowly were usually killed by the pathogen, whereas seeds that germinated quickly frequently escaped. Pyrenophora semeniperda reduced B. tectorum seed banks. Populations in drier habitats sustained 50 times more seed mortality than a population in a mesic habitat. Older carry-over seeds experienced 30 % more mortality than younger seeds. CONCLUSIONS: Given the dramatic levels of seed death and the ability of this pathogen to reduce seed carry-over, it is intriguing to consider whether P. semeniperda could be used to control B. tectorum through direct reduction of its seed bank.