Parsing Dynamics of Protein Backbone NH and Side-Chain Methyl Groups using Molecular Dynamics Simulations.

Experimental NMR spectroscopy and theoretical molecular dynamics (MD) simulations provide complementary insights into protein conformational dynamics and hence into biological function. The present work describes an extensive set of backbone NH and side-chain methyl group generalized order parameters for the Escherichia coli ribonuclease HI (RNH) enzyme derived from 2-µs microsecond MD simulations using the OPLS4 and AMBER-FF19SB force fields. The simulated generalized order parameters are compared with values derived from NMR 15N and 13CH2D spin relaxation measurements. The squares of the generalized order parameters, S2 for the N-H bond vector and Saxis2 for the methyl group symmetry axis, characterize the equilibrium distribution of vector orientations in a molecular frame of reference. Optimal agreement between simulated and experimental results was obtained by averaging S2 or Saxis2 calculated by dividing the simulated trajectories into 50 ns blocks (∼five times the rotational diffusion correlation time for RNH). With this procedure, the median absolute deviations (MAD) between experimental and simulated values of S2 and Saxis2 are 0.030 (NH) and 0.061 (CH3) for OPLS4 and 0.041 (NH) and 0.078 (CH3) for AMBER-FF19SB. The MAD between OPLS4 and AMBER-FF19SB are 0.021 (NH) and 0.072 (CH3). The generalized order parameters for the methyl group symmetry axis can be decomposed into contributions from backbone fluctuations, between-rotamer dihedral angle transitions, and within-rotamer dihedral angle fluctuations. Analysis of the simulation trajectories shows that (i) backbone and side chain conformational fluctuations exhibit little correlation and that (ii) fluctuations within rotamers are limited and highly uniform with values that depend on the number of dihedral angles considered. Low values of Saxis2, indicative of enhanced side-chain flexibility, result from between-rotamer transitions that can be enhanced by increased local backbone flexibility.

Acute Liver Failure With Liver Enzymes >5,000 in Sickle Cell Disease.

Sickle cell disease is a hemoglobinopathy often complicated by painful vaso-occlusive episodes, acute chest syndrome, stroke, and myocardial infarction. Sickle cell intrahepatic cholestasis (SCIC) is a rare and potentially fatal complication of sickle cell disease. SCIC is thought to involve progressive hepatic injury due to sickling within sinusoids. We present the case of a young patient with SCIC and acute liver failure, requiring prompt treatment with exchange transfusion. Our case describes features that should raise suspicion for hepatic failure in SCIC and highlights exchange transfusion as a successful management approach in similar patients with an otherwise high risk of mortality.

Characterizing after-hours hematology/oncology clinic calls.

BACKGROUND: After-hour calls can be resource intensive and remain a significant challenge to medical practices, though they have historically been poorly or non-reimbursable services. This study reviews after-hour calls from hematology/oncology patients at a cancer center to characterize after-hour care needs, identify care gaps, and look for opportunities to improve outpatient healthcare delivery. METHODS: This descriptive, retrospective Institutional Review Board-approved study analyzed patient calls between June 2015 to February 2021 in an academic hematology/oncology practice. Data from 500 calls were reviewed and cataloged into a database including patient demographics, clinical history, and information surrounding the call (e.g., primary reason for the call, outcome of the call). Calls were also categorized as being urgent or not from a patient or provider's perspective. RESULTS: Among 500 calls, representing 398 unique patients, the average patient was 62 years old and 52% of calls were from females. Most calls were made to report symptoms (65%), followed by calls to follow-up on labs, tests, or imaging (13%), and clarifying treatment plans (10%). Oncology patients represented 67% of calls and hematology (malignant and benign) patients represented 33%. More specifically, patients with gastrointestinal cancer (25%), hematologic malignancies (24%), and thoracic cancer (13%) represented the diagnoses with the highest call volume. CONCLUSIONS: This study explores the complexity and variety of after-hour cancer patient calls. By systematically exploring patient calls, this data can provide insight into patients' needs outside of regular clinic times and help practices develop strategies to anticipate these needs, reduce after-hour call burden, and improve overall quality of care.

Maximalist Shoes: Separating Science From Hype.

