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Objective: To study unusual presentations of coronavirus-associated mucormycosis that are rarely seen in sinonasal mucormycosis cases. Method: The data of 400 rhino-orbito-cerebral mucormycosis patients admitted to Sawai Man Singh Hospital, Jaipur, from May 2021 to June 2021, were retrospectively collected. The diagnosis of mucormycosis was made by histological examination of biopsy samples. Results: Out of 400 patients, 62 had symptoms other than common symptoms of rhino-orbito-cerebral mucormycosis. Thirty-four patients had facial palsy, 19 complained of gum ulcers, 6 developed a cheek abscess, 2 complained of maggots in the nose along with common rhino-orbito-cerebral mucormycosis symptoms, and 1 had a cerebellar infarct. Conclusion: Mucormycosis is a disease with various presentations, and coronavirus-associated mucormycosis has added unusual presentations to the existing list of manifestations of rhino-orbito-cerebral mucormycosis. In this coronavirus disease era, mucormycosis should always be considered as a diagnosis in patients with these unusual presentations. [ABSTRACT FROM AUTHOR]

Treatment of proximal tibial defects is important to the survival of tibial prosthesis after total knee replacement. The objective of this finite element study was to determine a better understanding of the stresses produced by different treatment options for moderate uncontained type-2 defects. Methods analysed were the use of metal wedges, metal blocks, cement wedges, and cement blocks for the two defect angles 15 degrees and 30 degrees. The effect of a stem extension on the stress profiles was also analysed for each defect treatment and angle to establish the necessity of these extensions and consequent bone removal on the stability of the augments. Equivalent stresses in two regions of interest (ROIs) adjacent to the augments and shear stresses along the bone-cement interface of the defect were investigated. The lowest equivalent stresses were found in the metal block augment for both defect angles and ROIs. The highest equivalent stress in the ROIs and shear stress values along the bone-cement interface of the defect were found in the cement wedge augment model for both defect angles. Stem extensions were shown to increase equivalent stresses in the bone closer to the tibial stem but to decrease equivalent stresses closer to the cortical bone. The use of a stem extension significantly increased the shear stresses in the cement in all cases except in the metal block model. It is recommended that metal block augments are used without a stem extension in small-defect (i.e. peripheral defect angle of 15 degrees) total knee replacement procedures. [ABSTRACT FROM AUTHOR]

Loosening and migration of tibial prostheses have been identified as causes of early total knee replacement (TKR) failure. The problem is made more complex when defects occur in the proximal tibia compromising fixation and alignment. Clinical studies using metal augments have shown these to be an alternative to other means of defect treatment. Finite element (FE) analysis can be used to identify regions that may be prone to loosening and migration. In the current work, 3D FE models of TKR uncontained type-2 defects treated with block augments have been constructed and analysed. It has been shown that a metal augment is the most suitable. The use of bone cement (PMMA) to fill proximal defects is not considered suitable as stresses carried by the cement block exceed those of the fatigue limit of bone cement. It has been shown that the stresses in the proximal cancellous bone of block-augmented models are significantly below levels likely to cause damage due to overloading. Furthermore, the use of stem extensions has been shown to reduce the cancellous bone stresses in the proximal region thus increasing the likelihood of bone resorption. Given this, it is recommended that stem extensions are not required unless necessary to mitigate some other problem. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate margin positivity at apex utilizing preoperative magnetic resonance imaging [MRI], micro-ultrasound [MUS], prostate specific membrane antigen positron emission tomography PSMA PET] scan, biopsy location and intraoperative timing of deep venous complex [DVC] ligation during robot assisted radical prostatectomy [RARP]., Methods: Institution review board approved retrospective study underwent RARP between November 2022 to March 2024. All patients underwent preoperative MRI, MUS and PSMA PET scan. Patients underwent RARP using either standard DVC [done prior apical dissection] ligation or delayed DVC [after prostate removal] technique. All patients underwent intra operative frozen section analysis by an experienced genitourinary pathologist. Descriptive statistics were performed. Data analyzed using R software version 4.3.3., Results: Total 619 prostate cancer patients underwent RARP. Of these, 365 men underwent RARP using delayed DVC ligation technique and 254 men using standard DVC ligation technique. There was no statically significant difference in 2 groups on demographic parameters, MRI, MUS and PSMA-PET scan features. Sensitivity of MRI, MUS, PSMA-PET and prostate biopsy for detection of apical positive margin were 66%, 81%, 81% and 73% respectively. Specificity of MRI, MUS, PSMA-PET and prostate biopsy for detection of apical positive margin were 45%, 14%, 16% and 30% respectively. When all modalities are used accumulatively, apical cancer was missed only in 1% of cases., Conclusions: With proper preoperative understanding of apical lesion location, timing of DVC ligation [standard vs delayed] doesn't impact apical positive surgical margins. Combination of MRI, MUS, PSMA-PET and prostate biopsy reduce apical positive surgical margin rates significantly., Competing Interests: Disclosure Dr A.K. Tewari has served as a site-PI on pharma/industry-sponsored clinical trials from Kite Pharma, Lumicell Inc, Dendreon, and Oncovir Inc. He has received research funding (grants) to his institution from DOD, NIH, Axogen, Intuitive Surgical, AMBFF, and other philanthropy. Dr A.K. Tewari has served as an unpaid consultant to Roivant Biosciences and advisor to Promaxo. He owns equity in Promaxo. Rest all authors have nothing to disclose., (Copyright © 2024. Published by Elsevier Inc.)

