An Optimized Method for LC-MS-Based Quantification of Endogenous Organic Acids: Metabolic Perturbations in Pancreatic Cancer.

Accurate and reliable quantification of organic acids with carboxylic acid functional groups in complex biological samples remains a major analytical challenge in clinical chemistry. Issues such as spontaneous decarboxylation during ionization, poor chromatographic resolution, and retention on a reverse-phase column hinder sensitivity, specificity, and reproducibility in multiple-reaction monitoring (MRM)-based LC-MS assays. We report a targeted metabolomics method using phenylenediamine derivatization for quantifying carboxylic acid-containing metabolites (CCMs). This method achieves accurate and sensitive quantification in various biological matrices, with recovery rates from 90% to 105% and CVs ≤ 10%. It shows linearity from 0.1 ng/mL to 10 µg/mL with linear regression coefficients of 0.99 and LODs as low as 0.01 ng/mL. The library included a wide variety of structurally variant CCMs such as amino acids/conjugates, short- to medium-chain organic acids, di/tri-carboxylic acids/conjugates, fatty acids, and some ring-containing CCMs. Comparing CCM profiles of pancreatic cancer cells to normal pancreatic cells identified potential biomarkers and their correlation with key metabolic pathways. This method enables sensitive, specific, and high-throughput quantification of CCMs from small samples, supporting a wide range of applications in basic, clinical, and translational research.

Genetic Upregulation of Activated Protein C Mitigates Delayed Effects of Acute Radiation Exposure in the Mouse Plasma.

Exposure to ionizing radiation, accidental or intentional, may lead to delayed effects of acute radiation exposure (DEARE) that manifest as injury to organ systems, including the kidney, heart, and brain. This study examines the role of activated protein C (APC), a known mitigator of radiation-induced early toxicity, in long-term plasma metabolite and lipid panels that may be associated with DEARE in APCHi mice. The APCHi mouse model used in the study was developed in a C57BL/6N background, expressing the D168F/N173K mouse analog of the hyper-activatable human D167F/D172K protein C variant. This modification enables increased circulating APC levels throughout the mouse's lifetime. Male and female cohorts of C57BL/6N wild-type and APCHi transgenic mice were exposed to 9.5 Gy γ-rays with their hind legs shielded to allow long-term survival that is necessary to monitor DEARE, and plasma was collected at 6 months for LC-MS-based metabolomics and lipidomics. We observed significant dyslipidemia, indicative of inflammatory phenotype, upon radiation exposure. Additionally, observance of several other metabolic dysregulations was suggestive of gut damage, perturbations in TriCarboxylic Acid (TCA) and urea cycles, and arginine metabolism. We also observed gender- and genotype-modulated metabolic perturbations post radiation exposure. The APCHi mice showed near-normal abundance for several lipids. Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute γ-radiation exposure in a gender-specific manner can be established for the first time.

Digital health and inpatient palliative care: a cohort-controlled study.

OBJECTIVES: End of life has unacceptable levels of hospital admission and death. We aimed to determine the association of a novel digital specific system (Proactive Risk-Based and Data-Driven Assessment of Patients at the End of Life, PRADA) to modify such events. METHODS: A cohort-controlled study of those discharged alive, who died within 90 days of discharge, comparing PRADA (n=114) with standard care (n=3730). RESULTS: At 90 days, the PRADA group were more likely to die (78.9% vs 46.2%, p<0.001), had a shorter time to death (58±90 vs 178±186 days, p<0.001) but readmission (20.2% vs 37.9%, p<0.001) or death in hospital (4.4% vs 28.9%, p<0.001) was lower with reduced risk for a combined 90-day outcome of postdischarge non-elective admission or hospital death (OR 0.45, 95% CI 0.27-0.74, p<0.001). Tightening criteria with 1:1 matching (n=83 vs 83) showed persistent significant findings in PRADA contact with markedly reduced adverse events (OR 0.15, 95% CI 0.02-0.96, p<0.05). CONCLUSIONS: Being seen in hospital by a specialist palliative care team using the PRADA tool was associated with significantly improved postdischarge outcomes pertaining to those destined to die after discharge.

