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Assessing respiratory mechanics using pressure reconstruction method in mechanically ventilated spontaneous breathing patient

Damanhuri NS, Chiew YS, Othman NA, Docherty PD, Pretty CG, Shaw GM, et al.

Comput Methods Programs Biomed, 2016 Jul;130:175-85.
PMID: 27208532 DOI: 10.1016/j.cmpb.2016.03.025

BACKGROUND: Respiratory system modelling can aid clinical decision making during mechanical ventilation (MV) in intensive care. However, spontaneous breathing (SB) efforts can produce entrained "M-wave" airway pressure waveforms that inhibit identification of accurate values for respiratory system elastance and airway resistance. A pressure wave reconstruction method is proposed to accurately identify respiratory mechanics, assess the level of SB effort, and quantify the incidence of SB effort without uncommon measuring devices or interruption to care.
METHODS: Data from 275 breaths aggregated from all mechanically ventilated patients at Christchurch Hospital were used in this study. The breath specific respiratory elastance is calculated using a time-varying elastance model. A pressure reconstruction method is proposed to reconstruct pressure waves identified as being affected by SB effort. The area under the curve of the time-varying respiratory elastance (AUC Edrs) are calculated and compared, where unreconstructed waves yield lower AUC Edrs. The difference between the reconstructed and unreconstructed pressure is denoted as a surrogate measure of SB effort.
RESULTS: The pressure reconstruction method yielded a median AUC Edrs of 19.21 [IQR: 16.30-22.47]cmH2Os/l. In contrast, the median AUC Edrs for unreconstructed M-wave data was 20.41 [IQR: 16.68-22.81]cmH2Os/l. The pressure reconstruction method had the least variability in AUC Edrs assessed by the robust coefficient of variation (RCV)=0.04 versus 0.05 for unreconstructed data. Each patient exhibited different levels of SB effort, independent from MV setting, indicating the need for non-invasive, real time assessment of SB effort.
CONCLUSION: A simple reconstruction method enables more consistent real-time estimation of the true, underlying respiratory system mechanics of a SB patient and provides the surrogate of SB effort, which may be clinically useful for clinicians in determining optimal ventilator settings to improve patient care.
Fulltext Long non-coding RNA expression in primary human monocytes

Mirsafian H, Manda SS, Mitchell CJ, Sreenivasamurthy S, Ripen AM, Mohamad SB, et al.

Genomics, 2016 07;108(1):37-45.
PMID: 26778813 DOI: 10.1016/j.ygeno.2016.01.002

Long non-coding RNAs (lncRNAs) have been shown to possess a wide range of functions in both cellular and developmental processes including cancers. Although some of the lncRNAs have been implicated in the regulation of the immune response, the exact function of the large majority of lncRNAs still remains unknown. In this study, we characterized the lncRNAs in human primary monocytes, an essential component of the innate immune system. We performed RNA sequencing of monocytes from four individuals and combined our data with eleven other publicly available datasets. Our analysis led to identification of ~8000 lncRNAs of which >1000 have not been previously reported in monocytes. PCR-based validation of a subset of the identified novel long intergenic noncoding RNAs (lincRNAs) revealed distinct expression patterns. Our study provides a landscape of lncRNAs in monocytes, which could facilitate future experimental studies to characterize the functions of these molecules in the innate immune system.
Fulltext The Epstein-Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling

Morris MA, Dawson CW, Laverick L, Davis AM, Dudman JP, Raveenthiraraj S, et al.

Sci Rep, 2016;6:19533.
PMID: 26782058 DOI: 10.1038/srep19533

Approximately 20% of global cancer incidence is causally linked to an infectious agent. Epstein-Barr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifies novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1's ability to induce the expression of the extracellular matrix protein, fibronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its effects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fibronectin induction. LMP1 also induces the expression and activation of the major fibronectin receptor, α5β1 integrin, an effect that is accompanied by increased focal adhesion formation and turnover. Taken together, these findings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells.
Treating pulmonary embolism in Pacific Asia with direct oral anticoagulants

Cohen A, Jeyaindran S, Kim JY, Park K, Sompradeekul S, Tambunan KL, et al.

