Development and initial validation of a video-based peroral endoscopic myotomy assessment tool.

BACKGROUND AND AIMS: Video analysis has emerged as a potential strategy for performance assessment and improvement. We aimed to develop a video-based skill assessment tool for peroral endoscopic myotomy (POEM). METHODS: POEM was deconstructed into basic procedural components through video analysis by an expert panel. A modified Delphi approach and 2 validation exercises were conducted to refine the POEM assessment tool (POEMAT). Twelve assessors used the final POEMAT version to grade 10 videos. Fully crossed generalizability (G) studies investigated the contributions of assessors, endoscopists' performance, and technical elements to reliability. G coefficients below .5 were considered unreliable, between .5 and .7 as modestly reliable, and above .7 as indicative of satisfactory reliability. RESULTS: After task deconstruction, discussions, and the modified Delphi process, the final POEMAT comprised 9 technical elements. G analysis showed low variance for endoscopist performance (.8%-24.9%) and high interrater variability (range, 63.2%-90.1%). The G score was moderately reliable (≥.60) for "submucosal tunneling" and "myotomy" and satisfactorily reliable (≥.70) for "active hemostasis" and "mucosal closure." CONCLUSIONS: We developed and established initial content and response process validity evidence for the POEMAT. Future steps include appraisal of the tool using a wider range of POEM videos to establish and improve the discriminative validity of this tool.

Synthesis, In vitro and In silico Studies of Novel Bis-triazolopyridopyrimidines from Curcumin Analogues as Potential Aromatase Agents.

Breast cancer remains a major global health issue, particularly affecting women and contributing significantly to mortality rates. Current treatments for estrogen receptor-positive breast cancers, such as aromatase inhibitors, are effective but often come with side effects and resistance issues. This study addresses these gaps by targeting aromatase, an enzyme crucial for estrogen synthesis, which plays a pivotal role in breast cancer progression. The innovative approach involves synthesizing novel bis-triazolopyridopyrimidines, designed to leverage the combined pharmacological benefits of pyridopyrimidine and 1,2,4-triazole structures, known for their potent aromatase inhibition and anti-cancer properties. These compounds were synthesized and characterized using 1H-NMR, 13C-NMR, and MS spectral analyses, and their anticancer efficacy was evaluated through MTT assays against MCF-7 breast cancer cell lines in vitro. Molecular docking analyses revealed strong binding energies with aromatase, particularly for compounds 5 b, 5 c, 10 a, and 10 b, indicating their potential as effective aromatase inhibitors. The study highlights these compounds as promising candidates for further development as therapeutic agents against breast cancer.

Mechanistic Insights of Neuroprotective Efficacy of Verapamil-Loaded Carbon Quantum Dots against LPS-Induced Neurotoxicity in Rats.

Alzheimer's disease (AD) is a neurodegenerative disease that badly impacts patients and their caregivers. AD is characterized by deposition of amyloid beta (Aß) and phosphorylated tau protein (pTau) in the brain with underlying neuroinflammation. We aimed to develop a neuroprotective paradigm by loading verapamil (VRH) into hyaluronic acid-modified carbon quantum dots (CQDs) and comparing its effectiveness with the free form in an AD-like model in rats induced by lipopolysaccharide (LPS). The experimental rats were divided into seven groups: control, LPS, CQDs, early free VRH (FVRH), late FVRH, early verapamil carbon quantum dots (VCQDs), and late VCQDs. Characterizations of VCQDs, the behavioral performance of the rats, histopathological and immunohistochemical changes, some AD hallmarks, oxidative stress biomarkers, neuro-affecting genes, and DNA fragmentation were determined. VRH was successfully loaded into CQDs, which was confirmed by the measured parameters. VRH showed enhancement in cognitive functions, disruption to the architecture of the brain, decreased Aß and pTau, increased antioxidant capacity, modifiable expression of genes, and a decline in DNA fragmentation. The loaded therapy was superior to the free drug. Moreover, the early intervention was better than the late, confirming the implication of the detected molecular targets in the development of AD. VRH showed multifaceted mechanisms in combating LPS-induced neurotoxicity through its anti-inflammatory and antioxidant properties, thereby mitigating the hallmarks of AD. Additionally, the synthesized nanosystem approach exhibited superior neuroprotection owing to the advantages offered by CQDs. However, finding new actionable biomarkers and molecular targets is of decisive importance to improve the outcomes for patients with AD.

