CD4+CD57+ senescent T cells as promoters of systemic lupus erythematosus pathogenesis and the therapeutic potential of senolytic BCL-2 inhibitor.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune-mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B-lymphoma-2 (BCL-2) family and interferon-induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL-15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL-2 family and ISGs. Further, treatment with ABT-263 (a senolytic BCL-2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L-PD-1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T-bet+ age-related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL-2 inhibitor ABT-263 may be the potential treatment in ameliorating lupus phenotypes.

Metronidazole-Induced Acute Cerebellitis in a Young Patient: Unusual Onset, Delayed Remission, and Characteristic Imaging Features.

Metronidazole-induced acute cerebellitis is an exceptionally rare condition resulting from severe adverse reactions to metronidazole, a medication generally employed in the management of infections caused by anaerobic microbes. Although neuropathy has been linked to metronidazole use, reports of acute cerebellitis are infrequent. The neurological effects associated with metronidazole can include weakness, dysarthria, postural instability, seizures, giddiness, vertigo, ataxia, confusion, encephalopathy, headaches, and tremors. The onset of cerebellitis can vary, occurring as early as one day or after several weeks of metronidazole treatment. This article presents a case of a young girl who presented to us with weakness in both upper and lower limbs, dysarthria, and postural instability after exposure to 12 grams of metronidazole (suicidal, 30 tablets of 400 mg). With the above-mentioned complaints, the patient was advised of magnetic resonance imaging of the brain, which showed the features of cerebellitis.

Disrupting B and T cell Collaboration in Autoimmune Disease: T cell engagers versus CAR T cell therapy?

B and T cells collaborate to drive autoimmune disease (AID). Historically, B and T cell (B-T cell) co-interaction was targeted through different pathways such as alemtuzumab, abatacept, and dapirolizumab with variable impact on B cell depletion (BCD), whereas the majority of patients with AID including rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and organ transplantation benefit from targeted BCD with anti-CD20 monoclonal antibodies such as rituximab, ocrelizumab or ofatumumab. Refractory AID is a significant problem for patients with incomplete BCD with a greater frequency of IgD-CD27+ switched memory B cells, CD19+CD20- B cells and plasma cells that are not directly targeted by anti-CD20 antibodies, whereas most lymphoid tissue plasma cells express CD19. Furthermore, B-T cell collaboration is predominant in lymphoid tissues and at sites of inflammation such as the joint and kidney, where BCD may be inefficient, due to limited access to key effector cells. In the treatment of cancer, chimeric antigen receptor (CAR) T cell therapy and T cell engagers (TCE) that recruit T cells to induce B cell cytotoxicity have delivered promising results for anti-CD19 CAR T cell therapies, the CD19 TCE blinatumomab and CD20 TCE such as mosunetuzumab, glofitamab or epcoritamab. Limited evidence suggests that anti-CD19 CAR T cell therapy may be effective in managing refractory AID whereas we await evaluation of TCE for use in non-oncological indications. Therefore, here, we discuss the potential mechanistic advantages of novel therapies that rely on T cells as effector cells to disrupt B-T cell collaboration toward overcoming rituximab-resistant AID.

Navigating the Complexity of Scoring Systems in Sepsis Management: A Comprehensive Review.

This comprehensive review navigates the intricate landscape of sepsis scoring systems, aiming to provide healthcare professionals and researchers with a nuanced understanding of their role in contemporary sepsis management. Beginning with a succinct overview of sepsis, the review emphasizes the significance of scoring systems in standardizing assessments and guiding clinical decision-making. Through a detailed analysis of prominent systems such as SOFA, APACHE, and qSOFA, the review delineates their unique attributes, strengths, and limitations. The implications for sepsis management and patient outcomes are discussed, highlighting the potential for these tools to enhance early detection and intervention. The review concludes with a compelling call to action, urging healthcare professionals to integrate scoring systems into routine practice and researchers to explore novel approaches. By synthesizing current knowledge and addressing future directions, this review serves as a valuable resource for those seeking clarity and guidance in the dynamic landscape of sepsis management.

