Deciphering the complex interplay of obesity, epithelial barrier dysfunction, and tight junction remodeling: Unraveling potential therapeutic avenues.

Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions.

A retrospective study comparing the results of continuous glucose monitoring to self-blood glucose monitoring for pregnant women with type 1 diabetes mellitus.

BACKGROUND: Type 1 diabetes mellitus (T1DM) is associated with adverse maternal and fetal outcomes. Continuous glucose monitoring (CGM) during pregnancy is associated with better glycemic control in women with T1DM. However, no clear benefits have been demonstrated in reducing adverse feto-maternal outcomes in pregnant women with T1DM. DESIGN AND METHODS: This is a retrospective, single-center study of pregnant women with T1DM to evaluate the impact of CGM use on glycemic control and feto-maternal outcomes in pregnant women with T1DM. RESULTS: Of 265 women with T1DM, 92 (34.7%) used CGM, and 173 (65.3%) were managed with capillary blood glucose (CBG) monitoring. The mean (SD) age and BMI at the first visit were 29.4 (4.7) years and 27.2 (5.2) kg/m2, respectively. The mean (SD) HbA1c at the first-trimester visit was 63 (1) mmol/mol, and in the last trimester was 51 (1%). There was no difference in the mean changes in HbA1c between the two groups. Women using CGM had lower insulin requirements (1.02 + 0.37 vs. 0.87 + 0.04 units/kg, p = 0.01). The two groups had no significant differences in maternal or fetal outcomes. CONCLUSION: CGM use in pregnant T1DM women is not associated with improved fetomaternal outcomes.

Integrated care of diabetes during pregnancy: a Qatari nationwide cohort.

Background: Diabetes in pregnancy (DIP) is associated with adverse fetal and maternal outcomes. DIP is classified as either pre-existing or new-onset diabetes mellitus (DM), which is classified into gestational DM (GDM) and newly detected type 2 (N-T2D). All pregnant women in Qatar who are not known to have pre-existing DM are offered screening for DIP during the first antenatal care visit and after 24 weeks gestation. The study aims to report the DIP screening rates, the prevalence of DIP, and the impact of the universal screening program on adverse pregnancy outcomes. Methods: This retrospective study included all women who gave birth in Hamad Medical Corporation (HMC) hospitals between 2019 and 2022. New-onset DIP was defined using the WHO-2013 criteria. The primary outcomes were the screening rates and the prevalence of DIP in Qatar. The secondary outcomes were the difference in preterm delivery, C-section, macrosomia, large for gestational age (LGA), small for gestational age (SGA), and intra-uterine fetal death (IUFD) between women with or without GDM. Findings: We included 94,422 women who gave birth to 96,017 neonates (85.7%) out of 112,080 neonates born nationwide. The number of women with pre-existing diabetes was 2496 women. Of 91,926 eligible women, 77,372 (84.2%) were screened for DIP. The prevalence of GDM is 31.6% (95% CI: 31.3-32.0%); N-T2D is 2.2% (95% CI: 2.1-2.3%), and pre-existing Type 2 DM and Type 1 DM was 2.6% (95% CI: 0.8-3.0%) and 0.2% (0.19-0.25), respectively. Compared to the non-GDM group, women with GDM were older (30.8 ± 5.3 versus 29.7 ± 5.2 years, p < 0.001). After adjusting for age, women with GDM had lower risk of IUFD and SGA (0.63 [95% CI 0.50-0.80, p < 0.001], 0.88 [95% CI 0.84-0.92, p < 0.001] respectively) but higher risk of C-section and LFD (1.07 [95% CI 1.04-1.10, p < 0.001], 1.09 [95% CI 1.01-1.15, p = 0.01], respectively, compared to women with no-GDM. Interpretation: Of the women eligible for screening, 84.2% were screened by the DIP program in Qatar. The prevalence of DIP in Qatar is 36.9%. Integrated care is critical for the screening and management of diabetes during pregnancy. Fundings: The authors did not receive any funding for this project.

Genome-wide association study and trans-ethnic meta-analysis identify novel susceptibility loci for type 2 diabetes mellitus.

