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Fulltext Using primary care prescribing databases to determine drug switching and continuation of care

Mohamed IN, Helms PJ, McLay JS

Basic Clin Pharmacol Toxicol, 2012 Dec;111(6):396-401.
PMID: 22734606 DOI: 10.1111/j.1742-7843.2012.00917.x

Drug switching is a common medical practice. It indicates continuation of treatment regardless of the reason why the original therapy was stopped and switched. Therefore, the aims of this study were to develop a novel method for determining drug switching from routinely acquired NHS health data and to explore the aspect of continuation of care for patients. Patients who were first prescribed ramipril, simvastatin and an angiotensin receptor blocker (ARB) between 1 March 2004 and 28 February 2007 and discontinued their medication within 6 months of the index prescription were identified from the PTI database. The identified patients were then categorized into three groups: i) patients who were switched to a different drug for the same medical condition, ii) patients who were being prescribed with other types of antihypertensive/lipid-regulating drug prior to the initiation of study; and iii) patients who were without any continuation of care or therapy. Twenty percent (808), 29%(1429) and 14%(455) of the identified patients discontinued ramipril, simvastatin and ARB, respectively, within 6 months of an index prescription. Among the ramipril discontinuation group, 36.4% of the patients were switched to another antihypertensive, while another 31.6% of them were without continuation of care. In patients discontinuing ARB, 30.6% were switched, while another 30.1% were without continuation of treatment. In patients discontinuing simvastatin, 28.8% were switched to another lipid-regulating medicine, while another 63.1% of them were without continuation of care. The results of this study confirm that primary care prescribing databases can be used to determine drug-switching information and continuation of care/therapy.
Fulltext A simple, high-throughput, colourimetric, field applicable loop-mediated isothermal amplification (HtLAMP) assay for malaria elimination

Britton S, Cheng Q, Sutherland CJ, McCarthy JS

Malar J, 2015;14:335.
PMID: 26315027 DOI: 10.1186/s12936-015-0848-3

To detect all malaria infections in elimination settings sensitive, high throughput and field deployable diagnostic tools are required. Loop-mediated isothermal amplification (LAMP) represents a possible field-applicable molecular diagnostic tool. However, current LAMP platforms are limited by their capacity for high throughput.
Docking of noncompetitive inhibitors into dengue virus type 2 protease: understanding the interactions with allosteric binding sites

Othman R, Kiat TS, Khalid N, Yusof R, Newhouse EI, Newhouse JS, et al.

J Chem Inf Model, 2008 Aug;48(8):1582-91.
PMID: 18656912 DOI: 10.1021/ci700388k

A group of flavanones and their chalcones, isolated from Boesenbergia rotunda L., were previously reported to show varying degrees of noncompetitive inhibitory activities toward Dengue virus type 2 (Den2) protease. Results obtained from automated docking studies are in agreement with experimental data in which the ligands were shown to bind to sites other than the active site of the protease. The calculated K(i) values are very small, indicating that the ligands bind quite well to the allosteric binding site. Greater inhibition by pinostrobin, compared to the other compounds, can be explained by H-bonding interaction with the backbone carbonyl of Lys74, which is bonded to Asp75 (one of the catalytic triad residues). In addition, structure-activity relationship analysis yields structural information that may be useful for designing more effective therapeutic drugs against dengue virus infections.
Evaluation of factors influencing the development of late Marek's disease virus-induced immunosuppression: virus pathotype and host sex

Faiz NM, Cortes AL, Guy JS, Fletcher OJ, Cimino T, Gimeno IM

Avian Pathol, 2017 Aug;46(4):376-385.
PMID: 28151004 DOI: 10.1080/03079457.2017.1290214

