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Introduction: Cervical cancer is common cancer and ranked in fourth place in both incidence and mortality worldwide. It is 3rd most common female cancer in Malaysia with a lifetime risk of 1 in 116. Infection with high-risk oncogenic human papillomavirus (HPV) is recognized as one of the substantial risk factors for the development of cervical cancers. Methods: It was a cross-sectional study conducted to determine the prevalence of HPV infection and its subtypes among women with various degrees of abnormal smears, who were seen in the colposcopy clinic of Sarawak General Hospital within six months’ period from January to June 2018. We recruited 56 participants. There were 23 each for an atypical squamous cell of undetermined significance (ASC-US) and low-grade squamous intraepithelial lesion (LSIL) and 10 high- grade squamous intraepithelial lesion (HSIL). DNA was extracted, and HPV genotypes were determined via polymerase chain reaction (PCR) using two primer pairs MY09/MY11 and GP5+/GP6+. Results: The age ranged from 23 to 56 years, with a mean age of 42.96 years. HPV was detected in 20 out of 56 (35.7%). There were 6 high-risk oncogenic HPVs (18, 51, 52, 56, 58, 68) detected in participants and the most prevalent subtypes were 18, 52, and 58 (20% each). Four low-risk HPVs detected were 6, 53, 70, and 84. There was a significant association between the severity of cervical lesions and HPV positivity (P < 0.004). HSIL had the highest positive predictive value to have HPV infection as 70% compared to 43.4% of LSIL and 9.3% of ASC-US. Conclusion: Distribution of HPV subtypes from women with abnormal smears from Sarawak indicated a high prevalence of HPV 18, 52, and 58. We also identified HPV 70, which has never been reported in West Malaysia. These findings could contribute valuable information for HPV vaccination strategies, particularly for Sarawakian women.

Background/objectives The Hospital Elder Life Program emerged 20 years ago as the reference model for delirium prevention in hospitalized older patients. However, implementation has been achieved at only 200 hospitals worldwide over the last 20 years. Among the barriers to implementation for some institutions is an unwillingness of hospital administration to assume the costs associated with implementing programs that service all hospitalized older patients at risk for delirium. Facing such a situation, we implemented a unique and self-evolving model of care of older hospitalized patients who had already developed delirium. Design Hypothesis testing was carried out using a pretest-posttest design on program administrative data. Setting Mount Sinai Hospital, New York, NY, a tertiary-care teaching facility. PARTICIPANTS A total of 9,214 consecutively admitted older patients to non-intensive care (ICU) inpatient units over a 5.5-year period, regardless of the suspected presence of delirium or risk status for developing delirium. Intervention A delirium intervention program targeting patients in whom delirium has already developed, with a modified delirium team supported by extensive workflow automation with custom tools in our electronic medical records system. Measurements Length of stay (LOS) for delirious and non-delirious patients on units where this program was piloted. Benzodiazepine, opiate, and antipsychotic use on the same units. Results There was a significant drop in LOS by 1.98 days (95% confidence interval = .24-3.71), a decrease in the average morphine dose equivalents administered from .38 mg to .21 mg per patient hospital day, diazepam dose equivalents from .22 mg to .15 mg per patient hospital day, and quetiapine administered from .17 mg to .14 mg per patient hospital day for delirious patients on the program pilot units. Conclusion Elements of our unique active delirium treatment program may provide some direction to other program developers working on improving the care of older hospitalized delirious patients. However, the supporting evidence presented is limited, and a more rigorous prospective study is needed.