BACKGROUND: The genetic basis of type 2 diabetes (T2D) is under-investigated in the Middle East, despite the rapidly growing disease prevalence. We aimed to define the genetic determinants of T2D in Qatar. METHODS: Using whole genome sequencing of 11,436 participants (2765 T2D cases and 8671 controls) from the population-based Qatar Biobank (QBB), we conducted a genome-wide association study (GWAS) of T2D with and without body mass index (BMI) adjustment. RESULTS: We replicated 93 known T2D-associated loci in a BMI-unadjusted model, while 96 known loci were replicated in a BMI-adjusted model. The effect sizes and allele frequencies of replicated SNPs in the Qatari population generally concurred with those from European populations. We identified a locus specific to our cohort located between the APOBEC3H and CBX7 genes in the BMI-unadjusted model. Also, we performed a transethnic meta-analysis of our cohort with a previous GWAS on T2D in multi-ancestry individuals (180,834 T2D cases and 1,159,055 controls). One locus in DYNC2H1 gene reached genome-wide significance in the meta-analysis. Assessing polygenic risk scores derived from European- and multi-ancestries in the Qatari population showed higher predictive performance of the multi-ancestry panel compared to the European panel. CONCLUSION: Our study provides new insights into the genetic architecture of T2D in a Middle Eastern population and identifies genes that may be explored further for their involvement in T2D pathogenesis.

Time to Move Beyond a Binary Criterion for Gestational Diabetes?

Over the years, several international guidelines have been developed by specialist organizations for the diagnosis of gestational diabetes mellitus (GDM). However, these guidelines vary and lack consensus on what level of glycemia defines GDM and worryingly, there is now evidence of over- or- under-diagnosis of women with GDM by current criteria. Towards this end, the National Priorities Research Program (NPRP) funded a program of research aimed at elucidating the problem with GDM diagnosis. It was determined, on completion of the project, that the solution required diagnosis of graded levels of dysglycemia in pregnancy and not just a diagnosis of presence or absence of GDM. A new diagnostic criterion (called the NPRP criterion) was created based on a single numerical summary of the three readings from the oral glucose tolerance test (GTT) that diagnosed women in pregnancy into four levels: normal, impaired, GDM and high risk GDM. This paper now examines existing GDM criteria vis-à-vis the NPRP criterion. It is noted that no significant change has happened over the years for existing criteria except for a gradual reduction in the threshold values of individual time-points or the number of time points, bringing us towards over-diagnosis of GDM in pregnancy. The new criterion unifies all readings from the GTT into one numerical value and, because it results in four levels of glycemia, represents a new way forwards for GDM diagnosis and can potentially reduce the rates of under diagnosis and over diagnosis of GDM.

Extracellular vesicles as tools and targets in therapy for diseases.

Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.

Inflammatory protein signatures in individuals with obesity and metabolic syndrome.

There is variability in the metabolic health status among individuals presenting with obesity; some may be metabolically healthy, while others may have developed the metabolic syndrome, a cluster including insulin resistance, hypertension, dyslipidemia, and increased risk of cardiovascular disease and type 2 diabetes. The mechanisms contributing to this metabolic heterogeneity are not fully understood. To address this question, plasma samples from 48 individuals with BMI ≥ 35 kg/m2 were examined (27 with and 21 without metabolic syndrome). Fasting plasma samples were subjected to Olink proteomics analysis for 184 cardiometabolic and inflammation-enriched proteins. Data analysis showed a clear differentiation between the two groups with distinct plasma protein expression profiles. Twenty-four proteins were differentially expressed (DEPs) between the two groups. Pathways related to immune cell migration, leukocyte chemotaxis, chemokine signaling, mucosal inflammatory response, tissue repair and remodeling were enriched in the group with metabolic syndrome. Functional analysis of DEPs revealed upregulation of 15 immunological pathways. The study identifies some of the pathways that are altered and reflect metabolic health in individuals with obesity. This provides valuable insights into some of the underlying mechanisms and can lead to identification of therapeutic targets to improve metabolic health in individuals with obesity.

Circulating microRNA signatures in patients with chronic Urticaria.

