Coumarin-amino acid hybrids as promising anticancer agents: design, synthesis, docking studies and CK2 inhibition.

A series of mono-peptide, di-peptide and tri-peptide derivatives linked to a coumarin scaffold (5a-c, 7a-c, and 9a-c) were synthesized via the azide-coupling method from corresponding hydrazides 4, 6, and 8. These compounds were tested for anticancer activity against HepG-2, PC-3, and Hct-116 cell lines. Compounds, 7c, and 5b showed significant cytotoxicity, outperforming doxorubicin, with IC50 values of 34.07, 16.06, and 16.02 µM for 7c and 42.16, 59.74, and 35.05 µM for 5b. Compound 7b also displayed promising results with IC50 values of 72.13, 70.82, and 61.01 µM. Moreover, the key structural features of amino acids indicated that mono-peptide and di-peptide derivatives play a key role in increasing their anticancer activities compared with tri-peptides. In addition, the most potent compound 5b also exhibited strong CK2 kinase inhibition with an IC50 value of 0.117 ± 0.005 µM compared with roscovetine as a control drug with an IC50 value of 0.251 ± 0.011 µM. Finally, the binding mode of the chemical inhibitors at the active site of CK2 receptor was also investigated using a docking study which confirmed that the presence of the amino acid functionality is an important feature for anticancer activity and the synthesized compounds showed favorable ADME properties. Besides that, SAR analysis was implemented for the target compounds.

Analysis of BRCA1 germline variants (exons 5, 11 and 20) in breast cancer families from Libya.

Breast cancer (BC) is a leading cause of cancer deaths in Libyan women. BRCA1 variants differ globally due to the diversity of genetic makeup and populations history. Their distribution, prevalence, and significance in Libyans remain largely unexplored. This study investigated the characteristics and distribution of BRCA1 variants in exons 5, 11, and 20 in Libyan families with BC. Thirty-six BC patients at ≤ 45 years, between 46-50 years and with a family history of breast, ovarian, pancreatic or prostate cancer in close relatives, or with triple-negative BC, were selected from 33 unrelated families during 2018-2020 at the National Cancer Institute, Sabratha, Libya. From these 33 families, 20 women (18 BC patients and two unaffected) were screened for BRCA1 exons 5, 11 and 20 using Sanger sequencing. All families completed an epidemiology and family history questionnaire. Twenty-seven variants (26 in exon 11 and 1 in exon 20, minor allele frequency of < 0.01) were detected in 10 of 18 unrelated families (55.6%.) Among the 27 variants, 26 (96%) were heterozygous. A frameshift pathogenic variant, c.2643del, and one novel variant c.1366A>G were identified. Furthermore, seven variants with unknown clinical significance were detected: c.1158T>A, c.1346C>G, c.1174C>G, c.3630 G>T, c.3599A>T, and c.3400 G>C in exon 11, and c.5244T>A in exon 20. Six variants with conflicting pathogenicity interpretations, c. 3460T>A, c. 3572 G>A, c. 3700 G>C, c. 1246C>G, c. 1344C>G, and c. 1054 G>A, were also identified. Twelve benign/likely benign variants were identified. Rare BRCA1 variants that have not been reported in North Africa were found in Libyan patients. These findings provide preliminary insights into the BRCA1 variants that could contribute to hereditary BC risk in Libyans. Further functional, computational, and population analyses are essential to determine their significance and potential impact on BC risk, which could ultimately lead to more personalized management strategies.

Early vs late anticoagulation in acute ischemic stroke with indications outside atrial fibrillation.

