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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 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.

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.

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.

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.

Abstract Literature review demonstrated a surprising lack of publications on digital e-learning pathology resources for senior medical undergraduates and interns. An interactive Digital Pathology Repository (iDPR) integrating two- and three-dimensional (2D, 3D) high-resolution anatomical pathology images with correlated digital histopathology was developed. The novel iDPR was rigorously evaluated using mixed methods to assess pathology knowledge gains (pre- and post-tests), quality impact analysis (questionnaire), user feedback (focus group discussions) and user visual behaviour (eye gaze tracking analysis of 2D/ 3D images). Exposure to iDPR appeared to improve user pathology knowledge, as observed by significantly increased test scores on topic-related quizzes (n = 69, p

Abstract Background Persons living with HIV infection (PLHIV) who are diagnosed in community settings in sub-Saharan Africa are particularly vulnerable to barriers to care that prevent or delay many from obtaining antiretroviral therapy (ART). Methods We conducted a retrospective cohort study to assess if a package of peer-delivered linkage case management and treatment navigation services (CommLink) was more effective than peer-delivered counseling, referral, and telephone follow-up (standard linkage services, SLS) in initiating and retaining PLHIV on ART after diagnosis in community settings in Eswatini. HIV-test records of 773 CommLink and 769 SLS clients aged ≥ 15 years diagnosed between March 2016 and March 2018, matched by urban and rural settings of diagnosis, were selected for the study. CommLink counselors recorded resolved and unresolved barriers to care (e.g., perceived wellbeing, fear of partner response, stigmatization) during a median of 52 days (interquartile range: 35—69) of case management. Results Twice as many CommLink than SLS clients initiated ART by 90 days of diagnosis overall (88.4% vs. 37.9%, adjusted relative risk (aRR): 2.33, 95% confidence interval (CI): 1.97, 2.77) and during test and treat when all PLHIV were eligible for ART (96.2% vs. 37.1%, aRR: 2.59, 95% CI: 2.20, 3.04). By 18 months of diagnosis, 54% more CommLink than SLS clients were initiated and retained on ART (76.3% vs. 49.5%, aRR: 1.54, 95% CI: 1.33, 1.79). Peer counselors helped resolve 896 (65%) of 1372 identified barriers of CommLink clients. Compared with clients with ≥ 3 unresolved barriers to care, 42% (aRR: 1.42, 95% CI: 1.19, 1.68) more clients with 1–2 unresolved barriers, 44% (aRR: 1.44, 95% CI: 1.25, 1.66) more clients with all barriers resolved, and 54% (aRR: 1.54, 95% CI: 1.30, 1.81) more clients who had no identified barriers were initiated and retained on ART by 18 months of diagnosis. Conclusions To improve early ART initiation and retention among PLHIV diagnosed in community settings, HIV prevention programs should consider providing a package of peer-delivered linkage case management and treatment navigation services. Clients with multiple unresolved barriers to care measured as part of that package should be triaged for differentiated linkage and retention services.

Abstract Background SARS-CoV-2 rapid antigen (Ag) detection kits are widely used in addition to quantitative reverse transcription PCR PCR (RT-qPCR), as they are cheaper with a rapid turnaround time. As there are many concerns regarding their sensitivity and specificity, in different settings, we evaluated two WHO approved rapid Ag kits in a large cohort of Sri Lankan individuals. Methods Paired nasopharangeal swabs were obtained from 4786 participants for validation of the SD-Biosensor rapid Ag assay and 3325 for the Abbott rapid Ag assay, in comparison to RT-qPCR. A short questionnaire was used to record symptoms at the time of testing, and blood samples were obtained from 2721 of them for detection of SARS-CoV-2 specific antibodies. Results The overall sensitivity of the SD-Biosensor Ag kit was 36.5% and the Abbott Ag test was 50.76%. The Abbott Ag test showed specificity of 99.4% and the SD-Biosensor Ag test 97.5%. At Ct values 30 (46.1 to 82.9%). 32.1% of those who gave a positive result with the SD-Biosensor Ag test and 26.3% of those who gave positive results with the Abbott Ag test had SARS-CoV-2 antibodies at the time of detection. Conclusions Both rapid Ag tests appeared to be highly sensitive in detecting individuals at lower Ct values, in a community setting in Sri Lanka, but it will be important to further establish the relationship to infectivity.

Abstract The use of external fixators (EFs) dates back to 377 BC Hippocrates’ time, and it has a wide range of orthopaedic applications. External fixator has expanded its use in the management of fractures and other musculoskeletal conditions. It is widely used all over the world to manage complex musculoskeletal injuries. It has many advantages as compared to internal fixation in some trauma scenarios. However, the cost of the external fixators presents a dilemma to the healthcare system in developing countries. The goals of this review article are to explain the importance of EFs in developing countries in managing fractures, to determine the problems encountered at present during external fixation by developing countries, to identify solutions that could be used to address these issues, expand the use of external fixation into other domains of treatment, the impact of COVID-19 pandemic on fracture management based on existing literature. In conclusion, EFs are very expensive, researches have been conducted to overcome these barriers in developing countries. However, there are limitations in implementing in developing countries. It is important to have affordable and clinically acceptable EFs available in developing countries.