One of the most discussed but misunderstood topics in foot and ankle is shoe wear choices and the purported benefits of each type of shoe versus their actual scientific advantages. All foot and ankle care providers should be familiar with the various shoe wear types available to patients to improve their overall foot health. Recently, mainstream popularity and media coverage of maximalist shoes has created increased interest in the science and potential clinical benefits of maximalist shoes. The purpose of this review is to present the current biomechanical evidence of maximalist shoes and to help inform the foot and ankle community of their potential therapeutic applications.Levels of Evidence: Level V.

Sex Differences in Patient-Reported Outcomes and Range of Motion After Total Ankle Arthroplasty.

BACKGROUND: As the popularity of total ankle arthroplasty (TAA) increases, there is a growing need to examine the effects of sex on postoperative outcomes. This study compares patient-reported outcome measures and ankle range of motion (ROM) in the postoperative period, as stratified by sex. METHODS: Patients who underwent TAA during 2013 to 2018 with a minimum follow-up of 2 years were included (N = 133). American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot Score, Visual Analog Scale (VAS), and 12-Item Short-Form Survey (SF-12) were administered preoperatively and at 6 months, 1 year, and 2 years postoperatively. ROM was recorded at these same time points. RESULTS: Preoperatively and at 6 months postoperatively, the cohorts did not differ in any of the measured outcomes. At 1 year postoperatively, females had lower SF-12 Physical Composite Scores (female = 44.1, male = 47.1, P = .019) and less plantarflexion (female = 20.5 degrees, male = 23.5 degrees, P = .029). By 2 years postoperative, females had lower AOFAS scores (female = 80.3, male = 85.4, P = .040). A greater complication rate amongst the female cohort approached significance at 18.6% versus 9% for males (P = .124). DISCUSSION: These results support TAA as a reliable means of treating ankle arthritis in both sexes, despite important differences. Understanding these outcome differences is critical for effectively managing expectations and treating both female and male populations. LEVELS OF EVIDENCE: Level III: Retrospective cohort study.

A Case of Pneumocystis jirovecci in a Patient with Non-Small Cell Lung Cancer Treated with Immunotherapy.

Immune checkpoint inhibitors have become the standard of care in the management of metastatic non-small cell lung cancer (NSCLC) and are associated with improved outcomes when compared to traditional chemotherapy regimens. However, they present with their own unique set of immune-related side effects. One immune-related adverse effect that can arise is pneumonitis, where patients present with dyspnea with nonspecific radiologic findings, making it challenging to differentiate from other etiologies causing dyspnea. We present a case of a 58-year-old woman with NSCLC previously treated with immunotherapy, who presented with shortness of breath. She was initially thought to have immune-related pneumonitis and was treated with immunosuppressive therapy. After several days of treatment, bronchoscopy demonstrated a positive polymerase chain reaction (PCR) for Pneumocystis jirovecii (PJP) after an initial negative direct fluorescent antibody (DFA). The patient was started on appropriate management for PJP and no further immunosuppressive therapy was given.

Contrasting Strategies in Bouveret's Syndrome: A Series of Two Cases.

Bouveret's syndrome is a rare complication of cholelithiasis, characterized by gastric outlet obstruction caused by a migrated gallstone. Diagnosis of Bouveret's syndrome necessitates urgent treatment as it carries a high mortality rate. The treatment of Bouveret's syndrome has traditionally been surgical. However, there have been increasing reports of successful endoscopic therapy for Bouveret's syndrome. This case series aims to compare and contrast two cases of Bouveret's syndrome. The gallstone was retrieved via endoscopic access in one case while the other was removed with surgery. For each case, we discuss the various factors that contributed to the decision of which treatment modality to use. In addition, we propose an endoscopic technique that may improve the safety and success rate of endoscopic treatment of Bouveret's syndrome.

Clinical activity of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3ß) inhibitor, in refractory adult T-Cell leukemia/lymphoma.

