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1.
Phys Med Biol ; 69(12)2024 Jun 11.
Article in English | MEDLINE | ID: mdl-38821109

ABSTRACT

Objective.The validation of deformable image registration (DIR) for contour propagation is often done using contour-based metrics. Meanwhile, dose accumulation requires evaluation of voxel mapping accuracy, which might not be accurately represented by contour-based metrics. By fabricating a deformable anthropomorphic pelvis phantom, we aim to (1) quantify the voxel mapping accuracy for various deformation scenarios, in high- and low-contrast regions, and (2) identify any correlation between dice similarity coefficient (DSC), a commonly used contour-based metric, and the voxel mapping accuracy for each organ.Approach. Four organs, i.e. pelvic bone, prostate, bladder and rectum (PBR), were 3D printed using PLA and a Polyjet digital material, and assembled. The latter three were implanted with glass bead and CT markers within or on their surfaces. Four deformation scenarios were simulated by varying the bladder and rectum volumes. For each scenario, nine DIRs with different parameters were performed on RayStation v10B. The voxel mapping accuracy was quantified by finding the discrepancy between true and mapped marker positions, termed the target registration error (TRE). Pearson correlation test was done between the DSC and mean TRE for each organ.Main results. For the first time, we fabricated a deformable phantom purely from 3D printing, which successfully reproduced realistic anatomical deformations. Overall, the voxel mapping accuracy dropped with increasing deformation magnitude, but improved when more organs were used to guide the DIR or limit the registration region. DSC was found to be a good indicator of voxel mapping accuracy for prostate and rectum, but a comparatively poorer one for bladder. DSC > 0.85/0.90 was established as the threshold of mean TRE ⩽ 0.3 cm for rectum/prostate. For bladder, extra metrics in addition to DSC should be considered.Significance. This work presented a 3D printed phantom, which enabled quantification of voxel mapping accuracy and evaluation of correlation between DSC and voxel mapping accuracy.


Subject(s)
Pelvis , Phantoms, Imaging , Humans , Pelvis/diagnostic imaging , Radiation Dosage , Image Processing, Computer-Assisted/methods , Tomography, X-Ray Computed , Male , Printing, Three-Dimensional
2.
J Appl Clin Med Phys ; : e14348, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38561975

ABSTRACT

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

3.
Phys Imaging Radiat Oncol ; 29: 100552, 2024 Jan.
Article in English | MEDLINE | ID: mdl-38405428

ABSTRACT

Background and purpose: High-density dental fillings pose a non-negligible impact on head and neck cancer treatment. For proton therapy, stopping power ratio (SPR) prediction will be significantly impaired by the associated image artifacts. Dose perturbation is also inevitable, compromising the treatment plan quality. While plenty of work has been done on metal or amalgam fillings, none has touched on composite resin (CR) and glass ionomer cement (GIC) which have seen an increasing usage. Hence, this work aims to provide a detailed characterisation of SPR and dose perturbation in proton therapy caused by CR and GIC. Materials and methods: Four types of fillings were used: CR, Fuji Bulk (FB), Fuji II (FII) and Fuji IX (FIX). The latter three belong to GIC category. Measured SPR were compared with SPR predicted using single-energy computed tomography (SECT) and dual-energy computed tomography (DECT). Dose perturbation of proton beams with lower- and higher-energy levels was also quantified using Gafchromic films. Results: The measured SPR for CR, FB, FII and FIX were 1.68, 1.77, 1.77 and 1.76, respectively. Overall, DECT could predict SPR better than SECT. The lowest percentage error achieved by DECT was 19.7 %, demonstrating the challenge in estimating SPR, even for fillings with relatively lower densities. For both proton beam energies and all four fillings of about 4.5 mm thickness, the maximum dose perturbation was 3 %. Conclusion: This study showed that dose perturbation by CR and GIC was comparatively small. We have measured and recommended the SPR values for overriding the fillings in TPS.

