Economic evaluation of a clinical protocol for diagnosing emergency patients with suspected pulmonary embolism

BACKGROUND: The objective of this paper is to estimate the amount of cost-savings to the Australian health care system from implementing an evidence-based clinical protocol for diagnosing emergency patients with suspected pulmonary embolism (PE) at the Emergency department of a Victorian public hospital with 50,000 presentations in 2001–2002. METHODS: A cost-minimisation study used the data collected in a controlled clinical trial of a clinical protocol for diagnosing patients with suspected PE. Thenumber and type of diagnostic tests in a historic cohort of 185 randomly selected patients, who presented to the emergency department with suspectedPE during an eight month period prior to the clinical trial (January 2002 -August 2002) were compared with the number and type of diagnostic tests in745 patients, who presented to the emergency department with suspected PE from November 2002 to August 2003. Current Medicare fees per test were usedas unit costs to calculate the mean aggregated cost of diagnostic investigation per patient in both study groups. A t-test was used to estimate the statistical significance of the difference in the cost of resources used for diagnosing PE in the control and in the intervention group. RESULTS: The trial demonstrated that diagnosing PE using an evidence-based clinical protocol was as effective as the existing clinical practice. The clinical protocol offers the advantage of reducing the use of diagnostic imaging, resulting in an average cost savings of at least $59.30 per patient. CONCLUSION: Extrapolating the observed cost-savings of$59.30 per patient to the wholeof Australia could potentially result in annual savings between $3.1 million to$3.7 million

Pre-exposure prophylaxis for preventing acquisition of HIV: A cross-sectional study of patients, prescribers, uptake, and spending in the United States, 2015-2016

BACKGROUND: In 2015, there were approximately 40,000 new HIV diagnoses in the United States. Pre-exposure prophylaxis (PrEP) is an effective strategy that reduces the risk of HIV acquisition; however, uptake among those who can benefit from it has lagged. In this study, we 1) compared the characteristics of patients who were prescribed PrEP with individuals newly diagnosed with HIV infection, 2) identified the specialties of practitioners prescribing PrEP, 3) identified metropolitan statistical areas (MSAs) within the US where there is relatively low uptake of PrEP, and 4) reported median amounts paid by patients and third-party payors for PrEP. METHODS AND FINDINGS: We analyzed prescription drug claims for individuals prescribed PrEP in the Integrated Dataverse (IDV) from Symphony Health for the period of September 2015 to August 2016 to describe PrEP patients, prescribers, relative uptake, and payment methods in the US. Data were available for 75,839 individuals prescribed PrEP, and findings were extrapolated to approximately 101,000 individuals, which is less than 10% of the 1.1 million adults for whom PrEP was indicated. Compared to individuals with newly diagnosed HIV infection, PrEP patients were more likely to be non-Hispanic white (45% versus 26.2%), older (25% versus 19% at ages 35-44), male (94% versus 81%), and not reside in the South (30% versus 52% reside in the South).Using a ratio of the number of PrEP patients within an MSA to the number of newly diagnosed individuals with HIV infection, we found MSAs with relatively low uptake of PrEP were concentrated in the South. Of the approximately 24,000 providers who prescribed PrEP, two-thirds reported primary care as their specialty. Compared to the types of payment methods that people living with diagnosed HIV (PLWH) used to pay for their antiretroviral treatment in 2015 to 2016 reported in the Centers for Disease Control and Prevention (CDC) HIV Surveillance Special Report, PrEP patients were more likely to have used commercial health insurance (80% versus 35%) and less likely to have used public healthcare coverage or a publicly sponsored assistance program to pay for PrEP (12% versus 45% for Medicaid). Third-party payors covered 95% of the costs of PrEP. Overall, we estimated the median annual per patient out-of-pocket spending on PrEP was approximately US$72. Limitations of this study include missing information on prescription claims of patients not included in the database, and for those included, some patients were missing information on patient diagnosis, race/ethnicity, educational attainment, and income (34%-36%). CONCLUSIONS: Our findings indicate that in 2015-2016, many individuals in the US who could benefit from being on PrEP were not receiving this HIV prevention medication, and those prescribed PrEP had a significantly different distribution of characteristics from the broader population that is at risk for acquiring HIV. PrEP patients were more likely to pay for PrEP using commercial or private insurance, whereas PLWH were more likely to pay for their antiretroviral treatment using publicly sponsored programs. Addressing the affordability of PrEP and otherwise promoting its use among those with indications for PrEP represents an important opportunity to help end the HIV epidemic

