Effect of morning versus night-time administration of proton pump inhibitor (pantoprazole) on thyroid function test in levothyroxine-treated primary hypothyroidism: a prospective cross-over study.

BACKGROUND: One of the common causes of suboptimal control of thyroid stimulating hormone (TSH) in levothyroxine-treated hypothyroidism is coadministration of proton pump inhibitors (PPIs). Morning administration of pantoprazole has been shown to suppress intragastric pH to a greater extent. We therefore aimed to determine the effect of pantoprazole at different time points of the day on thyroid function test (TFT) in levothyroxine-treated overt primary hypothyroidism. METHODS: In this single centre, hospital based, prospective, two arm cross-over study (AB, BA), participants were randomized into 2 groups based on morning (6:00 am - 7:00 am simultaneously with the scheduled levothyroxine tablet) (group M) and evening (30 min before dinner) intake of 40 mg pantoprazole tablet (group N). After the initial 6 weeks (period 1), a washout period of 1 week for pantoprazole was given, and then both the groups crossed over for another 6 weeks (period 2). Patients were instructed to continue the same brand of levothyroxine tablet at empty stomach 1-hour before breakfast. Serum TSH was measured at baseline, week 6, and week 13. RESULTS: Data from 30 patients, who completed the study with 100% compliance, were analysed. Mean TSH values of the study participants were significantly higher both at week 6 and week 13 compared to the baseline. Mean baseline serum TSH concentrations for groups M and N were 2.70 (± 1.36), and 2.20 (± 1.06) µlU/mL, respectively. Mean serum TSH concentrations at the end periods 1 and 2 for group M were 3.78 (± 4.29), and 3.76 (± 2.77) while the levels in group N were 3.30 (± 1.90), and 4.53 (± 4.590) µlU/mL, respectively. There was a significant rise in serum TSH concentration across periods 1 and 2 in both the groups (F2, 58 = 3.87, p = 0.03). Within group changes in TSH across periods 1 and 2 were not statistically significant. Similarly difference in TSH between the groups, either at 6 weeks or at 13 weeks, were also not statistically significant. CONCLUSIONS: Concomitant use of pantoprazole, even for 6 weeks, leads to significant elevation in serum TSH in levothyroxine-treated patients who are biochemically euthyroid, irrespective of timing of pantoprazole intake. Early morning and night-time administration of pantoprazole have similar effect on TFT in these patients.

Diagnostic approach in 46, XY DSD: an endocrine society of bengal (ESB) consensus statement.

OBJECTIVES: 46, XY difference/disorder of sex development (DSD) is a relatively uncommon group of heterogeneous disorders with varying degree of underandrogenization of male genitalia. Such patients should be approached systematically to reach an aetiological diagnosis. However, we lack, at present, a clinical practice guideline on diagnostic approach in 46, XY DSD from this part of the globe. Moreover, debate persists regarding the timing and cut-offs of different hormonal tests, performed in these cases. The consensus committee consisting of 34 highly experienced endocrinologists with interest and experience in managing DSD discussed and drafted a consensus statement on the diagnostic approach to 46, XY DSD focussing on relevant history, clinical examination, biochemical evaluation, imaging and genetic analysis. CONTENT: The consensus was guided by systematic reviews of existing literature followed by discussion. An initial draft was prepared and distributed among the members. The members provided their scientific inputs, and all the relevant suggestions were incorporated. The final draft was approved by the committee members. SUMMARY: The diagnostic approach in 46, XY DSD should be multidisciplinary although coordinated by an experienced endocrinologist. We recommend formal Karyotyping, even if Y chromosome material has been detected by other methods. Meticulous history taking and thorough head-to-toe examination should initially be performed with focus on external genitalia, including location of gonads. Decision regarding hormonal and other biochemical investigations should be made according to the age and interpreted according to age-appropriate norms Although LC-MS/MS is the preferred mode of steroid hormone measurements, immunoassays, which are widely available and less expensive, are acceptable alternatives. All patients with 46, XY DSD should undergo abdominopelvic ultrasonography by a trained radiologist. MRI of the abdomen and/or laparoscopy may be used to demonstrate the Mullerian structure and/or to localize the gonads. Genetic studies, which include copy number variation (CNV) or molecular testing of a candidate gene or next generation sequencing then should be ordered in a stepwise manner depending on the clinical, biochemical, hormonal, and radiological findings. OUTLOOK: The members of the committee believe that patients with 46, XY DSD need to be approached systematically. The proposed diagnostic algorithm, provided in the consensus statement, is cost effective and when supplemented with appropriate genetic studies, may help to reach an aetiological diagnosis in majority of such cases.