Introduction: Alternatively using gradient lower-body negative pressure (LBNP) and ergometer exercise (LBNP + ergo) under a flight schedule framework was explored to detect its orthostatic capacity maintenance effects in female subjects after 15 days of -6° head-down bed rest (HDBR). Methods: Twenty-two female university students were divided into a control group (n = 8), an LBNP group (n = 7), and an LBNP + ergo group (n = 7). Ergometer exercise consisted of an interval exercise protocol with 2 min intervals alternating between 41% and 70% VO2max. Gradient LBNP was decompressed in 10 mm Hg intervals to -40 mmHg every 5 min. intermittent ergometer exercise and LBNP were alternatively performed. Tilt test was performed 2 days before HDBR (R-2), on the day of HDBR termination (R+1), and 5 days after HDBR (R+5). Results: Fifty percent of the participants (11/22) did not pass the tilt test on R+1. The orthostatic tolerance time decreased from 20 to 16.1 ± 2.1 min in the control group, to 10.0 ± 2.7 min in the LBNP group (p = 0.01) and to 16.3 ± 2.0 min in the LBNP + ergo group. The HRs and BPs were at similar level among three groups during tilt test on different test days. Compared with the control group, the LBNP + ergo group had higher SV and CO percentage changes at R+1(p < 0.023) and R+5 (p < 0.00001) during the tilt test. Conclusion: LBNP combined with ergometer exercises fails to prevent orthostatic intolerance but it induced some positive hemodynamic changes during tilt test after 15 days HDBR.

Community nurses in Singapore support vulnerable older persons with chronic health condition(s). In the situation of scaled-down community health and social services during the COVID-19 outbreak, the community nursing team adopted measures for pandemic preparedness. This report is to share the Singapore General Hospital community nursing experience, preparation and transforming efforts during the pandemic. Team segregation, active screening and triage before visits and other precautionary measures were executed to minimise the risk of exposure to COVID-19. There was a shift from face-to-face to teleconsultation to meet the requirement of safe social-distancing. Community nursing teams continued to play an active role in supporting older persons during the pandemic, despite the challenges. Moving to the lockdown phase (‘circuit breaker’), teleconsultation, virtual meetings and integrated partnerships were essential to ensure healthcare accessibility and continuity of care. The experience gleaned was valuable to advance future community nursing services in the evolving healthcare landscape. Structured teleconsultation and technology advancement are useful to complement the service.

Objective Coronaviruses (CoVs) are natural commensals of bats. Two subgenera, namely Sarbecoviruses and Merbecoviruses have a high zoonotic potential and have been associated with three separate spillover events in the past 2 decades, making surveillance of bat-CoVs crucial for the prevention of the next epidemic. The study was aimed to elucidate the presence of coronavirus in fresh bat guano sampled from Wind Cave Nature Reserve (WCNR) in Sarawak, Malaysian Borneo. Samples collected were placed into viral transport medium, transported on ice within the collection day, and preserved at − 80 °C. Nucleic acid was extracted using the column method and screened using consensus PCR primers targeting the RNA-dependent RNA polymerase (RdRp) gene. Amplicons were sequenced bidirectionally using the Sanger method. Phylogenetic tree with maximum-likelihood bootstrap and Bayesian posterior probability were constructed. Results CoV-RNA was detected in ten specimens (47.6%, n = 21). Six alphacoronavirus and four betacoronaviruses were identified. The bat-CoVs can be phylogenetically grouped into four novel clades which are closely related to Decacovirus-1 and Decacovirus-2, Sarbecovirus, and an unclassified CoV. CoVs lineages unique to the Island of Borneo were discovered in Sarawak, Malaysia, with one of them closely related to Sarbecovirus. All of them are distant from currently known human coronaviruses.

Objective. Neuroblastoma (NB) is a highly metastatic tumor in children that develops in the sympathetic nervous system and has a low curative rate. Saikosaponin A (SSA), an active ingredient isolated from the root of Radix Bupleuri, is a natural compound with various pharmacological activities and shows good application prospects in antitumors. This study investigated the antihuman NB activity of SSA and underlying mechanisms associated with its actions. Materials and Methods. The MTT method was used to detect the activity of SSA in inhibiting human NB cell SK-N-AS proliferation. Cell morphology was observed. The flow cytometry technology was used in analyzing the cell apoptosis rate. The Transwell assay evaluated cell migration and invasion following SSA treatment, apoptosis-related protein expression, and angiogenesis-related protein expression, and EMT-related proteins were detected by western blot analysis. Results. SSA showed an inhibitory effect on SK-N-AS cells with the IC50 values of 14.14 μM at 24 h and 12.41 μM at 48 h. Results indicated that SSA has proapoptotic activity, and its proapoptotic activity is positively correlated with the Bax/Bcl-2/caspase-9/caspase-7/PARP pathway. Furthermore, SSA inhibited the invasion and migration of SK-N-AS cells via regulating the angiogenesis-related VEGFR2/Src/Akt pathway and the epithelial-mesenchymal transition- (EMT-) related protein expression. Conclusion. SSA exerts an antihuman NB effect and thus provides foundations for NB treatment.