4.
Nucleic Acids Res ; 52(5): 2578-2589, 2024 Mar 21.
Article in English | MEDLINE | ID: mdl-38261972

ABSTRACT

The loading of RecA onto ssDNA by RecBCD is an essential step of RecBCD-mediated homologous recombination. RecBCD facilitates RecA-loading onto ssDNA in a χ-dependent manner via its RecB nuclease domain (RecBn). Before recognition of χ, RecBn is sequestered through interactions with RecBCD. It was proposed that upon χ-recognition, RecBn undocks, allowing RecBn to swing out via a contiguous 70 amino acid linker to reveal the RecA-loading surface, and then recruit and load RecA onto ssDNA. We tested this hypothesis by examining the interactions between RecBn (RecB928-1180) and truncated RecBCD (RecB1-927CD) lacking the nuclease domain. The reconstituted complex of RecB1-927CD and RecBn is functional in vitro and in vivo. Our results indicate that despite being covalently severed from RecB1-927CD, RecBn can still load RecA onto ssDNA, establishing that RecBn does not function while only remaining tethered to the RecBCD complex via the linker. Instead, RecBCD undergoes a χ-induced intramolecular rearrangement to reveal the RecA-loading surface.


Subject(s)
Escherichia coli Proteins , Exodeoxyribonuclease V , Rec A Recombinases , DNA, Single-Stranded/genetics , Endonucleases/metabolism , Escherichia coli Proteins/metabolism , Exodeoxyribonuclease V/metabolism , Exodeoxyribonucleases/metabolism , Rec A Recombinases/metabolism
5.
J Appl Clin Med Phys ; 25(2): e14154, 2024 Feb.
Article in English | MEDLINE | ID: mdl-37683120

ABSTRACT

BACKGROUND: Tolerance limit is defined on pre-treatment patient specific quality assurance results to identify "out of the norm" dose discrepancy in plan. An out-of-tolerance plan during measurement can often cause treatment delays especially if replanning is required. In this study, we aim to develop an outlier detection model to identify out-of-tolerance plan early during treatment planning phase to mitigate the above-mentioned risks. METHODS: Patient-specific quality assurance results with portal dosimetry for stereotactic body radiotherapy measured between January 2020 and December 2021 were used in this study. Data were divided into thorax and pelvis sites and gamma passing rates were recorded using 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria. Statistical process control method was used to determine six different site and criterion-specific tolerance and action limits. Using only the inliers identified with our determined tolerance limits, we trained three different outlier detection models using the plan complexity metrics extracted from each treatment field-robust covariance, isolation forest, and one class support vector machine. The hyperparameters were optimized using the F1-score calculated from both the inliers and validation outliers' data. RESULTS: 308 pelvis and 200 thorax fields were used in this study. The tolerance (action) limits for 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria in the pelvis site are 99.1% (98.1%), 95.8% (91.1%), and 91.7% (86.1%), respectively. The tolerance (action) limits in the thorax site are 99.0% (98.7%), 97.0% (96.2%), and 91.5% (87.2%). One class support vector machine performs the best among all the algorithms. The best performing model in the thorax (pelvis) site achieves a precision of 0.56 (0.54), recall of 1.0 (1.0), and F1-score of 0.72 (0.70) when using the 2%/2 mm (2%/1 mm) criterion. CONCLUSION: The model will help the planner to identify an out-of-tolerance plan early so that they can refine the plan further during the planning stage without risking late discovery during measurement.


Subject(s)
Radiosurgery , Radiotherapy, Intensity-Modulated , Humans , Radiotherapy Planning, Computer-Assisted/methods , Radiotherapy Dosage , Algorithms , Pelvis , Radiometry/methods , Radiotherapy, Intensity-Modulated/methods , Quality Assurance, Health Care
7.
Phys Med Biol ; 68(15)2023 07 28.
Article in English | MEDLINE | ID: mdl-37437590

