Master File Research Articles

Association of Intraoperative Occult Hypoxemia With 30-Day and 1-Year Mortality.

Despite the widespread use of pulse oximetry for intraoperative estimation of arterial oxygen saturation, there is growing evidence that certain patient populations may be vulnerable to inaccurate pulse oximetry measurements and that unrecognized hypoxemia is associated with end-organ damage and adverse outcomes. In this single-center retrospective cohort study, we sought to better elucidate the relationship between intraoperative occult hypoxemia and postoperative mortality among patients undergoing anesthesia and surgery. Data were collected from our departmental data warehouse for adult patients (≥18 years) undergoing anesthesia between 2008 and 2019 with at least 1 intraoperative arterial blood gas recorded. The number of occult hypoxemic events, defined as arterial oxygen saturation (Sao2) of <88% despite oxygen saturation measured by pulse oximetry (Spo2) >92%, were determined. Mortality data were obtained from the Social Security Death Master File and used to determine 30-day and 1-year postoperative mortality. Propensity score overlap-weighted Firth logistic regression and Cox proportional-hazard modeling were performed to analyze whether at least 1 occult hypoxemic event was predictive of 30-day and 1-year mortality. There were 25,234 patients and 62,707 paired readings included in the final analysis. There were 351 patients (1.4%) with at least 1 occult hypoxemic reading. The overall 30-day mortality rate was 3.3% and 1-year mortality rate was 10.2%. In the overlap-weighted models, patients who experienced at least 1 occult hypoxemic event had significantly higher odds of both 30-day mortality (odds ratio [OR] = 2.89, 95% confidence interval [CI], 1.46-5.72, P = .002) and 1-year mortality (hazard ratio [HR] = 1.90, CI, 1.48-2.43, P < .001). There was no significant interaction between occult hypoxemia and self-reported race/ethnicity for predicting mortality. Intraoperative occult hypoxemic events are associated with significantly higher odds of 30-day and 1-year mortality, independent of self-reported race/ethnicity.

Tooth vitality and periapical healing: is Biodentine at par with MTA in regenerative endodontics?

The study is a prospective, double-blinded randomised control trial that compares the mineral trioxide aggregate (MTA) and Biodentine as the pulp space barrier material after induction of a periapical blood clot by over-instrumentation for endodontic regeneration in single-rooted mature permanent anterior tooth (closed apex) with apical periodontitis (periapical pathology of more than 3 mm) and having necrosed pulp. A total of 36 patients were included in the study and after randomisation were allocated equally to both the groups out of which 31 patients returned for follow-up over an 18-month period. The treatment protocol consisted of two separate appointments. At the first appointment, a standardised and custom-made radiographic guide was prepared for each patient to ensure uniformity and repeatability of the radiographs at subsequent follow-up visits. This was followed by access to the pulp chamber and biomechanical preparation of the single canal up to master apical file size. The irrigant used in each case was 1.5% sodium hypochlorite and also calcium hydroxide intracanal medicament was placed during this visit. The interval between the two appointments was not fixed and depended on the patient's symptoms following the first visit; however, the maximum allowable time frame was set at 3 weeks. During the second visit after irrigation with 17% ethylenediaminetetraacetic acid (EDTA) over instrumentation was done to induce bleeding that was allowed to fill the canal. The clot was stabilised by collagen plug and the pulp space sealer (either MTA or Biodentine) was placed below the cementoenamel junction following which composite restoration was done. The radiographs were taken before the treatment, after both the appointments and at 6, 9, 12 and 18 months subsequently by a single experienced examiner. Pre-operatively, a periapical index score (PAI) was given to each case and the sensibility test was performed at 6, 12, 18 months postoperatively using an electric pulp tester (EPT). Participants were recruited from the Department of Endodontics outpatient clinic. The patients were aged between 10-35 years and had no systemic conditions. For inclusion in the study, participants were required to have mature anterior tooth (single root canal) with closed apex associated with apical periodontitis and necrotic pulp having periapical radiolucency of more than 3 mm on the radiograph. Patients suffering from periodontitis (ensured by periodontal probing) and those having developmental anomalies of the teeth were excluded from the study. The normalcy of the data was assessed by Shapiro-Wilk test. Continuous data was analysed by Mann Whitney U test and the categorical data was analysed by Chi-square test and Fisher's exact test. With the level of significance set at 0.05. Firstly, the author presented the overall healing of the periapical lesion from Fisher's exact test, which showed that after 18 months, out of 31 patients, 21 cases (67.7%) had completely healed and 10 cases (32.3%) showed signs of healing and no case remained unhealed. The difference between the Biodentine and MTA was non-significant as derived from the Chi-square test for comparison of postoperative lesion sizes score at 18 months postoperatively. Secondly, based on EPT, the author presented the regain of tooth sensibility from Fisher's exact test which shows that out of 31 cases, 22 (71%) showed a positive response to EPT and 9 cases (29%) showed no response. Again, the difference between Biodentine and MTA was non-significant. Both Biodentine and MTA when used as pulp space barrier in regenerative endodontic procedures showed promising results. In both groups significant reduction in the size of periapical radiolucency was noted along with resolution of patient's symptoms. There was also significant regain in the tooth sensibility postoperatively. As there was no significant difference between the two in the treatment outcomes, both of these biomaterials can be used to treat apical periodontitis in mature permanent tooth as an alternative to conventional endodontic treatment in which the vitality of tooth is lost.

