Target Product Profiles for medical tests: a systematic review of current methods

Background: A Target Product Profile (TPP) outlines the necessary characteristics of an innovative product to address an unmet clinical need. TPPs could be used to better guide manufacturers in the development of ‘fit for purpose’ tests, thus increasing the likelihood that novel tests will progress from bench to bedside. However, there is currently no guidance on how to produce a TPP specifically for medical tests. Methods: A systematic review was conducted to summarise the methods currently used to develop TPPs for medical tests, the sources used to inform these recommendations and the test characteristics for which targets are made. Database and website searches were conducted in November 2018. TPPs written in English for any medical test were included. Based on an existing framework, test characteristics were clustered into commonly recognised themes. Results: Forty-four TPPs were identified, all of which focused on diagnostic tests for infectious diseases. Three core decision-making phases for developing TPPs were identified: scoping, drafting and consensus-building. Consultations with experts and the literature mostly informed the scoping and drafting of TPPs. All TPPs provided information on unmet clinical need and desirable analytical performance, and the majority specified clinical validity characteristics. Few TPPs described specifications for clinical utility, and none included cost-effectiveness. Conclusions: We have identified a commonly used framework that could be beneficial for anyone interested in drafting a TPP for a medical test. Currently, key outcomes such as utility and cost-effectiveness are largely overlooked within TPPs though and we foresee this as an area for further improvement

Microwave-assisted synthesis, characterizations, antimicrobial activities, and DFT studies on some pyridine derived Schiff base

This study reports a joint experimental, theoretical and microbiological investigation on the (E)-N,N-dimethyl-4-((pyridine-2-ylmethylene)amino)aniline (5), (E)-N,N-dimethyl-4-((pyridine-4-ylmethylene)amino)aniline (6) and (E)-N,N-dimethyl-4-((pyridine-3-ylmethylene)amino)aniline (7). These compounds were synthesized with microwave method and their structures characterized by FT-IR, 1H-NMR, 13C-NMR, and elemental analysis tecniques. In the theoretical studies, torsional barriers analysis, ground state structure, Fourier Transform Infrared spectra (FT-IR), and Nuclear Magnetic Resonance spectra (NMR) of 5, 6, and, 7 were calculated by Density Functional Theory (DFT) computations. The conformers obtained from the torsional barrier scanning were optimized by B3LYP/6-31G(d,p) level. The harmonic vibrational frequencies, potential energy distribution (PED), infrared intensities, and NMR chemical shifts of the most stable conformers were determined using the B3LYP/6-311++G(d,p). Theoretically, predicted spectral data were compared with experimental results. Antimicrobial studies of the synthesized compounds were performed against various microbial strains. Antimicrobial activities of 5, 6, and, 7 were tested against selected bacteria and yeast through minimum inhibitory concentration (MIC) and diffusion method. Compound 7 was found to be the most active against bacteria and yeast, while compound 5 was found to be moderately active. Compounds 6 (against S. aureus and C. albicans) and, 7 were found to have a very high minimum inhibitory concentration, ranging between 1.95 and 7.81 g/mL (against P. aeruginosa and E. coli). Compounds (6 and 7) showed zone of inhibition values in the range of 10–20 mm against other bacteria except L. monocytogenes and S. thyphimurium. © 2022 Elsevier B.V

Optical imaging and spectroscopy for the study of the human brain: status report

This report is the second part of a comprehensive two-part series aimed at reviewing an extensive and diverse toolkit of novel methods to explore brain health and function. While the first report focused on neurophotonic tools mostly applicable to animal studies, here, we highlight optical spectroscopy and imaging methods relevant to noninvasive human brain studies. We outline current state-of-the-art technologies and software advances, explore the most recent impact of these technologies on neuroscience and clinical applications, identify the areas where innovation is needed, and provide an outlook for the future directions. Keywords: DCS; NIRS; diffuse optics; functional neuroscience; optical imaging; optical spectroscop

Detection of α-Thalassemia by Using Multiplex Ligation-Dependent Probe Amplification as an Additional Method for Rare Mutations in Southern Turkey

α-thalassemia is the most common single gene disorder in the Cukurova Region in Turkey. It is therefore routinely screened, including premaritally, in our region. The heterogeneous molecular basis of the disease makes α-thalassemia mutation detection difficult and complex. Besides well established methods, multiplex ligation dependent probe amplification (MLPA) is known as an effective, simple and specific method for the detection and characterization of deletions and duplications. We employed MLPA testing to 30 patients with hematological parameters suggestive of α-thalassemia carrier status but was negative for α-thalassemia with conventional reverse dot blot hybridization (RDB). We found α-globin gene deletions in 3 out of 30 (10 %) patients with MLPA. We propose that MLPA can be used as a second tier test in addition to other techniques such as RDB to identify α-thalassemia carriers in high prevalence regions such as ours, thereby allowing clinicians to provide accurate genetic counselling

Proteomic and Biological Analysis of the Effects of Metformin Senomorphics on the Mesenchymal Stromal Cells