Analysis of Exosomal MicroRNA Dynamics in Response to Rhinovirus Challenge in a Longitudinal Case-Control Study of Asthma.

Asthma symptoms are often exacerbated by the common-cold-causing rhinovirus (RV). In this study, we characterized the temporal behavior of circulating exosomal microRNAs (ExoMiRNAs) in a longitudinal bi-phasic case-control study of mild asthmatics (n = 12) and matched non-atopic healthy controls (n = 12) inoculated with rhinovirus. We aimed to define clinical and immunologic characteristics associated with differentially expressed (DE) miRNAs. In total, 26 DE ExoMiRNAs, including hsa-let-7f-5p, hsa-let-7a-5p, hsa-miR-122-5p, hsa-miR-101-3p, and hsa-miR-126-3p, were identified between asthmatic and healthy subjects after inoculation with RV. Time series clustering identified a unique Cluster of Upregulated DE ExoMiRNAs with augmenting mean expression and a distinct Cluster of Downregulated DE ExoMiRNAs with mean expression decline in asthmatic subjects upon RV challenge. Notably, the Upregulated Cluster correlated with Th1 and interferon-induced cytokines/chemokines (IFN-γ and IFN-γ-inducible protein-10) and interleukin-10 (IL-10). Conversely, the Downregulated Cluster correlated with IL-13, a Th2 cytokine, pulmonary function measurements (FVC%, FEV1%, and PEF%), and inflammatory biomarkers (FeNO, eosinophil%, and neutrophil%). Key ExoMiRNA-target gene and anti-viral defense mechanisms of the Upregulated and Downregulated Clusters were identified by network and gene enrichment analyses. Our findings provide insight into the regulatory role of ExoMiRNAs in RV-induced asthma.

Koopman Operator-Based Knowledge-Guided Reinforcement Learning for Safe Human-Robot Interaction.

We developed a novel framework for deep reinforcement learning (DRL) algorithms in task constrained path generation problems of robotic manipulators leveraging human demonstrated trajectories. The main contribution of this article is to design a reward function that can be used with generic reinforcement learning algorithms by utilizing the Koopman operator theory to build a human intent model from the human demonstrated trajectories. In order to ensure that the developed reward function produces the correct reward, the demonstrated trajectories are further used to create a trust domain within which the Koopman operator-based human intent prediction is considered. Otherwise, the proposed algorithm asks for human feedback to receive rewards. The designed reward function is incorporated inside the deep Q-learning (DQN) framework, which results in a modified DQN algorithm. The effectiveness of the proposed learning algorithm is demonstrated using a simulated robotic arm to learn the paths for constrained end-effector motion and considering the safety of the human in the surroundings of the robot.

A LoC Ion Imaging Platform for Spatio-Temporal Characterisation of Ion-Selective Membranes.

