Browse publications by year: 2024

  1. Rahman NA, Ariaratnam S, Hashim NA, Azhar ZI
    PLoS One, 2024;19(7):e0307992.
    PMID: 39058752 DOI: 10.1371/journal.pone.0307992
    BACKGROUND: Managing chronic pain was not only a major challenge but also a source of significant disability associated with mental illness. Studies on generalized anxiety disorder (GAD) in chronic pain population was rather limited. This study was aimed to determine the prevalence of GAD and its associated factors among patients attending a pain clinic at a general hospital.

    METHODS: This cross-sectional study recruited 201 patients. The Hospital Anxiety Depression Scale (HADS) was used to determine anxiety level. Subsequently, patients who had scored 8 and above on the HADS were interviewed using Mini International Neuropsychiatric Interview (M.I.N.I) to ascertain the diagnosis of GAD. Whilst the Numerical Rating Scale (NRS) assessed pain severity. Multiple logistic regression analysis was used to determine factors associated with GAD.

    RESULTS: Among those patients with chronic pain, the prevalence of GAD was 18.9%. Gender (AOR:7.94; 95% CI:2.34, 26.93), duration of the pain (AOR:1.30; 95% CI:1.03,1.63) and pain severity (AOR:18.75; CI:1.23,285.13) were significant factors associated with GAD.

    CONCLUSION: GAD is a prevalent condition among chronic pain patients.

