A Review of the Impact of Pharmacogenetics and Metabolomics on the Efficacy of Metformin in Type 2 Diabetes.

Metformin is the most often prescribed drug for people with type 2 diabetes (T2D). More than 120 million patients with T2D use metformin worldwide. However, monotherapy fails to achieve glycemic control in a third of the treated patients. Genetics contribute to some of the inter-individual variations in glycemic response to metformin. Numerous pharmacogenetic studies have demonstrated that variations in genes related to pharmacokinetics and pharmacodynamics of metformin's encoding transporters are mainly associated with metformin response. The goal of this review is to evaluate the current state of metformin pharmacogenetics and metabolomics research, discuss the clinical and scientific issues that need to be resolved in order to increase our knowledge of patient response variability to metformin, and how to improve patient outcomes. Metformin's hydrophilic nature and absorption as well as its action mechanism and effectiveness on T2D initiation are discussed. The impacts of variations associated with various genes are analysed to identify and evaluate the effect of genetic polymorphisms on the therapeutic activity of metformin. The metabolic pattern of T2D and metformin is also indicated. This is to emphasise that studies of pharmacogenetics and metabolomics could expand our knowledge of metformin response in T2D.

Hemin-Modified Multi-Walled Carbon Nanotube-Incorporated PVDF Membranes: Computational and Experimental Studies on Oil-Water Emulsion Separations.

The separation of oil/water emulsions has attracted considerable attention for decades due to the negative environmental impacts brought by wastewater. Among the various membranes investigated for separation, polyvinylidene fluoride (PVDF) membranes have shown significant advantages of ease of fabrication, high selectivity, and fair pore distribution. However, PVDF membranes are hydrophobic and suffer from severe fouling resulting in substantial flux decline. Meanwhile, the incorporation of wettable substrates during fabrication has significantly impacted the membrane performance by lowering the fouling propensity. Herein, we report the fabrication of an iron-containing porphyrin (hemin)-modified multi-walled carbon nanotube incorporated PVDF membrane (HA-MWCNT) to enhance fouling resistance and the effective separation of oil-in-water emulsions. The fabricated membrane was thoroughly investigated using the FTIR, SEM, EDX, AFM, and contact angle (CA) analysis. The HA-MWCNT membrane exhibited a water CA of 62° ± 0.5 and excellent pure water permeance of 300.5 L/m2h at 3.0 bar (400% increment), in contrast to the pristine PVDF, which recorded a CA of 82° ± 0.8 and water permeance of 59.9 L/m2h. The hydrophilic HA-MWCNT membrane further showed an excellent oil rejection of >99% in the transmembrane pressure range of 0.5−2.5 bar and a superb flux recovery ratio (FRR) of 82%. Meanwhile, the classical molecular dynamics (MD) simulations revealed that the HA-MWCNT membrane had greater solvent-accessible pores, which enhanced water permeance while blocking the hydrocarbons. The incorporation of the hemin-modified MWCNT is thus an excellent strategy and could be adopted in the design of advanced membranes for oil/water separation.

Molecular Engineering of E. coli Bacterioferritin: A Versatile Nanodimensional Protein Cage.

Currently, intense interest is focused on the discovery and application of new multisubunit cage proteins and spherical virus capsids to the fields of bionanotechnology, drug delivery, and diagnostic imaging as their internal cavities can serve as hosts for fluorophores or bioactive molecular cargo. Bacterioferritin is unusual in the ferritin protein superfamily of iron-storage cage proteins in that it contains twelve heme cofactors and is homomeric. The goal of the present study is to expand the capabilities of ferritins by developing new approaches to molecular cargo encapsulation employing bacterioferritin. Two strategies were explored to control the encapsulation of a diverse range of molecular guests compared to random entrapment, a predominant strategy employed in this area. The first was the inclusion of histidine-tag peptide fusion sequences within the internal cavity of bacterioferritin. This approach allowed for the successful and controlled encapsulation of a fluorescent dye, a protein (fluorescently labeled streptavidin), or a 5 nm gold nanoparticle. The second strategy, termed the heme-dependent cassette strategy, involved the substitution of the native heme with heme analogs attached to (i) fluorescent dyes or (ii) nickel-nitrilotriacetate (NTA) groups (which allowed for controllable encapsulation of a histidine-tagged green fluorescent protein). An in silico docking approach identified several small molecules able to replace the heme and capable of controlling the quaternary structure of the protein. A transglutaminase-based chemoenzymatic approach to surface modification of this cage protein was also accomplished, allowing for future nanoparticle targeting. This research presents novel strategies to control a diverse set of molecular encapsulations and adds a further level of sophistication to internal protein cavity engineering.

The Effect of Genetic Variants of SLC22A2 (rs662301 and rs315978) on the response to Metformin in type 2 Saudi diabetic patients.