Translation and validation study of obstructive sleep apnoea (OSA-18) questionnaire into Bahasa Malaysia (MALAY OSA-18).

INTRODUCTION: According to the American Academy of Sleep Medicine, obstructive sleep apnoea (OSA) is sleep-related breathing disorder that involves a decrease or complete halt in airflow despite an ongoing effort to breathe. The OSA-18 questionnaire is a short and self-administered questionnaire to assess paediatric patients' symptoms and quality of life with obstructive sleep apnoea. MATERIALS AND METHODS: This cross-sectional study is conducted at the Otorhinolaryngology-Head and Neck Surgery (ORL-HNS) clinic of Hospital Universiti Sains Malaysia. The forward and backward translation of the OSA- 18 questionnaire into the Malay language (Malay OSA-18) was performed and tested for content and face validity. The questionnaire's internal validity and reliability were tested using Pearson's correlation, Cronbach α and inter-reliability coefficient tests. The psychometric properties (validity, reliability and reproducibility) were assessed. RESULTS: We observed 84 patients ranging from six months up to 12 years of age. The mean age was 8 years old, and 63.1% were male patients. Among the samples, 96.4% presented with palatine tonsillar enlargement, and 84.5% presented with adenoid tonsillar enlargement. Based on the questionnaire the patient's caregiver answered, Pearson's correlation demonstrated that all the symptom scales correlate and measure the same things. The Cronbach's α coefficient value for each symptom scale was acceptable, within 0.6-0.8. The total Cronbach's α coefficient value was 0.89. The test-retest evaluation was excellent, with the value of intraclass correlation (ICC) more than 0.90. CONCLUSION: The Malay version of the OSA-18 questionnaire is equivalent to the original English version. It is an effective tool to assess the paediatric OSA patient's symptoms and quality of life based on the obtained validity, reliability and reproducibility values. Therefore, it is recommended to be a screening tool in daily practice.

Vegetable oil-based nanoemulsions for the preservation of muscle foods: A systematic review and meta-analysis.

This systematic review and meta-analysis quantified the effects of various vegetable oil-based nanoemulsion (NE) formulations on muscle foods' microbial and chemical quality by estimating the weighted overall response ratio (R*). Treatment of muscle foods with NE formulations reduced the growth rates of total mesophilic bacteria, total psychrophilic bacteria, lactic acid bacteria, and Enterobacteriaceae by 26.2% (R*=0.738), 19% (R*=0.810), 44.7% (R*=0.553), and 31.8% (R*=0.682) during the storage period, respectively. Moreover, the NE formulations retarded the increasing rates of volatile basic-nitrogen content, lipid and protein oxidation, and lipid hydrolysis by 41.4% (R*=0.586), 34% (R*=0.660), 55% (R*=0.450), and 37.1% (R*=0.629), respectively. The NE formulations prepared from safflower, olive, canola, and sunflower oil were more effective than the other vegetable oils to control microbial growth and slow down chemical changes in muscle foods. The combination of nanoemulsions (NEs) and essential oils (EOs) was more efficient than NEs to preserve muscle foods. Packaging NE-treated muscle foods under anaerobic conditions provided better control of microbial growth and chemical changes than packaging under aerobic conditions. Consequently, a combination of vegetable oil-based NEs and EOs followed by anaerobic packaging is the most effective treatment to improve the quality of muscle foods.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2057415 .

Genome-Wide B Cell, CD4+, and CD8+ T Cell Epitopes That Are Highly Conserved between Human and Animal Coronaviruses, Identified from SARS-CoV-2 as Targets for Preemptive Pan-Coronavirus Vaccines.