Leveraging Model Master Files for Long-Acting Injectables.

The U.S. Food and Drug Administration (FDA) and the Center for Research on Complex Generics (CRCG) hosted a public workshop on May 2-3, 2024, titled "Considerations and Potential Regulatory Applications for a Model Master File (Lachaine et al Can J Psychiatry. 60:S40-S47, 2015)". The workshop aimed to discuss the application of the Model Master File (MMF) concept in regulatory submissions that contain model integrated evidence (MIE), improving model sharing, model standardization, regulatory consistency, and regulatory efficiency. On Day 1, there was a session dedicated to MMF applications for long-acting injectables (LAIs). This perspective summarizes presentations, panel discussion, and small group discussion for the potential applications of MMFs in LAI product development, including case studies and potential situations in which MMFs can support regulatory submissions. The scientific presentations discussed the application of MMFs in mechanistic physiologically based pharmacokinetic (PBPK), multiphysics simulation, and population pharmacokinetics (popPK) models, as well as the potential utility of a model-integrated bioequivalence (MI-BE) framework. Additionally, challenges and considerations of implementing MMFs for LAIs were discussed in the panel and small groups. The anticipated benefits of MMFs are recognized among model developers, industries, and regulators.

The impact of the COVID-19 pandemic on the labour market outcomes of Indigenous persons living off-reserve in Canada

The recent COVID-19 pandemic had an impact on the labour force activity of many, but the effect of the crisis on the labour market outcomes of Indigenous peoples in Canada is relatively understudied. Using data from the master files of the Canadian Labour Force Survey (LFS), this analysis first considers the relative probability of four mutually exclusive labour force states: employed; unemployed; not in the labour force, but not discouraged; and not in the labour force due to being a discouraged worker. Differences in hours worked as well as earnings comparing Indigenous and non-Indigenous workers are then examined. The findings reveal that, regardless of the COVID-19 pandemic, Indigenous Canadians were relatively more likely to be either unemployed or not in the labour force (including being a discouraged worker) than to be employed as compared to their non-Indigenous counterparts. Indigenous workers earned roughly 3 percent less than their non-Indigenous counterparts. The earnings penalty experienced by Indigenous workers, was slightly smaller at the bottom of the wage distribution at 2 percent, increasing to roughly 3.3 percent at the top 90th percentile of the earnings function. During the COVID-19 period, while the risk of unemployment was lower for Indigenous persons, the risk of being a discouraged worker was even higher for Indigenous Canadians during the pandemic. Using an ad-hoc supplement to the LFS conducted by Statistics Canada in response to the pandemic, this study finds that Indigenous respondents were less likely than non-Indigenous respondents to either work from home or receive any form of Canada relief benefit from April 2020 to October 2021. The implications of these findings suggest a role for policy makers to improve access to funding supports for Indigenous workers and students seeking to pursue higher education to improve labour market outcomes. Additionally, employers play an important role in ensuring that Indigenous workers have fair access to job opportunities.

Effect of printing technology and orientation on the accuracy of three-dimensional printed retainers.

