Gold Score Research Articles

Identification of potential inhibitors against Corynebacterium diphtheriae MtrA response regulator protein; an in-silico drug discovery approach

Corynebacterium diphtheriae is a multi-drug resistant bacteria responsible for the life-threatening respiratory illness, diphtheria which can lead to severe Nervous system disorders, mainly infecting the lungs, heart, and kidneys if left untreated. In the current study, Corynebacterium diphtheriae MtrA response regulator protein was targeted, which regulates a two-component system of bacterial pathogenesis, and initiates DNA replication and cell division. In the current study a computational approach have been described for drug development against C. diphtheriae infections by inhibiting MtrA protein by small molecules acting as potential inhibitors against it. Molecular docking analysis of the equilibrated MtrA protein revealed compound-0.2970, compound-0.3029, and compound-0.3016 from Asinex Library as the promising inhibitors based on their lowest binding energies (−9.8 kJ/mol, −9.2 kJ/mol, and −8.9 kJ/mol), highest gold scores (40.53, 47.41, and 48.41), drug-likeness and pharmacokinetic properties. The MD simulation studies of the identified top-ranked inhibitors at 100 ns elucidated the system stability and fluctuations in the binding pocket of MtrA protein. Molecular Dynamics Simulations of the top three docked complexes further revealed that the standard binding pocket was retained ensuring the system stability. The rearrangements of H-bonds, van der Waals, pi-pi, and solid hydrophobic interactions were also observed. The binding free energy calculations (MM/PBSA and MM/GBSA) suggested a fundamental binding capability of the ligand to the target receptor MtrA. Therefore, the current study has provided excellent candidates acting as potent inhibitors for developing therapeutic drugs against C. diphtheriae infections. However, in vivo and in vitro animal experiments and accurate clinical trials are needed to validate the potential inhibitory effect of these compounds.

Goldfit Soccer: A Multidimensional Model for Talent Identification of Young Soccer Players

ABSTRACT Studies have provided empirical evidence on the prognostic relevance of test batteries and the “coach’s eye” for talent identification. The aims were 1) to compare objective and subjective assessments as well as a combined soccer-specific potential index between future selected and non-selected players and 2) to evaluate the prognostic validity of a multidimensional model as a tool for talent identification in soccer. The sample was composed by 132 male players (14,5 ± 1,4 years; regional competitive level) from U13 to U17 age groups of a Brazilian soccer talent development program. Athletes completed a multidimensional test battery and were subjectively rated by their coaches for sporting potential. Players’ success was evaluated five years later and was operationalized by achieving under-20 category of the Brazilian Championship or adult professional level (success rate, 15.9%). Confirming univariate prognostic validity, future selected outperformed non-selected players regarding 20-m sprint (p = .009), agility (p = .04), countermovement jump (p = .04), sit-and-reach (p = .001), Yo-Yo IR1 (p = .001), dribbling (p < .001), perceived competence (p = .007), peaking under pressure (p = .01), confidence/motivation (p = .03), coping skills (p = .03), intangibles (p < .001) and player potential (p < .001). A combined index (objective tests, athlete’s assessments and coach’s eye) named Gold Score Soccer (GSS) showed high prognostic validity (p < .001). A binary logistic regression estimated the probability of success (yes/not) with GSS, ambidextrous and predicted age at peak height velocity as predictors. This multidimensional model named GoldFit Soccer showed high prognostic validity (sensitivity = 85.7%; specificity = 83.8%; accuracy = 84.1%; area under the ROC curve = .93 [.87–.98]). Thus, GoldFit Soccer is a valid multidimensional scientific model for talent identification in soccer.

A cross-sectional questionnaire study: Impaired awareness of hypoglycaemia remains prevalent in adults with type 1 diabetes and is associated with the risk of severe hypoglycaemia.

