Isolation.

This comic tells the true story of a hospitalist physician learning from a patient how to slow down. It is a commentary on the isolating experience of hospitalization-magnified for patients by infection control precautions and hospital restrictions and for clinicians by long hours away from family and friends, particularly during peaks of the COVID-19 pandemic.

Turning the world upside down: reversal-of-vision metamorphopsia in a patient with syncope.

An elderly man with recurrent syncope was admitted with a globe rupture following a syncopal attack. After an initial unremarkable evaluation, the patient reported inversion of the room's wall clock during a bedside evaluation. This symptom is called reversal-of-vision metamorphopsia (RVM) and is a rare visual disturbance that typically results from organic processes localised to the retina and/or posterior cortex of the brain or in some cases is psychogenic in nature. In this case, both the syncope and RVM were caused by impaired circulation in the posterior cortex, and management included an antiplatelet agent, statin and permissive blood pressure targets, which resulted in the correction of RVM.

Human skeletal muscle tissue chip autonomous payload reveals changes in fiber type and metabolic gene expression due to spaceflight.

Microphysiological systems provide the opportunity to model accelerated changes at the human tissue level in the extreme space environment. Spaceflight-induced muscle atrophy experienced by astronauts shares similar physiological changes to muscle wasting in older adults, known as sarcopenia. These shared attributes provide a rationale for investigating molecular changes in muscle cells exposed to spaceflight that may mimic the underlying pathophysiology of sarcopenia. We report the results from three-dimensional myobundles derived from muscle biopsies from young and older adults, integrated into an autonomous CubeLab™, and flown to the International Space Station (ISS) aboard SpaceX CRS-21 as part of the NIH/NASA funded Tissue Chips in Space program. Global transcriptomic RNA-Seq analyses comparing the myobundles in space and on the ground revealed downregulation of shared transcripts related to myoblast proliferation and muscle differentiation. The analyses also revealed downregulated differentially expressed gene pathways related to muscle metabolism unique to myobundles derived from the older cohort exposed to the space environment compared to ground controls. Gene classes related to inflammatory pathways were downregulated in flight samples cultured from the younger cohort compared to ground controls. Our muscle tissue chip platform provides an approach to studying the cell autonomous effects of spaceflight on muscle cell biology that may not be appreciated on the whole organ or organism level and sets the stage for continued data collection from muscle tissue chip experimentation in microgravity. We also report on the challenges and opportunities for conducting autonomous tissue-on-chip CubeLabTM payloads on the ISS.

Validation of Human Skeletal Muscle Tissue Chip Autonomous Platform to Model Age-Related Muscle Wasting in Microgravity.

Microgravity-induced muscle atrophy experienced by astronauts shares similar physiological changes to muscle wasting experienced by older adults, known as sarcopenia. These shared attributes provide a rationale for investigating microgravity-induced molecular changes in human bioengineered muscle cells that may also mimic the progressive underlying pathophysiology of sarcopenia. Here, we report the results of an experiment that incorporated three-dimensional myobundles derived from muscle biopsies from young and older adults, that were integrated into an autonomous CubeLabâ"¢, and flown to the International Space Station (ISS) aboard SpaceX CRS-21 in December 2020 as part of the NIH/NASA funded Tissue Chips in Space program. Global transcriptomic RNA-Seq analysis comparing the myobundles in space and on the ground revealed downregulation of shared transcripts related to myoblast proliferation and muscle differentiation for those in space. The analysis also revealed differentially expressed gene pathways related to muscle metabolism unique to myobundles derived from the older cohort exposed to the space environment compared to ground controls. Gene classes related to inflammatory pathways were uniquely modulated in flight samples cultured from the younger cohort compared to ground controls. Our muscle tissue chip platform provides a novel approach to studying the cell autonomous effects of microgravity on muscle cell biology that may not be appreciated on the whole organ or organism level and sets the stage for continued data collection from muscle tissue chip experimentation in microgravity. Thus, we also report on the challenges and opportunities for conducting autonomous tissue-on-chip CubeLab TM payloads on the ISS.

Improving Consumer Experiences in Permanent Supportive Housing Co-Located With Health Centers: A Case Study From the Department of Veterans Affairs.