PURPOSE: To investigate the allelic and genotypic frequencies of the two genetic variations, NC_000006.12: g.160275887C > T (rs662301) and NC_000006.12:g.160231826 T > C (rs315978), in the SLC22A2 gene among the Saudi population. The primary goal is to elucidate potential associations with these genetic variations and the response to metformin therapy over 6 months to enhance our knowledge of the genetic basis of Type 2 Diabetes Mellitus (T2DM) and its clinical management in the Saudi population. MATERIALS/METHODS: 76 newly diagnosed T2DM patients, aged 30 to 60, of both sexes and Saudi origin, were treated with metformin monotherapy. Blood samples were collected before and after 6 months of therapy,80 healthy individuals were included as controls. Genomic DNA was extracted. Genotyping of the SLC22A2 genetic variations was performed using TaqMan® SNP Genotyping Assays. Binary logistic regression was utilized to evaluate how certain clinical parameters influence T2DM concerning the presence of SLC22A2 gene variants. RESULTS: Among these patients, 73.3 % were responders, and 26.7 % were non-responders. For these variants, no statistically significant differences in genotype or allele frequencies were observed between responders and non-responders (p = 0.375 and p = 0.384 for rs662301; p = 0.473 and p = 0.481 for rs315978, respectively). For the SLC22A2 variant rs662301, the C/C genotype was significantly associated with increased T2DM risk with age and elevated HbA1c levels. Similarly, rs315978 revealed higher T2DM susceptibility and HbA1c elevation in C/C genotype carriers, specifically with advancing age compared to individuals with C/T and T/T genotypes. CONCLUSION: The study offers insights into the genetic landscape of T2DM in Saudi Arabia. Despite the absence of significant associations with treatment response, the study suggests potential age-specific associations, this highlights the complexity of the disease. This research underscores the necessity for expanded research, considering diverse populations and genetic factors, to develop personalized treatment approaches. This study serves as a foundation for future investigations into the Saudi population, recognizing the need for a larger sample size.

Laparoscopic mesh placement during inguinal hernia repair: a meta-analysis of two methods of repair.

BACKGROUND: There are several modifications in the technique for the placement of mesh during laparoscopic inguinal hernia repair. One of these is a slit on the mesh to surround the cord structures which proponents of it suggest that it decreases the recurrence rate due to better anchoring of the mesh and lower risk of displacement. There is only low-level evidence in current literature examining the two methods. The present study aimed to provide stronger evidence in establishing whether the slit mesh technique is superior to the non-slit mesh technique. METHODS: The reporting of this systematic review was guided by the standards of the preferred reporting items for systematic review and meta-analysis statement and registered with PROSPERO (ID: CRD42022300629). Eligible studies had to compare the two methods of mesh placement slit Vs nonslit in laparoscopic Inguinal hernia repair and also report on at least one outcome. The outcomes were expressed in odd ratios with their 95% confidence intervals. Where significant heterogeneity existed a random effects model was used otherwise a fixed effects model was used. RESULTS: Five studies met the criteria for inclusion in quantitative analysis. Overall, there were 10 (1.5%) recurrences in the slit group compared to 12 (2.5%) in the non-slit group OR 0.62, 95% CI (0.27-1.41). There was no difference in the incidence of post-operative bleeding (OR 1.21, 95%CI 0.4-3.66), seroma formation (OR1.5, 95% CI 0.81-2.76), or post-operative neuralgia (OR 0.98, 95%CI 0.11-8.92) between the two groups. CONCLUSION: There was no difference between the two methods.

Changes in the Emergency General Surgery Operations in the Setting of COVID-19 and Impact of Strategy of Non-Operative Management on Outcomes in Acute Appendicitis.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has posed significant challenges to the provision of elective and emergency general surgical care. Patterns of presentation have changed and management pathways have also been adapted, moving to more non-operative management (NOM) for some conditions. We investigated how COVID-19 changed the volume of emergency general surgery operating in our district general hospital (DGH). We aimed to evaluate the impact of NOM on outcomes in acute appendicitis. METHODS: A retrospective case review of operating lists, patient handover lists, and patient notes was undertaken for patients presented between 1st January 2020 and 3rd June 2020. The study period was divided into two, with the period between 1st January 2020 and 23rd March 2020 representing the pre-COVID cohort. RESULTS: Some 393 emergency general surgery operations were performed in the study period. There was a clear reduction in operating volume after 23rd March 2020. During that same period, 325 patients were assessed with right iliac fossa (RIF) pain. Median age was 21 (range 5-87) and 201 patients were female (61.8%). The rate of NOM for suspected acute appendicitis was 8.8% in the pre-COVID group, which increased to 36.4% in the COVID group. The incidence of normal histology following appendicectomy did not change with this difference in management (16.1% compared to 17.9%, p = 0.78). CONCLUSIONS: This study summarizes the changes brought to the provision of emergency general surgery in the setting of a DGH by the COVID-19 pandemic. In particular, NOM was the preferred option for acute appendicitis but this did not alter the negative appendicectomy rate.