In this paper, a complete Lab-on-Chip (LoC) ion imaging platform for analysing Ion-Selective Membranes (ISM) using CMOS ISFET arrays is presented. An array of 128 × 128 ISFET pixels is employed with each pixel featuring 4 transistors to bias the ISFET to a common drain amplifier. Column-level 2-step readout circuits are designed to compensate for array offset variations in a range of up to ±1 V. The chemical signal associated with a change in ionic concentration is stored and fed back to a programmable gain instrumentation amplifier for compensation and signal amplification through a global system feedback loop. This column-parallel signal pipeline also integrates an 8-bit single slope ADC and an 8-bit R-2R DAC to quantise the processed pixel output. Designed and fabricated in the TSMC 180 nm BCD process, the System-on-Chip (SoC) operates in real time with a maximum frame rate of 1000 fps, whilst occupying a silicon area of 2.3 mm × 4.5 mm. The readout platform features a high-speed digital system to perform system-level feedback compensation with a USB 3.0 interface for data streaming. With this platform we show the first reported analysis and characterisation of ISMs using an ISFETs array through capturing real-time high-speed spatio-temporal information at a resolution of 16 µm in 1000 fps, extracting time-response and sensitivity. This work paves the way of understanding the electrochemical response of ISMs, which are widely used in various biomedical applications.

Paper based microfluidics: A forecast toward the most affordable and rapid point-of-care devices.

The microfluidic industry has evolved through years with acquired scientific knowledge from different, and already developed industries. Consequently, a wide range of materials like silicon from the electronic industry to all the way, silicone, from the chemical engineering industry, has been spotted to solve similar challenges. Although a typical microfluidic chip, fabricated from glass or polymer substrates offers definite benefits, however, paper-based microfluidic analytical devices (µPADs) possess numerous special benefits for practical implementation at a lower price. Owing to these features, in recent years, paper microfluidics has drawn immense interest from researchers in industry and academia alike. These devices have wider applications with advantages like lower cost, speedy detection, user-easiness, biocompatibility, sensitivity, and specificity etc. when compared to other microfluidic devices. Therefore, these sensitive but affordable devices fit themselves into point-of-care (POC) testing with features in demand like natural disposability, situational flexibility, and the capability to store and analyze the target at the point of requirement. Gradually, advancements in fabrication technologies, assay development techniques, and improved packaging capabilities, have contributed significantly to the real-time identification and health investigation through paper microfluidics; however, the growth has not been limited to the biomedical field; industries like electronics, energy storage and many more have expanded substantially. Here, we represent an overall state of the paper-based microfluidic technology by covering the fundamentals, working principles, different fabrication procedures, applications for various needs and then to make things more practical, the real-life scenario and practical challenges involved in launching a device into the market have been revealed. To conclude, recent contribution of µPADs in the 2020 pandemic and potential future possibilities have been reviewed.

Indian Expert Review on Use of Teneligliptin in patients with Diabetes and its Safety and Efficacy (INTENSE).

INTRODUCTION: Management of diabetes in India remains less than satisfactory despite a huge prevalence of type 2 diabetes (T2D). Associated obesity, inadequate lifestyle modifications and burden of treatment costs are certain major issues contributing to inadequate management of diabetes in India. AIM: To evaluate the use of Teneligliptin in patients with diabetes and its safety, efficacy and cost effectiveness especially in Indian patients with T2D. METHODS: A detailed analysis of the best available scientific evidence (clinical trials, meta-analyses and real-world experience) was performed to create an evidence driven understanding of teneligliptin's efficacy, safety and cost effectiveness. Fourteen leading endocrinologists contributed as experts and the modified Delphi process was followed. Evidences and clinical questions were discussed over a series of web and in a live meeting. Final draft was created based on the opinions endorsed by the experts. RESULTS: Teneligliptin is the most commonly used gliptin in India and exhibits pharmacokinetic and pharmacodynamic advantages as well as greater cost effectiveness compared to other gliptins. It has been recognized as an efficacious and well tolerated antidiabetic agent both as monotherapy and in combination based on multiple clinical trials, meta-analyses and real world studies. Teneligliptin as add on therapy to other antidiabetic drugs (OADs) or insulin has provided significant reductions in HbA1c, fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels and is generally well tolerated with low risk of hypoglycemia both in short term and long term. Studies have also proven its efficacy in ameliorating glucose fluctuations, reducing post prandial insulin requirement, increasing active incretin levels and improving pancreatic ß cells function. Efficacy and safety has also been proven in all age groups, all stages of renal disease and mild to moderate hepatic disease. QT prolongation is not seen even with maximum recommended dose of 40 mg/day. CONCLUSION: Teneligliptin has firmly positioned itself as a very important drug in the armamentarium for managing T2D. It offers efficacy, safety and cost-effective therapeutic choice in Indian patients with T2D.

