Understanding the mechanisms of antimicrobial resistance and potential therapeutic approaches against the Gram-negative pathogen Acinetobacter baumannii.

Globally, the emergence of anti-microbial resistance in pathogens has become a serious threat to human health and well-being. Infections caused by drug-resistant microorganisms in hospitals are associated with increased morbidity, mortality, and healthcare costs. Acinetobacter baumannii is a Gram-negative bacterium belonging to the ESKAPE group and is widely associated with nosocomial infections. It persists in hospitals and survives antibiotic treatment, prompting acute infections such as urinary tract infections, pneumonia, bacteremia, meningitis, and wound-related infections. An innovation void in drug discovery and the lack of new therapeutic measures against A. baumannii continue to afflict infection control against the rising drug-resistant cases. The emergence of drug-resistant A. baumannii strains has also led to the incessant collapse of newly discovered antibiotics. Therefore exploring novel strategies is requisite to give impetus to A. baumannii drug discovery. The present review discusses the bacterial research community's efforts in the field of A. baumannii, focusing on the strategies adapted to identify potent scaffolds and novel targets to bolster and diversify the chemical space available for drug discovery. Firstly, we have discussed existing chemotherapy and various anti-microbial resistance mechanisms in A. baumannii bacterial strains. Next, we elaborate on multidisciplinary approaches and strategies that may be the way forward to combat the current menace caused by the drug-resistant A. baumannii strains. The review highlights the recent advances in drug discovery, including combinational therapy, high-throughput screening, drug repurposing, nanotechnology, and anti-microbial peptides, which are imperative tools to fight bacterial pathogens in the future.

Correction: Chromatographic fingerprinting of epiphytic fungal strains isolated from Withania somnifera and biological evaluation of isolated okaramine H.

Correction for 'Chromatographic fingerprinting of epiphytic fungal strains isolated from Withania somnifera and biological evaluation of isolated okaramine H' by Vandana Sharma et al., Anal. Methods, 2024, https://doi.org/10.1039/D4AY00901K.

Chromatographic fingerprinting of epiphytic fungal strains isolated from Withania somnifera and biological evaluation of isolated okaramine H.

Medicinal plants are "goldmines" of natural products, and continue to provide key scaffolds for drug development. They have immense therapeutic potential, encapsulating a plethora of metabolites within them, which have yet to be explored. Withania somnifera (L.) Dunal is one such medicinal plant known since time immemorial for its therapeutic activity in the Ayurveda system of medicine. Studies have revealed Nature's marvel of these medicinal plants harbouring endophytic and epiphytic microorganisms from phyllosphere to rhizosphere. Chromatographic fingerprinting was carried out using HPTLC and HPLC on five epiphytic strains isolated from the leaves, stem and fruits of Withania somnifera. Out of five filamentous fungi, one fungus identified as Aspergillus aculeatus S20 was well explored. An indole alkaloid, okaramine H, was isolated using systematic chromatographic investigation at a retention time of 26.278 min showing λmax at 206, 236, 284 and 370 nm. Confirmation was achieved using NMR and mass spectrometry (MS) as analytical techniques. Structure elucidation was done by studying the fragmentation pattern using MS/MS and an accurate mass was determined using HR-ESI-QTOF-MS showing m/z of 521.2546 [M + H]+. The percentage purity of isolated okaramine H was found to be >90. Well known for its insecticidal activity, okaramine H was explored for its antileishmanial activity against the Leishmania donovani parasite for the first time. Under in vitro conditions, the compound showed an inhibitory effect on Leishmania donovani promastigotes with an IC50 of 147 µg mL-1.

Exploring natural product library as potential target against sterol C-24 methyltransferase protein of Leishmania donovani.

