Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

A Universal Approximation for Conductance Blockade in Thin Nanopore Membranes.

Nanopore-based sensing platforms have transformed single-molecule detection and analysis. The foundation of nanopore translocation experiments lies in conductance measurements, yet existing models, which are largely phenomenological, are inaccurate in critical experimental conditions such as thin and tightly fitting pores. Of the two components of the conductance blockade, channel and access resistance, the access resistance is poorly modeled. We present a comprehensive investigation of the access resistance and associated conductance blockade in thin nanopore membranes. By combining a first-principles approach, multiscale modeling, and experimental validation, we propose a unified theoretical modeling framework. The analytical model derived as a result surpasses current approaches across a broad parameter range. Beyond advancing our theoretical understanding, our framework's versatility enables analyte size inference and predictive insights into conductance blockade behavior. Our results will facilitate the design and optimization of nanopore devices for diverse applications, including nanopore base calling and data storage.

Toward Post-Hartree-Fock Accuracy for Protein-Ligand Affinities Using the Molecules-in-Molecules Fragmentation-Based Method.

The complexity and size of large molecular systems, such as protein-ligand complexes, pose computational challenges for accurate post-Hartree-Fock calculations. This study delivers a thorough benchmarking of the Molecules-in-Molecules (MIM) method, presenting a clear and accessible strategy for layer/theory selections in post-Hartree-Fock computations on substantial molecular systems, notably protein-ligand complexes. An approach is articulated, enabling augmented computational efficiency by strategically canceling out common subsystem energy terms between complexes and proteins within the supermolecular equation. Employing DLPNO-based post-Hartree-Fock methods in conjunction with the three-layer MIM method (MIM3), this study demonstrates the achievement of protein-ligand binding energies with remarkable accuracy (errors <1 kcal mol-1), while significantly reducing computational costs. Furthermore, noteworthy correlations between theoretically computed interaction energies and their experimental equivalents were observed, with R2 values of approximately 0.90 and 0.78 for CDK2 and BZT-ITK sets, respectively, thus validating the efficacy of the MIM method in calculating binding energies. By highlighting the crucial role of diffuse or small Pople-style basis sets in the middle layer for reducing energy errors, this work provides valuable insights and practical methodologies for interaction energy computations in large molecular complexes and opens avenues for their application across a diverse range of molecular systems.

Magnetic Control of Nonmagnetic Living Organisms.

Living organisms inspire the design of microrobots, but their functionality is unmatched. Next-generation microrobots aim to leverage the sensing and communication abilities of organisms through magnetic hybridization, attaching magnetic particles to them for external control. However, the protocols used for magnetic hybridization are morphology specific and are not generalizable. We propose an alternative approach that leverages the principles of negative magnetostatics and magnetophoresis to control nonmagnetic organisms with external magnetic fields. To do this, we disperse model organisms in dispersions of Fe3O4 nanoparticles and expose them to either uniform or gradient magnetic fields. In uniform magnetic fields, living organisms align with the field due to external torque, while gradient magnetic fields generate a negative magnetophoretic force, pushing objects away from external magnets. The magnetic fields enable controlling the position and orientation of Caenorhabditis elegans larvae and flagellated bacteria through directional interactions and magnitude. This control is diminished in live spermatozoa and adult C. elegans due to stronger internal biological activity, i.e., force/torque. Our study presents a method for spatiotemporal organization of living organisms without requiring magnetic hybridization, opening the way for the development of controllable living microbiorobots.

REKOVER study protocol: a pRospective patient treatment rEgistry of tramadol and dexKetoprofen trometamol oral fixed-dose combination (SKUDEXA) in mOderate to seVere acutE pain in Real-world setting in Asia.