Post-burn Cervicofacial Necrotizing Fasciitis With Diabetic Ketoacidosis: A Report of a Case With a Favorable Outcome.

Post-burn necrotizing fasciitis (PBNF) is a serious and potentially life-threatening infection that occurs after a burn injury. It is characterized by rapid destruction of soft tissue and muscle and is usually caused by a bacterial infection. Diabetic ketoacidosis (DKA) is another serious complication of diabetes, which can occur when the body does not have enough insulin to break down glucose for energy. This causes the body to start breaking down fat for energy instead, leading to various complications. The present study discusses the association between PBNF and DKA in a patient with diabetes. Here is a case of a post-auricular abscess and a precipitated DKA. The abscess was located near the site of the previous burn injury that happened 20 years ago and was believed to have developed as a result of thick scar tissue. The patient was given adequate hydration, intravenous antibiotics, and insulin therapy. However, the abscess continued to grow with increasing insulin requirements and the patient underwent incision and drainage to remove the infected tissue, and an aggressive debridement was carried out. Thus, this case highlights the importance of closely monitoring blood sugar levels in patients with a history of burn injury and diabetes, as well as the potential for infections to precipitate DKA. Timely intervention, including incision and drainage, can lead to successful resolution of symptoms and improved outcomes.

Beyond the Shadows: Unravelling the Menace of Methanol-Induced Posterior Reversible Encephalopathy Syndrome.

Posterior reversible encephalopathy syndrome (PRES) is a clinical-radiological illness characterized by neurological symptoms and reversible changes in neuroimaging. We discuss the case of a 45-year-old patient with an alcohol use disorder who presented with an altered mental state in the emergency room. Home-made alcohol, known to contain significant quantities of methanol, was recently consumed in excess by the said patient. The diagnosis of PRES was supported by magnetic resonance imaging (MRI), which showed bilateral hyperintense regions in the temporo-occipital lobes and diffuse cerebral edema. The development of PRES and chronic alcoholism, as well as binge drinking and possible endothelial dysfunction, are all highlighted in this case study. For individuals with PRES, early identification and adequate care are essential for reducing complications and improving outcomes.

Pantothenate Kinase-Associated Neurodegeneration (PKAN) With Concomitant Blepharospasm: Unveiling a Clinical Enigma.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare and complex neurodegenerative disorder. It occurs due to mutations in the sequencing of the PANK2 gene. Here, we describe the case of a 22-year-old male patient who presented with severe blepharospasm; he had abnormal facial distortions, shaky limbs, rigid muscles, and a slow pace of movement, making a diagnosis tricky. Accumulation of iron in excessive amounts in the basal ganglia, a part of the brain that governs movement, is linked to PKAN. In this case, the "eye of the tiger" indication, a distinctive pattern only seen by MRI, supported PKAN. The anticholinergic medications helped him alleviate his symptoms to some extent, but he still had some degree of impairment. This instance emphasizes the mysterious character of PKAN and the significance of keeping an eye out for unusual symptoms in neurodegenerative conditions. This case report emphasizes the significance of recognizing unexpected effects that brain disorders can have on people's lives and calls for increased clinician awareness and understanding.

A 10-Year Retrospective Review of the Histology of Symptomatic and Asymptomatic Unilateral Nasal Polyps.

