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Background: Favipiravir, an anti-influenza drug, has in vitro antiviral activity against SARS-CoV-2. Clinical trial evidence to date is inconclusive. Favipiravir has been recommended for the treatment of COVID-19 in some countries. Methods: In a multicentre open-label, randomised, controlled, adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomised to one of ten treatment arms including high dose oral favipiravir (3.6g on day 0 followed by 1.6g daily to complete 7 days treatment) or no study drug. The primary outcome assessed in a modified intention-to-treat population (mITT) was the rate of viral clearance (derived under a linear mixed-effects model from the daily log10 viral densities in standardised duplicate oropharyngeal swab eluates taken daily over 8 days [18 swabs per patient]). The safety population included all patients who received at least one dose of the allocated intervention. This ongoing adaptive platform trial is registered at ClinicalTrials.gov (NCT05041907). Results: In the final analysis, the mITT population contained data from 114 patients randomised to favipiravir and 126 patients randomised concurrently to no study drug. Under the linear mixed-effects model fitted to all oropharyngeal viral density estimates in the first 8 days from randomisation (4,318 swabs), there was no difference in the rate of viral clearance between patients administered favipiravir and patients receiving no study drug -1% (95% CI: -14 to 14% change). High dose favipiravir was well tolerated. Interpretation: Favipiravir does not accelerate viral clearance in early symptomatic COVID-19.

BackgroundPrimaquine is the only widely available treatment to prevent relapses ofPlasmodium vivaxmalaria, but is underused because of concerns over haemolysis in glucose-6-phosphate dehydrogenase deficient (G6PDd) individuals. G6PDd is common in malaria endemic areas but testing is often not available.MethodsWe conducted a pharmacometric study to characterise the relationship between primaquine dose and haemolysis in G6PDd. The aim was to explore shorter and safer pri-maquine radical cure regimens compared to those currently recommended, potentially obviating the need for G6PD testing. Hemizygous G6PDd healthy adult Thai male volunteers were admitted to the Hospital for Tropical Diseases in Bangkok. In Part 1, volunteers were given ascending dose primaquine regimens whereby daily doses were increased from 7.5 mg up to 45 mg over 15 to 20 days. In Part 2, a single primaquine 45 mg dose was given.Results24 volunteers were enrolled in Part 1, and 16 in Part 2 (13 participated in both studies). In three volunteers the ascending dose regimen was stopped because of primaquine related safety concerns (two had increased levels of transaminases, one haemolysis). Other-wise the ascending regimens were well tolerated with no drug-related serious adverse events. In Part 1, haemoglobin concentrations fell 3.7 g/dL (median; range: 2.1 to 5.9; relative fall of -26% [range: -15 to 40%]). Primaquine doses up to 0.87 mg/kg/day were tolerated subsequently without clinically significant further falls in haemoglobin. In Part 2, the haemoglobin concentrations fell by 1.7 g/dL (median; range -0.9 to 4.1; relative fall of 12% [range: 7 to 30%]). The ascending dose primaquine regimens gave 7 times more drug but resulted in only double the haemoglobin fall.Conclusions and InterpretationIn patients with Southeast Asian G6PDd variants full radical cure treatment can be given in under three weeks compared with the current 8 week regimen.FundingMRC (MR/R015252/1); Wellcome (223099/Z/21/Z)