Over the last two decades, there have been three deadly human outbreaks of coronaviruses (CoVs) caused by SARS-CoV, MERS-CoV, and SARS-CoV-2, which has caused the current COVID-19 global pandemic. All three deadly CoVs originated from bats and transmitted to humans via various intermediate animal reservoirs. It remains highly possible that other global COVID pandemics will emerge in the coming years caused by yet another spillover of a bat-derived SARS-like coronavirus (SL-CoV) into humans. Determining the Ag and the human B cells, CD4+ and CD8+ T cell epitope landscapes that are conserved among human and animal coronaviruses should inform in the development of future pan-coronavirus vaccines. In the current study, using several immunoinformatics and sequence alignment approaches, we identified several human B cell and CD4+ and CD8+ T cell epitopes that are highly conserved in 1) greater than 81,000 SARS-CoV-2 genome sequences identified in 190 countries on six continents; 2) six circulating CoVs that caused previous human outbreaks of the common cold; 3) nine SL-CoVs isolated from bats; 4) nine SL-CoV isolated from pangolins; 5) three SL-CoVs isolated from civet cats; and 6) four MERS strains isolated from camels. Furthermore, the identified epitopes: 1) recalled B cells and CD4+ and CD8+ T cells from both COVID-19 patients and healthy individuals who were never exposed to SARS-CoV-2, and 2) induced strong B cell and T cell responses in humanized HLA-DR1/HLA-A*02:01 double-transgenic mice. The findings pave the way to develop a preemptive multiepitope pan-coronavirus vaccine to protect against past, current, and future outbreaks.

Photocatalytic Degradation of Methylene Blue and Anticancer Response of In2O3/RGO Nanocomposites Prepared by a Microwave-Assisted Hydrothermal Synthesis Process.

The incorporation of graphene with metal oxide has been widely explored in various fields, including energy storage devices, optical applications, biomedical applications, and water remediation. This research aimed to assess the impact of reduced graphene oxide (RGO) doping on the photocatalytic and anticancer properties of In2O3 nanoparticles. Pure and In2O3/RGO nanocomposites were effectively synthesized using the single-step microwave hydrothermal process. XRD, TEM, SEM, EDX, XPS, Raman, UV-Vis, and PL spectroscopy were carefully utilized to characterize the prepared samples. XRD data showed that synthesized In2O3 nanoparticles had high crystallinity with a decreased crystal size after RGO doping. TEM and SEM images revealed that the In2O3 NPs were spherical and uniformly embedded onto the surface of RGO sheets. Elemental analysis of In2O3/RGO NC confirmed the presence of In, O, and C without impurities. Raman analysis indicated the successful fabrication of In2O3 onto the RGO surface. Uv-Vis analysis showed that the band gap energy was changed with RGO addition. Raman spectra confirmed that In2O3 nanoparticles were successfully anchored onto the RGO sheet. PL results indicated that the prepared In2O3/RGO NCs can be applied to enhance photocatalytic activity and biomedical applications. In the degradation experiment, In2O3/RGO NCs exhibited superior photocatalytic activity compared to that of pure In2O3. The degradation efficiency of In2O3/RGO NCs for MB dye was up to 90%. Biological data revealed that the cytotoxicity effect of In2O3/RGO NCs was higher than In2O3 NPs in human colorectal (HCT116) and liver (HepG2) cancer cells. Importantly, the In2O3/RGO NCs exhibited better biocompatibility against human normal peripheral blood mononuclear cells (PBMCs). All the results suggest that RGO addition improves the photocatalytic and anticancer activity of In2O3 NPs. This study highlights the potential of In2O3/RGO NCs as an efficient photocatalyst and therapeutic material for water remediation and biomedicine.

Development, validation, and evaluation of allergic rhinitis symptoms and impact assessment (ARSIA) questionnaire.

