Do newer drugs treat fewer diseases, controlling for time since launch? Evidence from France and the U.S.

Background: More recently approved drugs have significantly fewer indications than drugs approved many years ago. One possible reason for this may be that, controlling for the number of years since approval or launch, more recently approved drugs have fewer indications (e.g. at the time of launch). The role of precision and personalised medicine has increased, and the goal of precision medicine is to provide a more precise approach for the prevention, diagnosis and treatment of disease. Drugs that have fewer indications may be 'more precise' than drugs that have many indications. Methods: We use different kinds of data from two countries - France and the U.S. - to analyze the relationship across many drugs between the number of indications of a drug, the drug's vintage - i.e. the year in which the drug was first marketed or approved - and its age - the number of years it has been marketed. Results: All the evidence from both countries indicates that, controlling for drug age, more recently approved drugs tend to have fewer indications than drugs approved many years ago. In the U.S., a 10-year increase in vintage is associated with a 10.7% decline in the effective number of indications of all drugs, and a 19.4% decline in the effective number of indications of drugs approved after 1989. In France, the positive effect on the number of indications of the increase in drug age was more than offset by the negative effect of the increase in drug vintage. Conclusions: More recently approved drugs are less likely to be 'general-purpose technologies' (or even multi-purpose technologies) than older drugs. The relative importance of 'precision medicine' has increased in recent decades. Drugs that have fewer indications may be 'more precise' than drugs that have many indications.

REPRESENTATION AND EXTRAPOLATION: EVIDENCE FROM CLINICAL TRIALS.

This article examines the consequences and causes of low enrollment of Black patients in clinical trials. We develop a simple model of similarity-based extrapolation that predicts that evidence is more relevant for decision-making by physicians and patients when it is more representative of the group being treated. This generates the key result that the perceived benefit of a medicine for a group depends not only on the average benefit from a trial but also on the share of patients from that group who were enrolled in the trial. In survey experiments, we find that physicians who care for Black patients are more willing to prescribe drugs tested in representative samples, an effect substantial enough to close observed gaps in the prescribing rates of new medicines. Black patients update more on drug efficacy when the sample that the drug is tested on is more representative, reducing Black-white patient gaps in beliefs about whether the drug will work as described. Despite these benefits of representative data, our framework and evidence suggest that those who have benefited more from past medical breakthroughs are less costly to enroll in the present, leading to persistence in who is represented in the evidence base.

Double metals sites synergistically enhanced photocatalytic N2 fixation performance over Bi24O31Br10@Bi/Ti3C2Tx Ohm junctions.

At present, it is a research hotspot to realize green synthetic ammonia by using solar energy. Exploring cheap and efficient co-catalysts for enhancing the performance of photocatalysts is a challenge in the field of energy conversion. In order to boost the charge separation/transfer of the photocatalyst and widen the visible light absorption, Bi24O31Br10@Bi/Ti3C2Tx with double Ohm junction is successfully fabricated by in situ growth of metal Bi and loading Ti3C2Tx MXene on the surface of Bi24O31Br10. The dual active sites of Bi and Ti3C2Tx MXene not only broaden the light adsorption of Bi24O31Br10 but also serve as excellent 'electronic receptor' for synergically enhancing the separation/transfer efficiency of photogenerated electrons/holes. Meanwhile, temperature programmed desorption (TPD) result revealed that MXene and Bi can promote N2 adsorption/activation and NH3 desorption over Bi24O31Br10@Bi/Ti3C2Tx. As a result, under mild conditions and without the presence of hole scavenger, the ammonia synthesis efficiency of Bi24O31Br10@Bi/Ti3C2Tx-20 % reached 53.86 µmol g-1cat for three hours which is 3.2 and 53.8 times of Bi24O31Br10 and Ti3C2Tx, respectively. This study offers a novel scheme for the construction of photocatalytic systems and demonstrates Ti3C2Tx MXene and metal Bi as a promising and cheap co-catalyst.

Interconnecting sustainable development goals 7 and 13: the role of renewable energy innovations towards combating the climate change.

ABSTRACTThis research examines the trends in environmental footprints through energy innovations, digital trade, economic freedom, and environmental regulation from the context of G7 economies. Quarterly observations from 1998-2020 have been utilized for the advanced-panel model entitled Method of Moments Quantile Regression (MMQR). The initial findings confirm slope heterogeneity, interdependence between the cross-sectional units, stationarity properties, and panel cointegration. The results through FM-OLS, D-OLS, and FE-OLS justify that energy innovations, digital trade, and environmental regulations control ecological damages. In contrast, economic freedom and growth are causing more damage to nature, like ecological footprints (EFP). Similarly, the results through MMQR confirm that the impact of energy innovations, digital trade, and environmental regulations is accepted as a panacea to control environmental degradation in G7. However, the magnitude of the coefficient varies across different quantiles. More specifically, the findings show that the impact of energy innovations is highly significant at 0.50th quantile. In contrast, through digital trade, the impact on EFP is only significant under medium and higher order quantiles (i.e. 0.50th, 0.75th-1.0th). Contrarily, economic freedom is causing more EFP across all the quantiles, where the findings are highly significant at 0.75th quantile. Besides, a few other policy implications are also discussed.