INTRODUCTION: Satisfactory management of acute pain remains a major medical challenge despite the availability of multiple therapeutic options including the fixed-dose combination (FDC) drugs. Tramadol and dexketoprofen trometamol (TRAM/DKP) 75/25 mg FDC was launched in 2018 in Asia and is widely used in the management of moderate to severe acute pain. There are limited data on its effectiveness and safety in Asian patients, and therefore, a need to better understand its usage patterns in clinical practice. We aim to understand the usage pattern of TRAM/DKP FDC, its effectiveness and tolerability in patients with moderate to severe acute pain in Asia. METHODS AND ANALYSIS: REKOVER is a phase-IV, multicountry, multicentre, prospective, real-world observational study. A total of 750 postsurgical and non-surgical patients (male and female, aged 18-80 years) will be recruited from 13 tertiary-care hospitals (15 sites) in Singapore, Thailand, the Philippines and Malaysia. All patients prescribed with TRAM/DKP FDC and willing to participate in the study will be enrolled. The recruitment duration for each site will be 6 months. The severity of pain will be collected using Numeric Pain Rating Scale through the treatment period from day 1 to day 5, while satisfaction with the treatment will be evaluated using Patient Global Evaluation Scale at the end of treatment. Any adverse event reported during the study duration will be recorded for safety analysis (up to day 6). The study data will be entered into the ClaimIt portal and mobile application (app) (ObvioHealth, USA). All the inpatient data will be entered into the portal by the study site and for outpatient it will be done by patients through an app. ETHICS AND DISSEMINATION: The study has been approved by the local ethics committee from each study sites in Singapore, Thailand, the Philippines and Malaysia. Findings will be disseminated through local and global conference presentations, publications in peer-reviewed scientific journals and continuing medical education.

The High Sensitivity of the Multi-Cancer Detection Test ONCOVERYX-F Offers a Promising Platform for Ovarian Cancer Screening.

We evaluated the potential relevance of our multi-cancer detection test, OncoVeryx-F, for ovarian cancer screening. For this, we compared its accuracy with that of CA125-based screening. We demonstrate here that, in contrast to CA125-based detection, OncoVeryx-F detected ovarian cancer with very high sensitivity and specificity. Importantly here, Stage I cancers too could be detected with an accuracy of >98%. Furthermore, again unlike CA 125, the detection accuracy of OncoVeryx-F remained comparable in both Caucasian and South Asian/Indian women. Thus, the robustness and accuracy of OncoVeryx-F, particularly for early-stage detection, underscores its potential utility for ovarian cancer screening.

Assessment of frailty and quality of life and their correlation in the haemodialysis population at Palmerston North Hospital, New Zealand.

AIM: End-stage kidney disease (ESKD) is increasingly becoming a healthcare concern in New Zealand and haemodialysis remains the most common modality of treatment. Frailty and health-related quality of life (HRQOL) are established predictors of prognosis and have already been shown to be poor in the dialyzing population. Existing data show correlation between these measures in the ESKD population, however there is little evidence for those on haemodialysis specifically. Our study aimed to assess for a correlation between frailty and HRQOL in the haemodialysis population at Palmerston North Hospital, and to assess for any differences in frailty and HRQOL scores between indigenous Maori and non-Maori subgroups. METHODS: A cross-sectional study was conducted involving 93 in-centre haemodialysis patients from Palmerston North Hospital, New Zealand. Baseline demographic data was measured alongside frailty and HRQOL scores, which were measured using the Kidney Disease Quality of Life tool (KDQOL-36) and the Edmonton Frail Scale. RESULTS: A statistically significant negative correlation was observed between frailty and all aspects of HRQOL (p < .05), with the strongest correlation observed between frailty and the physical component (r = -.64, p = <.001). Independent samples t-test showed no statistically significant difference between scores for Maori and non-Maori in frailty (M = 7.4, SD = 3.3 vs. M = 6.8, SD = 3.2; t (91) = -0.92, p = .80), or HRQOL (p values > .05 in all components). CONCLUSION: A negative correlation was observed between frailty and HRQOL. This information can be beneficial in guiding discussions around treatment modality and for future patients and useful in enabling better predictions of prognosis. No statistically significant differences in frailty and HRQOL scores were observed between Maori and non-Maori groups, however the generalizability of this finding is limited due to the insufficient size of the study population.

Hilar Anatomy in 3035 Living Liver Donors: A Novel Classification for Donor Surgery and Suitability, Hepatic Surgeries, and Hepatobiliary Interventions.