Background: Chronic Urticaria (CU) is a complex skin disease that appears as recurrent raised itchy rash/angioedema or both for more than six weeks. The pathophysiology of CU is complex and has yet to be understood entirely. It is predominantly a mast cell-driven disease with the possible involvement of type 2 inflammation. Current evidence largely favors mast cell activation by an IgE-mediated autoallergic mechanism or an autoimmune mechanism by IgG autoantibodies to IgE/ high-affinity receptor of IgE. MicroRNAs (miRNA) are small coding RNAs regulating gene expression at the post-transcription level. This study aimed to investigate the circulating miRNA as potential biomarkers in CU patients compared to healthy controls. Methods: The miRNA gene expression was done in seven patients with CU and seven healthy controls. The expression of miRNA is done using TaqMan openArray human advanced miRNA Panel. ExpressionSuite Software (Thermo Fischer Scientific, Waltham, MA, USA) is used for data analysis to quantify the miRNA expressions. P<0.05 is considered to be statistically significant. Results: A significant upregulation (p<0.05) in the miR-451a, miR-9-5p, miR-150-5p, miR-296-5p, and miR-182-5p was observed in CU compared to controls. Dysregulation of miR-451a is identified as an early biomarker in allergic diseases. Functional enrichment analysis with the KEGG pathway and disease ontology databases showed that these miRNAs were associated with skin diseases and inflammation. The differentially expressed miRNAs contribute to determining the genes regulated in CU. miRNA-based therapies that target different genes in a given pathway might be a potential candidate for treating CU. Conclusion: miRNA field has grown steadily over the past few years, but the role of circulating miRNAs in CU remains relatively unexplored. This study showed that the upregulated circulating miRNA might play an essential role in CU pathogenesis and inflammation. Also, our study highlights the importance of miRNAs as a future biomarker and potential therapeutic target to be investigated.

Evaluation of the Impact of a New Cooling Cell Processor System on Islet Cell Isolation Facility.

Standard cell therapy equipment, including the gold standard cell processor to purify human islets for clinical transplantation, is rarely refrigerated, potentially exposing cells to elevated temperatures during the centrifugation step. Custom cooling systems have a direct benefit on human islet viability and function. The current study was designed to test the effectiveness of a newly developed, readily available cooled cell processor system requiring minimal modifications and to evaluate its impact on human cell viability and the GMP cleanroom environment. The cooler system, a mechanically refrigerated heat exchanger set at -30 °C was used to deliver cooled medical grade dry air to the cell processor bowl through a hole drilled in the centrifuge cover. With the limited availability of pancreas donors in Qatar, system validation was done with continuous density gradient purification of pooled human bone marrow buffy coat. Sterility, turbulence, and particle count were measured in class C and class B clean room environments. No turbulence developed around the cooled cell processor, and no excess 0.5 µm and 5 µm airborne particulates were generated as per cleanroom GMP standards. At the beginning and end of the collection steps, the temperature rose respectively to 21.50 °C ± 0.34 °C and 21.93 °C ± 0.20 °C in the non-cooled cell processor and to only 10.9 °C ± 0.17 °C and 11.16 °C ± 0.35 °C in the cooled- cell processor (p <0.05). The cooled cell processor led to both improved recovery (98%) of the mononuclear cell fraction and viability (100% ± 2%) post-processing. The new cooling system effectively reduces the heat produced by the cell processor while having no particulate impact on the GMP clean room environment. The cooled cell processor described here is an inexpensive ($16,000 without including taxes, customs clearance, and transportation) and minimally invasive method to provide robust cooling. Currently, this technology in the GMP cell therapy facility is being applied to human islet cell isolation and transplantation for the clinical program.

The impact of prior obesity surgery on glucose metabolism after body contouring surgery: A pilot study.

