Critical Bone Defect Affecting the Outcome of Management in Anatomical Type IV Chronic Osteomyelitis.

Background: The Cierny and Mader classification assists with decision-making by stratifying host status and the pathoanatomy of the disease. However, the anatomical type IV represents a heterogenous group with regard to treatment requirements and outcomes. We propose that modification of the Cierny and Mader anatomical classification with an additional type V classifier (diffuse corticomedullary involvement with an associated critical bone defect) will allow more accurate stratification of patients and tailoring of treatment strategies. Methods: A retrospective review of 83 patients undergoing treatment for Cierny and Mader anatomical type IV osteomyelitis of the appendicular skeleton at a single centre was performed. Results: Risk factors for the presence of a critical bone defect were female patients [OR 3.1 (95% CI, 1.08-8.92)] and requirement for soft tissue reconstruction [OR 3.35 (95% CI, 1.35-8.31)]; osteomyelitis of the femur was negatively associated with the presence of a critical bone defect [OR 0.13 (95% CI, 0.03-0.66)]. There was no statistically significant risk of adverse outcomes (failure to eradicate infection or achieve bone union) associated with the presence of a critical-sized bone defect. The median time to the bone union was ten months (95% CI, 7.9-12.1 months). There was a statistically significant difference in the median time to bone union between cases with a critical bone defect [12.0 months (95% CI, 10.2-13.7 months)] and those without [6.0 months (95% CI, 4.8-7.1 months)]. Conclusion: This study provided evidence to support the introduction of a new subgroup of the Cierny and Mader anatomical classification (Type V). Using a standardised approach to management, comparable early outcomes can be achieved in patients with Cierny and Mader anatomical type V osteomyelitis. However, to achieve a successful outcome, there is a requirement for additional bone and soft tissue reconstruction procedures with an associated increase in treatment time. How to cite this article: Tsang STJ, Epstein GZ, Ferreira N. Critical Bone Defect Affecting the Outcome of Management in Anatomical Type IV Chronic Osteomyelitis. Strategies Trauma Limb Reconstr 2024;19(1):26-31.

A Case of Non-Seminomatous Germ Cell Tumor Complicated by Tumor Thrombus in an Active Duty Soldier.

Testicular malignancies commonly affect adolescent and young adult males. Although they tend to respond well to cisplatin-based chemotherapy with excellent overall survival, complications such as inferior vena cava tumor thrombus are rare and can be associated with high morbidity and mortality. We present a case of tumor thrombus in a 21-year-old active duty male with a newly diagnosed stage IIIB non-seminomatous germ cell tumor presenting with extensive left lower extremity swelling. Ultrasound with Doppler was notable for significant thrombus of the left common femoral, femoral, and popliteal vein. Computed tomography imaging revealed extensive thrombus of the inferior vena cava, left iliac veins, and left gonadal vein with sparing of the left renal vein. Endovascular thrombectomy was performed with pathologic analysis confirming the presence of malignant cells consistent with tumor thrombus. The patient continued subsequent non-seminomatous germ cell tumor treatment without complications.

A Rare Case of Extranodal Natural Killer/T-cell Lymphoma, Nasal Type Associated With Hemophagocytic Lymphohistiocytosis in a Patient With Recurrent Sinusitis.

