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Primaquine for radical cure of Plasmodium vivax malaria poses a potentially life-threatening risk of haemolysis in G6PD-deficient patients. Herein, we review five events of acute haemolytic anaemia following the administration of primaquine in four malaria trials from Indonesia, the Solomon Islands, and Vietnam. Five males aged 9 to 48 years were improperly classified as G6PD-normal by various screening procedures and included as subjects in trials of anti-relapse therapy with daily primaquine. Routine safety monitoring by physical examination, urine inspection, and blood haemoglobin (Hb) assessment were performed in all those trials. Early signs of acute haemolysis, i.e., dark urine and haemoglobin drop >20%, occurred only after day 3 and as late as day 8 of primaquine dosing. All patients were hospitalized and fully recovered, all but one following blood transfusion rescue. Hb nadir was 4.7 to 7.9 g/dL. Hospitalization was for 1 to 7 days. Hb levels returned to baseline values 3 to 10 days after transfusion. Failed G6PD screening procedures in these trials led G6PD-deficient patients to suffer harmful exposures to primaquine. The safe application of primaquine anti-relapse therapy requires G6PD screening and anticipation of its failure with a means of prompt detection and rescue from the typically abrupt haemolytic crisis. [ABSTRACT FROM AUTHOR]

Objectives: To compare outpatient attendance rates for Aboriginal and Torres Strait Islander ('Aboriginal') and non-Aboriginal patients at a large metropolitan health service in Melbourne, Australia, and to describe the barriers and enablers experienced by urban-dwelling Aboriginal patients in attending hospital outpatient appointments. Methods: This study used a mixed-method approach. Proportions of referred patients who booked and attended outpatient appointments were extracted from a health service database. Aboriginal versus non-Aboriginal cohorts were compared using chi-squared tests. Eleven patients, one parent of a patient and two community nurses were interviewed by telephone to investigate perceived barriers and enablers to attending outpatient appointments among Aboriginal patients. Results: Outpatient referrals were greater among Aboriginal than non-Aboriginal people; however, referrals were significantly less likely to result in an outpatient clinic booking and attendance for Aboriginal compared to non-Aboriginal people. Interview participants reported several barriers to attending appointments, related to logistical, quality of care and cultural factors. Suggested facilitators to make appointment attendance easier included: provision of transport support, improving clinic scheduling, utilising a variety of appointment reminder formats, providing food in waiting rooms, flexible appointment timing options, outreach services, access to Aboriginal support workers, improving communication and relationships with Aboriginal people, cultural awareness training for staff and the provision of culturally appropriate spaces. Conclusion: Some barriers faced by Aboriginal patients in attending hospital outpatient appointments in urban areas can be addressed through implementation of enablers suggested by participants. Data have informed the development of a tailored, inclusive, culturally and consumer-focused appropriate hospital outpatient service model of care. What is known about the topic? Health outcomes are poorer and burden of disease greater among Aboriginal and Torres Strait Islander people than non-Aboriginal and Torres Strait Islander people. What does this paper add? Compared to non-Aboriginal and Torres Strait Islander people, among Aboriginal and Torres Strait Islander people in urban settings, more outpatient referrals are made, but these referrals are significantly less likely to result in an outpatient clinic booking and attendance. Barriers and enablers to urban-dwelling Aboriginal and Torres Strait Islander people attending outpatient hospital appointments relate to logistical, quality of care and cultural factors. What are the implications for practitioners? Identifying and understanding the barriers and enablers to healthcare access for urban-dwelling Aboriginal and Torres Strait Islander people provides a foundation on which practitioners and organisations can facilitate urban hospital outpatient service development, with the aim to better support healthcare engagement and appointment attendance. [ABSTRACT FROM AUTHOR]