BACKGROUND: This study examines the vascular and biliary variations in 3035 liver donors. We propose a novel classification of hepatic arteries, portal veins, and bile ducts and clinically relevant donor classification. METHODS: Preoperative imaging and operative details of 3035 donors from 2005 to 2020 were reviewed. Hilar anatomical variations were identified and grouped on the basis of incidence and clinical relevance. RESULTS: Hilar structures are classified according to the numbers supplying or draining the graft: for the hepatic artery, right (R) and left (L), RA1/LA1 (1 artery), RA2/LA2 (2 arteries), and RA3/LA3 (3 arteries), respectively, further defined on the basis of the inflow trunk into C (for common hepatic artery), S (for superior mesenteric artery), and L (for left gastric artery); for the portal vein, RP1 (1 vein) and RP2 (2 veins) for the right lobe; and for the hepatic duct, RB1/LB1 (1 duct), RB2/LB2 (2 ducts), RB3 (3 right ducts), and RB4 (4 right ducts). Donors were classified on the basis of anatomical variations into 3 groups: class 1 and class 2 donors, who can donate liver with acceptable risks, and class 3 donors, who are high-risk donors because they are anatomically unacceptable ( Figures S1 to S4, SDC , http://links.lww.com/TP/C918 ). CONCLUSIONS: Defining hilar anatomical variations and donor grouping into anatomy-based clinical classes helps in operative planning of donors, hepatobiliary surgeries, and interventional procedures.

Vibrational Analysis of Constrained Molecular Systems.

Vibrational spectroscopy, including infrared (IR), Raman spectroscopy, and vibrational circular dichroism, is instrumental in determining the structure and composition of molecules. These techniques are highly sensitive to molecular conformations. However, full molecular optimization, necessary for theoretical vibrational spectra, can lead to unintended conformational changes, especially in large biomolecules like polypeptides. To address this, dihedral angle constraints can be imposed during optimization to preserve the molecule's native conformation. Constraint-optimized molecular geometries, not being true stationary points in the full configurational space, pose challenges for traditional vibrational analysis. We address this by considering such geometries as subspace minima, reformulating vibrational analysis to incorporate constraints. Normal modes and spectra consistent with these constraints are obtained by projecting the force constant matrix onto a space orthogonal to the constrained coordinates. This method, illustrated by the example of enkephalin, yields 3N - 6 - m nonzero frequencies after constraint projection, demonstrating its applicability to biomolecules with flexible conformations. Our approach offers a comprehensive mathematical framework to compute vibrational spectra of molecules with conformationally flexible subunits under environmental constraints.

Perineural low dexamethasone dose as adjuvant in supraclavicular brachial plexus block for arteriovenous fistula creation in end stage renal disease: a randomized controlled trial

Abstract Background and aims: Dexamethasone as adjunct to local anesthetic solution improves the quality of brachial plexus block (BPB). However, evidence for its efficacy at low doses (< 4 mg) is lacking. This study was designed to evaluate the duration of analgesia attained with low dose dexamethasone as adjuvant to local anesthetic for creation of arteriovenous fistula (AVF) under BPB. Methods: Sixty-six patients scheduled for AVF creation were randomly allocated to receive either saline (control) or 2 mg dexamethasone, together with 0.5% ropivacaine and 0.2% lignocaine. The primary outcome was duration of analgesia, defined as time from performing the block to the first analgesic request. The secondary outcomes were time from injection to complete sensory block, time from injection to complete motor block, duration of motor block, postoperative analgesic consumption, and fistula patency at three months. Results: All the blocks were effective. In the group that received dexamethasone, the time to first analgesic request was significantly delayed (432 ± 43.8 minutes vs. 386.4 ± 40.2 minutes; p < 0.01). The onset of sensory and motor blockade occurred faster in dexamethasone group and overall analgesic consumption was also reduced. However, dexamethasone addition did not prolong the duration of motor block. There was no statistically significant difference in the patency of fistulas between the two groups at three months. (p = 0.34). Conclusion: Addition of low-dose perineural dexamethasone to local anesthetic solution significantly prolonged the duration of analgesia. Further trials are warranted to compare the adverse effects between dexamethasone doses of 4 mg and lower.

Structural and Functional Changes in Non-Paraneoplastic Autoimmune Retinopathy.