GSK-3ß is a serine/threonine kinase implicated in tumorigenesis and chemotherapy resistance. GSK-3ß blockade downregulates the NF-κB pathway, modulates immune cell PD-1 and tumor cell PD-L1 expression, and increases CD8 + T cell and NK cell function. We report a case of adult T-cell leukemia/lymphoma (ATLL) treated with 9-ING-41, a selective GSK-3ß inhibitor in clinical development, who achieved a durable response. A 43-year-old male developed diffuse lymphadenopathy, and biopsy of axillary lymph node showed acute-type ATLL. Peripheral blood flow cytometry revealed a circulating clonal T cell population, and CSF was positive for ATLL involvement. After disease progression on the 3rd line of treatment, he started treatment with 9-ING-41 monotherapy in a clinical trial (NCT03678883). CT imaging after seven months showed a partial response. Sustained reduction of peripheral blood ATLL cells lasted 15 months. Treatment of patient-derived CD8 + T cells with 9-ING-41 increased the secretion of IFN-γ, granzyme B, and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). In conclusion, treatment of a patient with refractory ATLL with the GSK-3ß inhibitor 9-ING-41 resulted in a prolonged response. Ongoing experiments are investigating the hypothesis that 9-ING-41-induced T cell activation and immunomodulation contributes to its clinical activity. Further clinical investigation of 9-ING-41 for treatment of ATLL is warranted.

Thrombosis in COVID 2022: An Updated Narrative Review of Current Literature and Inpatient Management.

Early in the pandemic, it was recognized that infection with COVID-19 was associated with an increased incidence in both venous and arterial thrombotic events leading to poor patient outcomes. Given the rapid rise of the pandemic, anticoagulation strategies were initially based upon retrospective and observational data with few high-quality randomized control trials to help direct strategies regarding the use of thromboprophylaxis during hospitalization, empiric therapeutic anticoagulation, and extended-duration thromboprophylaxis after discharge. Over the past year, several randomized control trials have now been published evaluating these strategies. In this article, we hope to review the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and the use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.

Metformin suppresses pro-inflammatory cytokines in vitreous of diabetes patients and human retinal vascular endothelium.

Metformin is a traditional anti-hyperglycemic medication that has recently been shown to benefit vascular complications of diabetes via an anti-inflammatory mechanism other than glycemic control. This study aims to test the hypothesis that metformin suppresses diabetic retinopathy (DR) associated intraocular inflammation. Human vitreous from control and proliferative diabetic retinopathy (PDR) patients with or without long-term metformin treatment (> 5 years) were collected for multiple inflammatory cytokines measurements with a cytokine array kit. The vast majority of the measurable cytokines in PDR vitreous has a lower level in metformin group than non-metformin group. Although the p values are not significant due to a relatively small sample size and large deviations, the 95% confidence interval (CI) for the mean difference between the two groups shows some difference in the true values should not be neglected. Using quantitative ELISA, soluble intercellular adhesion molecule -1 (ICAM-1) and monocyte chemoattractant protein -1 (MCP-1) presented with significantly lower concentrations in metformin group versus non-metformin group. Metformin group also has significantly less up-regulated cytokines and diminished positive correlations among the cytokines when compared to non-metformin group. Possible role of AMP-activated protein kinase (AMPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in metformin's anti-inflammatory effects were studied in human retinal vascular endothelial cells (hRVECs) cultured in normal glucose (NG) and high glucose (HG) conditions. Metformin inhibited HG-induced ICAM-1, IL-8, and MCP-1 via AMPK activation, whereas pharmacological AMPK inhibition had no effect on its inhibition of NF-κB p65, sICAM-1, and tumor necrosis factor-α (TNF-α). Metformin-induced suppression of the inflammatory cytokines could also be mediated through its direct inhibition of NF-κB, independent of AMPK pathway. This is a proof-of-concept study that found metformin treatment was associated with reduced inflammatory responses in vitreous of diabetes patients and retinal vascular endothelial cells, supporting the rationale for using metformin to treat DR at an early stage.

Predictive factors and outcomes for ibrutinib in relapsed/refractory marginal zone lymphoma: a multicenter cohort study.