Background and Aims: A relationship between diabetes, glucose and COVID‐19 outcomes has been reported in international cohorts. This study aimed to assess the relationship between diabetes, hyperglycaemia and patient outcomes in those hospitalised with COVID‐19 during the first year of the Victorian pandemic prior to novel variants and vaccinations. Design, setting: Retrospective cohort study from March to November 2020 across five public health services in Melbourne, Australia. Participants: All consecutive adult patients admitted to acute wards of participating institutions during the study period with a diagnosis of COVID‐19, comprising a large proportion of patients from residential care facilities and following dexamethasone becoming standard‐of‐care. Admissions in patients without known diabetes and without inpatient glucose testing were excluded. Results: The DINGO COVID‐19 cohort comprised 840 admissions. In 438 admissions (52%), there was no known diabetes or in‐hospital hyperglycaemia, in 298 (35%) patients had known diabetes, and in 104 (12%) patients had hyperglycaemia without known diabetes. ICU admission was more common in those with diabetes (20%) and hyperglycaemia without diabetes (49%) than those with neither (11%, P < 0.001 for all comparisons). Mortality was higher in those with diabetes (24%) than those without diabetes or hyperglycaemia (16%, P = 0.02) but no difference between those with in‐hospital hyperglycaemia and either of the other groups. On multivariable analysis, hyperglycaemia was associated with increased ICU admission (adjusted odds ratio (aOR) 6.7, 95% confidence interval (95% CI) 4.0–12, P < 0.001) and longer length of stay (aOR 173, 95% CI 11–2793, P < 0.001), while diabetes was associated with reduced ICU admission (aOR 0.55, 95% CI 0.33–0.94, P = 0.03). Neither diabetes nor hyperglycaemia was independently associated with in‐hospital mortality. Conclusions: During the first year of the COVID‐19 pandemic, in‐hospital hyperglycaemia and known diabetes were not associated with in‐hospital mortality, contrasting with published international experiences. This likely mainly relates to hyperglycaemia indicating receipt of mortality‐reducing dexamethasone therapy. These differences in published experiences underscore the importance of understanding population and clinical treatment factors affecting glycaemia and COVID‐19 morbidity within both local and global contexts. [ABSTRACT FROM AUTHOR]

Purpose: To assess the association of mobility deterioration during community-acquired pneumonia (CAP) illness on length of stay (LOS), readmissions, and institutional costs. Methods: This longitudinal observational study included 347 individuals hospitalized with CAP. All were offered routine early mobilization with a physiotherapist within 24 hours of admission and then daily during hospital stay. The exposure of interestwas mobility status at time of clinical stability when compared with the premorbid level. Modelling adjusted for factors such as age, residential status, premorbidmobility level, comorbidities, and pneumonia severity. Results: One hundred forty-one (41%) individuals met the definition of mobility deterioration during the acute illness. The mean (95% confidence interval [CI]) time from achievement of clinical stability to hospital discharge for the groups with and without mobility deterioration was 5.7 (4.2-7.2) and 2.3 (1.4-3.2) days, respectively, with associated higher hospitalization costs (arithmetic mean ratio [95% CI] 1.61 [1.24-2.10]) in the mobility deterioration group. There was no evidence of an association betweenmobility deterioration and 90-day readmission (odds ratio [95%CI]: 1.34 [0.81-2.24]). Conclusions: Mobility deterioration during acute pneumonia illness has a significant impact on hospital LOS and resource use even in a hospital system that has an early mobility program. Further research is needed to investigate these associations and alternative interventions. Trial registration: ClinicalTrials.gov, Identifier: NCT02835040. [ABSTRACT FROM AUTHOR]

Background: The effect of workflow factors, such as timing of admission and changes in treating team, on patient outcomes remains inconclusive. Aims: To investigate the impact of weekend admission and changes in treating team on four pre‐defined outcomes in patients admitted to hospital with community‐acquired pneumonia (CAP). Methods: We performed an observational cohort study by utilising prospective longitudinal data collected during the IMPROVE‐GAP trial, a stepped‐wedge randomised study investigating an evidence‐based bundle of care in the management of CAP. We assessed the effect of two exposure variables, day of admission and change of treating team, on four pre‐specified outcomes: (i) length of stay; (ii) time to clinical stability; (iii) readmission within 30 days; and (iv) mortality at 30 days. Our analysis was restricted to patients with a primary diagnosis of CAP and employed multivariable Cox regression and logistic regression to adjust for potential measured confounders. Results: Of 753 participants, 224 (29.7%) were admitted on the weekend and 71 (9.4%) changed treating team during admission. Weekend admissions had significantly longer hospital stays than weekday admissions (hazard ratio (95% confidence interval; P‐value) 0.82 (0.70–0.98; 0.03)) and took longer to reach clinical stability (0.80 (0.68–0.95; 0.01)). Change of treating team doubled the odds of readmission at 30 days (odds ratio 1.95 (1.08–3.58; 0.03)). Conclusions: These results suggest workflow factors can negatively impact both health service and patient outcomes. Systems interventions aimed at improving out of hours service and reducing changes in treating team should be considered. [ABSTRACT FROM AUTHOR]