BACKGROUND: Current literature lacks guidance on the safety of administering anticoagulation in acute ischemic stroke with emergent indications that require anticoagulation other than atrial fibrillation. Therefore, we tend to rely on studies investigating acute ischemic stroke in atrial fibrillation for anticoagulation recommendations. METHODS: We retrospectively reviewed data for patients with acute ischemic stroke who had a non-atrial fibrillation emergent indication for anticoagulation (e.g., intra-arterial thrombus, intracardiac thrombus, acute coronary syndrome, acute limb ischemia, deep vein thrombosis and pulmonary embolism) diagnosed within 3 days of acute ischemic stroke. Patients who received anticoagulation ≤ 3 days of stroke onset (Group A) were compared to those who either received it afterwards or did not receive it at all (Group B). RESULTS: Out of the 558 patients, only 88 patients met our inclusion criteria. Of the total cohort, 55.7 % patients were males, and basic demographics were similar in both groups except for milder strokes in Group A (national institute of health stroke scale 6 vs. 12.5, p = 0.03). Only 2 patients in Group A and 1 patient in Group B developed intracranial hemorrhage, which was not statistically significant. Group A patients had a lower incidence of both new diagnosis (2 % vs. 34.2 % %, p < 0.001) and propagation of an established venous thromboembolism. They also had a lower rate of any thromboembolic complication (2 % vs. 42 %, p < 0.001). CONCLUSION: Early anticoagulation (i.e., ≤ 3 days) in non-atrial fibrillation ischemic stroke patients with an emergent indication may be safe and carry a lower risk of thromboembolic complications than later anticoagulation.

Global perceived improvement and health-related quality of life after physical therapy in Lebanese patients with chronic non-specific low back pain.

BACKGROUND: The effectiveness of physical therapy (PT) in patients with chronic non-specific low back pain (CNSLBP) is mainly evaluated through pain, disability, and health-related quality of life (HRQOL). However, recent studies have recommended the consideration of improvement from patients' perspectives. OBJECTIVE: This study aimed to investigate the relationship between the global perception of improvement in Lebanese patients with CNSLBP who have undergone PT, the HRQOL levels, as well as pain intensity. METHODS: 132 patients with CNSLBP who have undergone PT completed a questionnaire consisting of sociodemographic and CNSLBP characteristics questions, pain intensity numeric scale (NRS), 12-Item Short-Form Health Survey (SF-12), and the Global Perceived Effect scale (GPE). Binary logistic regressions and Pearson correlation coefficient were used for analyses. RESULTS: Global perceived improvement of PT varies according to HRQOL levels. A significant correlation was found between pain intensity after PT, perceived improvement from PT, and HRQOL. Educational level and pain irradiation have been shown to be predictive factors of perceived improvement after PT. CONCLUSION: Pain and HRQOL are interrelated and contributed to elucidating the global perception of improvement after PT in patients with CNSLBP. The findings suggest that patients' global perception of improvement should be considered in evaluating the benefits of physical therapy in addition to pain and HRQOL.

Screening of interleukin 17F gene polymorphisms and eight subgingival pathogens in chronic periodontitis in Libyan patients.

Background: Chronic periodontitis (CP) is triggered by periodontal pathogens influenced by genetic and environmental factors. Recent studies have suggested that anti-inflammatory cytokines such as interleukin 17 (IL-17) play a prominent role in the pathogenesis of CP.Aim: This study aimed to investigate the association between eight sub-gingival pathogens and interleukin 17F (IL-17F) gene single nucleotide polymorphisms with CP among Libyans.Materials and Methods: A case-control study was conducted on 100 individuals between the ages of 25-65 years. Species-specific 16S rRNA primers for each pathogen were used in a multiplex PCR reaction to detect sub-gingival pathogens from a paper point sample. DNA was also extracted from buccal swab samples and IL-17F polymorphisms were detected by Sanger sequencing.Results: A highly significant association between the seven sub-gingival pathogens and CP, (p-value 0.0001) and a high prevalence of P. intermedia (100%), T. forsythia (96%), T. denticola and E. corrodens (92%), P. gingivalis (82%), C. rectus (74%), P. nigrescens (72%), A. actinomvcetcmcomitans (40%) were found in the case group compared with control group. A novel variant in the c. *34 G>A in IL-17F gene caused a change in glutamic amino acid to lysine amino acid, position on chromosome number (6) in the third exon, mRNA/genomic position 597, found in 14.6% of CP patients (p-value = 0.010) while the IL-17F (rs763780) SNP showed no association with CP (p-value = 0.334).Conclusion: P. intermedia appear as keystone pathogen for CP in the Libyan population. A novel variant in the IL-7F gene may be related to the severity of CP.

Evaluation of the selection of cerebrospinal fluid testing in suspected meningitis and encephalitis.

