Role of patient-reported outcomes and other efficacy endpoints in the drug approval process in Europe (2008-2012)

The present study aimed at systematically reviewing the role and extent of patient-reported outcomes (PROs) usage within the package of scientific evidence considered for marketing authorization (MA). All regulatory information published by the European Medicines Agency (EMA) for products authorized between January 2008 and December 2012 and appearing in the European Public Assessment Report (EPAR) database was examined for efficacy endpoints. The endpoints here considered included: PROs, clinician reported outcomes (CROs), and laboratory reported outcomes (LROs). LROs were the most frequently reported endpoints. Out of the 180 products here selected, 99 (55%), 67 (37%), and 30 (17%), respectively, used LROs, CROs and PROs as primary endpoints (PEs). PROs as any endpoints were used in 82 (46%) products. Out of these, PROs were documented as PE in 30 (37%), with 27 (33%) products having used PROs both as primary and non-PEs. PRO usage was most frequently identified with nervous system and antineoplastic agents. During the study period, the use of all the three types of endpoints appeared to be static. Both the regulatory bodies and the industry should ensure complete and clear reporting of all endpoints used, including PROs, to improve transparency.Peer reviewedFinal Published versio

Capnography as an aid in localizing the phrenic nerve in brachial plexus surgery. Technical note

<p>Abstract</p> <p>Background</p> <p>To determine whether monitoring end- tidal Carbon Dioxide (capnography) can be used to reliably identify the phrenic nerve during the supraclavicular exploration for brachial plexus injury.</p> <p>Methods</p> <p>Three consecutive patients with traction pan-brachial plexus injuries scheduled for neurotization were evaluated under an anesthetic protocol to allow intraoperative electrophysiology. Muscle relaxants were avoided, anaesthesia was induced with propofol and fentanyl and the airway was secured with an appropriate sized laryngeal mask airway. Routine monitoring included heart rate, noninvasive blood pressure, pulse oximetry and time capnography. The phrenic nerve was identified after blind bipolar electrical stimulation using a handheld bipolar nerve stimulator set at 2–4 mA. The capnographic wave form was observed by the neuroanesthetist and simultaneous diaphragmatic contraction was assessed by the surgical assistant. Both observers were blinded as to when the bipolar stimulating electrode was actually in use.</p> <p>Results</p> <p>In all patients, the capnographic wave form revealed a notch at a stimulating amplitude of about 2–4 mA. This became progressively jagged with increasing current till diaphragmatic contraction could be palpated by the blinded surgical assistant at about 6–7 mA.</p> <p>Conclusion</p> <p>Capnography is a sensitive intraoperative test for localizing the phrenic nerve during the supraclavicular approach to the brachial plexus.</p

Glucosamine HCl-based solid dispersions to enhance the biopharmaceutical properties of acyclovir

The objective of the work presented here was to assess the feasibility of using glucosamine HCl as a solid-dispersion (SD) carrier to enhance the biopharmaceutical properties of a BCS class III/IV drug, acyclovir (ACV). The solid-dispersions of acyclovir and glucosamine HCl were prepared by an ethanol-based solvent evaporation method. The prepared formulations characterized by photomicroscopy, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), Fourier transforms infrared spectrophotometry (FTIR), powder x-ray diffractometry (PXRD) and drug content analysis. The functional characterization of ACV-SD was performed by aqueous solubility evaluation, dissolution studies, fasted versus fed state dissolution comparison, ex vivo permeability, and stability studies. Photomicroscopy and SEM analysis showed different surface morphologies for pure ACV, glucosamine HCl and ACV-SD. The physical-chemical characterization studies supported the formation of ACV-SD. A 12-fold enhancement in the aqueous solubility of ACV was observed in the prepared solid dispersions, compared to pure ACV. Results from in vitro dissolution demonstrated a significant increase in the rate and extent of ACV dissolution from the prepared ACV-SD formulations, compared to pure ACV. The rate and extent of ACV permeability across everted rat intestinal membrane were also found to be significantly increased in the ACV-SD formulations. Under fed conditions, the rate and extent of the in vitro dissolution of ACV from the formulation was appreciably greater compared to fasted conditions. Overall, the results from the study suggest the feasibility of utilizing glucosamine HCl as a solid dispersion carrier/excipient for enhancement of biopharmaceutical properties of acyclovir, and similar drugs with low solubility/permeability characteristics

Biomass partitioning, yield and economic performance of green gram (Vigna radiate L.) genotypes as influenced by different irrigation levels