    MeSH terms: Adult; Aged; Cross-Sectional Studies; Female; Humans; Malaysia/epidemiology; Male; Middle Aged; Prevalence; Young Adult
  2. Rajendram N, Mansor M, Rahim NA, Bakar MZA, Sobani MA
    Braz J Otorhinolaryngol, 2024;90(5):101466.
    PMID: 39059322 DOI: 10.1016/j.bjorl.2024.101466
    MeSH terms: Female; Humans; Male
  3. Mubarak AA, Ilyas RA, Nordin AH, Ngadi N, Alkbir MFM
    Int J Biol Macromol, 2024 Oct;277(Pt 1):134165.
    PMID: 39059537 DOI: 10.1016/j.ijbiomac.2024.134165
    In recent years, there has been an increase in research devoted to the advancement of cellulose and nanocellulose-based materials, which are advantageous due to their renewable nature, strength, rigidity, and environmental friendliness. This exploration complies with the fundamental tenets of environmental stewardship and sustainability. An area of industrial biotechnology where cellulosic agricultural residues have the potential to be economically utilized is through the conversion of such residues; sugarcane bagasse is currently leading this charge. SCB, a plentiful fibrous byproduct produced during the sugarcane industry's operations, has historically been utilized in various sectors, including producing paper, animal feed, enzymes, biofuel conversion, and biomedical applications. Significantly, SCB comprises a considerable amount of cellulose, approximately 40 % to 50 %, rendering it a valuable source of cellulose fibre for fabricating cellulose nanocrystals. This review sheds light on the significant advances in surface modification techniques, encompassing physical, chemical, and biological treatments, that enhance sugarcane bagasse fibres' adsorption capacity and selectivity. Furthermore, the paper investigates the specific advancements related to the augmentation of sugarcane bagasse fibres' efficacy in adsorbing a wide range of pollutants. These pollutants span a spectrum that includes heavy metals, dyes, organic pollutants, and emerging contaminants. The discussion provides a comprehensive overview of the targeted removal processes facilitated by applying modified fibres. The unique structural and chemical properties inherent in sugarcane bagasse fibres and their widespread availability position them as highly suitable adsorbents for various pollutants. This convergence of attributes underscores the potential of sugarcane bagasse fibres in addressing environmental challenges and promoting sustainable solutions across multiple industries.
    MeSH terms: Adsorption; Biotechnology/methods
  4. Ahmad NH, Huang L, Hwang CA
    Food Res Int, 2024 Sep;191:114701.
    PMID: 39059953 DOI: 10.1016/j.foodres.2024.114701
    This study was conducted to evaluate the effect of sodium nitrite (NaNO2, 100-200 ppm), sodium erythorbate (SE, 0-547 ppm), sodium tripolyphosphate (STPP, 0-0.5 %), and sodium chloride (NaCl, 2-3 %) on growth of C. perfringens using a solid growth medium and to develop a growth/no-growth boundary (critical control surface, or CCS) to prevent its growth in cooked cured meat under the optimal temperature condition. Melted Shahidi Ferguson Perfringens (SFP) agar, inoculated with a 3-strain spore cocktail and mixed with NaNO2, SE, STPP, and NaCl according to a Box-Behnken response surface experimental design, was dispersed in 96-well microplates and incubated anaerobically in an incubator programmed to remain at 4 °C for 24 h, heat to 80 °C in 1.75 h, quickly (0.5 h) cool to 46 °C (optimum temperature), and then maintain at 46 °C overnight. The plates were examined optically and visually for colony formation. Any well free of growth was designated as no-growth. Logistic regression was used to analyze the growth probability (P) as affected by NaNO2, SE, STPP, and NaCl and define a CSS as meeting the criterion of P 
  5. Marzuki AA, Banca P, Garofalo S, Degni LAE, Dalbagno D, Badioli M, et al.
    Transl Psychiatry, 2024 Jul 26;14(1):308.
    PMID: 39060253 DOI: 10.1038/s41398-024-03028-1
    Compulsive behaviour may often be triggered by Pavlovian cues. Assessing how Pavlovian cues drive instrumental behaviour in obsessive-compulsive disorder (OCD) is therefore crucial to understand how compulsions develop and are maintained. An aversive Pavlovian-to-Instrumental transfer (PIT) paradigm, particularly one involving avoidance/cancellation of negative outcomes, can enable such investigation and has not previously been studied in clinical-OCD. Forty-one participants diagnosed with OCD (21 adults; 20 youths) and 44 controls (21 adults; 23 youths) completed an aversive PIT task. Participants had to prevent the delivery of unpleasant noises by moving a joystick in the correct direction. They could infer these correct responses by learning appropriate response-outcome (instrumental) and stimulus-outcome (Pavlovian) associations. We then assessed whether Pavlovian cues elicited specific instrumental avoidance responses (specific PIT) and induced general instrumental avoidance (general PIT). We investigated whether task learning and confidence indices influenced PIT strength differentially between groups. There was no overall group difference in PIT performance, although youths with OCD showed weaker specific PIT than youth controls. However, urge to avoid unpleasant noises and preference for safe over unsafe stimuli influenced specific and general PIT respectively in OCD, while PIT in controls was more influenced by confidence in instrumental and Pavlovian learning. Thus, in OCD, implicit motivational factors, but not learnt knowledge, may contribute to the successful integration of aversive Pavlovian and instrumental cues. This implies that compulsive avoidance may be driven by these automatic processes. Youths with OCD show deficits in specific PIT, suggesting cue integration impairments are only apparent in adolescence. These findings may be clinically relevant as they emphasise the importance of targeting such implicit motivational processes when treating OCD.
    MeSH terms: Adolescent; Adult; Compulsive Behavior/physiopathology; Compulsive Behavior/psychology; Cues*; Female; Humans; Male; Young Adult