Natural product offers an ocean of biologically active compounds that have diverse functionality. Thus, the present study aims for the exploration of natural product molecules for their leishmanicidal potency. Primary evaluation at 50 µM concentration revealed that out of 560 molecules, 38 compounds demonstrated a percentage killing of >50%. Next, the dose-dependent investigation showed that six active hits displayed the IC50 value ranging from 0.47 to 14.2 µM. Further, the molecular docking analysis using the alpha fold structure of Sterol C-24 methyltransferase of Leishmania donovani (LdSMT) (an enzyme absent in mammalian host) unveiled the strong binding affinity with top two hits namely shatavarin IV (-7.9 kcal/mol) and 6-methoxydihydrochelerythrine (-7.6 kcal/mol). Also, in silico studies were supported by the alterations in ergosterol content in the parasites treated with these two potent hits. In conclusion, our study suggests that the two potent hits inhibit the Leishmania parasite growth by hindering sterol biosynthesis.

Optical coherence tomography assessment of the impact of colchicine on non-culprit coronary plaque composition after myocardial infarction.

BACKGROUND: Low-dose colchicine reduces the risk of cardiovascular events after myocardial infarction (MI). The purpose of this study was to assess the effect of colchicine post-MI on coronary plaque morphology in non-culprit segments by optical coherence tomography (OCT). METHODS AND RESULTS: COCOMO-ACS was a double-blind, placebo-controlled trial that randomized 64 patients (median age 61.5 years; 9.4% female) with acute non-ST-segment elevation MI to colchicine 0.5 mg daily or placebo for a median of 17.8 months in addition to guideline-recommended therapy. Participants underwent serial OCT imaging within a matched segment of non-culprit coronary artery which contained at least one lipid-rich plaque causing ≥20% stenosis. The primary outcome was the change in minimum fibrous cap thickness (FCT) in non-culprit segments from baseline to final visit. Of those randomized, 57 (29 placebo, 28 colchicine) had evaluable imaging at baseline and follow-up. Overall, colchicine had no effect on relative (placebo +48.0±35.1% vs. colchicine +62.4±38.1%, P=0.18) or absolute changes in minimum FCT (+29.2±20.9 µm vs. +37.2±21.3 µm, P=0.18), or change in maximum lipid arc (-38.8±32.2° vs. -54.8±46.9°, P=0.18) throughout the imaged non-culprit segment. However, in patients assigned colchicine, cap rupture was less frequent (placebo 27.6% vs. colchicine 3.6%, P=0.03). In post-hoc analysis of 43 participants who had been followed for at least 16 months, minimum FCT increased to a greater extent in the colchicine group (placebo +38.7±25.4% vs. colchicine +64.7±34.1%, P=0.005). CONCLUSION: In this study, OCT failed to detect an effect of colchicine on the minimum FCT or maximum lipid arc of plaques in non-culprit segments post-MI. The post-hoc observation that minimum FCT increased to a greater extent with colchicine after more prolonged treatment suggests longer-term studies may be required to detect the effect of anti-inflammatory therapies on plaque morphology by OCT. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Identifier, ACTRN12618000809235, registered on the 11th of May 2018.

Repurposing FDA approved drugs against Sterol C-24 methyltransferase of Leishmania donovani: A dual in silico and in vitro approach.

Leishmaniasis is a disease caused by the parasite Leishmania donovani affecting populations belonging to developing countries. The present study explores drug repurposing as an innovative strategy to identify new uses for approved clinical drugs, reducing the time and cost required for drug discovery. The three-dimensional structure of Leishmania donovani Sterol C-24 methyltransferase (LdSMT) was modeled and 1615 FDA-approved drugs from the ZINC database were computationally screened to identify the potent leads. Fulvestrant, docetaxel, indocyanine green, and iohexol were shortlisted as potential leads with the highest binding affinity and fitness scores for the concerned pathogenic receptor. Molecular dynamic simulation studies showed that the macromolecular complexes of indocyanine green and iohexol with LdSMT remained stable throughout the simulation and can be further evaluated experimentally for developing an effective drug. The proposed leads have further demonstrated promising safety profiles during cytotoxicity analysis on the J774.A1 macrophage cell line. Mechanistic analysis with these two drugs also revealed significant morphological alterations in the parasite, along with reduced intracellular parasitic load. Overall, this study demonstrates the potential of drug repurposing in identifying new treatments for leishmaniasis and other diseases affecting developing countries, highlighting the importance of considering approved clinical drugs for new applications.