Introduction Pneumonia is a leading cause of death in Malaysia. Whilst many studies have reported the aetiology of pneumonia in Western countries, the epidemiology of pneumonia in Malaysia remains poorly understood. As carriage is a prerequisite for disease, we sought to improve our understanding of the carriage and antimicrobial resistance (AMR) of respiratory tract pathogens in Malaysia. The rural communities of Sarawak are an understudied part of the Malaysian population and were the focus of this study, allowing us to gain a better understanding of bacterial epidemiology in this population. Methods A population-based survey of bacterial carriage was undertaken in participants of all ages from rural communities in Sarawak, Malaysia. Nasopharyngeal, nasal, mouth and oropharyngeal swabs were taken. Bacteria were isolated from each swab and identified by culture-based methods and antimicrobial susceptibility testing conducted by disk diffusion or E test. Results 140 participants were recruited from five rural communities. Klebsiella pneumoniae was most commonly isolated from participants (30.0%), followed by Staphylococcus aureus (20.7%), Streptococcus pneumoniae (10.7%), Haemophilus influenzae (9.3%), Moraxella catarrhalis (6.4%), Pseudomonas aeruginosa (6.4%) and Neisseria meningitidis (5.0%). Of the 21 S. pneumoniae isolated, 33.3 and 14.3% were serotypes included in the 13 valent PCV (PCV13) and 10 valent PCV (PCV10) respectively. 33.8% of all species were resistant to at least one antibiotic, however all bacterial species except S. pneumoniae were susceptible to at least one type of antibiotic. Conclusion To our knowledge, this is the first bacterial carriage study undertaken in East Malaysia. We provide valuable and timely data regarding the epidemiology and AMR of respiratory pathogens commonly associated with pneumonia. Further surveillance in Malaysia is necessary to monitor changes in the carriage prevalence of upper respiratory tract pathogens and the emergence of AMR, particularly as PCV is added to the National Immunisation Programme (NIP).

Proteolytic activation of cytokines regulates immunity in diverse organisms. In animals, cysteine-dependent aspartate-specific proteases (caspases) play central roles in cytokine maturation. Although the proteolytic production of peptide cytokines is also essential for plant immunity, evidence for a plant caspase is still lacking. In this study, we discovered that proteolysis of a caspase-like substrate motif “CNYD” within Pathogenesis-related protein 1 (AtPR1) in Arabidopsis generates an immunomodulatory cytokine (AtCAPE9). Salicylic acid enhances CNYD-targeted protease activity and the proteolytic release of AtCAPE9 from AtPR1 in Arabidopsis. We show that this process involves a caspase, identified as Xylem cysteine peptidase 1 (XCP1). XCP1 exhibits a calcium-modulated pH-activity profile and a comparable activity to human caspases. XCP1 is required to induce systemic immunity triggered by pathogen-associated molecular patterns. This work reveals XCP1 as the first known plant caspase, which produces the cytokine AtCAPE9 from the canonical salicylic acid signaling marker PR1 to activate systemic immunity.