Soil-transmitted helminths, such as roundworms (Ascaris lumbricoides), whipworms (Trichuris trichiura) and hookworms (Necator americanus and Ancylostoma spp.), are gastrointestinal parasites that occur predominantly in low- to middle-income countries worldwide and disproportionally impact children. Depending on the STH species, health status of the host and infection intensity, direct impacts of these parasites include malnutrition, anaemia, diarrhoea and physical and cognitive stunting. The indirect consequences of these infections are less well understood. Specifically, gastrointestinal infections may exert acute or chronic impacts on the natural gut microfauna, leading to increased risk of post-infectious gastrointestinal disorders, and reduced gut and overall health through immunomodulating mechanisms. To date a small number of preliminary studies have assessed the impact of helminths on the gut microbiome, but these studies are conflicting. Here, we assessed STH burden in 273 pre-school and school-aged children in Tha Song Yang district, Tak province, Thailand receiving annual oral mebendazole treatment. Ascaris lumbricoides (107/273) and Trichuris trichiura (100/273) were the most prevalent species and often occurred as co-infections (66/273). Ancylostoma ceylanicum was detected in a small number of children as well (n = 3). All of these infections were of low intensity (<4,999 or 999 eggs per gram for Ascaris and Trichuris respectively). Using this information, we characterised the baseline gut microbiome profile and investigated acute STH-induced alterations, comparing infected with uninfected children at the time of sampling. We found no difference between these groups in bacterial alpha-diversity, but did observe differences in beta-diversity and specific differentially abundant OTUs, including increased Akkermansia muciniphila and Bacteroides coprophilus, and reduced Bifidobacterium adolescentis, each of which have been previously implicated in STH-associated changes in the gut microfauna. Author summary: Soil-transmitted helminth infections exhibit a significant negative impact on population health worldwide. In particular in endemic regions sub-groups such as children suffer disproportionally from infection due to impoverished living conditions. Yet many of these regions have no or limited availability of infection prevalence data to inform intervention strategies. Application of low sensitivity diagnostic tools such as microscopy exacerbate this issue. Moving towards molecular tools is key in order to establish a more accurate and complete epidemiological profile that can serve as a reference standard for future studies. Recently, a number of studies investigated the microbiota as an important factor determining overall patient health. The gut microbiota can be altered through medication, lifestyle factors and co-inhabitation of the same environmental niche with STHs. However, these microbiota studies often lack a characterised baseline. The current study provides baseline epidemiology data for a cohort of pre-school and school-age Thai children using a molecular diagnostic technique. We estimate the STH infection prevalence and intensity and characterise the host gut microbiota profile at a single cross-sectional timepoint comparing infected with uninfected children. This data can serve as a starting point for future studies investigating the impact of environmental factors and parasitic infections on patient health. [ABSTRACT FROM AUTHOR]

Abstract Background Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy.

