Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Fibreglass dermatitis: diagnostic challenges and occupational interventions.

Fibreglass dermatitis is a common occupationally acquired irritant contact dermatitis, where small spicules of fibreglass lodging in the stratum corneum result in mechanical irritation. We present two patients, an air-conditioning ducting worker and an injection moulding machine operator, who both presented with generalized pruritus. In the first case, polarized microscopy of a skin biopsy specimen demonstrated rare small spicules, with a diameter of 1 µm, lodged in the stratum corneum. In the second case, skin tape stripping demonstrated fibreglass particles, not found on skin biopsy. Proper work practices, personal hygiene and use of impervious barrier materials were recommended. The first patient did not return for follow-up, and the second patient's dermatitis resolved after handling of fibreglass-containing material was eliminated from his job scope. In conclusion, we present two cases of fibreglass dermatitis to illustrate the challenges in diagnosis and highlight strategies for prevention.

Usefulness of ultrasound fusion technology for hepatocellular carcinoma localisation, pre- and post-thermal ablation.

Introduction: Percutaneous thermal ablation of inconspicuous lesions can be challenging. Fusion ultrasound (FUS) allows the use of previously performed diagnostic imaging like computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET-CT) to localise hepatocellular carcinoma (HCC) for treatment. This paper illustrates FUS case studies of pre-, intra- and post-ablation imaging of inconspicuous HCC, supplemented by use of contrast-enhanced ultrasound (CEUS). Method: Four prospective cases during September 2014 to October 2018, with HCC amenable to ablation, which were poorly identified on ultrasound, underwent FUS. FUS pre-screening was scheduled within three months of the previous CT or MRI, and between one to four weeks prior to the scheduled ablation date. Post-ablation imaging with FUS was performed between four to six weeks to coincide with their routine follow-up CT or MRI. Findings: There were potential benefits observed in the cases with combined techniques of FUS and CEUS for limiting circumstances such as heat sink effect, multiple lesions targeting, inconspicuous lesion detection and pre-ablation technical feasibility assessment. Discussion: The combined use of FUS and CEUS improves tumour visibility, increases operator imaging confidence and reduces heat sink effect during percutaneous thermal ablation. Conclusion: FUS imaging is helpful in targeting poor conspicuity lesions that cannot be detected on grey-scale ultrasound. It facilitates in ensuring optimal treatment of hepatic lesions for improvement of patient prognosis and follow-up imaging.

The impact on patients' time-to-theatre following colour coding classification in emergency operation theatre, Sarawak General Hospital.

INTRODUCTION: A proper prioritisation system of emergency cases allows appropriate timing of surgery and efficient allocation of resources and staff expertise. The aim of this study was to determine the impact of colour coding classification on Time-to- theatre (TTT) of patients in comparison with the normal practice. METHOD: Categorisation was a surgical judgment call after thorough clinical assessment. There were 4 levels of urgency with their respective TTT; Red (2 hours), Yellow (8 hours), Green (24 hours), Blue (72 hours). Caesarean cases were excluded in colour coding due to pre - existing classification. The data for mean TTT was collected 4 weeks before the implementation (Stage 1), and another 4 weeks after implementation (Stage II). As there was a violation in the assumption for parametric test, Mann Whitney U test was used to compare the means between these two groups. Using logarithmic (Ln) transformation for TTT, Analysis of Covariance (ANCOVA) was conducted for multivariate analysis to adjust the effect of various departments. The mean TTT for each colour coding classification was also calculated. RESULTS: The mean TTT was reduced from 13 hours 48 min to 10 hours, although more cases were completed in Stage II (428 vs 481 cases). Based on Mann-Whitney U test, the difference in TTT for Stage I (Median=6.0, /IQR=18.9) and Stage II (Median=4.2, IQR=11.5) was significantly different (p=0.023). The result remained significant (p=0.039) even after controlled for various department in the analysis. The mean/median TTT after colour coding was Red- 2h 24min/1h, Yellow- 8h 26min/3h 45 min, Green- 15h 8min/8h 15min, and Blue- 13h 46min/13h 5min. CONCLUSION: Colour coding classification in emergency Operation (OT) was effective in reducing TTT of patients for non-caesarean section cases.

A case of atypical imaging of Nasopharyngeal Carcinoma in an adolescent: A diagnostic challenge.