We present a rare case of hemophagocytic lymphohistiocytosis (HLH) secondary to nasal-type extranodal natural killer/T-cell lymphoma (ENKL). Nasal-type ENKL is a rare subtype of non-Hodgkin's lymphoma usually associated with Epstein-Barr virus (EBV). The patient was a 19-year-old woman who presented with facial numbness, diminished hearing, and dysgeusia. She was febrile with palatal necrosis, loss of gag reflex, and cranial nerve palsies. Labs revealed neutropenia. Broad-spectrum antimicrobials, including amphotericin, were started. Given concern for invasive fungal disease, she underwent surgical debridement, which revealed inflamed fibrous tissue and extensive necrosis. Pathology showed no fungal elements or malignancy. Lack of clinical improvement and worsening palatal necrosis prompted additional debridement. Histology identified an atypical CD3+/CD56+ cellular infiltrate. Bone marrow biopsy showed prominent hemophagocytosis, but no malignancy. She met the criteria for HLH and high-dose dexamethasone was started. Her fevers resolved. Additional labs and nasal tissue sampling with EBV-encoded RNA staining were recommended. Flow cytometry was negative, but histology revealed ENKL nasal-type, with positive EBV-encoded RNA in situ hybridization. Plasma EBV DNA level was 11,518 IU/mL. The M-SMILE (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and etoposide) regimen was initiated; one cycle led to marked improvement. EBV level returned to zero. Subsequent radiation and chemotherapy, followed by autologous stem cell transplant consolidation, led to complete remission. We conclude that ENKL may mimic invasive sinusitis clinically. Fibrinoid necrosis in vessels and surrounding tissues often leads to diagnostic delay. It is important to have a high degree of clinical suspicion for malignancy in cases of HLH and sinusitis unresponsive to appropriate therapy. Obtaining proper tissue, communication with the pathologist, and prompt initiation of therapy are crucial.

Standardized indolent systemic mastocytosis evaluations across a health care system: implications for screening accuracy.

ABSTRACT: Timely diagnosis of systemic mastocytosis (SM) remains challenging because of care heterogeneity. We implemented a standardized approach for SM screening and diagnosis using a novel health care system-wide international screening registry. A retrospective analysis assessed rates of SM, cutaneous mastocytosis (CM), and molecular diagnoses before and 2 years after care standardization. The accuracy of individual and combined SM screening tests, basal serum tryptase (BST) ≥11.5 and ≥20.0 ng/mL, REMA ≥2, monomorphic maculopapular CM (MPCM), and elevated BST based upon tryptase genotype, was analyzed. Tryptase genotyping and high-sensitivity KIT p.D816V testing increased substantially 2 years after care standardization. SM diagnoses doubled from 47 to 94, and KIT p.D816V molecular diagnoses increased from 24 to 79. Mean BST and KIT p.D816V variant allele frequency values were significantly lower in patients diagnosed after standardization. Hereditary-alpha tryptasemia prevalence was increased in SM before care standardization (4/30 [13.3%]) but reflected the general population prevalence 2 years later at (5/76 [6.6%]). Elevated BST based upon genotype and BST ≥11.5 ng/mL had the highest sensitivities at 84.2% and 88.3%, respectively. The presence of monomorphic MPCM, elevated BST based upon tryptase genotype, and the combination of REMA ≥2 with elevated BST based upon tryptase genotype had specificities >90%. BST >20.0 ng/mL had low sensitivity and specificity and was not required to establish any indolent SM (ISM) diagnosis. Care standardization increased SM diagnosis rates, particularly in patients with low BSTs. Stratifying BST based upon genotype had the best overall sensitivity and specificity of any ISM screening test and improved the REMA score specificity.

Extraislet expression of islet antigen boosts T cell exhaustion to partially prevent autoimmune diabetes.

Persistent antigen exposure results in the differentiation of functionally impaired, also termed exhausted, T cells which are maintained by a distinct population of precursors of exhausted T (TPEX) cells. T cell exhaustion is well studied in the context of chronic viral infections and cancer, but it is unclear whether and how antigen-driven T cell exhaustion controls progression of autoimmune diabetes and whether this process can be harnessed to prevent diabetes. Using nonobese diabetic (NOD) mice, we show that some CD8+ T cells specific for the islet antigen, islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) displayed terminal exhaustion characteristics within pancreatic islets but were maintained in the TPEX cell state in peripheral lymphoid organs (PLO). More IGRP-specific T cells resided in the PLO than in islets. To examine the impact of extraislet antigen exposure on T cell exhaustion in diabetes, we generated transgenic NOD mice with inducible IGRP expression in peripheral antigen-presenting cells. Antigen exposure in the extraislet environment induced severely exhausted IGRP-specific T cells with reduced ability to produce interferon (IFN)γ, which protected these mice from diabetes. Our data demonstrate that T cell exhaustion induced by delivery of antigen can be harnessed to prevent autoimmune diabetes.

