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Abstract Background Numerous medical resource demand models have been created as tools for governments or hospitals, aiming to predict the need for crucial resources like ventilators, hospital beds, personal protective equipment (PPE), and diagnostic kits during crises such as the COVID-19 pandemic. However, the reliability of these demand models remains uncertain. Methods Demand models typically consist of two main components: hospital use epidemiological models that predict hospitalizations or daily admissions, and a demand calculator that translates the outputs of the epidemiological model into predictions for resource usage. We conducted separate analyses to evaluate each of these components. In the first analysis, we validated various hospital use epidemiological models using a recent validation framework designed for epidemiological models. This allowed us to quantify the accuracy of the models in predicting critical aspects such as the date and magnitude of local COVID-19 peaks, among other factors. In the second analysis, we evaluated a range of demand calculators for ventilators, medical gowns, and COVID-19 test kits. To achieve this, we decoupled these demand calculators from the underlying epidemiological models and provided ground truth data for their inputs. This approach enabled a direct comparison of the demand calculators, comparing them against each other and actual usage data when available. The code is available at https://doi.org/10.5281/zenodo.13712387 . Results Performance varied greatly across the epidemiological models, with greater variability in COVID-19 hospital use predictions than for COVID-19 deaths as analyzed previously. Some models did not have any peaks. Among those that did, the models under-estimated date of peak approximately as often as they over-estimated, but were more likely to under-estimate magnitude of peak, with typical relative errors around 50%. Regarding demand calculator predictions, there was significant variability, including five-fold differences in predictions for gown models. Validation against actual or surrogate usage data illustrated the potential value of demand models while demonstrating their limitations. Conclusions The emerging field of demand modeling holds promise in averting medical resource shortages during future public health emergencies. However, achieving this potential necessitates focused efforts on standardization, transparency, and rigorous model validation before placing reliance on demand models in critical public health decision-making.

Abstract Background The effect of nirmatrelvir/ritonavir on preventing post-COVID condition (PCC) in the BA4, BA5, and XBB Omicron predominant periods is not well understood. The purpose of this study was to assess how nirmatrelvir/ritonavir treatment affected both PCC and health-related quality of life. Methods This retrospective cohort study enrolled 2,524 adults aged 18 years and older who were eligible for nirmatrelvir/ritonavir between July 14 to November 14, 2022. All outcomes were observed from the patient’s first visit to the primary health clinic, 1 week, 1 month, 3 months, and 6 months after testing positive for COVID-19. The primary outcome was the presence of PCC. Secondary outcomes included the effects on health-related quality of life, such as walking, bathing and dressing, activities, cause adverse emotions or signs that prevent individuals from leading normal lives over a 180-day observation period. Results There were no significant differences observed between the nirmatrelvir/ritonavir and those not administered (control group) in terms of PCC symptoms at 3 months (OR 0.71 95% CI 0.31, 1.64) and 6 months (OR 1.30 95% CI 0.76, 2.21). At 3 months, the use of nirmatrelvir/ritonavir was associated with a 26% reduction in symptoms causing negative emotions (OR 0.74 95% CI 0.60, 0.92) and an increased likelihood of symptoms limiting walking (OR 1.58 95% CI 1.10, 2.27). However, there were no significant differences between the nirmatrelvir/ritonavir and the control group in terms of the impact of PCC on health-related quality of life at 6 months. Conclusions Our study indicates that the administration of nirmatrelvir/ritonavir does not significantly reduce PCC after 3 months and 6 months in a population with high vaccination coverage.

Abstract Triple-negative breast cancers (TNBCs) are a subset of breast cancers that have remained difficult to treat. A proportion of TNBCs arising in non-carriers of BRCA pathogenic variants have genomic features that are similar to BRCA carriers and may also benefit from PARP inhibitor treatment. Using genomic data from 129 TNBC samples from the Malaysian Breast Cancer (MyBrCa) cohort, we developed a gene expression-based machine learning classifier for homologous recombination deficiency (HRD) in TNBCs. The classifier identified samples with HRD mutational signature at an AUROC of 0.93 in MyBrCa validation datasets and 0.84 in TCGA TNBCs. Additionally, the classifier strongly segregated HRD-associated genomic features in TNBCs from TCGA, METABRIC, and ICGC. Thus, our gene expression classifier may identify triple-negative breast cancer patients with homologous recombination deficiency, suggesting an alternative method to identify individuals who may benefit from treatment with PARP inhibitors or platinum chemotherapy.