Thromb Res, 2015 Aug;136(2):196-207.
PMID: 26139085 DOI: 10.1016/j.thromres.2015.05.024

Pulmonary embolism (PE) is the principal preventable cause of in-hospital deaths. Prevalence of PE in Asians is uncertain but undoubtedly underestimated. Asians and Caucasians have similar non-genetic risk factors for PE, and there is mounting evidence that PE affects Asians much more commonly than previously supposed; incidence, especially among high-risk patients, may approach that in Caucasians. Furthermore, PE incidence in Asia is increasing, due to both increased ascertainment, and also population ageing and growing numbers of patients with predisposing risk factors. Despite being warranted, thromboprophylaxis for high-risk patients is not routine in Pacific Asian countries/regions. There also appears to be scope to implement venous thromboembolism (VTE) management guidelines more assiduously. Anticoagulants, primarily heparins and warfarin, have been the mainstays of VTE management for years; however, these agents have limitations that complicate routine use. The complexity of current guidelines has been another barrier to applying evidence-based recommendations in everyday practice. Updated management approaches have considerable potential to improve outcomes. New oral anticoagulants that are easier to administer, require no, or much less, monitoring or dose-adjustment and have a favourable risk/benefit profile compared with conventional modalities, may offer an alternative with the potential to simplify VTE management. However, more information is required on practical management and the occurrence and treatment of bleeding complications. Increasing recognition of the burden of PE and new therapeutic modalities are altering the VTE management landscape in Pacific Asia. Consequently, there is a need to further raise awareness and bridge gaps between the latest evidence and clinical practice.
A prospective study of mycobacterial viability in refrigerated, unpreserved sputum batched for up to 8 weeks

Rashid Ali MR, Parameswaran U, William T, Bird E, Wilkes CS, Lee WK, et al.

Int J Tuberc Lung Dis, 2015 May;19(5):620-1.
PMID: 25868033 DOI: 10.5588/ijtld.14.0938
Fulltext A prospective study of tuberculosis drug susceptibility in Sabah, Malaysia, and an algorithm for management of isoniazid resistance

Rashid Ali MR, Parameswaran U, William T, Bird E, Wilkes CS, Lee WK, et al.

J Trop Med, 2015;2015:261925.
PMID: 25838829 DOI: 10.1155/2015/261925

Introduction. The burden of tuberculosis is high in eastern Malaysia, and rates of Mycobacterium tuberculosis drug resistance are poorly defined. Our objectives were to determine M. tuberculosis susceptibility and document management after receipt of susceptibility results.
Methods. Prospective study of adult outpatients with smear-positive pulmonary tuberculosis (PTB) in Sabah, Malaysia. Additionally, hospital clinicians accessed the reference laboratory for clinical purposes during the study.
Results. 176 outpatients were enrolled; 173 provided sputum samples. Mycobacterial culture yielded M. tuberculosis in 159 (91.9%) and nontuberculous Mycobacterium (NTM) in three (1.7%). Among outpatients there were no instances of multidrug resistant M. tuberculosis (MDR-TB). Seven people (4.5%) had isoniazid resistance (INH-R); all were switched to an appropriate second-line regimen for varying durations (4.5-9 months). Median delay to commencement of the second-line regimen was 13 weeks. Among 15 inpatients with suspected TB, 2 had multidrug resistant TB (one extensively drug resistant), 2 had INH-R, and 4 had NTM.
Conclusions. Current community rates of MDR-TB in Sabah are low. However, INH-resistance poses challenges, and NTM is an important differential diagnosis in this setting, where smear microscopy is the usual diagnostic modality. To address INH-R management issues in our setting, we propose an algorithm for the treatment of isoniazid-resistant PTB.
Study site: Tuberculosis clinic, Klinik Kesihatan Luyang, Kota Kinabalu, Sabah, Malaysia
Characteristics and outcome of autoimmune liver disease in Asian children

Lee WS, Lum SH, Lim CB, Chong SY, Khoh KM, Ng RT, et al.