Background: There is a high risk of Plasmodium vivax parasitaemia following treatment of falciparum malaria. Our study aimed to quantify this risk and the associated determinants using an individual patient data meta-analysis in order to identify populations in which a policy of universal radical cure, combining artemisinin-based combination therapy (ACT) with a hypnozoitocidal antimalarial drug, would be beneficial.Methods and Findings: A systematic review of Medline, Embase, Web of Science, and the Cochrane Database of Systematic Reviews identified efficacy studies of uncomplicated falciparum malaria treated with ACT that were undertaken in regions coendemic for P. vivax between 1 January 1960 and 5 January 2018. Data from eligible studies were pooled using standardised methodology. The risk of P. vivax parasitaemia at days 42 and 63 and associated risk factors were investigated by multivariable Cox regression analyses. Study quality was assessed using a tool developed by the Joanna Briggs Institute. The study was registered in the International Prospective Register of Systematic Reviews (PROSPERO: CRD42018097400). In total, 42 studies enrolling 15,341 patients were included in the analysis, including 30 randomised controlled trials and 12 cohort studies. Overall, 14,146 (92.2%) patients had P. falciparum monoinfection and 1,195 (7.8%) mixed infection with P. falciparum and P. vivax. The median age was 17.0 years (interquartile range [IQR] = 9.0-29.0 years; range = 0-80 years), with 1,584 (10.3%) patients younger than 5 years. 2,711 (17.7%) patients were treated with artemether-lumefantrine (AL, 13 studies), 651 (4.2%) with artesunate-amodiaquine (AA, 6 studies), 7,340 (47.8%) with artesunate-mefloquine (AM, 25 studies), and 4,639 (30.2%) with dihydroartemisinin-piperaquine (DP, 16 studies). 14,537 patients (94.8%) were enrolled from the Asia-Pacific region, 684 (4.5%) from the Americas, and 120 (0.8%) from Africa. At day 42, the cumulative risk of vivax parasitaemia following treatment of P. falciparum was 31.1% (95% CI 28.9-33.4) after AL, 14.1% (95% CI 10.8-18.3) after AA, 7.4% (95% CI 6.7-8.1) after AM, and 4.5% (95% CI 3.9-5.3) after DP. By day 63, the risks had risen to 39.9% (95% CI 36.6-43.3), 42.4% (95% CI 34.7-51.2), 22.8% (95% CI 21.2-24.4), and 12.8% (95% CI 11.4-14.5), respectively. In multivariable analyses, the highest rate of P. vivax parasitaemia over 42 days of follow-up was in patients residing in areas of short relapse periodicity (adjusted hazard ratio [AHR] = 6.2, 95% CI 2.0-19.5; p = 0.002); patients treated with AL (AHR = 6.2, 95% CI 4.6-8.5; p < 0.001), AA (AHR = 2.3, 95% CI 1.4-3.7; p = 0.001), or AM (AHR = 1.4, 95% CI 1.0-1.9; p = 0.028) compared with DP; and patients who did not clear their initial parasitaemia within 2 days (AHR = 1.8, 95% CI 1.4-2.3; p < 0.001). The analysis was limited by heterogeneity between study populations and lack of data from very low transmission settings. Study quality was high.Conclusions: In this meta-analysis, we found a high risk of P. vivax parasitaemia after treatment of P. falciparum malaria that varied significantly between studies. These P. vivax infections are likely attributable to relapses that could be prevented with radical cure including a hypnozoitocidal agent; however, the benefits of such a novel strategy will vary considerably between geographical areas. [ABSTRACT FROM AUTHOR]

The article focuses on how the antimalarial chloroquine and its rheumatological counterpart hydroxychloroquine were adapted against severe acute respiratory syndrome coronavirus 2. It mentions the use of hydroxychloroquine received widespread media attention. It also mentions that existing knowledge of chloroquine's pharmacokinetic and safety profile suggested high-toxicity risks.

Objective: To evaluate the safety and feasibility of vestibular physiotherapy in the ED, and its impact on adherence to evidence‐based clinical practice. Methods: This prospective pre‐post implementation study of adults presenting with dizziness symptoms of potential vestibular aetiology measured the proportion of participants safely completing vestibular physiotherapy assessment and treatment. Results: A total of 52 participants were recruited (20 usual care and 32 vestibular physiotherapy). Thirty (93.8%) of 32 completed all components of physiotherapy assessment, and there were no adverse events recorded. Conclusion: The results of the present study support extending the role of physiotherapists to managing peripheral vestibular dysfunction in the ED. [ABSTRACT FROM AUTHOR]

Lead poisoning is an uncommon and challenging diagnosis to make. In 2018, The Victorian Department of Health issued a health warning following four cases of lead poisoning associated with illicit opium use in Melbourne, Australia. We present these cases to highlight clinical features and the relevant investigations leading to diagnosis. All cases occurred in recent immigrants to Australia, who had access to non‐traditional sources of opioids. Health care professionals should consider lead poisoning in patients with appropriate symptoms and a history of illicit opium use. [ABSTRACT FROM AUTHOR]

