Bulletin of Computer Science and Electrical Engineering (BCSEE)
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Moral Partiality and Duties of Love
No full textIn this paper, I make a case for the view that we have special relationship duties (also known as “associative duties”) that are not identical to or derived from our non-associative impartial moral obligations. I call this view “moral partialism”. On the version of moral partialism I defend, only loving relationships can normatively ground special relationship duties. I propose that for two capable adults to have a loving relationship, they must have mutual non-trivial desires to promote each other’s interests or flourishing and to respect each other’s core values. Along the way, I critically ascertain three alternative accounts of what normatively grounds special relationship duties and argue that my proposed view avoids the problems plaguing the alternatives
Association Between Fuchs Endothelial Corneal Dystrophy, Diabetes Mellitus, and Multimorbidity
No full textThe aim of this study was to assess risk for demographic variables and other health conditions that are associated with Fuchs endothelial corneal dystrophy (FECD).
We developed a FECD case-control algorithm based on structured electronic health record data and confirmed accuracy by individual review of charts at 3 Veterans Affairs (VA) Medical Centers. This algorithm was applied to the Department of VA Million Veteran Program cohort from whom sex, genetic ancestry, comorbidities, diagnostic phecodes, and laboratory values were extracted. Single-variable and multiple variable logistic regression models were used to determine the association of these risk factors with FECD diagnosis.
Being a FECD case was associated with female sex, European genetic ancestry, and a greater number of comorbidities. Of 1417 diagnostic phecodes evaluated, 213 had a significant association with FECD, falling in both ocular and nonocular conditions, including diabetes mellitus (DM). Five of 69 laboratory values were associated with FECD, with the direction of change for 4 being consistent with DM. Insulin dependency and type 1 DM raised risk to a greater degree than type 2 DM, like other microvascular diabetic complications.
Female sex, European ancestry, and multimorbidity increased FECD risk. Endocrine/metabolic clinic encounter codes and altered patterns of laboratory values support DM increasing FECD risk. Our results evoke a threshold model in which the FECD phenotype is intensified by DM and potentially other health conditions that alter corneal physiology. Further studies to better understand the relationship between FECD and DM are indicated and may help identify opportunities for slowing FECD progression
A portable, encapsulated microbial whole-cell biosensing system for the detection of bioavailable copper (II) in soil
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•A sensing-reporting fluorescent protein based microbial whole cell biosensor (MWCB) for copper (II) ions was developed.•In combination with a portable imaging system, polyacrylate-alginate encapsulated biosensor (BSD8) beads were able to measure bioavailable copper in spiked soil samples.•Calibration curves using from ImageJ and a microtiter plate reader were generated and compared.•Biosensor beads were stable for over a month when stored at room temperature and at 4 °C and could maintain their fluorescence and ability to detect copper throughout that time period.
A portable, field deployable whole-cell biosensor was developed that can withstand the complex matrices of soil and requires minimal to no sample preparation to monitor bioavailable concentrations of the essential micronutrient copper (II). Conventional measurement of micronutrients is often complex, laboratory-based, and not suitable for monitoring their bioavailable concentration. To address this need, we developed a fluorescence based microbial whole-cell biosensing (MWCB) system encoding for a Cu2+-responsive protein capable of generating a signal upon binding to Cu2+. The sensing-reporting protein was designed by performing circular permutation on the green fluorescent protein (GFP) followed by insertion of a Cu2+ binding motif into the structure of GFP. The design included insertion of several binding motifs and creating plasmids that encoded the corresponding sensing proteins. The signal generated by the sensing-reporting protein is directly proportional to the concentration of Cu2+ in the sample. Evaluation of the resulting biosensing systems carrying these plasmids was performed prior to selection of the optimal fluorescence emitting Cu2+-binding protein. The resulting optimized biosensing system was encapsulated in polyacrylate-alginate beads and embedded in soil for detection of the analyte. Once exposed to the soil, the beads were interrogated to measure the fluorescence signal emitted by the sensing-reporting protein using a portable imaging device. The biosensor was optimized for detection of Cu2+ in terms of selectivity, sensitivity, matrix effects, detection limits, and reproducibility in both liquid and soil matrices. The limit of detection (LoD) of the optimized encapsulated biosensor was calculated as 0.27 mg/L and 1.26 mg/kg of Cu2+ for Cu2+ in solution and soil, respectively. Validation of the portable imaging tools as a potential biosensing device in the field was performed
A phase 1 study of AGEN2373, a novel CD137 agonist antibody designed to avoid hepatoxicity, in patients with advanced solid tumors
No full text2524 Background: We present results from the completely enrolled monotherapy arm of the first-in-human dose escalation study of AGEN2373, a novel CD137 agonist antibody engineered to maximize efficacy by circumventing the dose-limiting hepatotoxicity reported for prior CD137 agonists (NCT04121676). AGEN2373 binds to a unique epitope of CD137 on effector T and NK cells in the tumor and tumor-draining lymph nodes, promoting co-engagement of activating Fcγ receptors. CD137 (4-1BB) is a tumor necrosis factor receptor superfamily protein and co-stimulatory receptor that promotes anti-tumor activity of adaptive and innate immune cells, making it an attractive target for immunotherapy. Methods: 46 patients (pts) received AGEN2373 IV every 2 weeks (Q2W), Q3W, or Q4W at doses between 0.03 and 10 mg/kg in a 3+3 design. Key endpoints included safety, tolerability, PK, preliminary efficacy, and PD markers. Imaging was Q8W. Results: Pts were enrolled between Oct 2019 and May 2022 with a median follow-up of 7.2 months. The median age was 64 (range 33-82). The most common tumor types were colorectal cancer, 13 pts (28%) and sarcoma, 8 (17%). Median prior therapies were 4 (range 1-14) including 48% with prior immunotherapy. There were no dose-limiting toxicities (DLTs) and no treatment-related hepatitis. 