In vivo selection of anti-HIV-1 gene-modified human hematopoietic stem/progenitor cells to enhance engraftment and HIV-1 inhibition.

Hematopoietic stem/progenitor cell (HSPC)-based anti-HIV-1 gene therapy holds great promise to eradicate HIV-1 or to provide long-term remission through a continuous supply of anti-HIV-1 gene-modified cells without ongoing antiretroviral therapy. However, achieving sufficient engraftment levels of anti-HIV gene-modified HSPC to provide therapeutic efficacy has been a major limitation. Here, we report an in vivo selection strategy for anti-HIV-1 gene-modified HSPC by introducing 6-thioguanine (6TG) chemoresistance through knocking down hypoxanthine-guanine phosphoribosyl transferase (HPRT) expression using RNA interference (RNAi). We developed a lentiviral vector capable of co-expressing short hairpin RNA (shRNA) against HPRT alongside two anti-HIV-1 genes: shRNA targeting HIV-1 co-receptor CCR5 and a membrane-anchored HIV-1 fusion inhibitor, C46, for efficient in vivo selection of anti-HIV-1 gene-modified human HSPC. 6TG-mediated preconditioning and in vivo selection significantly enhanced engraftment of HPRT-knockdown anti-HIV-1 gene-modified cells (>2-fold, p < 0.0001) in humanized bone marrow/liver/thymus (huBLT) mice. Viral load was significantly reduced (>1 log fold, p < 0.001) in 6TG-treated HIV-1-infected huBLT mice compared to 6TG-untreated mice. We demonstrated that 6TG-mediated preconditioning and in vivo selection considerably improved engraftment of HPRT-knockdown anti-HIV-1 gene-modified HSPC and repopulation of anti-HIV-1 gene-modified hematopoietic cells in huBLT mice, allowing for efficient HIV-1 inhibition.

Evaluating the Downstream Revenues of a Self-Pay Bi-Parametric Prostate MRI Program.

OBJECTIVE: To quantify downstream healthcare utilization and revenue associated with a self-pay bi-parametric prostate MRI (bpMRI) program. METHODS: Medical records of 592 patients who underwent bpMRI between August 2017 and March 2020 were examined for follow-up clinical activities. These include prostate biopsy, radical prostatectomy, external beam radiation therapy, brachytherapy, androgen deprivation therapy, CT Chest, Abdomen and Pelvis, PET/CT, MRI Pelvis, and Nuclear Medicine Bone Scans. The charges for each clinical activity were derived from the Medicare Physician Fee Schedule to conservatively estimate revenues. This patient population was further divided into four groups: Group A, patients who demonstrated an MRI lesion and underwent prostatectomy; Group B, patients who did not demonstrate lesion but underwent prostatectomy; Group C, patients who demonstrated lesion but did not undergo prostatectomy; and Group D, patients who neither demonstrated lesion nor underwent prostatectomy. Revenues for each group were categorized by Urology, Radiation Oncology and Radiology subspecialties. RESULTS: Conservative estimates yielded $520 of downstream revenue per patient who underwent bpMRI. Group A patients yielded 47% of total revenue ($1974 per patient). Group B patients, the smallest group, yielded $1828 per patient. Group C patients made up the largest group and grossed $398 per patient. Group D demonstrated the lowest per patient revenue of $179. Groups A and B yielded most relative revenue for Urology. Group C yielded most relative revenue for Radiation Oncology, and Group D yielded most relative revenue for Radiology. CONCLUSION: A self-pay bpMRI program has the potential to improve patient access to prostate cancer screening while remaining financial sustainable.

Inflammatory gene expression during acute high-altitude exposure.

The molecular signalling pathways that regulate inflammation and the response to hypoxia share significant crosstalk and appear to play major roles in high-altitude acclimatization and adaptation. Several studies demonstrate increases in circulating candidate inflammatory markers during acute high-altitude exposure, but significant gaps remain in our understanding of how inflammation and immune function change at high altitude and whether these responses contribute to high-altitude pathologies, such as acute mountain sickness. To address this, we took an unbiased transcriptomic approach, including RNA sequencing and direct digital mRNA detection with NanoString, to identify changes in the inflammatory profile of peripheral blood throughout 3 days of high-altitude acclimatization in healthy sea-level residents (n = 15; five women). Several inflammation-related genes were upregulated on the first day of high-altitude exposure, including a large increase in HMGB1 (high mobility group box 1), a damage-associated molecular pattern (DAMP) molecule that amplifies immune responses during tissue injury. Differentially expressed genes on the first and third days of acclimatization were enriched for several inflammatory pathways, including nuclear factor-κB and Toll-like receptor (TLR) signalling. Indeed, both TLR4 and LY96, which encodes the lipopolysaccharide binding protein (MD-2), were upregulated at high altitude. Finally, FASLG and SMAD7 were associated with acute mountain sickness scores and peripheral oxygen saturation levels on the first day at high altitude, suggesting a potential role of immune regulation in response to high-altitude hypoxia. These results indicate that acute high-altitude exposure upregulates inflammatory signalling pathways and might sensitize the TLR4 signalling pathway to subsequent inflammatory stimuli. KEY POINTS: Inflammation plays a crucial role in the physiological response to hypoxia. High-altitude hypoxia exposure causes alterations in the inflammatory profile that might play an adaptive or maladaptive role in acclimatization. In this study, we characterized changes in the inflammatory profile following acute high-altitude exposure. We report upregulation of novel inflammation-related genes in the first 3 days of high-altitude exposure, which might play a role in immune system sensitization. These results provide insight into how hypoxia-induced inflammation might contribute to high-altitude pathologies and exacerbate inflammatory responses in critical illnesses associated with hypoxaemia.