Hepatol Int, 2015 Apr;9(2):292-302.
PMID: 25788179 DOI: 10.1007/s12072-014-9558-0

BACKGROUND: Little is known about autoimmune liver disease (AILD) in Asian children. We studied the clinical features and predictors of outcome in childhood AILD in an Asian population.

METHODS: Retrospective review of AILD [autoimmune hepatitis type 1 and 2 (AIH1, AIH2), primary sclerosing cholangitis (PSC) and autoimmune sclerosing cholangitis (ASC)] seen at two pediatric liver units in Malaysia.

RESULTS: At presentation, 17 (56%) of the 32 children [19 females, 59%; median (range) age 7.7 (1.8-15.5) years] with AILD (AIH1 = 18, AIH2 = 5, PSC = 0, ASC = 9) had liver cirrhosis. At final review [median (range) duration of follow-up 4.8 (0.4-12) years], 24 patients (75%) survived with a native liver. Twenty-one (66%) were in remission; 19 (AIH1 = 11; AIH2 = 4, ASC = 4) were on prednisolone and/or azathioprine, one on cyclosporine and another on mycophenolate mofetil. Three (AIH1 = 3) were in partial remission. Of the two who underwent liver transplantation (LT; 6.5%; both ASC), one died of primary graft failure after LT. Six patients (19%) died without LT (acute liver failure, n = 1; end-stage liver disease, n = 5). The overall survival rate (native liver and survival post-LT) was 78%. A delay in seeking treatment adversely affected the final outcome [survival with native liver vs. LT or death (duration between onset of disease and treatment; median ± standard error) = 2.5 ± 2.9 months vs. 24.0 ± 13.3 months; p = 0.012].

CONCLUSIONS: Although remission was achieved in the majority of patients with prednisolone and/or azathioprine therapy, delay in seeking diagnosis and treatment adversely affects the outcome of childhood AILD in Malaysia.
Fulltext Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes

Valli H, Ahmad S, Sriharan S, Dean LD, Grace AA, Jeevaratnam K, et al.

Clin Exp Pharmacol Physiol, 2018 03;45(3):278-292.
PMID: 29027245 DOI: 10.1111/1440-1681.12870

Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.
Fulltext Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts

Valli H, Ahmad S, Chadda KR, Al-Hadithi ABAK, Grace AA, Jeevaratnam K, et al.

Mech Ageing Dev, 2017 Oct;167:30-45.
PMID: 28919427 DOI: 10.1016/j.mad.2017.09.002

INTRODUCTION: Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF).
MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).
RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.
Fulltext Re-examining the effect of door-to-balloon delay on STEMI outcomes in the context of unmeasured confounders: a retrospective cohort study

Foo CY, Andrianopoulos N, Brennan A, Ajani A, Reid CM, Duffy SJ, et al.

Sci Rep, 2019 12 27;9(1):19978.
PMID: 31882674 DOI: 10.1038/s41598-019-56353-7

Literature studying the door-to-balloon time-outcome relation in coronary intervention is limited by the potential of residual biases from unobserved confounders. This study re-examines the time-outcome relation with further consideration of the unobserved factors and reports the population average effect. Adults with ST-elevation myocardial infarction admitted to one of the six registry participating hospitals in Australia were included in this study. The exposure variable was patient-level door-to-balloon time. Primary outcomes assessed included in-hospital and 30 days mortality. 4343 patients fulfilled the study criteria. 38.0% (1651) experienced a door-to-balloon delay of >90 minutes. The absolute risk differences for in-hospital and 30-day deaths between the two exposure subgroups with balanced covariates were 2.81 (95% CI 1.04, 4.58) and 3.37 (95% CI 1.49, 5.26) per 100 population. When unmeasured factors were taken into consideration, the risk difference were 20.7 (95% CI -2.6, 44.0) and 22.6 (95% CI -1.7, 47.0) per 100 population. Despite further adjustment of the observed and unobserved factors, this study suggests a directionally consistent linkage between longer door-to-balloon delay and higher risk of adverse outcomes at the population level. Greater uncertainties were observed when unmeasured factors were taken into consideration.
Fulltext Change in public awareness of colorectal cancer symptoms following the Be Cancer Alert Campaign in the multi-ethnic population of Malaysia