An atypical presentation of CNS tuberculosis manifesting with meningoencephalitis and tuberculoma in a New York taxi driver.

Mycobacterium Tuberculous (MTb) meningitis is a rare manifestation of extrapulmonary tuberculosis (Tb) but remains the most common form of Central Nervous System (CNS) manifestation of tuberculosis. It is associated with significant morbidity and mortality yet difficult to diagnose given the low sensitivity and specificity of diagnostic testing with cerebral spinal fluid (CSF) analysis which typically shows CSF findings of lymphocytic pleocytosis, elevated protein, and low glucose and is confirmed by acid fast bacillus (AFB) culture. Here, we describe a case of severe meningoencephalopathy in the setting of disseminated tuberculosis with atypical radiological findings of tuberculoma.

Aero to the heart: A case of aortic valve endocarditis caused by Aerococcus Urinae in an elderly woman.

Aerococcus urinae (A. urinae) is an infrequent cause of infective endocarditis (IE) and few cases have been reported especially in older women. As of this publication, there are 31 reported cases of IE caused by aerococcus urinae, and of these, 4 are of women, 3 of which are aged > 75 years. Here, we describe a case of A. urinae endocarditis in an 80-year-old woman presenting with worsening fatigue. A diagnosis of native aortic valve endocarditis was established based on characteristic findings of aortic valvular vegetation on transesophageal echocardiogram along with isolation of A. urinae on blood cultures.

The potential advantages and workflow challenges of long axial field of view PET/CT.

Recently developed Long (≥100 cm) axial field of view (AFOV) PET/CT scanners are capable of producing images with higher signal-to-noise ratio, or performing faster whole-body acquisitions, or scanning with lower radiation dose to the patient, compared with conventional PET/CT scanners. These benefits, which arise due to their substantially higher, by more than an order of magnitude, geometric efficiency, have been well described in the recent literature. The introduction of Long AFOV PET/CT technology into the clinic also has important implications for the design and workflow of PET/CT facilities and their effects on radiation exposure to staff and patients. Maximising the considerable benefits of this technology requires a thorough understanding of the relationships between these factors to optimise workflows while appropriately managing radiation exposure. This article reviews current knowledge on PET/CT facility design, workflows and their effects on radiation exposure, identifies gaps in the literature and discusses the challenges that need to be considered with the introduction of Long AFOV PET/CT into the clinic.

Muscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice.

Dysregulation of mTOR complex 1 (mTORC1) activity drives neuromuscular junction (NMJ) structural instability during aging; however, downstream targets mediating this effect have not been elucidated. Here, we investigate the roles of two mTORC1 phosphorylation targets for mRNA translation, ribosome protein S6 kinase 1 (S6K1) and eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), in regulating NMJ structural instability induced by aging and sustained mTORC1 activation. While myofiber-specific deletion of S6k1 has no effect on NMJ structural integrity, 4EBP1 activation in murine muscle induces drastic morphological remodeling of the NMJ with enhancement of synaptic transmission. Mechanistically, structural modification of the NMJ is attributed to increased satellite cell activation and enhanced post-synaptic acetylcholine receptor (AChR) turnover upon 4EBP1 activation. Considering that loss of post-synaptic myonuclei and reduced NMJ turnover are features of aging, targeting 4EBP1 activation could induce NMJ renewal by expanding the pool of post-synaptic myonuclei as an alternative intervention to mitigate sarcopenia.

MALDI-TOF mass spectrometry rapid pathogen identification and outcomes of patients with bloodstream infection: A systematic review and meta-analysis.