Ibrutinib is effective in the treatment of relapsed/refractory (R/R) marginal zone lymphoma (MZL) with an overall response rate (ORR) of 48%. However, factors associated with response (or lack thereof) to ibrutinib in R/R MZL in clinical practice are largely unknown. To answer this question, we performed a multicenter (25 US centers) cohort study and divided the study population into three groups: "ibrutinib responders"-patients who achieved complete or partial response (CR/PR) to ibrutinib; "stable disease (SD)"; and "primary progressors (PP)"-patients with progression of disease as their best response to ibrutinib. One hundred and nineteen patients met the eligibility criteria with 58%/17% ORR/CR, 29% with SD, and 13% with PP. The median PFS and OS were 29 and 71.4 months, respectively, with no difference in PFS or OS based on the ibrutinib line of therapy or type of therapy before ibrutinib. Patients with complex cytogenetics had an inferior PFS (HR = 3.08, 95% CI 1.23-7.67, p = 0.02), while those with both complex cytogenetics (HR = 3.00, 95% CI 1.03-8.68, p = 0.04) and PP (HR = 13.94, 95% CI 5.17-37.62, p < 0.001) had inferior OS. Only primary refractory disease to first-line therapy predicted a higher probability of PP to ibrutinib (RR = 3.77, 95% CI 1.15-12.33, p = 0.03). In this largest study to date evaluating outcomes of R/R MZL treated with ibrutinib, we show that patients with primary refractory disease and those with PP on ibrutinib are very high-risk subsets and need to be prioritized for experimental therapies.

Periprosthetic Fracture After Hindfoot Fusion Nail Treated With Spanning Antegrade Tibial Nail.

LEVEL OF EVIDENCE: Level V.

Foot and Ankle Injections in Athletes.

CONTEXT: Injections are commonly used by health care practitioners to treat foot and ankle injuries in athletes despite ongoing questions regarding efficacy and safety. EVIDENCE ACQUISITION: An extensive literature review was performed through MEDLINE, Google Scholar, and EBSCOhost from database inception to 2021. Keywords searched were injections, athletes, sports, foot and ankle, corticosteroids, platelet-rich plasma, and placental tissue. Search results included articles written in the English language and encompassed reviews, case series, empirical studies, and basic science articles. STUDY DESIGN: Clinical review. LEVEL OF EVIDENCE: Level 4. RESULTS: Corticosteroids, platelet-rich plasma/autologous blood, anesthetic, and placental tissue injections are commonly used in the treatment of foot and ankle injuries. Primary indications for injections in athletes include plantar fasciitis, Achilles tendinosis, isolated syndesmotic injury, and ankle impingement with varying clinical results. CONCLUSIONS: Despite promising results from limited case series and comparative studies, the data for safety and efficacy of injections for foot and ankle injuries in athletes remain inconclusive.

CD5 expression in marginal zone lymphoma predicts differential response to rituximab or bendamustine/rituximab.

We examined outcomes of 244 patients with marginal zone lymphoma (MZL) diagnosed in 2010-2020, of which 25 (10%) expressed CD5. CD5 expression was present in 22% of splenic, 8% of nodal, and 5% of extranodal MZL, and showed frequent blood/bone marrow involvement, elevated lactate dehydrogenase, and TP53 deletions. CD5 expression was not associated with progression-free or overall survival, but it conferred a significantly higher risk of histologic transformation (22% versus 4% at 5 years, p = 0.002). Among patients receiving first-line rituximab monotherapy, CD5 expression was associated with lower response rate (30% versus 77%, p = 0.006), PFS (25% versus 45% at 3 years, p = 0.003) and OS (44% versus 77%, p = 0.010), whereas CD5 status did not significantly affect outcomes of patients receiving bendamustine with rituximab (P for interaction = 0.012 for progression-free survival). CD5-positive MZL may have a propensity to leukemic dissemination, histologic transformation, and may derive benefit from first-line bendamustine/rituximab rather than rituximab alone.

Treatment-induced sarcoidosis in a patient with metastatic clear cell ovarian cancer.

Sarcoidosis is a granulomatous disease that commonly presents with lung or lymphatic system manifestations. Diagnosis is often delayed due to variable clinical presentation. This is a case of a patient with metastatic clear cell ovarian cancer who developed disease reoccurence after definitive treatment with surgery and adjuvant chemotherapy. She was treated with multiple lines of therapy, including investigational agents. During this time, she developed mediastinal lymphadenopathy and hypercalcaemia. Due to suspicion that her presentation was not a manifestation of her malignancy, she underwent two lymph node biopsies revealing granulomatous disease. She was initiated on prednisone for management of sarcoidosis, which led to radiologic, laboratory and symptomatic improvement. Although the precipitating factor for this patient's sarcoidosis cannot be definitively determined, nivolumab is a possible culprit. This case highlights the importance of a broad differential diagnosis when a patient undergoing antineoplastic treatment develops mediastinal lymphadenopathy or hypercalcaemia.

Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma.

The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)-based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.