Abstract Introduction Osteoarthritis (OA) is a chronic condition. Physiotherapy is known to be beneficial for people with OA. Patient adherence to physiotherapy exercise is essential for the effective management of OA. Objectives To determine different methods used to enhance physiotherapy exercise adherence for a period of more than 12 months among patients with OA and to report the most effective methods to enhance exercise adherence among people with lower limb OA. Design Systematic review. Methods PubMed, Pedro, Web of Science, and EMBASE databases were searched for randomized controlled trials, cohort studies, case-control studies, and cross-sectional studies published in the English language from 2000 to 2020. The literature search was done on 27 August 2020. Two researchers independently conducted the screening, eligibility assessment, data extraction, methodology quality assessment using the PEDro scale, and risk of bias assessment using RoB2. A narrative synthesis of key outcomes is presented, percentage of adherence rate; Preferred Reporting Items for Systematic Review was used to report the review. Meta-analysis was not performed due to heterogeneity of studies. The study protocol was registered in Prospero (Prospero ID: CRD42020205653). Results The primary search strategy identified 5839 potentially relevant articles, of which 5157 remained after discarding duplicates. After screening based on title and abstract, 40 papers were potentially eligible for inclusion. Five of these papers met all predefined eligibility criteria. Introducing methods to enhance exercise adherence has caused a significant increase in exercise adherence for less than 6 or 12 months. There were no significant differences in adherence for more than 12 months with different methods. The results indicate that booster-sessions (89.69%) and telephone-linked communication (86%) had higher percentages for exercise adherence. Secondary outcomes such as pain, stiffness and function show positive outcomes with increasing exercise adherence. However, there were no significant differences on these secondary outcomes. Conclusion The booster sessions and telephone-linked communication appear to enhance exercise adherence for more than 12 months among patients with OA. However, the number of high-quality studies is inadequate to confirm our findings. Therefore, more studies with higher methodological quality are needed to determine the best strategies to enhance long-term exercise adherence among people with OA.

Abstract Background Electronic Medical Records (EMRs) are one of a range of digital health solutions that are key enablers of the data revolution transforming the health sector. They offer a wide range of benefits to health professionals, patients, researchers and other key stakeholders. However, effective implementation has proved challenging. Methods A qualitative methodology was used in the study. Interviews were conducted with 12 clinical and administrative staff of a cancer centre at one-month pre-launch and eight clinical and administrative staff at 12-months post-launch of an EMR. Data from the interviews was collected via audio recording. Audio recordings were transcribed, de-identified and analysed to identify staff experiences with the EMR. Results Data from the pre-implementation interviews were grouped into four categories: 1) Awareness and understanding of EMR; 2) Engagement in launch process; 3) Standardisation and completeness of data; 4) Effect on workload. Data from the post-launch interviews were grouped into six categories: 1) Standardisation and completeness of data; 2) Effect on workload; 3) Feature completeness and functionality; 4) Interaction with technical support; 5) Learning curve; 6) Buy-in from staff. Two categories: Standardisation and completeness of data and effect on workload were common across pre and post-implementation interviews. Conclusion Findings from this study contribute new knowledge on barriers and enablers to the implementation of EMRs in complex clinical settings. Barriers to successful implementation include lack of technical support once the EMR has launched, health professional perception the EMR increases workload, and the learning curve for staff adequately familiarize themselves with using the EMR.

Abstract Introduction Methanol poisoning usually occurs in a cluster and initial diagnosis can be challenging. Mortality is high without immediate interventions. This paper describes a methanol poisoning outbreak and difficulties in managing a large number of patients with limited resources. Methodology A retrospective analysis of a methanol poisoning outbreak in September 2018 was performed, describing patients who presented to a major tertiary referral centre. Result A total of 31 patients were received over the period of 9 days. Thirty of them were males with a mean age of 32 years old. They were mostly foreigners. From the 31 patients, 19.3% were dead on arrival, 3.2% died in the emergency department and 38.7% survived and discharged. The overall mortality rate was 61.3%. Out of the 12 patients who survived, two patients had toxic optic neuropathy, and one patient had uveitis. The rest of the survivors did not have any long-term complications. Osmolar gap and lactate had strong correlations with patient’s mortality. Serum pH, bicarbonate, lactate, potassium, anion gap, osmolar gap and measured serum osmolarity between the alive and dead patients were significant. Post-mortem findings of the brain were unremarkable. Conclusion The mortality rate was higher, and the morbidity includes permanent visual impairment and severe neurological sequelae. Language barrier, severity of illness, late presentation, unavailability of intravenous ethanol and fomipezole and delayed dialysis may have been the contributing factors. Patient was managed based on clinical presentation. Laboratory parameters showed difference in median between group that survived and succumbed for pH, serum bicarbonate, lactate, potassium and osmolar and anion gap. Management of methanol toxicity outbreak in resource-limited area will benefit from a well-designed guideline that is adaptable to the locality.