GP assessment of unmet need in a complex multimorbid population using a data-driven and clinical triage system: a prospective cohort study.

BACKGROUND: Patients with unmet healthcare needs are more likely to access unscheduled care. Identifying these patients through data-driven and clinical risk stratification for active case management in primary care can help address patient need and reduce demand on acute services. AIM: To determine how a proactive digital healthcare system can be used to undertake comprehensive needs analysis of patients at risk of unplanned admission and mortality. DESIGN & SETTING: Prospective cohort study of six general practices in a deprived UK city. METHOD: To identify those with unmet needs, the study's population underwent digitally-driven risk stratification into Escalated and Non-escalated groups using seven risk factors. The Escalated group underwent further stratification using GP clinical assessment into Concern and No concern groups. The Concern group underwent Unmet Needs Analysis (UNA). RESULTS: From 24 746 patients, 516 (2.1%) were triaged into the Concern group and 164 (0.7%) underwent UNA. These patients were more likely to be older (t = 4.69, P<0.001), female (X2 = 4.46, P<0.05), have a Patients At Risk of Re-hospitalisation (PARR) score ≥80 (X2 = 4.31, P<0.05), be a nursing home resident (X2 = 6.75, P<0.01), or on an end-of-life (EOL) register (X2 = 14.55, P<0.001). Following UNA, 143 (87.2%) patients had further review planned or were referred for further input. The majority of patients had four domains of need. In those who GPs would not be surprised if they died within the next few months, n = 69 (42.1%) were not on an EOL register. CONCLUSION: This study showed how an integrated, patient-centred, digital care system working with GPs can highlight and implement resources to address the escalating care needs of complex individuals.

Associations of antidiabetic drugs with diabetic retinopathy in people with type 2 diabetes: an umbrella review and meta-analysis.

Background: Diabetic retinopathy (DR) is the most frequent complication of type 2 diabetes and remains the leading cause of preventable blindness. Current clinical decisions regarding the administration of antidiabetic drugs do not sufficiently incorporate the risk of DR due to the inconclusive evidence from preceding meta-analyses. This umbrella review aimed to systematically evaluate the effects of antidiabetic drugs on DR in people with type 2 diabetes. Methods: A systematic literature search was undertaken in Medline, Embase, and the Cochrane Library (from inception till 17th May 2022) without language restrictions to identify systematic reviews and meta-analyses of randomized controlled trials or longitudinal studies that examined the association between antidiabetic drugs and DR in people with type 2 diabetes. Two authors independently extracted data and assessed the quality of included studies using the AMSTAR-2 (A MeaSurement Tool to Assess Systematic Reviews) checklist, and evidence assessment was performed using the GRADE (Grading of recommendations, Assessment, Development and Evaluation). Random-effects models were applied to calculate relative risk (RR) or odds ratios (OR) with 95% confidence intervals (CI). This study was registered with PROSPERO (CRD42022332052). Results: With trial evidence from 11 systematic reviews and meta-analyses, we found that the use of glucagon-like peptide-1 receptor agonists (GLP-1 RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i), or dipeptidyl peptidase-4 inhibitors (DPP-4i) was not statistically associated with the risk of DR, compared to either placebo (RR: GLP-1 RA, 0.98, 0.89-1.08; SGLT-2i, 1.00, 95% CI 0.79-1.27; DPP-4i, 1.17, 0.99-1.39) or other antidiabetic drugs. Compared to other antidiabetic drugs, meglitinides (0.34, 0.01-8.25), SGLT-2i (0.73, 0.10-5.16), thiazolidinediones (0.92, 0.67-1.26), metformin (1.15, 0.81-1.63), sulphonylureas (1.24, 0.93-1.65), and acarbose (4.21, 0.44-40.43) were not statistically associated with the risk of DR. With evidence from longitudinal studies only, insulin was found to have a higher risk of DR than other antidiabetic drugs (OR: 2.47, 95% CI: 2.04-2.99). Conclusion: Our results indicate that antidiabetic drugs are generally safe to prescribe regarding the risk of DR among people with type 2 diabetes. Further robust and large-scale trials investigating the effects of insulin, meglitinides, and acarbose on DR are warranted. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=332052, identifier CRD42022332052.

