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Lung cancer is the world's leading cause of cancer death and shows strong ancestry disparities. By sequencing and assembling a large genomic and transcriptomic dataset of lung adenocarcinoma (LUAD) in individuals of East Asian ancestry (EAS; n = 305), we found that East Asian LUADs had more stable genomes characterized by fewer mutations and fewer copy number alterations than LUADs from individuals of European ancestry. This difference is much stronger in smokers as compared to nonsmokers. Transcriptomic clustering identified a new EAS-specific LUAD subgroup with a less complex genomic profile and upregulated immune-related genes, allowing the possibility of immunotherapy-based approaches. Integrative analysis across clinical and molecular features showed the importance of molecular phenotypes in patient prognostic stratification. EAS LUADs had better prediction accuracy than those of European ancestry, potentially due to their less complex genomic architecture. This study elucidated a comprehensive genomic landscape of EAS LUADs and highlighted important ancestry differences between the two cohorts.

Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.

Background and objectives: Studies on osteoporosis risk factors are limited in Malaysia, so this study assesses the factors associated with bone health assessed using dual-energy X-ray absorptiometry (DXA) among Malaysians aged ≥40 years. Subjects and Methods: Data on demography, medical history, dietary and lifestyle practices of 786 Malaysians (51.4% women) aged ≥40 years recruited in Klang Valley were obtained. Their body composition and bone health were determined using DXA. The association between risk factors and bone health status was assessed using binary logistic regression. Results: The prevalence of suboptimal bone health and osteoporosis was higher in women (59.4% and 16.1%) than men (40.8% and 8.4%). Overall, the predictors of suboptimal bone health and osteoporosis among the subjects were increased age and higher fat mass. Lower monthly income was positively associated with osteoporosis. Being menopausal was a risk factor for both suboptimal bone health and osteoporosis in women. Women with no formal education were more likely to get osteoporosis. Being a smoker and Chinese were positively related to suboptimal bone health among men. Meanwhile, predictors of osteoporosis among men were regular alcohol and dairy product consumption, higher fat mass and having a tertiary education. Conclusions: This study calls for immediate and effective interventions for middle-aged and elderly populations with risk factors to halt the progression of bone loss.

Background & Aims: Chronic liver inflammation leads to fibrosis and cirrhosis and is associated with an accumulation of intrahepatic TNFα-secreting CD206 + macrophages, which may participate in maintaining chronic liver disease in a GM-CSF-dependent manner. We aimed to elucidate the exact role of GM-CSF in the development and progression of chronic liver disease., Methods: Liver immunohistochemistry and serum quantification were performed in patients with viral and non-viral-related liver disease to compare CD206 + monocyte/macrophages, fibrosis and GM-CSF. This was followed by functional validations in vitro and in vivo in humanised mice., Results: Using multiplex immunofluorescence and histo-cytometry, we show that highly fibrotic livers had a greater density of CD206 + macrophages that produced more TNFα and GM-CSF in the non-tumour liver regions of patients with hepatocellular carcinoma (n = 47), independent of aetiology. In addition, the absolute number of CD206 + macrophages strongly correlated with the absolute number of GM-CSF-producing macrophages. In non-HCC chronic HCV + patients (n = 40), circulating GM-CSF levels were also increased in proportion to the degree of liver fibrosis and serum viral titres. We then demonstrated in vitro that monocytes converted to TNFα-producing CD206 + macrophage-like cells in response to bacterial products (lipopolysaccharide) in a GM-CSF-dependent manner, confirming the in vivo normalisation of serum GM-CSF concentration following oral antibiotic treatment observed in HBV-infected humanised mice. Finally, anti-GM-CSF neutralising antibody treatment reduced intrahepatic CD206 + macrophage accumulation and abolished liver fibrosis in HBV-infected humanised mice., Conclusions: While the direct involvement of CD206 + macrophages in liver fibrosis remains to be demonstrated, these findings show that GM-CSF may play a central role in liver fibrosis and could guide the development of anti-GM-CSF antibody-based therapy for the management of patients with chronic liver disease., Lay Summary: Liver fibrosis is a major driver of liver disease progression. Herein, we have shown that granulocyte-macrophage colony-stimulating factor (GM-CSF) plays an important role in the development of liver fibrosis. Our findings support the use of anti-GM-CSF neutralising antibodies for the management of patients with chronic liver disease resulting from both viral and non-viral causes., (© 2019 The Author(s).)

Background: The ageing population and the changing disease profile have been driving the demand for community nurses. However, few nursing students in Singapore aspire to have a career in community nursing following graduation., Objectives: To explore undergraduate nursing students' perceptions of a career in community nursing and to identify strategies to promote community nursing among nursing students., Methods: An exploratory qualitative design was used. Four focus group discussions were conducted with a purposive sample of 24 undergraduate nursing students from a university. Interview transcripts were analysed using thematic analysis., Findings: Four key themes emerged as follows: 'mid-life career', 'limited career progression', 'a difficult transition' and 'international nurses-dominated workforce'., Discussion: While most participants rejected a career in community nursing immediately after graduation, they planned to join it at the later stages of their lives to accommodate changing life priorities. Limited career progression and increased difficulty in career transition from community nursing to acute care nursing were identified as deterrent factors in the participants' choices of community nursing as a career. Feelings of marginalization and a lack of role models in community nursing were perceived to be the result of the international nurses-dominated community workforce., Conclusion: Community nursing remains an underrated career. There is a need to foster an optimistic career outlook and mobility in community nursing to entice nursing students into this career track., Implications for Nursing Policy: Strategies to enhance community nursing recruitment should focus on providing more quality and diverse community placement opportunities in various community care settings, implementing a clearly defined career developmental plan to elucidate the role of community nurses, and improving community care and cultural competencies to develop a skilled and diverse community nursing workforce., (© 2019 International Council of Nurses.)

The concordance between osteoporosis self-assessment tool for Asians (OSTA) and dual-energy X-ray absorptiometry (DXA) was fair in the study. Modification of OSTA cutoff values improved its sensitivity to identify subjects at risk for suboptimal bone health (osteopenia/osteoporosis) and osteoporosis., Purpose: Osteoporosis self-assessment tool for Asians (OSTA) is a convenient screening algorithm used widely to identify patients at risk of osteoporosis. Currently, the number of studies validating OSTA in Malaysian population is limited. This study aimed to validate the performance of OSTA in identifying subjects with osteoporosis determined with DXA., Methods: This cross-sectional study recruited 786 Malaysians in Klang Valley, Malaysia. Their bone health status was assessed by DXA and OSTA. The association and agreement between OSTA and bone mineral density assessment by DXA were determined by Pearson's correlation and Cohen's kappa, respectively. Receiver operating characteristics (ROC) curves were used to determine the sensitivity, specificity, and area under the curve (AUC) for OSTA., Results: OSTA and DXA showed a fair association in the study (r = 0.382, κ = 0.159, p < 0.001). OSTA (cutoff < - 1) revealed a sensitivity of 32.3%, specificity of 92.3%, and AUC of 0.618 in identifying subjects with suboptimal bone health. The sensitivity of OSTA (cutoff < - 4) in determining subjects at risk of osteoporosis was better among women (sensitivity = 20%) than men (sensitivity = 0%). Modified OSTA cutoff values improved the sensitivity of OSTA in identifying subjects with suboptimal bone health (men = 81.0% at cutoff 3.4, women = 82.8% at cutoff 2.0) and osteoporosis (men = 81.8% at cutoff 1.8, women = 81.3% at cutoff 0.8)., Conclusion: OSTA with its original cutoff values is ineffective in identifying individuals at risk for osteoporosis. Adjusting the cutoff values significantly increases the sensitivity of OSTA, thus highlighting the need to validate this instrument among the local population before using it for osteoporosis screening clinically.