Burden of diseases due to high systolic blood pressure in the Middle East and North Africa region from 1990 to 2019.

High systolic blood pressure (HSBP) is associated with several metabolic and non-metabolic disorders. This research aimed to document the deaths and disability-adjusted life-years (DALYs) attributable to HSBP in the Middle East and North Africa (MENA) region between 1990 and 2019, by age, sex, underlying cause and socio-demographic index (SDI). We used the methodological framework and data drawn from the Global Burden of Disease study 2019 to identify the burden of diseases attributable to HSBP, from 1990 to 2019, in the MENA region. The estimates reported were presented as counts, population-attributable fractions, and age-standardised rates (per 100,000), along with 95% uncertainty intervals. In 2019, 803.6 thousand (687.1 to 923.8) deaths were attributed to HSBP in MENA, which accounted for 25.9% (22.9-28.6%) of all deaths. The number of regional DALYs caused by HSBP in 2019 was 19.0 million (16.3-21.9 million), which accounted for 11.6% (10.1-13.3%) of all DALYs, and was 23.4% (15.9-31.5%) lower than in 1990. The highest age-standardised DALY rate for 2019 was observed in Afghanistan, with the lowest in Kuwait. Additionally, the DALY rate in MENA rose with age for both sexs. Furthermore, a negative linear relationship was found between SDI and the age-standardised DALY rates. The region has a substantial HSBP-related burden. Policymakers and healthcare professionals should prioritize interventions that effectively promote the early detection of HSBP, access to quality healthcare, and lifestyle modifications to mitigate the HSBP burden in the MENA countries.

Anhydroparthenin as a dual-target inhibitor against Sterol C-24 methyltransferase and Sterol 14-α demethylase of Leishmania donovani: A comprehensive in vitro and in silico study.

Parthenium hysterophorus plant has a diverse chemical profile and immense bioactive potential. It exhibits excellent pharmacological properties such as anti-cancer, anti-inflammatory, anti-malarial, microbicidal, and anti-trypanosomal. The present study aims to evaluate the anti-leishmanial potential and toxicological safety of anhydroparthenin isolated from P. hysterophorus. Anydroparthenin was extracted from the leaves of P. hysterophorus and characterized through detailed analysis of 1H, 13C NMR, and HRMS. Dye-based in vitro and ex vivo assays confirmed that anhydroparthenin significantly inhibited both promastigote and amastigote forms of the Leishmania donovani parasites. Both the cytotoxicity experiment and hemolytic assay revealed its non-toxic nature and safety index in the range of 10 to 15. Further, various mechanistic assays suggested that anhydroparthenin led to the generation of oxidative stress, intracellular ATP depletion, alterations in morphology and mitochondrial membrane potential, formation of intracellular lipid bodies, and acidic vesicles, ultimately leading to parasite death. As a dual targeting approach, computational studies and sterol quantification assays confirmed that anhydroparthenin inhibits the Sterol C-24 methyl transferase and Sterol 14-α demethylase proteins involved in the ergosterol biosynthesis in Leishmania parasites. These results suggest that anhydroparthenin could be a promising anti-leishmanial molecule and can be developed as a novel therapeutic stratagem against leishmaniasis.

A stepwise approach to coronary artery stenting in acute type A aortic dissection.

We present three cases of acute coronary obstruction postsurgical repair of type A aortic dissection, which were successfully treated with percutaneous coronary intervention. We describe a step-by-step approach to performing percutaneous coronary intervention in selective cases of coronary obstruction related to type A aortic dissection.