To evaluate the impact of printer technology and print orientation on the accuracy of directly printed retainers. Digital retainers were printed with two different printing technologies: digital light processing (DLP) and stereolithography (SLA), using two different orientations: 0° and 90°. After printing, the retainers (n = 40) were scanned using cone-beam computed tomography. The DICOM files were then converted into standard tessellation language (STL) files. Comparison of the printed retainers with a master file was done by superimposition using a three-dimensional (3D) best-fit tool in Geomagic software. A ±0.25 mm tolerance was set to detect differences between the superimposed files. Statistical analysis was conducted (Kruskal-Wallis and Wilcoxon-Mann-Whitney tests, with Bonferroni correction). The lowest median average deviation was observed for the DLP horizontally printed models (median, [interquartile range (IQR)] = 0.01 mm, [-0.01, 0.02]) followed by the SLA horizontally printed retainers (median, [IQR] = 0.05 mm, [0.03, 0.07]). The highest median inside the tolerance levels ratio was observed for the horizontally SLA printed retainers (median, [IQR] = 78.9%, [74.4, 82.4%]) followed by the horizontally DLP printed retainers (median, [IQR] = 78.2%, [74.5, 80.7%]). Both technologies (DLP and SLA) showed 3D printed results compatible with orthodontic clinical needs. Printing orientation was more important than printer type regarding its accuracy. Additional studies are needed to evaluate the accuracy of direct printed appliances clinically.

Specific aspects of bacteriophage regulation: international practices and future developments

INTRODUCTION. The increasing prevalence of multidrug-resistant strains of pathogens determines the need for fundamentally new antibacterial agents, including bacteriophage preparations. The consistent implementation of phage therapy is hindered by the lack of generally accepted standardised regulatory documents governing the legal and methodological aspects of the production and preclinical and clinical studies of bacteriophage preparations.AIM. This study aimed to analyse the international experience with the production and lifecycle management of bacteriophage preparations, as well as the main regulatory requirements for the control of their quality, safety, and efficacy.DISCUSSION. It is difficult to develop virulent bacteriophage preparations in accordance with the existing requirements for other medicinal products because of the biological characteristics of bacteriophages, the wide variety of bacteriophage strains, and the potential for rapid changes both in the bacteriophage population and in the pathogen population. Therefore, it is reasonable to develop streamlined marketing authorisation routes for phage therapies and methods for the assessment of their safety and efficacy. As part of these efforts, it is necessary to assess the adverse events specific to this group of medicinal products, such as the risks of lysogeny, resistance to bacteriophages, and antibiotic resistance gene transfer between bacterial strains. The pharmaceutical development of bacteriophage preparations can be based on several approaches. Many countries worldwide, including the United States, are implementing the concept of Quality by Design, considering approaches based on the Biological Master File, and conducting Expanded Access programmes. The Active Substance Master File procedure allows the submission of a separate document package covering only part of the registration dossier for regulatory approval. Expanded Access programmes provide individual patients with access to innovative medicinal products without approved treatment protocols. In the Russian Federation, the commercial production of bacteriophage medicinal products is conducted in accordance with the quality standards specified in the State Pharmacopoeia of the Russian Federation.CONCLUSIONS. There are fundamental differences in the approaches to phage therapy and its regulation around the world and in the Russian Federation. It is reasonable to supplement the current national guidelines for the safety and efficacy evaluation of bacteriophage preparations, in particular, to specify the requirements for conducting preclinical studies.

Incidence of cardiovascular disease in a cohort of mine workers exposed to ultrafine aluminum powder in Ontario, Canada.