BACKGROUND: To describe longitudinal changes in patients with non-paraneoplastic autoimmune retinopathy (npAIR) by utilizing different diagnostic modalities/tests. METHODS: The index study is a retrospective longitudinal review of sixteen eyes of eight patients from a tertiary care eye hospital diagnosed with npAIR. Multiple diagnostic modalities such as wide-angle fundus photography (WAFP), WA fundus autofluorescence (WAFAF), spectral-domain optical coherence tomography (SD-OCT), Goldmann visual field (GVF) perimetry, microperimetry (MP), electrophysiologic testing, and adaptive optics scanning laser ophthalmoscopy (AOSLO) were reviewed and analyzed. RESULTS: At the baseline visits, anomalies were detected by multimodal diagnostic tests on all patients. Subjects were followed up for a median duration of 11.5 [3.0-18.7] months. Structural changes at the baseline were detected in 14 of 16 (87.5%) eyes on WAFP and WAFAF and 13 of 16 (81.2%) eyes on SD-OCT. Eight of the ten (80%) eyes that underwent AOSLO imaging depicted structural changes. Functional changes were detected in 14 of 16 (87.5%) eyes on GVF, 15 of 16 (93.7%) eyes on MP, and 11 of 16 (68.7%) eyes on full-field electroretinogram (ff-ERG). Multifocal electroretinogram (mf-ERG) and visual evoked potential (VEP) tests were performed in 14 eyes, of which 12 (85.7%) and 14 (100%) of the eyes demonstrated functional abnormalities, respectively, at baseline. Compared to all the other structural diagnostic tools, AOSLO had a better ability to demonstrate deterioration in retinal microstructures occurring at follow-ups. Functional deterioration at follow-up was detected on GVF in 8 of 10 (80%) eyes, mf-ERG in 4 of 8 (50%) eyes, and MP in 7 of 16 (43.7%) eyes. The ff-ERG and VEP were stable in the majority of cases at follow-up. CONCLUSIONS: The utilization of multimodal imaging/tests in the diagnosing and monitoring of npAIR patients can aid in identifying anomalous changes over time. Analysis of both the anatomical and functional aspects by these devices can be supportive of detecting the changes early in such patients. AOSLO shows promise as it enables the capture of high-resolution images demonstrating quantifiable changes to retinal microstructure.

Evaluation of terlipressin-related patient outcomes in hepatorenal syndrome-acute kidney injury using point-of-care echocardiography.

BACKGROUND AND AIMS: Treatment of hepatorenal syndrome-acute kidney injury (HRS-AKI), with terlipressin and albumin, provides survival benefits, but may be associated with cardiopulmonary complications. We analyzed the predictors of terlipressin response and mortality using point-of-care echocardiography (POC-Echo) and cardiac and renal biomarkers. APPROACH: Between December 2021 and January 2023, patients with HRS-AKI were assessed with POC-Echo and lung ultrasound within 6 hours of admission, at the time of starting terlipressin (48 h), and at 72 hours. Volume expansion was done with 20% albumin, followed by terlipressin infusion. Clinical data, POC-Echo data, and serum biomarkers were prospectively collected. Cirrhotic cardiomyopathy (CCM) was defined per 2020 criteria. RESULTS: One hundred and forty patients were enrolled (84% men, 59% alcohol-associated disease, mean MELD-Na 25±SD 5.6). A median daily dose of infused terlipressin was 4.3 (interquartile range: 3.9-4.6) mg/day; mean duration 6.4 ± SD 1.9 days; the complete response was in 62% and partial response in 11%. Overall mortality was 14% and 16% at 30 and 90 days, respectively. Cutoffs for prediction of terlipressin nonresponse were cardiac variables [ratio of early mitral inflow velocity and mitral annular early diastolic tissue doppler velocity > 12.5 (indicating increased left filling pressures, C-statistic: 0.774), tissue doppler mitral velocity < 7 cm/s (indicating impaired relaxation; C-statistic: 0.791), > 20.5% reduction in cardiac index at 72 hours (C-statistic: 0.885); p < 0.001] and pretreatment biomarkers (CysC > 2.2 mg/l, C-statistic: 0.640 and N-terminal proBNP > 350 pg/mL, C-statistic: 0.655; p <0.050). About 6% of all patients with HRS-AKI and 26% of patients with CCM had pulmonary edema. The presence of CCM (adjusted HR 1.9; CI: 1.8-4.5, p = 0.009) and terlipressin nonresponse (adjusted HR 5.2; CI: 2.2-12.2, p <0.001) were predictors of mortality independent of age, sex, obesity, DM-2, etiology, and baseline creatinine. CONCLUSIONS: CCM and reduction in cardiac index, reliably predict terlipressin nonresponse. CCM is independently associated with poor survival in HRS-AKI.

Locally optimal geometry for surface-enhanced diffusion.