BackgroundUncertainty over the therapeutic benefit provided by parenteral remdesivir in COVID-19 has resulted in varying treatment guidelines. Early in the pandemic the monoclonal antibody cocktail, casirivimab/imdevimab, proved highly effective in clinical trials but because of weak or absentin vitroactivity against the SARS-CoV-2 Omicron BA.1 subvariant, it is no longer recommended.MethodsIn a multicenter open label, randomized, controlled adaptive platform trial, low-risk adult patients with early symptomatic COVID-19 were randomized to one of eight treatment arms including intravenous remdesivir (200mg followed by 100mg daily for five days), casirivimab/imdevimab (600mg/600mg), and no study drug. The primary outcome was the viral clearance rate in the modified intention-to-treat population derived from daily log10viral densities (days 0-7) in standardized duplicate oropharyngeal swab eluates. This ongoing adaptive trial is registered atClinicalTrials.gov(NCT05041907).ResultsAcceleration in mean estimated SARS-CoV-2 viral clearance, compared with the contemporaneous no study drug arm (n=64), was 42% (95%CI 18 to 73%) for remdesivir (n=67). Acceleration with casirivimab/imdevimab was 58% (95%CI: 10 to 120) in Delta (n=13), and 20% (95%CI: 3 to 43) in Omicron variant (n=61) infections compared with contemporaneous no study drug arm (n=84). In apost hocsubgroup analysis viral clearance was accelerated by 8% in BA.1 (95%CI: −21 to 59) and 23% (95%CI: 3 to 49) in BA.2 and BA.5 Omicron subvariants.ConclusionsParenteral remdesivir accelerates viral clearance in early symptomatic COVID-19. Despite substantially reducedin vitroactivities, casirivimab/imdevimab retainsin vivoantiviral activity against COVID-19 infections caused by currently prevalent Omicron subvariants.Brief summaryIn early symptomatic COVID-19 remdesivir accelerated viral clearance by 42% while the monoclonal antibody cocktail casirivimab/imdevimab accelerated clearance by approximately 60% in SARS-CoV-2 Delta variant infections, and by approximately 25% in infections with Omicron subvariants BA.2 and BA.5.

BackgroundThere is no generally accepted methodology for in vivo assessment of antiviral activity in SARS-CoV-2 infection. Ivermectin has been recommended widely as a treatment of COVID-19, but whether it has significant antiviral activity in vivo is uncertain.MethodsIn a multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one of six treatment arms including high dose ivermectin (600µg/kg daily for seven days), the monoclonal antibodies casirivimab and imdevimab (600mg/600mg), and no study drug. Viral clearance rates were derived from daily duplicate oropharyngeal quantitative PCR measurements. This ongoing trial is registered at ClinicalTrials.gov (NCT05041907).ResultsRandomization to the ivermectin arm was stopped after enrolling 205 patients into all arms, as the prespecified futility threshold was reached. Compared with the no study drug arm, the mean estimated SARS-CoV-2 viral clearance following ivermectin was 9.1% slower [95%CI -27.2% to +11.8%; n=45 versus n=41], whereas in a preliminary analysis of the casirivimab/imdevimab arm it was 52.3% faster [95%CI +7.0% to +115.1%; n=10 (Delta variant) versus n=41].ConclusionsHigh dose ivermectin did not have measurable antiviral activity in early symptomatic COVID-19. Measured in this way viral clearance rate is a valuable pharmacodynamic measure in assessing antiviral COVID-19 therapeutics in vivo.Funding“Finding treatments for COVID-19: A phase 2 multi-centre adaptive platform trial to assess antiviral pharmacodynamics in early symptomatic COVID-19 (PLAT-COV)” is funded by the Wellcome Therapeutics Accelerator (223195/Z/21/Z).ImpactRate of viral clearance determined from daily duplicate oropharyngeal swabs over one week is an efficient measure of antiviral efficacy in early COVID-19 infection.High dose ivermectin did not demonstrate measurable antiviral activity in early symptomatic COVID-19 infection.

Objective: To determine household and health-care provider costs associated with Plasmodium vivax infection across a range of endemic settings. Methods: We collected cost data alongside three multicentre clinical trials of P. vivax treatment in Afghanistan, Brazil, Colombia, Ethiopia, Indonesia, Philippines, Peru, Thailand and Viet Nam conducted between April 2014 to December 2017. We derived household costs from trial participant surveys administered at enrolment and again 2 weeks later to determine the costs of treatment and transportation, and the number of days that patients and their household caregivers were unable to undertake their usual activities. We determined costs of routine care by health-care providers by micro-costing the resources used to diagnose and treat P. vivax at the study sites. Findings: The mean total household costs ranged from 8.7 United States dollars (US$; standard deviation, SD: 4.3) in Afghanistan to US$ 254.7 (SD: 148.4) in Colombia. Across all countries, productivity losses were the largest household cost component, resulting in mean indirect costs ranging from US$ 5.3 (SD: 3.0) to US$ 220.8 (SD: 158.40). The range of health-care provider costs for routine care was US$ 3.6-6.6. The cost of administering a glucose-6-phosphate-dehydrogenase rapid diagnostic test, ranged from US$ 0.9 to 13.5, consistently lower than the costs of the widely-used fluorescent spot test (US$ 6.3 to 17.4). Conclusion: An episode of P. vivax malaria results in high costs to households. The costs of diagnosing and treating P. vivax are important inputs for future cost-effectiveness analyses to ensure optimal allocation of resources for malaria elimination.