A retrospective cohort study was conducted to estimate associations between an ultrafine aluminum powder, McIntyre Powder (MP), and cardiovascular disease incidence in a cohort of mine workers from Ontario, Canada. Disease outcomes included ischemic heart disease (IHD), acute myocardial infarction (AMI), congestive heart failure (CHF), and strokes and transient ischemic attacks (STIA). Using work history records from the Ontario Mining Master File (MMF) mine workers were followed for disease incidence in administrative health records. The analysis included 25,813 mine workers who were exposed to MP between 1943 and 1979 and followed for cardiovascular disease (CVD) diagnoses between 2006 and 2018. Cardiovascular disease cases were ascertained using physician, hospital, and ambulatory care records. Poisson regression models were used to estimate age and birth-year adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) for associations between MP exposure and CVD outcomes. Ever-exposure to MP was positively associated with modest increases in the incidence rate of IHD, AMI, and CHF, but not STIA, using both assessment approaches. Duration of self-reported MP exposure was positively associated with monotonically increasing rates of IHD and AMI compared to never-exposed miners, with the greatest association observed among miners with >20 years of exposure (for IHD: RR 1.24, 95% CI: 0.91-1.68; and for AMI: RR 1.52, 95% CI 1.01-2.28). Mine workers ever-exposed to MP had modestly elevated rates of CVD. The rate of CVD diagnoses appeared to increase with longer duration of exposure when assessed by both self-reported exposure and through historical records.

Regulatory requirement and filling procedure of drug master file in India under central drug standard control organization (CDSCO) in comparison with South Korea

The Drug master file (DMF) is a type of Confidential file that submitted to regulatory authorities about the ingredients, process, packing and storage of any drugs intended to human use. Drug master file plays an important role in production of drug. The Indian regulatory agency is a CDSCO that manages and encourage DMFs in India and in South Korea MFDS manages the DMFs. Unveiling the difference in regulatory requirements and filling procedure of DMF in India and South Korea as per CDSCO and MFDS respectively. Make certain the Protection, Grade, and Effectiveness of Drug Products.

Cesarean delivery, labor duration, and mothers’ mortality risk over 50 years of follow-up

BackgroundPregnancy complications have been recognized as a window to future health. Though cesarean delivery is common, it is unknown whether labor duration and mode of delivery are associated with maternal long-term mortality. ObjectiveTo examine whether labor duration and mode of delivery were associated with all-cause and cause-specific mortality. Study DesignParticipants were mothers from the multisite Collaborative Perinatal Project (CPP) cohort (1959–1966; n=43,646, limited to last CPP delivery). We ascertained all-cause and specific causes of death as of 2016 via linkage to the National Death Index and Social Security Death Master File. Hazard ratios (HR) testing mode of delivery and labor duration were estimated using Cox proportional hazards models adjusted for demographic and clinical characteristics. We further stratified analyses by parity. ResultsAmong participants with a recorded delivery mode, 5.9% (2486/42,335) had a cesarean delivery. Participants who had a cesarean were older (26.9 vs 24.3 years), with higher body mass index (24.0 vs 22.7 kg/m2), were less likely to be nulliparous (21% vs 30%), and more likely to have a household income of at least $6000 (22% vs 17%), to smoke ≥1 pack/d (18% vs 15%), to have diabetes mellitus (12% vs 1%) and to have a prior medical condition (47% vs 34%), compared to participants with a vaginal delivery. Delivery mode was similar by race/ethnicity, marital status, and education. Median labor duration was 395 minutes among participants who had an intrapartum cesarean delivery and 350 minutes among participants delivered vaginally. By 2016, 52.2% of participants with a cesarean delivery and 38.5% of participants with a vaginal delivery had died. Cesarean vs vaginal delivery was significantly associated with increased risk for all-cause mortality (HR=1.16 (95% confidence interval [CI]: 1.09, 1.23); in nulliparas, HR=1.27 (95% CI: 1.09, 1.47); in multiparas, HR=1.13 (95% CI: 1.06, 1.21) as well as increased risk of death from cardiovascular disease, diabetes, respiratory disease, infection, and kidney disease. Associations with death from cardiovascular disease, infection, and kidney disease were stronger for multiparas than nulliparas, though the association with death from diabetes was stronger among nulliparas. Labor duration was not significantly related to overall mortality. ConclusionIn a historic United States cohort with a low cesarean delivery rate, cesarean delivery was an indicator for subsequent increased mortality risk, particularly related to cardiovascular disease and diabetes. Future studies with long-term follow-up are warranted given the current high prevalence of cesarean delivery.