INTRODUCTION: Allergic rhinitis (AR) is an inflammatory disease of the nasal mucosa. It is among the most common diseases globally and usually persists throughout life. Allergic Rhinitis and Its Impact on Asthma (ARIA) is a wellestablished guideline applicable to AR and was updated regularly since 2001, aiming to improve the care for AR patients. We proposed a new questionnaire that addresses the severity of allergic rhinitis symptoms, specifically nasal symptoms, and its impact on quality of life in terms of specific vital activities such as sleeping, working, school performance, leisure, or sport, based on the ARIA guideline. The objective was to develop, validate and evaluate Allergic Rhinitis Symptoms and Impact Assessment (ARSIA) questionnaire among allergic rhinitis patients in Hospital Sultan Abdul Halim, Sungai Petani (HSAH), and Hospital Universiti Sains Malaysia (HUSM). MATERIALS AND METHODS: This is a prospective observational study to develop, validate and evaluate the ARSIA questionnaire based on ARIA guidelines. The sample will be obtained from the list of patients under follow-up in the ORL clinic HSAH and HUSM with ages of 18 to 60 years, patients clinically diagnosed with allergic rhinitis, and with positive skin prick test. RESULTS: A total of 150 patients with a positive skin prick test participated in this study. In the 'nasal symptom' and 'impact on daily activities' domains, calculated Cronbach's alpha shows a value of 0.878 and 0.811 respectively. The inter-item correlation was calculated to analyse internal consistency reliability. Items B3 and B4 were dropped from the questionnaire as both showed a low correlation with other items. New Cronbach's alpha for the daily activities domain was 0.830, which showed better internal consistency reliability. All of the items were analysed for sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Clinician diagnosis from the proforma was used as a comparison to the participant's responses. In the analysis, a cut-off points of 12 was used to classify the patient's nasal symptoms into intermittent or persistent, with a sensitivity of 75%, specificity of 86%, PPV of 95%, and NPV of 51%. Whereas, a cut-off point of 15 was used to classify the rhinitis impact on daily activities into mild or moderate/severe, with a sensitivity of 58%, specificity of 100%, PPV of 100%, and NPV of 42%. The only item in the 'control' domain has been dropped out following a consensus of experts and judgement as it has not been used in the clinician diagnosis and thus, is unable to test for sensitivity, specificity, PPV, and NPV. CONCLUSION: This newly developed, validated, and evaluated questionnaire is a good tool for the evaluation of allergic rhinitis symptoms and their impact on daily activities. It is important to understand that AR symptoms could have a significant impact on daily activities. Although further study and testing are needed, it provides an initial means for evaluating the patient condition and control level, as well as patients' perception of their rhinitis control.

Performance of the World Health Organisation suspected COVID-19 case definition in cluster-associated and sporadic SARS-CoV-2 transmission in Malaysia.

INTRODUCTION: Cluster-associated transmission has contributed to the majority of COVID-19 cases in Malaysia. Although widely used, the performance of the World Health Organization (WHO) case definition for suspected COVID19 in environments with high numbers of such cases has not been reported. MATERIALS AND METHODS: All suspected cases of COVID-19 that self-presented to hospitals or were cluster screened from 1st April to 31st May 2020 were included. Positive SARS-CoV-2 rRT-PCR was used as the diagnostic reference for COVID-19. RESULTS: 540 individuals with suspected COVID-19 were recruited. Two-third of patients were identified through contact screening, while the rest presented sporadically. Overall COVID-19 positivity rate was 59.4% (321/540) which was higher in the cluster screened group (85.6% vs. 11.6%, p<0.001). Overall, cluster-screened COVID-19 cases were significantly younger, had fewer comorbidities and were less likely to be symptomatic than those present sporadically. Mortality was significantly lower in the cluster-screened COVID-19 cases (0.3% vs. 4.5%, p<0.05). A third of all chest radiographs in confirmed COVID-19 cases were abnormal, with consolidation, ground-glass opacities or both predominating in the peripheral lower zones. The WHO suspected case definition for COVID-19 accurately classified 35.4% of all COVID-19 patients, a rate not improved by the addition of baseline radiographic data. Misclassification rate was higher among the cluster-associated cases (80.6%) compared to sporadic cases (35.3%). CONCLUSION: COVID-19 cases in Malaysia identified by active tracing of community cluster outbreaks had lower mortality rate. The WHO suspected COVID-19 performed poorly in this setting even when chest radiographic information was available, a finding that has implications for future spikes of the disease in countries with similar transmission characteristics.

A mutation panel comprising BRAFV600E, NRASQ61R, and NRASQ61H replicated retrospective histopathological examination findings in differentiating benign goitre from malignant papillary thyroid cancer in a cohort of Malaysian patients.

