The impact of peritoneal dialysis on oxypurinol and urate elimination in people with gout.

Gout affects 15%-30% of individuals with advanced kidney disease. Allopurinol which is rapidly and extensively metabolised to an active metabolite, oxypurinol, is the most commonly prescribed urate-lowering therapy. Oxypurinol is almost entirely eliminated by the kidneys (>95%) and has an elimination half-life of 18-30 h in those with normal kidney function. However, oxypurinol pharmacokinetics are poorly understood in individuals with kidney failure on peritoneal dialysis. This study characterised the elimination of oxypurinol and urate in people with gout receiving peritoneal dialysis. Oxypurinol steady-state oral clearance (CL/F), elimination half-life as well as kidney (CLk) and peritoneal (CLpd) clearances for oxypurinol and urate were calculated from the plasma, urine and dialysate concentration data for each individual. Our results demonstrate that oxypurinol and urate are removed by peritoneal dialysis, accounting for more than 50% of oxypurinol and urate clearances. An allopurinol dose about 50%-60% lower than the usual dose used for a patient with normal kidney function will provide adequate urate-lowering therapy.

Structure Guided Design, Synthesis, and Biological Evaluation of Oxetane-Containing Indole Analogues.

The oxetane functional group offers a variety of potential advantages when incorporated within appropriate therapeutic agents as a ketone surrogate. OXi8006, a 2-aryl-3-aroyl-indole analogue, functions as a small-molecule inhibitor of tubulin polymerization that has a dual mechanism of action as both an antiproliferative agent and a tumor-selective vascular disrupting agent. Replacement of the bridging ketone moiety in OXi8006 with an oxetane functional group has expanded structure activity relationship (SAR) knowledge and provided insights regarding oxetane incorporation within this class of molecules. A new synthetic method using an oxetane-containing tertiary alcohol subjected to Lewis acid catalyzed conditions led to successful Friedel-Crafts alkylation and yielded fourteen new oxetane-containing indole-based molecules. This synthetic approach represents the first method to successfully install an oxetane ring at the 3-position of a 2-aryl-indole system. Several analogues showed potent cytotoxicity (micromolar GI50 values) against human breast cancer cell lines (MCF-7 and MDA-MB-231) and a pancreatic cancer cell line (PANC-1), although they proved to be ineffective as inhibitors of tubulin polymerization. Molecular docking studies comparing colchicine with the OXi8006-oxetane analogue 5m provided a rationale for the differential interaction of these molecules with the colchicine site on the tubulin heterodimer.

Air Pollution, Greenhouse Gas, and Traffic Externality Benefits and Costs of Shifting Private Vehicle Travel to Ridesourcing Services.

On-demand ridesourcing services from transportation network companies (TNCs), such as Uber and Lyft, have reshaped urban travel and changed externality costs from vehicle emissions, congestion, crashes, and noise. To quantify these changes, we simulate replacing private vehicle travel with TNCs in six U.S. cities. On average, we find a 50-60% decline in air pollutant emission externalities from NOx, PM2.5, and VOCs due to avoided "cold starts" and relatively newer, lower-emitting TNC vehicles. However, increased vehicle travel from deadheading creates a ∼20% increase in fuel consumption and associated greenhouse gas emissions and a ∼60% increase in external costs from congestion, crashes, and noise. Overall, shifting private travel to TNCs increases external costs by 30-35% (adding 32-37 ¢ of external costs per trip, on average). This change in externalities increases threefold when TNCs displace transit or active transport, drops by 16-17% when TNC vehicles are zero-emission electric, and potentially results in reduced externalities when TNC rides are pooled.

Computer Models and Thatcherist Futures: From Monopolies to Markets in British Telecommunications.

Prime Minister Margaret Thatcher's 1984 privatization of British Telecom was a landmark moment for neoliberalism. It served to popularize and vindicate the sale of state utilities around the world. This article shows how computer models of the future were central for British telecommunications', and thus for Britain's, transition from social democracy to neoliberalism, from monopoly to market. The British telecommunications network was a key interest in both the social democratic and neoliberal British state's plans for the digitalization of Britain. I argue that computers were crucial to the rise of neoliberalism, both as a managerial tool that simulated futures of free markets and as a technology that symbolized and supported the contraction of the British state. This article traces the history of the British telecommunications system's Long Range Planning Department, which was at the heart of British Telecom's privatization. In doing so, it argues that the history of technology is in a unique position to study how tools such as computers both forecast and symbolize the political power of the future.

Current and Future United States Light-Duty Vehicle Pathways: Cradle-to-Grave Lifecycle Greenhouse Gas Emissions and Economic Assessment.