Evolution of ad hoc and routine data linkage in Australia

Australia has a rich history of utilising linked administrative data for health and human services research. The Population Health Research Network (PHRN), established in 2009, has developed national population-based data linkage capability and infrastructure. Australia-wide, specialist data linkage units have successfully linked their core population health data for over a decade, and within the network over 200 data collections are routinely linked. Data collections are typically classified as either routinely linked or linked on a project-by-project, ad hoc basis. Over time, linkage of data collections that were originally considered ad hoc, for example some longitudinal cohorts and clinical registries, has become ‘routine’. This paper reports on findings of a study that evaluated the volume and proportion of data linkage requests that have been facilitated through the PHRN over the past 5 years that include ad hoc linkage. The paper also reports on the type of data collections that have been linked on an ad hoc basis and details the type of research projects and fields of research currently supported via ad hoc linkage. Quantifying and characterising the type and most sought-after data collections for ad hoc linkage and the breadth of research being undertaken informs future planning and resource allocation for expanding the Australian national linkage capability. This paper explores the integration of ad hoc data linkage within the evolving landscape of expanded master linkage files and national linked data assets, responding to a growing range of data sources and research that could benefit from population-based data linkage.

Implementing Linkage Quality Assessments in Large-Scale Privacy Preserving Infrastructure: Did we kill them a second time and why are there zombies?

The National Clinical Cohort Collaborative (N3C) uses privacy-preserving record linkage (PPRL) to formulate longitudinal patient histories and for de-duplication across disparate data including electronic health records, administrative claims, and mortality data. The N3C employs a linkage honest broker implementation model which separates the entity holding de-identified PPRL tokens, from the entity holding the substantive data payloads. As a result of this data governance structure, linkage quality assessments are necessarily distributed into 2 distinct processes: 1) Linkage Honest Broker receipt and processing of linkages, 2) Data Aggregation entity assembling data based on received linkage crosswalks. Data is released on a weekly basis. This presentation will focus on Step 2 for the Mortality data linkages where the downstream data linkage pipelines must assess linkage quality across several dimensions of quality, focused on plausibility. There are 4 types of mortality data spanning the electronic health record, government Social Security Administration death master files, third-party obituary data, and administrative claims. Each of these sources has different levels of authoritativeness and data latency, compounding the challenges of reconciling fact of death including accurate death reporting dates. To address these challenges, we implemented an automated linkage quality pipeline which generates reports that assess linkage plausibility across the various data types, classifying concordance and discordance between data sources including age, dates of death, surfacing plausible and non-plausible activities post-death. Sharing our real-world implementation will aid conference attendees in understanding how to plan for such activities when considering specific implementation models for privacy-preserving linkages.

Unlocking the benefits of Drug Master File filing in the Indian pharmaceutical industries.

Ensuring the safety and quality of drugs is a crucial component for the development of any pharmaceutical industry. This requires stringent regulation in the process of drug manufacturing and marketing. A Drug Master File (DMF) serves as a comprehensive document containing information about the quality, safety, and manufacturing procedure/facility of a drug or drug substance. Many countries with highly regulated markets use the DMF system extensively to protect their intellectual property rights while providing accurate and detailed information about their products to regulatory bodies. In India, the regulatory body, the Central Drug Standard Control Organization, does not currently mandate the submission of a DMF. However, adopting a DMF system may have immense benefits to regulatory bodies, pharmaceutical industries, as well as to patients. This review aims to provide a comprehensive overview of DMF and highlight the significance of its adoption in India.

Microwave-assisted green synthesis and molecular docking study of some new 4-thiazolidinone derivatives as possible bioactive agents

We have developed an economical and environmentally friendly microwave-assisted efficient method for the synthesis of a series of new 4-oxo-thiazolidine derivatives (4a-d). The method involves microwave irradiated cyclocondensation reaction of Schiff bases (3a-d) and thioglycolic acid in drug master file (DMF). 4-oxo-thiazolidine derivatives (4a-d) was also synthe 4-Oxo-Thiazolidine derivatives were also synthesized by conventional heating procedures and consequence were Compared with Microwave assisted green method. The results suggest that microwave-assisted syntheses lead to higher yields within very short reaction times. Antimicrobial screening of all the synthesized compounds was carried out using Gram-positive strains Staphylococcus aureus and Gram-negative strain encompassing Escherichia coli, Proteus vulgaris, and Salmonella typhi. The results were compared with the standard drug chloramphenicol. All the synthesized compounds were subsequently examined using molecular docking experiments against peptide deformylase (PDB ID: 1G2A), which evaluates the binding interaction of ligands with enzyme active sites.. KEYWORDS :Microwave irradiation, Thiazolidinone, Molecular docking, Peptide deformylase, Antimicrobial screening.