ABSTRACT

Objective. Automatic deformable image registration (DIR) is a critical step in adaptive radiotherapy. Manually delineated organs-at-risk (OARs) contours on planning CT (pCT) scans are deformably registered onto daily cone-beam CT (CBCT) scans for delivered dose accumulation. However, evaluation of registered contours requires human assessment, which is time-consuming and subjects to high inter-observer variability. This work proposes a deep learning model that allows accurate prediction of Dice similarity coefficients (DSC) of registered contours in prostate radiotherapy.Approach. Our dataset comprises 20 prostate cancer patients with 37-39 daily CBCT scans each. The pCT scans and planning contours were deformably registered to each corresponding CBCT scan to generate virtual CT (vCT) scans and registered contours. The DSC score, which is a common contour-based validation metric for registration quality, between the registered and manual contours were computed. A Siamese neural network was trained on the vCT-CBCT image pairs to predict DSC. To assess the performance of the model, the root mean squared error (RMSE) between the actual and predicted DSC were computed.Main results. The model showed promising results for predicting DSC, giving RMSE of 0.070, 0.079 and 0.118 for rectum, prostate, and bladder respectively on the holdout test set. Clinically, a low RMSE implies that the predicted DSC can be reliably used to determine if further DIR assessment from physicians is required. Considering the event where a registered contour is classified as poor if its DSC is below 0.6 and good otherwise, the model achieves an accuracy of 92% for the rectum. A sensitivity of 0.97 suggests that the model can correctly identify 97% of poorly registered contours, allowing manual assessment of DIR to be triggered.Significance. We propose a neural network capable of accurately predicting DSC of deformably registered OAR contours, which can be used to evaluate eligibility for plan adaptation.


Subject(s)
Head and Neck Neoplasms , Male , Humans , Radiotherapy Planning, Computer-Assisted/methods , Tomography, X-Ray Computed/methods , Cone-Beam Computed Tomography/methods , Neural Networks, Computer , Image Processing, Computer-Assisted/methods , Algorithms
8.
Intern Med J ; 53(4): 517-524, 2023 04.
Article in English | MEDLINE | ID: mdl-34748260

ABSTRACT

BACKGROUND: Warfarin for the prevention of non-valvular atrial fibrillation (AF)-related thromboembolic stroke in patients on maintenance haemodialysis is controversial. Despite the exclusion of haemodialysis patients in randomised control trials, the American Heart Association/American College of Cardiology has recommended warfarin in high-risk AF patients. AIMS: To retrospectively examine the utility of warfarin anticoagulation therapy in our prevalent haemodialysis patients over 10 years of follow up. METHODS: Eligible patients were retrospectively identified and stratified to two cohorts based on whether warfarin was prescribed. The outcomes of interest were ischaemic stroke, haemorrhagic stroke and death from any cause. Rate ratio and Cox proportional hazard regression model were used to compare the differences in outcome between the two cohorts. The Kaplan-Meier method was used to analyse survival. RESULTS: Three ischaemic strokes and four haemorrhagic strokes occurred in the unexposed group of 166 patients over 484.44 patient-years of follow up. One ischaemic stroke and no cases of haemorrhagic stroke occurred in the exposed warfarin group of 16 patients over 39.32 patient-years of follow up. Eighty-seven percent of patients in both groups were indigenous. More than 90% of each cohort had a CHA2DS2-VaSc score ≥2. One hundred and one deaths, 90 in the unexposed group and 11 in the warfarin group, occurred in the follow-up period. A non-statistically significant trend towards increasing mortality was observed in the warfarin group (hazard ratio = 1.63; P = 0.13). CONCLUSION: This retrospective study of prevalent haemodialysis patients with co-existing history of non-valvular AF failed to demonstrate sufficient evidence for the routine use of warfarin for prophylaxis of thromboembolic stroke.


Subject(s)
Atrial Fibrillation , Brain Ischemia , Stroke , United States , Humans , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Warfarin/adverse effects , Retrospective Studies , Stroke/epidemiology , Stroke/prevention & control , Stroke/etiology , Brain Ischemia/complications , Anticoagulants/adverse effects , Renal Dialysis/adverse effects , Risk Factors
9.
Phys Med ; 105: 102513, 2023 Jan.
Article in English | MEDLINE | ID: mdl-36565555

ABSTRACT

This paper aims to review on fetal dose in radiotherapy and extends and updates on a previous work1 to include proton therapy. Out-of-field doses, which are the doses received by regions outside of the treatment field, are unavoidable regardless of the treatment modalities used during radiotherapy. In the case of pregnant patients, fetal dose is a major concern as it has long been recognized that fetuses exposed to radiation have a higher probability of suffering from adverse effects such as anatomical malformations and even fetal death, especially when the 0.1Gy threshold is exceeded. In spite of the low occurrence of cancer during pregnancy, the radiotherapy team should be equipped with the necessary knowledge to deal with fetal dose. This is crucial so as to ensure that the fetus is adequately protected while not compromising the patient treatment outcomes. In this review paper, various aspects of fetal dose will be discussed ranging from biological, clinical to the physics aspects. Other than fetal dose resulting from conventional photon therapy, this paper will also extend the discussion to modern treatment modalities and techniques, namely proton therapy and image-guided radiotherapy, all of which have seen a significant increase in use in current radiotherapy. This review is expected to provide readers with a comprehensive understanding of fetal dose in radiotherapy, and to be fully aware of the steps to be taken in providing radiotherapy for pregnant patients.