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and immunosuppression in chickens. MDV-induced immunosuppression (MDV-IS) is complex and can be divided into two phases: early-MDV-IS associated with cytolytic infection in the lymphoid organs in chickens lacking maternal antibodies against MDV (MAbs) and late-MDV-IS that appears later in the pathogenesis and occurs even in chickens bearing MAbs. We have recently developed a model to reproduce late-MDV-IS under laboratory conditions. This model evaluates late-MDV-IS indirectly by assessing the effect of MDV infection on the efficacy of infectious laryngotracheitis (ILT) vaccines against challenge with ILT virus. In the present study, we have used this model to investigate the role of two factors (MDV pathotype and host sex) on the development of late-MDV-IS. Five MDV strains representing three different pathotypes: virulent (vMDV; 617A, GA), very virulent (vvMDV; Md5), and very virulent plus (vv+MDV; 648A, 686), were evaluated. Only vv+ strains were able to induce late-MDV-IS. An immunosuppression rank (IS-rank) was established based on the ability of MDV to reduce the efficacy of chicken embryo origin vaccine (values go from 0 to 100, with 100 being the highest immunosuppressive ability). The IS-rank of the evaluated MDV strains ranged from 5.97 (GA) to 20.8 (617A) in the vMDV strains, 5.97 to 16.24 in the vvMDV strain Md5, and 39.08 to 68.2 in the vv+ strains 648A and 686. In this study both male and female chickens were equally susceptible to MDV-IS by vv+MDV 686. Our findings suggest that late-MDV-IS is a unique feature of vv+ strains.
Early infection with Marek's disease virus can jeopardize protection conferred by laryngotracheitis vaccines: a method to study MDV-induced immunosuppression

Faiz NM, Cortes AL, Guy JS, Fletcher OJ, West M, Montiel E, et al.

Avian Pathol, 2016 Dec;45(6):606-615.
PMID: 27207594

Marek's disease virus (MDV) is a herpesvirus that induces lymphomas and immunosuppression in chickens. MDV-induced immunosuppression (MDV-IS) is divided into two phases: early-MDV-IS occurring mainly in chickens lacking maternal antibodies (MAb) against MDV and associated with lymphoid organ atrophy; and late-MDV-IS occurring once MDV enters latency and during tumour development. Our objectives were to document the impact of late-MDV-IS on commercial poultry (meat-type chickens bearing MAb against MDV and that were vaccinated or unvaccinated against MD) and to optimize a model to study late-MDV-IS under laboratory conditions. The impact of late-MDV-IS was evaluated by assessing the effect of early infection (day of age) with a very virulent plus MDV (vv+MDV) on the efficacy of chicken-embryo-origin (CEO) infectious laryngotracheitis (ILT) virus vaccine against ILT challenge. The CEO ILT vaccine was administered in water at 14 days of age and ILT virus (ILTV) challenge was done intratracheally at 30 days of age. Development of ILT was monitored by daily evaluation of clinical signs, development of gross and histological lesions in trachea, and quantification of ILTV transcripts in trachea. Infection with vv+MDV strain 648A resulted in total abrogation of protection conferred by the CEO vaccine against ILTV challenge even in chickens vaccinated at 1 day of age with either HVT, HVT+SB-1, or CVI988. Chickens exposed to vv+MDV prior to vaccination with CEO ILTV vaccine had similar (P
Fulltext A rapid and sensitive system for recovery of nucleic acids from Mycobacteria sp. on archived glass slides

A Talip B, Snelling WJ, Sleator RD, Lowery C, Dooley JSG

BMC Microbiol, 2018 11 26;18(1):196.
PMID: 30477427 DOI: 10.1186/s12866-018-1335-0

BACKGROUND: The field of diagnostics continues to advance rapidly with a variety of novel approaches, mainly dependent upon high technology platforms. Nonetheless much diagnosis, particularly in developing countries, still relies upon traditional methods such as microscopy. Biological material, particularly nucleic acids, on archived glass slides is a potential source of useful information both for diagnostic and epidemiological purposes. There are significant challenges faced when examining archived samples in order that an adequate amount of amplifiable DNA can be obtained. Herein, we describe a model system to detect low numbers of bacterial cells isolated from glass slides using (laser capture microscopy) LCM coupled with PCR amplification of a suitable target.
RESULTS: Mycobacterium smegmatis was used as a model organism to provide a proof of principle for a method to recover bacteria from a stained sample on a glass slide using a laser capture system. Ziehl-Neelsen (ZN) stained cells were excised and catapulted into tubes. Recovered cells were subjected to DNA extraction and pre-amplified with multiple displacement amplification (MDA). This system allowed a minimum of 30 catapulted cells to be detected following a nested real-time PCR assay, using rpoB specific primers. The combination of MDA and nested real-time PCR resulted in a 30-fold increase in sensitivity for the detection of low numbers of cells isolated using LCM.
CONCLUSIONS: This study highlights the potential of LCM coupled with MDA as a tool to improve the recovery of amplifiable nucleic acids from archived glass slides. The inclusion of the MDA step was essential to enable downstream amplification. This platform should be broadly applicable to a variety of diagnostic applications and we have used it as a proof of principle with a Mycobacterium sp. model system.
Fulltext A Sensitive, Colorimetric, High-Throughput Loop-Mediated Isothermal Amplification Assay for the Detection of Plasmodium knowlesi

