Atomistic insight towards the impact of polymer architecture and grafting density on structure-dynamics of PEGylated bovine serum albumin and their applications.

Macromolecules such as proteins conjugated to polyethylene glycol (PEG) have been employed in therapeutic drug applications, and recent research has emphasized the potential of varying polymer architectures and conjugation strategies to achieve improved efficacy. In this study, we performed atomistic molecular dynamics simulations of bovine serum albumin (BSA) conjugated to 5 kDa PEG polymers in an array of schemes, including varied numbers of attached chains, grafting density, and nonlinear architectures. Nonlinear architectures included U-shaped PEG, Y-shaped PEG, and poly(oligoethylene glycol methacrylate) (POEGMA). Buried surface area calculations and polymer volume map analyses revealed that volume exclusion behaviors of the high grafting density conjugate promoted additional protein-polymer interactions when compared to simply increasing numbers of conjugated chains uniformly across the protein surface. Investigation of nonlinear polymer architectures showed that stable polymer-lysine loop-like conformations seen in previous conjugate designs were more variable in prevalence, especially in POEGMA, which contained short oligomer PEG chains. The findings of this comprehensive study of alternate PEGylation schemes of BSA provide critical insight into molecular patterns of interaction within bioconjugates and highlight their importance in the future of controlled modification of conjugate system parameters.

PEGylation within a confined hydrophobic cavity of a protein.

The conjugation of polyethylene glycol (PEG) to proteins, known as PEGylation, has increasingly been employed to expand the efficacy of therapeutic drugs. Recently, research has emphasized the effect of the conjugation site on protein-polymer interactions. In this study, we performed atomistic molecular dynamics (MD) simulations of lysine 116 PEGylated bovine serum albumin (BSA) to illustrate how conjugation near a hydrophobic pocket affects the conjugate's dynamics and observed altered low mode vibrations in the protein. MD simulations were performed for a total of 1.5 µs for each PEG chain molecular mass from 2 to 20 kDa. Analysis of preferential PEG-BSA interactions showed that polymer behavior was also affected as proximity to the attractive protein surface patches promoted interactions in small (2 kDa) PEG chains, while the confined environment of the conjugation site reduced the expected BSA surface coverage when the polymer molecular mass increased to 10 kDa. This thorough analysis of PEG-BSA interactions and polymer dynamics increases the molecular understanding of site-specific PEGylation and enhances the use of protein-polymer conjugates as therapeutics.

Progressive Dyspnea on Exertion in an 82-Year-Old.

An older patient with hereditary hemorrhagic telangiectasia and right lower lobe segmental pulmonary embolism presented with dyspnea that had worsened over 5 years; physical examination and laboratory testing showed jugular venous distension, a cardiac systolic murmur, right ventricular heave, bilateral lower extremity edema to the knees, and elevated brain-type natriuretic peptide level. What is the diagnosis and what would you do next?

Heterozygous desmoplakin (DSP) variants presenting with early onset cardiomyopathy and refractory ventricular tachycardia.

Arrhythmogenic cardiomyopathy is a non-ischaemic cardiomyopathy characterised by the presence of myocardial dysfunction and inherited conduction disease that predisposes patients to malignant ventricular arrhythmias and sudden cardiac death. There is a growing awareness of the diverse phenotypic presentation of arrhythmogenic cardiomyopathy, which may demonstrate preferential involvement of the left, right or both ventricles. A subset of arrhythmogenic cardiomyopathy may be due to mutations of desmosomes, intercellular junctions of the myocardium that promote structural and electrical integrity. Mutations of desmoplakin, encoded by the DSP gene and a critical constituent protein of desmosomes, have been implicated in the onset of arrhythmogenic cardiomyopathy. We present a structured case report of desmoplakin arrhythmogenic cardiomyopathy secondary to novel heterozygous DSP mutations (c.1061T>C and c.795G>C) manifesting as early onset non-ischaemic cardiomyopathy and recurrent ventricular tachycardia refractory to multiple modalities of therapy, including oral antiarrhythmics, cardiac ablation and bilateral sympathectomy, as well as frequent implantable cardioverter-defibrillator discharges.

Passenger lymphocyte syndrome following minor ABO-mismatched liver transplantation.