Schliemann D, Paramasivam D, Dahlui M, Cardwell CR, Somasundaram S, Ibrahim Tamin NSB, et al.

BMC Cancer, 2020 Mar 25;20(1):252.
PMID: 32213173 DOI: 10.1186/s12885-020-06742-3

BACKGROUND: Colorectal cancer (CRC) cases are detected late in Malaysia similar to most Asian countries. The Be Cancer Alert Campaign (BCAC) was a culturally adapted mass media campaign designed to improve CRC awareness and reduce late detection in Malaysia. The evaluation of the BCAC-CRC aimed to assess campaign reach, campaign impact and health service use.
METHODS: Participants aged ≥40 years (n = 730) from randomly selected households in Selangor State Malaysia, completed interview-based assessments. Campaign reach was assessed in terms of responses to an adapted questionnaire that was used in evaluations in other countries. The impact of the campaign was assessed in terms of awareness, confidence to detect symptoms and self-efficacy to discuss symptoms with a doctor as captured by the Cancer Awareness Measure (CAM). CAM was administered before-and-after campaign implementation and responses by BCAC recognisers (i.e. participants who recognised one or more of the BCAC television, radio or print advertisements when prompted) and non-recognisers (i.e. participants who did not recognise any of the BCAC advertisements) were compared analytically. Logistic regression analysed comparative differences in cancer awareness by socio-demographic characteristics and recognition of the BCAC materials.
RESULTS: Over 65% of participants (n = 484) recognised the BCAC-CRC. Campaign-recognisers were significantly more likely to be aware of each CRC symptom at follow-up and were more confident about noticing symptoms (46.9% vs 34.9%, p = 0.018) compared to non-recognisers. There was no difference between groups in terms of self-efficacy to see a doctor about symptoms. Improved symptoms awareness at follow-up was lower for Indians compared to Malays (adjusted odds ratio (OR) 0.53, 95% Confidence Interval (CI): 0.34, 0.83, p = 0.005). Health service use data did not indicate an increase in screening activity during or immediately after the campaign months.
CONCLUSION: Overall, the findings of the evaluation indicated that the culturally adapted, evidence-based mass media intervention improved CRC symptom awareness among the Malaysian population; and that impact is more likely when a campaign operates a differentiated approach that matches modes of communication to the ethnic and social diversity in a population.
Phenotypic and mutational spectrum of 21 Chinese patients with Alström syndrome

Rethanavelu K, Fung JLF, Chau JFT, Pei SLC, Chung CCY, Mak CCY, et al.

Am J Med Genet A, 2020 02;182(2):279-288.
PMID: 31755649 DOI: 10.1002/ajmg.a.61412