Britton S, Cheng Q, Grigg MJ, William T, Anstey NM, McCarthy JS

Am J Trop Med Hyg, 2016 07 06;95(1):120-2.
PMID: 27162264 DOI: 10.4269/ajtmh.15-0670

The simian parasite Plasmodium knowlesi is now the commonest cause of malaria in Malaysia and can rapidly cause severe and fatal malaria. However, microscopic misdiagnosis of Plasmodium species is common, rapid antigen detection tests remain insufficiently sensitive and confirmation of P. knowlesi requires polymerase chain reaction (PCR). Thus available point-of-care diagnostic tests are inadequate. This study reports the development of a simple, sensitive, colorimetric, high-throughput loop-mediated isothermal amplification assay (HtLAMP) diagnostic test using novel primers for the detection of P. knowlesi. This assay is able to detect 0.2 parasites/μL, and compared with PCR has a sensitivity of 96% for the detection of P. knowlesi, making it a potentially field-applicable point-of-care diagnostic tool.
Differential attenuation of Marek's disease virus-induced tumours and late-Marek's disease virus-induced immunosuppression

Faiz NM, Cortes AL, Guy JS, Reddy SM, Gimeno IM

J Gen Virol, 2018 07;99(7):927-936.
PMID: 29767614 DOI: 10.1099/jgv.0.001076

Marek's disease virus (MDV) is a herpesvirus that induces lymphoma and a variety of non-neoplastic syndromes in chickens. Furthermore, very virulent plus (vv+) MDVs induce a form of immunosuppression (late-MDV-IS) that might involve both neoplastic and non-neoplastic mechanisms. The objective of this study was to evaluate whether the attenuation of MDV-induced tumours and late-MDV-IS occurs simultaneously or can be dissociated. The immunosuppressive ability of three viruses derived from vv+ MDV strain 686 (wild-type 686, the somewhat attenuated molecular clone 686-BAC, and the nononcogenic molecular clone lacking the two copies of the oncogene meq 686-BACΔMEQ) was evaluated. Late-MDV-IS was evaluated indirectly by assessing the negative effect of MDV strains on the protection conferred by infectious laryngotracheitis (ILT) vaccines. Our results showed that the ability to induce late-MDV-IS was attenuated before the ability to induce tumours. Strain 686 induced both tumours and late-MDV-IS, 686-BAC induced tumours but did not induce late-MDV-IS and 686-BACΔMEQ did not induce either tumours or late-MDV-IS. Further comparison of strains 686 and 686-BAC revealed that strain 686 reduced the humoral immune responses to ILTV (1132 vs 2167) more severely, showed higher levels of meq transcripts (2.1E+09 vs 4.98E+8) and higher expression of MDV microRNAs (mdv1-miR-M4-5p and mdv1-miR-M2-3p) in the spleen, and further reduced the percentage of CD45+-MHC-I+splenocytes (13 vs32 %) compared to molecular clone 686-BAC. This study suggests that the immunosuppressive ability of MDV might follow a continuous spectrum and only the most virulent MDVs can overcome a certain threshold level and induce clinical MDV-IS in the ILT model.
Fulltext Health and saliva microbiomes of a semi-urbanized indigenous tribe in Peninsular Malaysia