Impaired awareness of hypoglycaemia (IAH) is a risk factor for severe hypoglycaemia (SH) in type 1 diabetes (T1D). Much of the IAH prevalence data comes from older studies where participants did not have the benefit of the latest insulins and technologies. This study surveyed the prevalence of IAH and SH in a tertiary adult clinic population and investigated the associated factors. Adults (≥18 years) attending a tertiary T1D clinic completed a questionnaire, including a Gold and Clarke score. Background information was collected from health records. 189 people (56.1% female) with T1D (median [IQR] disease duration 19.3 [11.5, 29.1] years and age of 41.0 [29.0, 52.0] years) participated. 17.5% had IAH and 16.0% reported ≥1 episode of SH in the previous 12 months. Those with IAH were more likely to report SH (37.5% versus 11.7%, p = 0.001) a greater number of SH episodes per person (median [IQR] 0 [0,2] versus 0 [0,0] P<0.001) and be female (72.7% versus 52.6%, p = 0.036). Socio-economic deprivation was associated with IAH (p = 0.032) and SH (p = 0.005). Use of technology was the same between IAH vs aware groups, however, participants reporting SH were more likely to use multiple daily injections (p = 0.026). Higher detectable C-peptide concentrations were associated with a reduced risk of SH (p = 0.04). Insulin pump and continuous glucose monitor use was comparable in IAH versus aware groups. Despite this, IAH remains a risk factor for SH and is prevalent in females and in older people. Socioeconomic deprivation was associated with IAH and SH, making this an important population to target for interventions.

Heterogeneity of glycaemic phenotypes in type 1 diabetes

Aims/hypothesisOur study aims to uncover glycaemic phenotype heterogeneity in type 1 diabetes.MethodsIn the Study of the French-speaking Society of Type 1 Diabetes (SFDT1), we characterised glycaemic heterogeneity thanks to a set of complementary metrics: HbA1c, time in range (TIR), time below range (TBR), CV, Gold score and glycaemia risk index (GRI). Applying the Discriminative Dimensionality Reduction with Trees (DDRTree) algorithm, we created a phenotypic tree, i.e. a 2D visual mapping. We also carried out a clustering analysis for comparison.ResultsWe included 618 participants with type 1 diabetes (52.9% men, mean age 40.6 years [SD 14.1]). Our phenotypic tree identified seven glycaemic phenotypes. The 2D phenotypic tree comprised a main branch in the proximal region and glycaemic phenotypes in the distal areas. Dimension 1, the horizontal dimension, was positively associated with GRI (coefficient [95% CI]) (0.54 [0.52, 0.57]), HbA1c (0.39 [0.35, 0.42]), CV (0.24 [0.19, 0.28]) and TBR (0.11 [0.06, 0.15]), and negatively with TIR (−0.52 [−0.54, −0.49]). The vertical dimension was positively associated with TBR (0.41 [0.38, 0.44]), CV (0.40 [0.37, 0.43]), TIR (0.16 [0.12, 0.20]), Gold score (0.10 [0.06, 0.15]) and GRI (0.06 [0.02, 0.11]), and negatively with HbA1c (−0.21 [−0.25, −0.17]). Notably, socioeconomic factors, cardiovascular risk indicators, retinopathy and treatment strategy were significant determinants of glycaemic phenotype diversity. The phenotypic tree enabled more granularity than traditional clustering in revealing clinically relevant subgroups of people with type 1 diabetes.Conclusions/interpretationOur study advances the current understanding of the complex glycaemic profile in people with type 1 diabetes and suggests that strategies based on isolated glycaemic metrics might not capture the complexity of the glycaemic phenotypes in real life. Relying on these phenotypes could improve patient stratification in type 1 diabetes care and personalise disease management.Graphical

Diabetic autonomic neuropathy does not impede improvement in hypoglycaemia awareness in adults: Sub-study results from the HypoCOMPaSS trial.