Osteoporosis is a skeletal disorder commonly found among the elderly, in which the bones become weak, brittle, and more susceptible to fracture. Adequate knowledge and positive attitude towards the disease and osteoprotective activities may prevent osteoporosis, but comprehensive studies to verify this hypothesis are limited in Malaysia. This study aims to bridge the research gap by determining the levels of knowledge, beliefs, and practices regarding osteoporosis and their associations with bone mineral density (BMD) among men and women ≥ 40 years in Klang Valley, Malaysia. In this cross-sectional study, 786 Malaysians (382 men, 404 women) completed a questionnaire on knowledge, beliefs, and osteoprotective practices, and underwent BMD scan using a dual-energy X-ray absorptiometry device. The current study found moderate levels of knowledge and beliefs regarding osteoporosis but poor osteoprotective practices. Osteoporosis knowledge, beliefs, and practices were significantly different based on subjects' demographic characteristics ( p < 0.05). Osteoporosis knowledge and beliefs were correlated significantly with osteoprotective practices ( p < 0.05). Bone health status of the subjects was associated positively with calcium supplement intake, and negatively with exercise barriers and smoking status of the subjects ( p < 0.05). However, no significant correlation was noted between osteoporosis knowledge and bone health ( p > 0.05). Conclusively, despite some correlations between individual components, the detachment between bone health knowledge and beliefs, and osteoprotective practices among Malaysians is apparent. Integrating all three components into a comprehensive osteoporosis prevention program is warranted.

Osteomyelitis (OM), or inflammation of bone tissue, occurs most frequently as a result of bacterial infection and severely perturbs bone structure. OM is predominantly caused by Staphylococcus aureus , and even with proper treatment, OM has a high rate of recurrence and chronicity. While S. aureus has been shown to infect osteoblasts, it remains unclear whether osteoclasts (OCs) are also a target of intracellular infection. Here, we demonstrate the ability of S. aureus to intracellularly infect and divide within OCs. OCs were differentiated from bone marrow macrophages (BMMs) by exposure to receptor activator of nuclear factor kappa-B ligand (RANKL). By utilizing an intracellular survival assay and flow cytometry, we found that at 18 h postinfection the intracellular burden of S. aureus increased dramatically in cells with at least 2 days of RANKL exposure, while the bacterial burden decreased in BMMs. To further explore the signals downstream of RANKL, we manipulated factors controlling OC differentiation, NFATc1 and alternative NF-κB, and found that intracellular bacterial growth correlates with NFATc1 levels in RANKL-treated cells. Confocal and time-lapse microscopy in mature OCs showed a range of intracellular infection that correlated inversely with S. aureus -phagolysosome colocalization. The propensity of OCs to become infected, paired with their diminished bactericidal capacity compared to BMMs, could promote OM progression by allowing S. aureus to evade initial immune regulation and proliferate at the periphery of lesions where OCs are most abundant. IMPORTANCE The inflammation of bone tissue is called osteomyelitis, and most cases are caused by an infection with the bacterium Staphylococcus aureus To date, the bone-building cells, osteoblasts, have been implicated in the progression of these infections, but not much is known about how the bone-resorbing cells, osteoclasts, participate. In this study, we show that S. aureus can infect osteoclasts and proliferate inside these cells, whereas bone-residing macrophages, immune cells related to osteoclasts, destroy the bacteria. These findings elucidate a unique role for osteoclasts to harbor bacteria during infection, providing a possible mechanism by which bacteria could evade destruction by the immune system., (Copyright © 2019 Krauss et al.)

Roselle ( Hibiscus sabdariffa Linn) has been traditionally used as folk medicine for hypertension and maintaining cardiovascular health, with therapeutic potential in protecting against numerous cardiovascular diseases. However, it remains unclear whether roselle can be used for management of cardiac hypertrophy seen after myocardial infarction (MI). This study therefore investigated the effects of aqueous roselle extract on cardiac hypertrophy arising from myocardial infarction both in vivo and in vitro . For in vivo study, male Sprague-Dawley rats were divided into control or MI groups (receiving 85 mg/kg isoproterenol s.c. for 2 days) and were given roselle extract (100 mg/kg, p.o daily) for 28 days. Cardiac structure and functional changes were evaluated at study end-point using histology, Langendorff analysis and gene expression analysis. In vitro effects of roselle were also assessed on ANG II-induced cardiomyocytes hypertrophy using H9c2 cells, simulating cardiac hypertrophy evident after MI. Roselle significantly ameliorated MI-induced cardiac systolic and diastolic dysfunction, as seen across improvement in left ventricular developed pressure (LVDP) and its derivative (LVdP/dt max ) and isovolumic relaxation (Tau). Oxidative stress evident across elevated pro-oxidant markers (NOX2 subunit of NADPH oxidase and 8-isoprostane) as well as reduced antioxidant markers (superoxide dismutase and glutathione) were also significantly attenuated by roselle. Furthermore, roselle treatment markedly reduced markers of cardiac remodeling (cardiac hypertrophy and fibrosis) compared to the untreated MI rats. On in vitro analysis, roselle significantly attenuated ANG II-induced cardiomyoycte hypertrophy in dose-dependent manner. This study demonstrated that roselle attenuates cardiac hypertrophy and dysfunction seen after MI both in vivo and in vitro , and these effects are likely mediated by phenolic compounds found in roselle extract., (Copyright © 2019 Si et al.)

Human mononuclear phagocytes comprise phenotypically and functionally overlapping subsets of dendritic cells (DCs) and monocytes, but the extent of their heterogeneity and distinct markers for subset identification remains elusive. By integrating high-dimensional single-cell protein and RNA expression data, we identified distinct markers to delineate monocytes from conventional DC2 (cDC2s). Using CD88 and CD89 for monocytes and HLA-DQ and FcεRIα for cDC2s allowed for their specific identification in blood and tissues. We also showed that cDC2s could be subdivided into phenotypically and functionally distinct subsets based on CD5, CD163, and CD14 expression, including a distinct subset of circulating inflammatory CD5 - CD163 + CD14 + cells related to previously defined DC3s. These inflammatory DC3s were expanded in systemic lupus erythematosus patients and correlated with disease activity. These findings further unravel the heterogeneity of DC subpopulations in health and disease and may pave the way for the identification of specific DC subset-targeting therapies., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Loss-of-function mutations in the Wnt inhibitor secreted frizzled receptor protein 4 (SFRP4) cause Pyle's disease (OMIM 265900), a rare skeletal disorder characterized by wide metaphyses, significant thinning of cortical bone, and fragility fractures. In mice, we have shown that the cortical thinning seen in the absence of Sfrp4 is associated with decreased periosteal and endosteal bone formation and increased endocortical resorption. While the increase in Rankl/Opg in cortical bone of mice lacking Sfrp4 suggests an osteoblast-dependent effect on endocortical osteoclast (OC) activity, whether Sfrp4 can cell-autonomously affect OCs is not known. We found that Sfrp4 is expressed during bone marrow macrophage OC differentiation and that Sfrp4 significantly suppresses the ability of early and late OC precursors to respond to Rankl-induced OC differentiation. Sfrp4 deletion in OCs resulted in activation of canonical Wnt/β-catenin and noncanonical Wnt/Ror2/Jnk signaling cascades. However, while inhibition of canonical Wnt/β-catenin signaling did not alter the effect of Sfrp4 on OCgenesis, blocking the noncanonical Wnt/Ror2/Jnk cascade markedly suppressed its regulation of OC differentiation in vitro. Importantly, we report that deletion of Ror2 exclusively in OCs ( CtskCreRor2 fl/fl ) in Sfrp4 null mice significantly reversed the increased number of endosteal OCs seen in these mice and reduced their cortical thinning. Altogether, these data show autocrine and paracrine effects of Sfrp4 in regulating OCgenesis and demonstrate that the increase in endosteal OCs seen in Sfrp4 -/- mice is a consequence of noncanonical Wnt/Ror2/Jnk signaling activation in OCs overriding the negative effect that activation of canonical Wnt/β-catenin signaling has on OCgenesis., Competing Interests: The authors declare no conflict of interest.