Yeo LF, Aghakhanian FF, Tan JSY, Gan HM, Phipps ME

F1000Res, 2019;8:175.
PMID: 31275564 DOI: 10.12688/f1000research.17706.3

Background: The indigenous people of Peninsular Malaysia, also known as Orang Asli, have gradually been urbanized. A shift towards non-communicable diseases commonly associated with sedentary lifestyles have been reported in many tribes. This study engaged with a semi-urbanized Temiar tribe from Kampong Pos Piah, Perak, who are experiencing an epidemiological transition. Methods: Weight, height, waist circumference, blood pressure, HbA1C and lipid levels were measured as indicators of cardio-metabolic health. DNA was extracted from saliva using salting-out method followed by PCR amplification of the V3-V4 region of the 16S rRNA gene and sequencing on Illumina MiSeq. Microbiome analysis was conducted on Qiime v1.9. Statistical analysis was conducted using Qiime v1.9 and R. Results: The study revealed that 60.4% of the Temiar community were overweight/obese, with a higher prevalence among women. HbA1C levels showed that 45% of Temiar had pre-diabetes. Insulin resistance was identified in 21% of Temiar by using a surrogate marker, TG/HDL. In total, 56.5% of Temiar were pre-hypertensive, and the condition was prevalent across all age-groups. The saliva microbiome profiles of Temiar revealed significant differences by gender, BMI, abdominal obesity as well as smoking status. The relative abundance of the genus Bifidobacterium was increased in men whereas the genera Prevotella, Capnocytophaga, Leptotrichia, Neisseria and Streptococcus were increased in women. Proteobacteria was significantly depleted in smokers. Conclusions: Temiar from Pos Piah had a high prevalence of cardio-metabolic risks, including general and abdominal obesity, pre-diabetes, prehypertension and hypertension. This phenomenon has not been previously reported in this tribe. The saliva microbiome profiles were significantly different for individuals of different gender, BMI, abdominal obesity and smoking status.
Fulltext Association of dietary omega-3 fatty acids with prevalence of metabolic syndrome: the National Heart, Lung, and Blood Institute Family Heart Study

Lai YH, Petrone AB, Pankow JS, Arnett DK, North KE, Ellison RC, et al.

Clin Nutr, 2013 Dec;32(6):966-9.
PMID: 23711994 DOI: 10.1016/j.clnu.2013.05.002

Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, and insulin resistance is a major public health concern in the United States. Omega-3 fatty acids have been relatively well studied in relation to many individual cardiovascular risk factors; however, their effects on MetS are not well established.
Fulltext Divergent effects of climate change on future groundwater availability in key mid-latitude aquifers

Wu WY, Lo MH, Wada Y, Famiglietti JS, Reager JT, Yeh PJ, et al.

Nat Commun, 2020 07 24;11(1):3710.
PMID: 32709871 DOI: 10.1038/s41467-020-17581-y

Groundwater provides critical freshwater supply, particularly in dry regions where surface water availability is limited. Climate change impacts on GWS (groundwater storage) could affect the sustainability of freshwater resources. Here, we used a fully-coupled climate model to investigate GWS changes over seven critical aquifers identified as significantly distressed by satellite observations. We assessed the potential climate-driven impacts on GWS changes throughout the 21st century under the business-as-usual scenario (RCP8.5). Results show that the climate-driven impacts on GWS changes do not necessarily reflect the long-term trend in precipitation; instead, the trend may result from enhancement of evapotranspiration, and reduction in snowmelt, which collectively lead to divergent responses of GWS changes across different aquifers. Finally, we compare the climate-driven and anthropogenic pumping impacts. The reduction in GWS is mainly due to the combined impacts of over-pumping and climate effects; however, the contribution of pumping could easily far exceed the natural replenishment.
The giant mudskipper Periophthalmodon schlosseri facilitates active NH(4)(+) excretion by increasing acid excretion and decreasing NH(3) permeability in the skin

Ip YK, Randall DJ, Kok TK, Barzaghi C, Wright PA, Ballantyne JS, et al.

J Exp Biol, 2004 Feb;207(Pt 5):787-801.
PMID: 14747411

Periophthalmodon schlosseri is an amphibious and obligatory air-breathing teleost, which is extremely tolerant to environmental ammonia. It actively excretes NH(4)(+) in ammonia loading conditions. For such a mechanism to operate efficaciously the fish must be able to prevent back flux of NH(3). P. schlosseri could lower the pH of 50 volumes (w/v) of 50% seawater in an artificial burrow from pH 8.2 to pH 7.4 in 1 day, and established an ambient ammonia concentration of 10 mmol l(-1) in 8 days. It could alter the rate of titratable acid efflux in response to ambient pH. The rate of net acid efflux (H(+) excretion) in P. schlosseri was pH-dependent, increasing in the order pH 6.0<7.0<8.0<8.5. Net acid flux in neutral or alkaline pH conditions was partially inhibited by bafilomycin, indicating the possible involvement of a V-type H(+)-ATPase. P. schlosseri could also increase the rate of H(+) excretion in response to the presence of ammonia in a neutral (pH 7.0) external medium. Increased H(+) excretion in P. schlosseri occurred in the head region where active excretion of NH(4)(+) took place. This would result in high concentrations of H(+) in the boundary water layer and prevent the dissociation of NH(4)(+), thus preventing a back flux of NH(3) through the branchial epithelia. P. schlosseri probably developed such an 'environmental ammonia detoxification' capability because of its unique behavior of burrow building in the mudflats and living therein in a limited volume of water. In addition, the skin of P. schlosseri had low permeability to NH(3). Using an Ussing-type apparatus with 10 mmol l(-1) NH(4)Cl and a 1 unit pH gradient (pH 8.0 to 7.0), the skin supported only a very small flux of NH(3) (0.0095 micromol cm(-2) min(-1)). Cholesterol content (4.5 micromol g(-1)) in the skin was high, which suggests low membrane fluidity. Phosphatidylcholine, which has a stabilizing effect on membranes, constituted almost 50% of the skin phospholipids, with phosphatidyleserine and phsophatidylethanolamine contributing only 13% and 15%, respectively. More importantly, P. schlosseri increased the cholesterol level (to 5.5 micromol g(-1)) and altered the fatty acid composition (increased total saturated fatty acid content) in its skin lipid after exposure to ammonia (30 mmol l(-1) at pH 7.0) for 6 days. These changes might lead to an even lower permeability to NH(3) in the skin, and reduced back diffusion of the actively excreted NH(4)(+) as NH(3) or the net influx of exogenous NH(3), under such conditions.
Fulltext Antiphosphatidylserine Immunoglobulin M and Immunoglobulin G Antibodies Are Higher in Vivax Than Falciparum Malaria, and Associated With Early Anemia in Both Species