Impaired awareness of hypoglycaemia (IAH) increases the risk of severe hypoglycaemia in people with type 1 diabetes mellitus (T1DM). IAH can be reversed through meticulous avoidance of hypoglycaemia. Diabetic autonomic neuropathy (DAN) has been proposed as an underlying mechanism contributing to IAH; however, data are inconsistent. The aim of this study was to examine the effects of cardiac autonomic neuropathy (CAN) on IAH reversibility inT1DM. Participants with T1DM and IAH (Gold score ≥4) recruited to the HypoCOMPaSS (24-week 2 × 2 factorial randomised controlled) trial were included. All underwent screening for cardiac autonomic function testing at baseline and received comparable education and support aimed at avoiding hypoglycaemia and improving hypoglycaemia awareness. Definite CAN was defined as the presence of ≥2 abnormal cardiac reflex tests. Participants were grouped according to their CAN status, and changes in Gold score were compared. Eighty-three participants (52 women [62.7%]) were included with mean age (SD) of 48 (12) years and mean HbA1c of 66 (13) mmol/mol (8.2 [3.3] %). The mean duration of T1DM was 29 (13) years. The prevalence of CAN was low with 5/83 (6%) participants having definite autonomic neuropathy with 11 (13%) classified with possible/early neuropathy. All participants, regardless of the autonomic function status, showed a mean improvement in Gold score of ≥1 (mean improvement -1.2 [95% CI -0.8, -1.6]; p < 0.001). IAH can be improved in people with T1DM, and a long duration of disease, with and without cardiac autonomic dysfunction. These data suggest that CAN is not a prime driver for modulating IAH reversibility.

Associations Between Hypoglycemia Awareness Status and Symptoms of Hypoglycemia Among Adults with Type 1 or Insulin-Treated Type 2 Diabetes Using the Hypo-METRICS Smartphone Application.

Introduction: This study examined associations between hypoglycemia awareness status and hypoglycemia symptoms reported in real-time using the novel Hypoglycaemia-MEasurement, ThResholds and ImpaCtS (Hypo-METRICS) smartphone application (app) among adults with insulin-treated type 1 (T1D) or type 2 diabetes (T2D). Methods: Adults who experienced at least one hypoglycemic episode in the previous 3 months were recruited to the Hypo-METRICS study. They prospectively reported hypoglycemia episodes using the app for 10 weeks. Any of eight hypoglycemia symptoms were considered present if intensity was rated between "A little bit" to "Very much" and absent if rated "Not at all." Associations between hypoglycemia awareness (as defined by Gold score) and hypoglycemia symptoms were modeled using mixed-effects binary logistic regression, adjusting for glucose monitoring method and diabetes duration. Results: Of 531 participants (48% T1D, 52% T2D), 45% were women, 91% white, and 59% used Flash or continuous glucose monitoring. Impaired awareness of hypoglycemia (IAH) was associated with lower odds of reporting autonomic symptoms than normal awareness of hypoglycemia (NAH) (T1D odds ratio [OR] 0.43 [95% confidence interval {CI} 0.25-0.73], P = 0.002); T2D OR 0.51 [95% CI 0.26-0.99], P = 0.048), with no differences in neuroglycopenic symptoms. In T1D, relative to NAH, IAH was associated with higher odds of reporting autonomic symptoms at a glucose concentration <54 than >70 mg/dL (OR 2.18 [95% CI 1.21-3.94], P = 0.010). Conclusion: The Hypo-METRICS app is sensitive to differences in hypoglycemia symptoms according to hypoglycemia awareness in both diabetes types. Given its high ecological validity and low recall bias, the app may be a useful tool in research and clinical settings. The clinical trial registration number is NCT04304963.

Preventing severe hypoglycemia in adults with type 2 diabetes (PHT2): Design, delivery and evaluation framework for a randomized controlled trial

BackgroundSevere hypoglycemia is a common and feared complication of medications used to lower blood glucose levels in individuals with diabetes. Psychoeducational interventions can prevent severe hypoglycemia in individuals with type 1 diabetes (T1D). We aim to determine the effectiveness of this approach among adults with type 2 diabetes (T2D) at elevated risk for severe hypoglycemia. MethodsPreventing Hypoglycemia in Type 2 diabetes (PHT2) is a two-arm, parallel, randomized controlled trial. Participants are eligible if they are adults with T2D receiving care at an integrated group practice in Washington state and have experienced one or more episodes of severe hypoglycemia in the prior 12 months or have impaired awareness of hypoglycemia (Gold score ≥ 4). Participants are randomized to proactive nurse care management with or without my hypo compass, an evidence-based, psychoeducational intervention combining group and individual self-management training. For this study, my hypo compass was adapted to be suitable for adults with T2D and from an in-person to a virtual intervention over videoconference and telephone. The primary outcome is any self-reported severe hypoglycemia in the 12 months following the start of the intervention. Secondary outcomes include biochemical measures of hypoglycemia, self-reported hypoglycemia awareness, fear of hypoglycemia, and emergency department visits and hospitalizations for severe hypoglycemia. The study includes a process evaluation to assess implementation fidelity and clarify the causal pathway. ConclusionThe PHT2 trial will compare the effectiveness of two approaches for reducing severe hypoglycemia in adults with T2D.Trial registration: clinicaltrials.gov, # NCT04863872