Background: The implementation of early warning scoring systems and medical emergency teams that aim to reduce failure to rescue in general wards is only effective if frontline nurses can recognize and act on clinical deterioration in a timely manner. While much of the research to date has primarily focused on registered nurses as recognizers of clinical deterioration, little research has sought to explore the role of enrolled nurses in recognizing clinical deterioration and to provide a big picture of how enrolled and registered nurses recognize clinical deterioration in general ward patients., Objectives: To conduct an exploration of the experiences of enrolled and registered nurses in recognizing clinically deteriorating patients in general wards., Design: A qualitative, descriptive design., Setting: General wards at a 1,000-bed acute general hospital in Singapore., Participants: A purposive sample of 22 enrolled and registered nurses who had at least 6 months of nursing experience and who were working in the general wards., Methods: Individual semi-structured interviews were conducted between October 2016 and February 2017. Interviews were transcribed verbatim and analyzed using thematic analysis., Results: Four salient themes emerged from the data analysis. The first, 'Having a sense of knowing', illustrates how knowing a patient and past experiences facilitated the early recognition of clinical deterioration before the patient turned haemodynamically unstable. The second, 'Patient assessment practices', depicts the physical assessment skills that nurses used to detect clinical deterioration. The third, 'Delegation of routine patient care and assessment to enrolled nurses', demonstrates that nursing activities were delegated to enrolled nurses with lesser directional and supervisory aspects that "delegation" implies, which can potentially compromise patient safety. The fourth, 'Missing the big picture', identifies overwhelming workload and fixation on specific parameters of a patient as reasons for both enrolled and registered nurses missing the big picture of the patient's deterioration., Conclusions: This study provides a snapshot of the recognition of clinical deterioration among enrolled and registered nurses in general wards. Our findings illuminate the need to support the roles of enrolled and registered nurses, with an emphasis on patient assessment and strengthening collaborative practices among nurses, to improve early recognition and timely treatment of clinically deteriorating ward patients., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: This research study aims to evaluate the effectiveness of an expanded cognitive stimulation therapy (CST) model that combines a CST group and tai chi on improving the cognitive ability of community-dwelling Chinese elderly with mild stage dementia (EwMD)., Method: A randomized waitlist controlled trial design was adopted in this study. The treatment group participated in a structured CST group followed by tai chi twice a week, with a total of 14 sessions throughout the study period. The waitlist control group received treatment as usual at the initial stage and expanded CST model at a later stage. The Chinese Mattis Dementia Rating Scale (DRS) and the Chinese Mini Mental State Examination (MMSE) were used to assess the cognitive ability of EwMD in the pre- and post- treatment periods., Results: At baseline, the treatment group (n = 51) and control group (n = 50) did not differ significantly in any demographic or clinical variables. Overall, the participants had a mean baseline MMSE score of 20.67 (SD = 2.30). The 2 × 2 repeated measures ANCOVA demonstrated that the treatment group was significantly more effective than the control group in improving the MMSE score (F = 12.31, p< .01) with a moderate effect size (partial eta square = .11) after controlling for group difference in age, gender, education, and having a diagnosis of dementia., Conclusion: The present study demonstrates the effectiveness of the expanded CST model on the improvement of cognitive ability of community-dwelling EwMD. More research is needed to further investigate this intervention model across cultures and societies.

Osteoporosis is a growing health problem in Asian countries with a rapidly expanding aging population. Adequate knowledge and positive health beliefs regarding osteoporosis will encourage individuals to adopt measures to protect bone health. This study aimed to investigate the association between knowledge, beliefs, and practices regarding osteoporosis and bone health among Malaysians Chinese aged 40 years and above. A cross-sectional study was conducted among 367 Malaysians Chinese (182 men, 185 women) aged ≥ 40 years in Klang Valley, Malaysia. They completed a questionnaire on knowledge, beliefs, and practices of osteoporosis and underwent bone mineral density scan using a dual-energy X-ray absorptiometry device. The subjects showed moderate knowledge and high level of health beliefs regarding osteoporosis, but poor osteoprotective practices. Osteoporosis knowledge and beliefs were significantly different based on subjects' demographic characteristics (p < 0.05). Additionally, osteoporosis knowledge was correlated positively with beliefs, coffee or tea intake ( p < 0.05) but not with other lifestyle practices. Osteoporosis health beliefs was associated positively with physical activity, dairy and calcium intake ( p < 0.05). However, bone health was not associated with knowledge, beliefs and practices regarding osteoporosis ( p > 0.05). The present findings highlight the need of formulating osteoporosis prevention program targeting Malaysians Chinese, especially men, to improve their knowledge, health beliefs, and practice., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Extracorporeal membrane oxygenation (ECMO) education, in particular with regards to crisis management during the provision of venoarterial extracorporeal membrane oxygenation (VA ECMO), is challenging due to its intrinsic characteristics-a complex, high risk, low volume clinical activity which requires dynamic decision making, interdisciplinary teamwork and communication, and rapid response. Simulation training that focuses on crisis resource management and interprofessional communication is well-suited to address these training needs. Institutional commitment to provide both capital and human resources is instrumental to the success of ECMO training programs. Future multicenter studies with standardized training curricula are required to investigate the impact of ECMO simulation training on patient outcome., Competing Interests: Conflicts of Interest: SW Sin and PC Lai are the education co-chairs of the Asia-Pacific Chapter of Extracorporeal Life Support Organization at the time of manuscript submission. The other authors have no conflicts of interest to declare.

Osteoclasts are large multinucleated cells exquisitely adapted to resorb bone matrix. Like other eukaryotes, osteoclasts possess an elaborate ensemble of intracellular organelles through which solutes, proteins and other macromolecules are trafficked to their target destinations via membrane-bound intermediaries. During bone resorption, membrane trafficking must be tightly regulated to sustain the structural and functional polarity of the osteoclasts' membrane domains. Of these, the ruffled border (RB) is most characteristic, functioning as the osteoclasts' secretory apparatus. This highly convoluted organelle is classically considered to be formed by the targeted fusion of acidic vesicles with the bone-facing plasma membrane. Emerging findings disclose new evidence that the RB is far more complex than previously envisaged, possessing discrete subdomains that are serviced by several intersecting endocytic, secretory, transcytotic and autophagic pathways. Bone-resorbing osteoclasts therefore serve as a unique model system for studying polarized membrane trafficking. Recent advances in high-resolution microscopy together with the convergence of genetic and cell biological studies in humans and in mice have helped illuminate the major membrane trafficking pathways in osteoclasts and unmask the core molecular machinery that governs these distinct vesicle transport routes. Among these, small Rab GTPases, their binding partners and members of the endocytic sorting nexin family have emerged as critical regulators. This mini review summarizes our current understanding of membrane trafficking in osteoclasts, the key molecular participants, and discusses how these transport machinery may be exploited for the development of new therapies for metabolic disorders of bone-like osteoporosis., (© 2019 The Author(s).)

Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz. l- and d-[Cu(phen)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.

Previously, Moringa oleifera leaf (MOL) standardised aqueous extract-loaded films were successfully developed and they showed potential wound healing activity in vitro. The objective of this study was to evaluate in vivo dermal safety as well as wound healing efficacy of these MOL film dressings (containing 0.1, 0.5 and 1% MOL) on diabetic rat model. The acute dermal toxicity was carried out on healthy rats, and signs of toxicity over 14 days were observed. For wound healing studies, excision and abrasion wounds were created out on the STZ/HFD-induced diabetic rat model and the wound healing was studied over 21 days. The wound healing evaluation determined by histology staining, hydroxyproline assay and ELISA assays on wound healing related-growth factors, cytokines and chemokines. MOL film formulations exhibited no signs of dermal toxicities. In excision wound model, 0.5% film significantly enhanced the wound closure by 77.67 ± 7.28% at day 7 compared to control group. While in abrasion wounds, 0.5% MOL films accelerated wound closure significantly at 81 ± 4.5% as compared to the control. The histology findings and hydroxyproline assay revealed that high collagen deposition and complete re-epithelialisation were observed for the wounds treated with 0.5 and 1% MOL films. All MOL film dressings had successfully tested non-toxic via in vivo safety dermal toxicity. It was concluded that the 0.5% MOL extract-loaded film had proven to be the most promising approach to accelerate diabetic wound healing process in both full-thickness excision and partial thickness abrasion wounds on the HFD/STZ-induced diabetic type II model.