Trends in Medicare Part B Payments and Utilization for Imaging Services Between 2009 and 2019.

BACKGROUND: In 2019, the total National Healthcare Expenditure (NHE) reached $3.8 trillion, or nearly 20% of the total Gross Domestic Product. This represents a 4-fold increase in its Gross Domestic Product share since 1960. Given the magnitude and growth of such expenditures, healthcare cost containment is central to the country's financial sustainability. Moreover, as Medicare represents nearly 20% of the total NHE, it is a primary target for piloting, implementing and scaling initiatives that reduce expenditures. OBJECTIVE: To assess trends in Medicare Physician Fee Schedule for Service (Part B) payments and utilization for Imaging relative to other services from 2009 through 2019. MATERIALS AND METHODS: We conducted a retrospective observational study of annual expenditures and utilization of imaging services using data from Centers for Medicare and Medicaid Services Medicare Part B. Data was grouped according to the Berenson-Eggers Type of Service Classification. The values were adjusted for inflation and we calculated the annual changes and the compound annual growth rates and the price elasticity of supply. RESULTS: For the 10-year period, Imaging represented on average 8% of the total Medicare Part B expenditures, an equivalent of 1.4% of total Medicare expenditures or 0.05% of the NHE. While NHE, overall Medicare and overall Part B had positive growth rates of total expenditures, Imaging did not. Moreover, Imaging had the most negative CAGR compared to all other categories, including Drugs, Procedures, Evaluation and Management and Durable Medical Equipment. CONCLUSION: Imaging did not contribute to the increase in Medicare Part B expenditures, and it might have been disproportionately affected by cost containment policies.

Utility and Clinical Implications of Appendicular Skeleton Magnetic Resonance Imaging in Multiple Myeloma: A Single-Institutional 15-Year Experience.

OBJECTIVE: The aim of this study was to evaluate the utility of appendicular skeleton magnetic resonance imaging (MRI) in the management of multiple myeloma over 15 years. METHODS: A total of 107 appendicular MRIs were obtained from 67 patients. Variables including age, sex, diagnosis, stage, indication, transplant status, MRI result, and treatment course were analyzed. RESULTS: The most common indication was pain (76.6%). The most commonly affected bone groups were the proximal lower (54.3%) and upper extremity (47.6%). Most (83%) positive examinations demonstrated focal disease. Advanced Durie-Salmon stage was associated with increase in appendicular disease (P = 0.0056). Increasing age and prior negative positron emission tomography/computed tomography were associated with a decrease in appendicular disease (P = 0.0036 and 0.0011). When neoplasm was seen, 58.5% underwent management alteration. Advanced stage and history of relapse were associated with treatment alterations (P = 0.0096 and 0.0031). CONCLUSION: Appendicular MRIs comprised 9.6% of MRIs ordered. Appendicular MRI elucidates both neoplastic and nonneoplastic causes of pain. Most examinations with MRI positive for myeloma had subsequent skeletal disease and resulted in altered management.

Hypoxia and Inflammation: Insights From High-Altitude Physiology.

The key regulators of the transcriptional response to hypoxia and inflammation (hypoxia inducible factor, HIF, and nuclear factor-kappa B, NF-κB, respectively) are evolutionarily conserved and share significant crosstalk. Tissues often experience hypoxia and inflammation concurrently at the site of infection or injury due to fluid retention and immune cell recruitment that ultimately reduces the rate of oxygen delivery to tissues. Inflammation can induce activity of HIF-pathway genes, and hypoxia may modulate inflammatory signaling. While it is clear that these molecular pathways function in concert, the physiological consequences of hypoxia-induced inflammation and how hypoxia modulates inflammatory signaling and immune function are not well established. In this review, we summarize known mechanisms of HIF and NF-κB crosstalk and highlight the physiological consequences that can arise from maladaptive hypoxia-induced inflammation. Finally, we discuss what can be learned about adaptive regulation of inflammation under chronic hypoxia by examining adaptive and maladaptive inflammatory phenotypes observed in human populations at high altitude. We aim to provide insight into the time domains of hypoxia-induced inflammation and highlight the importance of hypoxia-induced inflammatory sensitization in immune function, pathologies, and environmental adaptation.

Are asymptomatic gastrointestinal findings on imaging more common in COVID-19 infection? Study to determine frequency of abdominal findings of COVID-19 infection in patients with and without abdominal symptoms and in patients with chest-only CT scans.