Body contouring surgery enhances physical appearance by means of surgical subcutaneous fat removal (SSFR). However, it remains unclear how SSFR may affect glucose metabolism and its broader effects on the endocrine system, especially in individuals who have undergone obesity (bariatric) surgery. This study aimed to evaluate the impact of SSFR on glucose excursion and insulin resistance in such patients, by examining them over three visits (within 1 week before surgery, 1 week after surgery, and 6 weeks after surgery). The independent impact of SSFR and history of obesity surgery on glucose homeostasis was evaluated in 29 participants, of whom ten patients (34%) had a history of obesity surgery. Indices of glucose metabolism were evaluated using cluster robust-error logistic regression. Results indicated that SSFR led to a gross improvement in insulin resistance at 6 weeks after the surgery in all patient's irrespective of BMI, type 2 diabetes mellitus (T2D) status, or history of obesity surgery (OR 0.22; p = 0.042). However, no effect was observed on glucose excursion except for a transient increase at visit 2 (1 week after surgery) in those without prior obesity surgery. Interestingly, participants with a history of obesity surgery had approximately half the odds being in the upper tertile for HOMA-IR (OR 0.44; p = 0.142) and ten-folds lower odds of having severely abnormal glucose excursion (OR 0.09; p = 0.031), irrespective of their BMI, T2D status, or time post SSFR. In conclusion, this study showed that body contouring surgery through SSFR resulted in (at least) short-term improvement in insulin resistance (independent of the participant's BMI, T2D status, or history of obesity surgery) without affecting glucose excursion under the GTT. On the contrary, obesity surgery may have a long-term effect on glucose excursion, possibly due to sustained improvement of pancreatic ß-cell function.

Immediate and contributory causes of death in patients hospitalized with COVID-19.

OBJECTIVES: Accurate determination of the immediate causes of death in patients with COVID-19 is important for optimal care and mitigation strategies. METHODS: All deaths in Qatar between March 01, 2020, and August 31, 2022, flagged for likely relationship to COVID-19 were reviewed by two independent, trained reviewers using a standardized methodology to determine the immediate and contributory causes of death. RESULTS: Among 749 flagged deaths, the most common admitting diagnoses were respiratory tract infection (91%) and major adverse cardiac event (MACE, 2.3%). The most common immediate causes of death were COVID-19 pneumonia (66.2%), MACE (7.1%), hospital-associated pneumonia (HAP, 6.8%), bacteremia (6.3%), disseminated fungal infection (DFI, 5.2%), and thromboembolism (4.5%). After COVID-19 pneumonia, MACE was the predominant cause of death in the first 2 weeks but declined thereafter. No death occurred due to bacteremia, HAP, or DFI in the first week after hospitalization, but became increasingly common with increased length of stay in the hospital accounting for 9%, 12%, and 10% of all deaths after 4 weeks in the hospital, respectively. CONCLUSION: Nearly one-third of patients with COVID-19 infection die of non-COVID-19 causes, some of which are preventable. Mitigation strategies should be instituted to reduce the risk of such deaths.

An integrated multi-omic approach demonstrates distinct molecular signatures between human obesity with and without metabolic complications: a case-control study.

OBJECTIVES: To examine the hypothesis that obesity complicated by the metabolic syndrome, compared to uncomplicated obesity, has distinct molecular signatures and metabolic pathways. METHODS: We analyzed a cohort of 39 participants with obesity that included 21 with metabolic syndrome, age-matched to 18 without metabolic complications. We measured in whole blood samples 754 human microRNAs (miRNAs), 704 metabolites using unbiased mass spectrometry metabolomics, and 25,682 transcripts, which include both protein coding genes (PCGs) as well as non-coding transcripts. We then identified differentially expressed miRNAs, PCGs, and metabolites and integrated them using databases such as mirDIP (mapping between miRNA-PCG network), Human Metabolome Database (mapping between metabolite-PCG network) and tools like MetaboAnalyst (mapping between metabolite-metabolic pathway network) to determine dysregulated metabolic pathways in obesity with metabolic complications. RESULTS: We identified 8 significantly enriched metabolic pathways comprising 8 metabolites, 25 protein coding genes and 9 microRNAs which are each differentially expressed between the subjects with obesity and those with obesity and metabolic syndrome. By performing unsupervised hierarchical clustering on the enrichment matrix of the 8 metabolic pathways, we could approximately segregate the uncomplicated obesity strata from that of obesity with metabolic syndrome. CONCLUSIONS: The data suggest that at least 8 metabolic pathways, along with their various dysregulated elements, identified via our integrative bioinformatics pipeline, can potentially differentiate those with obesity from those with obesity and metabolic complications.

Evaluation of mortality attributable to SARS-CoV-2 vaccine administration using national level data from Qatar.

