A clinical audit on the diagnosis and management of infective endocarditis in a tertiary heart centre in Malaysia.

INTRODUCTION: Infective endocarditis (IE) has a high mortality rate in developing countries including Malaysia. This clinical audit aims to identify the shortcomings in the diagnosis and management of IE patients in a local tertiary centre to implement changes for improvement. MATERIALS AND METHODS: This retrospective audit had two cycles - the first includes all IE patients in Sarawak Heart Centre, Malaysia from January 2020 to December 2022 with different parameters (blood culture, echocardiogram, the appropriateness of antibiotics and surgery) assessed against Malaysian Clinical Practice Guideline (CPG); and reaudit from July 2023 to December 2023. Interventions before re-audit include presentation at different hospital levels and continuing medical education. RESULTS: Fifty patients were recruited (37 in the first cycle, 13 in the second cycle). The median age was 48.5 years with male predominance. Valve prosthesis (12.0%) and rheumatic heart disease (10.0%) were the commonest predisposing factors. Native mitral (44.0%) and aortic valves (28.0%) were most commonly involved. Twenty-eight (56.0%) patients were culture-positive. In the first cycle, most parameters (culture technique 0.0%, vegetation measured 54.1%, empirical 5.4%, culture-guided 29.7% antibiotics therapy, indicated surgery 0.0%) did not achieve the expected standard except timeliness of echocardiograms and blood culture incubation period. After initial interventions, all parameters showed statistically significant improvement (culture technique p<0.001, echocardiography p<0.001, empirical p<0.001, culture-guided p=0.021, surgery p<0.001) during the re-audit. CONCLUSION: Compliance with clinical practice guidelines (CPG) on IE management was suboptimal during the first audit but improved after interventions. Hence, regular continuing medical education (CME) is essential, and a written hospital protocol may be useful. Regular audits alongside multidisciplinary teamwork are crucial efforts.

The clinical and geographical characteristics, health-seeking behaviours of ST-segment elevation myocardial infarction patients with their total ischaemic time and short-term cardiac mortality outcomes: a local geographical perspective from a developing country.

INTRODUCTION: Ischaemic heart disease including ST-segment elevation myocardial infarction (STEMI) is the leading cause of death among Malaysians. Total ischaemic time (TIT) which consists of patient delay and systemic delay is a strong predictor of cardiovascular outcome in STEMI. Primary percutaneous coronary intervention (PPCI) is superior to medical thrombolysis in improving STEMI patients' survival outcomes. Our study aims to provide an insight into the clinical and geographical characteristics of STEMI patients, their health-seeking behaviour, TIT, interventions received and short-term cardiac mortality outcomes in the effort to improve the existing coronary care service. MATERIALS AND METHODS: This is a descriptive study looking into patients who were diagnosed with STEMI and presented to or were referred to Sarawak Heart Centre between 1st July 2022 and 31st December 2022. RESULTS: A total of 183 patients were recruited and 33.3% were <50 years old. The majority were in a different division during symptom onset from where the local PPCI centre is located and some underwent one or two transits before arrival at the revascularisation centre. More presented outof- hour and they were more likely to present within the PPCI window. The median TIT for the study population was 3.3 hours. The short-term cardiac mortalities were 9.3% and only the Killip class was found to have a significant association. In this study, TIT was not significantly associated with short-term mortalities but those who died had a longer median TIT. CONCLUSION: A local STEMI network should be set up using the 'Hub-and-Spoke' model in a staged-wise approach to reduce TIT given that PPCI is now the gold standard of treatment alongside continuous effort in patient education.

Factors associated with in-hospital mortality among infective endocarditis patients.