Abstract This work proposes a functional data analysis approach for morphometrics in classifying three shrew species (S. murinus, C. monticola, and C. malayana) from Peninsular Malaysia. Functional data geometric morphometrics (FDGM) for 2D landmark data is introduced and its performance is compared with classical geometric morphometrics (GM). The FDGM approach converts 2D landmark data into continuous curves, which are then represented as linear combinations of basis functions. The landmark data was obtained from 89 crania of shrew specimens based on three craniodental views (dorsal, jaw, and lateral). Principal component analysis and linear discriminant analysis were applied to both GM and FDGM methods to classify the three shrew species. This study also compared four machine learning approaches (naïve Bayes, support vector machine, random forest, and generalised linear model) using predicted PC scores obtained from both methods (a combination of all three craniodental views and individual views). The analyses favoured FDGM and the dorsal view was the best view for distinguishing the three species.

Abstract Background and objectives Nirmatrelvir/ritonavir was administered orally to manage mild to moderate symptoms of COVID-19 in adult patients. The objectives of this study were to (i) evaluate the cost-effectiveness of prescribing nirmatrelvir/ritonavir within 5 days of a COVID-19 illness in order to avert hospitalization within a 30-day period in the Malaysia setting; (ii) determine how variations in pricing and hospitalization rates will affect the cost-effectiveness of nirmatrelvir/ritonavir. Methods The 30-day hospitalization related to COVID-19 was determined using 1 to 1 propensity score-matched real-world data in Malaysia from 14 July 2022 to 14 November 2022. To determine the total per-person costs related to COVID-19, we added the cost of drug (nirmatrelvir/ritonavir or control), clinic visits and inpatient care. Incremental cost-effectiveness ratio (ICER) per hospitalization averted was calculated. Results Our cohort included 31,487 patients. The rate of hospitalization within 30 days was found to be 0.35% for the group treated with nirmatrelvir/ritonavir, and 0.52% for the control group. The nirmatrelvir/ritonavir group cost an additional MYR 1,625.72 (USD 358.88) per patient. This treatment also resulted in a reduction of 0.17% risk for hospitalization, which corresponded to an ICER of MYR 946,801.26 (USD 209,006.90) per hospitalization averted. Conclusion In Malaysia, where vaccination rates were high, nirmatrelvir/ritonavir has been shown to be beneficial in the outpatient treatment of adults with COVID-19 who have risk factors; however, it was only marginally cost effective against hospitalization for healthy adults during the Omicron period.

Abstract Breast cancer exhibits significant heterogeneity, manifesting in various subtypes that are critical in guiding treatment decisions. This study aimed to investigate the existence of distinct subtypes of breast cancer within the Asian population, by analysing the transcriptomic profiles of 934 breast cancer patients from a Malaysian cohort. Our findings reveal that the HR + /HER2− breast cancer samples display a distinct clustering pattern based on immune phenotypes, rather than conforming to the conventional luminal A-luminal B paradigm previously reported in breast cancers from women of European descent. This suggests that the activation of the immune system may play a more important role in Asian HR + /HER2− breast cancer than has been previously recognized. Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2− samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

Steel poles are extensively used as street light posts and various other applications within the power distribution network. For partially buried pole, the effect of corrosion below and at the ground level significantly controls the overall load capacity. In this study, number of in-service steel pole specimens extracted from field were assessed for the corrosion damage. The level of corrosion was estimated by remaining wall thickness measured using ultrasonic testing and the surface corrosion was estimated using 3D laser scanning to adopt an appropriate existing model for buried steel structures. A relationship between maximum and average corrosion pit depth and loss of embedment depth was then developed. Finally, the corrosion parameters, combined with uncertainty in loading and soil properties were employed to perform time-dependent reliability assessment for steel light poles which can be used to assist the asset maintenance team in planning the replacement or strengthening works for steel pole.