Accurate determination of mortality attributable to SARS-CoV-2 vaccination is critical in allaying concerns about their safety. We reviewed every death in Qatar that occurred within 30 days of any SARS-CoV-2 vaccine administration between January 1, 2021 and June 12, 2022. Probability of association with SARS-CoV-2 vaccination was determined by four independent trained reviewers using a modified WHO algorithm. Among 6,928,359 doses administered, 138 deaths occurred within 30 days of vaccination; eight had a high probability (1.15/1,000,000 doses), 15 had intermediate probability (2.38/1,000,000 doses), and 112 had low probability or no association with vaccination. The death rate among those with high probability of relationship to SARS-CoV-2 vaccination was 0.34/100,000 unique vaccine recipients, while death rate among those with either high or intermediate probability of relationship to SARS-CoV-2 vaccination was 0.98/100,000 unique vaccine recipients. In conclusion, deaths attributable to SARS-CoV-2 vaccination are extremely rare and lower than the overall crude mortality rate in Qatar.

Metabolic changes after surgical fat removal: A dose-response meta-analysis.

BACKGROUND: Bariatric surgery averts obesity-induced insulin resistance and the metabolic syndrome. By contrast, surgical fat removal is considered merely an esthetic endeavor. The aim of this article was to establish whether surgical fat removal, similar to bariatric surgery, exerts measurable, lasting metabolic benefits. METHODS: PubMed, Embase, and Scopus were searched using the Polyglot Search Translator to find studies examining quantitative expression of metabolic markers. Quality assessment was done using the MethodologicAl STandard for Epidemiological Research scale. The robust-error meta-regression model was employed for this synthesis. RESULTS: Twenty-two studies with 493 participants were included. Insulin sensitivity improved gradually with a maximum reduction in fasting insulin and homeostatic model assessment for insulin resistance of 17 pmol/L and 1 point, respectively, at postoperative day 180. Peak metabolic benefits manifest as a reduction of 2 units in body mass index, 3 kg of fat mass, 5 cm of waist circumference, 15 µg/L of serum leptin, 0.75 pg/ml of tumor necrosis factor-alpha, 0.25 mmol/L of total cholesterol, and 3.5 mmHg of systolic and diastolic blood pressure that were observed at day 50 but were followed by a return to preoperative levels by day 180. Serum high-density lipoproteins peaked at 50 days post-surgery before falling below the baseline. No significant changes were observed in lean body mass, serum adiponectin, resistin, interleukin-6, C-reactive protein, triglyceride, low-density lipoproteins, free fatty acids, and fasting blood glucose. CONCLUSION: Surgical fat removal exerts several metabolic benefits in the short term, but only improvements in insulin sensitivity last beyond 6 months.

Metabolic aspects of surgical subcutaneous fat removal: An umbrella review and implications for future research.

Although obesity is a preventable disease, maintaining a normal body weight can be very challenging and difficult, which has led to a significant increase in the demand for surgical subcutaneous fat removal (SSFR) to improve physical appearance. The need for SSFR is further exacerbated because of the global rise in the number of bariatric surgeries, which is currently the single most durable intervention for mitigating obesity. Fat tissue is now recognized as a vital endocrine organ that produces several bioactive proteins. Thus, SSFR-mediated weight (fat) loss can potentially have significant metabolic effects; however, currently, there is no consensus on this issue. This review focuses on the metabolic sequelae after SSFR interventions for dealing with cosmetic body appearance. Data was extracted from existing systematic reviews and the diversity of possible metabolic changes after SSFR are reported along with gaps in the knowledge and future directions for research and practice. We conclude that there is a potential for metabolic sequelae after SSFR interventions and their clinical implications for the safety of the procedures as well as for our understanding of subcutaneous adipose tissue biology and insulin resistance are discussed.

MicroRNA Changes Up to 24 h following Induced Hypoglycemia in Type 2 Diabetes.