In vitro studies have shown that deletion of nef and deleterious mutation in the Nef dimerization interface attenuates HIV replication and associated pathogenesis. Humanized rodents with human immune cells and lymphoid tissues are robust in vivo models for investigating the interactions between HIV and the human immune system. Here, we demonstrate that nef deletion impairs HIV replication and HIV-induced immune dysregulation in the blood and human secondary lymphoid tissue (human spleen) in bone marrow-liver-thymus-spleen (BLTS) humanized mice. Furthermore, we also show that nef defects (via deleterious mutations in the dimerization interface) impair HIV replication and HIV-induced immune dysregulation in the blood and human spleen in BLTS-humanized mice. We demonstrate that the reduced replication of nef-deleted and nef-defective HIV is associated with robust antiviral innate immune response, and T helper 1 response. Our results support the proposition that Nef may be a therapeutic target for adjuvants in HIV cure strategies., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: While some patients may require surgical treatment a lot of patients do recover on conservative treatment alone while the optimal treatment being unclear. The purpose of this study was to treat the PT-RCTs conservatively for a period of 6 months and to determine its clinical outcome, radiological outcome on MRI and the baseline clinical factors predictive of that outcome., Methodology: All patients with a partial tear of supraspinatus and/or infraspinatus on their 1st MRI and aged 18-80 years were eligible and 47 patients (22 males, 25 females) were enrolled. Patients were evaluated using a standardised format including clinical history, imaging, and ASES(American Shoulder and Elbow Surgeons) score. Patients underwent a course of physical therapy for a period of minimum of 6 months which was augmented with the use of analgesics and/or anti-inflammatory drugs, multivitamins and supplements which were patient specific. Patients were followed up at 3 months and 6 months, ASES score was calculated, and a follow-up MRI was done at 6 months to determine if their tear had healed, remained the same, or progressed. A patient that had a better ASES score at 6 months was tagged as "clinically improved". Radiologically, patients were considered treated "successfully" if the tear size was reduced or remained the same while some "failed" that had an increased size of tear., Result: Non-operatively treated patients demonstrated a mean ASES score of 63.45 ± 16.24 at the end of 6 months. Overall, 35 patients (74.5 %) had the same size, seven patients (14.9 %) demonstrated tear progression and 5 (10.6 %) patients showed a decrease in size of their tear on MRI done at 6 months. In the end, 30 (63.8 %) patients improved clinically and 40 (85.1 %) patients improved radiologically. Statistical analysis also showed that patients with their non-dominant side involved and with an atraumatic onset of their injury were more likely to improve clinically., Conclusion: Conservative treatment of PT-RCTs may lead to a successful clinical outcome but it may or may not reveal itself radiologically. ASES score is an effective tool to evaluate and manage various conditions of the shoulder and not just the rotator cuff. The baseline factors such as onset (traumatic versus atraumatic) and shoulder involved (dominant versus non-dominant) can predict the outcome of conservative treatment., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Delhi Orthopedic Association. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.

