Time to review the role of surrogate endpoints in health policy: state of the art and the way forward

The efficacy of medicines, medical devices, and other health technologies should be proved in trials that assess final patient-relevant outcomes such as survival or morbidity. However, market access and coverage decisions are often based on surrogate endpoints, biomarkers, or intermediate endpoints, which aim to substitute and predict patient-relevant outcomes that are unavailable due to methodological, financial, or practical constraints. We provide a summary of the current use of surrogate endpoints in healthcare policy, discussing the case for and against their adoption and reviewing validation methods. We introduce a three-step framework for policy makers to handle surrogates, which involves establishing the level of evidence, assessing the strength of the association, and quantifying relations between surrogates and final outcomes. Although use of surrogates can be problematic, they can, when selected and validated appropriately, offer important opportunities for more efficient clinical trials and faster access to new health technologies that benefit patients and healthcare systems

IRS2 silencing increases apoptosis and potentiates the effects of ruxolitinib in jak2v617f-positive myeloproliferative neoplasms

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)The recurrent V617F mutation in JAK2 (JAK2(V617F)) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indicates the need for identifying pathways that cooperate with JAK2. Activated JAK2 was found to be associated with the insulin receptor substrate 2 (IRS2) in non-hematological cells. We identified JAK2/IRS2 binding in JAK2(V617F) HEL cells, but not in the JAK2(WT) U937 cell line. In HEL cells, IRS2 silencing decreased STAT5 phosphorylation, reduced cell viability and increased apoptosis; these effects were enhanced when IRS2 silencing was combined with ruxolitinib. In U937 cells, IRS2 silencing neither reduced cell viability nor induced apoptosis. IRS1/2 pharmacological inhibition in primary MPN samples reduced cell viability in JAK2(V617F)-positive but not JAK2(WT) specimens; combination with ruxolitinib had additive effects. IRS2 expression was significantly higher in CD34(+) cells from essential thrombocythemia patients compared to healthy donors, and in JAK2(V617F) MPN patients when compared to JAK2(WT). Our data indicate that IRS2 is a binding partner of JAK2(V617F) in MPN. IRS2 contributes to increased cell viability and reduced apoptosis in JAK2-mutated cells. Combined pharmacological inhibition of IRS2 and JAK2 may have a potential clinical application in MPN.The recurrent V617F mutation in JAK2 (JAK2V617F) has emerged as the primary contributor to the pathogenesis of myeloproliferative neoplasms (MPN). However, the lack of complete response in most patients treated with the JAK1/2 inhibitor, ruxolitinib, indi7669486959sem informaçãoConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)sem informaçã

Exact solution of Schrodinger equation for Pseudoharmonic potential

Exact solution of Schrodinger equation for the pseudoharmonic potential is obtained for an arbitrary angular momentum. The energy eigenvalues and corresponding eigenfunctions are calculated by Nikiforov-Uvarov method. Wavefunctions are expressed in terms of Jacobi polynomials. The energy eigenvalues are calculated numerically for some values of l and n with n<5 for some diatomic molecules.Comment: 10 page

Modulation of radial blood flow during Braille character discrimination task

Purpose: Human hands are excellent in performing sensory and motor function. We have hypothesized that blood flow of the hand is dynamically regulated by sympathetic outflow during concentrated finger perception. To identify this hypothesis, we measured radial blood flow (RBF), radial vascular conductance (RVC), heart rate (HR), and arterial blood pressure (AP) during Braille reading performed under the blind condition in nine healthy subjects. The subjects were instructed to read a flat plate with raised letters (Braille reading) for 30 s by the forefinger, and to touch a blank plate as control for the Braille discrimination procedure. Results: HR and AP slightly increased during Braille reading but remained unchanged during the touching of the blank plate. RBF and RVC were reduced during the Braille character discrimination task (decreased by -46% and -49%, respectively). Furthermore, the changes in RBF and RVC were much greater during the Braille character discrimination task than during the touching of the blank plate (decreased by -20% and -20%, respectively). Conclusions: These results have suggested that the distribution of blood flow to the hand is modulated via sympathetic nerve activity during concentrated finger perception

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Evaluating the relationship between ciprofloxacin prescription and non-susceptibility in Salmonella Typhi in Blantyre, Malawi: an observational study

Background: Ciprofloxacin is the first-line drug for treating typhoid fever in many countries in Africa with a high disease burden, but the emergence of non-susceptibility poses a challenge to public health programmes. Through enhanced surveillance as part of vaccine evaluation, we investigated the occurrence and potential determinants of ciprofloxacin non-susceptibility in Blantyre, Malawi. Methods: We conducted systematic surveillance of typhoid fever cases and antibiotic prescription in two health centres in Blantyre, Malawi, between Oct 1, 2016, and Oct 31, 2019, as part of the STRATAA and TyVAC studies. In addition, blood cultures were taken from eligible patients presenting at Queen Elizabeth Central Hospital, Blantyre, as part of routine diagnosis. Inclusion criteria were measured or reported fever, or clinical suspicion of sepsis. Microbiologically, we identified Salmonella enterica serotype Typhi (S Typhi) isolates with a ciprofloxacin non-susceptible phenotype from blood cultures, and used whole-genome sequencing to identify drug-resistance mutations and phylogenetic relationships. We constructed generalised linear regression models to investigate associations between the number of ciprofloxacin prescriptions given per month to study participants and the proportion of S Typhi isolates with quinolone resistance-determining region (QRDR) mutations in the following month. Findings: From 46 989 blood cultures from Queen Elizabeth Central Hospital, 502 S Typhi isolates were obtained, 30 (6%) of which had either decreased ciprofloxacin susceptibility, or ciprofloxacin resistance. From 11 295 blood cultures from STRATAA and TyVAC studies, 241 microbiologically confirmed cases of typhoid fever were identified, and 198 isolates from 195 participants sequenced (mean age 12·8 years [SD 10·2], 53% female, 47% male). Between Oct 1, 2016, and Aug 31, 2019, of 177 typhoid fever cases confirmed by whole-genome sequencing, four (2%) were caused by S Typhi with QRDR mutations, compared with six (33%) of 18 cases between Sept 1 and Oct 31, 2019. This increase was associated with a preceding spike in ciprofloxacin prescriptions. Every additional prescription of ciprofloxacin given to study participants in the preceding month was associated with a 4·2% increase (95% CI 1·8–7·0) in the relative risk of isolating S Typhi with a QRDR mutation (p=0·0008). Phylogenetic analysis showed that S Typhi isolates with QRDR mutations from September and October, 2019, belonged to two distinct subclades encoding two different QRDR mutations, and were closely related (4–10 single-nucleotide polymorphisms) to susceptible S Typhi endemic to Blantyre. Interpretation: We postulate a causal relationship between increased ciprofloxacin prescriptions and an increase in fluoroquinolone non-susceptibility in S Typhi. Decreasing ciprofloxacin use by improving typhoid diagnostics, and reducing typhoid fever cases through the use of an efficacious vaccine, could help to limit the emergence of resistance. Funding: Wellcome Trust, Bill & Melinda Gates Foundation, and National Institute for Health and Care Research (UK)