Alström syndrome (AS) is a monogenic syndromic ciliopathy caused by mutations in the ALMS1 (Alström Syndrome 1) gene. A total of 21 subjects with AS from 20 unrelated Chinese families were recruited. Our cohort consists of 9 females and 12 males, between 5 months and 20 years old. The first symptom(s) appeared between 3 and 24 months. They were recorded to be either visual impairments (83%) or dilated cardiomyopathy (17%). Median time from symptom onset to seeking medical attention was 6 months (3-36 months) and the median time needed to reach the final molecular diagnosis is 54 months (6-240 months). System involvement at the time of the survey was as follows: visual symptoms (100%), hearing Impairment (67%), endocrine symptoms (43%), neurological symptoms (19%), hepatic symptoms (14%), and renal Involvement (14%). These findings are comparable to data reported in the literature. However, the proportion of subjects with cognitive impairment (33%) and behavioral problems (19%) were higher. Thirty-three unique mutations were identified in the ALMS1 gene, of which 18 are novel mutations classified as pathogenic/likely pathogenic according to the American College of Medical Genetics (ACMG) guideline. Four recurrent mutations were identified in the cohort, in particular; c.2084C>A, p. (Ser695Ter), is suggestive to be a founder mutation in people of Chinese ancestry. The participation of AS subjects of differing ethnicities is essential to improve the algorithm in facial recognition/phenotyping, as well as to understand the mutation spectrum beyond than just those of European ancestry.
Fulltext De novo genome assembly and annotation of Australia's largest freshwater fish, the Murray cod (Maccullochella peelii), from Illumina and Nanopore sequencing read

Austin CM, Tan MH, Harrisson KA, Lee YP, Croft LJ, Sunnucks P, et al.

Gigascience, 2017 08 01;6(8):1-6.
PMID: 28873963 DOI: 10.1093/gigascience/gix063

One of the most iconic Australian fish is the Murray cod, Maccullochella peelii (Mitchell 1838), a freshwater species that can grow to ∼1.8 metres in length and live to age ≥48 years. The Murray cod is of a conservation concern as a result of strong population contractions, but it is also popular for recreational fishing and is of growing aquaculture interest. In this study, we report the whole genome sequence of the Murray cod to support ongoing population genetics, conservation, and management research, as well as to better understand the evolutionary ecology and history of the species. A draft Murray cod genome of 633 Mbp (N50 = 109 974bp; BUSCO and CEGMA completeness of 94.2% and 91.9%, respectively) with an estimated 148 Mbp of putative repetitive sequences was assembled from the combined sequencing data of 2 fish individuals with an identical maternal lineage; 47.2 Gb of Illumina HiSeq data and 804 Mb of Nanopore data were generated from the first individual while 23.2 Gb of Illumina MiSeq data were generated from the second individual. The inclusion of Nanopore reads for scaffolding followed by subsequent gap-closing using Illumina data led to a 29% reduction in the number of scaffolds and a 55% and 54% increase in the scaffold and contig N50, respectively. We also report the first transcriptome of Murray cod that was subsequently used to annotate the Murray cod genome, leading to the identification of 26 539 protein-coding genes. We present the whole genome of the Murray cod and anticipate this will be a catalyst for a range of genetic, genomic, and phylogenetic studies of the Murray cod and more generally other fish species of the Percichthydae family.
Fulltext Epidemiology of tuberculosis in Sabah, Malaysia, 2012-2018

Goroh MMD, Rajahram GS, Avoi R, Van Den Boogaard CHA, William T, Ralph AP, et al.

Infect Dis Poverty, 2020 Aug 26;9(1):119.
PMID: 32843089 DOI: 10.1186/s40249-020-00739-7

BACKGROUND: Tuberculosis (TB) is of high public health importance in Malaysia. Sabah State, located on the island of Borneo, has previously reported a particularly high burden of disease and faces unique contextual challenges compared with peninsular Malaysia. The aim of this study is to describe the epidemiology of TB in Sabah to identify risk groups and hotspots of TB transmission.
METHODS: We conducted a retrospective review of TB cases notified in Sabah, Malaysia, between 2012 and 2018. Using data from the state's 'myTB' notification database, we calculated the case notification rate and described trends in the epidemiology, diagnostic practices and treatment outcomes of TB in Sabah within this period. The Chi-squared test was used for determining the difference between two proportions.
RESULTS: Between 2012 and 2018 there were 33 193 cases of TB reported in Sabah (128 cases per 100 000 population). We identified several geographic hotspots, including districts with > 200 cases per 100 000 population per year. TB rates increased with age and were highest in older males. Children
Fulltext Simultaneous quantification of ten key Kratom alkaloids in Mitragyna speciosa leaf extracts and commercial products by ultra-performance liquid chromatography-tandem mass spectrometry

Sharma A, Kamble SH, León F, Chear NJ, King TI, Berthold EC, et al.