  6. Khan R, Haram Z, Ahmad W, Sohni S, Xu J, Ilyas M
    Sci Rep, 2024 Jul 26;14(1):17236.
    PMID: 39060270 DOI: 10.1038/s41598-024-66429-8
    The negative impact of refinery wastewater is of great concern to the aquatic, terrestrial, and aerial environment. In this study, N-hexadecylchitosan (NHDC) was successfully synthesized to deal with low mechanical strength, poor adsorption capacity, and limited selectivity of native chitosan. The NHDC was characterized by fourier-transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM) and X-Ray diffraction analysis (XRD) to study its composition, morphology, and structural attributes. The adsorption of hydrocarbon pollutants from refinery wastewater was studied in batch mode experiments. The results indicated that the removal of COD attained by chitosan and NHDC was 21 and 63%, respectively. COD removal was found to be maximal, i.e., 96% using 0.08 g of NHDC at 60 min in a solution of pH 6.5 maintained at 60 °C. Furthermore, kinetic data revealed that the adsorption system followed pseudo-second order kinetics, whereas equilibrium studies supported both monolayer and multilayer adsorption mechanisms. The designed adsorption platform was able to capture hydrocarbon pollutants under very mild optimized conditions. Furthermore, NHDC demonstrated long term stability when subjected to five successive cycles, which contributed to the sustainability of water treatment systems. On the basis of the outcome of this work, it is advocated that new biobased NHDC can be used as an efficient adsorbent for the remediation of organic contaminants laden wastewater streams generated from oil refineries.
  7. Li J, Soh KG, Loh SP
    Sci Rep, 2024 Jul 26;14(1):17213.
    PMID: 39060296 DOI: 10.1038/s41598-024-67995-7
    The optimal intermittent time for post-activation potentiation (PAP) training remains uncertain and contentious. This study employed a meta-analysis to systematically evaluate the effect of different intermittent times on PAP in relation to explosive vertical jump height. Relevant literature was sourced from CNKI, Wanfang, VIP, CBM, PubMed, Web of Science, and Google Scholar databases using keywords such as "postactivation potentiation," "activation enhancement effect," "PAP," "explosive vertical jump," "explosive vertical high jump," and "intermittent time." The search covered publications from the inception of each database until June 2024. Studies involving athletes (regardless of sport type) undergoing PAP training were included, with no restrictions on the methods used to induce PAP. Comparative analysis focused on the heights of countermovement jumps (CMJ) and peak ground reaction force (GRF) before and after interventions. The quality of the included studies was assessed using the Cochrane Risk of Bias Tool, and data were analyzed using RevMan5.3. The study included a total of 21 papers with 327 subjects, primarily using the squat as the method of PAP induction. The meta-analysis revealed that intermittent times of 4 min [MD = - 0.03, 95% CI: - 0.04 ~ - 0.01; Z = 2.71, P = 0.007] and 5-8 min [MD = - 0.03, 95% CI: - 0.04 ~ - 0.01; Z = 3.07, P = 0.002] significantly increased the height of explosive vertical CMJs. However, intermittent times of 1-3 min [MD = -0.00, 95% CI: - 0.01 ~ 0.01; Z = 0.38, P = 0.70] and 10-24 min [MD = - 0.01, 95% CI: - 0.02 ~ 0.00; Z = 1.43, P = 0.15] did not show significant effects on CMJ height. These findings indicate that 4-min and 5-8 min intervals significantly enhance CMJ height, while intervals shorter than 4 min or longer than 8 min do not have a significant impact.
    MeSH terms: Humans; Time Factors; Muscle Strength/physiology; Athletes
  8. Terna PT, Mohamed Nor NMI, Azuddin NF, Zakaria L
    Sci Rep, 2024 Jul 26;14(1):17146.
    PMID: 39060380 DOI: 10.1038/s41598-024-68428-1
    Endophytic fungi are widely known as fungi that infect internal tissues of host plants for all or part of their life cycles, without causing visible symptoms of disease. The present study was carried out to identify and investigate the pathogenicity of endophytic fungi residing in husks, silks, and kernels of corn. Endophytic fungi were isolated from surface-sterilised silks, kernels, and husks of healthy corn plants and identified using sequencing of multiple markers comprising TEF-1α, β-tubulin, calmodulin, ITS, LSU, and ACT. A total of 56 isolates of endophytic fungi belonging to 17 species, namely Fusarium pseudocircinatum (n = 8), F. verticillioides (n = 2), F. andiyazi (n = 4), F. sacchari (n = 1), F. mangiferae (n = 1), F. fujikuroi (n = 1), F. proliferatum (n = 3), F. incarnatum (n = 2), Penicillium oxalicum (n = 2), P. polonicum (n = 2), P. citrinum (n = 11), Aspergillus flavus (n = 10), A. tubingensis (n = 1), Cladosporium tenuissimum (n = 3), Aureobasidium pullulans (n = 3), Curvularia lunata (n = 1), and Epicoccum sorghinum (n = 1) were identified. Pathogenicity test showed that all endophytic fungi induced varying severities of disease symptoms on corn plants such as leaf chlorosis and necrosis, stem malformation, wilt, and stunted growth with F. verticillioides being the most virulent. The study revealed that corn tissues harbour diverse genera of endophytic fungi that can infect corn plants and may cause harmful effects to the host plants.
    MeSH terms: Fungi/classification; Fungi/genetics; Fungi/isolation & purification; Fungi/pathogenicity; Fusarium/genetics; Fusarium/isolation & purification; Fusarium/pathogenicity; Phylogeny; Virulence
  9. Moore JE, Millar BC
    Lung, 2024 Oct;202(5):741-751.
    PMID: 39060416 DOI: 10.1007/s00408-024-00732-z
    OBJECTIVES: Readability of patient-facing information of oral antibiotics detailed in the WHO all oral short (6 months, 9 months) has not been described to date. The aim of this study was therefore to examine (i) how readable patient-facing TB antibiotic information is compared to readability reference standards and (ii) if there are differences in readability between high-incidence countries versus low-incidence countries.