INTRODUCTION: Despite recent advancements in the diagnosis and management of infective endocarditis (IE), it is associated with substantial morbidity and mortality. Our study objective is to determine the factors associated with in-hospital mortality in IE patients among the local population. MATERIALS AND METHODS: All IE patients who were diagnosed with definite or possible IE and were treated at Sarawak Heart Centre from 1st January 2020 to 31st December 2022 were recruited. We examined the demographic features of the subjects and the factors that contributed to in-hospital mortality. Multivariate logistic regression was used to analyse the associated factors and in-hospital mortality. RESULTS: Our study population comprised a total of 37 patients with a mean age of 46.4 years and male predominance. The in-hospital mortality rate of IE in this study was 44.4%. Haemodynamic instability and anaemia were found to be strong predictors of IE survival outcome, with an odds ratio of 51.5 and 35.7 respectively. Patients with vascular phenomenon and heart failure were at 10.5- and 6.0-times higher odds of dying, however, these two associations were found to be not statistically significant. CONCLUSION: The in-hospital mortality due to IE in our study was among the highest in developing countries. Factors of hypotension and optimal response to individual hemodynamic parameters may confer lower mortality. While anaemia is demonstrable as a risk factor for inpatient mortality, a target has yet to be reasonably established.

Characteristics of patients with tuberculosis and the associated factors with TB-related mortality in a rural setting in Sarawak, Malaysia: A single-centre study.

INTRODUCTION: Tuberculosis (TB) in Malaysia has estimated incidence and mortality rates of 81 cases per 100,000 people-year and 4.9 per 100,000 populations, respectively. This study aimed to study the characteristics of rural TB patients and their mortality outcomes. MATERIALS AND METHODS: This is a retrospective observational study involving real-world data analysis, looking into TB patients in Lubok Antu Health Clinic by obtaining data through clinic cards, from 1 January 2019 till 31 December 2020. Statistical significance was p < 0.05. RESULTS: Eighty-four patients were included. Fifty-two (61.9%) were male. Median age was 58.5 (39-67). Forty-six (54.8%) had smear-positive TB. Seventy-eight (92.9%) were alive at treatment completion. Fifteen (17.9%) experienced adverse drug reactions. Estimated prevalence and mortality rate were 7.1% and 10.7 per 100,000 populations, respectively. Regression analyses revealed that drug reaction was significantly associated with compliance [OR = 8.38 (95% CI: 1.26, 55.53), p = 0.029]. Patients compliant with treatment were more likely to survive [OR = 12.5 (95% CI: 1.61, 97.34), p = 0.028]. CONCLUSION: Compliance with TB treatment should be emphasised to reduce TB-related mortality.

Machine learning based approach to pH imaging and classification of single cancer cells.

The ability to identify different cell populations in a noninvasive manner and without the use of fluorescence labeling remains an important goal in biomedical research. Various techniques have been developed over the last decade, which mainly rely on fluorescent probes or nanoparticles. On the other hand, their applications to single-cell studies have been limited by the lengthy preparation and labeling protocols, as well as issues relating to reproducibility and sensitivity. Furthermore, some of these techniques require the cells to be fixed. Interestingly, it has been shown that different cell types exhibit a unique intracellular environment characterized by specific acidity conditions as a consequence of their distinct functions and metabolism. Here, we leverage a recently developed pH imaging modality and machine learning-based single-cell segmentation and classification to identify different cancer cell lines based on their characteristic intracellular pH. This simple method opens up the potential to perform rapid noninvasive identification of living cancer cells for early cancer diagnosis and further downstream analyses.

Metastatic efficiency of tumour cells can be impaired by intraoperative cell salvage process: truth or conjecture?

The use of salvaged blood in oncological surgery has been a matter of controversy over the years. This is due to the concern of systemic dissemination of reinfused tumour cells. Recent literature, across disciplines, has shed considerable light on its safety in terms of tumour recurrence, progression and overall survival rates. This clinical safety demonstrates the apparent metastatic inefficiency of reinfused tumour cells. The proof of this concept comes from various studies that have shown that salvaged blood has no tumour cells, or has a significantly lower count as compared to the patient's original circulatory tumour load. Recently, we took a step further and found that the tumour cells in the salvaged blood lose the capacity to replicate. In this review, we revisited the safety of salvaged blood from the point of view of metastatic potential. We have presented basic and applied science evidence regarding the innocuous nature of tumour cells that have been subjected to the cell salvage process. The understanding of the metastatic efficiency or the lack of it in tumour cells subjected to salvage process is key to allay the concerns conventionally associated with the use of salvaged blood in tumour surgery. Based on the available literature, we surmise that the prevalent apprehensions on the usage of salvaged blood are ill-founded and further substantiate why tumour cells in the salvaged blood could be regarded as cells with non-metastatic potential.