Molecular diffusion in bulk liquids proceeds according to Fick's law, which stipulates that the particle current is proportional to the conductive area. This constrains the efficiency of filtration systems in which both selectivity and permeability are valued. Previous studies have demonstrated that interactions between the diffusing species and solid boundaries can enhance or reduce particle transport relative to bulk conditions. However, only cases that preserve the monotonic relationship between particle current and conductive area are known. In this paper, we expose a system in which the diffusive current increases when the conductive area diminishes. These examples are based on the century-old theory of a charged particle interacting with an electrical double layer. This surprising discovery could improve the efficiency of filtration and may advance our understanding of biological pore structures.

14 examples of how LLMs can transform materials science and chemistry: a reflection on a large language model hackathon.

Large-language models (LLMs) such as GPT-4 caught the interest of many scientists. Recent studies suggested that these models could be useful in chemistry and materials science. To explore these possibilities, we organized a hackathon. This article chronicles the projects built as part of this hackathon. Participants employed LLMs for various applications, including predicting properties of molecules and materials, designing novel interfaces for tools, extracting knowledge from unstructured data, and developing new educational applications. The diverse topics and the fact that working prototypes could be generated in less than two days highlight that LLMs will profoundly impact the future of our fields. The rich collection of ideas and projects also indicates that the applications of LLMs are not limited to materials science and chemistry but offer potential benefits to a wide range of scientific disciplines.

Diffusiophoresis-enhanced Turing patterns.

Turing patterns are fundamental in biophysics, emerging from short-range activation and long-range inhibition processes. However, their paradigm is based on diffusive transport processes that yield patterns with shallower gradients than those observed in nature. A complete physical description of this discrepancy remains unknown. We propose a solution to this phenomenon by investigating the role of diffusiophoresis, which is the propulsion of colloids by a chemical gradient, in Turing patterns. Diffusiophoresis enables robust patterning of colloidal particles with substantially finer length scales than the accompanying chemical Turing patterns. A scaling analysis and a comparison to recent experiments indicate that chromatophores, ubiquitous in biological pattern formation, are likely diffusiophoretic and the colloidal Péclet number controls the pattern enhancement. This discovery suggests that important features of biological pattern formation can be explained with a universal mechanism that is quantified straightforwardly from the fundamental physics of colloids.

A non-invasive method for concurrent detection of multiple early-stage cancers in women.

Untargeted serum metabolomics was combined with machine learning-powered data analytics to develop a test for the concurrent detection of multiple cancers in women. A total of fifteen cancers were tested where the resulting metabolome data was sequentially analysed using two separate algorithms. The first algorithm successfully identified all the cancer-positive samples with an overall accuracy of > 99%. This result was particularly significant given that the samples tested were predominantly from early-stage cancers. Samples identified as cancer-positive were next analysed using a multi-class algorithm, which then enabled accurate discernment of the tissue of origin for the individual samples. Integration of serum metabolomics with appropriate data analytical tools, therefore, provides a powerful screening platform for early-stage cancers.

Bluegrass Biodesign: Why an Integrated Biomedical Engineering Curriculum is Crucial for Medical Education.

Background Medical education often overlooks the significance of design and innovation literacy, resulting in a knowledge gap in undergraduate medical education (UME) regarding formal training in these areas. Incorporating innovation into UME's core curriculum is crucial as future physicians will encounter evolving technologies, and fostering a transdisciplinary approach can enable collaborative problem-solving and improve patient health outcomes. Methodology We developed a comprehensive medical biodesign curriculum focused on innovation, including problem identification, prototype testing, and product commercialization. Participants were selected based on applications, interviews, and diverse criteria. A survey was conducted before and after the program to assess students' biodesign experiences and knowledge, with data analyzed using descriptive statistics and paired t-tests. Results Of the 41 participants, 24 (58.5%) completed both pre- and post-program surveys. These five-point Likert surveys showed a significant shift from pre-program to responses demonstrating increased "comfort levels in explaining and applying biodesign principles" (p < 0.0001). Specifically, the "comfort level in taking a product to market" increased from 33% to 67% (p = 0.01), while the "comfort level in applying the biodesign process" increased from 29% to 92% (p < 0.0001). Moreover, 58.3% of participants expressed interest in continuing their current projects, and 70.8% of students stated feeling confident in generating ideas and solutions with their team members. Conclusions The medical biodesign curriculum demonstrated success in exposing undergraduate medical and engineering students to the concepts of medical innovation and biodesign. The program has led to a significant improvement in students' knowledge and comfort levels in applying the biodesign process and taking a product to market. The high level of interest and participation in the program highlight the need for incorporating innovative training in UME to foster creativity and prepare future physicians to contribute to the advancements in healthcare.