Passenger lymphocyte syndrome is an immunologic disorder observed in solid organ and haematopoietic stem cell transplantation in which B lymphocytes within a donor graft are transferred to the recipient and subsequently produce circulating antibodies against host red blood cell antigens. The syndrome is most likely to occur in minor ABO blood group mismatched or Rh incompatible transplantation. Although generally mild and self-limited, the resulting haemolytic burden has the potential to increase the risk of infection, graft failure and death. The phenomenon is observed in the transplantation of any solid organ with lymphoid tissue, including the liver. We present a structured case report of passenger lymphocyte syndrome following minor ABO-mismatched liver transplantation, which was initially complicated by blood loss anaemia early in the postoperative period. By reviewing the limited literature of this disorder following liver transplantation, we emphasise common clinical findings and treatment strategies as well as introduce chimerism analysis to confirm resolution.

A 35-Year-Old Woman With Placenta Previa and Postpartum Cardiovascular Collapse.

CASE PRESENTATION: A 35-year-old woman at 36 weeks and 4 days gestation with known complete anterior placenta previa and no other medical history presented for routine obstetric follow-up. She reported increasing fatigue in the prior week but otherwise endorsed no new concerns. She denied recent vaginal bleeding or discharge, abdominal pain, contractions, or extremity swelling. On evaluation, her BP was 126/74 mm Hg with a heart rate of 72 beats per min. The results from the physical examination were normal. There was a category II fetal heart rate tracing and a 6/10 biophysical profile (ie, no fetal breathing movements, nonreactive nonstress test), which prompted referral to the hospital. On admission, sonogram confirmed cephalic presentation and redemonstrated complete anterior placenta previa with no evidence of hemorrhage. She received antenatal steroids and was scheduled for a cesarean section delivery. She received bupivacaine spinal anesthesia for the procedure. The surgical procedure progressed with a low transverse uterine incision and subsequent delivery of the baby with no complications noted. Immediately after delivery of the baby and during gentle traction of the placenta, the patient experienced rapid cardiovascular collapse in the form of hypotension and bradycardia.

Recurrence of Drug-Induced Lupus Secondary to Vedolizumab Use in a Patient With Crohn's Disease.

Drug-induced lupus is an autoimmune phenomenon characterized by the development of systemic lupus erythematosus-like clinical features after drug exposure. The entity is a clinical diagnosis. Evaluation consists of recognizing systemic lupus erythematosus-like features, identifying an appropriate causative agent, observing elevations of characteristic autoantibodies, and obtaining positive response with drug discontinuation. Vedolizumab is an anti-α4ß7 antibody used in the treatment of ulcerative colitis and Crohn's disease. We report a novel case of drug-induced lupus recurrence secondary to vedolizumab use in a patient with Crohn's disease, emphasizing diagnostic evaluation, and provide a brief review of the published literature.

Vaccines: a promising therapy for myelodysplastic syndrome.

Myelodysplastic neoplasms (MDS) define clonal hematopoietic malignancies characterized by heterogeneous mutational and clinical spectra typically seen in the elderly. Curative treatment entails allogeneic hematopoietic stem cell transplant, which is often not a feasible option due to older age and significant comorbidities. Immunotherapy has the cytotoxic capacity to elicit tumor-specific killing with long-term immunological memory. While a number of platforms have emerged, therapeutic vaccination presents as an appealing strategy for MDS given its promising safety profile and amenability for commercialization. Several preclinical and clinical trials have investigated the efficacy of vaccines in MDS; these include peptide vaccines targeting tumor antigens, whole cell-based vaccines and dendritic cell-based vaccines. These therapeutic vaccines have shown acceptable safety profiles, but consistent clinical responses remain elusive despite robust immunological reactions. Combining vaccines with immunotherapeutic agents holds promise and requires further investigation. Herein, we highlight therapeutic vaccine trials while reviewing challenges and future directions of successful vaccination strategies in MDS.

Systemic capillary leak syndrome secondary to decompression sickness.

Systemic capillary leak syndrome is a rare derangement of endothelial function characterised by extravasation of plasma and proteins into the interstitial space. Primary capillary leak syndrome is a rare, episodic medical illness of unknown molecular pathology while secondary capillary leak syndrome may be precipitated by any number of inflammatory and infectious syndromes. Decompression sickness, a disorder of depressurisation, has been identified as a very rare trigger. We present a structured case report of systemic capillary leak syndrome secondary to decompression sickness following deep diving, informing physicians of this potential complication. No pharmacological therapy has substantial evidence in the treatment of acute systemic capillary leak syndrome. By review of current recommendations for acute management, we also emphasise an observed positive response to judicious fluid resuscitation and an oral cyclic AMP-elevating agent (ie, terbutaline).