Subject(s)
Fetus , Pregnancy Complications, Neoplastic , Radiotherapy Dosage , Female , Humans , Pregnancy , Fetus/radiation effects , Proton Therapy/adverse effects , Pregnancy Complications, Neoplastic/radiotherapy
10.
Cells ; 11(22)2022 11 13.
Article in English | MEDLINE | ID: mdl-36429016

ABSTRACT

Lung cancer is the leading cause of cancer death in the world. In particular, non-small-cell lung cancer (NSCLC) represents the majority of the lung cancer population. Advances in DNA sequencing technologies have significantly contributed to revealing the roles, functions and mechanisms of gene mutations. However, the driver mutations that cause cancers and their pathologies remain to be explored. Here, we performed next-generation sequencing (NGS) on tumor tissues isolated from 314 Chinese NSCLC patients and established the mutational landscape in NSCLC. Among 656 mutations, we identified TP53-p.Glu358Val as a driver mutation in lung cancer and found that it activates mitophagy to sustain cancer cell growth. In support of this finding, mice subcutaneously implanted with NSCLC cells expressing TP53-p.Glu358Val developed larger tumors compared to wild-type cells. The pharmaceutical inhibition of autophagy/mitophagy selectively suppresses the cell proliferation of TP53-null or TP53-p.Glu358Val-expressing lung cancer cells. Together, our study characterizes a new TP53 mutation identified from Chinese lung cancer patients and uncovers its roles in regulating mitophagy, providing a new insight into NSCLC treatment.


Subject(s)
Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Animals , Mice , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/pathology , Genes, p53 , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Mitophagy/genetics , Mutation/genetics , Tumor Suppressor Protein p53/genetics , Humans
11.
Otol Neurotol ; 43(8): 856-863, 2022 09 01.
Article in English | MEDLINE | ID: mdl-35941671

ABSTRACT

OBJECTIVE: IgG4-related disease (IgG4-RD) involving the temporal bone is an uncommon and underrecognized pathology often mistaken for malignancy. This systematic review is the first that aims to thoroughly analyze IgG4-RD of the temporal bone. DATABASES REVIEWED: Ovid MEDLINE, EMBASE, Cochrane Library, and Google Scholar. METHODS: We used the following search keywords: "lgG4-RD," "skull," "skull base," "cranial," "temporal bone," "inner ear." We additionally manually searched the bibliographies of relevant articles. The JBI Critical Appraisal Checklist for Case Reports and Case Series was used to assess the risk of bias; because of the scarcity of the reports, data were available through limited case series and reports; thus, data synthesis was not possible. RESULTS: We identified 17 studies with 22 cases with temporal bone involvement. The most common presenting symptoms were hearing loss, otalgia, and headache. The mastoid and petrous bone were the most affected anatomical areas. Both computed tomography and magnetic resonance imaging were used. Biopsies showed the characteristic lymphoplasmacytic infiltrate in all cases, with histopathology being the diagnostic modality that set the diagnosis. Most patients were treated with corticosteroids ± surgery or a combination of corticosteroids and immunosuppressants with 95.5% symptomatic response and disease control. CONCLUSION: IgG4-RD of the temporal bone radiologically manifests as space-occupying, lytic lesions; clinically, it presents with vague otological symptoms. Diagnosis involves a thorough workup, with histopathology being crucial in setting a definite diagnosis. IgG4-RD tends to respond well to systemic corticosteroids, whereas surgery is mostly required for diagnostic purposes.