Thyroid malignancy status is usually confirmed through histopathological examination (HPE) following thyroidectomy. In Malaysia, the application of molecular markers in pre-operative diagnosis of thyroid cancer remains unexplored. In this study, BRAF and NRAS gene mutation panel was assessed, and the results were compared with retrospective HPE findings. Malaysian patients with benign goitre (BTG: n=33) and papillary thyroid cancer (PTC: n=25; PTCa: n=20, PTCb: n=5) were recruited at Universiti Malaya Medical Centre from September 2019 to December 2022. PCR-direct DNA sequencing of BRAFV600, NRASG12, NRASG13, and NRASQ61 was conducted on DNA extracted from the patients' thyroid tissue specimens following thyroidectomy and HPE. BRAFV600E and NRASQ61R mutations showed absolute PTC-specificity with PTC-sensitivity of 32% and 28%, respectively. NRASQ61H demonstrated lower PTC-specificity (94%) but higher PTC-sensitivity (72%) compared to the BRAFV600E and NRASQ61R mutations. Although the NRASG12 and NRASG13 variants were absent in this study, a novel NRASV14D mutation was detected in a PTCa patient. Unlike PTCb, coexistence of BRAFV600E and NRASQ61 variants was commonly observed among the PTCa patients. Notably, all PTCb patients had NRASQ61H mutation with one patient carried both the NRASQ61H and BRAFV600E mutations. Association analysis revealed potential link between gender, BRAFV600E mutation and lymph node metastasis. In conclusion, mutation panel comprising BRAFV600E, NRASQ61R, and NRASQ61H did not discriminate the two PTC subtypes but replicated the retrospective HPE findings in differentiating BTG from PTC. The application of this mutation panel in pre-operative diagnosis of thyroid nodules requires further validation in a larger sample size, preferably incorporating fineneedle aspirate biopsies.

What Is It That You Want Me To Do? Guidance for Ethics Consultants in Complex Discharge Cases.

Some of the most difficult consultations for an ethics consultant to resolve are those in which the patient is ready to leave the acute-care setting, but the patient or family refuses the plan, or the plan is impeded by deficiencies in the healthcare system. Either way, the patient is "stuck" in the hospital and the ethics consultant is called to help get the patient "unstuck." These encounters, which we call "complex discharges," are beset with tensions between the interests of the institution and the interests of the patient as well as tensions within the ethics consultant whose commitments are shaped both by the values of the organization and the values of their own profession. The clinical ethics literature on this topic is limited and provides little guidance. What is needed is guidance for consultants operating at the bedside and for those participating at a higher organizational level. To fill this gap, we offer guidance for facilitating a fair process designed to resolve the conflict without resorting to coercive legal measures. We reflect on three cases to argue that the approach of the consultant is generally one of mediation in these types of disputes. For patients who lack decision making capacity and lack a surrogate decision maker, we recommend the creation of a complex discharge committee within the organization so that ethics consultants can properly discharge their duties to assist patients who are unable to advocate for themselves through a fair and transparent process.

Predictive value of immunological markers after bacille Calmette-Guérin induction in bladder cancer.

OBJECTIVES: To investigate the predictive value of different immunological markers on treatment outcomes after bacille Calmette-Guérin (BCG) induction in high-risk non-muscle-invasive bladder cancer (NMIBC). PATIENTS AND METHODS: Patients who underwent transurethral resection of bladder tumour for NMIBC were assessed for study eligibility. Urine and blood samples were taken from patients at baseline (immediately before first dose of induction) and after induction (4 h after last [sixth] dose). Urine samples were evaluated for interleukin (IL)-2 and IL-10 by solid-phase enzyme-linked immunosorbent assay. Blood samples were evaluated for tumour necrosis factor α (TNF-α), cytotoxic T-lymphocyte antigen 4 (CTLA-4) and transcription factors (TFs) (GATA-binding protein 3 [GATA3], T-box expressed in T cells [T-bet], and forkhead box protein 3 [FoxP3]) using quantitative reverse transcriptase-polymerase chain reaction analysis. Change pattern and fold change of each evaluable marker was assessed in relation to different treatment outcomes (initial complete response [ICR]/recurrence/progression). RESULTS: Between July 2013 and May 2019, 204 patients were included. Among evaluable markers, urinary IL-2 and serum TNF-α increased in all patients, serum CTLA-4 and FoxP3+ showed a predominant decreased pattern in 188 (92.2%) and 192 (94.1%) patients, respectively. An ICR was achieved in 186 (91.2%) patients. Serum TNF-α fold change and urinary IL-10 change pattern were significantly associated with an ICR (P = 0.001 and P = 0.03, respectively). At a median (range) follow-up of 37 (20-88) months, 104 (56%) patients developed recurrence. Urinary IL-10, serum CTLA-4, T-bet+ , FoxP3+ change patterns and GATA3+ /T-bet+ ratio were significantly associated with tumour recurrence (P = 0.001, P = 0.001, P = 0.02, P = 0.009 and P = 0.001, respectively). Tumour progression occurred in 34 (18.3%) patients. Urinary IL-10, serum CTLA-4, serum T-bet+ change patterns and GATA3+ /T-bet+ ratio were independent predictors of tumour progression (P = 0.001, P = 0.001, P = 0.02 and P = 0.001, respectively). CONCLUSIONS: Urinary IL-10 and serum TNF-α can significantly predict ICR. Moreover, change pattern of urinary IL-10, serum CTLA-4, TFs (GATA3, T-bet and FoxP3) and GATA3+ /T-bet+ ratio after BCG induction can independently predict further BCG response. These markers could be implemented in clinical practice when management options are discussed or in systems with severe BCG shortage.