Background: Glaucoma is a multifactorial optic neuropathy progressively characterized by structural loss of Retinal Ganglion Cells (RGCs) and irreversible loss of vision. High Intraocular Pressure (HIOP) is a high-risk factor for glaucoma. It has been reported that the mechanisms of the loss of RGCs are explored in-depth after acute HIOP injury, such as apoptosis, autophagy, and necrosis. However, pyroptosis, a novel type of pro-inflammatory cell programmed necrosis, is rarely reported after HIOP injury. Research studies also showed that melatonin (MT) possesses substantial anti-inflammatory properties. However, whether melatonin could alleviate retinal neuronal death, especially pyroptosis, by HIOP injury is still unclear. Objective: This study explored pyroptosis of retinal neurons and the effects of melatonin in preventing retinal neurons from pyroptosis after acute HIOP injury. Methods: An acute HIOP model of rats was established by increasing the IOP followed by reperfusion. Western Blot (WB) was adopted to detect molecules related to pyroptosis at the protein level, such as GSDMD, GASMDp32, Caspase-1, and caspase-1 p20, and the products of inflammatory reactions, such as IL -18 and IL-1β. At the same time, immunofluorescence (IF) was used to co-localize caspase-1 with retinal neurons to determine the position of caspase-1 expression. Morphologically, ethidium homodimer III staining, a method commonly used to evaluate cell death, was carried out to stain dead cells. Subsequently, Lactate Dehydrogenase (LDH) cytotoxicity assay kit was used to quantitatively analyze the LDH released after cell disruption. Results: The results suggested that pyroptosis played a vital role in retinal neuronal death, especially in the Ganglion Cell Layer, by acute HIOP injury and peaked at 6h after HIOP injury. Furthermore, it was found that melatonin (MT) might prevent retinal neurons of pyroptosis via NF-κ B/NLRP3 axis after HIOP injury in rats. Conclusion: Melatonin treatment might be considered a new strategy for protecting retinal neurons against pyroptosis following acute HIOP injury.

Introduction Acute kidney injury (AKI) is common in the intensive care unit (ICU) with a high risk of morbidity and mortality. The high incidence of AKI in our population may be attributed to sepsis. We investigated the incidence, risk factors, and outcome of AKI in four tertiary Malaysian ICUs. We also evaluated its association with sepsis. Materials and Methods This retrospective cohort study extracted de-identified data from the Malaysian Registry of Intensive Care in four Malaysian tertiary ICUs between January 2010 and December 2014. The study was registered under the NMRR and approved by the ethics committee. AKI was defined as twice the baseline creatinine or urine output

Introduction. Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) can be misdiagnosed for the more common genetic neuropathies such as Charcot-Marie-Tooth (CMT) disease. We present a case of childhood-onset demyelinating polyneuropathy who was initially diagnosed as CMT before a revised diagnosis of CIDP was made. Results. A 14-year-old boy with bilateral pes cavus presented with progressive history of ataxic gait, generalized areflexia and proprioceptive sensory loss. Nerve conduction studies showed demyelinating features including markedly slow motor conduction velocities and prolonged distal motor latencies resembling CMT1. Despite the absence of a family history of genetic neuropathies, a diagnosis of CMT1 was considered most likely. The patient represented two years later with an acute onset of worsening instability and muscle weakness. A detailed history revealed functional improvement following the last presentation along with two separate episodes of exacerbations suggesting a relapsing-remitting form of neuropathy. Cerebrospinal fluid analysis showed cytoalbuminergic dissociation. Nerve ultrasound demonstrated enlarged peripheral nerves, particularly in the proximal and non-entrapment sites. Genetic testing was negative for known mutations in common CMT genes. A course of intravenous immunoglobulin resulted in clinically significant improvement. Conclusion. This report highlights the diagnostic challenges in childhood-onset demyelinating neuropathies and the importance of not missing a potentially treatable immune-mediated neuropathy.