A multiplexed nanoliter array-based microfluidic platform for quick, automatic antimicrobial susceptibility testing.

Antimicrobial resistance stemming from indiscriminate usage of antibiotics has emerged as a global healthcare issue with substantial economic implications. The inefficacy of commonly used antibiotics combined with superfluous consumption has worsened the issue. Rapid antimicrobial susceptibility testing (AST) to antibiotics can be advantageous in thwarting bacterial infections. Therefore, this study developed a simple nanoliter array-based microfluidic platform for performing rapid AST, which can handle and manipulate liquids both in nanoliter and microliter volumes. The platform consisted of two microfluidic devices, one for performing AST and another for diluting antibiotics and these two were suitably integrated. The microfluidic device used for generating microarrays for AST experiments is single-layered (no air layer) and has no active microvalves and air hole, which makes the device easy to fabricate and use. The loading process ensures uniform distribution of bacteria and relies on displacing the air from microarrays through porous polydimethylsiloxane membranes. Furthermore, the chip for dilution consisted of active microfluidic components, and could prepare and test seven different concentrations of antibiotics, which make the platform multiplexed and be capable of evaluating minimum inhibitory concentrations (MICs), a clinically relevant parameter. MIC determination requires less number of bacteria (∼2000) and hence shortens the pre-culture step, i.e. bacteria culture in blood and urine. This automated system demonstrated AST and evaluated MICs using Escherichia coli and two antibiotics, including ampicillin and streptomycin, and the results were ascertained using a gold standard method. It only took 8-9 h to perform AST, which is substantially less compared to a conventional process and hence is of high clinical utility.

Increased day-to-day fluctuations in exhaled breath profiles after a rhinovirus challenge in asthma.

BACKGROUND: Early detection/prediction of flare-ups in asthma, commonly triggered by viruses, would enable timely treatment. Previous studies on exhaled breath analysis by electronic nose (eNose) technology could discriminate between stable and unstable episodes of asthma, using single/few time-points. To investigate its monitoring properties during these episodes, we examined day-to-day fluctuations in exhaled breath profiles, before and after a rhinovirus-16 (RV16) challenge, in healthy and asthmatic adults. METHODS: In this proof-of-concept study, 12 atopic asthmatic and 12 non-atopic healthy adults were prospectively followed thrice weekly, 60 days before, and 30 days after a RV16 challenge. Exhaled breath profiles were detected using an eNose, consisting of 7 different sensors. Per sensor, individual means were calculated using pre-challenge visits. Absolute deviations (|%|) from this baseline were derived for all visits. Within-group comparisons were tested with Mann-Whitney U tests and receiver operating characteristic (ROC) analysis. Finally, Spearman's correlations between the total change in eNose deviations and fractional exhaled nitric oxide (FeNO), cold-like symptoms, and pro-inflammatory cytokines were examined. RESULTS: Both groups had significantly increased eNose fluctuations post-challenge, which in asthma started 1 day post-challenge, before the onset of symptoms. Discrimination between pre- and post-challenge reached an area under the ROC curve of 0.82 (95% CI = 0.65-0.99) in healthy and 0.97 (95% CI = 0.91-1.00) in asthmatic adults. The total change in eNose deviations moderately correlated with IL-8 and TNFα (ρ ≈ .50-0.60) in asthmatics. CONCLUSION: Electronic nose fluctuations rapidly increase after a RV16 challenge, with distinct differences between healthy and asthmatic adults, suggesting that this technology could be useful in monitoring virus-driven unstable episodes in asthma.