37% of pts had treatment-related AEs (TRAEs). TRAEs >10% were limited to fatigue (17%) and nausea (15%). There were no G3, 4 or 5 TRAEs. Pharmacokinetic parameters including half-life, clearance, and volume of distribution were consistent with a human IgG1 Fc backbone. Induction of soluble CD137 was dose dependent with 2 mg/kg as the lowest saturating dose and minimum predicted efficacious dose. In 19 pts treated at 2 mg/kg or higher who had at least one post-baseline scan, the overall response rate (ORR) was 11% (n=2); 37% had SD (n=7) resulting in a disease control rate (DCR) (CR, PR or SD) of 47%. Notable responses include: a pt with vulvar SCC who had progressed rapidly on pembrolizumab and had a confirmed partial response (cPR) while remaining on AGEN2373 x 2 mg/kg q2w for ~40 wks, and a pt with ampullary carcinoma with 4 prior regimens had a cPR on AGEN2373 x 6 mg/kg q3w with complete resolution of the pancreatic lesion. A pt with CRPC had a 38% tumor reduction in liver target lesions (confirmed) on AGEN2373 x 10mg/kg q3w but was non-evaluable due to palliative radiation to bone metastases. Conclusions: AGEN2373 showed objective responses as monotherapy in heavily pretreated pts with solid tumors and was well-tolerated with no evidence of hepatotoxicity. This distinguishes AGEN2373 from previous CD137-targeted agents that reported dose-limiting hepatotoxicity. Combination therapy with botensilimab, a novel Fc-enhanced CTLA-4 antagonist, is being studied in pts with PD(L)-1 pretreated melanoma. Clinical trial information: NCT04121676
Intracranial sub-second dopamine measurements during a risky decision-making task in patients with Alcohol Use Disorder suggest diminished dopaminergic signals about ‘relief’
No full textShaken Baby Syndrome - Chapter 49
No full textShaken baby syndrome (SBS) is a leading cause of childhood trauma and results in significant morbidity and mortality. Systemic evaluation should be performed in any child suspected of SBS including physical exam, fundus photography, skeletal survey, neuroimaging, and serologies. One of the hallmark findings of SBS is innumerable retinal hemorrhages extending anterior to the equator. Treatment of ocular findings centers around amblyopia management and visual development and may require anterior scatter laser in cases of ischemia, or vitrectomy for non-clearing vitreous hemorrhage obstructing the visual axis, macular hole, and retinal detachment. Many infants with SBS may suffer from significant cortical vision loss and bilateral optic atrophy regardless of their ocular findings and treatment. The long-term visual prognosis of SBS is guarded
Venetoclax Monotherapy as Front-Line Therapy for Blastic Plasmacytoid Dendritic Cell Neoplasm
No full textVenetoclax is an approved treatment of relapsed/refractory Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). We report a unique case of venetoclax monotherapy used for front-line induction and as a bridge to allogeneic hematopoietic stem cell transplantation (HCT). Venetoclax therapy resulted in rapid complete resolution of skin lesions, however, treatment interruption due to neutropenia led to brisk cancer recurrence. Fortunately, the patient responded to re-challenge and was able to undergo HCT. Venetoclax is active in the first-line treatment setting for BPDCN, however its effect on blood counts and durability of response should be further studied
HIV, opioid use, and alterations to the gut microbiome: elucidating independent and synergistic effects
No full textBackgroundThe microbiome is essential to immune development, defense against pathogens, and modulation of inflammation. Microbial dysbiosis has been reported in various diseases including human immunodeficiency virus (HIV) and opioid use disorder (OUD). Notably, people living with HIV (PLWH) have been reported to both have higher rates of OUD and use opioids at higher rates than the general public. Thus, studying gut microbial alterations in people living with HIV and with OUD could elucidate mechanisms pertaining to how these conditions both shape and are shaped by the microbiome. However, to date few studies have investigated how HIV and OUD in combination impact the microbiome.Aim of reviewHere, we review previous studies outlining interactions between HIV, opioid use, and microbial dysbiosis and describe attempts to treat this dysbiosis with fecal microbial transplantation, probiotics, and dietary changes.Key scientific concepts of reviewWhile the limited number of studies prevent overgeneralizations; accumulating data suggest that HIV and opioid use together induce distinct alterations in the gut microbiome. Among the three existing preclinical studies of HIV and opioid use, two studies reported a decrease in Lachnospiraceae and Ruminococcaceae, and one study reported a decrease in Muribaculaceae in the combined HIV and opioid group relative to HIV-alone, opioid-alone, or control groups. These bacteria are known to modulate immune function, decrease colonic inflammation, and maintain gut epithelial barrier integrity in healthy individuals. Accordingly, modulation of the gut microbiome to restore gut homeostasis may be attempted to improve both conditions. While mixed results exist regarding treating dysbiosis with microbial restoration in PLWH or in those with opioid dependency, larger well-defined studies that can improve microbial engraftment in hosts hold much promise and should still be explored
Music Outreach in Action: A Step-By-Step Guide to Creating Concerts in K-12 Schools for Instrumental Performance Majors
No full textMusic outreach has been a means for students to apply musical knowledge and instrumental skills that relate to real-world performance experiences that can also develop entrepreneurial skills necessary for today's professional musicians. Since university and conservatory performance degree programs do not incorporate an outside performance opportunity in the core curriculum, outreach can be used as a method of application for enhanced performance experience. To introduce this concept, I have created a performer's guide designed to help instrumental students engage in this activity. This step-by-step guide will teach instrumental music students how to secure and execute a successful outreach concert, develop new ways to communicate music and learn how to plan and execute their concert experience