BACKGROUND: Permanent Supportive Housing (PSH), which provides subsidies for independent housing and supportive services, is an evidence-based practice that improves health and housing for homeless experienced persons. Though most PSH is scattered-site, that is, housing dispersed throughout the mainstream rental market, project-based PSH offers housing and supportive services in dedicated facilities with on-site services. In 2013, the Veterans Health Administration (VA) at Greater Los Angeles opened a novel project-based PSH program located on a VA campus. To inform plans to expand project-based PSH at this VA, we examined participants' experiences in this program. We aimed to identify participant characteristics that suggested they were well suited for the planned PSH expansion; to characterize services that participants found valuable in this setting; and to highlight gaps between participants' needs and PSH services provided. METHODS: We performed semi-structured interviews with a convenience sample (n = 24) of participants who had engaged in this project-based PSH program. Interviews asked why participants selected housing on a VA campus and explored valued program characteristics, designs, and services. Using rapid analysis methods, we generated templated summaries of each participant's responses across the domains of our interview guide, then used matrix analyses to identify salient themes across the interviews. KEY FINDINGS: Participants appreciated the ease of access to medical and mental health services; however, as services were assumed to be optimized by virtue of co-location with VA healthcare, their PSH providers often did not link them with non-VA social services as assertively as desired. Many participants raised concerns about building safety and on-site substance use. A lack of participant engagement in program oversight, often leading to conflicts with staff and building management, was also highlighted in our interviews. DISCUSSION: Given the value placed on ease of access to healthcare, these data suggest the value of this PSH model for persons with healthcare vulnerabilities. Specific recommendations for the planned PSH expansion include: (1) continuation of proximate, open-access healthcare; (2) clear tenant policies; (3) tenant councils for each development; (4) staff knowledgeable of non-VA resources and social services; (5) Veteran-preferred hiring practices by Property/Service management; (6) gender-specific accommodations; and (7) robust 24/7 security on-site.

Five nanometer size highly positive silver nanoparticles are bactericidal targeting cell wall and adherent fimbriae expression.

To tackle growing antibiotic resistance (AR) and hospital-acquired infections (HAIs), novel antimicrobials are warranted that are effective against HAIs and safer for human use. We hypothesize that small 5 nm size positively charged nanoparticles could specifically target bacterial cell wall and adherent fimbriae expression, serving as the next generation antibacterial agent. Herein we show highly positively charged, 5 nm amino-functionalized silver nanoparticles (NH2-AgNPs) were bactericidal; highly negatively charged, 45 nm citrate-functionalized AgNPs (Citrate-AgNPs) were nontoxic; and Ag+ ions were bacteriostatic forming honeycomb-like potentially resistant phenotype, at 10 µg Ag/mL in E. coli. Further, adherent fimbriae were expressed with Citrate-AgNPs (0.5-10 µg/mL), whereas NH2-AgNPs (0.5-10 µg/mL) or Ag+ ions (only at 10 µg/mL) inhibited fimbriae expression. Our results also showed no lipid peroxidation in human lung epithelial and dermal fibroblast cells upon NH2-AgNPs treatments, suggesting NH2-AgNPs as a biocompatible antibacterial candidate. Potent bactericidal effects demonstrated by biocompatible NH2-AgNPs and the lack of toxicity of Citrate-AgNPs lend credence to the hypothesis that small size, positively charged AgNPs may serve as a next-generation antibacterial agent, potentially addressing the rising HAIs and patient health and safety.

Effect of age on brain metabotropic glutamate receptor subtype 5 measured with [18F]FPEB PET.

OBJECTIVE: Metabotropic glutamate receptor subtype 5 (mGluR5) is integral to the brain glutamatergic system and cognitive function. This study investigated whether aging is associated with decreased brain mGluR5 availability. METHODS: Cognitively normal participants (n = 45), aged 18 to 84 years, underwent [18F]FPEB positron emission tomography scans to quantify brain mGluR5. Distribution volume (VT) was computed using a venous or arterial input function and equilibrium modeling from 90 to 120 min. In the primary analysis, the association between age and VT in the hippocampus and association cortex was evaluated using a linear mixed model. Exploratory analyses assessed the association between age and VT in multiple brain regions. The contribution of gray matter tissue alterations and partial volume effects to associations with age was also examined. RESULTS: In the primary analysis, older age was associated with lower [18F]FPEB binding to mGluR5 (P = 0.026), whereas this association was not significant after gray matter masking or partial volume correction to account for age-related tissue loss. Post hoc analyses revealed an age-related decline in mGluR5 availability in the hippocampus of 4.5% per decade (P = 0.007) and a non-significant trend in the association cortex (P = 0.085). An exploratory analysis of multiple brain regions revealed broader inverse associations of age with mGluR5 availability, but not after partial volume correction. CONCLUSION: Reductions in mGluR5 availability with age appear to be largely mediated by tissue loss. Quantification of [18F]FPEB binding to mGluR5 may expand our understanding of age-related molecular changes and the relationship with brain tissue loss.