Submission of Documents on the Pharmacovigilance System as Part of the Registration Dossier within the Framework of the EAEU Procedures: Analysis of Requirements and Typical Errors

INTRODUCTION. Documents on the pharmacovigilance system of the marketing authorisation holder (MAH), including the Pharmacovigilance System Master File (PSMF) and the PSMF-based summary of the pharmacovigilance system (SPS), are a mandatory component of the registration dossier for a medicinal product. Applicants must submit and update these documents in strict accordance with the legislation of the Eurasian Economic Union (EAEU). Systematisation of the requirements for drafting and submitting documents on the pharmacovigilance system will help applicants streamline the documentation process.AIM. This study aimed to analyse the requirements for submitting either the PSMF or the SPS, depending on the EAEU marketing authorisation procedure, and to describe typical errors made by applicants when submitting these documents.DISCUSSION. The content of dossier documents on the pharmacovigilance system is regulated by the Rules of Good Pharmacovigilance Practice of the Eurasian Economic Union (Decision No. 87 of the Council of the Eurasian Economic Commission (EEC) dated 3 November 2016), and their submission is governed by the Rules of Marketing Authorisation and Assessment of Medicinal Products for Human Use (EEC Council Decision No. 78 dated 3 November 2016). MAHs are required to keep documents on the pharmacovigilance system and the corresponding registration dossiers up to date. This article summarises the specific requirements for submitting either the PSMF or the SPS, depending on the EAEU marketing authorisation procedure. Additionally, this article highlights typical errors made by MAHs when preparing documents on the pharmacovigilance system. According to the EAEU Rules of Good Pharmacovigilance Practice, the first application submitted for marketing authorisation of a medicinal product in the EAEU should include the PSMF, and subsequent applications should include the SPS as part of the registration dossier. Changes to the pharmacovigilance documents should be made in accordance with the classifier (EEC Council Decision No. 78 dated 3 November 2016).CONCLUSIONS. This analysis of the requirements for the PSMF or the SPS as part of various marketing authorisation procedures will facilitate compliance with the requirements of the EAEU legislative acts and ensure correct submission of necessary documents on the pharmacovigilance system by applicants. In addition, regulatory authorities will make fewer requests to submit missing information and grant more marketing authorisations.

Trends in the Completeness and Validity of Sources of Death Data Against the National Death Index From 2010 to 2018.

We investigated time trends in validation performance characteristics for six sources of death data available within the Healthcare Integrated Research Database (HIRD) over 8 years. We conducted a secondary analysis of a cohort of advanced cancer patients with linked National Death Index (NDI) data identified in the HIRD between 2010 and 2018. We calculated sensitivity, specificity, positive predictive value, and negative predictive value for six sources of death status data and an algorithm combining data from available sources using NDI data as the reference standard. Measures were calculated for each year of the study including all members in the cohort for at least 1 day in that year. We identified 27 396 deaths from any source among 40 692 cohort members. Between 2010 and 2018, the sensitivity of the Death Master File (DMF) decreased from 0.77 (95% CI = 0.76, 0.79) to 0.12 (95% CI = 0.11, 0.14). In contrast, the sensitivity of online obituary data increased from 0.43 (95% CI = 0.41, 0.45) in 2012 to 0.71 (95% CI = 0.68, 0.73) in 2018. The sensitivity of the composite algorithm remained above 0.83 throughout the study period. PPV was observed to be high from 2010 to 2016 and decrease thereafter for all sources. Specificity and NPV remained at high levels throughout the study. We observed that the sensitivity of mortality data sources compared with the NDI could change substantially between 2010 and 2018. Other validation characteristics were less variable. Combining multiple sources of mortality data may be necessary to achieve adequate performance particularly for multiyear studies.

Mortality Risk of Low BMI in Life Insurance Applicants.

