Purpose: To describe the presentation of lacrimal gland secretions mimicking a positive Seidel test following combined complex cataract surgery and endocyclophotocoagulation (ECP). Observation: The patient presented with a posterior subcapsular cataract (PSC) most likely secondary to chronic steroid use for a history of chemical burns from a firework injury in 2019. This injury resulted in symblepharon formation and limbal stem cell deficiency. He also developed glaucoma secondary to steroid response and angle structure damage. On postoperative day 1 (POD 1) after combined cataract surgery and ECP, the patient's paracentesis was Seidel positive and aqueous suppression was started. On postoperative week 1 (POW 1), the paracentesis was Seidel negative; however, it was noted at this visit that there were 3 pinpoint areas in the superotemporal conjunctiva that were Seidel positive. Digital pressure did not worsen the leak. Ultrasound biomicroscopy (UBM) was performed at POW 2.5 and showed lacrimal gland ducts in the superotemporal conjunctiva. Given this, it is likely that the "Seidel positive" finding was not due to aqueous humor leakage, but secretions from lacrimal gland tissue that may have been dragged more anteriorly due to conjunctiva scarring, thus producing a false positive Seidel sign. Conclusion & importance: This case highlights a false positive Seidel sign in the context of an eye with a complex ocular history and recent surgery. Clinicians should recognize that a false positive Seidel sign is possible if normal lacrimal gland anatomy has been disturbed.
Subcutaneous injection is the preferred route of administration for many antibody therapeutics for reasons that include its speed and convenience. However, the small volume limit (typically ≤2 mL) for subcutaneous delivery often necessitates antibody formulations at high concentrations (commonly ≥100 mg/mL), which may lead to physicochemical problems. For example, antibodies with large hydrophobic or charged patches can be prone to self-interaction giving rise to high viscosity. Here, we combined X-ray crystallography with computational modeling to predict regions of an anti-glucagon receptor (GCGR) IgG1 antibody prone to self-interaction. An extensive mutational analysis was undertaken of the complementarity-determining region residues residing in hydrophobic surface patches predicted by spatial aggregation propensity, in conjunction with residue-level solvent accessibility, averaged over conformational ensembles from molecular dynamics simulations. Dynamic light scattering (DLS) was used as a medium throughput screen for self-interaction of ~ 200 anti-GCGR IgG1 variants. A negative correlation was found between the viscosity determined at high concentration (180 mg/mL) and the DLS interaction parameter measured at low concentration (2-10 mg/mL). Additionally, anti-GCGR variants were readily identified with reduced viscosity and antigen-binding affinity within a few fold of the parent antibody, with no identified impact on overall developability. The methods described here may be useful in the optimization of other antibodies to facilitate their therapeutic administration at high concentration.
Antibodies, Monoclonal, Humanized , Complementarity Determining Regions , Viscosity , Molecular Dynamics Simulation , Immunoglobulin G/genetics
The effects of the hepatitis C virus (HCV) on the nervous system have been primarily reported with a pathology of the peripheral nervous system through the involvement of a vasculitic process via cryoglobulinemia. A review of the recent literature reinforced the likely association between chronic HCV infection and transverse myelitis (TM), but the causal relationship remains elusive. Here, we present a rare case of acute TM developing over the course of days from symptom onset and a concomitant new diagnosis of HCV infection. A 31-year-old male with a medical history of stimulant use disorder with intravenous methamphetamine use presented to the hospital for acute bilateral leg weakness. The weakness was predominantly in his thighs and later progressed to his calves over the course of days. He denied urinary or fecal incontinence; however, on hospital day two, he developed acute urinary retention requiring the insertion of a Foley catheter. An initial MRI of the spine revealed an intramedullary T2 hyperintense signal at the lower thoracic cord concerning for TM, multiple sclerosis, ischemia, or neoplasm. MRI of the brain was unremarkable. Lumbar puncture results also displayed no abnormalities. HCV screening should be considered in all patients who develop acute neurological deficits that are not otherwise explained, such as TM, given the significant morbidity associated with delayed treatment.