Background: Artemisinin-based combination therapy (ACT) is recommended for uncomplicated Plasmodium vivax malaria in areas of emerging chloroquine resistance. We undertook a systematic review and individual patient data meta-analysis to compare the efficacies of dihydroartemisinin-piperaquine (DP) and artemether-lumefantrine (AL) with or without primaquine (PQ) on the risk of recurrent P. vivax.Methods and Findings: Clinical efficacy studies of uncomplicated P. vivax treated with DP or AL and published between January 1, 2000, and January 31, 2018, were identified by conducting a systematic review registered with the International Prospective Register of Systematic Reviews (PROSPERO): CRD42016053310. Investigators of eligible studies were invited to contribute individual patient data that were pooled using standardised methodology. The effect of mg/kg dose of piperaquine/lumefantrine, ACT administered, and PQ on the rate of P. vivax recurrence between days 7 and 42 after starting treatment were investigated by Cox regression analyses according to an a priori analysis plan. Secondary outcomes were the risk of recurrence assessed on days 28 and 63. Nineteen studies enrolling 2,017 patients were included in the analysis. The risk of recurrent P. vivax at day 42 was significantly higher in the 384 patients treated with AL alone (44.0%, 95% confidence interval [CI] 38.7-49.8) compared with the 812 patients treated with DP alone (9.3%, 95% CI 7.1-12.2): adjusted hazard ratio (AHR) 12.63 (95% CI 6.40-24.92), p < 0.001. The rates of recurrence assessed at days 42 and 63 were associated inversely with the dose of piperaquine: AHRs (95% CI) for every 5-mg/kg increase 0.63 (0.48-0.84), p = 0.0013 and 0.83 (0.73-0.94), p = 0.0033, respectively. The dose of lumefantrine was not significantly associated with the rate of recurrence (1.07 for every 5-mg/kg increase, 95% CI 0.99-1.16, p = 0.0869). In a post hoc analysis, in patients with symptomatic recurrence after AL, the mean haemoglobin increased 0.13 g/dL (95% CI 0.01-0.26) for every 5 days that recurrence was delayed, p = 0.0407. Coadministration of PQ reduced substantially the rate of recurrence assessed at day 42 after AL (AHR = 0.20, 95% CI 0.10-0.41, p < 0.001) and at day 63 after DP (AHR = 0.08, 95% CI 0.01-0.70, p = 0.0233). Results were limited by follow-up of patients to 63 days or less and nonrandomised treatment groups.Conclusions: In this study, we observed the risk of P. vivax recurrence at day 42 to be significantly lower following treatment with DP compared with AL, reflecting the longer period of post-treatment prophylaxis; this risk was reduced substantially by coadministration with PQ. We found that delaying P. vivax recurrence was associated with a small but significant improvement in haemoglobin. These results highlight the benefits of PQ radical cure and also the provision of blood-stage antimalarial agents with prolonged post-treatment prophylaxis. [ABSTRACT FROM AUTHOR]

Background: The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations.Methods and Findings: A search in PubMed, Embase, ClinicalTrials.gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing <15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7.Conclusions: Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment. [ABSTRACT FROM AUTHOR]

Abstract: Background: Diabetes mellitus in hospital inpatients is most commonly present as a comorbidity rather than as the primary diagnosis. In some hospitals, the prevalence of comorbid diabetes mellitus across all inpatients exceeds 30%, which could add to complexity of care and resource utilisation. However, whether and to what extent comorbid diabetes mellitus contributes indirectly to greater hospitalisation costs is ill‐defined. Aim: To determine the attributable effect of comorbid diabetes mellitus on hospital resource utilisation in a General Internal Medical service in Melbourne, Australia. Methods: We extracted data from a database of all General Internal Medical discharge episodes from July 2012 to June 2013. We fitted multivariable regression models to compare patients with diabetes mellitus to those without diabetes mellitus with respect to hospitalisation cost, length of stay, admissions per year and inpatient mortality. Results: Of 4657 patients 1519 (33%) had diabetes mellitus, for whom average hospitalisation cost (AUD9910) was higher than those without diabetes mellitus (AUD7805). In multivariable analysis, this corresponded to a 1.22‐fold (95% confidence interval (CI) 1.12–1.33, P < 0.001) higher cost. Mean length of stay for those with diabetes was 8.2 days versus 6.8 days for those without diabetes, with an adjusted 1.19‐fold greater odds (95% CI 1.06–1.33, P = 0.001) of staying an additional day. Number of admissions and mortality were similar. Conclusion: Comorbid diabetes mellitus adds significantly to hospitalisation duration and costs in medical inpatients. Moreover, diabetes mellitus patients with chronic complications had a greater‐still cost and hospitalisation duration compared to those without diabetes mellitus. [ABSTRACT FROM AUTHOR]