Hypoglycemia, as a complication of type 2 diabetes (T2D), causes increased morbidity and mortality but the physiological response underlying hypoglycemia has not been fully elucidated. Small noncoding microRNA (miRNA) have multiple downstream biological effects. This pilot exploratory study was undertaken to determine if induced miRNA changes would persist and contribute to effects seen 24 h post-hypoglycemia. A parallel, prospective study design was employed, involving T2D (n = 23) and control (n = 23) subjects. The subjects underwent insulin-induced hypoglycemia (2 mmol/L; 36 mg/dL); blood samples were drawn at baseline, upon the induction of hypoglycemia, and 4 h and 24 h post-hypoglycemia, with a quantitative polymerase chain reaction analysis of miRNA undertaken. The baseline miRNAs did not differ. In the controls, 15 miRNAs were downregulated and one was upregulated (FDR < 0.05) from the induction of hypoglycemia to 4 h later while, in T2D, only four miRNAs were altered (downregulated), and these were common to both cohorts (miR-191-5p; miR-143-3p; let-7b-5p; let-7g-5p), correlated with elevated glucagon levels, and all were associated with energy balance. From the induction of hypoglycemia to 24 h, 14 miRNAs were downregulated and 5 were upregulated (FDR < 0.05) in the controls; 7 miRNAs were downregulated and 7 upregulated (FDR < 0.05) in T2D; a total of 6 miRNAs were common between cohorts, 5 were downregulated (miR-93-5p, let-7b-5p, miR-191-5p, miR-185-5p, and miR-652-3p), and 1 was upregulated (miR-369-3p). An ingenuity pathway analysis indicated that many of the altered miRNAs were associated with metabolic and coagulation pathways; however, of the inflammatory proteins expressed, only miR-143-3p at 24 h correlated positively with tumor necrosis factor-α (TNFa; p < 0.05 and r = 0.46) and negatively with toll-like receptor-4 (TLR4; p < 0.05 and r = 0.43). The MiRNA levels altered by hypoglycemia reflected changes in counter-regulatory glucagon and differed between cohorts, and their expression at 24 h suggests miRNAs may potentiate and prolong the physiological response. Trial registration: ClinicalTrials.gov NCT03102801.

Scenarios to Improve the Patient Experience Time in a Tertiary Academic Hospital Using Simulation.

Background Shortening the patient experience time (PET) in the emergency department (ED) improves patient quality and satisfaction and reduces mortality and morbidity. Worldwide, the PET target in the ED is ≤ 6 hours; however, the PET awaiting admission to inpatient Medicine at Hamad General Hospital (HGH) in the Qatar State, through ED is currently 15.3±6.4 (mean ± SD) hours. Aim Identify solutions to reduce the PET duration at HGH-ED to the international target. Method A cohort study was done using the Discrete-event simulation (DES) model, utilizing a commercial simulation software package (Process Model Inc., Utah, version 5.2.0). One-year data, January 1, 2019 - December 30, 2019, was analyzed and found to follow seven subprocesses. The duration of each subprocess was recorded, and the average time was calculated. A computer simulation scheme was developed for all the subprocesses of the actual PET duration. The simulated PET was validated, and scenarios were proposed and assessed for each subprocess separately and in combination, A constructed simulatory design using an iterative process involving a construction model. This model starts with the logical organization of submitted tasks based on their cycle times. A subject-matter expert interview was conducted to determine the appropriateness and frequency of actions. The duration of each activity in the considered process was defined using a triangular distribution. Results The actual PET duration for the Medical Department was 15.3±6.4 (mean + SD) hours. The three most prolonged PET subprocess durations were in the referral to internal medicine, the decision to admit, and finding a free bed; these represent 17.9%, 53.8%, and 16.7% of the PET, respectively. Adding two physicians to each shift, which shortens the subprocess of the decision to admit, reduced the PET duration by 27.5%. Moreover, creating a new admitting team (unit) that takes care of new patients admitted to the ED reduced PET duration by another 12.5%. Combining these two scenarios reduced the average PET duration to only 10.2±0.5 hours. In addition to these scenarios, the PET can be further decreased to six hours by increasing the number of inpatient beds. Conclusions The simulated scenarios indicated that restructuring the medical teams, adding two physicians to each shift, and creating an admissions team dedicated to the ED would reduce the total PET duration to 10.2 hours, Furthermore, PET's further reduction to six hours is predictable by increasing the bed number.

Metabolic and proteomic signatures of type 2 diabetes subtypes in an Arab population.