-This study seeks to quantify the mortality effect of low levels of body mass index (BMI) on life insurance applicants who, based on their laboratory profile and other information, appear to be suitable for life insurance coverage. -It has been demonstrated that low BMI is associated with higher mortality risk than normal or near-normal BMI. -Data were collected from over 4.7 million life insurance applicants with available BMI tested between 1995 and 2021, and vital status was assessed via the Social Security Death Master File. Cox models treating BMI as continuous and as a categorical variable were constructed, controlling for age, and split by sex after excluding those with laboratory or biometric test results, which were far enough outside the normal range to imply elevated mortality. -Models treating BMI as a continuous variable and allowing an interaction term for age showed that low BMI was strongly associated with mortality at ages 50 and above in both sexes. In the categorical models, only the lowest category of BMI (below the 1st percentile) in men aged 40-60, the lowest 2 categories (below the 5th percentile) in women aged 40-60, and the lowest 3 categories (below the 10th percentile) in those aged 60-80 years, were significantly associated with elevated mortality. No elevated mortality was detected in those under age 40 with low BMI. -Based on this study, low BMI is associated with elevated mortality in otherwise healthy applicants, but this association is dependent on age.

Dossier submission in the UK after Brexit

The withdrawal of the United Kingdom (UK) from the European Union (EU), commonly known as Brexit, occurred on January 31, 2020, triggering a transition period until December 31, 2020, during which the UK and EU negotiated their future relationship. Brexit has brought significant changes to regulatory frameworks, particularly in the pharmaceutical sector. This article examines the transition of dossier submission procedures in the UK following Brexit, focusing on the implications for marketing authorizations (MAs) and pharmacovigilance. The Medicines and Healthcare Products Regulatory Agency (MHRA) transitioned to an independent regulatory body, establishing new guidelines for pharmaceutical companies seeking MAs in the UK. Key changes in marketing authorization routes include the conversion of centrally authorized products (CAPs) to UK MAs, the introduction of the Decentralized and Mutual Recognition Reliance Procedure (MRDCRP), and the implementation of a 150-day assessment timeline for national procedures. This article compares dossier requirements before and after Brexit in the UK and highlights pharmacovigilance requirements post-Brexit, emphasizing adjustments to reporting obligations, Qualified Person for Pharmacovigilance (QPPV) responsibilities, and the establishment of UK-specific Pharmacovigilance System Master Files (PSMFs). Additionally, it addresses the dossier Module 1 administrative information requirements to provide a comprehensive overview of the changes in regulatory procedures in the UK pharmaceutical sector following Brexit. Overall, the article aims to serve as a valuable resource for industry professionals, regulatory experts, and other stakeholders seeking clarity on the regulatory changes and their implications for pharmaceutical products in the UK following Brexit.

Prosthetic outcomes after amputation and the impact of mobility level on survival

ObjectiveLower extremity amputation continues to be necessary in a significant number of patients with peripheral vascular disease. The 5-year survival following lower limb loss is markedly reduced. Many of these patients are never fitted with a prosthesis, and there is a dearth of knowledge regarding the barriers to prosthetic attainment. The goal of this study was to identify the risk factors for not receiving a prosthesis and the effect of mobility level on survival following major amputation. MethodsThis was a retrospective analysis of all patients that underwent lower extremity amputation by surgeons in our practice from January 1, 2010, to December 31, 2019. Abstracted data included: age, sex, race, body mass index, comorbidities, American Society of Anesthesiologists score, statin use, level of amputation, stump revision, fitting for prosthesis, type of prosthesis, and the United States’ Medicare Functional Classification Level, also called K level. Survival was determined using a combination of sources, including the Social Security Death Master File, searches of multiple genealogic registries, and general internet searches. Multivariable logistic regression was used to determine risk factors associated with prosthesis attainment. Multivariable Cox proportional hazard regression with time-dependent covariates was performed to assess risk factors associated with 5-year mortality. ResultsA total of 464 patients were included in this study. The mean age was 65 years, and mean body mass index was 27 kg/m2. The majority of patients were male (68%), White (56%), diabetic (62%), and hypertensive (76%), and underwent below-the-knee amputation (69%). Prosthetic attainment occurred in 185 (40%). On multivariable analysis, age >81 years and current tobacco use were associated with no prosthetic fitting. Overall 5-year survival was 41.9% (95% confidence interval [CI], 37.6%-46.6%) (below-the-knee amputation, 47.7% [95% CI, 42.5%-53.5%]; above-the-knee amputation, 28.7% [95% CI, 22.1%-37.2%]). On multivariable analysis, age >60 years, congestive heart failure, above-the-knee amputation, and no prosthetic attainment were associated with decreased survival. Increasing K level was incrementally associated with improved survival. ConclusionsThis study has identified several patient factors associated with prosthetic attainment, as well as multiple factors predictive of reduced survival after amputation. Being referred for prosthetic fitting was associated with improved survival not explained by patient characteristics and comorbidities. The Medicare Functional Classification Level K level predicts survival. More research is needed to determine the barriers to prosthetic attainment and if improving a patients K level will improve survival.