Observational cross-sectional study of the association of poor broadband provision with demographic and health outcomes: the Wolverhampton Digital ENablement (WODEN) programme.

OBJECTIVES: The association between impaired digital provision, access and health outcomes has not been systematically studied. The Wolverhampton Digital ENablement programme (WODEN) is a multiagency collaborative approach to determine and address digital factors that may impact on health and social care in a single deprived multiethnic health economy. The objective of this study is to determine the association between measurable broadband provision and demographic and health outcomes in a defined population. DESIGN: An observational cross-sectional whole local population-level study with cohorts defined according to broadband provision. SETTING/PARTICIPANTS: Data for all residents of the City of Wolverhampton, totalling 269 785 residents. PRIMARY OUTCOMES: Poor broadband provision is associated with variation in demographics and with increased comorbidity and urgent care needs. RESULTS: Broadband provision was measured using the Broadband Infrastructure Index (BII) in 158 City localities housing a total of 269 785 residents. Lower broadband provision as determined by BII was associated with younger age (p<0.001), white ethnic status (p<0.001), lesser deprivation as measured by Index of Multiple Deprivation (p<0.001), a higher number of health comorbidities (p<0.001) and more non-elective urgent events over 12 months (p<0.001). CONCLUSION: Local municipal and health authorities are advised to consider the variations in broadband provision within their locality and determine equal distribution both on a geographical basis but also against demographic, health and social data to determine equitable distribution as a platform for equitable access to digital resources for their residents.

Available tools to evaluate digital health literacy and engagement with eHealth resources: A scoping review.

Background: As eHealth and use of information and communication technologies (ICT) within healthcare becomes widespread, it is important to ensure that these forms of healthcare are accessible to the users. One factor that is key to accessing eHealth is digital health literacy. Objectives: This scoping review assesses available tools that can be used to evaluate digital health literacy. Methods: A systematic literature search was made in MEDLINE, CINAHL, APA PsychInfo, Ageline, AMED, and APA PsychArticles to present the tools currently in use to assess digital health literacy. A qualitative synthesis of the evidence was carried out using a data charting form created for this review. Extracted data included details of the population of investigation and digital health literacy tool used. A report was produced following PRISMA-ScR guidelines. Results: In total, 53 papers with adult participants and 3 with adolescent participants (aged between 12 and 19 years) were included in the scoping review. 5 questionnaires were identified that measured digital health literacy or attitudes towards the internet, of which the eHealth Literacy Scale (eHEALS) was the most commonly used questionnaire for both adults and children. Two children's questionnaires were often accompanied by a second task to verify the accuracy of the responses to the eHEALS questions. Conclusions: eHEALS is the most commonly used method to assess digital health literacy and assess whether an individual is able to engage actively with eHealthcare or virtual resources. However, care needs to be taken to ensure that its administration does not exclude digitally disadvantaged groups from completing it. Future research would benefit from assessing whether digital health literacy tools are appropriate for use in clinical settings, working to ensure that any scales developed in this area are practical and can be used to support the allocation of resources to ensure that people are able to access healthcare equitably.

A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells.