High-Precision Automated Workflow for Urinary Untargeted Metabolomic Epidemiology.

Urine is a noninvasive biofluid that is rich in polar metabolites and well suited for metabolomic epidemiology. However, because of individual variability in health and hydration status, the physiological concentration of urine can differ >15-fold, which can pose major challenges in untargeted liquid chromatography-mass spectrometry (LC-MS) metabolomics. Although numerous urine normalization methods have been implemented (e.g., creatinine, specific gravity-SG), most are manual and, therefore, not practical for population-based studies. To address this issue, we developed a method to measure SG in 96-well-plates using a refractive index detector (RID), which exhibited accuracy within 85-115% and <3.4% precision. Bland-Altman statistics showed a mean deviation of -0.0001 SG units (limits of agreement: -0.0014 to 0.0011) relative to a hand-held refractometer. Using this RID-based SG normalization, we developed an automated LC-MS workflow for untargeted urinary metabolomics in a 96-well-plate format. The workflow uses positive and negative ionization HILIC chromatography and acquires mass spectra in data-independent acquisition (DIA) mode at three collision energies. Five technical internal standards (tISs) were used to monitor data quality in each method, all of which demonstrated raw coefficients of variation (CVs) < 10% in the quality controls (QCs) and < 20% in the samples for a small cohort (n = 87 urine samples, n = 22 QCs). Application in a large cohort (n = 842 urine samples, n = 248 QCs) demonstrated CVQC < 5% and CVsamples < 16% for 4/5 tISs after signal drift correction by cubic spline regression. The workflow identified >540 urinary metabolites including endogenous and exogenous compounds. This platform is suitable for performing urinary untargeted metabolomic epidemiology and will be useful for applications in population-based molecular phenotyping.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20-40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (- 21.0%, confidence interval [CI] - 34.1 to - 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52-0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48-0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

Can Measurements of Inflammatory Biomarkers be Used to Spot Respiratory Viral Infections?

Accurate detection of human respiratory viral infections is highly topical. We investigated how strongly inflammatory biomarkers (FeNO, eosinophils, neutrophils, and cytokines in nasal lavage fluid) and lung function parameters change upon rhinovirus 16 infection, in order to explore their potential use for infection detection. To this end, within a longitudinal cohort study, healthy and mildly asthmatic volunteers were experimentally inoculated with rhinovirus 16, and time series of these parameters/biomarkers were systematically recorded and compared between the pre- and post-infection phases of the study, which lasted two months and one month, respectively. We found that the parameters'/biomarkers' ability to discriminate between the infected and the uninfected state varied over the observation time period. Consistently over time, the concentration of cytokines, in nasal lavage fluid, showed moderate to very good discrimination performance, thereby qualifying for disease progression monitoring, whereas lung function and FeNO, while quickly and non-invasively measurable using cheap portable devices (e.g., at airports), performed poorly.

False elevation of serum cortisol in chemiluminescence immunoassay by Siemens Advia Centaur XP system in 21-hydroxylase deficiency: an 'endocrine laboma'.

Liquid chromatography-mass spectrometry, the gold standard method for cortisol measurement, is expensive and not widely available in the developing countries. Chemiluminescent immunoassay, commonly used for cortisol measurement is prone to clinically meaningful inter-assay variability in some analysers. This occurs due to non-specific nature of anticortisol antibodies used in different platforms, having cross reactivity with structurally similar cortisol precursors like 17α-hydroxyprogesterone (17OHP), 11-deoxycortisol and 21-deoxycortisol. In patients with 21-hydroxylase deficiency, where 17OHP and 21-deoxycortisol are significantly elevated, older generation machines like Siemens Advia Centaur XP provide spuriously high cortisol concentration compared with values measured by Roche Cobas e 411 or Siemens Immulite 1000. Diagnosis of potentially life-threatening salt-wasting 21-hydroxylase deficiency may be missed and treatment may be delayed due to such interference. Two children with classic 21-hydroxylase deficiency are being reported here, in whom high cortisol values were observed in Siemens Advia Centaur XP system.