In silico clinical trials (ISCTs) are an emerging method in modeling and simulation where medical interventions are evaluated using computational models of patients. ISCTs have the potential to provide cost-effective, time-efficient, and ethically favorable alternatives for evaluating the safety and effectiveness of medical devices. However, ensuring the credibility of ISCT results is a significant challenge. This paper aims to identify unique considerations for assessing the credibility of ISCTs and proposes an ISCT credibility assessment workflow based on recently published model assessment frameworks. First, we review various ISCTs described in the literature, carefully selected to showcase the range of methodological options available. These studies cover a wide variety of devices, reasons for conducting ISCTs, patient model generation approaches including subject-specific versus 'synthetic' virtual patients, complexity levels of devices and patient models, incorporation of clinician or clinical outcome models, and methods for integrating ISCT results with real-world clinical trials. We next discuss how verification, validation, and uncertainty quantification apply to ISCTs, considering the range of ISCT approaches identified. Based on our analysis, we then present a hierarchical workflow for assessing ISCT credibility, using a general credibility assessment framework recently published by the FDA's Center for Devices and Radiological Health. Overall, this work aims to promote standardization in ISCTs and contribute to the wider adoption and acceptance of ISCTs as a reliable tool for evaluating medical devices.

Computational models of patients and medical devices can be combined to perform an in silico clinical trial (ISCT) to investigate questions related to device safety and/or effectiveness across the total product life cycle. ISCTs can potentially accelerate product development by more quickly informing device design and testing or they could be used to refine, reduce, or in some cases to completely replace human subjects in a clinical trial. There are numerous potential benefits of ISCTs. An important caveat, however, is that an ISCT is a virtual representation of the real world that has to be shown to be credible before being relied upon to make decisions that have the potential to cause patient harm. There are many challenges to establishing ISCT credibility. ISCTs can integrate many different submodels that potentially use different modeling types (e.g., physics-based, data-driven, rule-based) that necessitate different strategies and approaches for generating credibility evidence. ISCT submodels can include those for the medical device, the patient, the interaction of the device and patient, generating virtual patients, clinical decision making and simulating an intervention (e.g., device implantation), and translating acute physics-based simulation outputs to health-related clinical outcomes (e.g., device safety and/or effectiveness endpoints). Establishing the credibility of each ISCT submodel is challenging, but is nonetheless important because inaccurate output from a single submodel could potentially compromise the credibility of the entire ISCT. The objective of this study is to begin addressing some of these challenges and to identify general strategies for establishing ISCT credibility. Most notably, we propose a hierarchical approach for assessing the credibility of an ISCT that involves systematically gathering credibility evidence for each ISCT submodel in isolation before demonstrating credibility of the full ISCT. Also, following FDA Guidance for assessing computational model credibility, we provide suggestions for ways to clearly describe each of the ISCT submodels and the full ISCT, discuss considerations for performing an ISCT model risk assessment, identify common challenges to demonstrating ISCT credibility, and present strategies for addressing these challenges using our proposed hierarchical approach. Finally, in the Appendix we illustrate the many concepts described here using a hypothetical ISCT example.

A network of agronomists, researchers, and practitioners associated with cacao farming provided open access to their independent field trials across Latin America and the Caribbean (LAC). A centralized dataset was assembled using qualitative and quantitative data from 25 experimental field trials (hereafter referred to as “CacaoFIT”) spanning several LAC agroecosystems. This dataset was used to document the main traits and agroclimatic attributes of the cacao cultivation model being tested within the CacaoFIT network. By synthesizing data from an entire network of cacao trials, this study aimed to highlight specific design features and management practices that may contribute to better cacao farming sustainability. The CacaoFIT network comprises 200 ha of field trials testing over 150 cacao genotypes and set up under different shade canopy design, management, and research goals. Small-sized trials were common across Mesoamerica, whereas medium to large-size trials were distinct to South America. Cacao trials were 15 years old (on average) and ranged from 3 to 25 years of establishment. Most cacao trials were managed conventionally (i.e., 55%), while 20% were under organic practices, and the remaining 25% presented both conventional and organic management approaches. Most field trials (ca. 60%) planted an average of 10 international clones or national cultivars at high (1,230–1,500 plants ha−1) and medium density (833–1,111 plants ha−1). Mixed shade canopies were the dominant agroforestry model, while timber vs. leguminous shade canopies were also common. The diversity and depth of research domains examined across the CacaoFIT network varied widely. Agronomy and agroforestry topics dominated the research agenda across all trials, followed by environmental services domains. Cacao physiology and financial performance were researched to a lesser extent within the network. Five featured field trials from CacaoFIT offered technical guidelines to inform cacao farming within similar contexts. This collaborative work is a scaffold to encourage public–private partnerships, capacity building, and data sharing amongst cacao researchers across the tropics.