Corrigendum: A new gender-specific model for skin autofluorescence risk stratification.

This corrects the article DOI: 10.1038/srep10198.

A new gender-specific model for skin autofluorescence risk stratification.

Advanced glycation endproducts (AGEs) are believed to play a significant role in the pathophysiology of a variety of diseases including diabetes and cardiovascular diseases. Non-invasive skin autofluorescence (SAF) measurement serves as a proxy for tissue accumulation of AGEs. We assessed reference SAF and skin reflectance (SR) values in a Saudi population (n = 1,999) and evaluated the existing risk stratification scale. The mean SAF of the study cohort was 2.06 (SD = 0.57) arbitrary units (AU), which is considerably higher than the values reported for other populations. We show a previously unreported and significant difference in SAF values between men and women, with median (range) values of 1.77 AU (0.79-4.84 AU) and 2.20 AU (0.75-4.59 AU) respectively (p-value « 0.01). Age, presence of diabetes and BMI were the most influential variables in determining SAF values in men, whilst in female participants, SR was also highly correlated with SAF. Diabetes, hypertension and obesity all showed strong association with SAF, particularly when gender differences were taken into account. We propose an adjusted, gender-specific disease risk stratification scheme for Middle Eastern populations. SAF is a potentially valuable clinical screening tool for cardiovascular risk assessment but risk scores should take gender and ethnicity into consideration for accurate diagnosis.

Perceptions of medical students towards antibiotic prescribing for upper respiratory tract infections in Saudi Arabia.

INTRODUCTION: This survey evaluates knowledge, attitudes and practices of medical students towards use of antibiotics for upper respiratory infections (URTIs). METHODOLOGY: Cross-sectional questionnaire study among 1042 randomly selected medical students in Saudi Arabia. RESULTS: Respondents were mostly Saudis (97.5%), had previous knowledge of antibiotics (99.7%) and their usage (98.3%) against bacterial infections (93.7%). 18.1% thought that they could be used for viral infections. Nearly all students (97.2%) used antibiotics themselves during the previous year and self-medication without a prescription was high at 49% of cases. Most antibiotics were taken for URTI symptoms (61.8%). Female medical students had better knowledge on antibiotic effectiveness against bacteria and viruses, and overall knowledge increased with study year. Health seeking behaviour rates for symptoms of RTI and associated estimated necessity for antibiotics varied but were highest for cough with yellow/green phlegm. CONCLUSIONS: The depth of knowledge that healthcare professionals have in relation to the proper use of antibiotics is essential in spreading the right message within communities. This is the first large study among medical students in Saudi Arabia, shedding important light on areas for improvement in the medical curriculum as well as antibiotic practices of medical students themselves.

ATR-FTIR spectroscopy detects alterations induced by organotin(IV) carboxylates in MCF-7 cells at sub-cytotoxic/-genotoxic concentrations.

The environmental impact of metal complexes such as organotin(IV) compounds is of increasing concern. Genotoxic effects of organotin(IV) compounds (0.01 mug/ml, 0.1 mug/ml or 1.0 mug/ml) were measured using the alkaline single-cell gel electrophoresis (comet) assay to measure DNA single-strand breaks (SSBs) and the cytokinesis-block micronucleus (CBMN) assay to determine micronucleus formation. Biochemical-cell signatures were also ascertained using attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy. In the comet assay, organotin(IV) carboxylates induced significantly-elevated levels of DNA SSBs. Elevated micronucleus-forming activities were also observed. Following interrogation using ATR-FTIR spectroscopy, infrared spectra in the biomolecular range (900 cm-1 - 1800 cm-1) derived from organotin-treated MCF-7 cells exhibited clear alterations in their biochemical-cell fingerprint compared to control-cell populations following exposures as low as 0.0001 mug/ml. Mono-, di- or tri-organotin(IV) carboxylates (0.1 mug/ml, 1.0 mug/ml or 10.0 mug/ml) were markedly cytotoxic as determined by the clonogenic assay following treatment of MCF-7 cells with >/= 1.0 mug/ml. Our results demonstrate that ATR-FTIR spectroscopy can be applied to detect molecular alterations induced by organotin(IV) compounds at sub-cytotoxic and sub-genotoxic concentrations. This biophysical approach points to a novel means of assessing risk associated with environmental contaminants.PACS codes: 87.15.-v, 87.17.-d, 87.18.-h.