Lymphoma is a well-known complication related to HIV infection; of these, non-Hodgkin lymphoma (NHL) is the most common subtype with Hodgkin lymphoma (HL) occurring less frequently. We present a rare case of a 35-year-old male with a history of HIV/AIDS well-controlled on antiretroviral therapy (ART) with an atypical HL presentation. He arrived at the emergency department with rectal bleeding, 30-pound unintentional weight loss, and subjective fever. CT scan of the abdomen and pelvis showed a circumferential mass extending from the mid-rectum to the anus, with extensive local lymphadenopathy. He underwent multiple biopsies of the mass and adjacent lymph nodes. The pathology report showed EBV-positive lymphoma with features of classical Hodgkin lymphoma (cHL) (positive for EBV-EBER by in-situ hybridization). He was started on A+AVD (brentuximab plus doxorubicin, vinblastine and dacarbazine). The patient tolerated the chemotherapy well without significant complications. We want to encourage physicians and providers to include anorectal HL in their differential diagnosis for HIV/AIDS patients with atypical rectal malignancy presentations and subsequent reporting of these cases.
Background: Osteomyelitis of the diabetic foot remains a significant complication that may result in the need for amputation. Proximal surgical margin histopathology after limb-sparing amputation could be used to guide antimicrobial duration and prognostic management but remains debatable. Here we evaluate if negative proximal bone margins predict outcomes of diabetic foot osteomyelitis at 1 year. Methods: A retrospective study assessed adults with diabetes undergoing limb-sparing foot amputations from September 2016 to September 2019. Patients required histopathology confirmation of osteomyelitis, proximal margin histopathology report, and documented electronic medical record follow-up through 12 months. The primary outcome evaluated if no further amputation at the same site was required in the following 12 months. Results: Of 92 patients, 57 (61.9%) had pathology-confirmed negative margins for osteomyelitis. Patients with negative margins required less frequent subsequent amputations at the same site within 12 months compared to positive margins (86.0% vs 65.7%; P = .003). Antibiotic duration was shorter in patients with negative margins (mean, 18 vs 30 days; P = .001). Negative-margin patients also noted lower rates of readmission at 12 months (26.3% vs 51.4%; P = .015) for site-specific complications. Staphylococcus aureus was more predominant in patients with positive versus negative margins (57.1% vs 29.8%; P = .017). Conclusions: Negative proximal bone margin by histopathology was associated with lower frequency of further amputations at the index surgical site within 12 months. This group also received shorter courses of antibiotic therapy. It was also associated with lower rates of readmission at 12 months for surgical-site complications. Proximal margin histopathology results potentially can be integrated to guide antimicrobial duration and decrease the frequency of further amputation at the original site.
OBJECTIVE: The study aims to investigate whether machine learning-based predictive models for cardiovascular disease (CVD) risk assessment show equivalent performance across demographic groups (such as race and gender) and if bias mitigation methods can reduce any bias present in the models. This is important as systematic bias may be introduced when collecting and preprocessing health data, which could affect the performance of the models on certain demographic sub-cohorts. The study is to investigate this using electronic health records data and various machine learning models. METHODS: The study used large de-identified Electronic Health Records data from Vanderbilt University Medical Center. Machine learning (ML) algorithms including logistic regression, random forest, gradient-boosting trees, and long short-term memory were applied to build multiple predictive models. Model bias and fairness were evaluated using equal opportunity difference (EOD, 0 indicates fairness) and disparate impact (DI, 1 indicates fairness). In our study, we also evaluated the fairness of a non-ML baseline model, the American Heart Association (AHA) Pooled Cohort Risk Equations (PCEs). Moreover, we compared the performance of three different de-biasing methods: removing protected attributes (e.g., race and gender), resampling the imbalanced training dataset by sample size, and resampling by the proportion of people with CVD outcomes. RESULTS: The study cohort included 109,490 individuals (mean [SD] age 47.4 [14.7] years; 64.5% female; 86.3% White; 13.7% Black). The experimental results suggested that most ML models had smaller EOD and DI than PCEs. For ML models, the mean EOD ranged from -0.001 to 0.018 and the mean DI ranged from 1.037 to 1.094 across race groups. There was a larger EOD and DI across gender groups, with EOD ranging from 0.131 to 0.136 and DI ranging from 1.535 to 1.587. For debiasing methods, removing protected attributes didn't significantly reduced the bias for most ML models. Resampling by sample size also didn't consistently decrease bias. Resampling by case proportion reduced the EOD and DI for gender groups but slightly reduced accuracy in many cases. CONCLUSIONS: Among the VUMC cohort, both PCEs and ML models were biased against women, suggesting the need to investigate and correct gender disparities in CVD risk prediction. Resampling by proportion reduced the bias for gender groups but not for race groups.