Background: Moderately hypofractionated radiotherapy regimens or stereotactic body radiotherapy (SBRT) are standard of care for localised prostate cancer. However, some patients are unable or unwilling to travel daily to the radiotherapy department and do not have access to, or are not candidates for, SBRT. For many years, The Royal Marsden Hospital NHS Foundation Trust has offered a weekly ultra-hypofractionated radiotherapy regimen to the prostate (36 Gy in 6 weekly fractions) to patients unable/unwilling to travel daily. Methods: The current study is a retrospective analysis of all patients with non-metastatic localised prostate cancer receiving this treatment schedule from 2010 to 2015. Results: A total of 140 patients were included in the analysis, of whom 86 % presented with high risk disease, with 31 % having Gleason Grade Group 4 or 5 disease and 48 % T3 disease or higher. All patients received hormone treatment, and there was often a long interval between start of hormone treatment and start of radiotherapy (median of 11 months), with 34 % of all patients having progressed to non-metastatic castrate-resistant disease prior to start of radiotherapy. Median follow-up was 52 months. Median progression-free survival (PFS) and overall survival (OS) for the whole group was 70 months and 72 months, respectively. PFS and OS in patients with hormone-sensitive disease at time of radiotherapy was not reached and 75 months, respectively; and in patients with castrate-resistant disease at time of radiotherapy it was 20 months and 61 months, respectively. Conclusion: Our data shows that a weekly ultra-hypofractionated radiotherapy regimen for prostate cancer could be an option in those patients for whom daily treatment or SBRT is not an option.

Background: COVID-19 is primarily known as a respiratory illness; however, many patients present to hospital without respiratory symptoms. The association between non-respiratory presentations of COVID-19 and outcomes remains unclear. We investigated risk factors and clinical outcomes in patients with no respiratory symptoms (NRS) and respiratory symptoms (RS) at hospital admission. Methods: This study describes clinical features, physiological parameters, and outcomes of hospitalised COVID-19 patients, stratified by the presence or absence of respiratory symptoms at hospital admission. RS patients had one or more of: cough, shortness of breath, sore throat, runny nose or wheezing; while NRS patients did not. Results: Of 178,640 patients in the study, 86.4 % presented with RS, while 13.6 % had NRS. NRS patients were older (median age: NRS: 74 vs RS: 65) and less likely to be admitted to the ICU (NRS: 36.7 % vs RS: 37.5 %). NRS patients had a higher crude in-hospital case-fatality ratio (NRS 41.1 % vs. RS 32.0 %), but a lower risk of death after adjusting for confounders (HR 0.88 [0.83–0.93]). Conclusion: Approximately one in seven COVID-19 patients presented at hospital admission without respiratory symptoms. These patients were older, had lower ICU admission rates, and had a lower risk of in-hospital mortality after adjusting for confounders.

Background and purpose: MRI-guided radiotherapy (MRIgRT) offers multiple potential advantages over CT-guidance. This study examines the potential clinical benefits of MRIgRT for men with localised prostate cancer, in the setting of moderately hypofractionated radiotherapy. We evaluate two-year toxicity outcomes, early biochemical response and patient-reported outcomes (PRO), using data obtained from a multicentre international registry study, for the first group of patients with prostate cancer who underwent treatment on a 1.5 T MR-Linac. Materials and methods: Patients who were enrolled within the MOMENTUM study and received radical treatment with 60 Gy in 20 fractions were identified. PSA levels and CTCAE version 5.0 toxicity data were measured at follow-up visits. Those patients who consented to PRO data collection also completed EQ-5D-5L, EORTC QLQ-C30 and EORTC QLQ-PR25 questionnaires. Results: Between November 2018 and June 2022, 146 patients who had MRIgRT for localised prostate cancer on the 1.5 T MR-Linac were eligible for this study. Grade 2 and worse gastro-intestinal (GI) toxicity was reported in 3 % of patients at three months whilst grade 2 and worse genitourinary (GU) toxicity was 7 % at three months. There was a significant decrease in the median PSA at 12 months. The results from both the EQ-5D-5L data and EORTC global health status scale indicate a decline in the quality of life (QoL) during the first six months. The mean change in score for the EORTC scale showed a decrease of 11.4 points, which is considered clinically important. QoL improved back to baseline by 24 months. Worsening of hormonal symptoms in the first six months was reported with a return to baseline by 24 months and sexual activity in all men worsened in the first three months and returned to baseline at 12 months. Conclusion: This study establishes the feasibility of online-MRIgRT for localised prostate on a 1.5 T MR-Linac with low rates of toxicity, similar to that published in the literature. However, the clinical benefits of MRIgRT over conventional radiotherapy in the setting of moderate hypofractionation is not evident. Further research will focus on the delivery of ultrahypofractionated regimens, where the potential advantages of MRIgRT for prostate cancer may become more discernible.