Barber BE, Grigg MJ, Piera K, Amante FH, William T, Boyle MJ, et al.

J Infect Dis, 2019 09 26;220(9):1435-1443.
PMID: 31250022 DOI: 10.1093/infdis/jiz334

BACKGROUND: Anemia is a major complication of vivax malaria. Antiphosphatidylserine (PS) antibodies generated during falciparum malaria mediate phagocytosis of uninfected red blood cells that expose PS and have been linked to late malarial anemia. However, their role in anemia from non-falciparum Plasmodium species is not known, nor their role in early anemia from falciparum malaria.
METHODS: We measured PS immunoglobulin G (IgG) and immunoglobulin M (IgM) antibodies in Malaysian patients with vivax, falciparum, knowlesi, and malariae malaria, and in healthy controls, and correlated antibody titres with hemoglobin. PS antibodies were also measured in volunteers experimentally infected with Plasmodium vivax and Plasmodium falciparum.
RESULTS: PS IgM and IgG antibodies were elevated in patients with vivax, falciparum, knowlesi, and malariae malaria (P < .0001 for all comparisons with controls) and were highest in vivax malaria. In vivax and falciparum malaria, PS IgM and IgG on admission correlated inversely with admission and nadir hemoglobin, controlling for parasitemia and fever duration. PS IgM and IgG were also increased in volunteers infected with blood-stage P. vivax and P. falciparum, and were higher in P. vivax infection.
CONCLUSIONS: PS antibodies are higher in vivax than falciparum malaria, correlate inversely with hemoglobin, and may contribute to the early loss of uninfected red blood cells found in malarial anemia from both species.
Fulltext Lack of association of apolipoprotein E (Apo E) polymorphism with the prevalence of metabolic syndrome: the National Heart, Lung and Blood Institute Family Heart Study

Lai LY, Petrone AB, Pankow JS, Arnett DK, North KE, Ellison RC, et al.

Diabetes Metab Res Rev, 2015 Sep;31(6):582-7.
PMID: 25656378 DOI: 10.1002/dmrr.2638

OBJECTIVE: Metabolic syndrome (MetS), characterized by abdominal obesity, atherogenic dyslipidaemia, elevated blood pressure and insulin resistance, is a major public health concern in the United States. The effects of apolipoprotein E (Apo E) polymorphism on MetS are not well established.
METHODS: We conducted a cross-sectional study consisting of 1551 participants from the National Heart, Lung and Blood Institute Family Heart Study to assess the relation of Apo E polymorphism with the prevalence of MetS. MetS was defined according to the American Heart Association-National Heart, Lung and Blood Institute-International Diabetes Federation-World Health Organization harmonized criteria. We used generalized estimating equations to estimate adjusted odds ratios (ORs) for prevalent MetS and the Bonferroni correction to account for multiple testing in the secondary analysis.
RESULTS: Our study population had a mean age (standard deviation) of 56.5 (11.0) years, and 49.7% had MetS. There was no association between the Apo E genotypes and the MetS. The multivariable adjusted ORs (95% confidence interval) were 1.00 (reference), 1.26 (0.31-5.21), 0.89 (0.62-1.29), 1.13 (0.61-2.10), 1.13 (0.88-1.47) and 1.87 (0.91-3.85) for the Ɛ3/Ɛ3, Ɛ2/Ɛ2, Ɛ2/Ɛ3, Ɛ2/Ɛ4, Ɛ3/Ɛ4 and Ɛ4/Ɛ4 genotypes, respectively. In a secondary analysis, Ɛ2/Ɛ3 genotype was associated with 41% lower prevalence odds of low high-density lipoprotein [multivariable adjusted ORs (95% confidence interval) = 0.59 (0.36-0.95)] compared with Ɛ3/Ɛ3 genotype.
CONCLUSIONS: Our findings do not support an association between Apo E polymorphism and MetS in a multicentre population-based study of predominantly White US men and women.
Fulltext Artesunate-mefloquine versus chloroquine for treatment of uncomplicated Plasmodium knowlesi malaria in Malaysia (ACT KNOW): an open-label, randomised controlled trial