Cardiovascular Diseases , Humans , Female , Middle Aged , Male , Machine Learning , Algorithms , Random Forest , Logistic Models
We report a case of misdiagnosed tuberous sclerosis complex (TSC) in a patient without TSC gene variant presenting with bilateral renal angiomyolipomas and seizures in the context of strong family history of polycystic kidney disease. Clinical diagnosis of tuberous sclerosis complex was made and treatment with everolimus reduced size of renal angiomyolipomas. In this case, report we discuss the association between tuberous sclerosis complex and polycystic kidney disease and novel treatment for TSC.
By far the most prescient insights into the interior structure of the planet have been provided on the basis of elastic wave seismology. Analysis of the travel times of shear or compression wave phases excited by individual earthquakes, or through analysis of the elastic gravitational free oscillations that individual earthquakes of sufficiently large magnitude may excite, has been the central focus of Earth physics research for more than a century. Unfortunately, data provide no information that is directly relevant to understanding the solid state 'flow' of the polycrystalline outer 'mantle' shell of the planet that is involved in the thermally driven convective circulation that is responsible for powering the 'drift' of the continents and which controls the rate of planetary cooling on long timescales. For this reason, there has been an increasing focus on the understanding of physical phenomenology that is unambiguously associated with mantle flow processes that are distinct from those directly associated with the convective circulation itself. This paper reviews the past many decades of work that has been invested in understanding the most important of such processes, namely that which has come to be referred to as 'glacial isostatic adjustment' (GIA). This process concerns the response of the planet to the loading and unloading of the high latitude continents by the massive accumulations of glacial ice that have occurred with almost metronomic regularity over the most recent million years of Earth history. Forced by the impact of gravitationaln-body effects on the geometry of Earth's orbit around the Sun through the impact upon the terrestrial regime of received solar insolation, these surface mass loads on the continents have left indelible records of their occurrence in the 'Earth system' consisting of the oceans, continents, and the great polar ice sheets on Greenland and Antarctica themselves. Although this ice-age phenomenology has been clearly recognized since early in the last century, it was for over 50 years considered to be no more than an interesting curiosity, the understanding of which remained on the periphery of the theoretical physics of the Earth. This was the case in part because no globally applicable theory was available that could be applied to rigorously interpret the observations. Equally important to understanding the scientific lethargy that held back the understanding of this phenomenon involving mantle flow processes was the lack of appreciation of the wide range of observations that were in fact related to GIA physics. This paper is devoted to a review of the global theories of the GIA process that have since been developed as a means of interpreting the extensive variety of observations that are now recognized as being involved in the response of the planet to the loading and unloading of its surface by glacial ice. The paper will also provide examples of the further analyses of Earth physics and climate related processes that applications of the modern theoretical structures have enabled.
Staphylococcus hominis (S. hominis) is a Gram-positive, coagulase-negative bacteria that occurs as a normal commensal organism on the skin and may rarely cause native valve endocarditis (NVE). We present a 62-year-old male with type 2 diabetes mellitus, coronary artery disease, and hypertension presenting with fever and abdominal pain. CT (computerized tomography) of the abdomen revealed splenic and renal infarcts; further imaging with MRI (magnetic resonance imaging) revealed enhancements consistent with discitis in T5-6 and L1-2. Three sets of blood cultures were positive for S. hominis sensitive to methicillin on antimicrobial susceptibility tests, and echocardiogram showed posterior mitral valve vegetation. The patient was initially treated with 10 weeks of nafcillin IV (intravenous) 2 g q4 hours. He had recurrent bouts of S. hominis bacteremia that was treated with IV vancomycin. His clinical course was complicated by new-onset atrial fibrillation with rapid ventricular response and congestive heart failure. Once bacteremia was cleared, his infective endocarditis was successfully definitively treated with mitral valve replacement and tricuspid repair.