    METHODS: Ten antibiotics, including bedaquiline, clofazimine, ethambutol, ethionamide, isoniazid, levofloxacin, linezolid, moxifloxacin, pretomanid, pyrazinamide, were investigated. TB antibiotic information sources were examined, consisting of 85 Patient Information Leaflets (PILs) and 40 antibiotic web resouces. Of these 85 PILs, 72 were taken from the National Medicines Regulator from six countries (3 TB high-incidence [Rwanda, Malaysia, South Africa] + 3 TB low-incidence [UK, Ireland, Malta] countries). Readability data was grouped into three categories, including (i) high TB-incidence countries (n = 33 information sources), (ii) low TB-incidence countries (n = 39 information sources) and (iii) web information (n = 53). Readability was calculated using Readable software, to obtain four readability scores [(i) Flesch Reading Ease (FRE), (ii) Flesch-Kincaid Grade Level (FKGL), (iii) Gunning Fog Index and (iv) SMOG Index], as well as two text metrics [words/sentence, syllables/word].

    RESULTS: Mean readability scores of patient-facing TB antibiotic information for FRE and FKGL, were 47.4 ± 12.6 (sd) (target ≥ 60) and 9.2 ± 2.0 (target ≤ 8.0), respectively. There was no significant difference in readability between low incidence countries and web resources, but there was significantly poorer readability associated with PILs from high incidence countries versus low incidence countries (FRE; p = 0.0056: FKGL; p = 0.0095).

    CONCLUSIONS: Readability of TB antibiotic PILs is poor. Improving readability of PILs should be an important objective when preparing patient-facing written materials, thereby improving patient health/treatment literacy.

    MeSH terms: Administration, Oral; Anti-Bacterial Agents/administration & dosage; Anti-Bacterial Agents/therapeutic use; Humans; Ireland; Malaysia; Pamphlets; South Africa; World Health Organization; Incidence; Comprehension*; Health Literacy
  10. Puteh SEW, Kamarudin N', Hussein Z, Adam N, Shahari MR
    BMC Public Health, 2024 Jul 26;24(1):2003.
    PMID: 39061035 DOI: 10.1186/s12889-024-19475-w
    BACKGROUND: Cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) are non-communicable diseases that impose a significant economic burden on healthcare systems, particularly in low- and middle-income countries. The purpose of this study was to evaluate the hospital treatment cost for cardiovascular disease events (CVDEs) in patients with and without diabetes and identify factors influencing cost.