Abstract Background Sleep spindle activity is commonly estimated by measuring sigma power during stage 2 non-rapid eye movement (NREM2) sleep. However, spindles account for little of the total NREM2 interval and therefore sigma power over the entire interval may be misleading. This study compares derived spindle measures from direct automated spindle detection with those from gross power spectral analyses for the purposes of clinical trial design. Methods We estimated spindle activity in a set of 8,440 overnight electroencephalogram (EEG) recordings from 5,793 patients from the Sleep Heart Health Study using both sigma power and direct automated spindle detection. Performance of the two methods was evaluated by determining the sample size required to detect decline in age-related spindle coherence with each method in a simulated clinical trial. Results In a simulated clinical trial, sigma power required a sample size of 115 to achieve 95% power to identify age-related changes in sigma coherence, while automated spindle detection required a sample size of only 60. Conclusions Measurements of spindle activity utilizing automated spindle detection outperformed conventional sigma power analysis by a wide margin, suggesting that many studies would benefit from incorporation of automated spindle detection. These results further suggest that some previous studies which have failed to detect changes in sigma power or coherence may have failed simply because they were underpowered.

Objective: To determine if nirmatrelvir-ritonavir 300mg/100mg treatment for 5 days in high-risk outpatients with mild to moderate COVID-19 symptoms was associated with a reduction in hospitalization, intensive care unit (ICU) admission, and death. Methods: This 1:1 propensity score matched cohort study from 647 public health clinics in Malaysia included all patients with COVID-19 with positive tests aged 18 years and older, who were eligible for nirmatrelvir-ritonavir treatment within 5 days of illness from July 14, 2022, to November 14, 2022. The exposed group was patients with COVID-19 initiated with nirmatrelvir-ritonavir treatment, whereas those not initiated with the drug served as the control group. Data was analyzed from July 14, 2022 to December 31, 2022. Results: A total of 20,966 COVID-19 high-risk outpatients (n = 10,483 for nirmatrelvir-ritonavir group and n = 10,483 for control group) were included in the study. Nirmatrelvir-ritonavir treatment was associated with a 36% reduction (adjusted hazard ratio 0.64 [95% CI 0.43, 0.94]) in hospitalization compared with those not given the drug. There was a single ICU admission for the control group and one death each was reported in the nirmatrelvir-ritonavir and control group, respectively. Conclusions: Nirmatrelvir-ritonavir treatment was associated with reduced hospitalization in high-risk patients with COVID-19 even in highly vaccinated populations.

Hyponatraemia is an uncommon complication of external biliary drainage. We report on a 62-year-old male with hilar cholangiocarcinoma who developed refractory severe hyponatraemia despite sodium replacement during preoperative external biliary drainage. Nasojejunal bile refeeding restored sodium levels to normal.

Post COVID-19 condition is an important public health problem as we emerge from the COVID-19 pandemic. In this prospective cohort study, we aimed to determine the prevalence of this condition and assess its associated factors and impact on health-related quality of life in a population setting in Malaysia. Study was conducted from April to June 2022 when the Omicron variant predominated. All individuals testing positive for SARS-CoV-2 infection (RT-PCR, RTK-Ag) were invited for participation. Study questionnaires were delivered via the MySejahtera platform (mobile application). From the total of 44,386 participants who provided responses up to 3-months interval, 1,510 participants (3.4%) fulfilled the post COVID-19 condition criteria. Majority of the affected participants (83.8%, n = 1,265) experienced either cough, fatigue or forgetfulness-the three most common symptoms. Being females, having existing comorbidities, presence of symptoms and requiring hospital admission during the acute illness were associated with higher likelihoods of developing the post COVID-19 condition at 3-months interval. Amongst the 1,510 individuals, one in five had limitations in performing their usual daily activities while at least one in three expressed that their work was affected. Understanding this condition better is essential to guide strategic and responsive plans of action, which may require coordinated multidisciplinary interventions.

