Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 agonists as potential neuroprotective agents

Repositioning of dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists is a breakthrough in the field of neural regeneration research increasing glucagon like peptide-1 bioavailability, hence its neuroprotective activities. In this article, the authors suggest not only crossing blood-brain barrier and neurodegenerative disease as off target for dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists, but also for ophthalmic preparations for diabetic retinopathy, which may be the latest breakthrough in the field if prepared and used in an appropriate nano-formulation to target the retinal nerves. The relation of neurodegenerative diseases’ different mechanisms to the dipeptidyl peptidase-4 inhibitors and glucagon like peptide-1 receptor agonists should be further examined in preclinical and clinical settings. The repositioning of already marketed antidiabetic drugs for neurodegenerative diseases should save the high cost of the time-consuming normal drug development process. Drug repositioning is a hot topic as an alternative to molecular target based drug discovery or therapeutic switching. It is a relatively inexpensive pathway due to availability of previous pharmacological and safety data. The glucagon like peptide-1 produced in brain has been linked to enhanced learning and memory functions as a physiologic regulator in central nervous system by restoring insulin signaling. Intranasal administration of all marketed gliptins (or glucagon like peptide-1 receptor agonists) may show enhanced blood-brain barrier crossing and increased glucagon like peptide-1 levels in the brain after direct crossing of the drug for the olfactory region, targeting the cerebrospinal fluid. Further blood-brain barrier crossing tests may extend dipeptidyl peptidase-4 inhibitors’ effects beyond the anti-hyperglycemic control to intranasal spray, intranasal powder, or drops targeting the blood-brain barrier and neurodegenerative diseases with the most suitable formula. Moreover, novel nano-formulation is encouraged either to obtain favorable pharmacokinetic parameters or to achieve promising blood-brain barrier penetration directly through the olfactory region. Many surfactants should be investigated either as a solubilizing agent for hydrophobic drugs or as penetration enhancers. Different formulae based on in vitro and in vivo characterizations, working on sister gliptins (or glucagon like peptide-1 receptor agonists), different routes of administration, pharmacokinetic studies, dose response relationship studies, monitoring of plasma/brain concentration ratio after single and multiple dose, and neurodegenerative disease animal models are required to prove the new method of use (utility) for dipeptidyl peptidase-4 inhibitors as potential neuroprotective agents. Furthermore, investigations of glucagon like peptide-1 receptor agonists’ neuroprotective effects on animal models will be considered carefully because they crossed the blood-brain barrier in previous studies, enabling their direct action on the central nervous system. Combination therapy of dipeptidyl peptidase-4 inhibitors or glucagon like peptide-1 receptor agonists with already marketed drugs for neurodegenerative disease should be considered, especially regarding the novel intranasal route of administration

A new flat shell finite element for the linear analysis of thin shell structures

In this paper, a new rectangular flat shell element denoted ‘ACM_RSBE5’ is presented. The new element is obtained by superposition of the new strain-based membrane element ‘RSBE5’ and the well-known plate bending element ‘ACM’. The element can be used for the analysis of any type of thin shell structures, even if the geometry is irregular. Comparison with other types of shell elements is performed using a series of standard test problems. A correlation study with an experimentally tested aluminium shell is also conducted. The new shell element proved to have a fast rate of convergence and to provide accurate results

Polypharmacy among patients with hypertension attending primary healthcare centres

Introduction: Saudi Arabia has several hypertensive patients who require close attention and specialised care for their medications. Polypharmacy is one of the reasons for the failure of patient compliance with antihypertensive medications. Therefore, this study aims to gain a better perspective on polypharmacy in hypertensive patients attending primary healthcare (PHC) centres in Makkah, Saudi Arabia. Methods: This was an observational, cross-sectional, descriptive study of hypertensive patients followed up at 10 PHC centres in Makkah, Saudi Arabia, from 1 July 2019 to 30 June 2022. Frequencies and percentages were used to present categorical data, and Pearson’s χ2 test was used to measure differences. A P value less than 0.05 was considered statistically significant. Results: A total of 506 patients were included in this study. The mean age of the patients was 60 years, and more than half (69%) were females. Regarding antihypertensive medication use, 64% were on antihypertensive combination therapy, 76% on dual therapy, 21% on triple therapy, and 3% on quadruple therapy. Moreover, 21% of the hypertensive patients were exposed to polypharmacy. There was a significant relationship (P<0.001) between the overall number of chronic medications used per day and the duration of hypertension. Conclusion: More clinical research is needed to identify the impact of polypharmacy on the quality of healthcare in PHC centres in general and hypertensive patients specifically in different regions of Saudi Arabia