    METHOD: We conducted a retrospective, cross-sectional study using administrative data from three public tertiary hospitals in Malaysia. Data for hospital admissions between 1 March 2019 and 1 March 2020 with International Classification of Diseases 10th Revision (ICD-10) codes for acute myocardial infarction (MI), ischaemic heart disease (IHD), hypertensive heart disease, stroke, heart failure, cardiomyopathy, and peripheral vascular disease (PVD) were retrieved from the Malaysian Disease Related Group (Malaysian DRG) Casemix System. Patients were stratified by T2DM status for analyses. Multivariate logistic regression was used to identify factors influencing treatment costs.

    RESULTS: Of the 1,183 patients in our study cohort, approximately 60.4% had T2DM. The most common CVDE was acute MI (25.6%), followed by IHD (25.3%), hypertensive heart disease (18.9%), stroke (12.9%), heart failure (9.4%), cardiomyopathy (5.7%) and PVD (2.1%). Nearly two-thirds (62.4%) of the patients had at least one cardiovascular risk factor, with hypertension being the most prevalent (60.4%). The treatment cost for all CVDEs was RM 4.8 million and RM 3.7 million in the T2DM and non-T2DM group, respectively. IHD incurred the largest cost in both groups, constituting 30.0% and 50.0% of the total CVDE treatment cost for patients with and without T2DM, respectively. Predictors of high treatment cost included male gender, non-minority ethnicity, IHD diagnosis and moderate-to-high severity level.

    CONCLUSION: This study provides real-world cost estimates for CVDE hospitalisation and quantifies the combined burden of two major non-communicable disease categories at the public health provider level. Our results confirm that CVDs are associated with substantial health utilisation in both T2DM and non-T2DM patients.