Nasopharyngeal mass in paediatric population is usually benign and malignant nasopharyngeal tumours such as carcinoma is rare. We report a case of nasopharyngeal carcinoma (NPC) in an adolescent with atypical imaging findings that mimicked a benign mass. This highlights the importance of a comprehensive review on the distinctive radiographic features of paediatric nasopharyngeal mass. We discuss the imaging features of NPC in the paediatric group, which differ from the elderly patients. By recognising these distinctive imaging features, it may help in diagnosing typical case. This case report serves as a reminder that NPC, despite being uncommon, should be considered in the differential diagnosis of a juvenile nasopharyngeal mass.

Elevated plasma and synovial fluid interleukin-8 and interleukin-18 may be associated with the pathogenesis of knee osteoarthritis.

PURPOSE: Osteoarthritis (OA) of the knee is a multifactorial degenerative disease typically defined as the 'wear and tear' of articular joint cartilage. However, recent studies suggest that OA is a disease arising from chronic low-grade inflammation. We conducted a study to investigate the relationship between chronic inflammatory mediators present in both the systemic peripheral blood system and localised inflammation in synovial fluid (SF) of OA and non-OA knees; and subsequently made direct comparative analyses to understand the mechanisms that may underpin the processes involved in OA. METHODS: 20-Plex proteins were quantified using Human Magnetic Luminex® assay (R&D Systems, USA) from plasma and SF of OA (n = 14) and non-OA (n = 14) patients. Ingenuity Pathway Analysis (IPA) software was used to predict the relationship and possible interaction of molecules pertaining to OA. RESULTS: There were significant differences in plasma level for matrix metalloproteinase (MMP)-3, interleukin (IL)-27, IL-8, IL-4, tumour necrosis factor-alpha, MMP-1, IL-15, IL-21, IL-10, and IL-1 beta between the groups, as well as significant differences in SF level for IL-15, IL-8, vascular endothelial growth factor (VEGF), MMP-1, and IL-18. Our predictive OA model demonstrated that toll-like receptor (TLR) 2, macrophage migration inhibitory factor (MIF), TLR4 and IL-1 were the main regulators of IL-1B, IL-4, IL-8, IL-10, IL-15, IL-21, IL-27, MMP-1 and MMP-3 in the plasma system; whilst IL-1B, TLR4, IL-1, and basigin (BSG) were the regulators of IL-4, IL-8, IL-10, IL-15, IL-18, IL-21, IL-27, MMP-1, and MMP-3 in the SF system. CONCLUSION: The elevated plasma IL-8 and SF IL-18 may be associated with the pathogenesis of OA via the activation of MMP-3.

Surgical pleth index: prospective validation of the score to predict moderate-to-severe postoperative pain.

BACKGROUND: Reported outcome benefits after surgical pleth index (SPI, GE Healthcare, Helsinki, Finland) guided anaesthesia are conflicting. One potential explanation may be the lack of evidence for the selection of meaningful SPI target values. A recently published trial found an SPI cut-off of 30 as a 'best-fit' to predict moderate-to-severe acute postoperative pain. This prospective trial was designed to validate this target and to investigate the influence of patient age on SPI in this context. METHODS: After ethics approval, 200 patients undergoing non-emergency surgery were enrolled. Data related to SPI, heart rate (HR), and mean arterial pressure (MAP) were recorded for the last 5 min of surgery, just before arousal. After admission to recovery, pain scores (numeric rating scale [NRS], 0-10) were obtained every 5 min for 15 min. RESULTS: The data of 196 patients were analysed. Receiver-operating curve analysis showed a cut-off SPI value of 29 to be the optimum intraoperative target to discriminate between NRS 0-3 and 4-10. This confirms the 'best fit' cut-off for SPI published previously. Though still superior to HR and MAP, the sensitivity and specificity of the SPI were only poor. Age had no influence on the predictive accuracy of SPI. CONCLUSIONS: An SPI of approximately 30 was confirmed as having the best sensitivity/specificity to predict moderate-to-severe pain in the postanaesthesia care unit. However, the predictive accuracy was overall poor and not influenced by patient age. CLINICAL TRIAL REGISTRATION: ACTRN12617001475336.

Occurrence of gastrointestinal nematodes in captive nonhuman primates at Matang Wildlife Centre, Sarawak.