Background The aim of this study was to determine the histological diagnosis of unilateral nasal polyps and to determine the prevalence of neoplastic pathologies. This study also assessed difference in pathologies whether patients presented symptomatically or were asymptomatic (if they had a mass found incidentally for unrelated throat symptoms).  Method This was a 10-year retrospective study of patients undergoing unilateral nasal mass surgery between 2004 and 2014 at a UK district general hospital. We recorded patient demographics, laterality, histology, symptoms, clinical suspicion, and imaging findings. Results  123 patients were included who underwent unilateral surgery between 2004 and 2014 (male n=83, female n=40; mean age 56 years ± 19.5). The majority were of inflammatory origin (n=92; 74.8%). The most common benign neoplastic cause was inverted papilloma (n=19; 15.4%). A number of malignant neoplastic causes were also found, including: melanoma (n=3; 2.44%), olfactory neuroblastoma (n=2; 1.63%), and other non-inflammatory masses (n=7; 5.69%). 15 of these masses were found incidentally, with 14 being inflammatory, and one an olfactory neuroblastoma; therefore, 6.67% of our incidental unilateral nasal masses were found to be of neoplastic pathology. Conclusion This study's findings support the continued practice of routine biopsy of unilateral nasal masses for histological diagnosis, irrespective of whether they are symptomatic or found incidentally. The accuracy of both clinical suspicion and radiological suspicion on CT scans is not adequate to alter this practice.

Phenotyping of lymphoproliferative tumours generated in xenografts of non-small cell lung cancer.

Background: Patient-derived xenograft (PDX) models involve the engraftment of tumour tissue in immunocompromised mice and represent an important pre-clinical oncology research method. A limitation of non-small cell lung cancer (NSCLC) PDX model derivation in NOD-scid IL2Rgammanull (NSG) mice is that a subset of initial engraftments are of lymphocytic, rather than tumour origin. Methods: The immunophenotype of lymphoproliferations arising in the lung TRACERx PDX pipeline were characterised. To present the histology data herein, we developed a Python-based tool for generating patient-level pathology overview figures from whole-slide image files; PATHOverview is available on GitHub (https://github.com/EpiCENTR-Lab/PATHOverview). Results: Lymphoproliferations occurred in 17.8% of lung adenocarcinoma and 10% of lung squamous cell carcinoma transplantations, despite none of these patients having a prior or subsequent clinical history of lymphoproliferative disease. Lymphoproliferations were predominantly human CD20+ B cells and had the immunophenotype expected for post-transplantation diffuse large B cell lymphoma with plasma cell features. All lymphoproliferations expressed Epstein-Barr-encoded RNAs (EBER). Analysis of immunoglobulin light chain gene rearrangements in three tumours where multiple tumour regions had resulted in lymphoproliferations suggested that each had independent clonal origins. Discussion: Overall, these data suggest that B cell clones with lymphoproliferative potential are present within primary NSCLC tumours, and that these are under continuous immune surveillance. Since these cells can be expanded following transplantation into NSG mice, our data highlight the value of quality control measures to identify lymphoproliferations within xenograft pipelines and support the incorporation of strategies to minimise lymphoproliferations during the early stages of xenograft establishment pipelines.

Vestibular, Central, and Non-Vestibular Etiologies of Vertigo and Disequilibrium: A Rural Hospital-Based Cross-Sectional Comparative Analysis.

INTRODUCTION: Vertigo/dizziness is defined as disturbed postural awareness and could range from a feeling of sensation of spinning of self or surrounding. Dizziness or disturbed postural awareness is a common presentation in varying age groups. Vertigo has varied clinical presentations. Classically, there are four vertigo syndromes: vertigo, imbalance/disequilibrium, presyncope/lightheadedness, and psychogenic dizziness. The present study was conducted to examine the various etiologies involved in these syndromes and to help unmask the overlaps between them. This study also aimed to further classify the etiologies underlying these vertigo syndromes and overlaps into peripheral or vestibular, central, and non-vestibular. This would help develop a comprehensive management protocol for vertigo of any origin. METHODS: A prospective observational cross-sectional study was undertaken in a rural hospital in Central India. We studied patients with giddiness and categorized them into vertigo syndromes according to the site of origin of vertigo. We also compared overlaps in the presentation of vertigo. RESULTS: Out of the 80 patients that were studied, vertigo with disequilibrium was observed in 72.50% of the patients. Non-vestibular vertigo of cervicogenic origin was the common cause of vertigo seen in 36.25% of the patients occurring alone or in association with vestibular vertigo. Among patients with overlaps, vestibular vertigo with non-vestibular vertigo was the most common etiology observed in 89.65% of the patients with overlaps. CONCLUSION: The syndrome of "vertigo with disequilibrium" was the commonest presentation in the patients studied, followed by "vertigo syndrome" as an isolated symptom, not associated with "disequilibrium." Ours is probably the first study to report this observation of overlaps of two syndromes, with diagnostic implications.