Drug Test Anal, 2019 Aug;11(8):1162-1171.
PMID: 30997725 DOI: 10.1002/dta.2604

Kratom (Mitragyna speciosa) is a psychoactive plant popular in the United States for the self-treatment of pain and opioid addiction. For standardization and quality control of raw and commercial kratom products, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantification of ten key alkaloids, namely: corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine, mitragynine, mitraphylline, paynantheine, speciociliatine, and speciogynine. Chromatographic separation of diastereomers, or alkaloids sharing same ion transitions, was achieved on an Acquity BEH C18 column with a gradient elution using a mobile phase containing acetonitrile and aqueous ammonium acetate buffer (10mM, pH 3.5). The developed method was linear over a concentration range of 1-200 ng/mL for each alkaloid. The total analysis time per sample was 22.5 minutes. The analytical method was validated for accuracy, precision, robustness, and stability. After successful validation, the method was applied for the quantification of kratom alkaloids in alkaloid-rich fractions, ethanolic extracts, lyophilized teas, and commercial products. Mitragynine (0.7%-38.7% w/w), paynantheine (0.3%-12.8% w/w), speciociliatine (0.4%-12.3% w/w), and speciogynine (0.1%-5.3% w/w) were the major alkaloids in the analyzed kratom products/extracts. Minor kratom alkaloids (corynantheidine, corynoxine, corynoxine B, 7-hydroxymitragynine, isocorynantheidine) were also quantified (0.01%-2.8% w/w) in the analyzed products; however mitraphylline was below the lower limit of quantification in all analyses.
Realization of a Novel Free-Piston Engine Generator for Hybrid-Electric Vehicle Applications

Smallbone A, Hanipah MR, Jia B, Scott T, Heslop J, Towell B, et al.

Energy Fuels, 2020 Oct 15;34(10):12926-12939.
PMID: 33122874 DOI: 10.1021/acs.energyfuels.0c01647

Free-piston engine generators (FPEGs) have huge potential to be the principal energy conversion device for generating electricity from fuel as part of a hybrid-electric vehicle (EV) powertrain system. The principal advantages lay in the fact that they are theoretically more efficient, more compact, and more lightweight compared to other competing EV hybrid and range-extender solutions (internal combustion engines, rotary engines, fuel cells, etc.). However, this potential has yet to be realized. This article details a novel dual-piston FPEG configuration and presents the full layout of a system and provides technical evidence of a commercial FPEG system's likely size and weight. The work also presents the first results obtained from a project which set-out to realize an operational FPEG system in hardware through the development and testing of a flexible prototype test platform. The work presents the performance and control system characteristics, for a first of a kind system; these show great technical potential with stable and repeatable combustion events achieved with around 700 W per cylinder and 26% indicated efficiency.
Fulltext Ageing in Pgc-1β-/- mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology

Edling CE, Fazmin IT, Chadda KR, Ahmad S, Valli H, Grace AA, et al.

Biosci Rep, 2019 04 30;39(4).
PMID: 30914453 DOI: 10.1042/BSR20190127

Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β-/- ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β-/- ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β-/- genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
Fulltext Bioguided Fractionation of Local Plants against Matrix Metalloproteinase9 and Its Cytotoxicity against Breast Cancer Cell Models: In Silico and In Vitro Study

Hariono M, Rollando R, Karamoy J, Hariyono P, Atmono M, Djohan M, et al.