Diagnostic stewardship interventions can decrease unnecessary antimicrobial therapy and microbiology laboratory resources and costs. This retrospective cross-sectional study evaluated factors associated with inappropriate initial cerebrospinal fluid (CSF) testing in patients with suspected community-acquired meningitis or encephalitis. In 250 patients, 202 (80.8%) and 48 (19.2%) were suspected meningitis and encephalitis, respectively. 207 (82.8%) patients had inappropriate and 43 (17.2%) appropriate testing. Any inappropriate CSF test was greatest in the immunocompromised (IC) group (n = 54, 91.5%), followed by non-IC (n = 109, 80.1%) and HIV (n = 44, 80%). Ordering performed on the general ward was associated with inappropriate CSF test orders (adjOR 2.81, 95% CI [1.08-7.34]). Laboratory fee costs associated with excessive testing was close to $300,000 per year. A stepwise algorithm defining empiric and add on tests according to CSF parameters and patient characteristics could improve CSF test ordering in patients with suspected meningitis or encephalitis.

Single-centre study surveying neurology trainees' and faculty's perceptions of the impact of the COVID-19 pandemic on residents' medical education.

OBJECTIVE: To assess perceptions of our neurology residents and faculty regarding training experience and medical education during the early COVID-19 pandemic. METHODS: We distributed two online, voluntary and anonymous surveys to trainees and teaching faculty of our Neurology Department at Henry Ford Hospital. Surveys inquired about trainees' stress, well-being, clinical experience and satisfaction with medical education and available support resources during the first wave of the COVID-19 pandemic in Michigan (mid-March to June 2020). RESULTS: A total of 17/31 trainees and 25/42 faculty responded to the surveys. Eight (47%) trainees reported high stress levels. Nine (57%) were redeployed to cover COVID-19 units. Compared with non-redeployed trainees, redeployed residents reported augmented medical knowledge (89% vs 38%, p=0.05). There was no difference in the two groups regarding overall satisfaction with residency experience, stress levels and didactics attendance. Twenty-one (84%) faculty felt that the redeployment interfered with trainees education but was appropriate, while 10 (59%) trainees described a positive experience overall. Both trainees and faculty believed the pandemic positively impacted trainees' experience by increasing maturity level, teamwork, empathy, and medical knowledge, while both agreed that increased stress and anxiety levels were negative outcomes of the pandemic. Twelve (70%) trainees and 13 (52%) faculty were interested in pursuing more virtual didactics in the future. CONCLUSION: Our findings provide an objective assessment of residents' experience during the COVID-19 pandemic and can guide teaching programmes in their medical education response in the face of future global crises.

Whole-genome sequencing of SARS-COV-2 showed wide spread of B.1.525 in February 2021 in Libya.

Alpha (B.1.1.7) SARS-COV-2 variant was detected in September 2020 in minks and humans in Denmark and UK. This variant has several mutations in the spike region (S) which could increase the transmissibility of the virus 43-90% over previously circulating variants. The National Center for Disease Control (NCDC) announced on 24 February 2021 a 25% frequency of B.1.1.7 strain in Libya using a reverse-transcriptase quantitative PCR assay. This assay relies on the specific identification of the H69-V70 deletion in S gene which causes its failure of amplification (SGTF). This deletion is not specific for B.1.1.7, but is also characteristic of two other SARS-COV-2 variants. This study aimed to estimate the frequency of B.1.1.7 and identify other variants circulating in Libya in February 2021. We performed whole genome sequencing of 67 positive SARS-COV-2 samples collected on 25 February 2021 in Libya which were also tested by RT-qPCR for SGTF. Our results showed that 55% of samples had mutations specific to B.1.525 strain and only ~3% of samples belonged to B.1.1.7. These findings suggested that B.1.525 was spreading widely in Libya. The use of such RT-qPCR assay, although useful to track some variants, cannot discriminate between variants with H69-V70 deletion. RT-qPCR assays could be multiplexed to identify multiple variants and screen samples prior to sequencing. We emphasize on the need for providing whole-genome sequencing to the main COVID-19 diagnostic laboratories in Libya as well as establishing international collaboration for building capacity and advancing research in this time of the pandemic.

Travel during COVID-19 pandemic in Libya: reasons of travel, disease importation and travel regulations.