The human malaria parasite Plasmodium vivax is more resistant to malaria control strategies than Plasmodium falciparum, and maintains high genetic diversity even when transmission is low. To investigate whether declining P. vivax transmission leads to increasing population structure that would facilitate elimination, we genotyped samples from across the Southwest Pacific region, which experiences an eastward decline in malaria transmission, as well as samples from two time points at one site (Tetere, Solomon Islands) during intensified malaria control. Analysis of 887 P. vivax microsatellite haplotypes from hyperendemic Papua New Guinea (PNG, n = 443), meso-hyperendemic Solomon Islands (n = 420), and hypoendemic Vanuatu (n = 24) revealed increasing population structure and multilocus linkage disequilibrium yet a modest decline in diversity as transmission decreases over space and time. In Solomon Islands, which has had sustained control efforts for 20 years, and Vanuatu, which has experienced sustained low transmission for many years, significant population structure was observed at different spatial scales. We conclude that control efforts will eventually impact P. vivax population structure and with sustained pressure, populations may eventually fragment into a limited number of clustered foci that could be targeted for elimination. [ABSTRACT FROM AUTHOR]

Objectives: The majority of healthcare costs accrued managing cellulitis can be attributed to the small proportion of patients treated with parenteral antibiotics. Hospital in the home (HITH) instead of or following initial inpatient treatment is a safe and effective alternative, but there are few data evaluating its cost-effectiveness for cellulitis.Patients and Methods: Our retrospective cohort study included all treatment episodes (by either HITH or an inpatient service for >24 h) with an ICD-10 primary diagnosis code of lower-leg cellulitis at a tertiary-level health service in Melbourne, Australia over 12 months (2012-13). Data included demography, social factors and ICD-10 codes mapped to major comorbidities constituting the Charlson comorbidity index (CCI). Differences in length of stay (LOS) and individual clinical costing (ICC) between HITH- and non-HITH-treated patients were tested with univariable and multivariable (generalized linear model) analyses.Results: For 328 admissions in 294 patients, the average per-day costs were AU$431 for HITH and AU$761 for inpatient care. For 124 patients (38%) treated in HITH, both LOS [mean (95% CI) 7.48 days (6.76-8.20 days) versus 5.82 days (3.45-8.18 days)] and ICC [mean (95% CI) AU$5873 (AU$5212-AU$6534) versus AU$5196 (AU$4567- AU$5824)] were higher than those for patients with solely inpatient care. In multivariable analysis controlling for age, comorbidity, carer support and language, HITH remained associated with significantly longer LOS [1.63-fold (95% CI: 1.24- to 2.13-fold): P < 0.001] and non-significantly with higher cost [1.14-fold (95% CI: 0.97- to 1.34-fold): P = 0.11].Conclusions: Management of cellulitis represents a substantial cost burden for hospital services. Modest per-day cost savings from HITH can be offset by much longer HITH LOS. [ABSTRACT FROM AUTHOR]