A field experiment was conducted during the Kharif season of2020 with four main plot treatments consisting of irrigation levels (No post sowing irrigation, one irrigation at the flower initiation stage, one irrigation at the pod filling stage and two irrigations each at flower initiation and pod filling stage) and five subplot treatments as genotypes viz., MH 1142, MH 1468, MH 1703, MH 1762 and MH 1871 following split plot design by replicating thrice. Irrigating green gram, irrespective of the growth stage, increased the seed yield significantly. Two irrigations each at the flower initiation and podding stage bring about greater seed economic yield of green gram than 1 irrigation either at each stage. Among single irrigations, flower initiation stage provided significantly superior (8.6 %) seed yield compared to the pod filling stage. During the flower initiation stage, no rain and irrigation at this stage led to more development of crop plants, as is evident from a higher number of branches per plant and, ultimately, a higher number of pods. Two irrigations, i.e., each at flower initiation and podding phase, lead to considerably greater seed output than single irrigation at either growth stage, which may be attributed to the sufficient supply of water, which indirectly provided a smooth supply of nutrients to crop plants. The increase was 18.4 and 28.6 per cent over-irrigation at flowering and podding stage, respectively. Seed yield varied among green gram genotypes, which might be because of variations in the genetic potential of the genotypes. Genotype MH 1871 produced significantly higher seed yield among different genotypes. The cumulative effect of yield traits viz. pods per plant, branches per plant, seed index and seeds per pod attributed to the higher seed yield in MH 1871. This genotype was more efficient in utilizing radiations, as evident from the higher chlorophyll content recorded in this genotype. Genotype MH 1142 was the lowest yielder and MH 1762 although produced. To obtain a higher yield of green gram, genotype MH 1871 be taken with two irrigations each at flower initiation and pod filling stage

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of barrett-like metaplasia

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5+ gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling. © 2012 Elsevier Inc

महिषासुर: मिथक व परंपराएं

इक्कसवीं सदी के दूसरे दशक में भारत में महिषासुर आंदोलन द्विज संस्कृति के लिए चुनौती बनकर उभरा। इसके माध्यम से आदिवासियों, पिछड़ों और दलितों के एक बड़े हिस्से ने अपनी सांस्कृतिक दावेदारी पेश की। लेकिन यह आंदोलन क्या है, इसकी जड़ें समाज में कहां तक फैली हैं, बहुजनों की सांस्कृतिक परंपरा में इसका क्या स्थान है, मौजूदा लोक-जीवन में महिषासुर की उपस्थिति किन-किन रूपों में है, इसके पुरातात्विक साक्ष्य क्या हैं? गीतों-कविताओं व नाटकों में महिषासुर किस रूप में याद किए जा रहे हैं और अकादमिक-बौद्धिक वर्ग को इस आंदोलन ने किस रूप में प्रभावित किया है, उनकी प्रतिक्रियाएं क्या हैं? आदि प्रश्नों पर विमर्श हमें एक ऐसी बौद्धिक यात्रा की ओर ले जाने में सक्षम हैं, जिससे हममें अधिकांश अभी तक अपरिचित रहे हैं। क्या महिषासुर दक्षिण एशिया के अनार्यों के पूर्वज थे, जो बाद में एक मिथकीय चरित्र बन कर बहुजन संस्कृति के प्रतीक पुरुष बन गए? क्या यह बहुत बाद की परिघटना है, जब माकण्डेय पुराण, दुर्गासप्तशती जैसे ग्रंथ रच कर, एक कपोल-कल्पित देवी के हाथों महिषासुर की हत्या की कहानी गढ़ी गई? इस आंदोलन की सैद्धांतिकी क्या है? प्रमोद रंजन द्वारा संपादित किताब “महिषासुर: मिथक व परंपराएं” में लेखकों ने उपरोक्त प्रश्नों पर विचार किया है तथा विलुप्ति के कगार पर खड़े असुर समुदाय का विस्तृत नृवंशशास्त्रीय अध्ययन भी प्रस्तुत किया है। इस पुस्तक में समकालीन भारतीय साहित्य में महिषासुर पर लिखी गई कविताओं व गीतों का प्रतिनिधि संकलन भी है तथा महिषासुर की बहुजन कथा पर आधारित एक नाटक भी प्रकाशित है। समाज-विज्ञान व सांस्कृतिक विमर्श के अध्येताओं, सामाजिक-राजनीतिक कार्यकर्ताओं, साहित्य प्रेमियों के लिए यह एक आवश्यक पुस्तक है

Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus

OBJECTIVE: The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice. DESIGN: L2-IL-1β mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug. RESULTS: Hypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia. CONCLUSIONS: Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further

The global, regional, and national burden of adult lip, oral, and pharyngeal cancer in 204 countries and territories:A systematic analysis for the Global Burden of Disease Study 2019

Importance Lip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.Objective To analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence Review The incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.Findings In 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and Relevance In this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts

Global, regional, and national burden of colorectal cancer and its risk factors, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019

Funding: F Carvalho and E Fernandes acknowledge support from Fundação para a Ciência e a Tecnologia, I.P. (FCT), in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy i4HB; FCT/MCTES through the project UIDB/50006/2020. J Conde acknowledges the European Research Council Starting Grant (ERC-StG-2019-848325). V M Costa acknowledges the grant SFRH/BHD/110001/2015, received by Portuguese national funds through Fundação para a Ciência e Tecnologia (FCT), IP, under the Norma Transitória DL57/2016/CP1334/CT0006.proofepub_ahead_of_prin