New clusters of type 2 diabetes mellitus and their outcomes: relation between pharmacological treatment and previous cardiovascular events

Background Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes in adults, with 90% to 95% of cases. This study aims to establish clusters and have knowledge about the relationship between previous cardiovascular events and pharmacological treatment for T2DM. Methods 191 participants (EG) with T2DM with the average of 70.3 years (SD = 8.3) and 36 with pre-diabetes (CG) with an average of 62 years (SD = 10.3) who participated in clinical trials at Clinical Research Unit in Cardiology of Coimbra Hospital and Universitary Centre without cognitive difficulties, were divided in 5 different clusters. These were established based on six different variables: body mass index (BMI), age of each individual, age at diagnosis of DMT2, glycated haemoglobin value (HbA1c), homeostatic model that estimates the function of β cells (HOMA2-B) and insulin resistance (HOMA2-IR). Results Cluster 1 presented pre-diabetic individuals (15.9%), while diabetic individuals were divided into clusters 2 (1.8%), 3 (17.6%), 4 (21.1%) and 5 (43.6%). Regarding the study of the prevalence of previous cardiovascular events, the majority of individuals present in the different clusters had history of acute myocardial infarction (AMI). As for the prevalence of pharmacological treatment for DMT2, it was found that metformin was the most used drug. It was observed a relationship between previous AMI and metformin administration in clusters 3 (P = 0.0027; P < 0.05) and 5 (P = 0.0059; P < 0.05). Conclusions It was possible to create different clusters in a sample of the Portuguese population and to observe the existence of dependency relationships between different previous cardiovascular events and pharmacological treatment.

Novel clusters of type 2 diabetes mellitus and their outcomes: relationship between pharmacological treatment and microvascular complications

Background Type 2 Diabetes Mellitus (T2DM) is the most common form of diabetes in adults being characterized by an ineffective use of insulin or inefficient production by the pancreas. This study aims to study the relationship between microvascular complications and pharmacological treatment for T2DM. Methods 191 participants (EG) with T2DM with the average of 70.3 years (SD = 8.3) and 36 with pre-diabetes (CG) with an average of 62 years (SD = 10.3) who participated in clinical trials at Clinical Research Unit in Cardiology of Coimbra Hospital and Universitary Centre without cognitive difficulties, were divided in 5 different clusters. These were established based on six different variables: body mass index (BMI), age of each individual, age at diagnosis of DMT2, glycated haemoglobin value (HbA1c), homeostatic model that estimates the function of β cells (HOMA2-B) and insulin resistance (HOMA2-IR). Results Cluster 1 presented pre-diabetic individuals (15.9%), while diabetic individuals were divided into clusters 2 (1.8%), 3 (17.6%), 4 (21.1%) and 5 (43.6%). Regarding the study of the prevalence of microvascular complications, it was concluded that only chronic kidney disease (CKD) was found in most different groups. For the prevalence of pharmacological treatment for DMT2, it was found that metformin was the most used drug. It was observed a relationship between previous CKD and metformin administration in clusters 3 (P = 0.0012; P < 0.05), 4 (P = 9.41E-5; P < 0.05) and 5 (P = 0.0004; P < 0.05). Conclusions It was possible to observe the existence of dependency relationships between pharmacological treatment and different microvascular complications for DMT2.

Novel subgroups of adult-onset diabetes and their outcomes: relationship between previous cardiovascular events and microvascular complications

Background Type 2 Diabetes Mellitus (T2DM) is a global scale problem, closely related to genetic and environmental factors, such as aging, family history, diet, lack of physical exercise, physical inactivity and obesity, which contribute to the increase in its prevalence. Methods 191 participants (EG) with T2DM with the average of 70.3 years (SD = 8.3) and 36 with pre-diabetes (CG) with an average of 62 years (SD = 10.3) who participated in clinical trials at Clinical Research Unit in Cardiology of Coimbra Hospital and Universitary Centre without cognitive difficulties, were divided in 5 different clusters. These were established based on six different variables: body mass index (BMI), age of each individual, age at diagnosis of DMT2, glycated haemoglobin value (HbA1c), homeostatic model that estimates the function of β cells (HOMA2-B) and insulin resistance (HOMA2-IR). Results Cluster 1 presented pre-diabetic individuals (15.9%), while diabetic individuals were divided into clusters 2 (1.8%), 3 (17.6%), 4 (21.1%) and 5 (43.6%). Regarding the study of the prevalence of previous cardiovascular events, the majority of individuals present in the different clusters had history of acute myocardial infarction (AMI). For the prevalence of microvascular complications, only chronic kidney disease (CKD) was found in the vast majority of different groups. It was observed a dependency relationship between previous AMI and CKD in clusters 3 (P = 5.16E-5; P < 0.05), 4 (P = 0.0004; P < 0.05) and 5 (P = 0.0023; P < 0.05). Conclusions It was possible to create different clusters in a sample of the Portuguese population and to observe the existence of dependency relationships between different previous cardiovascular events and microvascular complications.