Restriction of mobility between countries is an important regulatory measure to combat pandemics such as the coronavirus disease 2019 (COVID-19). Currently, PCR testing is required to enter the Libyan borders. However, no post-travel quarantine is employed. In this report, we briefly discuss travel regulations in Libya during the COVID-19 pandemic and disease importation by travelers. The results showed that almost half of the sample travel because of health care and therapy reasons. Tunisia was the most visited destination mainly for trading and business and receiving healthcare. Importantly, 13% of asymptomatic travelers were SARS-CoV-2 positive. Issues regarding repeated testing among very frequent travelers and variant importation needs to be addressed in a more efficient manner.

Impact of the COVID-19 Pandemic on Acute Stroke Care, Time Metrics, Outcomes, and Racial Disparities in a Southeast Michigan Health System.

BACKGROUND: COVID-19 has impacted acute stroke care with several reports showing worldwide drops in stroke caseload during the pandemic. We studied the impact of COVID-19 on acute stroke care in our health system serving Southeast Michigan as we rolled out a policy to limit admissions and transfers. METHODS: in this retrospective study conducted at two stroke centers, we included consecutive patients presenting to the ED for whom a stroke alert was activated during the period extending from 3/20/20 to 5/20/20 and a similar period in 2019. We compared demographics, time metrics, and discharge outcomes between the two groups. RESULTS: of 385 patients presented to the ED during the two time periods, 58% were African American. There was a significant decrease in the number of stroke patients presenting to the ED and admitted to the hospital between the two periods (p <0.001). In 2020, patients had higher presenting NIHSS (median: 2 vs 5, p = 0.012), discharge NIHSS (median: 2 vs 3, p = 0.004), and longer times from LKW to ED arrival (4.8 vs 9.4 h, p = 0.031) and stroke team activation (median: 10 vs 15 min, p = 0.006). In 2020, stroke mimics rates were lower among African Americans. There were fewer hospitalizations (p <0.001), and transfers from outside facilities (p = 0.015). CONCLUSION: a trend toward faster stroke care in the ED was observed during the pandemic along with dramatically reduced numbers of ED visits, hospitalizations and stroke mimics. Delayed ED presentations and higher stroke severity characterized the African American population, highlighting deepening of racial disparities during the pandemic.

Challenges of acute phase neuroimaging in VA-ECMO, pitfalls and alternative imaging options.

Large vessel occlusion in patients on ECMO is challenging to appreciate clinically secondary to sedation or induced paralysis, thus placing more emphasis on neurovascular imaging. However, emergent CTA and CTP are both inaccurate and unreliable in ECMO patients due to altered circuitry and interference with normal physiologic hemodynamics. In this review, the utility of DSA is discussed in evaluating the altered hemodynamics of VA-ECMO circuits and patency of major vasculature. In addition, the potential use of TCD in ECMO patients is discussed.

Incidental diagnosis of 17 alpha-hydroxylase deficiency: a case report.

A 17 alpha-hydroxylase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia (CAH). In this article we discuss a case of 8-year-old girl presented with upper respiratory infection symptoms and a history of hospital admission of fatigue and dehydration. She was incidentally found to have hypertension and hypokalemia. After an endocrine workup her biochemical tests showed: metabolic alkalosis, low levels of cortisol, high levels of adrenocorticotropic hormone (ACTH) and follicle-stimulating hormone (FSH) with normal female phenotype and (46,XY) karyotype. These findings led to the diagnosis of 17OHD confirmed by regression of hypertension and hypokalemia with hydrocortisone prescription. This case shows the importance of vital signs measurement, medical history and commitment to a systematic approach.

Tales of a department: how the COVID-19 pandemic transformed Detroit's Henry Ford Hospital, Department of Neurology-part I: the surge.

The COVID-19 pandemic has reshaped the way healthcare systems operate around the world. The major hurdles faced have been availability of personal protective equipment, intensive care unit beds, ventilators, treatments and medical personnel. Detroit, Michigan has been an epidemic 'hotspot' in the USA with Wayne County among the hardest hit counties in the nation. The Department of Neurology at Henry Ford Hospital, in the heart of Detroit, has responded effectively to the pandemic by altering many aspects of its operations. The rapid engagement of the department and enhanced utilisation of teleneurology were two of the pivotal elements in the successful response to the pandemic. In this review, we describe the transformation our department has undergone, as it relates to its infrastructure redesigning, coverage restructuring, redeployment strategies, medical education adaptations and novel research initiatives.