This article presents a cradle-to-grave (C2G) assessment of greenhouse gas (GHG) emissions and costs for current (2015) and future (2025-2030) light-duty vehicles. The analysis addressed both fuel cycle and vehicle manufacturing cycle for the following vehicle types: gasoline and diesel internal combustion engine vehicles (ICEVs), flex fuel vehicles, compressed natural gas (CNG) vehicles, hybrid electric vehicles (HEVs), hydrogen fuel cell electric vehicles (FCEVs), battery electric vehicles (BEVs), and plug-in hybrid electric vehicles (PHEVs). Gasoline ICEVs using current technology have C2G emissions of ∼450 gCO2e/mi (grams of carbon dioxide equivalents per mile), while C2G emissions from HEVs, PHEVs, H2 FCEVs, and BEVs range from 300-350 gCO2e/mi. Future vehicle efficiency gains are expected to reduce emissions to ∼350 gCO2/mi for ICEVs and ∼250 gCO2e/mi for HEVs, PHEVs, FCEVs, and BEVs. Utilizing low-carbon fuel pathways yields GHG reductions more than double those achieved by vehicle efficiency gains alone. Levelized costs of driving (LCDs) are in the range $0.25-$1.00/mi depending on time frame and vehicle-fuel technology. In all cases, vehicle cost represents the major (60-90%) contribution to LCDs. Currently, HEV and PHEV petroleum-fueled vehicles provide the most attractive cost in terms of avoided carbon emissions, although they offer lower potential GHG reductions. The ranges of LCD and cost of avoided carbon are narrower for the future technology pathways, reflecting the expected economic competitiveness of these alternative vehicles and fuels.

Machine Learning in Spine Oncology: A Narrative Review.

STUDY DESIGN: Narrative Review. OBJECTIVE: Machine learning (ML) is one of the latest advancements in artificial intelligence used in medicine and surgery with the potential to significantly impact the way physicians diagnose, prognose, and treat spine tumors. In the realm of spine oncology, ML is utilized to analyze and interpret medical imaging and classify tumors with incredible accuracy. The authors present a narrative review that specifically addresses the use of machine learning in spine oncology. METHODS: This study was conducted in accordance with the Preferred Reporting Items of Systematic Reviews and Meta-Analysis (PRISMA) methodology. A systematic review of the literature in the PubMed, EMBASE, Web of Science, Scopus, and Cochrane Library databases since inception was performed to present all clinical studies with the search terms '[[Machine Learning] OR [Artificial Intelligence]] AND [[Spine Oncology] OR [Spine Cancer]]'. Data included studies that were extracted and included algorithms, training and test size, outcomes reported. Studies were separated based on the type of tumor investigated using the machine learning algorithms into primary, metastatic, both, and intradural. A minimum of 2 independent reviewers conducted the study appraisal, data abstraction, and quality assessments of the studies. RESULTS: Forty-five studies met inclusion criteria out of 480 references screened from the initial search results. Studies were grouped by metastatic, primary, and intradural tumors. The majority of ML studies relevant to spine oncology focused on utilizing a mixture of clinical and imaging features to risk stratify mortality and frailty. Overall, these studies showed that ML is a helpful tool in tumor detection, differentiation, segmentation, predicting survival, predicting readmission rates of patients with either primary, metastatic, or intradural spine tumors. CONCLUSION: Specialized neural networks and deep learning algorithms have shown to be highly effective at predicting malignant probability and aid in diagnosis. ML algorithms can predict the risk of tumor recurrence or progression based on imaging and clinical features. Additionally, ML can optimize treatment planning, such as predicting radiotherapy dose distribution to the tumor and surrounding normal tissue or in surgical resection planning. It has the potential to significantly enhance the accuracy and efficiency of health care delivery, leading to improved patient outcomes.

Extreme Ultraviolet Reflection Spectroscopy of Lanthanides and Actinides Using a High Harmonic Generation Light Source.

Absorption spectroscopy probing transitions from shallow-core d and f orbitals in lanthanides and actinides reveals information about bonding and the electronic structure in compounds containing these elements. However, spectroscopy in this photon energy range is challenging because of the limited availability of light sources and extremely short penetration depths. In this work, we address these challenges using a tabletop extreme ultraviolet (XUV), ultrafast, laser-driven, high harmonic generation light source, which generates femtosecond pulses in the 40-140 eV range. We present reflection spectroscopy measurements at the N4,5 (i.e., predominantly 4d to 5f transitions) and O4,5 (i.e., 5d to 5f transitions) absorption edges on several lanthanide and uranium oxide crystals. We compare these results to density functional theory calculations to assign the electronic transitions and predict the spectra for other lanthanides. This work paves the way for laboratory-scale XUV absorption experiments for studying crystalline and molecular f-electron systems, with applications ranging from surface chemistry, photochemistry, and electronic or chemical structure determination to nuclear forensics.