A National Web Conference on Integrated Siddha Approach in Clinical Practice and Research on COVID-19 Pandemic (ISACC)- Tirupati, December 2020

Siddha Clinical Research Unit (SCRU) Tirupati, working under the Central Council for Research in Siddha (CCRS), Ministry of AYUSH, Govt. of India, conducted a National Web conference titled “Integrated Siddha Approach in Clinical Practice and Research on COVID-19 Pandemic (ISACC)” on 23^rd Dec 2020, as a part of the fourth Pre-Siddha Day observance. Totally, 256 participants from Siddha colleges and various institutes of CCRS attended the Web conference and 9 eminent Speakers share their knowledge at the conference. The Technical session was separated by three panels, (i)Siddha Standalone and Integrative Clinical trials on COVID-19, (ii)Siddha Preventive and Prophylactic Measures on COVID-19, (iii)Experiences in Siddha Integrative Clinical Practice on COVID-19. The take home message of the conference insisted upon the three facts - the need for more clinical trials , need for increased experience sharing platforms for Siddha medical system and finally that Siddha standalone as well as integration for COVID-19 management gave significant outcome in both preventive and promotive healthcare. Central Council for Research in Siddha (CCRS), Ministry of AYUSH, Govt. of India and Directorate of Indian Medicine and Homeopathy (DIM&H), Government of Tamil Nadu, contributed a lot in Research and services in COVID-19 pandemic.

Progesterone Positive Feedback on Pulsatile LH Secretion and FSH Release May Be Blunted in Estradiol-Pretreated Women With PCOS

In women pretreated with estradiol (E2), exogenous progesterone (P4) acutely augments LH and FSH release (P4 positive feedback). Women with PCOS exhibit impaired P4 negative feedback on LH pulse frequency, but it remains unclear whether such women exhibit impaired P4 positive feedback on LH/FSH release. We sought to explore the latter notion as an a priori secondary hypothesis in a study primarily designed to assess whether P4 acutely suppresses LH pulse frequency. We studied 12 women with PCOS and 12 normally-cycling, non-hyperandrogenic controls. After 3 days of transdermal E2 pretreatment (0.2 mg/day), subjects were admitted to the Clinical Research Unit (CRU) for a 24-hour frequent blood sampling protocol starting at 2000 h. (CRU admissions occurred no earlier than cycle day 7 in PCOS and between days 7 and 11 inclusive in controls.) At 0600 h, subjects received either 100 mg oral micronized P4 or placebo (PBO). In a subsequent menstrual cycle, subjects underwent an identical CRU protocol except that P4 was exchanged for PBO or vice versa. LH secretion was analyzed using Autodecon, a deconvolution program that provides estimates of LH pulse frequency, pulsatile LH secretion (amount of LH secreted as pulses), and basal (non-pulsatile) LH secretion. Results were analyzed using 2-period crossover design analysis of covariance. In both groups, neither LH pulse frequency nor basal LH secretion changed significantly with P4 (compared to changes with PBO). Mean LH increased with P4 in both groups—3.1-fold (95% CI, 2.4–4.0) in controls and 2.7-fold (95% CI, 2.1–3.5) in PCOS; in both groups, P4-related changes were significantly greater than PBO-related changes (Bonferroni-corrected p=0.012 and 0.010, respectively). In controls, pulsatile LH secretion increased 3.5-fold (95% CI, 2.3–5.2) with P4—significantly more than with PBO (p=0.029); while in PCOS, a 2.6-fold (95% CI, 1.8–3.9) increase with P4 was not significantly different from changes with PBO (p=0.911). In controls, mean FSH increased 2.0-fold (95% CI, 1.7–2.3) with P4—significantly more than with PBO (p=0.004); but in PCOS, a 1.5-fold (95% CI, 1.3–1.8) increase was not significantly different from changes with PBO (p=0.072). Despite the above, between-group (PCOS vs. controls) differences in P4-induced changes in pulsatile LH secretion and mean FSH were not formally (statistically) demonstrable. Between-group differences representing potential confounders included age (median 25.5 vs. 19.0 y; p=0.029), body mass index (29.9 vs. 21.8 kg/m2; p=0.006), and cycle day of CRU admissions (day 45.0 vs. 10.4 for P4 admissions; 30.0 vs. 10.0 for PBO admissions). In summary, these data suggest that P4-induced increases in pulsatile LH secretion and mean FSH may be blunted in PCOS compared to controls, which could contribute to ovulatory dysfunction in PCOS. However, our results do not confirm this possibility, and further study is needed.

