Quantifying Isoniazid Levels in Small Hair Samples: A Novel Method for Assessing Adherence during the Treatment of Latent and Active Tuberculosis.

BackgroundTuberculosis (TB) is the leading cause of death from an infectious pathogen worldwide and the most prevalent opportunistic infection in people living with HIV. Isoniazid preventive therapy (IPT) reduces the incidence of active TB and reduces morbidity and mortality in HIV-infected patients independently of antiretroviral therapy. However, treatment of latent or active TB is lengthy and inter-patient variability in pharmacokinetics and adherence common. Current methods of assessing adherence to TB treatment using drug levels in plasma or urine assess short-term exposure and pose logistical challenges. Drug concentrations in hair assess long-term exposure and have demonstrated pharmacodynamic relevance in HIV.MethodsA large hair sample from a patient with active TB was obtained for assay development. Methods to pulverize hair and extract isoniazid were optimized and then the drug detected by liquid chromatography/ tandem mass spectrometry (LC/MS-MS). The method was validated for specificity, accuracy, precision, recovery, linearity and stability to establish the assay's suitability for therapeutic drug monitoring (TDM). Hair samples from patients on directly-observe isoniazid-based latent or active TB therapy from the San Francisco Department of Public Health TB clinic were then tested.ResultsOur LC/MS-MS-based assay detected isoniazid in quantities as low as 0.02ng/mg using 10-25 strands hair. Concentrations in spiked samples demonstrated linearity from 0.05-50ng/mg. Assay precision and accuracy for spiked quality-control samples were high, with an overall recovery rate of 79.5%. In 18 patients with latent or active TB on treatment, isoniazid was detected across a wide linear dynamic range.ConclusionsAn LC-MS/MS-based assay to quantify isoniazid levels in hair with performance characteristics suitable for TDM was developed and validated. Hair concentrations of isoniazid assess long-term exposure and may be useful for monitoring adherence to latent or active TB treatment in the setting of HIV

Current sample size conventions: Flaws, harms, and alternatives

<p>Abstract</p> <p>Background</p> <p>The belief remains widespread that medical research studies must have statistical power of at least 80% in order to be scientifically sound, and peer reviewers often question whether power is high enough.</p> <p>Discussion</p> <p>This requirement and the methods for meeting it have severe flaws. Notably, the true nature of how sample size influences a study's projected scientific or practical value precludes any meaningful blanket designation of <80% power as "inadequate". In addition, standard calculations are inherently unreliable, and focusing only on power neglects a completed study's most important results: estimates and confidence intervals. Current conventions harm the research process in many ways: promoting misinterpretation of completed studies, eroding scientific integrity, giving reviewers arbitrary power, inhibiting innovation, perverting ethical standards, wasting effort, and wasting money. Medical research would benefit from alternative approaches, including established <it>value of information </it>methods, simple choices based on cost or feasibility that have recently been justified, sensitivity analyses that examine a meaningful array of possible findings, and following previous analogous studies. To promote more rational approaches, research training should cover the issues presented here, peer reviewers should be extremely careful before raising issues of "inadequate" sample size, and reports of completed studies should not discuss power.</p> <p>Summary</p> <p>Common conventions and expectations concerning sample size are deeply flawed, cause serious harm to the research process, and should be replaced by more rational alternatives.</p

Agriculture 4.0: A systematic literature review on the paradigm, technologies and benefits

Demographics will increase the demand for food and reduce the availability of labour in many countries all over the world. Moreover, scarcity of natural resources, climate change and food waste these are issues that are strongly impacting the agricultural sector and undermining sus-tainability. Digitalisation is expected to be a driving force in tackling these problems that are characterising agriculture. In particular, the adoption of digital technologies to support processes in the primary sector goes by the name of Agriculture 4.0. Although the number of contributions related to these issues is constantly growing, several areas are still unexplored or not fully addressed. This paper addresses the adoption of digital technologies and investigates the appli-cation domain of these technologies, presenting a systematic review of the literature on this subject. Moreover, this research shed light on the technologies adopted and related benefits. Hence, the research has turned its attention to the description of the main pillars, such as the categorisation of its main application domains and enabling technologies. The results of the research show that the different technologies applied in the various fields of application provide benefits both in terms of efficiency (cost reduction, farm productivity) and reduced environ-mental impact and increased sustainability