Synthesis and biological evaluation of structurally diverse 6-aryl-3-aroyl-indole analogues as inhibitors of tubulin polymerization.

The synthesis and evaluation of small-molecule inhibitors of tubulin polymerization remains a promising approach for the development of new therapeutic agents for cancer treatment. The natural products colchicine and combretastatin A-4 (CA4) inspired significant drug discovery campaigns targeting the colchicine site located on the beta-subunit of the tubulin heterodimer, but so far these efforts have not yielded an approved drug for cancer treatment in human patients. Interest in the colchicine site was enhanced by the discovery that a subset of colchicine site agents demonstrated dual functionality as both potent antiproliferative agents and effective vascular disrupting agents (VDAs). Our previous studies led to the discovery and development of a 2-aryl-3-aroyl-indole analogue (OXi8006) that inhibited tubulin polymerization and demonstrated low nM IC50 values against a variety of human cancer cell lines. A water-soluble phosphate prodrug salt (OXi8007), synthesized from OXi8006, displayed promising vascular disrupting activity in mouse models of cancer. To further extend structure-activity relationship correlations, a series of 6-aryl-3-aroyl-indole analogues was synthesized and evaluated for their inhibition of tubulin polymerization and cytotoxicity against human cancer cell lines. Several structurally diverse molecules in this small library were strong inhibitors of tubulin polymerization and of MCF-7 and MDA-MB-231 human breast cancer cells. One of the most promising analogues (KGP591) caused significant G2/M arrest of MDA-MB-231 cells, disrupted microtubule structure and cell morphology in MDA-MB-231 cells, and demonstrated significant inhibition of MDA-MB-231 cell migration in a wound healing (scratch) assay. A phosphate prodrug salt, KGP618, synthesized from its parent phenolic precursor, KGP591, demonstrated significant reduction in bioluminescence signal when evaluated in vivo against an orthotopic model of kidney cancer (RENCA-luc) in BALB/c mice, indicative of VDA efficacy. The most active compounds from this series offer promise as anticancer therapeutic agents.

CT guided biopsy for osteodiscitis reduces cost of hospitalization in the landscape of increasing intravenous drug use: A single center retrospective analysis.

OBJECTIVE: Osteodiscitis has been demonstrated to show significant morbidity and mortality. Cultures and CT guided biopsy (CTB) are commonly used diagnosis of osteodiscitis. This study's purpose is to evaluate the cost burden of CTB and to evaluate how IVDU affects patient management in the setting of osteodiscitis. METHODS: Patients admitted for osteodiscitis from 2011-2021 were retrospectively reviewed and stratified into cohorts by CTB status. Additional cohorts were stratified by Intravenous Drug Use (IVDU). Patient demographics, total cost of hospitalization, length of hospitalization, time to biopsy, IVDU status, and other factors were recorded. T-Test, Chi-squared analysis, and ANOVA were used for statistical analysis. RESULTS: Total cost of hospitalization was recorded for 140 patients without CTB and 346 patients with CTB. Average cost of hospitalization for non-CTB was $227,317.86 compared to CTB at $119,799.20 (p < 0.001). Length of stay (LOS) was found to be 18.01 days for non-CTB and 14.07 days for CTB patients (0.00282). When stratified by days until biopsy, patients who had CTB sooner, had significantly reduced cost of hospitalization (p = 0.0003). Patients with IVDU history were significantly younger (p < 0.001) with lower BMI (p < 0.001) and a significantly different clinical profile. There was a significant difference in positive open biopsy when separated by IVDU status (p = 0.025). CONCLUSION: CTB was associated with significantly reduced cost of hospitalization and LOS compared to non-CTB. IVDU patients with osteodiscitis have significantly different clinical profiles than non-IVDU that may impact diagnosis and treatment. Further work is indicated to elucidate causes of these differences to provide high value care to patients with osteodiscitis.

Attitudes towards the mixing of COVID-19 vaccinated and unvaccinated patients in multi-bed hospital rooms.

AIM: To explore patient and staff views about the mixing of COVID-19 vaccinated and unvaccinated patients in multi-bed hospital rooms. METHODS: We conducted a mixed methods study with paper surveys and structured interviews. Self-administered surveys were undertaken with inpatients on the general medicine, general surgery, orthopaedic and respiratory wards in Dunedin Public Hospital. Face-to-face interviews were conducted with ward staff including consultants, registrars, charge nurses, registered nurses and nurse managers. The study was undertaken in February 2022, at the start of the first New Zealand wave of the Omicron variant. RESULTS: Of 118 eligible patients, 63 agreed to participate. Sixty (95%) of these patients were vaccinated for COVID-19. Most patients (59%) thought that vaccinated and unvaccinated people should be accommodated in separate hospital rooms. Vaccinated patients felt more comfortable sharing a multi-bed room with others of the same COVID-19 vaccination status as themselves than with unvaccinated patients. Participants who thought that they were at higher risk of severe illness from COVID-19 were more likely to support separation of patients based on vaccination status. Fifteen ward staff were interviewed: most would prefer the hospital to separate patients by vaccination status but were aware this would present practical and ethical problems and thought that current arrangements were adequate. CONCLUSION: While most vaccinated patients and staff wanted patients to be separated according to their COVID-19 vaccination status, the current precautionary measures for COVID-19 were viewed by most staff members as adequate.