Reconstruction of Disrupted Extensor Mechanism After Total Knee Arthroplasty.

BACKGROUND: Disruption of the extensor mechanism after total knee arthroplasty (TKA) is a debilitating complication that results in extension lag, limited range of motion, difficulty in walking, frequent falls, and chronic pain. This study presents the clinical and radiographic results of reconstruction after extensor mechanism disruption in TKA patients. METHODS: Consecutive patients with allograft reconstruction of extensor mechanism after TKA were identified retrospectively from an academic tertiary center for revision TKA. RESULTS: Sixteen patients with a mean age of 61 ± 14 years at extensor mechanism reconstruction with a minimum of 2-year follow-up were included. The mean follow-up was 3.3 ± 2.2 years. Knee Society score (KSS), before and at final follow-up extension lag, range of motion, and radiographic change in patellar height were reviewed. There were statistically significant improvements between preoperative and final follow-up KSS (P < .001; KSS for pain, preoperative 40 ± 14 points to final follow-up 67 ± 15 points [P < .001]; KSS for function, preoperative 26 ± 21 points to final follow-up 48 ± 25 points [P < .001]). The extension lag was also reduced from 35° ± 16° preoperatively to 14° ± 18° (P < .001) at final follow-up. There was an average proximal patellar migration of 8 ± 10 mm. Five (31%) cases had an extensor lag of >30° or revision surgery for repeat extensor mechanism reconstruction, infection, or arthrodesis. CONCLUSION: Our 10-year experience using allografts during extensor mechanism reconstruction demonstrates reasonable outcomes, but failures are to be anticipated in approximately one-third of patients.

Modeling collective cell migration in geometric confinement.

Monolayer expansion has generated great interest as a model system to study collective cell migration. During such an expansion the culture front often develops 'fingers', which we have recently modeled using a proposed feedback between the curvature of the monolayer's leading edge and the outward motility of the edge cells. We show that this model is able to explain the puzzling observed increase of collective cellular migration speed of a monolayer expanding into thin stripes, as well as describe the behavior within different confining geometries that were recently observed in experiments. These comparisons give support to the model and emphasize the role played by the edge cells and the edge shape during collective cell motion.

Occlusion in the Flow of New Drugs for Cardiovascular Disease.

There is a large misalignment between unmet need and both private and public investment activity in cardiovascular disease. In this paper, we quantify the magnitude of the gap, analyze a range of potential root causes in two main categories (issues of feasibility and valuation), and propose steps toward solutions to close the gap.

Deep branch of the radial nerve in lateral surgical approaches to the radial head - A cadaveric study.

INTRODUCTION: The traditional Kocher approach for lateral radial head exposure may be complicated by injury to the deep branch of the radial nerve (DBRN) and the radial collateral ligament. Kaplan approach is less commonly used, due to its known proximity to the DBRN. Extensor Digitorum Communis (EDC) splitting approach allows possible wide surgical exposure and low risk of radial collateral ligament injury. The comparison of the proximity of the DBRN to the surgical dissection at the level of radial head among approaches to the radial head has not previously been evaluated. We aimed to determine the anatomical proximity of the DBRN in these 3 common radial head approaches and to define a safe zone of dissection for the surgical exposure. METHODS: Cadaveric dissections of 9 pairs of fresh frozen upper extremities were performed using EDC splitting, Kaplan and Kocher approach to the radial head sequentially in a randomized order. A mark was made on the radial head upon initial exposure during dissection. Measurements from the marked point of the radial head to the DBRN were made at the level of radial head. RESULTS: The distance of DBRN to the radial head was 20 (17-22) mm in EDC splitting approach, 7 (3-11) mm in Kaplan approach and 29 (25-33) mm in Kocher approach. The EDC splitting approach was associated with a significantly lower chance of encountering the DBRN at the level of radial head as compared to the Kaplan approach (P<0.001). In all cases, lateral ligamentous complex was not exposed in Kaplan and EDC approaches, but were encountered in Kocher approach, risking injury to the radial collateral ligament. CONCLUSIONS: The EDC splitting approach provides adequate exposure without the need to elevate or retract the EDC and ECU muscle mass that could risk injuring the DBRN. The Kaplan approach should be done by experienced surgeons who are familiar with the anatomy in this region, with extreme caution due to proximity of the DBRN to the surgical dissection at the level of the radial head. Caution of the DBRN should be taken during anterior elevation and retraction of the muscle mass in Kocher approach. LEVEL OF EVIDENCE: IV.