Grigg MJ, William T, Menon J, Dhanaraj P, Barber BE, Wilkes CS, et al.

Lancet Infect Dis, 2016 Feb;16(2):180-188.
PMID: 26603174 DOI: 10.1016/S1473-3099(15)00415-6

BACKGROUND: The zoonotic parasite Plasmodium knowlesi has become the most common cause of human malaria in Malaysia and is present throughout much of southeast Asia. No randomised controlled trials have been done to identify the optimum treatment for this emerging infection. We aimed to compare artesunate-mefloquine with chloroquine to define the optimum treatment for uncomplicated P knowlesi malaria in adults and children.
METHODS: We did this open-label, randomised controlled trial at three district hospitals in Sabah, Malaysia. Patients aged 1 year or older with uncomplicated P knowlesi malaria were randomly assigned, via computer-generated block randomisation (block sizes of 20), to receive oral artesunate-mefloquine (target dose 12 mg/kg artesunate and 25 mg/kg mefloquine) or chloroquine (target dose 25 mg/kg). Research nursing staff were aware of group allocation, but allocation was concealed from the microscopists responsible for determination of the primary endpoint, and study participants were not aware of drug allocation. The primary endpoint was parasite clearance at 24 h. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01708876.
FINDINGS: Between Oct 16, 2012, and Dec 13, 2014, we randomly assigned 252 patients to receive either artesunate-mefloquine (n=127) or chloroquine (n=125); 226 (90%) patients comprised the modified intention-to-treat population. 24 h after treatment, we recorded parasite clearance in 97 (84% [95% CI 76-91]) of 115 patients in the artesunate-mefloquine group versus 61 (55% [45-64]) of 111 patients in the chloroquine group (difference in proportion 29% [95% CI 18·0-40·8]; p<0·0001). Parasite clearance was faster in patients given artesunate-mefloquine than in those given chloroquine (18·0 h [range 6·0-48·0] vs 24·0 h [6·0-60·0]; p<0·0001), with faster clearance of ring stages in the artesunate-mefloquine group (mean time to 50% clearance of baseline parasites 8·6 h [95% CI 7·9-9·4] vs 13·8 h [12·1-15·4]; p<0·0001). Risk of anaemia within 28 days was lower in patients in the artesunate-mefloquine group (71 [62%; 95% CI 52·2-70·6]) than in those in the chloroquine group (83 [75%; 65·6-82·5]; p=0·035). Gametocytaemia as detected by PCR for pks25 was present in 44 (86%) of 51 patients in the artesunate-mefloquine group and 41 (84%) of 49 patients in the chloroquine group at baseline, and in three (6%) of 49 patients and two (4%) of 48 patients, respectively, at day 7. Fever clearance was faster in the artesunate-mefloquine group (mean 11·5 h [95% CI 8·3-14·6]) than in the chloroquine group (14·8 h [11·7-17·8]; p=0·034). Bed occupancy was 2426 days per 1000 patients in the artesunate-mefloquine group versus 2828 days per 1000 patients in the chloroquine group (incidence rate ratio 0·858 [95% CI 0·812-0·906]; p<0·0001). One (<1%) patient in the artesunate-mefloquine group had a serious neuropsychiatric event regarded as probably related to study drug.
INTERPRETATION: Artesunate-mefloquine is highly efficacious for treatment of uncomplicated P knowlesi malaria. The rapid therapeutic response of the drug offers significant advantages compared with chloroquine monotherapy and supports a unified treatment policy for artemisinin-based combination therapy for all Plasmodium species in co-endemic areas.
FUNDING: Malaysian Ministry of Health, Australian National Health and Medical Research Council, and Asia Pacific Malaria Elimination Network.
Fulltext Effectiveness of blood flow restricted exercise compared with standard exercise in patients with recurrent low back pain: study protocol for a randomized controlled trial

Amano S, Ludin AF, Clift R, Nakazawa M, Law TD, Rush LJ, et al.