Role of L- glutamine and crizanlizumab in sickle cell anaemia painful crisis reduction

BackgroundPatients with sickle cell disease, frequently ‎ suffer from intense painful episodes. Till recently hydroxyurea was the only available medical therapy that approved for reduction of painful episodes.AimsTo summarize the available data from randomized controlled trials that aim to evaluate the efficacy of newly approved L-‎glutamine‎ (alters redox state of red blood cells ‎‎[RBCs]) ‎and ‎crizanlizumab (‎(anti-P-selectin)‎)‎ ‎on vaso-occlusive episodes in Sickle cell disease ‎ patients.Methods PubMed, ‎Google Scholar, and EBSCO ‎ databases were ‎‎systematically search for relevant articles. The terms ‎ ‎ ‎ L-glutamine, sickle cell disease, sickle cell ‎anaemia,‎ ‎‎crizanlizumab ‎and vaso-occlusive episodes‎ were used.Results Out of Four-hundred seventy-two records, only three fulfilled the inclusion criteria. Two trials were aimed to evaluate the efficacy of L-glutamine therapy on the frequency of painful crises in sickle cell anaemia patients. Both studies showed that L-glutamine therapy significantly reduce the frequency of VOEs. Only one trial examined the ability of crizanlizumab on VOEs reduction, and showed crizanlizumab successful reduce the occurrence of VOEs.‎ConclusionNewer agent ‎with different mechanism of action, such as ‎L-glutamine, ‎and crizanlizumab may consider if ‎hydroxyurea not effective or not ‎tolerable

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

Background Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide.Methods A multimethods analysis was performed as part of the GlobalSurg 3 study-a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital.Findings Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3.85 [95% CI 2.58-5.75]; p<0.0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63.0% vs 82.7%; OR 0.35 [0.23-0.53]; p<0.0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer.Interpretation Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Studying the effect of intrastromal anti-vascular endothelial growth factor injections on corneal neovascularization using optical coherence tomography angiography

Purpose To evaluate the effect of intrastromal injection of anti-vascular endothelial growth factor (Anti-VEGF) on corneal neovascularization using spectral domain Optical coherence tomography angiography imaging (OCTA). Patients and methods This is a pilot study that was conducted on 10 eyes of 10 patients with corneal neovascularization who were planned for keratoplasty or after keratoplasty. Intrastromal injection of 5 mg/0.2 ml [2.5%] bevacizumab using a 30 Gauge needle was performed. OCTA was done 48 h before the injection, 1 week and 1 month after the injection. OCTA images were compared to evaluate the effect of Anti-VEGF on corneal neovascularization. Results Comparing the OCTA pictures with the preoperative period, at 1 week period, 9 cases have shown decreased corneal neovascularization, with only 1 case that has not changed and seemed to be unresponsive to the single injection of Anti-VEGF. At 1 month period, 8 cases re-vascularized again but none of them reached the preoperative level, 1 case had decreased vascularization (completely disappeared) and 1 case remained the same with no change. Conclusion A single injection of bevacizumab has a temporal effect on corneal neovascularization. No local or systemic complications have been noted. OCTA was able to visualize vessels in 3-D image, even under vascularized corneal scars. OCTA was able to recognize subtle changes in corneal neovascularization that were not visible by slit lamp

An investigative study on the zoonotic potential of Helicobacter pylori

Abstract Background Helicobacter pylori is one of the most common bacterial infections and is widespread globally. It causes a variety of gastrointestinal disorders, though a great proportion of infections are asymptomatic. A total of 143 fresh stool samples were collected from apparently healthy farm and pet animals (43 cattle, 50 buffaloes, 50 sheep, 50 dogs, and 50 cats), in addition to 768 human stool samples. The samples were examined using stool antigen and rapid antibody tests, and further confirmation of glmM “human antigen-positive samples and animal milk samples” was conducted by polymerase chain reaction (PCR). Results The prevalence rates of H. pylori infection in animals were 22.2% and 16% in antibody and stool antigen tests, respectively. The detection rates were 28%, 24%, 12%, 10%, and 4.7% in cats, dogs, buffaloes, sheep, and cattle, respectively. On the other hand, the prevalence rate of H. pylori infection in human stool samples was 74.8%, and a statistically significant association was observed between prevalence and several factors, such as sex, age, and locality. PCR was performed to detect the glmM gene of H. pylori, and this gene was found in 21 of 27 human antigen-positive samples and 5 of 13 animal milk samples. Conclusions H. pylori was detected in both human and animal samples. Furthermore, glmM was found in milk and human samples. Our findings suggest that pet and farm animals could transmit H. pylori infection to humans