Complementary bodybuilding: A potential risk for permanent kidney disease.

We report our experience of renal disease associated with bodybuilders who had been on high-protein diet, anabolic androgenic steroids (AASs), and growth hormone (GH) for years. A total of 22 adult males who volunteered information about use of high protein diet and AAS or GH were seen over a six-year period with renal disease. Kidney biopsy revealed focal segmental glomerulosclerosis (FSGS) in eight, nephroangiosclerosis in four, chronic interstitial nephritis in three, acute interstitial nephritis in two, nephrocalcinosis with chronic interstitial nephritis in two, and single patients with membranous glomerulopathy, crescentic glomerulopathy, and sclerosing glomerulonephritis. Patients with FSGS had a longer duration of exposure, late presentation, and worse prognosis. Those with interstitial disease had shorter exposure time and earlier presentation and had improved or stabilized after discontinuation of their practice. There is a need for health education for athletes and bodybuilders to inform them about the risks of renal disease involved with the use of high-protein diet, AAS, and GH.

Evaluation of tumor necrosis factor alpha serum level in obese and lean women with clomiphene citrate-resistant polycystic ovary disease.

OBJECTIVE: The aim of this work was to investigate the level of the serum level of tumor necrosis factor alpha (TNF-α) as an inflammatory biomarker in lean and obese women with polycystic ovary disease (PCOD), who are resistant to clomiphene citrate (CCR-PCOD). PATIENTS AND DESIGN: It is a case-controlled study, where 150 (n = 150) PCOD women (study group), who are resistant to clomiphene citrate (CCR-PCOD) had been recruited, in addition to 100 (n = 100) women with PCOD, who are not resistant to clomiphene citrate (NCCR-PCOD) as the first control group, and another 100 women (n = 100) fertile women with normal reproductive health, as the second control group. All the recruited subjects had been divided into subgroups according to the BMI: One obese group with BMI ≥ 27 and the second lean group with BMI < 27. TNF-α had been measured in all women groups recruited, in addition to the other essential, basic and PCOD-relevant biochemical and hormonal tests. RESULTS: TNF-α level was found to be higher in all PCOD women, either the study or control PCOD groups, than the fertile control group (49.93 ± 3.39 versus 35.83 ± 2.47 pg/ml, p < 0.001). The level of TNF-α has come highest in the obese clomiphene citrate-resistant PCOD women (obese CCR-PCOD), while the lowest has come in the lean PCOD women, who are not resistant to clomiphene citrate (NCCR-PCOD). Free Androgen Index (FAI) and androgenic obesity with higher W/H ratio were clearly going with TNF-α pattern and have come higher in all PCOD compared to the fertile control group. Insulin resistance (IR) shows a positive correlation with BMI regardless off PCOD status and androgen level as well. The level of other basic and PCOD-relevant hormones like FSH, TSH and prolactin have never shown statistically significant differences between all the study and control groups, except LH serum level which has shown a nonsignificant higher level in all PCOD women included either resistant to CC or not. CONCLUSION: TNF-α serum level has come significantly higher in all women with PCOD, especially in those resistant to CC. Androgenic obesity with higher W/H ratio has shown a positive correlation with TNF-α level, which could consider it a good severity index of PCOD status and an informative predictor of CCR before its use.

Agreement Among Stroke Faculty and Fellows in Treating Ischemic Stroke Patients With Tissue-Type Plasminogen Activator and Thrombectomy.