GOLD SCORE ATHLETICS: MODELO DE DETECÇÃO DE TALENTOS PARA O ATLETISMO

ABSTRACT Introduction: Talent detection is a dynamic and multifactorial process that must start at school. Objective: Create a mathematical model for evaluating the sporting potential of schoolchildren for athletics in speed, throwing, and endurance events and to test its psychometric properties. Methods: 2871 schoolchildren of both sexes, from 11 to 17 years old, from a military school participated. Between 2015 and 2019, students were submitted to a multidimensional battery of tests containing anthropometric, physical-motor, psychological, socio-environmental, maturational, and performance indicators. In addition, ten teachers evaluated the students regarding the intangibles aspects of their sporting potential and the expectation of future success during this period. Adopting analytical and heuristic procedures, the Gold Score Athletics was created – linear, hybrid (tests + coaches´ eye), and weighted index, according to each indicator's importance, depending on the event type. Results: In the model validation sample (n = 1384), 13.9%, 16.6%, and 11.7% of boys and 10.9%, 10.1%, and 9.1% of girls were classified as high potential (Gold Score ≥ 60) for speed, throwing and endurance events, respectively. Internal consistency (r = 0.76 to 0.82) and diagnostic stability were high (r = 0.72 to 0.81). The Gold Score Athletics for sprinters, throwers, and long-distance runners, both for boys and girls, was higher in students selected for a national competition when compared to those not selected (p &lt; 0.001; d: 0.95 a 1.44) – construct validity – and higher in medalists in an athletics competition, held two years after diagnosis, when compared to non-medalists (p &lt; 0.05; d: 0.62 a 1.87) – predictive validity. Conclusion: The Gold Score Athletics is a valid and reliable scientific model for evaluating the sport's potential of schoolchildren, being useful in the talents detection for Athletics. Level of Evidence II; Diagnostic study.

High intensity interval training as a novel treatment for impaired awareness of hypoglycaemia in people with type 1 diabetes (HIT4HYPOS): a randomised parallel-group study

Aims/hypothesisImpaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH.MethodsHIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18–55 years with type 1 diabetes of at least 5 years’ duration and HbA1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic–hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT.ResultsEighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75–32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic–hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: −988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (–298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: −4 [2] vs 0 [2], p<0.05).Conclusions/interpretationIn this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia.Trial registrationISRCTN15373978.FundingSir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation.Graphical

Insulin independence following islet transplantation improves long-term metabolic outcomes.

Pancreatic islet allotransplantation is an effective therapy for type 1 diabetes mellitus, restoring glycaemic control and hypoglycaemic awareness in patients with recurrent severe hypoglycaemia. Insulin independence following transplant is being increasingly reported; however, this is not a primary endpoint in the UK. Having surpassed 10 years of islet transplantation in Scotland, we aimed to evaluate the impact of insulin independence following transplant on metabolic outcomes and graft survival. We conducted a retrospective analysis on data collected prospectively between 2011 and 2022. Patients who underwent islet transplantation in Scotland up to the 31st January 2020 were included. Primary endpoint was graft survival (stimulated C-peptide >50 pmol/L). Secondary endpoints included GOLD score, HbA1c, C-peptide and insulin requirement. Outcomes were compared between patients who achieved insulin independence at any point following transplant versus those who did not. 60 patients were included. 74.5% experienced >50 severe hypoglycaemic episodes in the year preceding transplant. There was a 55.0% decrease in insulin requirement following transplant and 30.0% achieved insulin independence. Mean graft survival time was 9.0 years (95% CI 7.2-10.9) in patients who achieved insulin independence versus 4.4 years (95% CI 3.4-5.3) in patients who did not. Insulin independence was associated with significantly improved graft function, glycaemic control and hypoglycaemic awareness at 1 year. This is the largest UK single-centre study on islet transplant to date. Our findings demonstrate significantly improved outcomes in patients who achieved insulin independence following islet transplantation.