Experimental and Numerical Investigation of Hot Extruded Inconel 718

Inconel 718 is a widely used superalloy, due to its unique corrosion resistance and mechanical strength properties at very high temperatures. Hot metal extrusion is the most widely used forming technique, if the manufacturing of slender components is required. As the current scientific literature does not comprehensively cover the fundamental aspects related to the process–structure relationships, in the present work, a combined numerical and experimental approach is employed. A finite element (FE) model was established to answer three key questions: (1) predicting the required extrusion force at different extrusion speeds; (2) evaluating the influence of the main processing parameters on the formation of surface cracks using the normalized Cockcroft Latham’s (nCL) damage criterion; and (3) quantitatively assessing the amount of recrystallized microstructure through Avrami’s equation. For the sake of modeling validation, several experimental investigations were carried out under different processing conditions. Particularly, it was found that the higher the initial temperature of the billet, the lower the extrusion force, although a trade-off must be sought to avoid the formation of surface cracks occurring at excessive temperatures, while limiting the required extrusion payload. The extrusion speed also plays a relevant role. Similarly to the role of the temperature, an optimal extrusion speed value must be identified to minimize the possibility of surface crack formation (high speeds) and to minimize the melting of intergranular niobium carbides (low speeds)

LA SUBSIDENZA NELL’ITALIA CENTRO-SETTENTRIONALE DA MISURE GPS

La grande diffusione negli ultimi anni di reti di stazioni GPS permanenti istituite per scopi commerciali come il posizionamento in tempo reale, può rappresentare un’importante integrazione alla già esistente rete scientifica di monitoraggio della deformazione crostale. Le stazioni commerciali sono solitamente equipaggiate con ricevitori a doppia frequenza e antenne tipo choke ring. Una possibile differenza fra queste e le stazioni scientifiche consiste nell’approccio utilizzato per la scelta del sito e per la monumentazione. Per questo motivo prima di utilizzare le osservazioni acquisite dalle stazioni commerciali per analisi di tipo scientifico bisogna verificare se i protocolli di installazione e gestione di questi non introducano nuove sorgenti di rumore nei dati o aumentino quelle già esistenti. In questo studio, abbiamo confrontato le caratteristiche principali delle serie temporali di 112 stazioni commerciali situate nell’Italia Centro–Settentrionale con quelle di 81 stazioni scientifiche presenti nella medesima zona (Fig. 1). Le osservazioni delle 112 stazioni commerciali prese in esame sono fornite dalle seguenti agenzie pubbliche e private: ASSOGEO, LABTOPO, Rete Regione Veneto, SOGER, IREALP, Rete Arpa Piemonte e Regione Abruzzo; e i dati delle 81 stazioni scientifiche sono stati invece acquisiti dagli archivi informatici di 5 diverse istituzioni pubbliche: ASI, INGV – RING, EUREF, FREDNET e Rete Toscana. Le osservazioni di tutte le stazioni considerate in questo lavoro sono state analizzate mediante il software GAMIT/GLOBK versione 10.34 e successive utilizzando la procedura denominata distributed processing (Dong et alii, 1998), che consente di analizzare reti con un alto numero di stazioni suddividendole in diverse sottoreti distinte, compensando successivamente i risultati ottenuti in un’unica soluz

Progression of Biopsy-Measured Liver Fibrosis in Untreated Patients with Hepatitis C Infection: Non-Markov Multistate Model Analysis

BACKGROUND: Fibrosis stages from liver biopsies reflect liver damage from hepatitis C infection, but analysis is challenging due to their ordered but non-numeric nature, infrequent measurement, misclassification, and unknown infection times. METHODS: We used a non-Markov multistate model, accounting for misclassification, with multiple imputation of unknown infection times, applied to 1062 participants of whom 159 had multiple biopsies. Odds ratios (OR) quantified the estimated effects of covariates on progression risk at any given time. RESULTS: Models estimated that progression risk decreased the more time participants had already spent in the current stage, African American race was protective (OR 0.75, 95% confidence interval 0.60 to 0.95, p = 0.018), and older current age increased risk (OR 1.33 per decade, 95% confidence interval 1.15 to 1.54, p = 0.0002). When controlled for current age, older age at infection did not appear to increase risk (OR 0.92 per decade, 95% confidence interval 0.47 to 1.79, p = 0.80). There was a suggestion that co-infection with human immunodeficiency virus increased risk of progression in the era of highly active antiretroviral treatment beginning in 1996 (OR 2.1, 95% confidence interval 0.97 to 4.4, p = 0.059). Other examined risk factors may influence progression risk, but evidence for or against this was weak due to wide confidence intervals. The main results were essentially unchanged using different assumed misclassification rates or imputation of age of infection. DISCUSSION: The analysis avoided problems inherent in simpler methods, supported the previously suspected protective effect of African American race, and suggested that current age rather than age of infection increases risk. Decreasing risk of progression with longer time already spent in a stage was also previously found for post-transplant progression. This could reflect varying disease activity, with recent progression indicating active disease and high risk, while longer time already spent in a stage indicates quiescent disease and low risk