Discovering novel uses for existing drugs, through drug repurposing, can reduce the time, costs, and risk of failure associated with new drug development. However, prioritizing drug repurposing candidates for downstream studies remains challenging. Here, we present a high-throughput approach to identify and validate drug repurposing candidates. This approach integrates human gene expression, drug perturbation, and clinical data from publicly available resources. We apply this approach to find drug repurposing candidates for two diseases, hyperlipidemia and hypertension. We screen >21,000 compounds and replicate ten approved drugs. We also identify 25 (seven for hyperlipidemia, eighteen for hypertension) drugs approved for other indications with therapeutic effects on clinically relevant biomarkers. For five of these drugs, the therapeutic effects are replicated in the All of Us Research Program database. We anticipate our approach will enable researchers to integrate multiple publicly available datasets to identify high priority drug repurposing opportunities for human diseases.
Drug Repositioning , Gene Expression , Hyperlipidemias , Hypertension , Computational Biology , Databases, Factual , High-Throughput Screening Assays , Humans , Pharmaceutical Preparations , Population Health
BACKGROUND: Sepsis is the most common contributing factor towards development of acute kidney injury (AKI), which is strongly associated to poor prognostic outcomes. There are numerous epidemiological studies about sepsis-associated acute kidney injury (S-AKI), however current literature is limited with the majority of studies being conducted only in the intensive care unit (ICU) setting. The aim of this study was to assess the epidemiology of S-AKI in all hospitalized in-patients. METHODS: This was a retrospective population-based study using a large regional population database in Beijing city from January, 2005 to December, 2017. It included patients with S-AKI. Patients with pre-existing end-stage kidney disease (ESKD), previous history of kidney transplantation, or being pregnant were excluded. Patients' demographic characteristics, incidence, risk factors and outcomes of S-AKI were analyzed. The contrast between different time periods, different levels of hospitals, and types of the hospitals (traditional Chinese medicine hospitals (TCMHs) and western medicine hospitals (WMHs)) was also compared using Mann-Whitney U-test. RESULTS: A total of 19,579 patients were included. The overall incidence of S-AKI in all in-patients was 48.1%. The significant risk factors by multivariate analysis for AKI included: age, male, being treated in a level-II hospital, pre-existing hypertension, chronic kidney disease (CKD), cirrhosis, atrial fibrillation (AF), ischemic heart disease (IHD), being admitted from emergency room, ICU admission, shock, pneumonia, intra-abdominal infection, bloodstream infection, respiratory insufficiency, acute liver injury, disseminated intravascular coagulation (DIC) and metabolic encephalopathy. The overall mortality rate in this cohort was 55%. The multivariate analysis showed that the significant risk factors for mortality included: age, being treated in a level-II hospital and TCMHs, being admitted from emergency room, pre-existing comorbidities (CKD, malignancy, cirrhosis and AF), shock, pneumonia, intra-abdominal infection, bloodstream infection, central nervous system (CNS) infection and respiratory insufficiency. CONCLUSION: AKI is a common complication in patients with sepsis, and its incidence increases over time, especially when ICU admission is required. Exploring interventional strategies to address modifiable risk factors will be important to reduce incidence and mortality of S-AKI.
Vascular calcification (VC) involves the deposition of calcium apatite in vascular intima or media. Individuals of advanced age, having diabetes mellitus or chronic kidney disease (CKD) are particularly at risk. The pathogenesis of CKD-associated VC evolves considerably. The core driver is the phenotypic change involving vascular wall constituent cells toward manifestations similar to that undergone by osteoblasts. Gender-related differences are observed regarding the expressions of osteogenesis-regulating effectors, and presumably the prevalence/risk of CKD-associated VC exhibits gender-related differences as well. Despite the wealth of data focusing on gender-related differences in the risk of atherosclerosis, few report whether gender modifies the risk of VC, especially CKD-associated cases. We systematically identified studies of CKD-associated VC or its regulators/modifiers reporting data about gender distributions, and extracted results from 167 articles. A significantly higher risk of CKD-associated VC was observed in males among the majority of original investigations. However, substantial heterogeneity exists, since multiple large-scale studies yielded neutral findings. Differences in gender-related VC risk may result from variations in VC assessment methods, the anatomical segments of interest, study sample size, and even the ethnic origins of participants. From a biological perspective, plausible mediators of gender-related VC differences include body composition discrepancies, alterations involving lipid profiles, inflammatory severity, diversities in matrix Gla protein (MGP), soluble Klotho, vitamin D, sclerostin, parathyroid hormone (PTH), fibroblast growth factor-23 (FGF-23), and osteoprotegerin levels. Based on our findings, it may be inappropriate to monotonously assume that male patients with CKD are at risk of VC compared to females, and we should consider more background in context before result interpretation.