Gastrointestinal nematodes can cause assorted health problems to human and other primates. The status of gastrointestinal nematodes in non-human primates remained less documented in Malaysia. This study aimed to determine the occurrence of gastrointestinal nematodes recovered from the fecal samples of captive non-human primates at the Matang Wildlife Centre (MWC), Sarawak. Fresh fecal samples were collected from 60 non-human primates of six species (i.e. Orangutan, Bornean gibbon, Silvered Leaf monkey, Slow loris, Pig-tailed macaque, and Long-tailed macaque) and processed using simple fecal floatation method and fecal sedimentation method. This study shows high prevalence of nematode infection (>=50%) and co-infection (22 from 45 infected individuals) in all species of captive non-human primates found in MWC, except one individual of young Silvered Leaf monkey was negative for nematode. From these, eight genera of 11 species and one unknown nematode larvae were recovered and among them Oesophagostomum sp., Ascaris sp., and Strongyloides sp. were the most common nematodes infecting the non-human primates. All the Bornean gibbon (n=7) were found to be infected with nematodes. Moreover, Long-tailed macaques at the centre were heavily infected by Ascaris sp. (number of total count, nt = 2132; total mean abundance, MA=113.70). This is the first report of high prevalence nematode infection on multiple species of captive non-human primates in a wildlife centre located in Sarawak. Some of the nematodes are of zoonotic potential. This information is important for health care management, both in-situ and ex-situ conservations of captive and free-ranging nonhuman primates.

Occurrence of gastrointestinal nematodes in captive nonhuman primates at Matang Wildlife Centre, Sarawak

@#Gastrointestinal nematodes can cause assorted health problems to human and other primates. The status of gastrointestinal nematodes in non-human primates remained less documented in Malaysia. This study aimed to determine the occurrence of gastrointestinal nematodes recovered from the fecal samples of captive non-human primates at the Matang Wildlife Centre (MWC), Sarawak. Fresh fecal samples were collected from 60 non-human primates of six species (i.e. Orangutan, Bornean gibbon, Silvered Leaf monkey, Slow loris, Pig-tailed macaque, and Long-tailed macaque) and processed using simple fecal floatation method and fecal sedimentation method. This study shows high prevalence of nematode infection (>50%) and co-infection (22 from 45 infected individuals) in all species of captive non-human primates found in MWC, except one individual of young Silvered Leaf monkey was negative for nematode. From these, eight genera of 11 species and one unknown nematode larvae were recovered and among them Oesophagostomum sp., Ascaris sp., and Strongyloides sp. were the most common nematodes infecting the non-human primates. All the Bornean gibbon (n=7) were found to be infected with nematodes. Moreover, Long-tailed macaques at the centre were heavily infected by Ascaris sp. (number of total count, nt = 2132; total mean abundance, MA=113.70). This is the first report of high prevalence nematode infection on multiple species of captive non-human primates in a wildlife centre located in Sarawak. Some of the nematodes are of zoonotic potential. This information is important for health care management, both in-situ and ex-situ conservations of captive and free-ranging nonhuman primates.

Oral administration of undenatured native chicken type II collagen (UC-II) diminished deterioration of articular cartilage in a rat model of osteoarthritis (OA).

OBJECTIVE: The aim of this study was to determine the ability of undenatured native chicken type II collagen (UC-II) to prevent excessive articular cartilage deterioration in a rat model of osteoarthritis (OA). METHODS: Twenty male rats were subjected to partial medial meniscectomy tear (PMMT) surgery to induce OA. Immediately after the surgery 10 rats received vehicle and another 10 rats oral daily dose of UC-II at 0.66 mg/kg for a period of 8 weeks. In addition 10 naïve rats were used as an intact control and another 10 rats received sham surgery. Study endpoints included a weight-bearing capacity of front and hind legs, serum biomarkers of bone and cartilage metabolism, analyses of subchondral and cancellous bone at the tibial epiphysis and metaphysis, and cartilage pathology at the medial tibial plateau using histological methods. RESULTS: PMMT surgery produced moderate OA at the medial tibial plateau. Specifically, the deterioration of articular cartilage negatively impacted the weight bearing capacity of the operated limb. Immediate treatment with the UC-II preserved the weight-bearing capacity of the injured leg, preserved integrity of the cancellous bone at tibial metaphysis and limited the excessive osteophyte formation and deterioration of articular cartilage. CONCLUSION: Study results demonstrate that a clinically relevant daily dose of UC-II when applied immediately after injury can improve the mechanical function of the injured knee and prevent excessive deterioration of articular cartilage.

Identification of germline alterations in breast cancer predisposition genes among Malaysian breast cancer patients using panel testing.