In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS.

Introduction: Disturbances of energy metabolism contribute to the clinical manifestations of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Previously, we found that B cells from ME/CFS patients have an increased expression of CD24, a modulator of many cellular functions including those of cell stress. The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand was compared. Methods: CD24, the ectonucleotidases CD39 and CD73, the NAD-degrading enzyme CD38, and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor and costimulation with either T-cell-dependent or Toll-like-receptor-9-dependent agonists. The levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analyzed in relation to cell growth and immunophenotype. Results: Proliferating B cells from patients with ME/CFS showed a lower mitochondrial mass and a significantly increased usage of essential amino acids compared with those from HC, with a significantly delayed loss of CD24 and an increased expression of CD38 following stimulation. Discussion: The immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with the increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.

Management of severe and symptomatic primary hyperparathyroidism in the first trimester of unplanned pregnancy.

Summary: Primary hyperparathyroidism (PHP) is the most common aetiology for hypercalcaemia. The incidence of PHP in pregnant women is reported to be 8/100 000 population/year. It presents a threat to the health of both mother (hyperemesis, nephrolithiasis) and fetus (fetal death, congenital malformations, and neonatal severe hypocalcaemia-induced tetany). However, there is a lack of clear guidance on the management of primary hyperparathyroidism in pregnancy. In this study, we describe the case of a 26-year-old female patient who presented with severe hypercalcaemia secondary to PHP and underwent successful parathyroid adenectomy under local anaesthesia. Learning points: Primary hyperparathyroidism is a rare complication in pregnancy, but the consequences for mother and fetus can be severe. A perceived risk of general anaesthesia to the fetus in the first trimester has resulted in a general consensus to delay parathyroid surgery to the second trimester when possible - although the increased risk of fetal loss may occur before planned surgery. If the patient presents with severe or symptomatic hypercalcaemia, minimally invasive surgery under local anaesthetic should be considered regardless of the gestational age of the pregnancy.

Symptomatic Thyroglossal Duct Cyst Presenting With Synchronous and Localized Tongue Base Extranodal Mantle Cell Lymphoma. A Unique Case Report Demonstrating Lymphoma Colonization of Cyst Wall, Potentially Relating to a Persistent Embryological Foramen Cecum Remnant.

A 77-year-old male presented with a progressively enlarging midline neck mass. On further investigation he was found to have synchronous thyroglossal duct cyst and extranodal mantle cell lymphoma (MCL) localized to the base of tongue. Both pathologies were managed simultaneously with a surgical approach and the patient remained in clinical remission at the time of publication without indication for systemic oncological treatment. Histology revealed primary extranodal nonblastoid MCL forming a base of tongue mass, with colonization of the thyroglossal duct cyst. Lymphoma was also found in the epithelium of a crypt-like tract traversing one of the tongue base tumor sections. This tract was anatomically and histologically consistent with documented descriptions of the foramen cecum. This case report illustrates a previously undescribed temporal, clinical, and histological association between a base of tongue MCL and symptomatic thyroglossal duct cyst. We provide evidence for a potential causal relationship for the presentation of the thyroglossal duct cyst as a result of oropharyngeal MCL, in the absence of clinical and histological evidence of disseminated disease, directly infiltrating from its tongue base origin to the infrahyoid neck region, potentially via an embryologic foramen cecum remnant. We also highlight the crucial role of the histopathologist in multidisciplinary clinicopathological discussion in demonstrating how fundamental embryological and microanatomical relationships can unite apparently separate diseases.

Long-term persistence of rituximab in patients with rheumatoid arthritis: an evaluation of the UCL cohort from 1998 to 2020.