Unveiling the role of serine o-acetyltransferase in drug resistance and oxidative stress tolerance in Leishmania donovani through the regulation of thiol-based redox metabolism.

Understanding the unique metabolic pathway of L. donovani is crucial for comprehending its biology under oxidative stress conditions. The de novo cysteine biosynthetic pathway of L. donovani is absent in humans and its product, cysteine regulates the downstream components of trypanothione-based thiol metabolism, important for maintaining cellular redox homeostasis. The role of serine o-acetyl transferase (SAT), the first enzyme of this pathway remains unexplored. In order to investigate the role of SAT protein, we cloned SAT gene into pXG-GFP+ vector for episomal expression of SAT in Amphotericin B sensitive L. donovani promastigotes. The SAT overexpression was confirmed by SAT enzymatic assay, GFP fluorescence, immunoblotting and PCR. Our study unveiled an upregulated expression of both LdSAT and LdCS of cysteine biosynthetic pathway and other downstream thiol pathway proteins in LdSAT-OE promastigotes. Additionally, there was an increase in enzymatic activities of LdSAT and LdCS proteins in LdSAT-OE, which was found similar to the Amp B resistant parasites, indicating a potential role of SAT protein in modulating drug resistance. We observed that the overexpression of SAT in Amp B sensitive parasites increases tolerance to drug pressure and oxidative stress via trypanothione-dependent antioxidant mechanism. Moreover, the in vitro J774A.1 macrophage infectivity assessment showed that SAT overexpression augments parasite infectivity. In LdSAT-OE promastigotes, antioxidant enzyme activities like APx and SOD were upregulated, intracellular reactive oxygen species were reduced with a corresponding increase in thiol level, emphasizing SAT's role in stress tolerance and enhanced infectivity. Additionally, the ROS mediated upregulation in the expression of LdSAT, LdCS, LdTryS and LdcTXNPx proteins reveals an essential cross talk between SAT and proteins of thiol metabolism in combating oxidative stress and maintaining redox homeostasis. Taken together, our results provide the first insight into the role of SAT protein in parasite infectivity and survival under drug pressure and oxidative stress.

DNA topoisomerases as a drug target in Leishmaniasis: Structural and mechanistic insights.

Leishmaniasis, caused by a protozoan parasite, is among humanity's costliest banes, owing to the high mortality and morbidity ratio in poverty-stricken areas. To date, no vaccine is available for the complete cure of the disease. Current chemotherapy is expensive, has undesirable side effects, and faces drug resistance limitations and toxicity concerns. The substantial differences in homology between leishmanial DNA topoisomerase IB compared with the human counterparts provided a new lead in the study of the structural determinants that can be targeted. Several research groups explored this molecular target, trying to fill the therapeutic gap, and came forward with various anti-leishmanial scaffolds. This article is a comprehensive review of knowledge about topoisomerases as an anti-leishmanial drug target and their inhibitors collected over the years. In addition to information on molecular targets and reported scaffolds, the review details the structure-activity relationship of described compounds with leishmanial Topoisomerase IB. Moreover, the work also includes information about the structure of the inhibitors, showing common interacting residues with leishmanial topoisomerases that drive their mode of action towards them. Finally, in search of topoisomerase inhibitors at the stage of clinical trials, we have listed all the drugs that have been in clinical trials against leishmaniasis.

Amphotericin B loaded nanoemulsion: Optimization, characterization and in-vitro activity against L. donovani promastigotes.