Introduction. Familial amyloid polyneuropathy (FAP) is a rare autosomal dominant peripheral neuropathy. We report a case series of Malaysian FAP patients. Methods. Patients with definite (genetically confirmed) FAP seen at the University of Malaya Medical Centre between 2008 till 2019 were included in the series. The patients’ demographic and clinical features and investigations including nerve conduction studies and electromyography (NCS/EMG), echocardiography, sural nerve biopsy and hATTR mutation are reported. Results. A total 21 index cases were seen. Nineteen (90%) were ethnic Chinese, one ethnic (5%) Malay and one (5%) ethnic Indian; Fourteen (67%) were men. Mean age of onset of symptoms was 56.1 ± 10.5 years (range: 31-73). Nineteen (90%) patients presented with numbness and weakness of the limbs while two had postural hypotension. Fifteen (71%) patients had positive family history. NCS/EMG showed sensorimotor polyneuropathy in 19 (90%) patients; fifteen (71%) showing axonal neuropathy. Amyloid deposits were seen on nerve biopsy in ten patients and rectal, leptomeningeal and endomyocardial biopsies in 1 patient respectively. The latter was diagnosed as familial amyloid cardiomyopathy (FAC). Sixteen patients (76%) had abnormal cardiac echocardiogram with amyloid deposits. Fifteen Chinese patients (71%) carried the Ala97Ser hATTR mutation while the FAC patient has Asp39Val mutation. Our Malay patient had Glu54Lys mutation and Indian patient had Gly67Val mutation. Two patients carried Val30Met mutation. Autonomic function test was abnormal in all 7 patients in whom they were carried out. Conclusion. FAP in Malaysians is seen mainly among ethnic Chinese, in whom Ala97Ser may be a common mutation. This is also the reported “hotspot” mutation for FAP reported in Taiwan but not in China. Similar to Taiwan, Chinese-Malaysians are descended from immigrants from Southern China. Similar to Taiwanese patients, our FAP patients with Ala97Ser mutation, present with late-onset progressive sensorimotor polyneuropathy and cardiac involvement was common.

Tumor-associated macrophages (TAMs) are the most abundant population type of tumor-infiltrating immune cells found in the tumor microenvironment (TME), and are evolutionarily associated with microvessel density in tumor tissues. TAMs can be broadly divided into M1-like and M2-like TAMs, which demonstrate antitumor and pro-tumor activity in the TME, respectively. Studies have indicated that: i) The predominate presence of M2-like TAMs in the TME can result in tumor immunosuppression and chemoresistance; ii) the ratio of M1-like to M2-like TAMs in the TME is positively correlated with better long-term prognosis of patients with cancer; iii) epigenetic silencing, preventing the secretion of M1-like TAM-associated molecules, is an important immune evasion mechanism during tumor progression; and iv) the transformation from M2-like to M1-like TAMs following exposure to specific conditions can result in tumor regression. The present study discusses the molecular events underlying the recruitment of macrophages and their polarization into M1-like or M2-like TAMs, and their differential roles in angiogenesis, angiostasis, invasion, metastasis and immune activity in the TME. This insight may inform the improved design of TAM-targeted cancer immunotherapy. Some of these therapeutic strategies show promising effects; however, challenges remain.

Epidermal melanocytes are skin cells specialized in melanin production. Activation of the melanocortin 1 receptor (MC1R) on melanocytes by α-melanocyte–stimulating hormone (α-MSH) induces synthesis of the brown/black pigment eumelanin that confers photoprotection from solar UV radiation (UVR). Contrary to keratinocytes, melanocytes are slow proliferating cells that persist in the skin for decades, in an environment with high levels of UVR-induced reactive oxygen species (ROS). We previously reported that in addition to its role in pigmentation, α-MSH also reduces oxidative stress and enhances the repair of DNA photoproducts in melanocytes, independent of melanin synthesis. Given the significance of ROS in carcinogenesis, here we investigated the mechanisms by which α-MSH exerts antioxidant effects in melanocytes. We show that activation of the MC1R by α-MSH contributes to phosphorylation of p53 on serine 15, a known requirement for stabilization and activation of p53, a major sensor of DNA damage. This effect is mediated by the cAMP/PKA pathway and by the activation of phosphoinositide 3-kinase (PI3K) ATR and DNA protein kinase (DNA-PK). α-MSH increases the levels of 8-oxoguanine DNA glycosylase (OGG1) and apurinic apyrimidinic endonuclease 1 (APE-1/Ref-1), enzymes essential for base excision repair. Nutlin-3, an HDM2 inhibitor, mimicked the effects of α-MSH resulting in reduced phosphorylation of H2AX (γ-H2AX), a marker of DNA damage. Conversely, the p53 inhibitor pifithrin-α or silencing of p53 abolished the effects of α-MSH and augmented oxidative stress. These results show that p53 is an important target of the downstream MC1R signaling that reduces oxidative stress and possibly malignant transformation of melanocytes. Mol Cancer Res; 10(6); 778–86. ©2012 AACR.