Senotherapeutics are new drugs that can modulate senescence phenomena within tissues and reduce the onset of age-related pathologies. Senotherapeutics are divided into senolytics and senomorphics. The senolytics selectively kill senescent cells, while the senomorphics delay or block the onset of senescence. Metformin has been used to treat diabetes for several decades. Recently, it has been proposed that metformin may have anti-aging properties as it prevents DNA damage and inflammation. We evaluated the senomorphic effect of 6 weeks of therapeutic metformin treatment on the biology of human adipose mesenchymal stromal cells (MSCs). The study was combined with a proteome analysis of changes occurring in MSCs’ intracellular and secretome protein composition in order to identify molecular pathways associated with the observed biological phenomena. The metformin reduced the replicative senescence and cell death phenomena associated with prolonged in vitro cultivation. The continuous metformin supplementation delayed and/or reduced the impairment of MSC functions as evidenced by the presence of three specific pathways in metformin-treated samples: 1) the alpha-adrenergic signaling, which contributes to regulation of MSCs physiological secretory activity, 2) the signaling pathway associated with MSCs detoxification activity, and 3) the aspartate degradation pathway for optimal energy production. The senomorphic function of metformin seemed related to its reactive oxygen species (ROS) scavenging activity. In metformin-treated samples, the CEBPA, TP53 and USF1 transcription factors appeared to be involved in the regulation of several factors (SOD1, SOD2, CAT, GLRX, GSTP1) blocking ROS

Subcortical Source and Modulation of the Narrowband Gamma Oscillation in Mouse Visual Cortex

Primary visual cortex exhibits two types of gamma rhythm: broadband activity in the 30-90 Hz range and a narrowband oscillation seen in mice at frequencies close to 60 Hz. We investigated the sources of the narrowband gamma oscillation, the factors modulating its strength, and its relationship to broadband gamma activity. Narrowband and broadband gamma power were uncorrelated. Increasing visual contrast had opposite effects on the two rhythms: it increased broadband activity, but suppressed the narrowband oscillation. The narrowband oscillation was strongest in layer 4 and was mediated primarily by excitatory currents entrained by the synchronous, rhythmic firing of neurons in the lateral geniculate nucleus (LGN). The power and peak frequency of the narrowband gamma oscillation increased with light intensity. Silencing the cortex optogenetically did not abolish the narrowband oscillation in either LGN firing or cortical excitatory currents, suggesting that this oscillation reflects unidirectional flow of signals from thalamus to cortex

An Evaluation of Periodontal Status and Cytokine Levels in Saliva and Gingival Crevicular Fluid of Patients with Inflammatory Bowel Diseases.

AIMS Periodontal diseases and inflammatory bowel diseases (IBD, ulcerative colitis [UC] and Crohn's disease [CD]) have been reported to present with increased salivary and gingival crevicular fluid (GCF) concentrations of cytokines. The aim of this study was to evaluate the salivary and GCF levels of TNF-α, IL-1β, IL-10, and IL-17A and their associations with the periodontal statuses of UC, CD and non-IBD patients, and to analyze the interrelationships among these cytokines, IBD conditions, and periodontal diseases. MATERIALS AND METHODS This cross-sectional study was performed with a total of 131 patients (62 women and 69 men, mean age 42.96±13.02 years). Patients were divided into three groups: UC, CD, and non-IBD. Periodontal status was defined according to the 2017 World Workshop Disease Classification. Salivary and GCF cytokine levels were analyzed using ELISA. RESULTS UC and CD patients diagnosed as having periodontitis and gingivitis presented with significantly higher levels of TNF-α and lower levels of IL-10 as compared with non-IBD patients (p<0.05). UC patients diagnosed with periodontitis exhibited significantly higher scores of bleeding on probing (p = 0.011) and increased salivary and GCF IL-1β levels as compared with CD patients (p = 0.005, and 0.012 respectively). Considering the active and remission status of IBD, salivary IL-1β was found to be correlated with the parameters representing the severity of periodontal diseases in active UC and CD patients. CONCLUSION(S) In the presence of periodontal diseases, UC and CD patients showed different expression levels of TNF-α, IL-1β, and IL-10 in oral secretions as compared with non-IBD patients. This article is protected by copyright. All rights reserved

Nitric Oxide Contributes to Vasomotor Tone in Hypertensive African Americans Treated With Nebivolol and Metoprolol

Endothelial dysfunction is more prevalent in African Americans (AAs) compared with whites. The authors hypothesized that nebivolol, a selective β1 -antagonist that stimulates nitric oxide (NO), will improve endothelial function in AAs with hypertension when compared with metoprolol. In a double-blind, randomized, crossover study, 19 AA hypertensive patients were randomized to a 12-week treatment period with either nebivolol 10 mg or metoprolol succinate 100 mg daily. Forearm blood flow (FBF) was measured using plethysmography at rest and after intra-arterial infusion of acetylcholine and sodium nitroprusside to estimate endothelium-dependent and independent vasodilation, respectively. Physiologic vasodilation was assessed during hand-grip exercise. Measurements were repeated after NO blockade with L-N(G) -monomethylarginine (L-NMMA) and after inhibition of endothelium-derived hyperpolarizing factor (EDHF) with tetraethylammonium chloride (TEA). NO blockade with L-NMMA produced a trend toward greater vasoconstriction during nebivolol compared with metoprolol treatment (21% vs 12% reduction in FBF, P=.06, respectively). This difference was more significant after combined administration of L-NMMA and TEA (P\u3c.001). Similarly, there was a contribution of NO to exercise-induced vasodilation during nebivolol but not during metoprolol treatment. There were significantly greater contributions of NO and EDHF to resting vasodilator tone and of NO to exercise-induced vasodilation with nebivolol compared with metoprolol in AAs with hypertension

Hallervorden-Spatz Syndrome

Background: A 28-year-old man was referred to the neurology department of our hospital with difficulty of social interaction, impairment in carrying out daily life activities and muscle rigidity. He had a history of head trauma 3 years ago. Neurological examination revealed bradykinesia, hypophonic speech, resting and postural tremor, rigidity, spasticity, hyperreflexia and psychosis