The present work aimed to develop and evaluate AmB-loaded nano-emulsion (AmB-NE) which will augment the solubility of AmB and lead to enhanced anti-leishmanial activity. The composition of AmB-NE was optimized by systematic screening followed by DoE-extreme vertices mixture design. The optimized NE revealed mean droplet size and PDI of 44.19 ± 5.5 nm, 0.265 ± 0.0723, respectively. The NE could efficiently encapsulate AmB with drug content and efficiency 83.509 ± 0.369% and 81.659 ± 0.013%, respectively. The presence of cholesterol and stearyl amine retarded the release (P < 0.0001) of AmB significantly compared to AmB suspension. The AmB-NE and pure AmB suspension demonstrated the IC50 of 0.06309 µg/mL and 0.3309 µg/mL against L.donovani promastigotes after 48 h incubation. The formulation was robust at all exaggerated stability conditions such as freeze-thaw and centrifugation. These findings indicate that AmB-NE is an attractive approach to treat visceral leishmaniasis with improved activity.

Enrichment of Native and Recombinant Extracellular Vesicles of Mycobacteria.

Most bacteria, including mycobacteria, generate extracellular vesicles (EVs). Since bacterial EVs (bEVs) contain a subset of cellular components, including metabolites, lipids, proteins, and nucleic acids, several groups have evaluated either the native or recombinant versions of bEVs for their protective potency as subunit vaccine candidates. Unlike native EVs, recombinant EVs are molecularly engineered to contain one or more immunogens of interest. Over the last decade, different groups have explored diverse approaches for generating recombinant bEVs. However, here, we report the design, construction, and enrichment of recombinant mycobacterial EVs (mEVs) in mycobacteria. Towards that, we use Mycobacterium smegmatis (Msm), an avirulent soil mycobacterium as the model system. We first describe the generation and enrichment of native EVs of Msm. Then, we describe the design and construction of recombinant mEVs that contain either mCherry, a red fluorescent reporter protein, or EsxA (Esat-6), a prominent immunogen of Mycobacterium tuberculosis. We achieve this by separately fusing mCherry and EsxA N-termini with the C-terminus of a small Msm protein Cfp-29. Cfp-29 is one of the few abundantly present proteins of MsmEVs. The protocol to generate and enrich recombinant mEVs from Msm remains identical to the generation and enrichment of native EVs of Msm.

Design, synthesis, and biological evaluation of 3,3'-diindolylmethane N-linked glycoconjugate as a leishmanial topoisomerase IB inhibitor with reduced cytotoxicity.

Leishmaniasis, one of the neglected diseases, ranks second to malaria in the cause of parasitic mortality and morbidity. The present chemotherapeutic regimen faces the limitations of drug resistance and toxicity concerns, raising a great need to develop new chemotherapeutic leads that are orally administrable, potent, non-toxic, and cost-effective. Several research groups came forward to fill this therapeutic gap with new classes of active compounds against leishmaniasis, one such being 3,3'-diindolylmethane (DIM) derivatives. We tried to link this concept with another promising approach of glycoconjugation to study how glycosylated groups work differently from non-glycosylated ones. In the present study, a series of 3,3'-DIM derivatives have been synthesized and screened for their anti-leishmanial potency on Leishmania donovani promastigotes. Next, we synthesized the ß-N,N' glycoside of potent compound 3d using indole-indoline conversion, Fischer-type glycosylation, 2,3-dichloro-5,6-dicyano-1,4-benzoquionone (DDQ) oxidation, and molecular iodine catalyzed coupling with a suitable aldehyde in reasonable overall yield. The biological evaluation revealed that glycosides had reduced cytotoxic effects on the J774A.1 macrophage cell line. The enzyme inhibition study confirms that the glycoside derivatives have significant inhibitory activity against the leishmanial topoisomerase IB enzyme. Molecular docking further displayed the better binding efficiency of glycoside 13 with the target enzyme, suggesting the involvement of more H-bond interactions in the case of glycosides as compared to free drugs. Therefore, this work helps in proposing the fact that the addition of sugar moieties adds some favorable characteristics to free inhibitors, making it a promising approach for future clinical diagnostic and therapeutic applications, which can prove to be a valuable arsenal in combating such neglected diseases.

The burden of rheumatic heart disease in the Middle East and North Africa region, 1990-2019.