Comparative Evaluation of Solite RS3 and HyFlex Remover Retreatment Files in Conserving Remaining Dentin Thickness During Endodontic Retreatment Using Cone Beam Computed Tomography: An In Vitro Analysis.

Introduction Non-surgical retreatment is seen as a conservative choice for dealing with recurrent infections, instead of opting for periapical surgery. The retreatment processes should be promptly and efficiently carried out, utilizing a suitable armamentarium. The objective of this experiment is to evaluate the quantity of root dentin that remains following the removal of gutta-percha (GP) from the root canal employing two distinct retreatment files. Materials and methods Sixty single-rooted teeth were selected for the examination. The process of shaping and cleaning was performed using the step-back approach, with a master apical file size of 40. The smear layer was effectively eliminated by rinsing with a solution of 3% sodium hypochlorite and 17% ethylenediaminetetraacetic acid. Paper points were employed to desiccate the canals. The obturation process involved the utilization of the lateral compaction technique with the AH Plus sealer (Dentsply Sirona, NC, USA). The teeth were classified into two groups: Group I (n=30) underwent retreatment using HyFlex Remover (Coletene India, Pvt., Ltd.), whereas Group II (n=30) received therapy with Solite RS3 retreatment files (Solite Dental in Chennai, India). The remaining dentin thickness (RDT) was assessed by cone beam computed tomography at levels 3, 6, and 9 mm from the cemento enamel junction after the removal of GP. The acquired data underwent examination using an independent t-test to determine statistical significance. Results The findings demonstrate that the utilization of Solite RS3 files led to a higher level of dentin thickness remaining at 3 mm, 6 mm, and 9 mm on the mesial side in comparison to HyFlex Remover retreatment files. The observed difference was found to be statistically significant at a significance level of p<0.05 on the mesial side. Nevertheless, there was no notable disparity seen between the two file types at these three levels on the distal side (p>0.05). Conclusion Based on the obtained results of the study, it can be concluded that Solite RS3 files show promise in preserving the RDT. However, further studies encompassing diverse parameters are needed to establish a conclusive and definitive conclusion.

Comparative evaluation of incidence of dentinal defects after root canal preparation using three different endodontic retreatment systems - An in vitro study.

Safe and efficient removal of all root filling materials from the root canal system without compromising radicular dentin structure is essential for optimal nonsurgical retreatment. The aim of this study was to evaluate and compare the incidence of dentinal defects caused during root canal filling removal using conventional, rotary, and reciprocating retreatment file systems. A detailed protocol explaining purpose and procedures of the study was submitted to the Institutional Ethics Committee and ethical clearance obtained. Sixty human maxillary permanent central incisors were collected and decoronated to 12-mm standardized length. The canals prepared up to a master apical file size F3 with Protaper hand files, obturated using AH plus sealer, examined under the stereomicroscope (×40 magnification): Group I: Control (n = 15), Group II: Conventional (n = 15), Group III: Protaper Universal Retreatment Files (n = 15), and Group IV: Reciproc Blue (n = 15). After instrumentation, teeth were sectioned at 3, 6, and 9 mm from the apex to evaluate the presence of dentinal defects under the stereomicroscope. Statistics were performed using the SPSS, version, 25 (SPSS Inc., Chicago, IL, USA). Initially, normality test was done using the Shapiro-Wilk test and data were not normally distributed followed by Kruskal-Wallis test. P < 0.05 is considered statistically significant. Maximum percentage increase in dentinal defects was observed in Protaper Universal Retreatment Files followed by Conventional method and Reciproc Blue. Significantly Reciproc Blue reduced the incidence of dentinal defects after root canal preparation.