Although an association between protein-truncating variants and breast cancer risk has been established for 11 genes, only alterations in BRCA1, BRCA2, TP53 and PALB2 have been reported in Asian populations. Given that the age of onset of breast cancer is lower in Asians, it is estimated that inherited predisposition to breast cancer may be more significant. To determine the potential utility of panel testing, we investigated the prevalence of germline alterations in 11 established and 4 likely breast cancer genes in a cross-sectional hospital-based cohort of 108 moderate to high-risk breast cancer patients using targeted next generation sequencing. Twenty patients (19%) were identified to carry deleterious mutations, of whom 13 (12%) were in the BRCA1 or BRCA2, 6 (6%) were in five other known breast cancer predisposition genes and 1 patient had a mutation in both BRCA2 and BARD1. Our study shows that BRCA1 and BRCA2 account for the majority of genetic predisposition to breast cancer in our cohort of Asian women. Although mutations in other known breast cancer genes are found, the functional significance and breast cancer risk have not yet been determined, thus limiting the clinical utility of panel testing in Asian populations.

The role of organisational support in teleworker wellbeing: a socio-technical systems approach.

The prevalence of telework and other forms of mobile working enabled by digital technology is increasing markedly. Following a socio-technical systems approach, this study aims to examine the role of organisational social support and specific support for teleworkers in influencing teleworker wellbeing, the mediating role of social isolation, potentially resulting from a person-environment mismatch in these relationships, and possible differences in these relationships between low-intensity and hybrid teleworkers. Teleworkers' (n = 804) perceptions of support and telework outcomes (psychological strain, job satisfaction, and social isolation) were collected using an on-line survey of teleworking employees distributed within 28 New Zealand organisations where knowledge work was undertaken. Organisational social support and teleworker support was associated with increased job satisfaction and reduced psychological strain. Social isolation mediated the relationship between organisational social support and the two outcome variables, and some differences were observed in the structural relationships for hybrid and low-intensity teleworker sub-samples. These findings suggest that providing the necessary organisational and teleworker support is important for enhancing the teleworker-environment fit and thereby ensuring desirable telework outcomes.

When the phone rings - factors influencing its impact on the experience of patients and healthcare workers during primary care consultation: a qualitative study.

BACKGROUND: In the primary health care setting, patients interact directly with their healthcare workers (HCW), which include their primary physicians, nurses and pharmacists. Studies have shown that such interactions, when interrupted by phone calls received by either party, can lead to adverse outcomes and negative experiences. There is insufficient data however on the factors affecting the reaction and responses of both patients and HCWs when phone calls occur amidst their interaction. Understanding these factors will allow for the introduction of targeted measures to mitigate the negative impact of such interruptions and improve patient-HCW relationships. This study therefore aims to understand the impact of unplanned phone calls during primary health care consultations on patient-HCW interactions and the factors affecting the patient and the HCW responses. METHOD: This study used focus group discussions (FGD) to gather qualitative data from patients and HCWs who had visited or worked in a major public primary healthcare institution in Singapore. The FGDs were audio-recorded, transcribed, audited and analyzed using standard content analysis to identify emergent themes. RESULTS: 15 patients and 16 HCWs participated in 5 FGDs. The key themes that emerged from these FGDs were patients' and HCWs' attitudes toward professionalism and respect, task and thought interruption, call characteristics, the impact on patient safety and stakeholders' experiences. Phone calls during consultations answered by either party often resulted in the answering party feeling apologetic and would usually keep the phone conversations short as a sign of respect to the other party. Both stakeholders valued the consultation time and similarly reported negative experiences if the phone-call interruptions became prolonged. Calls from the desk phone answered by HCWs were perceived by most patients to be relevant to healthcare services, with the assumption that HCWs exercised professionalism and would not attend to personal calls during their clinical duties.HCWs expressed their concerns and distress about potential medical errors due to phone-calls interrupting their clinical tasks and thinking processes. However, they acknowledged that these same phone-calls were important to allow clarifications of instructions and improved the safety of other patients. CONCLUSION: Phone interruptions affected patient and HCW interaction during consultations and factors leading to their adverse reactions need to be recognized and addressed.

A hybrid approach for fusing 4D-MRI temporal information with 3D-CT for the study of lung and lung tumor motion.