BACKGROUND: Rheumatic heart disease (RHD) is a treatable and preventable condition resulting from acute rheumatic fever. AIM: To report the prevalence, mortality and disability-adjusted life-years (DALY) due to RHD in the Middle East and North Africa (MENA) region from 1990 to 2019, by sex, age group, country and sociodemographic index (SDI). METHODS: Information on the prevalence, mortality and DALY associated with RHD were obtained from the Global Burden of Disease Study 2019. Data were gathered for all countries in the MENA region over the period 1990-2019. These data included counts and age-standardized rates per 100,000, accompanied by 95% uncertainty intervals (UIs). RESULTS: The MENA region had an age-standardized point prevalence of 388.9 per 100,000 in 2019, which was 5.4% higher than in 1990. The annual incidence rate was 1.6, which was 63.4% lower than in 1990. There were 379.4 thousand DALY attributable to RHD in 2019, with an age-standardized rate of 67.1, which was 61.3% lower than in 1990. In 2019, an estimated 7.4 thousand deaths were due to RHD, and the age-standardized death rate was 63.4% lower in 2019 than in 1990. DALY rates rose steadily with increasing age in both males and females. The SDI correlated negatively with the rate of DALY for RHD throughout the study period. CONCLUSION: The burden of RHD in MENA declined from 1990 to 2019, demonstrating the importance of regularly updating health data and identifying risk factors, and developing effective guidelines on prevention.

Coronary "Microvascular Dysfunction": Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics.

Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

Rationale and Design of the Rivaroxaban Post-Transradial Access for the Prevention of Radial Artery Occlusion Trial (CAPITAL-RAPTOR).

INTRODUCTION: Transradial access (TRA) has rapidly emerged as the preferred vascular access site for coronary angiography and percutaneous coronary intervention. Radial artery occlusion (RAO) remains as an important complication of TRA as it precludes future ipsilateral transradial procedures. While intraprocedural anticoagulation has been studied extensively, the definitive role of postprocedural anticoagulation has not yet been established. METHODS AND ANALYSIS: The Rivaroxaban Post-Transradial Access for the Prevention of Radial Artery Occlusion trial is a multicentre, prospective, randomised, open-label, blinded-endpoint design study investigating the efficacy and safety of rivaroxaban to reduce the incidence of RAO. Eligible patients will undergo randomisation to receive either rivaroxaban 15 mg once daily for 7 days or to no additional postprocedural anticoagulation. Doppler ultrasound to assess radial artery patency will be performed at 30 days. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ottawa Health Science Network Research Ethics Board (approval number 20180319-01H). The study results will be disseminated via conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT03630055.

Meta-analysis assessing the sensitivity and specificity of 18F-FDG PET/CT for the diagnosis of prosthetic valve endocarditis (PVE) using individual patient data (IPD).

IMPORTANCE: The use of 18F-FDG PET/CT in diagnostic algorithms for PVE has increased since publication of studies and guidelines advocating its use. The assessment of test accuracy has been limited by small study sizes. We undertook a systematic review using individual patient data (IPD) meta-analysis techniques. OBJECTIVE: To estimate the summary sensitivity and specificity of 18F-FDG PET/CT in diagnosing PVE. We also assessed the effect of patient factors on test accuracy as defined by changes in the odds ratios associated with each factor. The effect of the PET/CT study on the final diagnosis was also assessed when compared to the preliminary Duke classification to determine in which patient group 18F-FDG PET/CT had the greatest utility. STUDY SELECTION: Studies were included if PET/CT was performed for suspicion of PVE and IPD of both the PET/CT result and final diagnosis defined by a gold-standard assessment was available. There were 3 possible final diagnoses ("definite PVE," "possible PVE," and "rejected PVE"). RESULTS: Seventeen studies were included with IPD available for 537 patients (from 538 scans). The summary sensitivity and specificity were 85% (95% CI 74.2%-91.8%) and 86.5% (95% CI 75.8%-92.9%) respectively when patients with final diagnosis of "possible PVE" were classified as positive for PVE. When this group was classified as negative for PVE, sensitivity was 87.4% (95% CI 80.4%-92.1%) and specificity was 84.9% (95% CI 71.5%-92.6%). Patients with a known pathogen (especially coagulase negative staphylococcal species), elevated CRP, a biological or aortic valve infection appeared more likely to have an accurate PET/CT diagnosis. Those with a mechanical valve, prior antibiotic treatment or a transcatheter aortic valve replacement valve were less likely to have an accurate test. Time since valve implantation and the presence of surgical adhesive did not appear to affect test accuracy. Of the patients with a preliminary Duke classification of "possible PVE," 84% received a more conclusive final diagnosis of "definite" or "rejected" PVE after the PET/CT study. CONCLUSIONS AND RELEVANCE: 18F-FDG PET/CT has high sensitivity and specificity in diagnosing PVE and the diagnostic utility is greatest in patients with a preliminary Duke classification of "possible PVE." Some patient factors appear to affect test accuracy, though these results should be interpreted with caution given low patient numbers for subgroup analyses.