Circulatory and Urinary B-Vitamin Responses to Multivitamin Supplement Ingestion Differ between Older and Younger Adults

Multivitamin and mineral (MVM) supplements are frequently used amongst older populations to improve adequacy of micronutrients, including B-vitamins, but evidence for improved health outcomes are limited and deficiencies remain prevalent. Although this may indicate poor efficacy of supplements, this could also suggest the possibility for altered B-vitamin bioavailability and metabolism in older people. This open-label, single-arm acute parallel study, conducted at the Liggins Institute Clinical Research Unit in Auckland, compared circulatory and urinary B-vitamer responses to MVM supplementation in older (70.1 ± 2.7 y, n = 10 male, n = 10 female) compared to younger (24.2 ± 2.8 y, n = 10 male, n = 10 female) participants for 4 h after the ingestion of a single dose of a commercial MVM supplement and standardized breakfast. Older adults had a lower area under the curve (AUC) of postprandial plasma pyridoxine (p = 0.02) and pyridoxal-5′phosphate (p = 0.03) forms of vitamin B6 but greater 4-pyridoxic acid AUC (p = 0.009). Urinary pyridoxine and pyridoxal excretion were higher in younger females than in older females (time × age × sex interaction, p < 0.05). Older adults had a greater AUC increase in plasma thiamine (p = 0.01), riboflavin (p = 0.009), and pantothenic acid (p = 0.027). In older adults, there was decreased plasma responsiveness of the ingested (pyridoxine) and active (pyridoxal-5′phosphate) forms of vitamin B6, which indicated a previously undescribed alteration in either absorption or subsequent metabolic interconversion. While these findings cannot determine whether acute B6 responsiveness is adequate, this difference may have potential implications for B6 function in older adults. Although this may imply higher B vitamin substrate requirements for older people, further work is required to understand the implications of postprandial differences in availability.

1286. Pharmacokinetics, Excretion, and Mass Balance of [14C]-Rezafungin Following Intravenous (IV) Administration in Healthy Adults

Background Rezafungin is a once-weekly novel echinocandin antifungal currently in Phase 3 development for treatment of candidemia and invasive candidiasis (ReSTORE) and for prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis in blood and marrow transplant recipients (ReSPECT). Nonclinical ADME studies in rats and monkeys show rezafungin is primarily excreted unchanged in feces, with urine as a minor route. This study was conducted to characterize the routes of elimination of [14C]-rezafungin and the pharmacokinetics of total radioactivity and plasma rezafungin in humans. Methods Nine healthy male subjects received a single IV 400-mg rezafungin infusion containing 200 µCi of [14C]-rezafungin. Serial blood samples, urine, and feces were collected at specified times over 60 days; subjects were initially confined in the clinical research unit (CRU) for 17 days postdose and returned for two follow-up visits (days 29 and 60). During the period of time subjects were away from the CRU, recovery of radioactivity was estimated by linear interpolation. Results Rezafungin exhibited a long plasma half-life and was mainly excreted in feces unchanged. Cumulative recovery of radioactivity from excreta collected through the first 17 days was 52% (38% in feces, 14% in urine), reinforcing the slow overall elimination of rezafungin. Overall recovery of the administered dose by day 60 was estimated to be 88.3% (65.6% in feces, 22.7% in urine) (Figure 1). Mean blood/plasma concentration ratios ranged from 0.860 to 1.02 through the last collection time point (day 60), which indicated low association of radioactivity with blood cells. Rezafungin was the predominant compound measured in plasma and feces across all collected time points. In the urine, as observed in rat and monkey metabolite profiling studies, low level, inactive, oxidative metabolites were identified as 2-, 3-, 4-hydroxylpentyl rezafungin, and despentyl-rezafungin Figure 1 Conclusion Results from this human excretion balance, metabolism and PK study are consistent with nonclinical results, which showed fecal excretion as the major route of elimination of rezafungin. Rezafungin was the predominant compound in plasma and feces. Disclosures Voon Ong, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Shawn Flanagan, PhD, Cidara Therapeutics, Inc. (Employee, Shareholder) Taylor Sandison, MD, MPH, Cidara Therapeutics, Inc. (Employee, Shareholder)