A sensitive photoelectrochemical aptasensor for enrofloxacin detection based on plasmon-sensitized bismuth-rich bismuth oxyhalide.

Highly sensitive detection of enrofloxacin (ENR) is crucial for contaminant detection and environmental protection. A sensitive and selective photoelectrochemical (PEC) aptasensor was assembled by Au nanoparticles sensitized Bi24O31Br10 (Au/Bi24O31Br10) composites for detecting ENR. Due to the synergistic effect of bismuth-rich strategy and surface plasmon resonance (SPR) effect, Au/Bi24O31Br10 possessed promoted visible light absorption capacity further enhancing PEC performance and detection sensitivity of the constructed PEC aptasensor. By chemically adsorption effect between the sulfhydryl modified aptamer and Au nanoparticles, the ENR-aptamer was introduced into the PEC sensor to achieve highly selective detection of ENR. The PEC ENR aptasensor based on Au/Bi24O31Br10 composites possessed a broad linear detection scope (0.72-36000 ng L-1), satisfactory limit of detection (0.30 ng L-1, S/N = 3), high selectivity and stability. This work provides a new way for the trace detection of antibiotics in environmental analysis field.

Enhancing measures of ESE to incorporate aspects of place: Personal reputation and place-based social legitimacy.

We argue that existing measures of entrepreneurial self-efficacy (ESE) are underspecified in the context of tight-knit communities, where personal reputation plays a major role. We propose a new place-based ESE dimension that measures assessment by individuals of their ability to elicit respect from their community. This integral ESE component points to the very meaning of entrepreneurship in highly relational contexts. Although our enhanced ESE measure incorporates some influences of place, other aspects, such as geographical context, continue to moderate the relationship between ESE and entrepreneurial aptitude. We conclude with a discussion of the relevance and utility of this enhanced measure.

A photoelectrochemical aptasensor of ciprofloxacin based on Bi24O31Cl10/BiOCl heterojunction.

A photoelectrochemical (PEC) aptasensor was designed and constructed by Bi24O31Cl10/BiOCl heterojunction as a photoelectric active material for realizing the determination of trace ciprofloxacin (CIP) in water. Compared with Bi24O31Cl10, Bi24O31Cl10/BiOCl heterojunction possessed the improvement of light harvesting and the enhancement of photocurrent signal. The formation of heterojunction between Bi24O31Cl10 and BiOCl can accelerate the transportation efficiency and inhibit the recombination rate of photoinduced carriers. Based on the excellent PEC performance, CIP aptamer was introduced on the modified Bi24O31Cl10/BiOCl/indium tin oxide (ITO) electrode for fabricating a PEC aptasensor. Owing to the combination between aptamer and CIP, CIP-aptamer complex can block the transfer of charge, leading to the reduction of photocurrent response. The PEC aptasensor possessed high sensitivity with a wide detection range (5.0~1.0 × 104 ng L-1) and a low detection limit (1.67 ng L-1, S/N = 3). The PEC aptasensor with good selectivity and reproducibility has been applied to the determination of CIP in water.

The improved survival rate and cost-effectiveness of a 7-day continuous subcutaneous insulin infusion set.

AIMS: The purpose of this article is to compare the insulin cost-savings of the Medtronic Extended Infusion Set (or EIS, a.k.a. Extended Wear Infusion Set) designed and labeled for up to 7-day use with rapid-acting insulins to the current standard of care, 2- to 3-day infusion sets. METHODS: There are three major improvements (reducing insulin waste, plastic waste, and adverse events) with the extended duration of infusion set wear. This analysis focuses on cost savings from reduced insulin wastage during set changes. Studies published on insulin infusion set survival and EIS clinical trial data (NCT04113694) were used to estimate device lifetime performance using a Markov chain Monte Carlo model, including the assessment of adverse effects and device failure. Total costs associated with infusion set change or failure were systematically found in published literature or estimated based on physical usage, and the direct impact on insulin costs was calculated. RESULTS: Based on the model and clinical data, EIS users can expect to change their infusion sets about 75 fewer times than standard set users each year. The costs related to unrecoverable insulin during an infusion set and reservoir change in the US were estimated to range from $19.79 to $22.48, resulting in approximately $1324 to $1677 in annual cost-savings for the typical user from minimizing insulin wastage. LIMITATIONS: The study only assessed devices used within a monitored setting, that is, clinical trials. In addition, the variability associated with healthcare standards and costs and individual treatment variability including insulin dosages, contribute to the uncertainties with the calculations. CONCLUSIONS: Our analysis demonstrates that by extending the duration of infusion set wear, there may be substantial cost savings by reducing insulin wastage.