PURPOSE: Accurate visualization of lung motion is important in many clinical applications, such as radiotherapy of lung cancer. Advancement in imaging modalities [e.g., computed tomography (CT) and MRI] has allowed dynamic imaging of lung and lung tumor motion. However, each imaging modality has its advantages and disadvantages. The study presented in this paper aims at generating synthetic 4D-CT dataset for lung cancer patients by combining both continuous three-dimensional (3D) motion captured by 4D-MRI and the high spatial resolution captured by CT using the authors' proposed approach. METHODS: A novel hybrid approach based on deformable image registration (DIR) and finite element method simulation was developed to fuse a static 3D-CT volume (acquired under breath-hold) and the 3D motion information extracted from 4D-MRI dataset, creating a synthetic 4D-CT dataset. RESULTS: The study focuses on imaging of lung and lung tumor. Comparing the synthetic 4D-CT dataset with the acquired 4D-CT dataset of six lung cancer patients based on 420 landmarks, accurate results (average error <2 mm) were achieved using the authors' proposed approach. Their hybrid approach achieved a 40% error reduction (based on landmarks assessment) over using only DIR techniques. CONCLUSIONS: The synthetic 4D-CT dataset generated has high spatial resolution, has excellent lung details, and is able to show movement of lung and lung tumor over multiple breathing cycles.

Omega-3 fatty acids in the management of autism spectrum disorders: findings from an open-label pilot study in Singapore.

The goal of this open-label trial was to examine the efficacy and safety of a 12-week omega-3 fatty acids supplementation among children suffering with Autism Spectrum Disorders (ASD). A total of 41 children and adolescents aged 7-18 years (36 boys, 5 girls; mean age = 11.66, s.d. = 3.05) diagnosed with ASD participated in the study. At post-treatment, participants showed significant improvements on all subscales of the Social Responsiveness Scale (P < 0.01) and the Social and Attention Problems syndrome scales of the Child Behavior Checklist (P < 0.05). Blood fatty acid levels were significantly correlated with changes in the core symptoms of ASD. Baseline levels of blood fatty acid levels were also predictive of response to the omega-3 treatment. Omega-3 fatty acids supplementation was well-tolerated and did not cause any serious side effects. Our findings lend some preliminary support for the use of omega-3 fatty acids supplementation in addressing ASD. Future randomized controlled trials of omega-3 fatty acids in ASD with blood fatty acid measurements with a larger sample and longer follow-up period is warranted.

Frequent occurrence of gastric cancer in Asian kindreds with Li-Fraumeni syndrome.

Type of cancer and age of onset in individuals with inherited aberrations in the tumour suppressor gene TP53 are variable, possibly influenced by genetic modifiers and different environmental exposure. Since 2009, the modified Chompret criteria (MCC) have been used to identify individuals for TP53 mutation screening. Using the TP53 mutation database maintained by the International Agency for Research on Cancer (IARC), we investigated if the MCC, mainly developed for a Caucasian population, was also applicable in Asia. We identified several differences in Asian families compared with similar Caucasian cohorts, suggesting that identification and management of Li-Fraumeni syndrome in Asia do not completely mirror that of North America and Western Europe. Early gastric cancer (<40 years) may be considered a new addition to the MCC especially for Asian families.

A review of breast cancer research in malaysia.

Four hundred and nineteen articles related to breast cancer were found in a search through a database dedicated to indexing all original data relevant to medicine published in Malaysia between the years 2000-2013. One hundred and fifty four articles were selected and reviewed on the basis of clinical relevance and future research implications. Overall, Malaysian women have poor survival from breast cancer and it is estimated that half of the deaths due to breast cancer could be prevented. Five-year survival in Malaysia was low and varies among different institutions even within the same disease stage, suggesting an inequity of access to optimal treatment or a lack of compliance to optimal treatment. Malaysian women have poor knowledge of the risk factors, symptoms and methods for early detection of breast cancer, leading to late presentation. Moreover, Malaysian women experience cancer fatalism, belief in alternative medicine, and lack of autonomy in decision making resulting in delays in seeking or avoidance of evidence-based medicine. There are ethnic differences in estrogen receptor status, HER2 overexpression and incidence of triple negative breast cancer which warrant further investigation. Malay women present with larger tumours and at later stages, and even after adjustment for these and other prognostic factors (stage, pathology and treatment), Malay women have a poorer survival. Although the factors responsible for these ethnic differences have not been elucidated, it is thought that pharmacogenomics, lifestyle factors (such as weight-gain, diet and exercise), and psychosocial factors (such as acceptance of 2nd or 3rd line chemotherapy) may be responsible for the difference in survival. Notably, survivorship studies show self-management programmes and exercise improve quality of life, highlighting the need to evaluate the psychosocial impact of breast cancer on Malaysian women, and to design culturally-, religiously- and linguistically-appropriate psycho-education programmes to help women cope with the disease and improve their quality of life. Research done in the Caucasian populations may not necessarily apply to local settings and it is important to embark on local studies particularly prevention, screening, diagnostic, prognostic, therapeutic and psychosocial research.