Trials, 2016;17:81.
PMID: 26867541 DOI: 10.1186/s13063-016-1214-7

Low back pain is a highly prevalent condition in the United States and has a staggeringly negative impact on society in terms of expenses and disability. It has previously been suggested that rehabilitation strategies for persons with recurrent low back pain should be directed to the medial back muscles as these muscles provide functional support of the lumbar region. However, many individuals with low back pain cannot safely and effectively induce trunk muscle adaptation using traditional high-load resistance exercise, and no viable low-load protocols to induce trunk extensor muscle adaptation exist. Herein, we present the study protocol for a randomized controlled trial that will investigate the "cross-transfer" of effects of a novel exercise modality, blood flow restricted exercise, on cross-sectional area (primary outcome), strength and endurance (secondary outcomes) of trunk extensor muscles, as well as the pain, disability, and rate of recurrence of low back pain (tertiary outcomes).
Fulltext Reduced circulating dendritic cells in acute Plasmodium knowlesi and Plasmodium falciparum malaria despite elevated plasma Flt3 ligand levels

Loughland JR, Woodberry T, Oyong D, Piera KA, Amante FH, Barber BE, et al.

Malar J, 2021 Feb 16;20(1):97.
PMID: 33593383 DOI: 10.1186/s12936-021-03642-0

BACKGROUND: Plasmodium falciparum malaria increases plasma levels of the cytokine Fms-like tyrosine kinase 3 ligand (Flt3L), a haematopoietic factor associated with dendritic cell (DC) expansion. It is unknown if the zoonotic parasite Plasmodium knowlesi impacts Flt3L or DC in human malaria. This study investigated circulating DC and Flt3L associations in adult malaria and in submicroscopic experimental infection.
METHODS: Plasma Flt3L concentration and blood CD141+ DC, CD1c+ DC and plasmacytoid DC (pDC) numbers were assessed in (i) volunteers experimentally infected with P. falciparum and in Malaysian patients with uncomplicated (ii) P. falciparum or (iii) P. knowlesi malaria.
RESULTS: Plasmodium knowlesi caused a decline in all circulating DC subsets in adults with malaria. Plasma Flt3L was elevated in acute P. falciparum and P. knowlesi malaria with no increase in a subclinical experimental infection. Circulating CD141+ DCs, CD1c+ DCs and pDCs declined in all adults tested, for the first time extending the finding of DC subset decline in acute malaria to the zoonotic parasite P. knowlesi.
CONCLUSIONS: In adults, submicroscopic Plasmodium infection causes no change in plasma Flt3L but does reduce circulating DCs. Plasma Flt3L concentrations increase in acute malaria, yet this increase is insufficient to restore or expand circulating CD141+ DCs, CD1c+ DCs or pDCs. These data imply that haematopoietic factors, yet to be identified and not Flt3L, involved in the sensing/maintenance of circulating DC are impacted by malaria and a submicroscopic infection. The zoonotic P. knowlesi is similar to other Plasmodium spp in compromising DC in adult malaria.
Fulltext Sensitive Detection of Plasmodium vivax Using a High-Throughput, Colourimetric Loop Mediated Isothermal Amplification (HtLAMP) Platform: A Potential Novel Tool for Malaria Elimination

Britton S, Cheng Q, Grigg MJ, Poole CB, Pasay C, William T, et al.

PLoS Negl Trop Dis, 2016 Feb;10(2):e0004443.
PMID: 26870958 DOI: 10.1371/journal.pntd.0004443