New technologies to improve healthcare in low- and middle-income countries: Global Grand Challenges satellite event, Oxford University Clinical Research Unit, Ho Chi Minh City, 17th-18th September 2019

We report the outputs of a satellite event in Ho Chi Minh City, Vietnam, organized as part of the “2nd Global Grand Challenges of Engineering Summit”. The event considered challenges and potential solutions for improving low- and middle-income country (LMIC) healthcare systems, with particular reference to critical care. Participants from key regional and local stakeholders in healthcare and engineering discussed how new advances in technology, especially in the field of Artificial Intelligence, could be of potential benefit. This article summarizes the perspectives and conclusions of a group of key stakeholders from LMICs across South and South East Asia.

The Male Fertility Gene Atlas: a web tool for collecting and integrating OMICS data in the context of male infertility

STUDY QUESTION How can one design and implement a system that provides a comprehensive overview of research results in the field of epi-/genetics of male infertility and germ cells? SUMMARY ANSWER Working at the interface of literature search engines and raw data repositories, the newly developed Male Fertility Gene Atlas (MFGA) provides a system that can represent aggregated results from scientific publications in a standardized way and perform advanced searches, for example based on the conditions (phenotypes) and genes related to male infertility. WHAT IS KNOWN ALREADY PubMed and Google Scholar are established search engines for research literature. Additionally, repositories like Gene Expression Omnibus and Sequence Read Archive provide access to raw data. Selected processed data can be accessed by visualization tools like the ReproGenomics Viewer. STUDY DESIGN, SIZE, DURATION The MFGA was developed in a time frame of 18 months under a rapid prototyping approach. PARTICIPANTS/MATERIALS, SETTING, METHODS In the context of the Clinical Research Unit ‘Male Germ Cells’ (CRU326), a group of around 50 domain experts in the fields of male infertility and germ cells helped to develop the requirements engineering and feedback loops. They provided a set of 39 representative and heterogeneous publications to establish a basis for the system requirements. MAIN RESULTS AND THE ROLE OF CHANCE The MFGA is freely available online at https://mfga.uni-muenster.de. To date, it contains 115 data sets corresponding to 54 manually curated publications and provides an advanced search function based on study conditions, meta-information and genes, whereby it returns the publications’ exact tables and figures that fit the search request as well as a list of the most frequently investigated genes in the result set. Currently, study data for 31 different tissue types, 32 different cell types and 20 conditions are available. Also, ∼8000 and ∼1000 distinct genes have been found to be mentioned in at least 10 and 15 of the publications, respectively. LARGE SCALE DATA Not applicable because no novel data were produced. LIMITATIONS, REASONS FOR CAUTION For the most part, the content of the system currently includes the selected publications from the development process. However, a structured process for the prospective literature search and inclusion into the MFGA has been defined and is currently implemented. WIDER IMPLICATIONS OF THE FINDINGS The technical implementation of the MFGA allows for accommodating a wide range of heterogeneous data from aggregated research results. This implementation can be transferred to other diseases to establish comparable systems and generally support research in the medical field. STUDY FUNDING/COMPETING INTEREST(S) This work was carried out within the frame of the German Research Foundation (DFG) Clinical Research Unit ‘Male Germ Cells: from Genes to Function’ (CRU326). The authors declare no conflicts of interest.