Exploring Circulating Tumor Cells in Cholangiocarcinoma Using a Novel Glycosaminoglycan Probe on a Microfluidic Platform.

The search of alternative approaches to epithelial cell adhesion molecule (EpCAM), for the isolation of circulating tumor cells (CTC), is on the rise. This work attempts at evaluating the feasibility of using a new glycosaminoglycan, SCH45, as a probe to isolate CTCs from the peripheral blood of 65 advanced/metastatic cholangiocarcinoma (CCA) patients. The positive enrichment of CTCs from 1 mL of blood using SCH45-bound magnetic beads and subsequent staining on an integrated microfluidic platform is demonstrated. Results detailing CTC concentrations averaging ≥1 CTCs mL-1 of blood are shown, and a conventional protein biomarker, EpCAM, has been used to corroborate the finding that 100% of the patients possess CTCs in their blood. Studies detailing the use of CTCs in the prognostic monitoring and treatment effectiveness of advanced/metastatic CCA are scarce, and the isolation of CTCs from all CCA patients tested has not been reported yet. A strong correlation between CTC counts and disease progression at the time of and/or in advance of radiographic imaging in patients receiving chemotherapy is also reported. This study is one of its kind with the new probe and reduced sample volume and has potential for use in CCA diagnosis and prognosis in the near future.

Child with '46, XX' disorder of sex development: clues to diagnose aromatase deficiency.

A diagnosis of congenital adrenal hyperplasia (CAH) in a '46, XX' newborn with ambiguous genitalia is like a 'knee jerk reaction' of the paediatrician because of its higher frequency and life-threatening consequences if remain undiagnosed and hence untreated. Aromatase deficiency (AD), a rare cause of '46, XX' disorder of sex development, mimics virilising CAH in many aspects; thus, the disease is often overlooked. Diagnosis of AD in women is much easier around puberty due to the presence of primary amenorrhoea, undeveloped breasts, androgen excess and tall stature with eunuchoid proportions. Diagnosing AD with confidence immediately after birth or during early childhood is a challenging task without genetic analysis. In resource-restricted settings, AD remains a diagnosis of exclusion particularly in this age group and history of maternal virilisation, non-progressive genital ambiguity, elevated gonadotrophins (follicle-stimulating hormone >>luteinising hormone), mildly delayed bone age with/without enlarged polycystic ovaries serve as important clues to the underlying AD.

Genetic variations in olfactory receptor gene OR2AG2 in a large multigenerational family with asthma.

It is estimated from twin studies that heritable factors account for at-least half of asthma-risk, of which genetic variants identified through population studies explain only a small fraction. Multi-generation large families with high asthma prevalence can serve as a model to identify highly penetrant genetic variants in closely related individuals that are missed by population studies. To achieve this, a four-generation Indian family with asthma was identified and recruited for examination and genetic testing. Twenty subjects representing all generations were selected for whole genome genotyping, of which eight were subjected to exome sequencing. Non-synonymous and deleterious variants, segregating with the affected individuals, were identified by exome sequencing. A prioritized deleterious missense common variant in the olfactory receptor gene OR2AG2 that segregated with a risk haplotype in asthma, was validated in an asthma cohort of different ethnicity. Phenotypic tests were conducted to verify expected deficits in terms of reduced ability to sense odors. Pathway-level relevance to asthma biology was tested in model systems and unrelated human lung samples. Our study suggests that OR2AG2 and other olfactory receptors may contribute to asthma pathophysiology. Genetic studies on large families of interest can lead to efficient discovery.