Aims: Pre-operatively diagnosed patent foramen ovale (PFO) is associated with an increased risk of ischaemic stroke within 30 days after surgery. This study aimed to assess the PFO-attributable ischaemic stroke risk beyond the perioperative period., Methods and Results: This observational study of adult patients without history of stroke undergoing non-cardiac surgery with general anaesthesia examined the association of PFO with ischaemic stroke 1 and 2 years after surgery using multivariable logistic regression. Of the 144 563 patients included, a total of 1642 (1.1%) and 2376 (1.6%) ischaemic strokes occurred within 1 and 2 years after surgery, 54 (4.7%) and 76 (6.6%) among patients with PFO, and 1588 (1.1%) and 2300 (1.6%) among patients without PFO, respectively. The odds of ischaemic stroke within 1 and 2 years after surgery were increased in patients with PFO: adjusted odds ratio (aOR) 2.01, 95% confidence interval (CI) 1.51-2.69; P < 0.001 and aOR 2.10, 95% CI 1.64-2.68; P < 0.001, respectively. Among patients who underwent contrast transoesophageal echocardiography, the frequency of PFO was 27%, and the increased stroke risk in patients with PFO was robust (aOR 3.80, 95% CI 1.76-8.23; P = 0.001 for year 1). The PFO-attributable risk was mitigated by post-operative prescription of combination antithrombotic therapy (odds ratio 0.41, 95% CI 0.22-0.75; P for interaction = 0.004)., Conclusion: Patients with PFO are vulnerable to ischaemic stroke for an extended period of time after surgery. Physicians should consider implementing PFO screening protocols in patients scheduled for major non-cardiac surgery., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Atypical femoral fractures (AFFs) are a rare but potentially devastating event, often but not always linked to bisphosphonate (BP) therapy. The pathogenic mechanisms underlying AFFs remain obscure, and there are no tests available that might assist in identifying those at high risk of AFF. We previously used exome sequencing to explore the genetic background of three sisters with AFFs and three additional unrelated AFF cases, all previously treated with BPs. We detected 37 rare mutations (in 34 genes) shared by the three sisters. Notably, we found a p.Asp188Tyr mutation in the enzyme geranylgeranyl pyrophosphate synthase, a component of the mevalonate pathway, which is critical to osteoclast function and is inhibited by N-BPs. In addition, the CYP1A1 gene, responsible for the hydroxylation of 17β-estradiol, estrone, and vitamin D, was also mutated in all three sisters and one unrelated patient. Here we present a detailed list of the variants found and report functional analyses of the GGPS1 p.Asp188Tyr mutation, which showed a severe reduction in enzyme activity together with oligomerization defects. Unlike BP treatment, this genetic mutation will affect all cells in the carriers. RNAi knockdown of GGPS1 in osteoblasts produced a strong mineralization reduction and a reduced expression of osteocalcin, osterix, and RANKL, whereas in osteoclasts, it led to a lower resorption activity. Taken together, the impact of the mutated GGPPS and the relevance of the downstream effects in bone cells make it a strong candidate for AFF susceptibility. We speculate that other genes such as CYP1A1 might be involved in AFF pathogenesis, which remains to be functionally proved. The identification of the genetic background for AFFs provides new insights for future development of novel risk assessment tools. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

The evaluation of the interaction of cells with biomaterials is fundamental to establish the suitability of the biomaterial for a specific application. In this study, the properties of bacterial nanocellulose/acrylic acid (BNC/AA) hydrogels fabricated with varying BNC to AA ratios and electron-beam irradiation doses were determined. The manner these hydrogel properties influence the behavior of human dermal fibroblasts (HDFs) at the cellular and molecular levels was also investigated, relating it to its application both as a cell carrier and wound dressing material. Swelling, hardness, adhesive force (wet), porosity, and hydrophilicity (dry) of the hydrogels were dependent on the degree of cross-linking and the amount of AA incorporated in the hydrogels. However, water vapor transmission rate, pore size, hydrophilicity (semidry), and topography were similar between all formulations, leading to a similar cell attachment and proliferation profile. At the cellular level, the hydrogel demonstrated rapid cell adhesion, maintained HDFs viability and morphology, restricted cellular migration, and facilitated fast transfer of cells. At the molecular level, the hydrogel affected nine wound-healing genes (IL6, IL10, MMP2, CTSK, FGF7, GM-CSF, TGFB1, COX2, and F3). The findings indicate that the BNC/AA hydrogel is a potential biomaterial that can be employed as a wound-dressing material to incorporate HDFs for the acceleration of wound healing.

Previous research from our laboratory has demonstrated a novel phenomenon whereby GPCRs play a role in inhibiting cytokine-mediated c-Jun N-terminal kinase (JNK) signalling. So far this novel phenomenon seems to have been vastly overlooked, with little research in the area. Therefore, in this study we explored this further; by assessing the potential of P2YRs to mediate inhibition of cytokine-mediated JNK signalling and related functional outcomes in human endothelial cells. We utilised primary endothelial cells, and employed the use of endogenous activators of P2YRs and well characterised pharmacological inhibitors, to assess signalling parameters mediated by P2YRs, Interleukin-1β (IL-1β), TNFα and JNK. Activation of P2YRs with adenosine tri-phosphate (ATP) resulted in a time- and concentration-dependent inhibition of IL-1β-mediated phosphorylation of JNK and associated kinase activity. The effect was specific for cytokine-mediated JNK signalling, as ATP was without effect on JNK induced by other non-specific activators (e.g. sorbitol, anisomycin), nor effective against other MAPK pathways such as p38 and the canonical NFκB cascade. Pharmacological studies demonstrated a role for the P2Y 11 receptor in mediating this effect, but not the P2Y 1 nor the adenosine receptors (A1, A2A, A2B & A3). The novel Gα q/11 inhibitor YM254890 and a protein kinase A (PKA) inhibitor H89 both partially reversed ATP-mediated inhibition of IL-1β-stimulated JNK indicating involvement of both Gα q/11 and Gα s mediated pathways. ATP also partially reversed IL-1β-mediated induction of cyclo‑oxygenase-2 (COX-2) and E-selectin. Collectively, these studies indicate the potential for activation of purinergic receptors to protect the endothelium from inflammatory driven JNK activation and may be a new target for inflammatory disease therapy., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Residual neuromuscular block (rNMB) after surgery is not difficult to identify if proper neuromuscular monitoring is used, but many clinicians do not use quantitative neuromuscular monitoring., Objective: The aim of this study was to develop a REsidual neuromuscular block Prediction Score (REPS) to predict postoperative rNMB and compare the predictive accuracy of the prediction score with train-of-four count (TOFC) measurement at the end of a surgical case., Design: Retrospective cohort study of data on file., Data Source: Electronic patient data and peri-operative data on vital signs, administered medications, and train-of-four ratio (TOFR) obtained in the postoperative recovery rooms [postanaesthesia care unit (PACU)] at Massachusetts General Hospital in Boston, Massachusetts, USA., Patients: Quantitative TOFR measurements obtained on admission to the PACU were available from 2144 adult noncardiac surgical patients., Main Outcome Measure: Presence of rNMB at PACU admission, defined as a TOFR of less than 0.9., Results: In the score development cohort (n=2144), rNMB occurred in 432 cases (20.2%). Ten independent predictors for residual paralysis were identified and used for the score development. The final model included: hepatic failure, neurological disease, high-neostigmine dose, metastatic tumour, female sex, short time between neuromuscular blocking agent administration and extubation, aminosteroidal neuromuscular blocking agent, BMI more than 35, absence of nurse anaesthetist and having an experienced surgeon. The model discrimination by C statistics was 0.63, 95% confidence interval (0.60 to 0.66), and risk categories derived from the REPS had a higher accuracy than the last documented intra-operative TOFC for predicting rNMB (net reclassification improvement score 0.26, standard error 0.03, P < 0.001)., Conclusion: The REPS can be used to identify patients at greater risk of rNMB. This tool may inform anaesthetists better than an intra-operative TOFC and thus enable peri-operative anaesthetic practices to be tailored to the patient and minimise the undesirable effects of rNMB., Trial Registry Number: Approved by Partners Human Research Committee (protocol number 2016P000940) at MGH in Boston, Massachusetts, USA on 25 April 2016.