There was inconsistent evidence regarding the use of matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) for microorganism identification with/without antibiotic stewardship team (AST) and the clinical outcome of patients with bloodstream infections (BSI). In a systematic review and meta-analysis, we evaluated the effectiveness of rapid microbial identification by MALDI-TOF MS with and without AST on clinical outcomes. We searched PubMed and EMBASE databases from inception to 1 February 2022 to identify pre-post and parallel comparative studies that evaluated the use of MALDI-TOF MS for microorganism identification. Pooled effect estimates were derived using the random-effects model. Twenty-one studies with 14,515 patients were meta-analysed. Compared with conventional phenotypic methods, MALDI-TOF MS was associated with a 23% reduction in mortality (RR = 0.77; 95% CI: 0.66; 0.90; I2  = 35.9%; 13 studies); 5.07-h reduction in time to effective antibiotic therapy (95% CI: -5.83; -4.31; I2  = 95.7%); 22.86-h reduction in time to identify microorganisms (95% CI: -23.99; -21.74; I2  = 91.6%); 0.73-day reduction in hospital stay (95% CI: -1.30; -0.16; I2  = 53.1%); and US$4140 saving in direct hospitalization cost (95% CI: $-8166.75; $-113.60; I2  = 66.1%). No significant heterogeneity sources were found, and no statistical evidence for publication bias was found. Rapid pathogen identification by MALDI-TOF MS with or without AST was associated with reduced mortality and improved outcomes of BSI, and may be cost-effective among patients with BSI.

Use of a Chemotherapy Toxicity Prediction Tool to Decrease Risks for Hospitalization in Older Patients.

Objectives Performance status (PS) scales such as the Eastern Cooperative Oncology Group (ECOG) PS and the Karnofsky Performance Index have limited utility in selecting therapies and predicting related adverse events in older patients with cancer. In July 2016, medical oncologists at our institution adopted the Cancer and Aging Research Group toxicity prediction score (CARG), a toxicity prediction tool, to identify patients who are "fit" for chemotherapy versus those who are "frail" and may experience severe complications. Methods Our retrospective review included referrals of beneficiaries 75 years of age and older who received standard systemic therapy and patients of the same age whose treatment was modified due to CARG. We compared the score's utilization six months before and after its incorporation and then assessed how its application impacted admissions, emergency department (ED) visits, and medical management. Results Thirty-eight patients with a mean age of 81 years met the inclusion criteria. Their diagnoses included gastrointestinal (37%), lung (21%), hematologic (18%), breast (10.5%), genitourinary (3%), and other (10.5%) malignancies. CARG was documented for 12.5% of systemic therapy recipients before its adoption and 41% of recipients after adoption. Its use was limited by the reliance on physicians to perform scoring during time-constrained patient encounters. Patients had fewer mean inpatient admissions (0.7 versus 2.3), admission days (4.3 versus 8), and ED visits (1.1 versus 2.5) when management was modified based on the score. Conclusion CARG assessment may facilitate a safer and more tailored approach to cancer care in older patients than conventional PS scales alone. Its integration into patient screening would increase its application and better define its potential predictive capacity to decrease risks for hospitalization.

Familial Essential Thrombocythemia With Novel MPL L502G and G208K Mutations.

Familial essential thrombocythemia is characterized by the inheritance of germline mutations to progeny, thereby increasing the risk for the development of essential thrombocythemia. Here, we present two cases of young women who developed thromboembolic phenomena, one of whom with an ischemic event despite adequate anticoagulation. Through extended mutational testing, both were characterized as having novel mutations in the myeloproliferative leukemia virus (MPL) gene, and both individuals have fathers being treated for essential thrombocythemia. This case provides insight that in familial essential thrombocythemia, there remain uncharacterized mutations in this inherited conditional landscape.

The Use of Orlistat in an Adult with Lipoprotein Lipase Deficiency: A Case Report.

Background: Patients with lipoprotein lipase (LPL) deficiency, an inherited disorder, develop hypertriglyceridemia, which can lead to recurrent pancreatitis. The mainstay of therapy is medical nutritional therapy. Case Report: We present the case of a 35-year-old woman with LPL deficiency who experienced recurrent hospitalizations for hypertriglyceridemia-induced pancreatitis, which was effectively treated with orlistat. Discussion: Other agents that have been studied for the treatment of LPL deficiency are costly and have limiting side effects. Studies have shown orlistat to be safe and effective for the treatment of LPL deficiency in children. No studies have been performed in adults with LPL deficiency. Conclusion: Orlistat may be a potential adjunctive treatment option for LPL deficiency in adults, given its availability and favorable safety profile. Further research regarding orlistat in the setting of LPL deficiency is needed.