Gene expression and oxidative stress markers profile associated with toxic metals in patients with renal cell carcinoma.

BACKGROUND: Toxic metals are associated with cancer progression. Studies have reported the relation between some toxic metals and renal cell carcinoma (RCC). METHODS AND RESULTS: Blood levels of Cd and Pb were determined in 94 RCC patients (RCC group) and 91 matched controls as well as blood level of malondialdehyde (MDA) and catalase (CAT) activity as markers of oxidative stress and antioxidant, respectively. Gene expression of MAP kinase pathway (P38 and JNK), hypoxia-inducible factor 1-alpha (HIF1α), vascular endothelial growth factor (VEGF), cytochrome C oxidase subunit 6 (COX6), metallothionein (MT2A), and heat shock protein (HSP90AA1) were evaluated in the obtained tissue specimens. Blood Cd and Pb levels were significantly higher in RCC group comparing to control group with preferential significant increase of Cd in chromophobe RCC (chRCC) sub-type. MDA level was significantly higher and CAT activity was lower in the RCC compared to controls. The difference was evident only in chRCC. The expressions of genes were significantly increased in the cancer tissues than in non-cancerous tissues in RCC sub-types and there was a significant correlation between Cd levels and expression of genes VEGF, MT2A, P38 and JNK in chRCC group. Immunohistochemical staining of clear cell RCC tissues shows a marked expression of VEGF and HIF-1α.While COX6 staining show marked expression in chRCC. CONCLUSIONS: There is a positive correlation between Cd toxicity and the development of RCC, especially chRCC sub-type. Cd is strongly incriminated in the pathogenesis of chRCC through the effort on some genes and oxidative stress markers.

Hybrid Satellite-Terrestrial Networks toward 6G: Key Technologies and Open Issues.

Future wireless networks will be required to provide more wireless services at higher data rates and with global coverage. However, existing homogeneous wireless networks, such as cellular and satellite networks, may not be able to meet such requirements individually, especially in remote terrain, including seas and mountains. One possible solution is to use diversified wireless networks that can exploit the inter-connectivity between satellites, aerial base stations (BSs), and terrestrial BSs over inter-connected space, ground, and aerial networks. Hence, enabling wireless communication in one integrated network has attracted both the industry and the research fraternities. In this work, we provide a comprehensive survey of the most recent work on hybrid satellite-terrestrial networks (HSTNs), focusing on system architecture, performance analysis, design optimization, and secure communication schemes for different cooperative and cognitive HSTN network architectures. Different key technologies are compared. Based on this comparison, several open issues for future research are discussed.

Design and Synthesis of Benzene Homologues Tethered with 1,2,4-Triazole and 1,3,4-Thiadiazole Motifs Revealing Dual MCF-7/HepG2 Cytotoxic Activity with Prominent Selectivity via Histone Demethylase LSD1 Inhibitory Effect.