Inappropriate dosing of neostigmine for antagonism of neuromuscular blockade has been associated with postoperative pulmonary complications. We evaluated the effects of a quality improvement initiative tailored to optimise the use of neostigmine in antagonising neuromuscular blockade on postoperative pulmonary complications, costs and duration of hospital stay. The quality improvement initiative consisted of: a reduction in available neostigmine aliquot sizes; a cognitive aid; an educational component; and a financial incentive for the intra-operative documentation of train-of-four measurement before administration of neostigmine. We conducted a pre-specified analysis of data obtained in our quality improvement study. Additional analyses were conducted in a propensity-matched cohort. An interrupted time series design was used to discriminate between the intervention and a counterfactual scenario. We analysed 12,025 consecutive surgical cases performed in 2015. Postoperative pulmonary complications occurred in 220 (7.5%) of 2937 cases pre-intervention and 568 (6.3%) of 9088 cases post-intervention. Adjusted regression analyses showed significantly a lower risk of postoperative pulmonary complications (OR 0.73 (95%CI 0.61-0.88); p = 0.001), lower costs (incidence rate ratio 0.95 (95%CI 0.93-0.97); p < 0.001) and shorter duration of hospital stay (incidence rate ratio 0.91 (95%CI 0.87-0.94); p < 0.001) after implementation of the quality improvement initiative. Analyses in a propensity-matched sample (n = 2936 per group) and interrupted time series analysis (n = 27,202 cases) confirmed the findings. Our data show that a local, multifaceted quality improvement initiative can enhance the quality of intra-operative neuromuscular blocking agent utilisation, thereby reducing the incidence of postoperative pulmonary complications., (© 2018 Association of Anaesthetists.)

OBJECTIVEWe report the utility of whole-genome sequencing (WGS) conducted in a clinically relevant time frame (ie, sufficient for guiding management decision), in managing a Streptococcus pyogenes outbreak, and present a comparison of its performance with emm typing.SETTINGA 2,000-bed tertiary-care psychiatric hospital.METHODSActive surveillance was conducted to identify new cases of S. pyogenes. WGS guided targeted epidemiological investigations, and infection control measures were implemented. Single-nucleotide polymorphism (SNP)-based genome phylogeny, emm typing, and multilocus sequence typing (MLST) were performed. We compared the ability of WGS and emm typing to correctly identify person-to-person transmission and to guide the management of the outbreak.RESULTSThe study included 204 patients and 152 staff. We identified 35 patients and 2 staff members with S. pyogenes. WGS revealed polyclonal S. pyogenes infections with 3 genetically distinct phylogenetic clusters (C1-C3). Cluster C1 isolates were all emm type 4, sequence type 915 and had pairwise SNP differences of 0-5, which suggested recent person-to-person transmissions. Epidemiological investigation revealed that cluster C1 was mediated by dermal colonization and transmission of S. pyogenes in a male residential ward. Clusters C2 and C3 were genomically diverse, with pairwise SNP differences of 21-45 and 26-58, and emm 11 and mostly emm120, respectively. Clusters C2 and C3, which may have been considered person-to-person transmissions by emm typing, were shown by WGS to be unlikely by integrating pairwise SNP differences with epidemiology.CONCLUSIONSWGS had higher resolution than emm typing in identifying clusters with recent and ongoing person-to-person transmissions, which allowed implementation of targeted intervention to control the outbreak.Infect Control Hosp Epidemiol 2018;852-860.

N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Veno-venous extracorporeal membrane oxygenation (VV-ECMO) has been traditionally delivered with two independent cannulae at different venous insertion sites. The bicaval dual lumen cannula has gained popularity as a cannula for simultaneous venous drainage and reinfusion of blood via the internal jugular vein (IJV). Its insertion requires special attention to details to prevent the occurrence of serious complications. In this review, we discuss different techniques of cannula insertion and tips for troubleshooting., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Ethnopharmacological Relevance: M.oleifera is a medicinal plant traditionally used for skin sores, sore throat and eye infections. Recently, the wound healing property of the leaves of M. oleifera was has been well demonstrated experimentally in both in vivo and in vitro models. However, there is a lack of research which focuses on formulating M.oleifera into a functional wound dressing. In this study, the M.oleifera leaf standardized aqueous extract with highest potency in vitro migration was formulated into a film for wound healing application., Materials and Methods: Firstly, M. oleifera leaf were extracted in various solvents (aqueous, 50%, 70% and 100% ethanolic extracts) and standardized by reference standards using UHPLC technique. The extracts were then tested for cell migration and proliferation using HDF and HEK cell lines. M. oleifera leaf aqueous extract was then incorporated into alginate-pectin (SA-PC) based film dressing. The film dressings were characterized for the physicochemical properties and the bioactives release from the M. oleifera leaf extract loaded film dressing was also investigated using Franz diffusion cells., Results: All extracts were found to contain vicenin-2, chlorogenic acid, gallic acid, quercetin, kaempferol, rosmarinic acid and rutin. Among all M. oleifera extracts, aqueous standardized leaf extracts showed the highest human dermal fibroblast and human keratinocytes cells proliferation and migration properties. Among the film formulations, SA-PC (3% w/v) composite film dressing containing M. oleifera aqueous leaf extract was found to possess optimal physicochemical properties as wound dressing., Conclusion: A potentially applicable wound dressing formulated as an alginate-pectin film containing aqueous extracts of M. oleifera has been developed. The dressing would be suitable for wounds with moderate exudates., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Importance: Perioperative stroke is a major complication for patients undergoing surgery. Patent foramen ovale (PFO) represents a possible anatomical link between venous thrombosis and stroke., Objective: To determine whether a preoperatively diagnosed PFO is associated with increased risk of perioperative ischemic stroke., Design, Setting, and Participants: Retrospective cohort study from Massachusetts General Hospital and 2 affiliated community hospitals between January 1, 2007, and December 31, 2015. Participants were 182 393 consecutive adults undergoing noncardiac surgery with general anesthesia., Exposures: Preoperatively diagnosed PFO., Main Outcomes and Measures: Perioperative ischemic stroke occurring within 30 days of surgery; stroke subtype by Oxfordshire Community Stroke Project classification and stroke severity by National Institute of Health Stroke Scale (NIHSS)., Results: Among the 150 198 patient cases analyzed (median [SD] age, 55 [16] years), 1540 (1.0%) had a diagnosis of PFO before surgery. A total of 850 (0.6%) ischemic strokes occurred within 30 days of surgery (49 [3.2%] among patients with PFO and 801 [0.5%] among patients without PFO). In adjusted analyses, patients with PFO had an increased risk of ischemic stroke compared with patients without PFO (odds ratio, 2.66 [95% CI, 1.96-3.63]; P < .001). The estimated risks of stroke were 5.9 for every 1000 patients with PFO and 2.2 for every 1000 patients without PFO (adjusted absolute risk difference, 0.4% [95% CI, 0.2%-0.6%). Patients with PFO also had an increased risk of large vessel territory stroke (relative risk ratio, 3.14 [95% CI, 2.21-4.48]; P < .001) and a more severe stroke-related neurologic deficit measured by NIHSS (median, 4 [interquartile range {IQR}, 2-10] vs median, 3 [IQR, 1-6] for those without PFO; P = .02)., Conclusions and Relevance: Among adult patients undergoing noncardiac surgery at 3 hospitals, having a preoperatively diagnosed PFO was significantly associated with increased risk of perioperative ischemic stroke within 30 days after surgery. Further research is needed to confirm these findings and to determine whether interventions would decrease this risk.