The burden of Parkinson's disease in the Middle East and North Africa region, 1990-2019: results from the global burden of disease study 2019.

BACKGROUND: Parkinson's disease (PD) remains a common disabling progressive neurodegenerative disorder. We aimed to report the prevalence, death and disability-adjusted life-years (DALYs) attributable to PD in the Middle East and North Africa (MENA) region and its 21 countries by age, sex and socio-demographic index (SDI), between 1990 and 2019. METHODS: Publicly available data on the burden of PD in the MENA countries were retrieved from the Global Burden of Disease (GBD) 2019 project. The results are presented with age-standardised numbers and rates per 100,000 population, along with their corresponding 95% uncertainty intervals (UIs). RESULTS: In 2019, PD had an age-standardised point prevalence of 82.6 per 100,000 population in MENA and an age-standardised death rate of 5.3, which have increased from 1990 to 2019 by 15.4% and 2.3%, respectively. In 2019, the age-standardised DALY rate of PD was 84.4, which was 0.9% higher than in 1990. The highest and lowest age-standardised DALY rates of PD in 2019 were found in Qatar and Kuwait, respectively. Also in 2019, the highest number of prevalent cases and number of DALYs were found in the 75-79 age group for both sexes. In 2019, females in MENA had an overall higher DALY rate. Furthermore, from 1990 to 2019 the burden of PD generally decreased with increasing socio-economic development, up to an SDI of around 0.4, and then increased with higher levels of SDI. CONCLUSION: An upward trend was observed in the point prevalence of PD over the last three decades. This highlights the need to allocate more resources for research. Furthermore, properly equipped healthcare services are needed for the increasing number of patients with PD.

Insights into the drug screening approaches in leishmaniasis.

Leishmaniasis, a tropically neglected disease, is responsible for the high mortality and morbidity ratio in poverty-stricken areas. Currently, no vaccine is available for the complete cure of the disease. Current chemotherapeutic regimens face the limitations of drug resistance and toxicity concerns indicating a great need to develop better chemotherapeutic leads that are orally administrable, potent, non-toxic, and cost-effective. The anti-leishmanial drug discovery process accelerated the desire for large-scale drug screening assays and high-throughput screening (HTS) technology to identify new chemo-types that can be used as potential drug molecules to control infection. Using the HTS approach, about one million compounds can be screened daily within the shortest possible time for biological activity using automation tools, miniaturized assay formats, and large-scale data analysis. Classical and modern in vitro screening assays have led to the progression of active compounds further to ex vivo and in vivo studies. In the present review, we emphasized on the HTS approaches employed in the leishmanial drug discovery program. Recent in vitro screening assays are widely explored to discover new chemical scaffolds. Developing appropriate experimental animal models and their related techniques is necessary to understand the pathophysiological processes and disease host responses, paving the way for unraveling novel therapies against leishmaniasis.