Abstract Background Recent genomics studies of breast cancer in Asian cohorts have found a higher prevalence of TP53 mutations in Asian breast cancer patients relative to Caucasian patients. However, the effect of TP53 mutations on Asian breast tumours has not been comprehensively studied. Methods Here, we report an analysis of 492 breast cancer samples from the Malaysian Breast Cancer cohort where we examined the impact of TP53 somatic mutations in relation to PAM50 subtypes by comparing whole exome and transcriptome data from tumours with mutant and wild-type TP53. Results We found that the magnitude of impact of TP53 somatic mutations appears to vary between different subtypes. TP53 somatic mutations were associated with higher HR deficiency scores as well as greater upregulation of gene expression pathways in luminal A and luminal B tumours compared to the basal-like and Her2-enriched subtypes. The only pathways that were consistently dysregulated when comparing tumours with mutant and wild-type TP53 across different subtypes were the mTORC1 signalling and glycolysis pathways. Conclusion These results suggest that therapies that target TP53 or other downstream pathways may be more effective against luminal A and B tumours in the Asian population.

Appendiceal diverticulitis is a rare pathology which is distinctly different to acute appendicitis and associated with higher rates of morbidity and mortality. Furthermore, diagnosis is often retrospective on histopathological analysis of appendicectomy specimens due to the atypical clinical and radiological features. Herein, we present a case of ruptured appendiceal diverticulitis in a young patient with atypical clinical features and a radiologically normal appearing appendix in close proximity to an inflammatory phlegmon. This case highlights the importance of maintaining a high clinical suspicion of surgical pathology and considering atypical diagnosis in patients with inflammatory changes in the right iliac fossa.

Introduction Knife-enabled crime is a UK public health issue leading to substantial impacts on society, victims and their families, as well as additional strain on the healthcare system. Despite the increase in knife-enabled crime and the overwhelming consequences, there is a lack of comprehensive studies exploring the long-term health outcomes of knife crime victims in the UK. The research gap hinders the development of more targeted secondary preventative interventions, resource allocation and public awareness campaigns. This systematic review aims to identify the long-term health outcomes of knife crime victims, therefore providing valuable knowledge for stakeholders, health practitioners and policymakers for a more effective public health response.Methods and analysis A comprehensive search strategy was developed, focusing on four key concepts: study design, knife-related offences, outcomes and risk. Databases being searched include MEDLINE, EMBASE, PsycINFO, ProQuest Criminology Collection, Web of Science Core Collection, Google Scholar and OpenGrey. Reference lists and forward citations will be inspected for further suitable literature. The study selection will involve two independent reviewers screening the studies from the search, with disagreements resolved by a third reviewer. All UK quantitative research on long-term health outcomes of knife crime victims will be included in the review. Covidence will be used to efficiently manage data. A data extraction form has been developed which will summarise key aspects of each study that will be included in the review. Methodological Index for Non-Randomised Studies quality assessment checklist will be used to assess the studies and the Newcastle-Ottawa Scale will assess the risk of bias in each study. Findings will be narratively synthesised, and if heterogeneity is sufficient, a meta-analysis will be conducted.Ethics and dissemination Ethics approval is not required for this study as no original data will be collected. The results will be disseminated through a peer-reviewed publication and conference presentation.

Recently, transition metal doped superlattice has shown an anomalous optical band gap of 1.6 eV, about 1 eV lower than either parent element (Barium) majorly, making it appropriate for several applications including magnetism and superconducting materials. In the current study, the structural, electronic, phonon, thermodynamic, and the magnetic ordering of BaXO3 (X = Cr, Mn, Co, and Ni) has been examined using density functional theory (DFT). From the results, the investigated materials show a ferromagnetic behavior with the band gap of range 0.95–1.04 eV, and average absolute magnetization are 2.64, 3.67, 3.19, and 0.01 Bohr magneton/cell for BaCrO3, BaMnO3, BaCoO3, and BaNiO3, respectively. Furthermore, it is conceivable that the Compton profiles of BaXO3(X= Cr, Mn, Co, and Ni) are magnetic due to the substantial exchange-correlation dependence of their Compton profiles, which is shown from the phonon and X-ray distributions, thermodynamic calculation, and mechanically portrayed features of BaXO3. It was further discovered that doping could increase each TM (Cr, Mn, Co, and Ni) atom's magnetic moment. This study demonstrates a novel method for utilizing this revolutionary kind of cubic ferrites for spintronic applications in solid-state electronics.