Procidentia is uncommon condition altering quality of life of young and nulliparous women. Its management poses significant dilemma and challenges as its associated body image, fertility and sexuality issues. Uterine preservation surgery described by Archibald Donald in 1888 known as Manchester -Fothergill procedure seems best option as alternative to vaginal hysterectomy. Despite its increasing popularity among surgeons and patients, robust clinical evidence is needed. We report a case of recurrent procidentia in a young nulliparous woman who had Manchester repair following vaginal sacrospinous hysteropexy. We concluded that Manchester repair is a useful and safe alternative for uterine-preserving technique.

Aim: The present research study aimed to identify and compare the clinical and non-clinical factors that predict the self-reported and proxy-reported health-related quality of life (HRQoL) of people with major neurocognitive disorder (PwND) who are living at home in a Chinese society., Methods: A total of 57 Chinese PwND-family caregiver dyads that were using the services of local senior centers were recruited through a cross-sectional survey with convenience sampling. Each PwND and caregiver rated the PwND's HRQoL independently by using the Quality of Life-Alzheimer's disease measure. Additional measures included the Rosenberg Self-Esteem Scale (RSES), Index for Managing Memory Loss, Geriatric Depression Scale, Cornell Scale for Depression in Dementia and Zarit Burden Inventory., Results: The results of hierarchical multiple linear regression analyses showed that the PwND's self-rated HRQoL and caregiver-rated HRQoL were found to be predicted by different clinical and non-clinical variables. In particular, the self-esteem of PwND had the highest predictive power for the self-rated HRQoL, whereas the caregiver burden is the only significant predictor for the caregiver-rated HRQoL., Conclusions: In the present study, the self-esteem of PwND and the caregiver's burden were found to be important factors predicting self-rated HRQoL and caregiver-rated HRQoL respectively, which is probably because of the influence of traditional Chinese cultural values. Thus, it is important for non-pharmacological interventions to address these special needs to promote HRQoL for this population. Geriatr Gerontol Int 2017; 17: 2319-2328., (© 2017 Japan Geriatrics Society.)

We thought that the rate of postoperative pulmonary complications might be higher after pressure-controlled ventilation than after volume-controlled ventilation. We analysed peri-operative data recorded for 109,360 adults, whose lungs were mechanically ventilated during surgery at three hospitals in Massachusetts, USA. We used multivariable regression and propensity score matching. Postoperative pulmonary complications were more common after pressure-controlled ventilation, odds ratio (95%CI) 1.29 (1.21-1.37), p < 0.001. Tidal volumes and driving pressures were more varied with pressure-controlled ventilation compared with volume-controlled ventilation: mean (SD) variance from the median 1.61 (1.36) ml.kg -1 vs. 1.23 (1.11) ml.kg -1 , p < 0.001; and 3.91 (3.47) cmH 2 O vs. 3.40 (2.69) cmH 2 O, p < 0.001. The odds ratio (95%CI) of pulmonary complications after pressure-controlled ventilation compared with volume-controlled ventilation at positive end-expiratory pressures < 5 cmH 2 O was 1.40 (1.26-1.55) and 1.20 (1.11-1.31) when ≥ 5 cmH 2 O, both p < 0.001, a relative risk ratio of 1.17 (1.03-1.33), p = 0.023. The odds ratio (95%CI) of pulmonary complications after pressure-controlled ventilation compared with volume-controlled ventilation at driving pressures of < 19 cmH 2 O was 1.37 (1.27-1.48), p < 0.001, and 1.16 (1.04-1.30) when ≥ 19 cmH 2 O, p = 0.011, a relative risk ratio of 1.18 (1.07-1.30), p = 0.016. Our data support volume-controlled ventilation during surgery, particularly for patients more likely to suffer postoperative pulmonary complications., (© 2017 The Association of Anaesthetists of Great Britain and Ireland.)

Our studies focused on improving the biocompatibility properties of two microfluidic prototyping substrates i.e. polyurethane methacrylate (PUMA) and off-stoichiometry thiol-ene (OSTE-80) polymer by Ar and N 2 plasma treatment. The contact angle (CA) measurement showed that both plasma treatments inserted oxygen and nitrogen moieties increased the surface energy and hydrophilicity of PUMA and OSTE-80 polymer which corresponded to an increase of nitrogen to carbon ratios (N/C), as measured by XPS, to provide a conducive environment for cell attachments and proliferation. Under the SEM observation, the surface topography of PUMA and OSTE-80 polymer showed minimal changes after the plasma treatments. Furthermore, ageing studies showed that plasma-treated PUMA and OSTE-80 polymer had stable hydrophilicity and nitrogen composition during storage in ambient air for 15days. After in vitro cell culture of human umbilical vein endothelial cells (HUVECs) on these surfaces for 24h and 72h, both trypan blue and alamar blue assays indicated that PUMA and OSTE-80 polymer treated with N 2 plasma had the highest viability and proliferation. The polar nitrogen moieties, specifically amide groups, encouraged the HUVECs adhesion on the plasma-treated PUMA and OSTE-80 surfaces. Interestingly, PUMA polymer treated with Ar and N 2 plasma showed different HUVECs morphology which was spindle and cobblestone-shaped respectively after 72h of incubation. On the contrary, a monolayer of well-spread HUVECs formed on the Ar and N 2 plasma-treated OSTE-80 polymers. These variable morphologies observed can be ascribed to the adherence HUVECs on the different elastic moduli of these surfaces whereby further investigation might be needed. Overall, Ar and N 2 plasma treatment had successfully altered the surface properties of PUMA and OSTE-80 polymer by increasing its surface energy, hydrophilicity and chemical functionalities to create a biocompatible surface for HUVECs adhesion and proliferation., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Clinacanthus nutans (C.nutans) is a plant consumed as a cancer treatment in tropical Asia. Despite the availability of numerous anecdotal reports, evaluation of active anticancer effects has remained elusive. Therefore we here examined antiproliferative, reactive oxygen species (ROS)-inducing and apoptosis mechanisms of whole plant extracts in different cancer cell lines. Methods: Antiproliferative actions of five solvent extracts (hexane, chloroform, ethyl acetate, methanol and water) of C.nutans were tested on non-small cell lung cancer (A549), nasopharygeal cancer (CNE1) and liver cancer (HepG2) cells using MTT assay. The most potent anticancer extract was then assessed by flow cytometry to study cell cycle changes . Intracellular levels of ROS were quantified by DCFH-DA assay. Involvement of the caspase pathway in induction of apoptosis was assessed using caspase assay kits. GC-MS analysis was performed to identify phytoconstituents in the extracts. Results: Hexane and chloroform extracts were antiproliferative against all three cell lines, while the ethyl acetate extract, at 300 μg/mL, was antiproliferative in the CNE1 but not A549 and HepG2 cases. Methanol and water extracts did not inhibit cancer cell proliferation. The most potent anticancer hexane extract was selected for further testing. It induced apoptosis in all three cell lines as shown by an increase in the percentage of cell in sub-G1 phase. Dose-dependent increase in ROS levels in all three cell lines indicated apoptosis to be possibly modulated by oxidative stress. At high concentrations (>100 μg/mL), hexane extracts upregulated caspases 8, 9 and 3/7 across all three cell lines. GC-MS analysis of the hexane extract revealed abundance of 31 compounds. Conclusion : Among the five extracts of C.nutans, that with hexane extract demonstrated the highest antiproliferative activity against all three cancer cell lines tested. Action appeared to be via ion of intracellular ROS, and induction of apoptosis via intrinsic and extrinsic caspase pathways., (Creative Commons Attribution License)