Helicobacter pylori has been reported as a health problem worldwide, affecting a sizable portion of people. Peptic ulcers, gastric cancer, and various extra gastric conditions are associated with this bacterium. The rampant overprescribing of antibiotics has led to the emergence of H. pylori strains resistant to multiple antibiotics, causing a decline in the effectiveness of current treatments. Recently, there has been growing interest in researching alternative treatment options for H. pylori infections that do not respond to initial therapy. Rifabutin, a rifamycin derivative initially designed for tuberculosis treatment and preventing Mycobacterium avium complex infection, has gained attention as a potential rescue medication. It has shown efficacy against H. pylori and the potential to eradicate the bacterium when combined with other antibiotics. This systematic review article focuses on using rifabutin-based regimens as a treatment option after initial treatments have failed. The authors screened literature published in the last five years, between 2017 and 2022, across various search engines and closely examined relevant studies following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. The search covered a variety of electronic databases and focused on H. pylori gastritis, rifabutin-based treatment plans, and in vivo investigations in healthy individuals. The comprehensive review provides convincing evidence that rifabutin-based regimens are effective rescue treatments for H. pylori infections. Multiple studies in various areas consistently demonstrated high eradication rates, ranging from 70% to 90%, when rifabutin-containing regimens were used. The analysis found that only a tiny percentage of H. pylori strains (1%) were resistant to rifabutin therapy, further supporting the viability of Rifabutin as an alternative when other antibiotics failed to eradicate H. pylori. The cost of Rifabutin is a significant factor that may limit its accessibility, particularly in resource-constrained settings where H. pylori infection is common. Moreover, the potential side effects of Rifabutin, such as hematological problems, rashes, and digestive issues, need to be considered. However, these side effects are typically manageable and can be reduced by combining Rifabutin with other antibiotics. In conclusion, this systematic review provides evidence supporting the effectiveness of regimens derived from Rifabutin in eliminating H. pylori infections after initial therapy failure. Due to the observation that Rifabutin effectively eradicates resistant H. pylori infections, it can be considered a suitable choice for rescue therapy. Rifabutin-containing regimens should be reserved as fourth- or later-line therapy options, considering economic factors, the risk of microbial resistance, potential side effects, and the availability of alternative medications. Future research should focus on optimizing rifabutin-based regimens and investigating combination therapies that have better H. pylori eradication rates while also addressing the problem of resistant strains., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Gugnani et al.)

Objective: This study aims to determine the diagnostic utility of galactomannan enzyme immunoassay (GM EIA) in invasive aspergillosis (IA) in children with hematological malignancy (high risk population) in terms of sensitivity, specificity, negative predictive value (NPV) and positive predictive values (PPV) at various cut offs while validating the revised EORTC/MSG 2019 criteria in order to obtain the best cut-off., Material and Methods: For 100 pediatric patients, serum and respiratory samples were collected. Clinical, mycological workup (potassium-hydroxide mount, fungal culture) and GM EIA was done to classify proven, probable, and possible IA as per EORTC-MSG guidelines,2019. Sensitivity, specificity, PPV and NPV were calculated of GM indices at cut-off 0.5, 0.7 and 1, and validated with revised EORTC -MSG, 2019., Results: Of 100 patients enrolled, 75 were diagnosed with ALL, 14 with AML, two with Hodgkin's, three had non-Hodgkin lymphoma, and six had undifferentiated leukemia. With routine mycological findings, 51 were classified as probable IA, 11 as possible IA, and 38 as no IA. Aspergillus flavus was the most prevalent on culture (56.9%, 29/51) followed by A. fumigatus (29%, 15/51) A. niger (7.8%, 4/51), A. terreus (3.9%, 2/51) and A. nidulans (2%, 1/51). GM EIA demonstrated sensitivity 82.3%, specificity 97.4%, PPV 98.1%, and NPV 77.1% at cut-off 0.67 when comparing probable/possible IA v/s no IA groups. The GM EIA had the best sensitivity (82.4%), specificity (81.8%), PPV (95.5%), and NPV (50%) at cut off 0.78 when the probable IA group was compared to the possible IA. Seven patients succumbed of whom 5 had GMI ≥ 2., Conclusion: This study deduces the optimal cut-off for serum GM EIA to be 0.67 obtained by ROC analysis when comparing possible and probable IA versus no IA and reinforces the definition of probable category of EORTC-MSG criteria, 2019. At 0.5 ODI the sensitivity (87.1%) and NPV (80.5%) are high, thus making it the most suitable cut-off for detecting true positive and ruling out IA respectively, in pediatric patients with hematological malignancy. GM EIA when performed adjunctive to clinico-radiological findings can prove to be screening, diagnostic and prognostic test for IA in pediatric hematological malignancy patients., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) because of low IL-12 receptor (IL-12R) expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing Il12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