INTRODUCTION: Plasmodium vivax malaria has a wide geographic distribution and poses challenges to malaria elimination that are likely to be greater than those of P. falciparum. Diagnostic tools for P. vivax infection in non-reference laboratory settings are limited to microscopy and rapid diagnostic tests but these are unreliable at low parasitemia. The development and validation of a high-throughput and sensitive assay for P. vivax is a priority.
METHODS: A high-throughput LAMP assay targeting a P. vivax mitochondrial gene and deploying colorimetric detection in a 96-well plate format was developed and evaluated in the laboratory. Diagnostic accuracy was compared against microscopy, antigen detection tests and PCR and validated in samples from malaria patients and community controls in a district hospital setting in Sabah, Malaysia.
RESULTS: The high throughput LAMP-P. vivax assay (HtLAMP-Pv) performed with an estimated limit of detection of 1.4 parasites/ μL. Assay primers demonstrated cross-reactivity with P. knowlesi but not with other Plasmodium spp. Field testing of HtLAMP-Pv was conducted using 149 samples from symptomatic malaria patients (64 P. vivax, 17 P. falciparum, 56 P. knowlesi, 7 P. malariae, 1 mixed P. knowlesi/P. vivax, with 4 excluded). When compared against multiplex PCR, HtLAMP-Pv demonstrated a sensitivity for P. vivax of 95% (95% CI 87-99%); 61/64), and specificity of 100% (95% CI 86-100%); 25/25) when P. knowlesi samples were excluded. HtLAMP-Pv testing of 112 samples from asymptomatic community controls, 7 of which had submicroscopic P. vivax infections by PCR, showed a sensitivity of 71% (95% CI 29-96%; 5/7) and specificity of 93% (95% CI87-97%; 98/105).
CONCLUSION: This novel HtLAMP-P. vivax assay has the potential to be a useful field applicable molecular diagnostic test for P. vivax infection in elimination settings.
Fulltext Liver Function Test Abnormalities in Experimental and Clinical Plasmodium vivax Infection

Odedra A, Webb L, Marquart L, Britton LJ, Chalon S, Moehrle JJ, et al.

Am J Trop Med Hyg, 2020 11;103(5):1910-1917.
PMID: 32815508 DOI: 10.4269/ajtmh.20-0491

Liver transaminase elevations after treatment in malaria volunteer infection studies (VISs) have raised safety concerns. We investigated transaminase elevations from two human Plasmodium vivax VISs where subjects were treated with chloroquine (n = 24) or artefenomel (n = 8) and compared them with studies in Thailand (n = 41) and Malaysia (n = 76). In the VISs, alanine transaminase (ALT) increased to ≥ 2.5 × upper limit of normal (ULN) in 11/32 (34%) volunteers, peaking 5-8 days post-treatment. Transaminase elevations were asymptomatic, were not associated with elevated bilirubin, and resolved by day 42. The risk of an ALT ≥ 2.5 × ULN increased more than 4-fold (odds ratio [OR] 4.28; 95% CI: 1.26-14.59; P = 0.02) for every log10 increase in the parasite clearance burden (PCB), defined as the log-fold reduction in parasitemia 24 hours post-treatment. Although an elevated ALT ≥ 2.5 × ULN was more common after artefenomel than after chloroquine (5/8 [63%] versus 6/24 [25%]; OR 5.0; 95% CI: 0.91-27.47; P = 0.06), this risk disappeared when corrected for PCB. Peak ALT also correlated with peak C-reactive protein (R = 0.44; P = 0.012). Elevations in ALT (≥ 2.5 × ULN) were less common in malaria-endemic settings, occurring in 1/41 (2.5%) Thai patients treated with artefenomel, and in none of 76 Malaysians treated with chloroquine or artemisinin combination therapy. Post-treatment transaminase elevations are common in experimental P. vivax infection but do not appear to impact on participant safety. Although the mechanism of these changes remains uncertain, host inflammatory response to parasite clearance may be contributory.
Efficient Semipolar (11-22) 550 nm Yellow/Green InGaN Light-Emitting Diodes on Low Defect Density (11-22) GaN/Sapphire Templates

Li H, Khoury M, Bonef B, Alhassan AI, Mughal AJ, Azimah E, et al.

ACS Appl Mater Interfaces, 2017 Oct 18;9(41):36417-36422.
PMID: 28960058 DOI: 10.1021/acsami.7b11718

We demonstrate efficient semipolar (11-22) 550 nm yellow/green InGaN light-emitting diodes (LEDs) with In0.03Ga0.97N barriers on low defect density (11-22) GaN/patterned sapphire templates. The In0.03Ga0.97N barriers were clearly identified, and no InGaN clusters were observed by atom probe tomography measurements. The semipolar (11-22) 550 nm InGaN LEDs (0.1 mm2 size) show an output power of 2.4 mW at 100 mA and a peak external quantum efficiency of 1.3% with a low efficiency drop. In addition, the LEDs exhibit a small blue-shift of only 11 nm as injection current increases from 5 to 100 mA. These results suggest the potential to produce high efficiency semipolar InGaN LEDs with long emission wavelength on large-area sapphire substrates with economical feasibility.

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