Background: Patients admitted to intensive care units (ICU) are often treated with intravenous (IV) vasopressors. Persistent hypotension and dependence on IV vasopressors in otherwise resuscitated patients lead to delay in discharge from ICU. Midodrine is an oral alpha-1 adrenergic agonist approved for treatment of symptomatic orthostatic hypotension. This trial aims to evaluate whether oral administration of midodrine is an effective adjunct to standard therapy to reduce the duration of IV vasopressor treatment, and allow earlier discharge from ICU and hospital., Methods: The MIDAS trial is an international, multicenter, randomized, double-blind, placebo-controlled clinical trial being conducted in the USA and Australia. We are targeting 120 patients. Adult patients admitted to the ICU who are resuscitated and otherwise stable on low dose IV vasopressors for at least 24 h will be considered for recruitment. Participants will be randomized to receive midodrine (20 mg) or placebo three times a day, in addition to standard care. The primary outcome is time (hours) from initiation of midodrine or placebo to discontinuation of IV vasopressors. Secondary outcomes include time (hours) from ICU admission to discharge readiness, ICU length of stay (LOS) (days), hospital LOS (days), rates of ICU readmission, and rates of adverse events related to midodrine administration., Discussion: Midodrine is approved by the Food and Drug Administration (FDA) for the treatment of symptomatic orthostatic hypotension. In August 2010, FDA proposed to withdraw approval of midodrine because of lack of studies that verify the clinical benefit of the drug. We obtained Investigational New Drug (IND 113,330) approval to study its effects in critically ill patients who require IV vasopressors but are otherwise ready for discharge from the ICU. A pilot observational study in a cohort of surgical ICU patients showed that the rate of decline in vasopressor requirements increased after initiation of midodrine treatment. We hypothesize that midodrine administration is effective to wean IV vasopressors and shorten ICU and hospital LOS. This trial may have significant implications on lowering costs of hospital care and obtaining FDA approval for new indications for midodrine., Trial Registration: This study has been registered at clinicaltrials.gov on 02/09/2012 (NCT01531959).

Hepatocellular carcinoma (HCC) has one of the poorest survival rates among cancers. Using multi-regional sampling of nine resected HCC with different aetiologies, here we construct phylogenetic relationships of these sectors, showing diverse levels of genetic sharing, spanning early to late diversification. Unlike the variegated pattern found in colorectal cancers, a large proportion of HCC display a clear isolation-by-distance pattern where spatially closer sectors are genetically more similar. Two resected intra-hepatic metastases showed genetic divergence occurring before and after primary tumour diversification, respectively. Metastatic tumours had much higher variability than their primary tumours, suggesting that intra-hepatic metastasis is accompanied by rapid diversification at the distant location. The presence of co-existing mutations offers the possibility of drug repositioning for HCC treatment. Taken together, these insights into intra-tumour heterogeneity allow for a comprehensive understanding of the evolutionary trajectories of HCC and suggest novel avenues for personalized therapy.

Medical imaging techniques have widely been in use in the diagnosis and detection of breast cancer. The drawback of applying these techniques is the large time consumption in the manual diagnosis of each image pattern by a professional radiologist. Automated classifiers could substantially upgrade the diagnosis process, in terms of both accuracy and time requirement by distinguishing benign and malignant patterns automatically. Neural network (NN) plays an important role in this respect, especially in the application of breast cancer detection. Despite the large number of publications that describe the utilization of NN in various medical techniques, only a few reviews are available that guide the development of these algorithms to enhance the detection techniques with respect to specificity and sensitivity. The purpose of this review is to analyze the contents of recently published literature with special attention to techniques and states of the art of NN in medical imaging. We discuss the usage of NN in four different medical imaging applications to show that NN is not restricted to few areas of medicine. Types of NN used, along with the various types of feeding data, have been reviewed. We also address hybrid NN adaptation in breast cancer detection.

Freshwater mussels (Bivalvia, Unionida) fulfil important ecosystem functions and are one of the most threatened freshwater taxa globally. Knowledge of freshwater mussel diversity, distribution and ecology in Peninsular Malaysia is extremely poor, and the conservation status of half of the species presumed to occur in the region has yet to be assessed. We conducted the first comprehensive assessment of Peninsular Malaysia's freshwater mussels based on species presence/absence and environmental data collected from 155 sites spanning all major river catchments and diverse habitat types. Through an integrative morphological-molecular approach we recognised nine native and one widespread non-native species, i.e. Sinanodonta woodiana. Two species, i.e. Pilsbryoconcha compressa and Pseudodon cambodjensis, had not been previously recorded from Malaysia, which is likely a result of morphological misidentifications of historical records. Due to their restriction to single river catchments and declining distributions, Hyriopsis bialata, possibly endemic to Peninsular Malaysia, Ensidens ingallsianus, possibly already extinct in the peninsula, and Rectidens sumatrensis, particularly require conservation attention. Equally, the Pahang, the Perak and the north-western river catchments are of particular conservation value due to the presence of a globally unique freshwater mussel fauna. Statistical relationships of 15 water quality parameters and mussel presence/absence identified acidification and nutrient pollution (eutrophication) as the most important anthropogenic factors threatening freshwater mussel diversity in Peninsular Malaysia. These factors can be linked to atmospheric pollution, deforestation, oil-palm plantations and a lack of functioning waste water treatment, and could be mitigated by establishing riparian buffers and improving waste water treatment for rivers running through agricultural and residential land., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Antibacterial coating is important to prevent the colonization of medical devices by biofilm forming bacteria that would cause infection and sepsis in patients. Current coating techniques such as immobilization of antimicrobial compounds, time-releasing antibiotic agents and silver nanoparticles, require multiple processing steps, and they have low efficacy and low stability. We proposed a single-step plasma polymerization of an essential oil known as carvone to produce a moderately hydrophobic antibacterial coating (ppCar) with an average roughness of <1nm. ppCar had a static water contact angle of 78°, even after 10days of air aging and it maintained its stability throughout 24h of LB broth immersion. ppCar showed promising results in the live-dead fluorescence assay and crystal violet assay. The biofilm assay showed an effective reduction of E. coli and S. aureus bacteria by 86% and 84% respectively. ppCar is also shown to rupture the bacteria membrane for its bactericidal effects. The cytotoxicity test indicated that the coating is not cytotoxic to the human cell line. This study would be of interest to researcher keen on producing a bacteria-resistance and biocompatible coating on different substrates in a cost-effective manner., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Prevalence of vancomycin-resistant enterococci (VRE) and use of daptomycin are increasing in Asia. To determine the prevalence of daptomycin non-susceptible enterococci (DNSE) and understand factors associated with reduced daptomycin susceptibility in VRE, we conducted a case-control study in a 1600-bed adult tertiary hospital in Singapore. All VRE isolates from inpatients in 2012 were tested for daptomycin susceptibility. Patients with VRE isolates of daptomycin minimum inhibitory concentration (MIC) ⩾3 µg/ml were classified as daptomycin-reduced susceptible VRE (DRS-VRE) and those with daptomycin MIC 4 µg/ml (DNSE). About half (135, 55%) had reduced susceptibility to daptomycin (MIC 3-4 µg/ml). None in the DS-VRE group had prior exposure to daptomycin. After adjusting for age, gender, comorbidity, hospitalization duration, surgical history, indwelling device use, and duration of antibiotic exposure in the prior 3 months, >1 movement between wards [odds ratio (OR) 0·35, 95% confidence interval (CI) 0·16-0·74, P = 0·006] and minocycline resistance (OR 0·45, 95% CI 0·25-0·84, P = 0·011) were independently associated with DRS-VRE. Our study suggests that daptomycin exposure, >1 movement between wards, and resistance to minocycline, were associated with reduced daptomycin susceptibility in VRE.