Objective: To compare the digital method and the conventional method of teaching surgical pathology to medical students., Methods: A prospective case-control study was conducted on second-year students during the period of August 20, 2022, through January 15, 2023. Students, divided into two groups of 45 each, were taught surgical pathology via both conventional and digital methods. Four specimens and four slides were taught in total to the same set of students. A pre-test and a post-test were used to evaluate students' performance and the impact of the teaching method. The answers were analyzed using a paired t-test. In the end, students' responses were obtained regarding their views on a better method of teaching on a Likert scale., Results: To study gross pathology, 50.7% of students were in favor of the digital method, and 21% were not in favor. For the microscopic examination of tissues, 56.92% of students were in favor of the digital method, and 15% were not in favor. There was a significant increase in post-test scores (12.54-9.79 = 2.75, p=0.007) when digital methods for teaching surgical pathology were applied., Conclusion: The Likert scale demonstrated that the digital method of teaching surgical pathology not only improved student performance but also resulted in a better understanding of the subject., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Chaudhari et al.)

Objectives: Tuberculosis (TB) is an important health problem specially in the developing countries. Although effective chemotherapy is available, compliance of patient is a major challenge. The aim of this study was to describe cytomorphological features of drug defaulters on lymph node on fine-needle aspiration cytology (FNAC) and compare it with newly diagnosed cases., Material and Methods: A cross-sectional study was done for a period of 18 months, in which all patients having tuberculous lymphadenitis were included after taking detailed history regarding previous anti-TB drug intake. Cytomorphological findings in drug defaulters were evaluated and compared with newly diagnosed cases., Results: There were a total of 150 cases with 120 newly diagnosed and 30 drug defaulters. Splintered epithelioid cell granuloma was seen in 40% of drug defaulters, while it was absent in case of newly diagnosed cases ( P < 0.0001). Well-formed epithelioid cell granuloma was most commonly seen in newly diagnosed cases (65.83%) followed by poorly formed granuloma (26.67%). Another significant finding was distribution of eosinophils which were significantly high in case of drug defaulters (56.67%) ( P < 0.0001)., Conclusion: Cytomorphological findings can help in identification of the drug defaulters on FNAC and thus plan further line of treatment., Competing Interests: The authors declare no potential conflicts of interest and no source of financial support., (© 2023 Cytopathology Foundation Inc, Published by Scientific Scholar.)

In the ongoing effort to develop a vaccine against HIV, vaccine approaches that promote strong germinal center (GC) responses may be critical to enable the selection and affinity maturation of rare B cell clones capable of evolving to produce broadly neutralizing antibodies. We previously demonstrated an approach for enhancing GC responses and overall humoral immunity elicited by alum-adjuvanted protein immunization via the use of phosphoserine (pSer) peptide-tagged immunogens that stably anchor to alum particles via ligand exchange with the alum particle surface. Here, using a clinically relevant stabilized HIV Env trimer termed MD39, we systematically evaluated the impact of several parameters relevant to pSer tag composition and trimer immunogen design to optimize this approach, including phosphate valency, amino acid sequence of the trimer C-terminus used for pSer tag conjugation, and structure of the pSer tag. We also tested the impact of co-administering a potent saponin/monophosphoryl lipid A (MPLA) nanoparticle co-adjuvant with alum-bound trimers. We identified MD39 trimer sequences bearing an optimized positively-charged C-terminal amino acid sequence, which, when conjugated to a pSer tag with four phosphates and a polypeptide spacer, bound very tightly to alum particles while retaining a native Env-like antigenicity profile. This optimized pSer-trimer design elicited robust antigen-specific GC B cell and serum IgG responses in mice. Through this optimization, we present a favorable MD39-pSer immunogen construct for clinical translation., (© 2023. Springer Nature Limited.)