    MeSH terms: Adult; Aged; Cross-Sectional Studies; Female; Hospitalization/economics; Hospitalization/statistics & numerical data; Humans; Malaysia/epidemiology; Male; Middle Aged; Retrospective Studies; Hospital Costs/statistics & numerical data
  11. Hon KW, Naidu R
    Antioxidants (Basel), 2024 Jul 07;13(7).
    PMID: 39061884 DOI: 10.3390/antiox13070815
    Colorectal cancer (CRC) is a leading cause of cancer deaths worldwide. Despite significant advances in medical treatment, chemotherapy as monotherapy can lead to substantial side effects and chemoresistance. This underscores the need for therapeutic approaches that are not only pharmacologically safe but also modulate multiple potent signaling pathways and sensitize cancer cells to overcome resistance to standard drugs. In recent years, scientists have been searching for natural compounds that can be used as chemosensitizers in addition to conventional medications for the synergistic treatment of CRC. Polyphenols represent a diverse group of natural compounds that can target multiple signaling pathways in cancer cells to induce anti-cancer effects. Additionally, polyphenols have been shown to work synergistically with chemotherapeutics and other natural compounds in cancer cells. This review aims to provide a comprehensive insight into the synergistic mechanisms of selected polyphenols as chemosensitizers in CRC cells. Further research and clinical trials are warranted to fully harness the synergistic mechanisms of selected polyphenols combined with chemotherapy or natural compounds in improving cancer treatment outcomes.
  12. Syed Hashim SA, Naina Mohamed I, Mohamed N
    Biomedicines, 2024 Jul 08;12(7).
    PMID: 39062088 DOI: 10.3390/biomedicines12071515
    Alcohol's detrimental effects on bone health are well established, yet some literature suggests moderate consumption may offer benefits. With alcohol use on the rise, we investigate the impact of acute and chronic alcohol administration, along with withdrawal, on male Wistar rat femurs. We observed a transient cortical thickness increase with acute alcohol (AA) compared to chronic exposure (CA) but no significant changes in trabecular parameters or mechanical properties. High osteocalcin and osteopontin expression levels were noted in AA, alongside elevated RANKL expression. Conversely, CA showed low TRAP levels. FGF23 expression significantly increased during alcohol withdrawal (AW), while GPX decreased after chronic exposure but rose during withdrawal. Although mechanical strength changes were insignificant, biochemical shifts suggest alcohol exposure promotes bone resorption, reduces antioxidant protection, and potentially hampers active vitamin D and phosphate reabsorption via FGF23 upregulation.
  13. Taghdi MH, Muttiah B, Chan AML, Fauzi MB, Law JX, Lokanathan Y
    Biomedicines, 2024 Jul 18;12(7).
    PMID: 39062178 DOI: 10.3390/biomedicines12071605
    Regenerative medicine represents a paradigm shift in healthcare, aiming to restore tissue and organ function through innovative therapeutic strategies. Among these, bioprinting and extracellular vesicles (EVs) have emerged as promising techniques for tissue rejuvenation. EVs are small lipid membrane particles secreted by cells, known for their role as potent mediators of intercellular communication through the exchange of proteins, genetic material, and other biological components. The integration of 3D bioprinting technology with EVs offers a novel approach to tissue engineering, enabling the precise deposition of EV-loaded bioinks to construct complex three-dimensional (3D) tissue architectures. Unlike traditional cell-based approaches, bioprinted EVs eliminate the need for live cells, thereby mitigating regulatory and financial obstacles associated with cell therapy. By leveraging the synergistic effects of EVs and bioprinting, researchers aim to enhance the therapeutic outcomes of skin regeneration while addressing current limitations in conventional treatments. This review explores the evolving landscape of bioprinted EVs as a transformative approach for skin regeneration. Furthermore, it discusses the challenges and future directions in harnessing this innovative therapy for clinical applications, emphasizing the need for interdisciplinary collaboration and continued scientific inquiry to unlock its full therapeutic potential.
  14. Arzine A, Hadni H, Boujdi K, Chebbac K, Barghady N, Rhazi Y, et al.
    Molecules, 2024 Jul 17;29(14).
    PMID: 39064944 DOI: 10.3390/molecules29143366
    This work describes the synthesis, characterization, and in vitro and in silico evaluation of the biological activity of new functionalized isoxazole derivatives. The structures of all new compounds were analyzed by IR and NMR spectroscopy. The structures of 4c and 4f were further confirmed by single crystal X-ray and their compositions unambiguously determined by mass spectrometry (MS). The antibacterial effect of the isoxazoles was assessed in vitro against Escherichia coli, Bacillus subtilis, and Staphylococcusaureus bacterial strains. Isoxazole 4a showed significant activity against E. coli and B. subtilis compared to the reference antibiotic drugs while 4d and 4f also exhibited some antibacterial effects. The molecular docking results indicate that the synthesized compounds exhibit strong interactions with the target proteins. Specifically, 4a displayed a better affinity for E. coli, S. aureus, and B. subtilis in comparison to the reference drugs. The molecular dynamics simulations performed on 4a strongly support the stability of the ligand-receptor complex when interacting with the active sites of proteins from E. coli, S. aureus, and B. subtilis. Lastly, the results of the Absorption, Distribution, Metabolism, Excretion and Toxicity Analysis (ADME-Tox) reveal that the molecules have promising pharmacokinetic properties, suggesting favorable druglike properties and potential therapeutic agents.
    MeSH terms: Bacillus subtilis/drug effects; Escherichia coli/drug effects; Microbial Sensitivity Tests; Staphylococcus aureus/drug effects; Structure-Activity Relationship; Molecular Structure; Molecular Dynamics Simulation*; Molecular Docking Simulation*
  15. Barman P, Basu S, Goyal T, Sharma S, Siniah S, Tyagi R, et al.
    PMID: 39066572 DOI: 10.1080/1744666X.2024.2386427
    INTRODUCTION: Inborn errors of immunity (IEI) are a group of genetically heterogeneous disorders with a wide-ranging clinical phenotype, varying from increased predisposition to infections to dysregulation of the immune system, including autoimmune phenomena, autoinflammatory disorders, lymphoproliferation, and malignancy. Lymphoproliferative disorder (LPD) in IEI refers to the nodal or extra-nodal and persistent or recurrent clonal or non-clonal proliferation of lymphoid cells in the clinical context of an inherited immunodeficiency or immune dysregulation. The Epstein-Barr virus (EBV) plays a significant role in the etiopathogenesis of LPD in IEIs. In patients with specific IEIs, lack of immune surveillance can lead to an uninhibited proliferation of EBV-infected cells that may result in chronic active EBV infection, hemophagocytic lymphohistiocytosis, and LPD, particularly lymphomas.