Subject(s)
Immunoglobulin G4-Related Disease , Adrenal Cortex Hormones , Humans , Immunoglobulin G , Immunoglobulin G4-Related Disease/diagnosis , Skull Base , Temporal Bone/diagnostic imaging
13.
BMC Public Health ; 22(1): 469, 2022 03 09.
Article in English | MEDLINE | ID: mdl-35264136

ABSTRACT

BACKGROUND: Combating viral outbreaks extends beyond biomedical and clinical approaches; thus, public health prevention measures are equally important. Public engagement in preventive efforts can be viewed as the social responsibility of individuals in controlling an infectious disease and are subjected to change due to human behaviour. Understanding individuals' perception of social responsibility is crucial and is not yet explored extensively in the academic literature. We adopted the grounded theory method to develop an explanatory substantive theory to illustrate the process of how individual responded to the outbreak from a social responsibility perspective. METHODS: In-depth interviews were conducted among 23 Malaysians either through telephone or face-to-face depending on the participant's preference. Both purposive and theoretical sampling were used. Participants were invited to share their understanding, perceptions and activities during the COVID-19 pandemic. They were further probed about their perceptions on complying with the public health interventions imposed by the authorities. The interviews were audio-recorded and transcribed verbatim. Data was analysed via open coding, focus coding and theoretical coding, facilitated by memoing, sketching and modelling. RESULTS: Study findings showed that, social responsibility is perceived within its role, the perceived societal role responsibility. In a particular context, an individual assumed only one of the many expected social roles with their perceived circle of responsibility. Individuals negotiated their actions from this perspective, after considering the perceived risk during the outbreak. The four types of behaviour depicted in the matrix diagram facilitate the understanding of the abstract concept of negotiation in the human decision-making process, and provide the spectrum of different behaviour in relation to public response to the COVID-19 pandemic. CONCLUSIONS: Our study adopted the grounded theory approach to develop a theoretical model that illustrates how individual response to COVID-19 preventive measures is determined by the negotiation between perceived societal role responsibility and perceived infection risk. This substantive theoretical model is abstract, thus has relevance for adoption within similar context of an outbreak.


Subject(s)
COVID-19 , Grounded Theory , Humans , Pandemics/prevention & control , SARS-CoV-2 , Social Responsibility
14.
Trials ; 22(1): 868, 2021 Dec 02.
Article in English | MEDLINE | ID: mdl-34857020

ABSTRACT

BACKGROUND: The effectiveness of erythropoiesis-stimulating agents, which are the main stay of managing anaemia of chronic kidney disease (CKD), is largely dependent on adequate body iron stores. The iron stores are determined by the levels of serum ferritin concentration and transferrin saturation. These two surrogate markers of iron stores are used to guide iron replacement therapy. Most Aboriginal and/or Torres Islander Australians of the Northern Territory (herein respectfully referred to as First Nations Australians) with end-stage kidney disease have ferritin levels higher than current guideline recommendations for iron therapy. There is no clear evidence to guide safe and effective treatment with iron in these patients. We aim to assess the impact of intravenous iron treatment on all-cause death and hospitalisation with a principal diagnosis of all-cause infection in First Nations patients on haemodialysis with anaemia, high ferritin levels and low transferrin saturation METHODS: In a prospective open-label blinded endpoint randomised controlled trial, a total of 576 participants on maintenance haemodialysis with high ferritin (> 700 µg/L and ≤ 2000 µg/L) and low transferrin saturation (< 40%) from all the 7 renal units across the Northern Territory of Australia will be randomised 1:1 to receive intravenous iron polymaltose 400 mg once monthly (200 mg during 2 consecutive haemodialysis sessions) (Arm A) or no IV iron treatment (standard treatment) (Arm B). Rescue therapy will be administered when the ferritin levels fall below 700 µg/L or when clinically indicated. The primary outcome will be the differences between the two study arms in the risk of hospitalisation with all-cause infection or death. An economic analysis and several secondary and tertiary outcomes analyses will also be performed. DISCUSSION: The INFERR clinical trial will address significant uncertainty on the safety and efficacy of iron therapy in First Nations Australians with CKD with hyperferritinaemia and evidence of iron deficiency. This will hopefully lead to the development of evidence-based guidelines. It will also provide the opportunity to explore the causes of hyperferritinaemia in First Nations Australians from the Northern Territory. TRIAL REGISTRATION: This trial is registered with The Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12620000705987 . Registered 29 June 2020.