Basic reproduction number of coxsackievirus type A6 and A16 and enterovirus 71: estimates from outbreaks of hand, foot and mouth disease in Singapore, a tropical city-state.

Coxsackievirus A6 (CV-A6), coxsackievirus A16 (CV-A16) and enterovirus 71 (EV-A71) were the major enteroviruses causing nationwide hand, foot and mouth disease (HFMD) epidemics in Singapore in the last decade. We estimated the basic reproduction number (R 0) of these enteroviruses to obtain a better understanding of their transmission dynamics. We merged records of cases from HFMD outbreaks reported between 2007 and 2012 with laboratory results from virological surveillance. R 0 was estimated based on the cumulative number of reported cases in the initial growth phase of each outbreak associated with the particular enterovirus type. A total of 33 HFMD outbreaks were selected based on the inclusion criteria specified for our study, of which five were associated with CV-A6, 13 with CV-A16, and 15 with EV-A71. The median R 0 was estimated to be 5·04 [interquartile range (IQR) 3·57-5·16] for CV-A6, 2·42 (IQR 1·85-3·36) for CV-A16, and 3·50 (IQR 2·36-4·53) for EV-A71. R 0 was not significantly associated with number of infected children (P = 0·86), number of exposed children (P = 0·94), and duration of the outbreak (P = 0·05). These enterovirus-specific R 0 estimates will be helpful in providing insights into the potential growth of future HFMD epidemics and outbreaks for timely implementation of disease control measures, together with disease dynamics such as severity of the cases.

Reprint of: Connections between single-cell biomechanics and human disease states: gastrointestinal cancer and malaria.

We investigate connections between single-cell mechanical properties and subcellular structural reorganization from biochemical factors in the context of two distinctly different human diseases: gastrointestinal tumor and malaria. Although the cell lineages and the biochemical links to pathogenesis are vastly different in these two cases, we compare and contrast chemomechanical pathways whereby intracellular structural rearrangements lead to global changes in mechanical deformability of the cell. This single-cell biomechanical response, in turn, seems to mediate cell mobility and thereby facilitates disease progression in situations where the elastic modulus increases or decreases due to membrane or cytoskeleton reorganization. We first present new experiments on elastic response and energy dissipation under repeated tensile loading of epithelial pancreatic cancer cells in force- or displacement-control. Energy dissipation from repeated stretching significantly increases and the cell's elastic modulus decreases after treatment of Panc-1 pancreatic cancer cells with sphingosylphosphorylcholine (SPC), a bioactive lipid that influences cancer metastasis. When the cell is treated instead with lysophosphatidic acid, which facilitates actin stress fiber formation, neither energy dissipation nor modulus is noticeably affected. Integrating recent studies with our new observations, we ascribe these trends to possible SPC-induced reorganization primarily of keratin network to perinuclear region of cell; the intermediate filament fraction of the cytoskeleton thus appears to dominate deformability of the epithelial cell. Possible consequences of these results to cell mobility and cancer metastasis are postulated. We then turn attention to progressive changes in mechanical properties of the human red blood cell (RBC) infected with the malaria parasite Plasmodium falciparum. We present, for the first time, continuous force-displacement curves obtained from in-vitro deformation of RBC with optical tweezers for different intracellular developmental stages of parasite. The shear modulus of RBC is found to increase up to 10-fold during parasite development, which is a noticeably greater effect than that from prior estimates. By integrating our new experimental results with published literature on deformability of Plasmodium-harbouring RBC, we examine the biochemical conditions mediating increases or decreases in modulus, and their implications for disease progression. Some general perspectives on connections among structure, single-cell mechanical properties and biological responses associated with pathogenic processes are also provided in the context of the two diseases considered in this work.