    AREAS COVERED: We intend to discuss the pathogenesis, diagnosis, and treatment modalities directed toward EBV-associated LPD in patients with distinct IEIs.

    EXPERT OPINION: EBV-driven lymphoproliferation in IEIs presents a diagnostic and therapeutic problem that necessitates a comprehensive understanding of host-pathogen interactions, immune dysregulation, and personalized treatment approaches. A multidisciplinary approach involving immunologists, hematologists, infectious disease specialists, and geneticists is paramount to addressing the diagnostic and therapeutic challenges posed by this intriguing yet formidable clinical entity.

  16. Alananzeh WA, Al-Qattan MN, Ayipo YO, Mordi MN
    Mol Divers, 2024 Jun;28(3):1273-1289.
    PMID: 37133710 DOI: 10.1007/s11030-023-10655-1
    Manipulating intracellular signals by interaction with transmembranal G-protein-coupled receptors (GPCRs) is the way of action of more than 30% of available medicines. Designing molecules against GPCRs is most challenging due to their flexible binding orthosteric and allosteric pockets, a property that lead to different mode and extent of activation of intracellular mediators. Here, in the current study we aimed to design N-substituted tetrahydro-beta-carbolines (THβC's) targeting Mu Opioid Receptors (MORs). We performed ligand docking study for reference and designed compounds against active and inactive states of MOR, as well as the active state bound to intracellular mediator of Gi. The reference compounds include 40 known agonists and antagonists, while the designed compounds include 25,227 N-substituted THβC analogues. Out of the designed compounds, 15 compounds were comparatively having better extra precision (XP) Gscore and were analyzed for absorption, distribution, metabolism, and excretion-toxicity (ADMET) properties, drug-likness, and molecular dynamic (MD) simulation. The results showed that N-substituted tetrahydro-beta-carbolines with and without C6-methoxy group substitutions (THBC/6MTHBC) analogues of A1/B1 and A9/B9 have relatively acceptable affinity and within pocket-stability toward MOR compared to the reference compounds of morphine (agonist) and naloxone (antagonist). Moreover, the designed analogues interact with key residue within the binding pocket of Asp 147 that is reported to be involved in receptor activation. In conclusion, the designed THBC analogues represent a good starting point for designing opioid receptor ligands other than morphinan scaffold, that have good synthetic accessibility which promotes feasible structural manipulation to tailor pharmacological effects with minimal side effects.
    MeSH terms: Humans; Ligands; Structure-Activity Relationship; Molecular Dynamics Simulation*; Molecular Docking Simulation*
  17. Lesmann H, Hustinx A, Moosa S, Klinkhammer H, Marchi E, Caro P, et al.
    medRxiv, 2024 May 21.
    PMID: 37503210 DOI: 10.1101/2023.06.06.23290887
    The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.
  18. Niranjan NT, Dastidar PG, Penukonda R, Lin GSS, Babannavar R, Jaysheel A, et al.
    Odontology, 2024 Jul;112(3):711-717.
    PMID: 38087010 DOI: 10.1007/s10266-023-00874-1
    To evaluate and compare the effect of calcium hydroxide [Ca(OH)2] and 2-hydroxyisocaproic acid (HICA) on the microhardness of root dentine. Fifty-one matured maxillary central incisors with straight root and type I canal configuration were decoronated to a standardized length of 16 mm. The root canals were cleaned and shaped using rotary instruments up to size F5. The tooth samples were then randomly assigned into three groups (n = 17) based on the intracanal medicament placed. Group A: control group with no intracanal medicament, Group B: root canals placed with Ca(OH)2, and Group C: root canals placed with HICA. After 1 week, the intracanal medicaments placed within the root canals were removed and the canals were dried. Subsequently, the specimens were split longitudinally into two halves and subjected to the Vickers microhardness test with indentations made at the coronal, middle, and apical-third root regions. The data were analyzed using one-way ANOVA and Tukey's post hoc tests. The control group showed significantly highest microhardness value (P 
    MeSH terms: Caproates; Hardness*; Humans; Incisor; Root Canal Irrigants/pharmacology; Tooth Root/drug effects; In Vitro Techniques
  19. GBD 2021 Risk Factors Collaborators
    Lancet, 2024 May 18;403(10440):2162-2203.
    PMID: 38762324 DOI: 10.1016/S0140-6736(24)00933-4
    BACKGROUND: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021.