Epidemiology of dermatologic disease in Palau: a cross-sectional study in the national public and community health service.

BACKGROUND: Dermatologic disease is a neglected public health challenge that disproportionately affects resource-poor settings. Globally, dermatologic disease contributes the fourth highest burden of nonfatal disability with the most acute impact in the Oceanic region, including the Republic of Palau. Efforts to address the dermatologic health inequality are hindered without the necessary epidemiologic evidence to guide health policy in the resource-poor setting of Palau. METHODS: We conducted a 4-year cross-sectional study of all Dermatology Service patients in the Belau National Hospital and outreach community health centers from 2015 to 2018. No other specialized dermatology service was available. Skin disease was classified by both diagnosis and Global Burden of Disease criteria and analyzed by age, gender, region, and surrounding Oceanic nations. RESULTS: The study enrolled 494 patients comprising 179 males and 315 females between 2015 and 2018. The most prevalent diseases were eczema (48.8%), superficial fungal infection (24.5%), and pruritus (22.7%). The neglected tropical disease of scabies was detected in four patients. Males were significantly more likely to present with cellulitis, keratinocyte carcinoma, stasis dermatitis, wounds, marine-related dermatitis, viral skin disease, tinea faciei, verruca, and xerosis and females with melasma and hyperpigmentation. CONCLUSION: This study presents the first primary epidemiologic data describing the prevalence of dermatologic disease in the Palauan adult population. The significant burden of disease in Palau compared with other Oceanic nations validates ongoing dermatology services and informs public health implications for resource allocation and disease management to achieve health equality in the resource-poor nation.

Reliability of software-based assessment of paediatric preparations for preformed metal crowns in the simulation laboratory.

PURPOSE: Using software for assessment of restorative work on typodonts in the simulation laboratory may enhance the objective evaluation of student work. The study aimed to evaluate the inter-rater and intra-rater reliability using 3-D scans from the Planmeca Emerald™ intra-oral scanner with Romexis Compare® software for assessing preparations for preformed metal crowns (PMCs). METHODS: Three operators independently recorded 3-D scans and digitally measured the features of 30 PMC preparations on typodont primary teeth (# 75). Using Romexis Compare® software, preparations were measured from mesial, distal and occlusal aspects. Measurements were repeated after 2 weeks. The intraclass correlation coefficient (ICC) was used to measure the reliability of measurements between operators and within the one operator. RESULTS: For measuring the extent of tooth reduction, there was excellent intra-rater reliability for each operator (ICC 0.96-0.99). The highest inter-rater reliability was for measurements of the occlusal surface (0.946 and 0.956), followed by the mesial surface (0.852 and 0.862) and then the distal surface (0.746 and 0.724). CONCLUSION: This method was useful and reliable for measuring features of PMC preparation, but with some limitations. Improving the software to provide specific assistance tools would empower greater uptake of this method as an adjunct to traditional visual grading tool in paediatric dentistry preclinical teaching.

Lenalidomide-Associated Hemophagocytic Lymphohistiocytosis With Plasma Cell Phagocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory syndrome that is often fatal. In the adult population, it is believed to develop secondary to immune dysregulation due to rheumatologic, infectious, malignant, and recently, immunomodulatory drugs. It's co-occurrence with phagocytosis by non-macrophage cells has not been previously well defined. We present a case of lenalidomide-associated HLH with concurrent plasma cell hemophagocytosis in a patient with controlled multiple myeloma (MM).

Tolerance to Proinsulin-1 Reduces Autoimmune Diabetes in NOD Mice.