Canonical Wnt signaling pathway, also known as Wnt/β-catenin signaling pathway, is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. Furthermore, the canonical Wnt signaling pathway has also been described as one of the critical signaling pathways for regulation of normal stem cells as well as cancer cells with stem cell-like features, termed cancer stem cells (CSC). In this review, we will briefly describe the basic mechanisms of Wnt signaling pathway and its crucial roles in the normal regulation of cellular processes as well as in the development of cancer. Next, we will highlight the roles of canonical Wnt signaling pathway in the regulation of CSC properties namely self-renewal, differentiation, metastasis, and drug resistance abilities, particularly in head and neck squamous cell carcinoma. Finally, we will examine the findings of several recent studies which explore druggable targets in the canonical Wnt signaling pathway which could be valuable to improve the treatment outcome for head and neck cancer.

Bone diseases such as osteoporosis, osteoarthritis, bone tumours and bone fractures are rather common and not just in the elderly. Parathyroid hormone (PTH) is responsible for maintaining calcium homeostasis, increasing bone mineral density (BMD), increasing cortical and trabecular bone thickness and thus increasing bone strength. Teriparatide (PTH 1-34) has the same effects as endogenous PTH and is pharmacologically used to treat bone diseases such as osteoporosis, osteoarthritis, bone fractures and bone tumours. This review discusses how PTH 1-34 plays a role in managing bone diseases. Clinical studies have shown that short or intermittent dosing of PTH 1-34 has minimal adverse effects, while long-term dosing (over two years) has been linked to de novo osteoarthritis and bone deformation. Currently PTH therapy is only approved in the treatment of post-menopausal osteoporosis, however it is also proven to have effects in treating osteoarthritis, bone tumours and bone fractures. If the patient undergoing therapy is closely monitored, the major pitfalls are very unlikely to take place, thus it is highly recommended that patients be closely monitored by a medical practitioner.

Bioceramics for regenerative medicine applications should have the ability to promote adhesion, proliferation and differentiation of osteoblast and osteoclast cells. Osteogenic properties of the material are essential for rapid bone regeneration and new bone formation. The aim of this study was to develop a silicate-based ceramic, gehlenite (GLN, Ca2Al2SiO7), and characterise its physiochemical, biocompatibility and osteogenic properties. A pure GLN powder was synthesised by a facile reactive sintering method and compacted to disc-shaped specimens. The sintering behaviour and degradation of the GLN discs in various buffer solutions were fully characterised. The cytotoxicity of GLN was evaluated by direct and indirect methods. In the indirect method, primary human osteoblast cells (HOBs) were exposed to diluted extracts (100, 50, 25, 12.5 and 6.25 mg ml(-1)) of fine GLN particles in culture medium. The results showed that the extracts did not cause any cytotoxic effect on the HOBs with the number of cells increasing significantly from day 1 to day 7. GLN-supported HOB attachment and proliferation, and significantly enhanced osteogenic gene expression levels (Runx2, osteocalcin, osteopontin and bone sialoprotein) were compared with biphasic calcium phosphate groups (BCP, a mixture of hydroxyapatite (60wt.%) and β-tricalcium phosphate(40wt.%)). We also demonstrated that in addition to supporting HOB attachment and proliferation, GLN promoted the formation of tartrate-acid resistance phosphatase (TRAP) positive multinucleated osteoclastic cells (OCs) derived from mouse bone marrow cells. Results also demonstrated the ability of GLN to support the polarisation of OCs, a prerequisite for their functional resorptive activity which is mainly influenced by the composition and degradability of biomaterials. Overall, the developed GLN is a prospective candidate to be used in bone regeneration applications due its effective osteogenic properties and biocompatibility.

The launch of the MinION Access Program has caused much activity within the scientific community. MinION represents a keenly anticipated, novel addition to the current melange of commercial sequencers. Driven by the nanopore sequencing mechanism that requires minimal sample manipulation, the device is capable of generating long sequence reads in sizes (up to or exceeding 50 kb) that surpass those of all other platforms. One notable advantage of this feature is that long-range haplotypes can be more accurately resolved; such advantage is particularly pertinent to the genotyping of complex loci such as genes encoding the human leukocyte antigens, which are pivotal determinants of drug hypersensitivity. With this timely, albeit brief, review, we set out to examine the applications on which MinION has been tested thus far, the bioinformatics workflow tailored to the unique characteristics of its extended sequence reads, the device's potential utility in the detection of genetic markers for drug hypersensitivity, and how it may eventually evolve to become fit for diagnostic purposes in the clinical setting.

Background: Sepsis-induced myocardial dysfunction is a well-recognized condition and confers worse outcomes in septic patients. Echocardiographic assessment by conventional parameters such as left ventricular ejection fraction (LVEF) is often affected by ongoing changes in preload and afterload conditions. Novel echocardiographic technologies such as speckle tracking echocardiography (STE) have evolved for direct assessment of the myocardial function. We investigate the measurement of myocardial strain by speckle tracking echocardiography for the diagnosis of sepsis-induced myocardial dysfunction., Methods: This is a case-control study at a university-affiliated medical intensive care unit. Consecutive adult medical patients admitted with a diagnosis of septic shock were included. Patients with other causes of myocardial dysfunction were excluded. They were compared to age-matched, gender-matched, and cardiovascular risk-factor-matched controls, who were admitted to hospital for sepsis but did not develop septic shock. Transthoracic echocardiography was performed on all patients within 24 hours of diagnosis, and a reassessment echocardiogram was performed in the study group of patients upon recovery., Results: Patients with septic shock (n = 33) (study group) and 29 matched patients with sepsis but no septic shock (control group) were recruited. The mean sequential organ failure assessment (SOFA) score for the study and control groups were 10.2 and 1.6, respectively (P < 0.001). In patients with septic shock, the mean arterial pressure was lower (76 mmHg vs 82 mmHg, P = 0.032), and the heart rate was higher (99 bpm vs 86 bpm, P = 0.008). The cardiac output (5.9 L/min vs 5.5 L/min, P = 0.401) and systemic vascular resistance (1090 dynes•sec/cm(5) vs 1194 dynes•sec/cm(5), P = 0.303) were similar. The study group had a greater degree of myocardial dysfunction measured by global longitudinal strain (GLS) (-14.5 % vs -18.3 %, P <0.001), and the myocardial strain differed upon diagnosis and recovery (-14.5 % vs -16.0 %, P = 0.010). Conventional echocardiographic measurements such as LVEF (59 % in the study group vs 61 % in the control group, P = 0.169) did not differ between the two groups., Conclusion: Speckle tracking echocardiography can detect significant left ventricular impairment in patients with septic shock, which was not otherwise detectable by conventional echocardiography. The reversible nature of myocardial dysfunction in sepsis was also demonstrable. This echocardiographic technique is useful in the diagnosis and monitoring of sepsis-induced myocardial dysfunction.

The parathyroid hormone 1 receptor (PTHR) is central to the process of bone formation and remodeling. PTHR signaling requires receptor internalization into endosomes, which is then terminated by recycling or degradation. Here we show that sorting nexin 27 (SNX27) functions as an adaptor that couples PTHR to the retromer trafficking complex. SNX27 binds directly to the C-terminal PDZ-binding motif of PTHR, wiring it to retromer for endosomal sorting. The structure of SNX27 bound to the PTHR motif reveals a high-affinity interface involving conserved electrostatic interactions. Mechanistically, depletion of SNX27 or retromer augments intracellular PTHR signaling in endosomes. Osteoblasts genetically lacking SNX27 show similar disruptions in PTHR signaling and greatly reduced capacity for bone mineralization, contributing to profound skeletal deficits in SNX27-knockout mice. Taken together, our data support a critical role for SNX27-retromer mediated transport of PTHR in normal bone development., (© 2016 Chan et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)