Background: Drug resistance remains a major obstacle to malaria treatment and control. It can arise and spread rapidly, and vary substantially even at sub-national level. National malaria programmes require cost-effective and timely ways of characterizing drug-resistance at multiple sites within their countries. Methods: An improved multiplexed post-PCR ligase detection reaction-fluorescent microsphere assay (LDR-FMA) was used to simultaneously determine the presence of mutations in chloroquine resistance transporter (crt), multidrug resistance 1 (mdr1), dihydrofolate reductase (dhfr) and dihydropteroate synthase (dhps) genes in Plasmodium falciparum (n = 727) and Plasmodium vivax (n = 574) isolates collected in 2006 from cross-sectional community population surveys in two geographically distinct regions (Madang and East Sepik) of Papua New Guinea (PNG) where strong regional differences in in vivo aminoquinoline and antifolate therapeutic efficacy had previously been observed. Data were compared to those of a follow-up survey conducted in 2010. Results: Despite some very low parasite densities, the assay successfully amplified all P. falciparum and P. vivax loci in 77 and 69 % of samples, respectively. In 2006, prevalences of pfdhfr (59R-108 N) double mutation/wild type pfdhps haplotype, pfcrt SVMNT haplotype (72S-76T double mutation), and 86Y pfmdr1 mutation all exceeded 90 %. For P. vivax, 65 % carried at least two pvdhfr mutations, 97 % the 647P pvdhps mutation and 54 % the 976F pvmdr1 mutation. Prevalence of mutant haplotypes was higher in Madang than East Sepik for pfcrt SVMNT (97.4 vs 83.3 %, p = 0.001), pfdhfr (59R-108 N) (100 vs 90.6 %, p = 0.001), pvdhfr haplotypes (75.8 vs 47.6 %, p = 0.001) and pvmdr1 976F (71.2 vs 26.2 %, p < 0.001). Data from a subsequent Madang survey in 2010 showed that the prevalence of pfdhps mutations increased significantly from <5 % to >30 % (p < 0.001) as did the prevalence of pvdhfr mutant haplotypes (from 75.8 to 97.4 %, p = 0.012). Conclusions: This LDR-FMA multiplex platform shows feasibility for low-cost, high-throughput, rapid characterization of a broad range of drug-resistance markers in low parasitaemia infections. Significant geographical differences in mutation prevalence correlate with previous genotyping surveys and in vivo trials and may reflect variable drug pressure and differences in health-care access in these two PNG populations. [ABSTRACT FROM AUTHOR]

The discovery and development of the artemisinin class of antimalarial drugs is one of the great recent success stories of global health. However, after at least two decades of successful use, resistance has finally emerged and appears to be spreading rapidly throughout South-East Asia in spite of our best efforts at containment. If this were also to occur in Africa, it would have disastrous implications for the continent subject to the world's greatest burden of Plasmodium falciparum. The earliest indications of incipient artemisinin resistance may be a slowing of the rate at which parasites are cleared from the blood following treatment. The Worldwide Antimalarial Resistance Network have analysed data from 29,493 patients from 84 clinical trials in order to define the nature and determinants of early parasite clearance following artemisinin-based treatment in African populations. In doing so, they lay the foundation for systems intended to enable the earliest possible detection of emerging artemisinin resistance in Africa. Please see related article: http://www.biomedcentral.com/1741-7015/13/212. [ABSTRACT FROM AUTHOR]

Background: Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking. Methods and Findings: We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%). The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P = 0.001); one child died (3.7%). The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P = 0.003 vs falciparum malaria). Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO). Conclusions: The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at ≤70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence. Methodology/Principal Findings: As part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002. Conclusions/Significance: SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities. Author Summary: Subacute sclerosing panencephalitis (SSPE) is a disabling and usually fatal brain disorder that typically occurs 3–10 years after acute measles infection. Papua New Guinea (PNG) has particularly high rates of SSPE. We report 22 cases of PNG children presenting to the provincial referral hospital in Madang Province who probably contracted acute measles when <12 months of age during a national epidemic in 2002 and who developed SSPE 5–7 years later. Based on these cases, the estimated annual SSPE incidence in Madang province in 2007–2009 was 54/million population aged <20 years. Four sub-districts had an annual incidence >100/million population aged <20 years, the highest rates ever reported. Young PNG children do not respond well to measles vaccine. Because of this, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune older people surrounding the youngest and most vulnerable members of PNG communities. [ABSTRACT FROM AUTHOR]

Background: Rectal administration of artemisinin derivatives has potential for early treatment for severe malaria in remote settings where injectable antimalarial therapy may not be feasible. Preparations available include artesunate, artemisinin, artemether and dihydroartemisinin. However each may have different pharmacokinetic properties and more information is needed to determine optimal dose and comparative efficacy with each another and with conventional parenteral treatments for severe malaria. Methods: Individual patient data from 1167 patients in 15 clinical trials of rectal artemisinin derivative therapy (artesunate, artemisinin and artemether) were pooled in order to compare the rapidity of clearance of Plasmodium falciparum parasitaemia and the incidence of reported adverse events with each treatment. Data from patients who received comparator treatment (parenteral artemisinin derivative or quinine) were also included. Primary endpoints included percentage reductions in parasitaemia at 12 and 24 hours. A parasite reduction of >90% at 24 hours was defined as parasitological success. Results: Artemisinin and artesunate treatment cleared parasites more rapidly than parenteral quinine during the first 24 hours of treatment. A single higher dose of rectal artesunate treatment was five times more likely to achieve >90% parasite reductions at 24 hours than were multiple lower doses of rectal artesunate, or a single lower dose administration of rectal artemether. Conclusion: Artemisinin and artesunate suppositories rapidly eliminate parasites and appear to be safe. There are less data on artemether and dihydroartemisinin suppositories. The more rapid parasite clearance of single high-dose regimens suggests that achieving immediate high drug concentrations may be the optimal strategy. [ABSTRACT FROM AUTHOR]