Assessing Genetic Algorithm-Based Docking Protocols for Prediction of Heparin Oligosaccharide Binding Geometries onto Proteins.

Although molecular docking has evolved dramatically over the years, its application to glycosaminoglycans (GAGs) has remained challenging because of their intrinsic flexibility, highly anionic character and rather ill-defined site of binding on proteins. GAGs have been treated as either fully "rigid" or fully "flexible" in molecular docking. We reasoned that an intermediate semi-rigid docking (SRD) protocol may be better for the recapitulation of native heparin/heparan sulfate (Hp/HS) topologies. Herein, we study 18 Hp/HS-protein co-complexes containing chains from disaccharide to decasaccharide using genetic algorithm-based docking with rigid, semi-rigid, and flexible docking protocols. Our work reveals that rigid and semi-rigid protocols recapitulate native poses for longer chains (5→10 mers) significantly better than the flexible protocol, while 2→4-mer poses are better predicted using the semi-rigid approach. More importantly, the semi-rigid docking protocol is likely to perform better when no crystal structure information is available. We also present a new parameter for parsing selective versus non-selective GAG-protein systems, which relies on two computational parameters including consistency of binding (i.e., RMSD) and docking score (i.e., GOLD Score). The new semi-rigid protocol in combination with the new computational parameter is expected to be particularly useful in high-throughput screening of GAG sequences for identifying promising druggable targets as well as drug-like Hp/HS sequences.

Hypoglycemia Awareness Trajectories in Young People with Type 1 Diabetes Using Flash Glucose Monitoring

Aim. The trajectories of the hypoglycemia awareness status (HAS) have not yet been studied in children and adolescents with Type 1 diabetes (T1D). Methods. This 2-year follow-up study included children and adolescents with T1D aged 6‒20 years old and using flash glucose monitoring. The HAS of each participant was determined by the Gold score and assessed at three time points, along with clinical data. The trajectories based on HAS progression over time were identified, and a logistic regression analysis was performed to compare their characteristics. Results. Among the 255 participants, we identified four HAS trajectories (T1–T4). T1: normal awareness of hypoglycemia (NAH) maintained over time (n = 82, 29%); T2: NAH recovered during follow-up (n = 40, 18%); T3: impaired awareness of hypoglycemia (IAH) developed during follow-up (n = 28, 12.4%); T4: IAH maintained over time (n = 59, 21%). Sixteen participants (7%) displayed no identifiable trajectory. Participants belonging to the T3 group were younger. Following a specific trajectory defined the risk of developing future severe hypoglycemia. Conclusions. HAS changed in a significant proportion of pediatric people with T1D over time. Participants with a trajectory toward IAH were younger. Frequent HAS assessments may help to improve hypoglycemia risk management, especially in young children with T1D.

Can Blood Biomarkers Be Used to Assess Oxidative Stress in COPD Patients After Pulmonary Rehabilitation.

To determine the level of oxidative stress in the body due to pulmonary rehabilitation (PR) with thiols and disulfide and to investigate their relationship with indirect markers such as creatine kinase (CK), creatine kinase - MB (CK-MB), and lactate dehydrogenase (LDH), which show cell destruction. Patients with chronic obstructive pulmonary disease (COPD) are included in inpatient and outpatient care. They were evaluated before and after for PR, and an exercise program was prescribed. In addition, native thiol (NT), total thiol (TT), disulfide (DS), LDH, CK, and CK-MB values were tested. The mean age of 21 patients was 63±7.31 years. Eleven of them were outpatients and 10 of them were inpatients. Most of the patients were male (M/F=20/1, 95.2/4.8%). There was a significant difference in pulmonary function tests (PFT), St. George Respiratory Questionnaire (SGRQ), and 1 repetition maximum (1RM) before and after the treatment (p<0.001). There was a correlation between PFT and 1RM upper extremity. While there was no significant difference between thiols and disulfide, according to GOLD scores, there was a significant difference in patients with level 3-MMRC. No correlation was found between LDH, CK, CK-MB, and thiols, DS. ΔCK was found to be associated with ΔDS, and ΔCK-MB with ΔNT, and ΔTT. PR contributes to the antioxidant process by improving respiration and reducing oxidative stress. The decrease in LDH, CK with PR, increase in CK-MB, and correlation of CK with thiols and DS gave a different interpretation. In this case, it should be considered that oxidative stress may also be increased in people with high CK values.