Abstract Background Whole-genome shotgun sequencing, which stitches together millions of short sequencing reads into a single genome, ushered in the era of modern genomics and led to a rapid expansion of the number of genome sequences available. Nevertheless, assembly of short reads remains difficult, resulting in fragmented genome sequences. Ultimately, only a sequencing technology capable of capturing complete chromosomes in a single run could resolve all ambiguities. Even “third generation” sequencing technologies produce reads far shorter than most eukaryotic chromosomes. However, the ciliate Oxytricha trifallax has a somatic genome with thousands of chromosomes averaging only 3.2 kbp, making it an ideal candidate for exploring the benefits of sequencing whole chromosomes without assembly. Results We used single-molecule real-time sequencing to capture thousands of complete chromosomes in single reads and to update the published Oxytricha trifallax JRB310 genome assembly. In this version, over 50% of the completed chromosomes with two telomeres derive from single reads. The improved assembly includes over 12,000 new chromosome isoforms, and demonstrates that somatic chromosomes derive from variable rearrangements between somatic segments encoded up to 191,000 base pairs away. However, while long reads reduce the need for assembly, a hybrid approach that supplements long-read sequencing with short reads for error correction produced the most complete and accurate assembly, overall. Conclusions This assembly provides the first example of complete eukaryotic chromosomes captured by single sequencing reads and demonstrates that traditional approaches to genome assembly can mask considerable structural variation.

Abstract Background The incidence of oropharyngeal squamous cell carcinoma (OPSCC) has been rising in Western countries and this has been attributed to human papillomavirus (HPV) infection. p16 expression is a marker for HPV infection and p16 positive OPSCC is now recognized as a separate disease entity. There are only limited data available regarding HPV-related OPSCC in Asian countries and no data from Malaysia. Methods We identified 60 Malaysian patients with OPSCC over a 12-year period (2004–2015) from four different hospitals in two major cities, Kuala Lumpur and Penang. The detection of HPV was carried out using p16 immunohistochemistry and high risk HPV DNA in situ hybridisation. Results Overall, 15 (25%) tumours were p16 positive by immunohistochemistry, 10 of which were also positive for high risk HPV DNA by in situ hybridisation. By comparison, a matched cohort of UK patients had a p16 positive rate of 49%. However, between 2009 and 2015, where cases were available from all four hospitals, 13 of 37 (35%) cases were p16 positive. In our Malaysian cohort, 53% of patients were of Chinese ethnicity and 80% of the p16 positive cases were found in these patients; no Indian patients had p16 positive disease, despite representing 35% of the total cohort. Conclusion The proportion of OPSCCs associated with HPV in Malaysia appears to be lower than in European and American cohorts and could possibly be more prevalent amongst Malaysians of Chinese ethnicity. Further, our data suggests that the burden of HPV-related OPSCC could be increasing in Malaysia. Larger cross-sectional studies of Malaysian patients are required to determine the public health implications of these preliminary findings.

Abstract Background Eukaryotes evolved from the symbiotic association of at least two prokaryotic partners, and a good deal is known about the timings, mechanisms, and dynamics of these evolutionary steps. Recently, it was shown that a new class of nuclear genes, symbiogenetic genes (S-genes), was formed concomitant with endosymbiosis and the subsequent evolution of eukaryotic photosynthetic lineages. Understanding their origins and contributions to eukaryogenesis would provide insights into the ways in which cellular complexity has evolved. Results Here, we show that chimeric nuclear genes (S-genes), built from prokaryotic domains, are critical for explaining the leap forward in cellular complexity achieved during eukaryogenesis. A total of 282 S-gene families contributed solutions to many of the challenges faced by early eukaryotes, including enhancing the informational machinery, processing spliceosomal introns, tackling genotoxicity within the cell, and ensuring functional protein interactions in a larger, more compartmentalized cell. For hundreds of S-genes, we confirmed the origins of their components (bacterial, archaeal, or generally prokaryotic) by maximum likelihood phylogenies. Remarkably, Bacteria contributed nine-fold more S-genes than Archaea, including a two-fold greater contribution to informational functions. Therefore, there is an additional, large bacterial contribution to the evolution of eukaryotes, implying that fundamental eukaryotic properties do not strictly follow the traditional informational/operational divide for archaeal/bacterial contributions to eukaryogenesis. Conclusion This study demonstrates the extent and process through which prokaryotic fragments from bacterial and archaeal genes inherited during eukaryogenesis underly the creation of novel chimeric genes with important functions.