Molecules, 2020 Oct 14;25(20).
PMID: 33066411 DOI: 10.3390/molecules25204691

Matrix metalloproteinase9 (MMP9) is known to be highly expressed during metastatic cancer where most known potential inhibitors failed in the clinical trials. This study aims to select local plants in our state, as anti-breast cancer agent with hemopexin-like domain of MMP9 (PEX9) as the selective protein target. In silico screening for PEX9 inhibitors was performed from our in house-natural compound database to identify the plants. The selected plants were extracted using methanol and then a step-by-step in vitro screening against MMP9 was performed from its crude extract, partitions until fractions using FRET-based assay. The partitions were obtained by performing liquid-liquid extraction on the methanol extract using n-hexane, ethylacetate, n-butanol, and water representing nonpolar to polar solvents. The fractions were made from the selected partition, which demonstrated the best inhibition percentage toward MMP9, using column chromatography. Of the 200 compounds screened, 20 compounds that scored the binding affinity -11.2 to -8.1 kcal/mol toward PEX9 were selected as top hits. The binding of these hits were thoroughly investigated and linked to the plants which they were reported to be isolated from. Six of the eight crude extracts demonstrated inhibition toward MMP9 with the IC50 24 to 823 µg/mL. The partitions (1 mg/mL) of Ageratum conyzoides aerial parts and Ixora coccinea leaves showed inhibition 94% and 96%, whereas their fractions showed IC50 43 and 116 µg/mL, respectively toward MMP9. Using MTT assay, the crude extract of Ageratum exhibited IC50 22 and 229 µg/mL against 4T1 and T47D cell proliferations, respectively with a high safety index concluding its potential anti-breast cancer from herbal.
Fulltext Is forced migration a barrier to treatment success? Similar HIV treatment outcomes among refugees and a surrounding host community in Kuala Lumpur, Malaysia

Mendelsohn JB, Schilperoord M, Spiegel P, Balasundaram S, Radhakrishnan A, Lee CK, et al.

AIDS Behav, 2014 Feb;18(2):323-34.
PMID: 23748862 DOI: 10.1007/s10461-013-0494-0

In response to an absence of studies among refugees and host communities accessing highly active antiretroviral therapy (HAART) in urban settings, our objective was to compare adherence and virological outcomes among clients attending a public clinic in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted among adult clients (≥18 years). Data sources included a structured questionnaire that measured self-reported adherence, a pharmacy-based measure of HAART prescription refills over the previous 24 months, and HIV viral loads. The primary outcome was unsuppressed viral load (≥40 copies/mL). Among a sample of 153 refugees and 148 host community clients, refugees were younger (median age 35 [interquartile range, IQR 31, 39] vs 40 years [IQR 35, 48], p
Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia

Ford AC, Moayyedi P, Black CJ, Yuan Y, Veettil SK, Mahadeva S, et al.

Aliment Pharmacol Ther, 2021 01;53(1):8-21.
PMID: 32936964 DOI: 10.1111/apt.16072

BACKGROUND: Functional dyspepsia (FD) is a relapsing and remitting condition affecting between 5% and 10% of people. Efficacious therapies are available, but their relative efficacy is unknown.
AIM: To perform a systematic review with network meta-analysis to resolve this uncertainty.
METHODS: We searched the medical literature through July 2020 for randomised controlled trials (RCTs) assessing efficacy of drugs for adults with FD, compared with each other, or placebo. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic with a 95% confidence interval (CI) to summarise efficacy of each comparison tested. Relative ranking was assessed with surface under the cumulative ranking curve (SUCRA) probabilities.
RESULTS: We identified 71 eligible RCTs (19 243 participants). Tricyclic antidepressants (TCAs) were ranked second for efficacy (RR of remaining symptomatic = 0.71; 95% CI 0.58-0.87, SUCRA 0.87), and first when only low risk of bias trials were included. Most RCTs that used TCAs recruited patients who were refractory to other drugs included in the network. Although sulpiride or levosulpiride were ranked first for efficacy (RR = 0.49; 95% CI 0.36-0.69, SUCRA 0.99), trial quality was low and only 86 patients received active therapy. TCAs were more likely to cause adverse events than placebo.
CONCLUSIONS: TCAs, histamine-2 receptor antagonists, standard- and low-dose proton pump inhibitors, sulpiride or levosulpiride, itopride and acotiamide were all more efficacious than placebo for FD.

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