OBJECTIVES: B cell depletion therapy based on rituximab in patients with RA was pioneered at University College London Hospitals/University College London in 1998. The objective of this study was to evaluate long-term persistence of rituximab and identify factors associated with discontinuation of treatment. METHODS: Retrospective review of medical records from all rituximab-treated RA patients followed up in a dedicated clinic (1998-2020). Data collected included gender, disease duration, previous DMARDs, autoantibody status, age and concomitant therapy at first cycle, length of follow-up, and number of cycles. Drug survival and factors associated with drug discontinuation were analysed using Kaplan-Meier survival curves, log-rank test and Cox regression analysis. RESULTS: A total of 404 patients were included. Median disease duration and age at time of first rituximab cycle were 10 and 57 years, respectively. Median total follow-up was 55 months and median number of cycles five. 93.1% of patients were seropositive. Overall, 31.2% of patients stopped rituximab, with the largest reason for discontinuing being primary inefficacy (42.1%). Comparison of Kaplan-Meier curves showed that rituximab drug survival was lower in seronegative patients and in patients who had previously failed at least one biologic DMARD (bDMARD). Cox regression analysis revealed that rituximab discontinuation was associated with a greater number of previous bDMARDs. CONCLUSION: Many patients with RA achieve good control of their disease with repeated cycles of rituximab treatment. The most common reasons for treatment discontinuation were either primary or secondary inefficacy. Patients who were seronegative and who had previously failed other bDMARDs were more at risk of drug discontinuation.

Disparity in peripheral and renal B-cell depletion with rituximab in systemic lupus erythematosus: an opportunity for obinutuzumab?

OBJECTIVES: To investigate key factors that may contribute to the variability of rituximab-mediated peripheral and renal B cell depletion (BCD) in SLE. METHODS: We analysed: (i) CD19+ B cell counts in patients with SLE before and 1, 2, 3 and 6 months after treatment with rituximab, comparing them with RA patients; (ii) the presence of B cells in renal biopsies after rituximab therapy; (iii) whether the duration of BCD correlated with patient demographics and B cell expression of CD20 and FcγRIIb; and (iv) the effect of B cell activation factor (BAFF) on the efficiency of rituximab and obinutuzumab at inducing BCD in whole blood assays, in vitro. RESULTS: In SLE (n = 71), the duration of BCD was shorter compared with RA (n = 27). B cells were detectable in renal biopsy samples (n = 6) after treatment with rituximab in all patients with poor response while peripheral blood B cells remained low or undetectable in the same patients. There were no significant relationships between peripheral BCD and patient age, disease duration, serum C3 levels or the level of expression of B cell surface proteins CD20 and FcγRIIb. Obinutuzumab was more efficient than rituximab at inducing BCD in whole blood assays, regardless of excess BAFF. CONCLUSIONS: BCD in SLE is less efficient than in RA. Renal B cell presence following rituximab treatment was associated with poor outcomes. No significant relationships between any measured B cell related, clinical or laboratory parameters and the efficiency of BCD by rituximab was found. Obinutuzumab was superior to rituximab at inducing BCD.

Realist evaluation of Autism ServiCe Delivery (RE-ASCeD): which diagnostic pathways work best, for whom and in what context? Findings from a rapid realist review.