Designating market maker behaviour in limit order book markets

Financial exchanges provide incentives for limit order book (LOB) liquidity provision to certain market participants, termed designated market makers or designated sponsors. While quoting requirements typically enforce the activity of these participants for a certain portion of the day, an argument that liquidity demand throughout the trading day is far from uniformly distributed is made, and thus this liquidity provision may not be calibrated to the demand. Furthermore, it is propose that quoting obligations also include requirements about the speed of liquidity replenishment, and then a recommendation that use of the Threshold Exceedance Duration (TED) for this purpose be considered. To support this argument a comprehensive regression modelling approach using GLM and GAMLSS models to relate the TED to the state of the LOB and identify the regression structures that are best suited to modelling the TED is presented. Such an approach can be used by exchanges to set target levels of liquidity replenishment for designated market makers

Multifunctional Compounds for Activation of the p53‐Y220C Mutant in Cancer

The p53 protein plays a major role in cancer prevention, and over 50 % of cancer diagnoses can be attributed to p53 malfunction. The common p53 mutation Y220C causes local protein unfolding, aggregation, and can result in a loss of Zn in the DNA‐binding domain. Structural analysis has shown that this mutant creates a surface site that can be stabilized using small molecules, and herein a multifunctional approach to restore function to p53‐Y220C is reported. A series of compounds has been designed that contain iodinated phenols aimed for interaction and stabilization of the p53‐Y220C surface cavity, and Zn‐binding fragments for metallochaperone activity. Their Zn‐binding affinity was characterized using spectroscopic methods and demonstrate the ability of compounds L4 and L5 to increase intracellular levels of Zn2+ in a p53‐Y220C‐mutant cell line. The in vitro cytotoxicity of our compounds was initially screened by the National Cancer Institute (NCI‐60), followed by testing in three stomach cancer cell lines with varying p53 status’, including AGS (WTp53), MKN1 (V143A), and NUGC3 (Y220C). Our most promising ligand, L5, is nearly 3‐fold more cytotoxic than cisplatin in a large number of cell lines. The impressive cytotoxicity of L5 is further maintained in a NUGC3 3D spheroid model. L5 also induces Y220C‐specific apoptosis in a cleaved caspase‐3 assay, reduces levels of unfolded mutant p53, and recovers p53 transcriptional function in the NUGC3 cell line. These results show that these multifunctional scaffolds have the potential to restore wild‐type function in mutant p53‐Y220C

Diversity of Plasmodium falciparum Chloroquine Resistance Transporter (pfcrt) Exon 2 Haplotypes in the Pacific from 1959 to 1979

Nearly one million deaths are attributed to malaria every year. Recent reports of multi-drug treatment failure of falciparum malaria underscore the need to understand the molecular basis of drug resistance. Multiple mutations in the Plasmodium falciparum chloroquine resistance transporter (pfcrt) are involved in chloroquine resistance, but the evolution of complex haplotypes is not yet well understood. Using over 4,500 archival human serum specimens collected from 19 Pacific populations between 1959 and 1979, the period including and just prior to the appearance of chloroquine treatment failure in the Pacific, we PCR-amplified and sequenced a portion of the pfcrt exon 2 from 771 P. falciparum-infected individuals to explore the spatial and temporal variation in falciparum malaria prevalence and the evolution of chloroquine resistance. In the Pacific, the prevalence of P. falciparum varied considerably across ecological zones. On the island of New Guinea, the decreases in prevalence of P. falciparum in coastal, high-transmission areas over time were contrasted by the increase in prevalence during the same period in the highlands, where transmission was intermittent. We found 78 unique pfcrt haplotypes consisting of 34 amino acid substitutions and 28 synonymous mutations. More importantly, two pfcrt mutations (N75D and K76T) implicated in chloroquine resistance were present in parasites from New Hebrides (now Vanuatu) eight years before the first report of treatment failure. Our results also revealed unexpectedly high levels of genetic diversity in pfcrt exon 2 prior to the historical chloroquine resistance selective sweep, particularly in areas where disease burden was relatively low. In the Pacific, parasite genetic isolation, as well as host acquired immune status and genetic resistance to malaria, were important contributors to the evolution of chloroquine resistance in P. falciparum