In this study, an efficient multistep synthesis of novel aromatic tricyclic hybrids incorporating different biological active moieties, such as 1,3,4-thiadiazole and 1,2,4-triazole, was reported. These target scaffolds are characterized by having terminal lipophilic or hydrophilic parts, and their structures are confirmed by different spectroscopic methods. Further, the cytotoxic activities of the newly synthesized compounds were evaluated using in vitro MTT cytotoxicity screening assay against three different cell lines, including HepG-2, MCF-7, and HCT-116, compared with the reference drug Taxol. The results showed variable performance against cancer cell lines, exhibiting MCF-7 and HepG-2 selectivities by active analogs. Among these derivatives, 1,2,4-triazoles 11 and 13 and 1,3,4-thiadiazole 18 were found to be the most potent compounds against MCF-7 and HepG-2 cancer cells. Moreover, structure-activity relationship (SAR) studies led to the identification of some potent LSD1 inhibitors. The tested compounds showed good LSD1 inhibitory activities, with an IC50 range of 0.04-1.5 µM. Compounds 27, 23, and 22 were found to be the most active analogs with IC50 values of 0.046, 0.065, and 0.074 µM, respectively. In addition, they exhibited prominent selectivity against a MAO target with apparent cancer cell apoptosis, resulting in DNA fragmentation. This research provides some new aromatic-centered 1,2,4-triazole-3-thione and 1,3,4-thiadiazole analogs as highly effective anticancer agents with good LSD1 target selectivity.

Enhanced microbial degradation of PET and PS microplastics under natural conditions in mangrove environment.

In-situ bioremediation of mangrove soil contaminated with polyethylene terephthalate (PET) and polystyrene (PS) microplastics was investigated using indigenous microbial consortium with adequate capacity to degrade the plastics. Eight (8) bacteria were isolated from plastic/microplastic-inundated mangrove soil and screened for the ability to degrade PET and PS microplastics. Optical density at 600 nm and colony forming unit counts were measured to evaluate the growth response of the microbes in the presence of PS and PET microplastics at different times of exposure. Structural and surface changes that occurred post biodegradation on the microplastics were determined through EDS and SEM analysis. The obtained results demonstrated the elongation and disappearance of peaks, suggesting that the microbial consortium could modify both types of microplastics. The overall results of the microplastic degradation showed varied degrees of weight loss after 90 experimental days, with the treated plot recorded 18% weight loss. The augmented soil was increased in the concentrations of Si S, and Fe and decreased in the concentrations of C, O, Na, Mg, Al, Cl, and K after bioremediation.

Effect of Two Different Rehabilitation Approaches on Pulmonary Functional Tests, Neuromuscular Functions and Quality of Life in Juvenile Myasthenia Gravis: A Randomized Controlled Trial Study.

Background and Objectives: Children with juvenile myasthenia gravis have a variety of symptoms, ranging from isolated intermittent ocular complaints to overall muscle weakness with or without respiratory insufficiency. This study aimed to investigate the efficacy of a specialized physical therapy with or without partial body weight supported treadmill training on pulmonary functional tests, neuromuscular functions, and quality of life. Materials and Methods: Thirty children, ranging in age from 13 to 16 years, were distributed randomly into two study groups (A or B). Both groups underwent a designed physical therapy program. In addition, group A underwent the partial body weight supported treadmill training. The treatment was conducted three times a week for 12 weeks successively. Pulmonary functional tests (FVC, FEV1, PEFR, and MVV), neuromuscular function tests (compound motor action potential, isometric muscle force of biceps brachii and rectus femoris, balance, walking endurance, and fatigue), and quality of life were measured before and after 12 successive weeks. Results: A significant improvement in all investigated variables were recorded in both groups in favor of group A. Conclusions: Both a specialized physical therapy and partial body weight supported treadmill training are effective in terms of enhancing pulmonary functional tests, neuromuscular functions, and quality of life. Partial body weight supported treadmill training is an excellent adjunctive to the physical therapy program.

Identification of warning signs in Malaysian patients having COVID-19 infection who progress to severe form of the illness.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is an infectious disease caused by a novel coronavirus, now widely known as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused 3 major pandemic waves in Malaysia. We aimed to identify the warning signs as indicators that predict the progression of disease. MATERIALS AND METHODS: This is a retrospective cohort study of adult patients more than 12 years of age presenting with laboratory-confirmed COVID-19 admitted in three separate hospitals around the country. RESULTS: Of the 228 patients initially admitted with mild illness, 47 had progressed requiring oxygen. The median time from admission to deterioration was 3 days (IQR 2 - 5). Age more than ≥50years old (median age = 42.5, IQR = 28.8 - 57.0), higher temperature (mean = 37.3, IQR 36.8 - 38.0), MEWS score >3 (9, 19.1%), Neutrophil-to-lymphocyte ratio (NLR) >3.13 , (18, 38.3%) C-reactive protein (CRP) >5. (12, 27.3%), multiple zonal involvement on the chest radiography on admission (2, IQR 1-3) were more common in the deteriorated group on admission. On multivariate analysis, multiple comorbidities (HR = 7.40, 95 percent CI 2.58-21.2, p0.001), presence of persistent fever (HR = 2.88, 95 percent CI 1.15 - 7.2, p = 0.024), MEWS scoring >3 (HR of 6.72 ;95 percent CI 2.81-16.0, p0.001) were associated with progression to severe illness. CONCLUSION: In our cohort, we found that several factors were associated with the severity of COVID19. Early detection of these factors could correctly identify patients who need more intensive monitoring, and early referral for ICU care.