Exploring an Unknown Corner of a Well-Known Topic: HIIE Influence on Renal Health and Filtration in Healthy Individuals Free of Cardiometabolic Diseases.

Aerobic exercise, specifically high-intensity interval exercise (HIIE), and its effects on renal health and filtration (RHF) are not well understood. Several studies support incorporating contemporary biomarkers serum cystatin C (CyC) and urine epidermal growth factor (uEGF) to combat the volatility of serum creatinine (sCr). Using these biomarkers, we examined the acute influences HIIE has on RHF to determine if there is a ceiling effect in healthy populations. The purpose was to determine the influence of an acute bout of HIIE on RHF. Thirty-six participants (n = 22 males; n = 14 females; age 37.6 ± 12.4 years.; BF% 19.2 ± 7.1%; VO2max 41.8 + 7.4 mL/kg/min) completed 30 min of HIIE on a treadmill (80% and 40% of VO2reserve in 3:2 min ratio). Blood and urine samples were obtained under standardized conditions before, 1 h, and 24 h post-exercise. CyC, sCR, uEGF, urine creatinine (uCr), uCr/uEGF ratio, and multiple estimates of glomerular filtration rate (eGFR) Modification of Diet in Renal Disease (MDRD) and CKD-EPI equations were used. The analysis employed paired sample t-tests and repeated measures ANOVAs. CyC, uEGF, uCr, and uCr/uEGF ratio concentrations were not altered between timepoints. sCr increased 1 h post-exercise (p > 0.002) but not at 24 h post-exercise. eGFR decreased in the MDRD and CKD-EPI equations at 1 h (p > 0.012) with no changes at 24 h post-exercise. CyC and sCr/CyC demonstrated no significant changes. CyC and uEGF are not altered by acute HIIE. The results demonstrate a potential ceiling effect in contemporary and traditional biomarkers of RHF, indicating improvements in RHF may be isolated to populations with reduced kidney function.

The impact of Uber and Lyft on vehicle ownership, fuel economy, and transit across U.S. cities.

We estimate the effects of transportation network companies (TNCs) Uber and Lyft on vehicle ownership, fleet average fuel economy, and transit use in U.S. urban areas using a set of difference-in-difference propensity score-weighted regression models that exploit staggered market entry across the U.S. from 2011 to 2017. We find evidence that TNC entry into urban areas causes an average 0.7% increase in vehicle registrations with significant heterogeneity in these effects across urban areas: TNC entry produces larger vehicle ownership increases in urban areas with higher initial ownership (car-dependent cities) and in urban areas with lower population growth (where TNC-induced vehicle adoption outpaces population growth). We also find no statistically significant average effect of TNC entry on fuel economy or transit use but find evidence of heterogeneity in these effects across urban areas, including larger transit ridership reductions after TNC entry in areas with higher income and more childless households.

TCBH Duncan Tanner Essay Prize Winner 2018 Financing the Information Age: London TeleCity, the Legacy of IT-82, and the Selling of British Telecom.

This article is a history of the privatization of British Telecom. BT's privatization occupies a central position in histories of Thatcherism as a pivotal moment in Thatcherism's ideological focus on popular capitalism. These histories, however, overlook the important intersection of financial institutions and information technology policy in shaping BT's privatization. Financial institutions in the City of London formed a lobbying group, the City Telecommunications Committee, that pressured for BT's privatization and secured preferential treatment for the City from BT, ending a decades-long policy of uniform telecommunications services across Britain. Margaret Thatcher's government positioned BT's privatization as central to the success of two of Britain's information industries, electronics manufacturing and the City of London. Her government also cast BT's privatization as essential to an 'information revolution' that, through personal, networked computing, would further personal freedom and free markets. BT's privatization thus performed two important and related functions. First, it oriented Britain's telecommunications network to the City of London's needs, and secondly, it enacted an 'information revolution' that was portrayed as essential to the success of the City of London and British electronics. I label this fusion of City finance, neoliberal politics, and British telecommunications the 'London ideology', and this ideology shaped the broadly-held assumption that privatizing telecommunications was essential to reaching the 'information age'.