Purpose of Review: In this review, we discuss the evidence that vitamin D affects cardiovascular disease through interventional and observational studies and their corresponding association mechanisms. We also highlight the need for further research to definitively conclude clinical recommendations based on preliminary data and determine the extent to which vitamin D levels may impact the incidence and prognosis of major cardiovascular diseases in the future., Recent Findings: Cardiovascular disease has long been recognized as the leading cause of morbidity and mortality worldwide, with many risk factors implicated in its pathogenesis. Vitamin D is a risk factor that, despite being known to be crucial for its role in maintaining bone health, also has several extra-skeletal effects due to vitamin D receptors in vascular smooth muscle and cardiomyocytes. Recent studies have documented a significant association between higher vitamin D levels and lower risk of each cardiovascular disease entity; 11 studies between serum vitamin D and heart failure, 7 studies between serum vitamin D and hypertension, 8 studies between serum vitamin D and coronary artery disease, and 5 studies between serum vitamin D and atrial fibrillation. More studies documenting a significant association between increased serum vitamin D and cardiovascular disease are in the context of heart failure compared to hypertension, coronary artery disease, and atrial fibrillation. Conversely, a significant association between increased serum vitamin D and a lower risk of atrial fibrillation is reported in fewer studies compared to the association of vitamin D with other cardiovascular disease entities. Although there is evidence documenting a clear significant association of vitamin D under each category, further research is still needed to definitively conclude the role of vitamin D in cardiovascular disease management., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Catalase is an antioxidant enzyme that catalyzes the rapid conversion of hydrogen peroxide to water and oxygen. Use of catalase as a cancer therapeutic has been proposed to reduce oxidative stress and hypoxia in the tumor microenvironment, both activities which are hypothesized to reduce tumor growth. Furthermore, exposing murine tumors to exogenous catalase was previously reported to have therapeutic benefit. We studied the therapeutic effect of tumor-localized catalases with the aim to further elucidate the mechanism of action. To do this, we engineered two approaches to maximize intratumoral catalase exposure: 1) an injected extracellular catalase with enhanced tumor retention, and 2) tumor cell lines that over-express intracellular catalase. Both approaches were characterized for functionality and tested for therapeutic efficacy and mechanism in 4T1 and CT26 murine syngeneic tumor models. The injected catalase was confirmed to have enzyme activity >30,000 U/mg and was retained at the injection site for more than one week in vivo. The engineered cell lines exhibited increased catalase activity and antioxidant capacity, with catalase over-expression that was maintained for at least one week after gene expression was induced in vivo. We did not observe a significant difference in tumor growth or survival between catalase-treated and untreated mice when either approach was used. Finally, bulk RNA sequencing of tumors was performed, comparing the gene expression of catalase-treated and untreated tumors. Gene expression analysis revealed very few differentially expressed genes as a result of exposure to catalase and notably, we did not observe changes consistent with an altered state of hypoxia or oxidative stress. In conclusion, we observe that sustained intratumoral catalase neither has therapeutic benefit nor triggers significant differential expression of genes associated with the anticipated therapeutic mechanism in the subcutaneous syngeneic tumor models used. Given the lack of effect observed, we propose that further development of catalase as a cancer therapeutic should take these findings into consideration., Competing Interests: Declaration of competing interest Y.A. and K.D.W. are named as inventors in a patent application filed by the Massachusetts Institute of Technology related to the data presented in this work (US20200405950A1). K.D.W is a co-founder of Ankyra Therapeutics, which has licensed right to the intellectual property mentioned above., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)