Validation of inducible basophil biomarkers: Time, temperature and transportation.

BACKGROUND: The short stability window of several hours from blood collection to measuring basophil activation has limited the use of flow cytometry-based basophil activation assays in clinical settings. We examine if it is possible to extend this window to 1 day allowing for shipment of samples between laboratories. Several options exist for reporting the results including reporting all the measured values directly, calculating ratios and reporting a single value covering all measured results. Each of these options have different stability and value to the physician. METHODS: Whole blood samples from peanut allergic patients were stimulated with four different peanut concentrations at Day 0, Day 1, and Day 2. Samples were stored under temperature-controlled conditions. Flow cytometry was used to analyze the samples. The basophil activation and degranulation were measured as percentage of positive CD63 basophils and CD203c MFI fold change. Shipped samples were transported under ambient conditions. RESULTS: The results show that CD63 is a stable marker at Day 1. The CD203c ratio decreases significantly at Day 1. Calculating the CD63/IgE ratio proves to be more stable than CD63 alone. The most stable readouts are the semi-quantitative results and the trajectory of the dose response curve. Finally, we confirmed that the stability can be extended to samples shipped overnight to the laboratory. CONCLUSIONS: It is possible to extend the stability of the basophil activation assay to 1 day for samples stored at 18-25°C as well as samples shipped under ambient conditions as long as the temperature is within the 2-37°C range.

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies.

IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.

Subtle case of dapsone-induced methaemoglobinaemia.

Methaemoglobinaemia is a rare disease that is typically caused by a medication or other exogenous agent, with dapsone being the most common. It occurs when the concentration of methaemoglobin rises via ferrous haeme irons becoming oxidised to the ferric state, which shifts the oxygen dissociation curve to the left. The net result of an elevated methaemoglobin concentration is functional anaemia and impaired oxygen delivery to tissues. At lower blood levels, this can cause symptoms such as cyanosis, lethargy, headache and fatigue, whereas at higher levels it can be fatal. Here we discuss a subtle case of dapsone-induced methaemoglobinaemia presenting as subacute mental status changes and apparent hypoxia, thus highlighting the association between methaemoglobinaemia and dapsone. This case demonstrates the importance of thorough medication reconciliation and maintaining a broad differential diagnosis, while also recognising the significance of conflicting data and their implications for the workup.

Web Exclusive. Annals Graphic Medicine - Attending on the Medicine Wards.

[Figure: see text].

The Association between Limited English Proficiency and Sepsis Mortality.

BACKGROUND: Limited English proficiency (LEP) has been implicated in poor health outcomes. Sepsis is a frequently fatal syndrome that is commonly encountered in hospital medicine. The impact of LEP on sepsis mortality is not currently known. OBJECTIVE: To determine the association between LEP and sepsis mortality. DESIGN: Retrospective cohort study. SETTING: 800-bed, tertiary care, academic medical center. PATIENTS: Electronic health record data were obtained for adults admitted to the hospital with sepsis between June 1, 2012 and December 31, 2016. MEASUREMENTS: The primary predictor was LEP. Patients were defined as having LEP if their self-reported primary language was anything other than English and interpreter services were required during hospitalization. The primary outcome was inpatient mortality. Mortality was compared across races stratified by LEP using chi-squared tests of significance. Bivariable and multivariable logistic regressions were performed to investigate the association between mortality, race, and LEP, adjusting for baseline characteristics, comorbidities, and illness severity. RESULTS: Among 8,974 patients with sepsis, we found that 1 in 5 had LEP, 62% of whom were Asian. LEP was highly associated with death across all races except those identifying as Black and Latino. LEP was associated with a 31% increased odds of mortality after adjusting for illness severity, comorbidities, and other baseline characteristics, including race (OR 1.31, 95% CI 1.06-1.63, P = .02). CONCLUSIONS: In a single-center study of patients hospitalized with sepsis, LEP was associated with mortality across nearly all races. This is a novel finding that will require further exploration into the causal nature of this association.