Lung cancer is one of the most common cancers and a leading cause of cancer-related mortality in Malaysia. This analysis aimed to evaluate the prevalence of actionable and common mutations, as well as co-mutations frequently occurring with EGFR variants in lung cancer. Mutational profiling of lung tumour samples was performed using next generation sequencing (NGS) panels at the Subang Jaya Medical Centre laboratory. A total of 469 lung tumour samples referred from several medical facilities in Malaysia were analysed and 84% were of the adenocarcinoma subtype. The three most frequent mutations found were EGFR (46.5%), TP53 (37.5%) and KRAS (14.3%). Actionable mutations with approved drug targets for lung cancer were detected in 63.5% of patient samples. Among patients with EGFR mutations, deletions in exon 19 were detected in 44.5% and p.L858R in 38.5% of samples. The most common co-mutations for samples with EGFR mutations were found in the TP53 gene (38.1%). A median turnaround time (TAT) of 3 working days was achievable with an automated NGS platform. NGS testing can provide valuable information on the mutational landscape and the prevalence of common or actionable mutations present in lung cancer patients. This real-world experience demonstrates the high percentage of actionable mutations detected and highlights the value of NGS testing in a clinical diagnostic setting.

This research analyzes the shifting of management of God's Kingdom to focus on saving human resources in the economic site due to COVID-19. The old paradigm of management of God's Kingdom, which is to save human resources biblically, shifts to humans from the low economic condition. This study aims to redefine the shifting of management of God's Kingdom as the form of human resources development from the economic perspective. This study systematically presents the economy's condition due to COVID-19, the Church's response to it, and the redefinition of God's Kingdom management through the descriptive qualitative method. This research confirms the redefinition of management of God's Kingdom as the Church's response to help human resources. Finally, this research aims to give out some charity programs and skill training in saving human resources in responding to the economic downward due to COVID-19.

Abstract Physiological closed-loop controlled (PCLC) medical devices monitor and automatically adjust the patient’s condition by using physiological variables as feedback, ideally with minimal human intervention to achieve the target levels set by a clinician. PCLC devices present a challenge when it comes to evaluating their performance, where conducting large clinical trials can be expensive. Virtual physiological patients simulated by validated mathematical models can be utilized to obtain pre-clinical evidence of safety and assess the performance of the PCLC medical device during normal and worst-case conditions that are unlikely to happen in a limited clinical trial. A physiological variable that plays a major role during fluid resuscitation is heart rate (HR). For in silico assessment of PCLC medical devices regarding fluid perturbation, there is currently no mathematical model of HR validated in terms of its predictive capability performance. This paper develops and validates a mathematical model of HR response using data collected from sheep subjects undergoing hemorrhage and fluid infusion. The model proved to be accurate in estimating the HR response to fluid perturbation, where averaged between 21 calibration datasets, the fitting performance showed a normalized root mean square error (NRMSE) of $$7.41 \pm 2.8 \%$$ 7.41 ± 2.8 % . The model was also evaluated in terms of model predictive capability performance via a leave-one-out procedure (21 subjects) and an independent validation dataset (6 subjects). Two different virtual cohort generation tools were used in each validation analysis. The generated envelope of virtual subjects robustly met the defined acceptance criteria, in which $$95\%$$ 95 % of the testing datasets presented simulated HR patterns that were within a deviation of 50% from the observed data. In addition, out of 16000 and 18522 simulated subjects for the leave-one-out and independent datasets, the model was able to generate at least one virtual subject that was close to the real subject within an error margin of $$9.56 \pm 3.15\%$$ 9.56 ± 3.15 % and $$11.1 \pm 1.22\%$$ 11.1 ± 1.22 % NRMSE, respectively. In conclusion, the model can generate valid virtual HR physiological responses to fluid perturbation and be incorporated into future non-clinical simulated testing setups for assessing PCLC devices intended for fluid resuscitation.