Although cancer-derived extracellular vesicles (cEVs) are thought to play a pivotal role in promoting cancer progression events, their precise effect on neighbouring normal cells is unknown. In this study, we investigated the impact of pancreatic cancer ductal adenocarcinoma (PDAC) derived EVs on recipient non-tumourigenic pancreatic normal epithelial cells upon internalization. We demonstrate that cEVs are readily internalized and induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) in treated normal pancreatic epithelial cells within 24 h. We further show that PDAC cEVs increase cell proliferation, migration, and invasion and that these changes are regulated at least in part, by the UPR mediator DDIT3. Subsequently, these cells release several inflammatory cytokines. Leveraging a layered multi-omics approach, we analysed EV cargo from a panel of six PDAC and two normal pancreas cell lines, using multiple EV isolation methods. We found that cEVs were enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including palmitic acid, sphingomyelins, metabolic regulators of tRNA charging and proteins which regulate trafficking and degradation. We further show that palmitic acid, at doses relevant to those found in cEVs, is sufficient to induce ER stress in normal pancreas cells. These results suggest that cEV cargo packaging may be designed to disseminate proliferative and invasive characteristics upon internalization by distant recipient normal cells, hitherto unreported. This study is among the first to highlight a major role for PDAC cEVs to induce stress in treated normal pancreas cells that may modulate a systemic response leading to altered phenotypes. These findings highlight the importance of EVs in mediating disease aetiology and open potential areas of investigation toward understanding the role of cEV lipids in promoting cell transformation in the surrounding microenvironment.

TGFß Drives Metabolic Perturbations during Epithelial Mesenchymal Transition in Pancreatic Cancer: TGFß Induced EMT in PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy wherein a majority of patients present metastatic disease at diagnosis. Although the role of epithelial to mesenchymal transition (EMT), mediated by transforming growth factor beta (TGFß), in imparting an aggressive phenotype to PDAC is well documented, the underlying biochemical pathway perturbations driving this behaviour have not been elucidated. We used high-resolution mass spectrometry (HRMS) based molecular phenotyping approach in order to delineate metabolic changes concomitant to TGFß-induced EMT in pancreatic cancer cells. Strikingly, we observed robust changes in amino acid and energy metabolism that may contribute to tumor invasion and metastasis. Somewhat unexpectedly, TGFß treatment resulted in an increase in intracellular levels of retinoic acid (RA) that in turn resulted in increased levels of extracellular matrix (ECM) proteins including fibronectin (FN) and collagen (COL1). These findings were further validated in plasma samples obtained from patients with resectable pancreatic cancer. Taken together, these observations provide novel insights into small molecule dysregulation that triggers a molecular cascade resulting in increased EMT-like changes in pancreatic cancer cells, a paradigm that can be potentially targeted for better clinical outcomes.

Morphological Analysis, Protein Profiling and Expression Analysis of Auxin Homeostasis Genes of Roots of Two Contrasting Cultivars of Rice Provide Inputs on Mechanisms Involved in Rice Adaptation towards Salinity Stress.

Plants remodel their root architecture in response to a salinity stress stimulus. This process is regulated by an array of factors including phytohormones, particularly auxin. In the present study, in order to better understand the mechanisms involved in salinity stress adaptation in rice, we compared two contrasting rice cultivars-Luna Suvarna, a salt tolerant, and IR64, a salt sensitive cultivar. Phenotypic investigations suggested that Luna Suvarna in comparison with IR64 presented stress adaptive root traits which correlated with a higher accumulation of auxin in its roots. The expression level investigation of auxin signaling pathway genes revealed an increase in several auxin homeostasis genes transcript levels in Luna Suvarna compared with IR64 under salinity stress. Furthermore, protein profiling showed 18 proteins that were differentially regulated between the roots of two cultivars, and some of them were salinity stress responsive proteins found exclusively in the proteome of Luna Suvarna roots, revealing the critical role of these proteins in imparting salinity stress tolerance. This included proteins related to the salt overly sensitive pathway, root growth, the reactive oxygen species scavenging system, and abscisic acid activation. Taken together, our results highlight that Luna Suvarna involves a combination of morphological and molecular traits of the root system that could prime the plant to better tolerate salinity stress.

A 5-year assessment of the epidemiology and natural history of possible diabetes in remission.