Intermittently scanned continuous glucose monitoring and hypoglycaemia awareness in drivers with diabetes: Insights from the Association of British Clinical Diabetologists Nationwide audit.

Frequent hypoglycaemia results in disruption to usual hypoglycaemic autonomic responses leading to impaired awareness of hypoglycaemia, which is associated with an increased risk of severe hypoglycaemia requiring third-party assistance (SH). The UK Driving and Vehicle Licensing Agency (DVLA) does not permit car driving if they have either a complete loss of hypoglycaemia awareness or more than one SH event a year. The FreeStyle Libre (FSL) Association of British Clinical Diabetologists (ABCD) Nationwide Audit consists of data collected by clinicians during routine clinical work, submitted into a secure web-based tool held within the National Health Service (NHS) N3 network. Analysis of paired baseline and follow-up data for people with type 1 diabetes who also held a driving licence was undertaken. The study consisted of 6304 people who had data recorded about driving status from 102 UK specialist diabetes centres, of which 4218 held a driving licence: 4178 a group 1, standard licence, 33 a group 2, large lorries and buses, seven a taxi licence; 1819 did not drive. Paired baseline and follow-up data were available for a sub-cohort of 1606/4218. At a mean follow-up of 6.9 months [95% CI (6.8, 7.1)], the Gold score had improved (2.3 ± 1.5 vs. 2.0 ± 1.3 p < .001), and the number of people who experienced an SH episode was also significantly lower (12.1% vs. 2.7%, p < .001). This study suggests that intermittently scanned continuous glucose monitoring may improve impaired awareness of hypoglycaemia and reduce the number of people with type 1 diabetes with a driving licence experiencing a severe hypoglycaemic episode.

A real-life comparison of hypoglycaemia symptomatology between insulin-treated type 2 diabetes participants with and without impaired awareness of hypoglycaemia.

We aim to compare and correlate Gold and Clarke questionnaire scores with hypoglycaemic symptomatic responses between insulin-treated type 2 diabetes participants with and without IAH in a real-life study. Insulin-treated type 2 diabetes participants attending an outpatient diabetes clinic in Singapore were asked to complete the Gold and Clarke questionnaires, record capillary blood glucose (CBG) and hypoglycaemic symptoms for 4 weeks. Data were collected from 153 participants (M:F = 98:55) with mean age 61.0 ± 9.4 years, duration of diabetes 19.5 ± 8.8 years and HbA1c 68 ± 17 mmol/mol (8.4 ± 1.5%). Gold and Clarke methods classified 19.6% and 26.8% of participants with IAH, respectively. Using CBG threshold of <3 mmol/L, significantly greater proportion of participants with intact awareness were experiencing autonomic symptoms than those with IAH with either method (Gold: 69% vs. 18%, p = 0.006; Clarke: 85% vs. 46%, p = 0.010). Significantly greater proportion of participants with IAH experienced no hypoglycaemia symptoms than those with intact awareness (Gold: 3.4% vs. 36%, p = 0.015; Clarke: 3.7% vs. 31%, p = 0.031). Participants with IAH had significantly higher rates of severe hypoglycaemia in the preceding year compared to those without (Gold: 17% vs. 3.3%; Clarke: 15% vs. 2.7%, p = 0.012). Gold and Clarke questionnaires are appropriate tools in ascertaining IAH status in insulin-treated type 2 diabetes participants. This is the first time whereby the hypoglycaemia symptomology has robustly validated the Gold and Clarke questionnaire in insulin-treated type 2 diabetes participants.