BACKGROUND AND PURPOSE: The aim of this study is to determine agreement among vascular neurology fellows and faculty in treating patients with acute ischemic stroke with intravenous tissue-type plasminogen activator and intra-arterial thrombectomy (IAT). METHODS: Patients were evaluated simultaneously by at least 2 vascular neurology. Agreement was determined using kappa (κ) and intraclass correlation coefficients. RESULTS: In 60 patients, agreement was substantial for tissue-type plasminogen activator (κ=0.75 [95% confidence interval, 0.57-0.92]) and IAT (κ=0.63 [95% confidence interval, 0.30-0.96]), with no difference between fellow-fellow versus fellow-faculty. Intraclass correlation coefficient for National Institutes of Health Stroke Scale was 0.94 (95% confidence interval, 0.90-0.97) and κ for Alberta Stroke Program Early CT Score was 0.53 (95% confidence interval, 0.20-0.78). Rapidly improving or mild deficits caused disagreement for both tissue-type plasminogen activator and IAT, whereas interpretation of computed tomographic perfusion led to disagreement for IAT. CONCLUSIONS: We found substantial agreement between vascular neurology fellows and faculty in treating with tissue-type plasminogen activator or IAT. Areas for improvement include recognition of stroke mimics, consensus on treating less severe strokes, and use/interpretation of imaging.

Decreased expression of circulating microRNA-126 in patients with type 2 diabetic nephropathy: A potential blood-based biomarker.

Circulating microRNAs (miRNAs) have been proposed as promising biomarkers for multiple diseases. miR-126 is reported to be associated with type 2 diabetes mellitus (T2D), diabetic nephropathy (DN) and end stage renal disease. The aim of this study was to investigate the expression of circulating miR-126 and to assess its potential as a blood-based biomarker for DN in T2D patients. In 52 patients with T2D without history of DN (with noromoalbuminuria), 50 patients with T2D and DN (29 with microalbuminuria and 21 with macroalbuminuria), and 50 non-diabetic healthy controls, the expression of circulating miR-126 in peripheral whole blood was evaluated by quantitative polymerase chain reaction. The expression levels of circulating miR-126 were significantly decreased in T2D patients and further decreased in DN patients compared with those in the controls. Multivariate logistic regression analysis confirmed the independent association of lower miR-126 levels with T2D [adjusted odds ratio (OR), 0.797; 95% confidence interval (CI), 0.613-0.960] and DN (adjusted OR, 0.513; 95% CI, 0.371-0.708). miR-126 levels were associated with the degree of albuminuria and showed significantly low expression in DN patients with microalbuminuria (adjusted OR, 0.781; 95% CI; 0.698-0.952) and further lower expression in DN patients with macroalbuminuria (adjusted OR, 0.433; 95% CI, 0.299-0.701), respectively compared with T2D patients with normoalbuminuria. miR-126 levels negatively correlated with albuminuria positively with glomerular filtration rate (P<0.05), and in addition, negatively correlated with fasting glucose, glycated hemoglobin, triglyceride and LDL (P<0.05). Stepwise multiple regression analysis identified albuminuria as a significant predictor of miR-126 (P<0.001). miR-126 in peripheral blood yielded area under the receiver operating characteristic curves of 0.854 (95% CI, 0.779-0.929) and 0.959 (95% CI, 0.916-1.000) in the differentiation of DN patients from T2D patients and DN patients from non-diabetic controls respectively. These data suggest that decreased expression of circulating miR-126 is associated with the development of DN in T2D patients, and may be a promising blood-based biomarker for DN risk estimation.

Development and Validation of a Simple Diagnostic Method to Detect Gain and Loss of Function Defects in Fibroblast Growth Factor-23.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that regulates the homeostasis of phosphate and vitamin D. Three substitutions in the hormone are reported to cause autosomal dominant hypophosphatemic rickets and seven substitutions to cause autosomal recessive hyperphosphatemic familial tumoral calcinosis (HFTC). Both disorders are rare in the general population and occur most often in the Eastern Mediterranean region and Africa. None of the mutations could be identified using standard restriction fragment length polymorphism. The only technique currently available to confirm the clinical diagnosis is DNA sequencing. METHODS: Using a tri-primer ARMS-PCR, in vitro site-directed mutagenesis and DNA sequencing, we developed, verified and validated a rapid and reliable diagnostic test for the ten mutations in FGF23. RESULTS: We generated a test for all ten mutations and confirmed each test by DNA sequencing. We increased the specificity of the test by introducing a mismatch at position -2 in the 3'-terminus of the reverse primer of the normal and the mutant sequences. Finally, using DNA sequencing, we validated the technique for FGF23/S129F substitution by testing samples from 80 individuals from two unrelated Arab families harboring HFTC. CONCLUSIONS: This inexpensive and specific method could be adopted where DNA sequencing is not available or affordable.