Background: The prostate demonstrates inter- and intra- fractional changes and thus adaptive radiotherapy would be required to ensure optimal coverage. Daily adaptive radiotherapy for MRI-guided radiotherapy can be both time and resource intensive when structure delineation is completed manually. Contours can be auto-generated on the MR-Linac via a deformable image registration (DIR) based mapping process from the reference image. This study evaluates the performance of automatically generated target structure contours against manually delineated contours by radiation oncologists for prostate radiotherapy on the Elekta Unity MR-Linac. Methods: Plans were generated from prostate contours propagated by DIR and rigid image registration (RIR) for forty fractions from ten patients. A two-dose level SIB (simultaneous integrated boost) IMRT plan is used to treat localised prostate cancer; 6000 cGy to the prostate and 4860 cGy to the seminal vesicles. The dose coverage of the PTV 6000 and PTV 4860 created from the manually drawn target structures was evaluated with each plan. If the dose objectives were met, the plan was considered successful in covering the gold standard (clinician-delineated) volume. Results: The mandatory PTV 6000 dose objective (D98% > 5580 cGy) was met in 81 % of DIR plans and 45 % of RIR plans. The SV were mapped by DIR only and for all the plans, the PTV 4860 dose objective met the optimal target (D98% > 4617 cGy). The plans created by RIR led to under-coverage of the clinician-delineated prostate, predominantly at the apex or the bladder-prostate interface. Conclusion: Plans created from DIR propagation of prostate contours outperform those created from RIR propagation. In approximately 1 in 5 DIR plans, dosimetric coverage of the gold standard PTV was not clinically acceptable. Thus, at our institution, we use a combination of DIR propagation of contours alongside manual editing of contours where deemed necessary for online treatments.

A shift of the daily plan can mitigate target position changes that occur between daily MR acquisition and treatment for MR-linac radiotherapy, but increases the session time. We demonstrated that our workflow strategy and decision-making process, to determine whether a subsequent shift is necessary, is appropriate.

Abstract Background Parathyroid carcinoma is an uncommon cause of PTH-dependent hypercalcemia. Only a handful of cases have been reported of parathyroid carcinoma during pregnancy. Case presentation Twenty-four – Year – old female presented with proximal myopathy was found to have hypercalcemia. Her serum corrected total calcium was – 15 mg/dl (8.5 – 10.3), serum phosphate – 2.3 mg/dl (2.5 – 4.5), intact PTH – 118 pg/ml (20 – 80), Vitamin D – 15 ng/ml and Urine Ca/Cr ratio – 2.1 (0.1 – 0.2). Her CECT–neck revealed a well-defined mass lesion posterior to the right lobe of the thyroid – 2.6 cm × 2.5 cm × 2.9 cm in size. She was started on vitamin D supplementation, and she underwent right lower focal parathyroidectomy. Her PTH levels normalized following surgery. Her histology revealed an atypical parathyroid adenoma. She was treated with calcium and vitamin D. Her follow up was uneventful. One year following initial surgery the patient became pregnant and at 16 weeks of POA, the patient presented with a rapidly enhancing neck mass for one week duration. Her biochemical investigations were suggestive of a recurrence of primary hyperparathyroidism. Her ultrasound scan of the neck revealed a well-defined discreate hypoechoic nodule, superior to the thyroid isthmus which was confirmed by a non-contrast MRI scan of the neck. She underwent an uncomplicated second trimester parathyroid tumour excision with normalization of post op PTH. Her histology revealed a parathyroid carcinoma with vascular and capsular invasion. Her genetic studies revealed a novel frameshift mutation of the CDC73 gene. She was treated with calcium and vitamin D supplementation and closely followed up with ionized calcium and PTH levels which were normal throughout the pregnancy. She had an uncomplicated caesarean section at a POA of 37 weeks. Currently she is twelve weeks post-partum, in remission of disease. Conclusion This case shows the importance of stringent follow up of atypical parathyroid adenoma patients, the benefit of second trimester surgery in management of hypercalcemia due to parathyroid carcinoma during pregnancy and the importance of identifying the novel CDC73 gene mutation.

Background The retention of doctors is an important issue for the National Health Service; yet evidence suggests that the proportion of doctors wanting to leave UK medicine is increasing. Some of these doctors chose to continue their medical careers in other countries, however, some decided to leave the profession entirely.Objectives This was the first study to interview a cohort of UK doctors who have left the medical profession to embark on alternative careers. Participants were asked about the reasoning behind their decision to leave medicine.Design Qualitative study using one-to-one, semi-structured virtual interviews.Participants 17 participants, recruited via purposive sampling.Setting Zoom interviews with 17 former UK doctors who had left medicine to pursue alternative careers were conducted between February and July 2021.Findings Data were analysed using thematic analysis and the theory of work adjustment was applied to findings. The most frequently discussed reasons for leaving were associated with factors preventing participants from providing a desired level of patient care, work-life balance, a lack of support, a lack of control over working lives and the pull of alternative careers. While reasons for leaving varied between participants, all participants reported greater satisfaction in their new careers.Conclusion New careers were able to address many of the issues that caused participants to leave UK medicine. Consequently, it is important that some of the key issues raised in this study are addressed to retain more doctors in the UK medical workforce.