Modelling the value of innovative treatments for Alzheimer's disease in the United States.

Alzheimer's disease (AD) is the predominant cause of dementia and a leading cause of death globally. With no cure or treatment to slow disease progression, AD-related healthcare costs are substantial and increase as the severity of the disease progresses. Given the complexity of this disease, including initial pathophysiological damage occurring decades before clinical manifestation, finding new impactful treatments for AD relies on highly innovative research and development. However, such sizable and sustained investments bring into question whether conventional value assessment models are fit for this purpose. In this article, we examine the importance and challenges of assimilating the perspectives of varied stakeholders, including patients, caregivers, health systems, payers, and society at large, into a comprehensive value assessment model that may be well suited for a breakthrough treatment for AD.

Oxygen-rich bismuth oxybromide nanosheets coupled with Ag2O as Z-scheme nano-heterostructured plasmonic photocatalyst: Solar light-activated photodegradation of dye pollutants.

In this research to enhance the photocatalytic activity of Bi24O31Br10, precipitation fabrication of the Z-scheme heterojunction with Ag-Ag2O has been investigated. The characterizations were carried out by XRD, FESEM, TEM, EDX, BET-BJH, DRS and pHpzc analyzes. The Ag-Ag2O/Bi24O31Br10 Z-scheme heterojunction nanophotocatalyst with weighted ratio of 3:1 exhibited the wide absorption in the visible light region and displayed the high photocatalytic activity for the photodegradation of acid orange 7 (96.5%, 94.1% and 90% for 10, 20 and 60 mg/L, respectively after 120 min) and eosin yellow (for 10 mg/L: 81.5%) compared to the other composites and pure Bi24O31Br10 and Ag-Ag2O samples. The highly enhanced photocatalytic activity of Ag-Ag2O/Bi24O31Br10 (3:1) was assigned to the surface plasmon resonance effect of silver nanoparticles, high solar-light-response and the structure of Z-scheme heterojunction, which effectively reduces the recombination of the photogenerated charge carriers. Moreover Ag-Ag2O/Bi24O31Br10(3:1) Z-scheme heterojunction nanophotocatalyst exhibited the good photocatalytic activity even after 4 runs.

How cancer registries can detect neoplasms in pathology laboratories that code with SNOMED CT terminology? An actual, simple and flexible solution.

BACKGROUND: Pathology laboratories are one of the main information sources for cancer registries and have traditionally been coded with SNOMED; some of them are migrating to SNOMED CT (SCT). Cancer registries encode topography and morphology of neoplasms by the International Classification of Diseases for Oncology (ICD-O). ICD-O updates morphology with WHO Classification of Tumors (Blue-Books). Morphological codes of the ICD-O, Blue-Books and SNOMED (former SNOMEDID) have always coincided. In 2017, SCT removed the SNOMEDID. OBJECTIVES: to define neoplastic and topographic subsets in SCT and map them to ICD-O-3.1/Blue-Books; reduce the original number of SCT concepts; correctly identify neoplasms in the laboratories in accordance with international cancer registry rules. METHODOLOGY: SCT neoplastic concepts were identified by manual revision and SCT resources ("is a", "Associated morphology" relationships; Simple Map Reference Set). Topographic concepts were extracted from the body structure hierarchy of SCT. Both subsets were mapped to ICD-O-3.1/Blue-Books, afterwards. Updating algorithms were designed to automate and update each subset with every SCT release. The process of neoplasms identification was validated in a sample of 5212 specimens with 7378 records from 8 Catalan hospitals. RESULTS: The number of concepts in neoplastic and topographic subsets (16,448 and 32,278) was reduced after the mapping to ICD-O-3.1/Blue-Books (2115 and 330, respectively). Neoplastic subset classified the specimens correctly in the 98.6% of the specimens. CONCLUSIONS: This article presents a flexible tool to exhaustively identify neoplasms in pathology laboratories that code with SCT, following international PBCRs standards and in line with the pathologists, oncologists and epidemiologists' needs.

Patent implications in the pharmaceutical industry: Are static high prices leading to dynamic innovations?