Subject(s)
Indigenous Peoples , Iron Deficiencies , Australia , Ferric Compounds , Ferritins , Humans , Iron , Iron Deficiencies/ethnology , Iron Deficiencies/therapy , Prospective Studies , Randomized Controlled Trials as Topic , Renal Dialysis
15.
Transpl Int ; 34(11): 2329-2340, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34339557

ABSTRACT

Social disparity is a major impediment to optimal health outcomes after kidney transplantation. In this study, we aimed to define the association between socio-economic status (SES) disparities and patient-relevant outcomes after kidney allograft failure. Using data from the Australia and New Zealand Dialysis and Transplant registry, we included patients with failed first-kidney allografts in Australia between 2005 and 2017. The association between residential postcode-derived SES in quintiles (quintile 1-most disadvantaged areas, quintile 5-most advantaged areas) with uptake of home dialysis (peritoneal or home haemodialysis) within the first 12-months post-allograft failure, repeat transplantation and death on dialysis were examined using competing-risk analysis. Of 2175 patients who had experienced first allograft failure, 417(19%) and 505(23%) patients were of SES quintiles 1 and 5, respectively. Compared to patients of quintile 5, quintile 1 patients were less likely to receive repeat transplants (adjusted subdistributional hazard ratio [SHR] 0.70,95%CI 0.55-0.89) and were more likely to die on dialysis (1.37 [1.04-1.81]), but there was no association with the uptake of home dialysis (1.02 [0.77-1.35]). Low SES may have a negative effect on outcomes post-allograft failure and further research is required into how best to mitigate this. However, small-scale variation within SES cannot be accounted for in this study.


Subject(s)
Kidney Failure, Chronic , Allografts , Health Services Accessibility , Humans , Kidney , Kidney Failure, Chronic/surgery , Registries , Renal Dialysis , Social Class , Treatment Outcome
16.
Bioorg Med Chem Lett ; 48: 128263, 2021 09 15.
Article in English | MEDLINE | ID: mdl-34271072

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.


Subject(s)
Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Cysteine Proteinase Inhibitors/chemistry , Peptidomimetics/chemistry , SARS-CoV-2/enzymology , Antiviral Agents/metabolism , Coronavirus 3C Proteases/metabolism , Cysteine Proteinase Inhibitors/metabolism , Enzyme Assays , Fluorescence Resonance Energy Transfer , Inhibitory Concentration 50 , Peptidomimetics/metabolism , Protein Binding
17.
Medicine (Baltimore) ; 100(16): e25590, 2021 Apr 23.
Article in English | MEDLINE | ID: mdl-33879720

ABSTRACT

RATIONALE: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been approved and marketed since March 2013. The proportion of patients with type 2 diabetes (T2D) taking SGLT2 inhibitors is increasing. The perioperative adverse effects of SGLT2 inhibitors, especially euglycemic diabetic ketoacidosis (euDKA), should be taken into consideration in perioperative patient evaluation in both elective and emergency surgeries. PATIENT CONCERNS: A 57-year-old woman taking SGLT2 inhibitors for T2D developed euDKA after undergoing an emergency orthopedic surgery; the euDKA diagnosis was delayed, thereby causing extremity gangrene. DIAGNOSES: EuDKA was diagnosed based on the presence of strongly positive ketonuria, elevated blood beta-hydroxybutyrate level, and severe metabolic acidosis. INTERVENTION: EuDKA was treated with insulin infusion with dextrose solution and intravenous fluid resuscitation. OUTCOME: Due to a delayed diagnosis of euDKA, the patient received a high-dose vasopressor, which led to limb gangrene and amputation 6 months later. LESSONS: EuDKA is often misdiagnosed due to the absence of hyperglycemia. Serum beta-hydroxybutyrate levels or urinalysis could be used as screening tools for euDKA in patients scheduled for emergency surgery, in order to preoperatively administer rapid fluid resuscitation and insulin infusion with dextrose solution, which should continue postoperatively along with serum beta-hydroxybutyrate monitoring.