INTRODUCTION: Type 2 diabetes is considered a chronic and progressive disease. The term diabetes in remission has no consensus definition and the question whether diabetes "remission" or "cure" can achieve any long-term benefits in people with type 2 diabetes remains unclear. The aim of our study was a review of our district wide diabetes population to determine the epidemiology and clinical characteristics of those who had a diagnosis of diabetes but did not meet the diagnostic criteria for diabetes at the point of assessment in 2014 and then to review their diabetes outcomes over a 5-year time frame. METHODS: In a whole population based non-interventional epidemiological study amongst 17,308 people with diabetes, we identified 991 with diet treated type 2 diabetes who met the baseline criteria for diabetes in remission (HbA1c < 48 mmol/mol (6.5%)). Over the next 5 years, 385 (39%) people had a cumulative HbA1c attainment of <48 mmol/mol (6.5%) and remained free of diabetes medication. RESULTS: In this erstwhile remission group only 130 (13%) were free of any vasculopathy, whilst 255 (26%) had some form of micro or macrovascular disease, of which 64 people had been without micro or macrovascular vascular complications at baseline. Only 20 people had a HbA1c consistently ≤37 mmol/mol (5.7%) who were free of diabetes vascular complications and of diabetes medication. CONCLUSIONS: The definition of 'diabetes in remission' remains unclear most especially regarding the inclusion of baseline prevalent or incident macro or microvascular disease, the durability of potential remission is poor, and the likelihood of cure is remote.

Risk of COVID-19 hospital admission and COVID-19 mortality during the first COVID-19 wave with a special emphasis on ethnic minorities: an observational study of a single, deprived, multiethnic UK health economy.

OBJECTIVES: The objective of this study was to describe variations in COVID-19 outcomes in relation to local risks within a well-defined but diverse single-city area. DESIGN: Observational study of COVID-19 outcomes using quality-assured integrated data from a single UK hospital contextualised to its feeder population and associated factors (comorbidities, ethnicity, age, deprivation). SETTING/PARTICIPANTS: Single-city hospital with a feeder population of 228 632 adults in Wolverhampton. MAIN OUTCOME MEASURES: Hospital admissions (defined as COVID-19 admissions (CA) or non-COVID-19 admissions (NCA)) and mortality (defined as COVID-19 deaths or non-COVID-19 deaths). RESULTS: Of the 5558 patients admitted, 686 died (556 in hospital); 930 were CA, of which 270 were hospital COVID-19 deaths, 47 non-COVID-19 deaths and 36 deaths after discharge; of the 4628 NCA, there were 239 in-hospital deaths (2 COVID-19) and 94 deaths after discharge. Of the 223 074 adults not admitted, 407 died. Age, gender, multimorbidity and black ethnicity (OR 2.1 (95% CI 1.5 to 3.2), p<0.001, compared with white ethnicity, absolute excess risk of <1/1000) were associated with CA and mortality. The South Asian cohort had lower CA and NCA, lower mortality compared with the white group (CA, 0.5 (0.3 to 0.8), p<0.01; NCA, 0.4 (0.3 to 0.6), p<0.001) and community deaths (0.5 (0.3 to 0.7), p<0.001). Despite many common risk factors for CA and NCA, ethnic groups had different admission rates and within-group differing association of risk factors. Deprivation impacted only the white ethnicity, in the oldest age bracket and in a lesser (not most) deprived quintile. CONCLUSIONS: Wolverhampton's results, reflecting high ethnic diversity and deprivation, are similar to other studies of black ethnicity, age and comorbidity risk in COVID-19 but strikingly different in South Asians and for deprivation. Sequentially considering population and then hospital-based NCA and CA outcomes, we present a complete single health economy picture. Risk factors may differ within ethnic groups; our data may be more representative of communities with high Black, Asian and minority ethnic populations, highlighting the need for locally focused public health strategies. We emphasise the need for a more comprehensible and nuanced conveyance of risk.

Comparison of Effect of pH Modulation on Wound Healing with Topical Application of Citric Acid Versus Superoxide Ions.