In silico analysis of Diosmetin as an effective chemopreventive agent against prostate cancer: molecular docking, validation, dynamic simulation and pharmacokinetic prediction-based studies

Prostate cancer is the second most dangerous cancer type worldwide. While various treatment options are present i.e. agonists and antagonists, their utilization leads to adverse effects and due to this resistance developing, ultimately the outcome is remission. So, to overcome this issue, we have undertaken an in-silico investigation to identify promising and unique flavonoid candidates for combating prostate cancer. Using GOLD software, the study assessed the effectiveness of 560 natural secondary polyphenols against CDKN2. Protein Data Bank was used to retrieve the 3D crystal structure of CDKN2 (PDB Id: 4EK3) and we retrieved the structure of selected secondary polyphenols from the PubChem database. The compound Diosmetin shows the highest GOLD score with the selected Protein i.e. CDKN2 which is 58.72. To better understand the 2-dimensional and 3-dimensional interactions, the interacting amino acid residues were visualised using Discovery Studio 3.5 and Maestro 13.5. Using Schrodinger-Glide, the Diosmetin and CDKN2 were re-docked, and decoy ligands were docked to CDKN2, which was used to further ascertain the study. The ligands with the highest Gold score were forecasted for pharmacokinetics characteristics, and the results were tabulated and analysed. Utilising the Gromacs software and Desmond packages, 100 ns of Diosmetin molecular dynamics simulations were run to evaluate the structural persistence and variations of protein-ligand complexes. Additionally, our investigation revealed that Diosmetin had a better binding affinity with CDKN2 measuring 58.72, and it also showed remarkable stability across a 100-ns simulation. Thus, following in-vitro and in-vivo clinical studies, diosmetin might lead to the Prostate regimen. Communicated by Ramaswamy H. Sarma

Hybrid Closed Loop Therapy in Adults With Type 1 Diabetes and Above-Target HbA1c: A Real-World Observational Study.

We explored longitudinal changes associated with switching to hybrid closed loop (HCL) insulin delivery systems in adults with type 1 diabetes and elevated HbA1c levels despite the use of intermittently scanned continuous glucose monitoring (isCGM) and insulin pump therapy. We undertook a pragmatic, preplanned observational study of participants included in the National Health Service England closed loop pilot. Adults using isCGM and insulin pump across 31 diabetes centers in England with an HbA1c ≥8.5% who were willing to commence HCL therapy were included. Outcomes included change in HbA1c, sensor glucometrics, diabetes distress score, Gold score (hypoglycemia awareness), acute event rates, and user opinion of HCL. In total, 570 HCL users were included (median age 40 [IQR 29-50] years, 67% female, and 85% White). Mean baseline HbA1c was 9.4 ± 0.9% (78.9 ± 9.1 mmol/mol) with a median follow-up of 5.1 (IQR 3.9-6.6) months. Of 520 users continuing HCL at follow-up, mean adjusted HbA1c reduced by 1.7% (95% CI 1.5, 1.8; P < 0.0001) (18.1 mmol/mol [95% CI 16.6, 19.6]; P < 0.0001). Time in range (70-180 mg/dL) increased from 34.2 to 61.9% (P < 0.001). Individuals with HbA1c of ≤58 mmol/mol rose from 0 to 39.4% (P < 0.0001), and those achieving ≥70% glucose time in range and <4% time below range increased from 0.8 to 28.2% (P < 0.0001). Almost all participants rated HCL therapy as having a positive impact on quality of life (94.7% [540 of 570]). Use of HCL is associated with improvements in HbA1c, time in range, hypoglycemia, and diabetes-related distress and quality of life in people with type 1 diabetes in the real world.

Association of Smartphone-Based Activity Tracking and Nocturnal Hypoglycemia in People With Type 1 Diabetes.