Immune-mediated herb-induced liver injury: a potential association with herbal artemisinin use as supported by the updated RUCAM.

Immune-mediated herb-induced liver injury (HILI) is an acute or chronic inflammatory liver disease precipitated by a hepatotoxic agent with a presentation similar to acute autoimmune hepatitis. It is distinguished in clinical course from true autoimmune hepatitis by remission on drug discontinuation and immunosuppressive treatment. We report a potential case of immune-mediated HILI associated with artemisinin use, an herb underlying first-line malarial treatments, in a woman undergoing radiotherapy for right-sided pelvic sarcoma. A probable association in this case is supported by causality assessment using the updated Roussel Uclaf Causality Assessment Method (score of 6). She achieved clinical improvement with a course of oral corticosteroids and remained stable without relapse following discontinuation. Increased awareness of this complication is imperative, as literature to date only documents direct hepatocellular and cholestatic liver injury from artemisinin use, and should augment clinician counsel regarding complementary medicine administration, especially in high-risk individuals like those with cancer.

Clinical characteristics, prognostic factors, and long-term outcomes associated with epithelial malignancies of the thymus: A 20-year single-institution experience.

BACKGROUND: Thymic epithelial tumors are rare and include thymomas and thymic carcinomas. There is scarce literature characterizing prognostic factors and long-term outcomes in these tumors. AIMS: This review aims to describe disease features of thymomas and thymic carcinomas and to report clinical differences among thymoma histological subtypes. METHODS AND RESULTS: A retrospective chart review was performed at the University of Florida Shands Hospital, a tertiary care academic medical center in Gainesville, Florida, USA. The review included clinical data of adults with thymic epithelial tumors diagnosed between 2001 and 2021. Significant associations among demographics, histology, stage, and outcomes were investigated. Thymoma subgroup analysis was performed using histological subtype and sex. Forty patients with thymoma and seven patients with thymic carcinoma were included in the final analysis. Among those with thymomas, patients with subtype B1, B2, or B3 tumors were younger, had larger tumors, and presented with higher stage disease when compared to those with subtypes A or AB. Tumor recurrence was most common in subtype B2 and B3 tumors (50.0% and 16.7% vs. 0%; p < .01). However, there was no significant difference in overall survival between histologic subtypes. Compared to females, males with thymomas had superior overall survival (103.0 vs. 62.9 months; p = .021) despite presenting with larger tumors (9.8 vs. 5.8 cm; p = .041). Concomitant myasthenia gravis was associated with increased recurrence but not worsened mortality. Compared to thymomas, patients with thymic carcinoma presented with higher-stage disease and had poorer 5-year survival (50.0% vs. 93.1%; p < .01). CONCLUSION: This study affirmed pathologic stage and resectability as prognostic factors for thymic epithelial tumors. New findings include inferior overall survival in female patients and higher recurrence rates in those with thymomas and concomitant myasthenia gravis.

Clinical presentation and neurovascular manifestations of cardiac myxomas and papillary fibroelastomas: a retrospective single-institution cohort study.

Background: Primary cardiac tumors are often benign and commonly present as cardiac myxomas (CMs) or papillary fibroelastomas (CPFEs). There is a paucity of prognostic indicators for tumor burden or potential for embolic cerebrovascular events (CVEs). This study was performed to address these gaps. Methods: Medical records at the University of Florida Health Shands Hospital between 1996 and 2021 were screened to identify patients with CMs or CPFEs. Clinical features, echocardiographic reports, and CVE outcomes were quantitatively assessed. Results: A total of 55 patients were included in the study: 28 CM (50.9%) and 27 CPFE (49.1%) patients. Baseline patient characteristics were similar among patients. The neutrophil-lymphocyte ratio was correlated (p < 0.005 in all cases) to three metrics of tumor size in both CM (r = 64-67%) and CPFE (r = 56-59%). CVEs were the presenting symptom in 30 (54.5%) patients. CVE recurrence was high; the 5-year CVE recurrence rate in patients with tumor resection was 24.0% compared to 60.0% without resection. No baseline patient characteristics or tumor features were associated with an initial presentation of CVEs compared to any other indication. Univariate analysis indicated that prolonged duration to surgical resection, left atrial enlargement, male sex, and a neutrophil-lymphocyte ratio >3.0 at the follow-up were significantly associated with 5-year CVE recurrence. Left atrial enlargement and a neutrophil-lymphocyte ratio >3.0 at the follow-up remained significantly associated with 5-year CVE recurrence in multivariate analysis. Conclusion: The neutrophil-lymphocyte ratio may prognosticate tumor size and recurrence of neurologic events. An increased risk of CVE within 5 years of mass resection is almost exclusive to patients initially presenting with CVEs.