To study the population pharmacokinetics of piperaquine after co-administration with dihydroartemisinin in uncomplicated malaria. The disposition of piperaquine was studied in 85 Cambodian patients with uncomplicated falciparum or vivax malaria treated with the piperaquine-dihydroartemisinin coformulation Artekin®. All patients were given Artekin® orally at 0, 6, 24 and 32 h with a total piperaquine dose of 32–35 mg base kg−1. Adults were given tablets while children received either tablets or a dispersible granule formulation. Patients underwent either intensive (17–19 samples) or sparse (2–5 samples) blood sampling schedules over 35 days and clinical/parasitological follow-up over > 28 days. Piperaquine in plasma was quantified by high performance liquid chromatography. All patients achieved fever clearance within 24 h and parasite clearance within 72 h. The 28-day cure rate was 97% in adults and 98% in children. A covariate-free two-compartment population model with first-order absorption and elimination gave the most robust representation of the plasma concentration-time data in both adults and children. In adults ( n = 38), the median (interquartile range) derived pharmacokinetic descriptors CL/ F, Vss/ F and t1/2,z were 0.9 l h−1 kg−1 (0.79–1.02 l h−1 kg−1), 574 l kg−1(371–711 l kg−1) and 23 days (19–28 days), respectively. In children ( n = 47), corresponding values were 1.8 l h−1 kg−1 (1.29–2.3 l h−1 kg−1), 614 l kg−1 (332–1205 l kg−1) and 14 days (10–18 days), respectively. Piperaquine is a highly lipid-soluble drug with a large Vss/ F, long t1/2,z and a clearance that is markedly higher in children than in adults. [ABSTRACT FROM AUTHOR]

To assess the haemodynamic, electrocardiographic and glycaemic effects of piperaquine-dihydroartemisinin (Artekin®) fixed combination therapy in uncomplicated malaria. Sixty-two Cambodians (32 children and 30 adults) with falciparum or vivax malaria were given Artekin ® given as four age-based oral doses over 32 h. Supine and erect blood pressure, the electrocardiographic QT interval and plasma glucose were measured before treatment and then at regular intervals during a 4-day admission period as part of efficacy and safety monitoring. QT intervals were rate-corrected (QTc) using Bazett's formula. Artekin® therapy was well tolerated and all patients responded to treatment. Average parasite and fever clearance times were 19 and 12 h, respectively. The pretreatment mean fall in systolic blood pressure on standing was 8 ± 6 mmHg and 6-hourly measurements over 72 h showed no significant change ( P = 0.48). There was a significant lengthening of the mean QTc to a maximum of 11 ms0.5 (95% confidence interval 4–18 ms0.5) relative to baseline at 24 h ( P = 0.003). The maximal QTc prolongation observed in any patient was 53 ms0.5. There was a mean 0.4 mmol l−1 reduction in the post-absorptive plasma glucose during the first 48 h but no episodes of hypoglycaemia (plasma glucose < 3.0 mmol l−1) were observed at any time. Artekin® is safe and effective combination therapy for uncomplicated malaria in children and adults. Although piperaquine is a long half-life drug related to other quinoline compounds including chloroquine and quinine, no clinically significant cardiovascular or metabolic effects were observed. [ABSTRACT FROM AUTHOR]

The article reports about the monkey malaria species, Plasmodium knowlesi (P. knowlesi), being capable of infecting humans and how the epidemiology of it is changing. Topics include how the geographic distribution reflects that of the definitive primate hosts, macaque monkeys, in which P. knowlesi prevalence is almost universal; and how the future human cases will remain restricted to a small ecological niche of people living in close proximity to monkey populations.