BACKGROUND: Wound healing is a dynamic process involving tissue repair and regeneration. Nonhealing and chronic wounds are a significant health problem that many patients all over the world are suffering from. Proper wound care is hence very important. Wound dressings have undergone continuous and significant changes over the time period. Optimal dressing should ensure a moist wound bed, help drainage, remove debris, and be anti-allergic and without immunogenicity. OBJECTIVES: The objective of the study is compare the effect of pH modulation on wound healing with topical application of citric acid versus superoxide ions. The aim is to study the efficacy and safety of citric acid versus superoxide ions in the prevention and control of infection and their effect on wound healing in similar wound types. MATERIALS AND METHODS: We conducted randomized, prospective comparative study in a total of 100 patients admitted at Guru Nanak Dev Hospital, attached to Government Medical College, Amritsar. The patients were divided into two groups: Group A where wound management was done using superoxide ions and Group B where citric acid was used. A standard grading was done in terms of a decrease in wound size, an increase in granulation tissue, and a reduction in wound discharge. RESULTS: The wounds treated with citric acid showed an average reduction in wound size of 73.43% by the 14th day as compared to 66.52% in the control group. The difference seen in the average reduction of wound size was statistically significant (P = 0.032). The wounds treated by citric acid application showed an average increase in granulation tissue of 56.66% as compared to 50.87% in the wounds treated by superoxide ions. The average hospital stay in patients of Group B was comparatively less than that of patients in Group A. CONCLUSION: Citric acid is safe and effective in all types of wound management and gives better efficacy and faster response as compared to superoxide ions. Citric acid promotes wound healing by the formation of granulation tissue and fibroblast proliferation.

Graft copolymerization of polyvinylpyrollidone onto Azadirachta indica gum polysaccharide in the presence of crosslinker to develop hydrogels for drug delivery applications.

In this work, graft-copolymerization of poly vinylpyrollidone onto Azadirachta indica gum polysaccharide in the presence of crosslinker has been carried out to prepare the hydrogel for use in drug delivery. The polymers were characterized by cryo-SEM, AFM, FTIR, and 13C NMR. The gel strength, cross-link density, mesh size, thrombogenicity, antioxidant and mucoadhesion properties of the gum-PVP hydrogels were determined along with the evaluation of drug release profile of methyl prednisolone, a colonic anti-inflammatory agent, from the drug loaded hydrogels. Cryo SEM images showed the porous crosslinked structure of the polymer network. The drug release from the polymer followed non-Fickian diffusion mechanism. The polymers showed 71.47 ±â€¯4.63% haemo-compatibility and 05.52 ±â€¯0.59 Nmm gel strength. The value of DPPH radical scavenging assay (73.16 ±â€¯04.85%) indicated that the gum-PVP polymers are antioxidant. The results of biocompatibility, antioxidant activity, mucoadhesion and drug release properties of the polymers inferred the use of this drug carrier for colonic drug delivery.

Attracting and retaining nurses through a clinical fellowship programme.

Shortages in nursing are the single biggest and most urgent workforce issue that the NHS needs to address. This article sets out the early success of the Nurse Clinical Fellowship Programme established by The Royal Wolverhampton NHS Trust. The unique programme aims to attract and retain nurses by offering a staff nurse post with supported access to academia, fully funded by the NHS Trust. To date, the Trust has attracted 90 nurses (both UK and international registered nurses) to the programme. The programme is also offered internally and the Trust has a cohort of 10 internal nursing staff enrolled onto the programme completing either their BSc (top-up) or Masters, with a second cohort of 60 internal nurses due to start in September 2019. To support international registered nurses with demonstrating their competence to meet Nursing and Midwifery Council requirements the Trust has also established an objective structured clinical examination preparation course designed to embrace and enhance the existing knowledge and skills, while guiding staff in transferring these in line with UK and Trust policies and practices.

The Description of Urodynamic Study for Bladder Dysfunction in Compressive Myelo- or Radiculo-pathy: A Prospective Study in an Institutional Setup.