Pulmonary hypertension in hereditary hemorrhagic telangiectasia: A clinical review.

Hereditary hemorrhagic telangiectasia (HHT) is a rare autosomal dominant hereditary disorder characterized by recurrent spontaneous epistaxis, mucocutaneous telangiectasias, and solid organ arteriovenous malformations (AVMs). Pulmonary hypertension (PH) is an increasingly recognized complication in patients with HHT, most often precipitated by high-output heart failure in the presence of hepatic AVMs as well as pulmonary arterial hypertension in the form of a proliferative vasculopathy. The presence of PH in patients with HHT is associated with significant elevations in rates of morbidity and mortality. Additionally, there is growing recognition of a thromboembolic propensity in this population that increases the risk of chronic thromboembolic PH, posing unique clinical considerations regarding the use of anticoagulation. Patients with HHT are also at risk of PH due to disorders commonly seen in the general population, including left-sided heart and lung disease. The etiology of PH in HHT is multifaceted and complex; the diagnostic approach and treatment strategies must consider the underlying pathophysiology of HHT. This comprehensive review summarizes current knowledge of PH in HHT, detailing the pathogenesis of known etiologies, diagnostic evaluation, and suggested treatment modalities as well as emerging therapies that may be of future interest.

Impact of genotype on clinical course in sickle cell disease and the utility of neutrophil-lymphocyte ratio: a ten-year single-institution experience.

BACKGROUND: Sickle cell disease (SCD) is a diverse group of blood disorders with significant global disease burden. Contemporary interest in the underlying inflammatory paradigm of SCD has emphasized the role of the neutrophil-lymphocyte ratio (NLR) as a prognostic inflammatory marker. METHODS: We retrospectively reviewed 268 hospitalized patients with SCDs of different genotypes (HbSS, HbSß0 thalassemia, HbSß+ thalassemia, and HbSC), totaling 3329 hospital admissions over a 10-year period. Patients were stratified into SS/Sß0 and Sß+/SC groups for statistical analysis of parameters collected at steady state and at hospital admission. RESULTS: At steady state, per unit increase of hemoglobin values was associated with reduced odds of ≥ 2 hospital admissions per year in SS/Sß0 and Sß+/SC groups; per unit increase in platelet count and white blood cell count was associated with increased odds only in the SS/Sß0 group. The NLR had no association in either group. During admission, a cutoff of NLR = 3.5 discerned infection with a sensitivity of 60% and specificity of 57%. Performance improved when excluding patients on outpatient hydroxyurea therapy (cutoff of NLR = 3.5; sensitivity of 68% and specificity of 64%). CONCLUSION: This study supports the utility of NLR as an accessible adjunctive clinical tool in SCD prognostication.

Importance of carbohydrate antigen (CA 19-9) and carcinoembrionic antigen (CEA) in the prognosis of patients with duodenal adenocarcinoma: a retrospective single-institution cohort study.

BACKGROUND: Duodenal adenocarcinoma (DA) is a rare malignancy without validated tumor markers. In practice, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA 19-9) are often used in the management of DA, though their prognostic value is unknown. MATERIALS AND METHODS: A single-institution retrospective review included patients diagnosed with biopsy-confirmed adenocarcinoma of the duodenum between 2006 and 2021. Peri-ampullary tumors were excluded. Levels of CA 19-9 and CEA were collected as continuous variables and were analyzed as binary variables: normal vs. high, using the maximum normal value as a cut-off (normal Ca 19-9 <35 U/ml; CEA <3 ng/ml). Survival analysis was conducted using Kaplan Meier curves, log-rank test and Cox proportional hazards model. RESULTS: There were 68 patients included in the final analysis. Median age was 67 years old and median follow-up time was 22.2 months. CA 19-9 and CEA were elevated in 36.8% and 48.5% of patients, respectively. A concomitant elevation of both tumor markers was associated with worsened OS (HR 2.140, 95% CI: 1.114-4.112; p = 0.019). After controlling for age and sex on multivariate analysis, elevation in both CA 19-9 ≥35 and CEA ≥3.0 remained significantly associated with increased mortality (HR 2.278, 95% CI: 1.162-4.466; p = 0.016). CONCLUSIONS: In summary, CA 19-9 and, to a lesser extent, CEA, show promise as prognostic markers in DA. Larger studies are needed to validate their use and to evaluate their performance as markers of recurrence.