OBJECTIVES: Waiting times in the UK for an autism diagnostic assessment have increased rapidly in the last 5 years. This review explored research (including 'grey' literature) to uncover the current evidence base about autism diagnostic pathways and what works best, for whom and in what circumstances, to deliver high quality and timely diagnosis. DESIGN: We performed a Rapid Realist Review consistent with recognised standards for realist syntheses. We collected 129 grey literature and policy/guidelines and 220 articles from seven databases (January 2011-December 2019). We developed programme theories of how, why and in what contexts an intervention worked, based on cross comparison and synthesis of evidence. The focus was on identifying factors that contributed to a clearly defined intervention (the diagnostic pathway), associated with specific outcomes (high quality and timely), within specific parameters (Autism diagnostic services in Paediatric and Child & Adolescent Mental Health services in the UK). Our Expert Stakeholder Group, including representatives from local parent forums, national advocacy groups and clinicians, was integral to the process. RESULTS: Based on 45 relevant articles, we identified 7 programme theories that were integral to the process of diagnostic service delivery. Four were related to the clinical pathway: initial recognition of possible autism; referral and triaging; diagnostic model; and providing feedback to parents. Three programme theories were pertinent to all stages of the referral and diagnostic process: working in partnership with families; interagency working; and training, service evaluation and development. CONCLUSIONS: This theory informed review of childhood autism diagnostic pathways identified important aspects that may contribute to efficient, high quality and family-friendly service delivery. The programme theories will be further tested through a national survey of current practice and in-depth longitudinal case studies of exemplar services. TRIAL REGISTRATION NUMBER: NCT04422483.

Digital-driven service improvement during the COVID-19 pandemic.

COVID-19 brought a lot of children's routine clinical services in the UK to a complete halt in March 2020. The NHS had to radically change the way clinical services are provided with the rapid introduction of telemedicine, virtual consultations, and video conferencing facilities to support team working. This paper describes how Peterborough Child Development Centre rapidly redesigned the services with digital tools to continue offering neurodevelopmental and neurodisability services more virtually. We demonstrate how we adapted our approaches to assess and manage complex long-term conditions with improved quality and outcomes by using digital tools. The changes to the clinical processes and systems are here to stay beyond the COVID-19 pandemic and have the potential to revolutionise the services.

Day case superficial parotidectomy-does it work?

PURPOSE: To establish if day case superficial parotidectomy is feasible, safe and does not result in excess readmissions. METHOD: A retrospective review was carried out of all patients listed for superficial parotidectomy with day case intent by a single surgeon between January 2016 and December 2019 inclusively. The reasons for failure of same day discharge were established. Postoperative complications and readmissions were recorded. Our approach for a superficial parotidectomy typically includes the use of a 10Fr suction drain which is removed at 4 h postoperatively if the output is less than 30 ml. RESULTS: Ninety-one consecutive superficial parotidectomies listed for day case surgery were eligible for inclusion. Seventeen patients failed to be discharged on the same day and were admitted giving a day case success rate of 81%. Most of these (n = 9) occurred in the first year of adopting day case surgery. The most common reason to admit patients was a late finish (n = 8, 47%). Six patients (25%) were admitted due to anaesthetic complications. One patient had a surgical complication requiring admission. CONCLUSION: Our series demonstrates that day case superficial parotidectomy using a surgical drain is feasible, safe and does not result in an unacceptable readmission rate. In our experience, surgical complications are an uncommon cause for day case failure. The most common cause for day case failure was a late finish. Postoperative complications including bleeding, seroma/salivary collection and facial nerve palsy were in keeping with or better than those quoted in the literature.

Anti-CD20 monoclonal antibodies in Systemic Lupus Erythematosus.

Systemic Lupus Erythematosus (SLE) is an autoimmune inflammatory condition with a wide spectrum of disease manifestations and severities, resulting in significant morbidity and mortality. The aetiopathogenesis of SLE is complex. Young women and certain ethnicities are commonly affected, suggesting a significant hormonal and genetic influence. Diverse immunological abnormalities have been described. A characteristic abnormality is the presence of autoantibodies, implicating a central role for B cells in disease pathogenesis and/or perpetuation. Whilst conventional therapies have improved outcomes, a great unmet need remains. Recently, biological therapies are being explored. B-cell depletion therapy with rituximab has been in use off-label for nearly two decades. Inconsistent results between uncontrolled and controlled studies have raised doubts about its efficacy. In this review, we will focus on B cell abnormalities and the rationale behind B-cell depletion therapy with anti-CD20 monoclonal antibody (mAb), rituximab, will be explored including an evaluation of clinical and trial experience. Finally, we will discuss the mechanistic basis for considering alternative anti-CD20 mAbs.