Nocturnal hypoglycemia (NH) remains a major burden for people with type 1 diabetes (T1D). Daytime physical activity (PA) increases the risk of NH. This pilot study tested whether cumulative daytime PA measured using a smartphone-based step tracker was associated with NH. Adults with T1D for ≥ 5 years (y) on multiple daily insulin or continuous insulin infusion, not using continuous glucose monitoring and HbA1c 6 to 10% wore blinded Freestyle Libre Pro sensors and recorded total daily carbohydrate (TDC) and total daily dose (TDD) of insulin. During this time, daily step count (DSC) was tracked using the smartphone-based Fitbit MobileTrack application. Mixed effects logistic regression was used to estimate the effect of DSC on NH (sensor glucose <70, <54 mg/dl for ≥15 minutes), while adjusting for TDC and TDD of insulin, and treating participants as a random effect. Twenty-six adults, with 65.4% females, median age 27 years (interquartile range: 26-32) mean body mass index 23.9 kg/m2, median HbA1c 7.6% (7.1-8.1) and mean Gold Score 2.1 (standard deviation 1.0) formed the study population. The median DSC for the whole group was 2867 (1820-4807). There was a significant effect of DSC on NH episodes <70 mg/dl. (odds ratio 1.11 [95% CI: 1.01-1.23, P = .04]. There was no significant effect on NH <54 mg/dl. Daily PA measured by a smartphone-based step tracker was associated with the risk of NH in people with type 1 diabetes.

IDIOPATHIC PULMONARY HEMOSIDERIN: ABOUT AN UNUSUAL CASE

Introduction: idiopathic pulmonary hemosiderosis is a rare disease of unknown etiology. Case report: This is a 12-year-old boy. The beginning of its symptomatology dates back to one year by several episodes of low-abundance hemoptysis associated with cough and night sweats. He had also a microcytic hypochromic anemia (Hb=4.4) transfused 3 times. . Clinical examination found discoloured skin paleness and conjunctival The count showed microcytic hypochromic anemia with HB:5.7 g/dl. A chest x-ray showed a discrete alveolar syndrome. A tuberculous assessment in particular an IDR tuberculin 3 BK expectorations and Gènexpert were negative. A chest CT scan showed bilateral interstitial syndrome. A bronchoscopy with bronchoalveolar lavage showed the existence of sidephages with a Golde score calculated on 240 Perls staining . A balance of system diseases including antinuclear antibodies were negative. Ac anti transglutaminase IgA were negative. A heart ultrasound did not show a pulmonary hypertension. In fine, the diagnosis was a primary pulmonary hemosidesis. Management consisted of a blood cell transfusion a prenisolone-based corticosteroid 2 mg/kg/d for 3 months. After two months, the improvement was full. Conclusion: We must think about Hemosidesis idiopathic if we have hemoptysis chronic anemia and pulmonary infiltrates and do a Bronchoalveolar lavage to confirm diagnosis.

Identification of factors associated with fear of hypoglycemia using the capability, opportunity, motivation and behavior model in people with type 2 diabetes mellitus: a cross-sectional study.

To examined the relationship between fear of hypoglycemia and certain variables in people with type 2 diabetes mellitus (T2DM) based on the Capability, Opportunity, Motivation, and Behavior model, combined with the context unique to people with diabetes to provide a basis for developing targeted nursing interventions. In this cross-sectional study, 212 people with T2DM were recruited from February 2021 to July 2021. Data were collected using the Hypoglycaemia Fear Survey, Gold score, Patient Assessment of Chronic Illness Care (PACIC) scale and Diabetic Self-Management Attitudes Scale. Multiple linear regression analysis was performed to determine the predictors of fear of hypoglycemia using SPSS 26.0. The mean fear of hypoglycemia score was 74.88 ± 18.28 (range: 37.00-132.00). In people with T2DM, the frequency of blood glucose monitoring, the frequency of hypoglycemia in the past half-year, degree of understanding of hypoglycemia, impaired awareness of hypoglycemia, PACIC, and self-management attitude of diabetes were the influencing factors of fear of hypoglycemia (adjusted R2 = 0.560, F[21,190] = 13.800, P < 0.001). These variables explained 56.0% of the variance in the fear of hypoglycemia. The level of fear of hypoglycemia in people with T2DM was relatively high. In addition to paying attention to the disease characteristics of people with T2DM, medical staff should also pay attention to patients' own perception and handling ability of disease and hypoglycemia, attitude toward self-management behavior and external environment support, all of which have a positive effect on improving the fear of hypoglycemia in people with T2DM, optimizing the self-management level and improving quality of life.