Covalent and non-covalent binding free energy calculations for peptidomimetic inhibitors of SARS-CoV-2 main protease.

COVID-19, the disease caused by the newly discovered coronavirus-SARS-CoV-2, has created a global health, social, and economic crisis. As of mid-January 2021, there are over 90 million confirmed cases and more than 2 million reported deaths due to COVID-19. Currently, there are very limited therapeutics for the treatment or prevention of COVID-19. For this reason, it is important to find drug targets that will lead to the development of safe and effective therapeutics against the disease. The main protease (Mpro) of the virus is an attractive target for the development of effective antiviral therapeutics because it is required for proteolytic cleavage of viral polyproteins. Furthermore, the Mpro has no human homologues, so drugs designed to bind to this target directly have less risk for off-target effects. Recently, several high-resolution crystallographic structures of the Mpro in complex with inhibitors have been determined-to guide drug development and to spur efforts in structure-based drug design. One of the primary objectives of modern structure-based drug design is the accurate prediction of receptor-ligand binding affinities for rational drug design and discovery. Here, we perform rigorous alchemical absolute binding free energy calculations and QM/MM calculations to give insight into the total binding energy of two recently crystallized inhibitors of SARS-CoV-2 Mpro, namely, N3 and α-ketoamide 13b. The total binding energy consists of both covalent and non-covalent binding components since both compounds are covalent inhibitors of the Mpro. Our results indicate that the covalent and non-covalent binding free energy contributions of both inhibitors to the Mpro target differ significantly. The N3 inhibitor has more favourable non-covalent interactions, particularly hydrogen bonding, in the binding site of the Mpro than the α-ketoamide inhibitor. Also, the Gibbs energy of reaction for the Mpro-N3 covalent adduct is greater than the Gibbs reaction energy for the Mpro-α-ketoamide covalent adduct. These differences in the covalent and non-covalent binding free energy contributions for both inhibitors could be a plausible explanation for their in vitro differences in antiviral activity. Our findings are consistent with the reversible and irreversible character of both inhibitors as reported by experiment and highlight the importance of both covalent and non-covalent binding free energy contributions to the absolute binding affinity of a covalent inhibitor towards its target. This information could prove useful in the rational design, discovery, and evaluation of potent SARS-CoV-2 Mpro inhibitors for targeted antiviral therapy.

Efficacy of two intervention approaches on functional walking capacity and balance in children with Duchene muscular dystrophy.

OBJECTIVES: Children with Duchene muscular dystrophy have weak muscles, which may impair postural adjustments. These postural adjustments are required for gait and dynamic balance during the daily living activities. The aim was to compare between the effect of bicycle ergometer versus treadmill on functional walking capacity and balance in children with Duchenne muscular dystrophy. METHODS: Thirty boys aged from 6 to 10 years old diagnosed as Duchene muscular dystrophy participated in this study. Children were assigned randomly into two groups (A&B). Children in group (A) underwent a designed program of physical therapy plus aerobic exercise training in form of bicycle ergometer while, group (B) received the same program as group (A) and aerobic exercise training by treadmill for one hour, at three times a week for three successive months. Functional walking capacity and balance were assessed before and after treatment by using the 6-minute walk test and Biodex balance system equipment respectively. RESULTS: The post treatment results revealed significant difference in all measured variables (P<0.05) as compared with its pre-treatment results. Post-treatment values indicated that there was a significant difference in all measured variables in favor of group B. CONCLUSIONS: treadmill training as an aerobic exercise can improve walking capacity and balance more effectively than bicycle ergometer in children with Duchenne muscular dystrophy.