PURPOSE: To identify incidence of abdominal findings in COVID-19 patients with and without abdominal symptoms on various imaging modalities including chest-only CT scans and to correlate them with clinical, laboratory and chest CT findings. MATERIALS AND METHODS: In this retrospective study, we searched our clinical database between March 1st, 2020 and May 22nd, 2020 to identify patients who had positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) on throat swabs for COVID-19, had availability of clinical, laboratory information and had availability of CT scan of chest or abdominal radiograph, abdominal ultrasound or CT scan within 2 weeks of the diagnosis. Abdominal imaging findings on all imaging modalities were documented. Chest CT severity score (CT-SS) was assessed in all patients. Clinical and laboratory findings were recorded from the electronic medical record. Statistical analysis was performed to determine correlation of abdominal findings with CT-SS, clinical and laboratory findings. RESULTS: Out of 264 patients with positive RT-PCR, 73 patients (38 males and 35 females; 35 African American) with mean age of 62.2 (range 21-94) years were included. The median CTSS was 13.5 (IQR 75-25 18-8). Most common finding in the abdomen on CT scans (n = 72) were in the gastrointestinal system in 13/72 patients (18.1%) with fluid-filled colon without wall thickening or pericolonic stranding (n = 12) being the most common finding. Chest-only CT (n = 49) found bowel findings in 3 patients. CTSS did not differ in terms of age, sex, race or number of comorbidities but was associated with longer duration of hospitalization (p = 0.0.0256), longer intensive care unit stay (p = 0.0263), more frequent serum lactate dehydrogenase elevation (p = 0.0120) and serum C-reactive protein elevation (p = 0.0402). No statistically significant correlation of occurrence of bowel abnormalities with CTSS, clinical or laboratory features. Deep venous thrombosis was seen in 7/72 patients (9.8%) with three patients developing pulmonary embolism CONCLUSION: Abnormal bowel is the most common finding in the abdomen in patients with COVID-19 infection, is often without abdominal symptoms and occurs independent of severity of pulmonary involvement, other clinical and laboratory features.

Interventional radiology procedural volume changes during COVID-19 initial phase: A tertiary level Midwest health system experience.

BACKGROUND: To evaluate Interventional Radiology (IR) procedural volume changes at a large Midwest health system between March 17, 2020 and April 30, 2020 following a state-mandated shutdown of nonessential procedures during the initial phase of COVID-19. METHODS: IR procedural volumes were compiled, stratified by location and compared with Diagnostic Radiology (DR) volumes during the same timeframe. Procedure volume was categorized by type, including oncology, dialysis interventions, and drainage procedures with comparisons made using Z-score test for proportions. IR and system-wide surgical procedural volume was compared with baseline values. RESULTS: System-wide IR procedural volume decreased by 35%, with a 41% decrease in outpatient and a 25% decrease in inpatient volume during the state-mandated order. DR volume decreased by 45%, with a 57% decrease in outpatient and a 22% decrease in inpatient volume. Total IR procedural volume during the mandate was 1077 versus 1518 during the preceding six weeks. The proportion of Interventional Oncology and dialysis interventions showed no significant change (p > 0.05) while that of drainage procedures increased (p < 0.05). Compared to baseline values, system-wide procedural volumes for IR, Vascular Surgery, Urology, General Surgery, Gastroenterology and Gynecology decreased by 3%, 11%, 25%, 20%, 38% and 31% in March 2020 and 25%, 47%, 68%, 63%, 79% and 73% in April 2020 respectively. CONCLUSION: Outpatient IR volumes were less impacted compared to DR during the initial phase of COVID-19. Oncology, dialysis and drainage interventions may be considered essential procedures due to their stability. IR volumes were less affected compared to other procedural specialties.

A Foundational Guide to Understanding Radiology Department Business Operations for Trainees.

The financial success of a radiology department is crucial to the well-being of both the hospital and the community it serves. Radiology trainees should therefore be conscious of how the department maintains its value within the health system. The purpose of this review is to provide a concise foundational resource for contemporary radiology residents and fellows to understand the basic financial operations of a hospital-based radiology department and to demonstrate its importance in supporting clinical activities. The radiology report is at the heart of reimbursement. Coders use this tool to assign International Classification of Diseases and Current Procedural Terminology codes to file reimbursement claims. Medicare, commanding the highest market share for third-party payers, sets algorithmic standards for compensation practices. Private insurers contract with hospitals, and providers use these systems or create their own contractual framework. Radiology leaders strategically balance these revenue streams with various departmental costs utilizing tools such as budgets and forecasts to ensure long-term organizational viability. Notably, payment practices in the United States are transforming from fee-for-service to value-based care. The roles of the radiologist and the radiology report are evolving with it. Examples of value-based payment models are accountable care organizations and bundled payments. Radiologists participating in these models are increasingly expected to be stewards of imaging utilization and effectively manage health care resources. Within this context of a globally changing incentive structure, trainees must reconceptualize their educational experience to equip themselves for both current and future types of clinical practice.