Magnetically locked Janus particle clusters with orientation-dependent motion in AC electric fields.

Active particles, or micromotors, locally dissipate energy to drive locomotion at small length scales. The type of trajectory is generally fixed and dictated by the geometry and composition of the particle, which can be challenging to tune using conventional fabrication procedures. Here, we report a simple, bottom-up method to magnetically assemble gold-coated polystyrene Janus particles into "locked" clusters that display diverse trajectories when stimulated by AC electric fields. The orientation of particles within each cluster gives rise to distinct modes of locomotion, including translational, rotational, trochoidal, helical, and orbital. We model this system using a simplified rigid beads model and demonstrate qualitative agreement between the predicted and experimentally observed cluster trajectories. Overall, this system provides a facile means to scalably create micromotors with a range of well-defined motions from discrete building blocks.

Predictive Framework Development for User-Friendly On-Site Glucose Detection.

This study explores a smartphone-based spot detection framework for glucose in a rapid, simple, and affordable paper-based analytical device (PAD), which employs machine-learning algorithms to estimate various glucose concentrations. Herein, two different detection mixtures were chosen with chitosan (C) and without chitosan (WC) for the color change analysis. Being a biopolymer, chitosan improves the analytical performance of PADs when used with a chromogenic agent. Moreover, the influence of the illumination conditions and camera optics on the professed color of glucose strips was observed by choosing various illumination conditions and different smartphones. Hence, this study focuses on developing a framework for smartphone-based simple and user-friendly spot-based glucose detection (with a concentration range of 10-40 mM) at any illumination conditions and in any direction of illumination. Additionally, the combination of color spaces and machine-learning algorithms was applied for the signal enhancement. It was observed that the machine learning classifiers, cubic support vector machine (SVM) and narrow neutral network show higher accuracy for the WC samples, which are 92.7 and 92.3%, respectively. The samples with chitosan show higher accuracy for the linear discriminant and quadratic SVM classifiers, which are 94.1 and 93.9%, respectively. Simultaneously, cubic SVM shows ∼93% accuracy for both cases. In order to assess the performance of the devices, a blind test was also conducted. This study demonstrates the potential of the developed system for initial disease screening at the user end. By incorporating machine learning techniques, the platform can provide reliable and accurate results, thus paving the way for estimating the accuracy of the results for improved initial healthcare screening and diagnosis of any disease.

Fluoroquinolone resistance mutations among Mycobacterium tuberculosis and their interconnection with treatment outcome.

Background: Fluoroquinolone (FQ) antibiotics are among the most potent second-line antitubercular drugs these days. The aim of the study was to analyze the frequency and pattern of genetic mutation in preextensive (pre-XDR) and extensively drug-resistant Mycobacterium tuberculosis using second-line line probe assay (LPA) and to compare drug-resistant mutations with different treatment outcomes. Methods: Sputum, lymph node aspirate, and cold accesses from patients with rifampicin-resistant Tuberculosis (TB) were subjected to first-line and second-line LPA (Genotype MTBDRsl by Hain Life Science, Germany) to assess additional drug resistance to fluoroquinolones (levofloxacin and moxifloxacin). Final treatment outcomes as per the National TB Elimination Program were assessed and compared with the mutation profile. Results: One hundred and fifty subjects were observed to have mutations associated with resistance to FQs and constituted the final study population. The most frequent mutation observed among GyrA drug resistance mutation was D94G (Gyr A MUT3C, 44/150, 66%) corresponding to high-level resistance to levofloxacin and moxifloxacin. The same mutation was associated with poor treatment outcome as died or treatment failure (odds ratio 2.50, relative risk 1.67, P = 0.043). The most common hetero-resistance mutation pattern observed in GyrA gene was wild type plus Asp94Gly mutation in 24.6% of isolates. Conclusions: GyrA MUT3C hybridization corresponding to single-point mutation of aspartic acid to glycine at codon 94 constitutes the most common mutation in GyrA gene locus in M. tuberculosis with significant association with treatment outcome as died compared to those with treatment outcome as cured.