Bilateral inhibition of HAUSP deubiquitinase by a viral interferon regulatory factor protein

Herpesvirus-associated ubiquitin specific protease (HAUSP) regulates the stability of p53 and MDM2, implicating HAUSP as a therapeutic target for tuning p53-mediated anti-tumor activity. Here, we report the structural analysis of HAUSP with Kaposi’s sarcoma-associated herpesvirus vIRF4 and the discovery of two vIRF4-derived peptides, vif1 and vif2, as potent and selective HAUSP antagonists. This analysis reveals a bilateral belt-type interaction resulting in inhibition of HAUSP. The vif1 peptide binds the HAUSP TRAF domain, competitively blocking substrate binding, while the vif2 peptide binds both the HAUSP TRAF and catalytic domains, robustly suppressing its deubiquitination activity. Consequently, peptide treatments comprehensively blocked HAUSP, leading to p53-dependent cell cycle arrest and apoptosis in culture and tumor regression in xenograft mouse model. Thus, the virus has developed a unique molecular strategy to target the HAUSP-MDM2-p53 pathway, and these virus-derived short peptides represent biologically active HAUSP antagonists

Global mapping of binding sites for Nrf2 identifies novel targets in cell survival response through ChIP-Seq profiling and network analysis

The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1−/−) or depletion (Nrf2−/−) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response

Direction-Selective Circuitry in Rat Retina Develops Independently of GABAergic, Cholinergic and Action Potential Activity

The ON-OFF direction selective ganglion cells (DSGCs) in the mammalian retina code image motion by responding much more strongly to movement in one direction. They do so by receiving inhibitory inputs selectively from a particular sector of processes of the overlapping starburst amacrine cells, a type of retinal interneuron. The mechanisms of establishment and regulation of this selective connection are unknown. Here, we report that in the rat retina, the morphology, physiology of the ON-OFF DSGCs and the circuitry for coding motion directions develop normally with pharmacological blockade of GABAergic, cholinergic activity and/or action potentials for over two weeks from birth. With recent results demonstrating light independent formation of the retinal DS circuitry, our results strongly suggest the formation of the circuitry, i.e., the connections between the second and third order neurons in the visual system, can be genetically programmed, although emergence of direction selectivity in the visual cortex appears to require visual experience

Future-ai:International consensus guideline for trustworthy and deployable artificial intelligence in healthcare

Despite major advances in artificial intelligence (AI) for medicine and healthcare, the deployment and adoption of AI technologies remain limited in real-world clinical practice. In recent years, concerns have been raised about the technical, clinical, ethical and legal risks associated with medical AI. To increase real world adoption, it is essential that medical AI tools are trusted and accepted by patients, clinicians, health organisations and authorities. This work describes the FUTURE-AI guideline as the first international consensus framework for guiding the development and deployment of trustworthy AI tools in healthcare. The FUTURE-AI consortium was founded in 2021 and currently comprises 118 inter-disciplinary experts from 51 countries representing all continents, including AI scientists, clinicians, ethicists, and social scientists. Over a two-year period, the consortium defined guiding principles and best practices for trustworthy AI through an iterative process comprising an in-depth literature review, a modified Delphi survey, and online consensus meetings. The FUTURE-AI framework was established based on 6 guiding principles for trustworthy AI in healthcare, i.e. Fairness, Universality, Traceability, Usability, Robustness and Explainability. Through consensus, a set of 28 best practices were defined, addressing technical, clinical, legal and socio-ethical dimensions. The recommendations cover the entire lifecycle of medical AI, from design, development and validation to regulation, deployment, and monitoring. FUTURE-AI is a risk-informed, assumption-free guideline which provides a structured approach for constructing medical AI tools that will be trusted, deployed and adopted in real-world practice. Researchers are encouraged to take the recommendations into account in proof-of-concept stages to facilitate future translation towards clinical practice of medical AI