Low levels of donor chimerism on day 28 after hematopoietic stem cell transplantation are highly predictive of a subsequent rejection of donor cells A recent report on nonmyeloablative transplants has demonstrated that patients who engrafted after transplantation had at least 10% donor cells detectable at this time point. A patient is described who received a nonmyeloablative umbilical cord blood transplant and experienced subsequent full engraftment of donor cells despite the absence of donor chimerism at 4 weeks posttransplantation.

Myofibroblast differentiation, characterized by α-smooth muscle actin (α-SMA) expression, is a key process in organ fibrosis. Our recent studies have shown that AcSDKP has a anti-fibrotic effect in the lung of rats with silicosis. Here we explore the underlying effect of AcSDKP on myofibroblast differentiation during the anti-fibrotic process. SiO 2 powders were instilled in trachea of rat to make the silicotic model, and caused 1) increased expressions of TGF-β, 2) escalated serum response factor (SRF) expression, 3) myofibroblast marked by o-SMA being detected in siliconic nodules, and 4) collagen deposition in lung. AcSDKP (both anti fibronic and prevention treatment) can inhibit these changes induced by silica significantly. AcSDKP could inhibit collagen synthesis throuth blocking myofibroblast differentiation in the lung of rats with silicosis, which is a new mechanism of its anti-silicotic effect.

To investigate the mechanism how Transforming growth factor-β(TGF-β) represses Interleukin-1β (IL-1β)-induced Proteinase-Activated Receptor-2 (PAR-2) expression in human primary synovial cells (h PSCs). Human chondrocytes and h PSCs isolated from cartilages and synovium of Osteoarthritis (OA) patients were cultured with 10% fetal bovine serum media or serum free media before treatment with IL-1β, TGF-β1, or Connective tissue growth factor (CTGF). The expression of PAR-2 was detected using reverse transcriptase-polymerase chain reaction (RT-PCR) and western blotting. Collagen zymography was performed to assess the activity of Matrix metalloproteinases-13 (MMP-13). It was demonstrated that IL-1β induces PAR-2 expression via p38 pathway in h PSCs. This induction can be repressed by TGF-β and was observed to persist for at least 48 hrs, suggesting that TGF-β inhibits PAR-2 expression through multiple pathways. First of all, TGF-β was able to inhibit PAR-2 activity by inhibiting IL-1β-induced p38 signal transduction and secondly the inhibition was also indirectly due to MMP-13 inactivation. Finally, TGF-β was able to induce CTGF, and in turn CTGF represses PAR-2 expression by inhibiting IL-1β-induced phospho-p38 level. TGF-β could prevent OA from progression with the anabolic ability to induce CTGF production to maintain extracellular matrix (ECM) integrity and to down regulate PAR-2 expression, and the anti-catabolic ability to induce Tissue inhibitors of metalloproteinase-3 (TIMP-3) production to inhibit MMPs leading to avoid PAR-2 over-expression. Because IL-1β-induced PAR-2 expressed in h PSCs might play a significantly important role in early phase of OA, PAR-2 repression by exogenous TGF-β or other agents might be an ideal therapeutic target to prevent OA from progression.

Phytoplasmas are insect-transmitted intracellular plant bacterial pathogens that secrete effector molecules into host cells that interfere with the host’s developmental or metabolic processes. Recently, the secreted Aster Yellows phytoplasma strain Witches’ Broom protein11 (SAP11) has been shown to act as a virulence factor that alters the development, hormone biosynthesis, phosphate (Pi) homeostasis, and defense responses in the affected plants. We found that SAP11 undergoes proteolytic processing in planta and self-interaction in vitro. These biochemical studies provide foundational insights necessary for the functional characterization of SAP11; however, the biological relevance of post-translational cleavage and self-interaction of SAP11 to its role as a virulence factor warrants further investigation.