Type 2 diabetes (T2D) has a heterogeneous etiology influencing its progression, treatment, and complications. A data driven cluster analysis in European individuals with T2D previously identified four subtypes: severe insulin deficient (SIDD), severe insulin resistant (SIRD), mild obesity-related (MOD), and mild age-related (MARD) diabetes. Here, the clustering approach was applied to individuals with T2D from the Qatar Biobank and validated in an independent set. Cluster-specific signatures of circulating metabolites and proteins were established, revealing subtype-specific molecular mechanisms, including activation of the complement system with features of autoimmune diabetes and reduced 1,5-anhydroglucitol in SIDD, impaired insulin signaling in SIRD, and elevated leptin and fatty acid binding protein levels in MOD. The MARD cluster was the healthiest with metabolomic and proteomic profiles most similar to the controls. We have translated the T2D subtypes to an Arab population and identified distinct molecular signatures to further our understanding of the etiology of these subtypes.

Dysregulated Metabolic Pathways in Subjects with Obesity and Metabolic Syndrome.

Background: Obesity coexists with variable features of metabolic syndrome, which is associated with dysregulated metabolic pathways. We assessed potential associations between serum metabolites and features of metabolic syndrome in Arabic subjects with obesity. Methods: We analyzed a dataset of 39 subjects with obesity only (OBO, n = 18) age-matched to subjects with obesity and metabolic syndrome (OBM, n = 21). We measured 1069 serum metabolites and correlated them to clinical features. Results: A total of 83 metabolites, mostly lipids, were significantly different (p < 0.05) between the two groups. Among lipids, 22 sphingomyelins were decreased in OBM compared to OBO. Among non-lipids, quinolinate, kynurenine, and tryptophan were also decreased in OBM compared to OBO. Sphingomyelin is negatively correlated with glucose, HbA1C, insulin, and triglycerides but positively correlated with HDL, LDL, and cholesterol. Differentially enriched pathways include lysine degradation, amino sugar and nucleotide sugar metabolism, arginine and proline metabolism, fructose and mannose metabolism, and galactose metabolism. Conclusions: Metabolites and pathways associated with chronic inflammation are differentially expressed in subjects with obesity and metabolic syndrome compared to subjects with obesity but without the clinical features of metabolic syndrome.

Elevated Adipsin and Reduced C5a Levels in the Maternal Serum and Follicular Fluid During Implantation Are Associated With Successful Pregnancy in Obese Women.

Introduction: Complement factors mediate the recruitment and activation of immune cells and are associated with metabolic changes during pregnancy. The aim of this study was to determine whether complement factors in the maternal serum and follicular fluid (FF) are associated with in vitro fertilization (IVF) outcomes in overweight/obese women. Methods: Forty overweight/obese (BMI = 30.8 ± 5.2 kg/m2) female patients, 33.6 ± 6.3 years old, undergoing IVF treatment for unexplained infertility were recruited. Baseline demographic information, including biochemical hormonal, metabolic, and inflammatory markers, and pregnancy outcome, was collected. Levels of 14 complement markers (C2, C4b, C5, C5a, C9, adipsin, mannose-binding lectin, C1q, C3, C3b/iC3b, C4, factor B, factor H, and properdin) were assessed in the serum and FF and compared to IVF outcome, inflammatory, and metabolic markers using multivariate and univariate models. Results: Out of 40 IVF cycles, 14 (35%) resulted in pregnancy. Compared to women with failed pregnancies, women with successful pregnancies had higher levels of adipsin in the serum and FF (p = 0.01) but lower C5a levels (p = 0.05). Serum adipsin levels were positively correlated with circulating levels of vitamin D (R = 0.5, p = 0.02), glucagon (R = 0.4, p = 0.03), leptin (R = 0.4, p = 0.01), resistin (R = 0.4, p = 0.02), and visfatin (R = 0.4, p = 0.02), but negatively correlated with total protein (R = -0.5, p = 0.03). Higher numbers of top-quality embryos were associated with increased levels of C3, properdin, C1q, factors H and B, C4, and adipsin, but with reduced C2 and C5a levels (p ≤ 0.01). Conclusions: Higher adipsin and lower C5a levels in the maternal serum during implantation are potential markers of successful outcome in obese women undergoing IVF-assisted pregnancies.