    METHODS: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk-outcome pairs. Pairs were included on the basis of data-driven determination of a risk-outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk-outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk-outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws.

    FINDINGS: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7-9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4-9·2]), smoking (5·7% [4·7-6·8]), low birthweight and short gestation (5·6% [4·8-6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8-6·0]). For younger demographics (ie, those aged 0-4 years and 5-14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9-27·7]) and environmental and occupational risks (decrease of 22·0% [15·5-28·8]), coupled with a 49·4% (42·3-56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9-21·7] for high BMI and 7·9% [3·3-12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6-1·9) for high BMI and 1·3% (1·1-1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4-78·8) for child growth failure and 66·3% (60·2-72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP).

    INTERPRETATION: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions.

    FUNDING: Bill & Melinda Gates Foundation.

    MeSH terms: Adolescent; Adult; Aged; Female; Humans; Male; Middle Aged; Risk Factors; Risk Assessment; Quality-Adjusted Life Years; Young Adult; Global Burden of Disease*
  20. Lesmann H, Hustinx A, Moosa S, Klinkhammer H, Marchi E, Caro P, et al.
    Res Sq, 2024 Jun 10.
    PMID: 38903062 DOI: 10.21203/rs.3.rs-4438861/v1
    The most important factor that complicates the work of dysmorphologists is the significant phenotypic variability of the human face. Next-Generation Phenotyping (NGP) tools that assist clinicians with recognizing characteristic syndromic patterns are particularly challenged when confronted with patients from populations different from their training data. To that end, we systematically analyzed the impact of genetic ancestry on facial dysmorphism. For that purpose, we established the GestaltMatcher Database (GMDB) as a reference dataset for medical images of patients with rare genetic disorders from around the world. We collected 10,980 frontal facial images - more than a quarter previously unpublished - from 8,346 patients, representing 581 rare disorders. Although the predominant ancestry is still European (67%), data from underrepresented populations have been increased considerably via global collaborations (19% Asian and 7% African). This includes previously unpublished reports for more than 40% of the African patients. The NGP analysis on this diverse dataset revealed characteristic performance differences depending on the composition of training and test sets corresponding to genetic relatedness. For clinical use of NGP, incorporating non-European patients resulted in a profound enhancement of GestaltMatcher performance. The top-5 accuracy rate increased by +11.29%. Importantly, this improvement in delineating the correct disorder from a facial portrait was achieved without decreasing the performance on European patients. By design, GMDB complies with the FAIR principles by rendering the curated medical data findable, accessible, interoperable, and reusable. This means GMDB can also serve as data for training and benchmarking. In summary, our study on facial dysmorphism on a global sample revealed a considerable cross ancestral phenotypic variability confounding NGP that should be counteracted by international efforts for increasing data diversity. GMDB will serve as a vital reference database for clinicians and a transparent training set for advancing NGP technology.
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