Supracondylar humeral fractures in children: beware the medial spike.

Supracondylar humeral fractures are common in children, but there are no classification systems or radiological parameters that predict the likelihood of having to perform an open reduction. In a retrospective case-control study we evaluated the use of the medial spike angle and fracture tip-skin distance to predict the mode of reduction (closed or open) and the operating time in fractures with posterolateral displacement. A total of 21 patients (4.35%) with a small medial spike angle (< 45°) were identified from a total of 494 patients, and 42 patients with a medial spike angle of > 45° were randomly selected as controls. The medial spike group had significantly smaller fracture tip-skin distances (p < 0.001), longer operating times (p = 0.004) and more complications (p = 0.033) than the control group. There was no significant difference in the mode of reduction and a composite outcome measure. After adjustments for age and gender, only fracture tip-skin distance remained significantly associated with the operating time (ß = -0.724, p = 0.042) and composite outcome (OR 0.863 (95% confidence interval 0.746 to 0.998); p = 0.048). Paediatric orthopaedic surgeons should have a lower threshold for open reduction when treating patients with a small medial spike angle and a small fracture tip-skin distance.

The effect of unloading on gene expression of healthy and injured rotator cuffs.

Tendon unloading following rupture of one of the rotator cuff tendons can induce alterations in muscle physiology and tendon structure, which can subsequently affect reparability and healing potential. Yet little is known about the effects of muscle and tendon unloading on the molecular response of the rotator cuff. We determined the effect of mechanical unloading on gene expression and morphology of healthy supraspinatus tendons and muscles, and the same muscles after acute injury and repair. Mechanical unloading was achieved by tenotomy and/or botulinum toxin A (BTX) chemical denervation in a rat rotator cuff model of injury and repair. Gene expression profiles varied across regions of the muscle, with the greatest changes seen in the distal aspect of the muscle for most genes. Myogenic and adipogenic genes were upregulated in muscle when unloaded (tenotomy and BTX). Tendon injury, with and without repair, resulted in upregulation of fibrosis- and tendon-specific gene expression. The expression of scleraxis, a transcription factor necessary for tendon development, was upregulated in response to injury and repair. In summary, tendon detachment and repair had the greatest effect on tendon gene expression, while unloading had the greatest effect on muscle gene expression.

A power-law rheology-based finite element model for single cell deformation.

Physical forces can elicit complex time- and space-dependent deformations in living cells. These deformations at the subcellular level are difficult to measure but can be estimated using computational approaches such as finite element (FE) simulation. Existing FE models predominantly treat cells as spring-dashpot viscoelastic materials, while broad experimental data are now lending support to the power-law rheology (PLR) model. Here, we developed a large deformation FE model that incorporated PLR and experimentally verified this model by performing micropipette aspiration on fibroblasts under various mechanical loadings. With a single set of rheological properties, this model recapitulated the diverse micropipette aspiration data obtained using three protocols and with a range of micropipette sizes. More intriguingly, our analysis revealed that decreased pipette size leads to increased pressure gradient, potentially explaining our previous counterintuitive finding that decreased pipette size leads to increased incidence of cell blebbing and injury. Taken together, our work leads to more accurate rheological interpretation of micropipette aspiration experiments than previous models and suggests pressure gradient as a potential determinant of cell injury.

Thermal treatments modulate bacterial adhesion to dental enamel.