Impacts of Heat Stress on Some Performance Parameters of Broiler Chicken Reared Under Different Stocking Densities

The current study was designed to investigate the impacts of heat stress (HS) on performance parameters of broiler chicken reared at different stocking densities, also study assessed the effects of anti-stress (vitamin) supplementation in the mitigation of different levels of stress. A total of 720 7th-day-old Cobb ® chicks were randomly distributed into 18 groups, (two replicates within each group). The experiment with a factorial arrangement of treatments (3x3x2), 3 levels of stocking densities (RSD: 10 chicks/m2, MSD: 14 chicks/m2, and HSD: 18 chicks/m2), 2 levels of vitamin supplementation (0 mg/l and combination of 250 mg/l ascorbic acid plus 0.5 ml/l Vit E + Se) and three temperatures (Thermoneutral temperature (TN), sudden chronic heat stress exposure (CHS) and gradual chronic heat stress exposure). Broilers were kept either under thermoneutral conditions (24 ± 1 ºC) during the whole life period or slowly introduced to CHS from 7th to 21st d of age and kept at high temperature thereafter and the third chamber had chicks that were exposed to CHS (32 ± 2 ºC for 8 h/day) during the period from 21st: 42nd day of age. Chicks were reared on a deep litter system and had free access to feed and water. Performance parameters (FI, BW, BWG, and FCR) were determined on the 42nd day of age. The results showed HSD had adverse effects on the growth performance of broilers reared under thermoneutral or CHS conditions where the differences between densities were significant (P&lt;0.05) under TN and sudden CHS conditions and insignificant in case of gradual CHS exposure conditions for most of the performance parameters. Vitamins supplementation had improved growth performance (BW and FCR) of broilers kept under MSD or HSD and exposed to thermoneutral or sudden CHS conditions as compared to corresponding not supplemented birds. While it was effective in combating the adverse effects of gradual HS exposure in RSD and MSD kept broilers only. In addition, there was no significant difference between RSD not supplemented broilers and MSD-supplemented birds under TN conditions; concluding that broilers can be stocked at MSD under thermoneutral conditions if they were supplemented with vitamins. &nbsp

Avoiding COVID-19 complications with diabetic patients could be achieved by multi-dose Bacillus Calmette–Guérin vaccine: A case study of beta cells regeneration

© 2020 Govi-Verlag Pharmazeutischer Verlag GmbH. All rights reserved. Diabetes mellitus (DM) is one of the major risk factors for COVID-19 complications as it is one of the chronic immune-compromising conditions especially if patients have uncontrolled diabetes, poor HbA1c and/or irregular blood glucose levels. Diabetic patients’ mortality rates with COVID-19 are higher than those of cardiovascular or cancer patients. Recently, Bacillus Calmette-Guérin (BCG) vaccine has shown successful results in reversing diabetes in both rats and clinical trials based on different mechanisms from aerobic glycolysis to beta cells regeneration. BCG is a multi-face vaccine that has been used extensively in protection from tuberculosis (TB) and leprosy and has been repositioned for treatment of bladder cancer, diabetes and multiple sclerosis. Recently, COVID-19 epidemiological studies confirmed that universal BCG vaccination reduced morbidity and mortality in certain geographical areas. Countries without universal policies of BCG vaccination (Italy, Nederland, USA) have been more severely affected compared to countries with universal and long-standing BCG policies that have shown low numbers of reported COVID-19 cases. Some countries have started clinical trials that included a single dose BCG vaccine as prophylaxis from COVID-19 or an attempt to minimize its side effects. This proposed research aims to use BCG vaccine as a double-edged weapon countering both COVID-19 and diabetes, not only as protection but also as therapeutic vaccination. The work includes a case study of regenerated pancreatic beta cells based on improved C-peptide and PCPRI laboratory findings after BCG vaccination for a 9 year old patient. The patient was re-vaccinated based on a negative tuberculin test and no scar at the site of injection of the 1st BCG vaccination at birth. The authors suggest and invite the scientific community to take into consideration the concept of direct BCG re-vaccination (after 4 weeks) because of the reported gene expressions and exaggerated innate immunity consequently. As the diabetic MODY-5 patient (mutation of HNF1B, Val2Leu) was on low dose Riomet® while eliminating insulin gradually, a simple analytical method for metformin assay was recommended to ensure its concentration before use as it is not approved yet by the Egyptian QC labs