T-cell responses to insulin and its precursor proinsulin are central to islet autoimmunity in humans and non-obese diabetic (NOD) mice that spontaneously develop autoimmune diabetes. Mice have two proinsulin genes proinsulin -1 and 2 that are differentially expressed, with predominant proinsulin-2 expression in the thymus and proinsulin-1 in islet beta-cells. In contrast to proinsulin-2, proinsulin-1 knockout NOD mice are protected from autoimmune diabetes. This indicates that proinsulin-1 epitopes in beta-cells maybe preferentially targeted by autoreactive T cells. To study the contribution of proinsulin-1 reactive T cells in autoimmune diabetes, we generated transgenic NOD mice with tetracycline-regulated expression of proinsulin-1 in antigen presenting cells (TIP-1 mice) with an aim to induce immune tolerance. TIP-1 mice displayed a significantly reduced incidence of spontaneous diabetes, which was associated with reduced severity of insulitis and insulin autoantibody development. Antigen experienced proinsulin specific T cells were significantly reduced in in TIP-1 mice indicating immune tolerance. Moreover, T cells from TIP-1 mice expressing proinsulin-1 transferred diabetes at a significantly reduced frequency. However, proinsulin-1 expression in APCs had minimal impact on the immune responses to the downstream antigen islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) and did not prevent diabetes in NOD 8.3 mice with a pre-existing repertoire of IGRP reactive T cells. Thus, boosting immune tolerance to proinsulin-1 partially prevents islet-autoimmunity. This study further extends the previously established role of proinsulin-1 epitopes in autoimmune diabetes in NOD mice.

Harnessing CD8+ T-cell exhaustion to treat type 1 diabetes.

Although immune interventions have shown great promise in type 1 diabetes mellitus (T1D) clinical trials, none are yet in routine clinical use or able to achieve insulin independence in patients. In addition to this, the principles of T1D treatment remain essentially unchanged since the isolation of insulin, almost a century ago. T1D is characterized by insulin deficiency as a result of destruction of insulin-producing beta cells mediated by autoreactive T cells. Therapies that target beta-cell antigen-specific T cells are needed to prevent T1D. CD8+ T-cell exhaustion is an emerging area of research in chronic infection, cancer immunotherapy, and more recently, autoimmunity. Recent data suggest that exhausted T-cell populations are associated with improved markers of T1D. T-cell exhaustion is both characterized and mediated by inhibitory receptors. This review aims to identify which inhibitory receptors may prove useful to induce T-cell exhaustion to treat T1D and identify limitations and gaps in the current literature.

Deficiency of the innate immune adaptor STING promotes autoreactive T cell expansion in NOD mice.

AIMS/HYPOTHESIS: Stimulator of IFN genes (STING) is a central hub for cytosolic nucleic acid sensing and its activation results in upregulation of type I IFN production in innate immune cells. A type I IFN gene signature seen before the onset of type 1 diabetes has been suggested as a driver of disease initiation both in humans and in the NOD mouse model. A possible source of type I IFN is through activation of the STING pathway. Recent studies suggest that STING also has antiproliferative and proapoptotic functions in T cells that are independent of IFN. To investigate whether STING is involved in autoimmune diabetes, we examined the impact of genetic deletion of STING in NOD mice. METHODS: CRISPR/Cas9 gene editing was used to generate STING-deficient NOD mice. Quantitative real-time PCR was used to assess the level of type I IFN-regulated genes in islets from wild-type and STING-deficient NOD mice. The number of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214-specific CD8+ T cells was determined by magnetic bead-based MHC tetramer enrichment and flow cytometry. The incidence of spontaneous diabetes and diabetes after adoptive transfer of T cells was determined. RESULTS: STING deficiency partially attenuated the type I IFN gene signature in islets but did not suppress insulitis. STING-deficient NOD mice accumulated an increased number of IGRP206-214-specific CD8+ T cells (2878 ± 642 cells in NOD.STING-/- mice and 728.8 ± 196 cells in wild-type NOD mice) in peripheral lymphoid tissue, associated with a higher incidence of spontaneous diabetes (95.5% in NOD.STING-/- mice and 86.2% in wild-type NOD mice). Splenocytes from STING-deficient mice rapidly induced diabetes after adoptive transfer into irradiated NOD recipients (median survival 75 days for NOD recipients of NOD.STING-/- mouse splenocytes and 121 days for NOD recipients of NOD mouse splenocytes). CONCLUSIONS/INTERPRETATION: Data suggest that sensing of endogenous nucleic acids through the STING pathway may be partially responsible for the type I IFN gene signature but not autoimmunity in NOD mice. Our results show that the STING pathway may play an unexpected intrinsic role in suppressing the number of diabetogenic T cells.