Numerous studies have demonstrated the effects of laser-induced heat on demineralization of enamel; however, no studies have investigated the link between heat/laser-induced changes in physicochemical properties and bacterial adhesion. In this study, we investigated the effects of thermal treatment on surface properties of enamel such as hydrophobicity and zeta potential. Bacterial adhesion to treated surfaces was characterized by confocal laser scanning microscopy, and adhesion force was quantified by atomic force microscopy. The hydrophobicity of enamel increased after heating (p < 0.05), and the zeta potential of heated enamel became more negative than that of the control (p < 0.01). Streptococcus oralis and S. mitis were more hydrophilic than S. sanguis, with more negative zeta potential (all p < 0.01). S. mitis and S. oralis occupied significantly less area on enamel after being heated (p < 0.05). Heating reduced the adhesion force of both S. mitis and S. oralis to enamel with or without saliva coating. Reduction of adhesion force was statistically significant for S. mitis (p < 0.01), whereas that of S. oralis was not statistically significant (p > 0.05). Heating did not affect the adhesion of S. sanguis with or without saliva coating. In conclusion, thermal treatment and photothermal/laser treatments may modulate the physicochemical properties of enamel, preventing the adhesion of some bacterial species.

Tissue scaffolds for skin wound healing and dermal reconstruction.

One of the major applications of tissue-engineered skin substitutes for wound healing is to promote the healing of cutaneous wounds. In this respect, many important clinical milestones have been reached in the past decades. However, currently available skin substitutes for wound healing often suffer from a range of problems including wound contraction, scar formation, and poor integration with host tissue. Engineering skin substitutes by tissue engineering approach has relied upon the creation of three-dimensional scaffolds as extracellular matrix (ECM) analog to guide cell adhesion, growth, and differentiation to form skin-functional and structural tissue. The three-dimensional scaffolds can not only cover wound and give a physical barrier against external infection as wound dressing, but also can provide support both for dermal fibroblasts and the overlying keratinocytes for skin tissue engineering. A successful tissue scaffold should exhibit appropriate physical and mechanical characteristics and provide an appropriate surface chemistry and nano and microstructures to facilitate cellular attachment, proliferation, and differentiation. A variety of scaffolds have been fabricated based on materials ranging from naturally occurring ones to those manufactured synthetically. This review discusses a variety of commercial or laboratory-engineered skin substitutes for wound healing. Central to the discussion are the scaffolds/materials, fabrication techniques, and their characteristics associated with wound healing. One specifically highlighted emerging fabrication technique is electrospinning that allows the design and fabrication of biomimetic scaffolds that offer tremendous potential applications in wound healing of skin.

Effects of implantation of bone marrow mesenchymal stem cells, disc distraction and combined therapy on reversing degeneration of the intervertebral disc.

Although success has been achieved with implantation of bone marrow mesenchymal stem cells (bMSCs) in degenerative discs, its full potential may not be achieved if the harsh environment of the degenerative disc remains. Axial distraction has been shown to increase hydration and nutrition. Combining both therapies may have a synergistic effect in reversing degenerative disc disease. In order to evaluate the effect of bMSC implantation, axial distraction and combination therapy in stimulating regeneration and retarding degeneration in degenerative discs, we first induced disc degeneration by axial loading in a rabbit model. The rabbits in the intervention groups performed better with respect to disc height, morphological grading, histological scoring and average dead cell count. The groups with distraction performed better than those without on all criteria except the average dead cell count. Our findings suggest that bMSC implantation and distraction stimulate regenerative changes in degenerative discs in a rabbit model.

The use of muscle flaps in the salvage of infected exposed implants for internal fixation.

The treatment of infected exposed implants which have been used for internal fixation usually involves debridement and removal of the implant. This can result in an unstable fracture or spinal column. Muscle flaps may be used to salvage these implants since they provide soft-tissue cover and fresh vascularity. However, there have been few reports concerning their use and these have concentrated on the eradication of the infection and successful soft-tissue cover as the endpoint. There is no information on the factors which may influence the successful salvage of the implant using muscle flaps. We studied the results and factors affecting outcome in nine pedicled muscle flaps used in the treatment of exposed metal internal fixation with salvage of the implant as the primary endpoint. This was achieved in four cases. Factors predicting success were age < 30 years, the absence of comorbid conditions and a favourable microbiological profile. The growth of multiple organisms, a history of smoking and the presence of methicillin-resistant Staphylococcus aureus on wound cultures indicated a poor outcome. The use of antibiotic beads, vacuum-assisted closure and dressing, the surgical site, the type of flap performed and the time from primary surgery to flap cover were not predictive of outcome.