Agreement on Trade Related aspects of Intellectual Property Rights (TRIPS) was laid on the premises of rewarding monopolistic patent rights to the innovator. Stronger patent protection was advocated to promote technology transfer from developed nations to the rest of the world. To boost domestic innovative potential and to maintain trade ties, most developing countries signed the TRIPS agreement. Impact of patent laws in the pharmaceutical industry was crucial as it posed threat to access health. This paper aims to analyze the impact of pharmaceutical product patent laws incorporated under the TRIPS agreement using 65 countries panel dataset from 1995 to 2016. The data is empirically analyzed using negative binomial regression and Poisson regression. Results clearly indicate that the number of pharmaceutical patents filed in US Patent and Trademark Office (USPTO) has decreased after TRIPS compliance in both low and middle income countries. However, the decline is larger in upper middle and lower middle income countries than in low income countries. The phenomenon of low patent activity has an increasingly declining trend across low and middle income countries. Hence the claimed hypothesis that stronger patent rights would increase innovative potential does not seem to stand true, which raises serious affordability concerns of bringing patents in the pharmaceutical sector.

Federal government-interest patent disclosures for recent top-selling drugs.

Objective: To provide updated evidence on government-interest patent disclosures in US patents for top-selling small-molecule drugs.Methods: IQVIA National Sales Perspectives data identified 300 top-selling drugs, defined by peak 2013-2017 US sales. For the 197 approved through New Drug Applications (NDAs), data were collected from a recently-released dataset of all patents listed in 1985-2016 Annual Editions of the FDA Orange Book. Data on patent assignees and Government Interest Statements (if any) were collected from the US Patent and Trademark Office online database. The percentage of drugs with at least one government-interest patent disclosure was calculated, as was the percentage of patents with a disclosure, by type (drug product, drug substance, or method of use). Government-interest patent disclosures were defined as those for which: the patent application contained a Government Interest Statement; and/or any of the patent assignees was a US government agency.Results: Few patents for the top-selling drugs had a government-interest patent disclosure, 2.6% on average. By patent type, figures ranged between 1.6% (for patents with drug product claims) and 3.6% (for patents with drug substance claims). Accounting for multiple patents per drug, 8.6% of top-selling drugs analyzed had at least one patent with a Government Interest Statement; 1.5% had at least one with a US government agency assignee; and 10.2% met either criterion (none met both).Limitations: Analyses were limited to top-selling NDA-approved drugs (generally excluding biologics) and Orange Book-listed patents. Patents with government-interest patent disclosures could also have relied on non-government funding. Patents were not characterized by relative economic investments, importance in the discovery and development process, or contribution to clinical value.Conclusion: Results were generally comparable to a prior analysis that found that 9.0% of new drugs approved between 1988 and 2005 had either a Government Interest Statement disclosure or a government agency first-listed patent assignee.

Oxygen Vacancy Engineering of Bi24 O31 Cl10 for Boosted Photocatalytic CO2 Conversion.

Unearthing an ideal model to describe the role of defect sites for boosting photocatalytic CO2 reduction is rational and necessary, but it still remains a significant challenge. Herein, oxygen vacancies are introduced on the surface of Bi24 O31 Cl10 photocatalyst (Bi24 O31 Cl10 -OV) for fine-tuning the photocatalytic efficiency. The formation of oxygen vacancies leads to a new donor level near the conduction band minimum, which enables a faster charge transfer and higher carrier density. Moreover, oxygen vacancies can considerably reduce the energy for the formation of COOH* intermediates during CO2 conversion. As a result, the activity of Bi24 O31 Cl10 -OV for selective photoreduction of CO2 to CO is significantly improved, with a CO generation rate of 0.9 µmol h-1 g-1 , which is nearly 4 times higher than that of pristine Bi24 O31 Cl10 . This study reinforces our understanding of defect engineering in Bi-based photocatalysts and underscores the potential importance of implanting oxygen vacancies as an effective strategy for solar energy conversion.

One-pot synthesis of bismuth oxyhalide/oxygen-rich bismuth oxyhalide heterojunction and its photocatalytic activity.

BiOBr/Bi24O31Br10 heterojunction photocatalysts were prepared by a facile solvothermal method for the first time. The X-ray diffraction (XRD), scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FT-IR), N2 sorption, UV-vis diffuse reflectance spectroscopy (UV-vis DRS) and photoluminescence (PL) were applied to investigate the structures, morphologies, surface areas and photocatalytic properties of as-prepared samples. The photocatalytic activity of the samples was evaluated by the photocatalytic degradation of Rhodamine B under the visible-light irradiation. The results showed that BiOBr/Bi24O31Br10 heterojunctions with the different Bi24O31Br10 contents could be obtained by simply adjusting the amount of NaOH solution, all of which exhibited enhanced photocatalytic activity compared with bare BiOBr or Bi24O31Br10. Among them, the BiOBr/Bi24O31Br10 heterojunction prepared with 1.5ml of NaOH solution possessed the highest photocatalytic activity. The photogenerated holes and ·O2(-) radicals were confirmed to be the main active species responsible for the photodegradation of RhB. The mechanism of enhanced photocatalytic activity was discussed and the transfer process of the photogenerated charges carrier between BiOBr and Bi24O31Br10 was proposed on the basis of the estimated energy band positions.