PURPOSE: To study the significance of filling cystometry with pressure flow studies and bladder electromyography (EMG) in assessment and management of neurogenic bladder with myelopathies and evaluated neurological recovery in the follow-up period. METHODS: The study was a 3-year prospective urodynamic study in 63 patients, with traumatic and nontraumatic myelopathy. Bladder management was advised based on the cystometric findings. Neurological recovery and mode of bladder management were evaluated during follow-up after a minimum of 6 months. RESULTS: Mean age was 44.6 years (range 10-80 years). Thoracolumbar area was most commonly involved. Cystometry revealed overactive detrusor in 46 patients, (17 had detrusor sphincter dyssynergia [DSD], 29 without DSD) and areflexic/underactive detrusor in 9 patients. Postvoid residual (>15% of voided urine) was significant in 27 patients. Neurological recovery was seen in 60.3%, whereas 22.2% showed no improvement (partial improvement in 4.8%) and 12.6% had normal bladder function both initially and at follow-up. Correlation between neurological recovery and bladder management was found to be insignificant (P > 0.05) using spearman's correlation coefficient. CONCLUSION: Filling cystometry with pressure flow studies and EMG study is valuable for the assessment and management of neurogenic bladder in patients with myelopathy. In neurogenic bladder management and follow-up, pressure flow studies help to prevent complications and upper urinary tract complications.

Potential Clinical Error Arising From Use of HbA1c in Diabetes: Effects of the Glycation Gap.

The glycation gap (GGap) and the similar hemoglobin glycation index (HGI) define consistent differences between glycated hemoglobin and actual glycemia derived from fructosamine or mean blood glucose, respectively. Such a disparity may be found in a substantial proportion of people with diabetes, being >1 U of glycated HbA1c% or 7.2 mmol/mol in almost 40% of estimations. In this review we define these indices and explain how they can be calculated and that they are not spurious, being consistent in individuals over time. We evaluate the evidence that GGap and HGI are associated with variation in risk of complications and mortality and demonstrate the potential for clinical error in the unquestioning use of HbA1c. We explore the underlying etiology of the variation of HbA1c from mean glucose in blood plasma, including the potential role of enzymatic deglycation of hemoglobin by fructosamine-3-kinase. We conclude that measurement of GGap and HGI are important to diabetes clinicians and their patients in individualization of therapy and the avoidance of harm arising from consequent inappropriate assessment of glycemia and use of therapies.

Developing a drug delivery carrier from natural polysaccharide exudate gum by graft-copolymerization reaction using high energy radiations.

Keeping in view the importance of natural polysaccharide exudate gum in developing drug formulations. Herein this work, for making sterile drug carrier, the chemical modification of the gum polysaccharides has been carried out by graft copolymerization reaction by high energy radiation in the presence of biocompatible hydrophilic monomer N-vinyl imidazole and graphene oxide (GO). Cryo-SEM showed the porous nature of the polymer matrix. The crosslinking density of the material was influenced by both, GO content and radiation dose used during polymerization reaction. Non-Fickian diffusion mechanism was observed for the release of an anticancer drug gemcitabine from the polymer matrix. Due to mucoadhesive and antioxidant nature of the polymer, it could be applied as material for gastrointestinal drug delivery system.

Identification of 2-benzoxazolinone derivatives as lead against molecular targets of diabetic complications.

Diabetic complications follow multiple pathophysiological pathways involving aldose reductase (ALR2)-mediated polyol pathway, advanced glycation end products (AGEs) and reactive oxygen species formation. Literature suggests ALR2 inhibitors such as epalrestat to possess significant potential in retinopathy and neuropathy. Thus, in this study, multiple pathophysiology directed molecules targeting ALR2, AGEs and free radicals formation were designed using in silico techniques. Initially, database was screened via in silico tools to obtain hits with affinity for the catalytic domain of ALR2. Additional focus was laid on the presence of structural attributes responsible for AGE's inhibitory and anti-oxidant potential. Out of obtained hits, 2-benzoxazolinone scaffold was selected and ten derivatives were synthesized accordingly. Finally, the synthesized molecules were evaluated for their ALR2 and AGEs inhibitory activities along with free radical scavenging potency.