Subject(s)
Diabetes Mellitus, Type 2/surgery , Diabetic Ketoacidosis/chemically induced , Gangrene/chemically induced , Hypoglycemic Agents/adverse effects , Postoperative Complications/chemically induced , Sodium-Glucose Transporter 2 Inhibitors/adverse effects , Diabetes Mellitus, Type 2/drug therapy , Female , Humans , Middle Aged
18.
J Vis Exp ; (168)2021 02 09.
Article in English | MEDLINE | ID: mdl-33645581

ABSTRACT

Spirocyclic heterocycles have recently been reported in literature to be potential drugs for cancer therapy. The synthesis of these novel orthogonal ring systems is challenging. An efficient methodology to synthesize these compounds was recently published that described the solid phase synthesis in four steps rather than the previously reported five steps. The advantage of this shorter synthesis is the elimination of the use of toxic reagents. Low-loading Regenerating Michael (REM) linker-based resin was found to be crucial in the synthesis as high-loading versions prevented the addition of reagents containing bulky phenyl and aromatic side chains. The colorimetric 3-(4',5'-dimethylthiazol-2'-yl)-2,5- diphenyltetrazolium bromide (MTT) assay was used to examine the cytotoxicity of micromolar concentrations of these novel spirocyclic molecules in vitro. MTT is readily available commercially and produces relatively fast, reliable results, making this assay ideal for these spirocyclic heterocycles. Orthogonal ring structures as well as furfurylamine (a precursor in the synthesis method containing a similar 5-member ring motif) were tested.


Subject(s)
Cell Proliferation , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/pharmacology , Solid-Phase Synthesis Techniques/methods , Spiro Compounds/chemical synthesis , Spiro Compounds/pharmacology , Animals , COS Cells , Chlorocebus aethiops
19.
Front Psychiatry ; 12: 772744, 2021.
Article in English | MEDLINE | ID: mdl-35046852

ABSTRACT

Postnatal depression is a major illness affecting maternal and family health. The rate of postnatal depression among mental health clients is postulated to be higher than in the community due to the added brain assault. Children of parents who are mental health clients are more likely to have psychological problems compared to children from other parents in the community. This study investigates the rate of postnatal depression among mental health clients and their offspring's psychological health. A total of 140 mental health clients were assessed using the Edinburgh Postnatal Depression Scale (EPDS). They subsequently completed the Strength and Difficulties Questionnaire (SDQ) regarding their children. The majority ethnicity was the Kadazan (40.7%). The mean age of mothers was 38.6 (7) years with most having a secondary education (53.6%) and a household income per month of < RM1000 per month (27.1%). The postnatal depression rate was 47.8%. Higher EPDS scores were associated with higher total SDQ scores in their offspring. Model 1 was unadjusted, giving an OR of 5.65 [95% CI (3.74, 7.55)], p < 0.001. After adjustment for confounders, Model 2 had an OR of 5.51 [95% CI (3.57, 7.46)], p < 0.001. More efforts need to be given to the early detection of maternal depression and its prompt treatment in mental health clients because of the relationship with the psychological health of the offspring.

20.
J Med Screen ; 28(3): 238-243, 2021 09.
Article in English | MEDLINE | ID: mdl-33202173

ABSTRACT

OBJECTIVE: To evaluate and discuss the outcomes of the universal newborn hearing screening program conducted at four public hospitals in Malaysia. METHOD: A retrospective analysis of the universal newborn hearing screening database from each hospital was performed. The database consisted of 28,432 and 30,340 screening results of babies born in 2015 and 2016, respectively. Quality indicators (coverage rate, referral rate, return for follow-up rate, and ages at screening and diagnosis) were calculated. RESULTS: Overall coverage rate across the four hospitals was 75% in 2015 and 87.4% in 2016. Over the two years, the referral rates for the first screening ranged from 2.7% to 33.93% with only one hospital achieving the recommended benchmark of <4% in both years. The return for follow-up rates for each participating hospital was generally below the recommended benchmark of ≥95%. The mean age at screening was 3.9 ± 1.2 days and 3.3 ± 0.4 days, respectively. The mean age at diagnosis for 70 infants diagnosed with permanent hearing loss was 4.7 ± 0.7 months in 2015 and 3.6 ± 0.9 months in 2016. CONCLUSIONS: Quality measures for the universal newborn hearing screening program in four public hospitals in Malaysia were lower than the required standards. Nevertheless, some quality indicators showed statistically significant improvements over the two years. Next steps involve identifying and implementing the best practice strategies to improve the outcome measures and thus the quality of the program.


Subject(s)
Neonatal Screening , Quality Indicators, Health Care , Child , Hearing , Hearing Tests , Humans , Infant , Infant, Newborn , Malaysia/epidemiology , Retrospective Studies
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