Synchronous Recto-Sigmoid Colorectal Carcinomas With Microsatellite Instability and an Activating PIK3CA Mutation.

Synchronous colorectal cancer is a rare subtype of colorectal carcinoma defined by the presence of 2 or more primary tumors simultaneously or within 6 months of initial detection. The overall impact of a synchronous presentation on prognosis is not yet clear. Surgical resection is the primary treatment. However, higher rates of local recurrence and metastasis in synchronous colorectal cancer demand greater exploration of the role of adjuvant therapy. The increased frequency of microsatellite instability observed in synchronous colorectal cancer also affects therapy selection. Similarly, activating PIK3CA mutations are regularly noted in colorectal cancer, but their role in a synchronous presentation has not yet been described. We report a case of a young patient with a synchronous recto-sigmoid colorectal carcinoma complicated by microsatellite instability and an activating PIK3CA mutation-a presentation as of yet unreported in literature. We also review the impact of these molecular events on the efficacy of several chemotherapies and targeted therapies.

Diffuse hepatocellular carcinoma secondary to cardiac cirrhosis in heterotaxy syndrome.

Heterotaxy syndrome is a rare congenital defect of left-right laterality of major visceral organs, often categorised by the presence of symmetric left or right atrial heart chambers with a single effective ventricle. Known as left or right atrial isomerism, these conditions may present with a distinct pattern of extracardiac anomalies. Heterotaxy is often palliated with the Fontan procedure and is suggested to be subject to similar long-term sequelae of congestive hepatopathy and ischaemia, increasing the risk for hepatocellular carcinoma. Few works document primary, localised hepatocellular carcinoma in patients with heterotaxy syndrome. We present a case of diffuse, multifocal metastatic hepatocellular carcinoma in a young patient with left atrial isomerism and dextrocardia. We also review suggested guidelines of surveillance for liver disease and hepatocellular carcinoma in this patient population.

Management of adrenal insufficiency in the setting of chronic HIV and advanced extra-adrenal Hodgkin lymphoma.

Adrenal insufficiency is one of the most common endocrine disorders that presents in patients with HIV. Aetiologies of adrenal dysfunction include opportunistic infection, malignancy, such as lymphoma or Kaposi sarcoma, and chronic cytokine-mediated disruption of the hypothalamic-pituitary-adrenal axis. In the case of lymphoma, the manifestation of adrenal insufficiency is most often via primary neoplastic infiltration. However, a spectrum of associated cytokine-mediated abnormal immune responses and coagulopathies may independently contribute to adrenal insufficiency. Literature regarding the presence of the endocrine disorder in patients with both HIV and lymphoma is scarce. We report a case of adrenal insufficiency in a patient with well-controlled HIV and advanced Hodgkin lymphoma without primary adrenal involvement with suboptimal response to corticosteroids who exhibited improvement following initiation of chemotherapy, demonstrating that chemotherapy should not be delayed until adrenal insufficiency resolves and in fact may aid in resolution of adrenal dysfunction.

A 26-Year-Old Woman With Retinal Telangiectasias, Onychodystrophy, and Persistent Dyspnea.

CASE PRESENTATION: A 26-year-old woman with no significant past medical history sought treatment for worsening dyspnea and hypoxia. The exertional dyspnea began 2 years prior and was associated with substernal chest discomfort. She did not report myalgia, edema, or worsening of dyspnea on supine or upright position. The patient reported no personal history of tobacco or illicit drug use. Family history was unremarkable. She was started on supplemental oxygen at 3 L/min. Initial workup included CT scan angiography of the chest, which showed no pulmonary embolism and normal lung parenchyma. Transthoracic echocardiography showed unremarkable results. She was not given a clear diagnosis for hypoxia and was treated empirically with antibiotics and bronchodilators without improvement. Over the course of 2 years, her condition progressed to requiring 6 L/min nasal canula at rest and associated dyspnea with minimal exertion and a 30-pound unintentional weight loss. During this time, pulmonary function tests noted normal spirometry results and lung volumes, but a decreased diffusing capacity for carbon monoxide of 33%. She also was discovered incidentally to be leukopenic and thrombocytopenic, with subsequent bone marrow biopsy revealing hypocellularity of 30% to 40%. The patient concurrently demonstrated bilateral visual impairment secondary to retinal telangiectasias with increased severity of deficit in the right eye. She subsequently was referred to our institution for further evaluation.