Background Amodiaquine is a 4-aminoquinoline antimalarial similar to chloroquine that is used extensively for the treatment and prevention of malaria. Data on the cardiovascular effects of amodiaquine are scarce, although transient effects on cardiac electrophysiology (electrocardiographic QT interval prolongation and sinus bradycardia) have been observed. We conducted an individual patient data meta-analysis to characterise the cardiovascular effects of amodiaquine and thereby support development of risk minimisation measures to improve the safety of this important antimalarial. Methods and findings Studies of amodiaquine for the treatment or prevention of malaria were identified from a systematic review. Heart rates and QT intervals with study-specific heart rate correction (QTcS) were compared within studies and individual patient data pooled for multivariable linear mixed effects regression. The meta-analysis included 2,681 patients from 4 randomised controlled trials evaluating artemisinin-based combination therapies (ACTs) containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged QTcS (mean = 16.9 ms, 95% CI: 15.0 to 18.8) less than chloroquine (21.9 ms, 18.3 to 25.6, p = 0.0069) and piperaquine (19.2 ms, 15.8 to 20.5, p = 0.0495), but more than lumefantrine (5.6 ms, 2.9 to 8.2, p < 0.001) and pyronaridine (−1.2 ms, −3.6 to +1.3, p < 0.001). In individuals aged ≥12 years, amodiaquine reduced heart rate (mean reduction = 15.2 beats per minute [bpm], 95% CI: 13.4 to 17.0) more than piperaquine (10.5 bpm, 7.7 to 13.3, p = 0.0013), lumefantrine (9.3 bpm, 6.4 to 12.2, p < 0.001), pyronaridine (6.6 bpm, 4.0 to 9.3, p < 0.001), and chloroquine (5.9 bpm, 3.2 to 8.5, p < 0.001) and was associated with a higher risk of potentially symptomatic sinus bradycardia (≤50 bpm) than lumefantrine (risk difference: 14.8%, 95% CI: 5.4 to 24.3, p = 0.0021) and chloroquine (risk difference: 8.0%, 95% CI: 4.0 to 12.0, p < 0.001). The effect of amodiaquine on the heart rate of children aged, In this meta-analysis, Xin Hui Supanee Chan and colleagues investigate the cardiovascular effects of amodiaquine and structurally-related antimalarials using individual patient data from trials., Author summary Why was this study done? Amodiaquine is a widely used antimalarial for the treatment and prevention of malaria. The artemisinin-based combination therapy (ACT) artesunate–amodiaquine (ASAQ) is a first-line treatment for uncomplicated malaria in >20 malaria endemic countries. Amodiaquine is also the backbone of amodiaquine + sulfadoxine–pyrimethamine, the only drug regimen recommended for seasonal malaria chemoprevention (SMC) given annually to millions of children aged 3 to 59 months across the African Sahel. As with other structurally related antimalarials, transient prolongation of the electrocardiographic QT interval and sinus bradycardia has been observed after amodiaquine, but these cardiovascular effects are not well understood. What did the researchers do and find? We conducted secondary analyses, including meta-analyses with multivariable linear mixed effects regression models, of individual patient data from studies of amodiaquine for malaria identified from a systematic review. We included data from 2,681 patients from 4 randomised controlled trials evaluating ACTs containing amodiaquine (n = 725), lumefantrine (n = 499), piperaquine (n = 716), and pyronaridine (n = 566), as well as monotherapy with chloroquine (n = 175) for uncomplicated malaria. Amodiaquine prolonged the QT interval assessed with study-specific heart rate correction (QTcS) less than chloroquine and piperaquine, but more than lumefantrine and pyronaridine. Amodiaquine was also associated with a higher risk of potentially symptomatic sinus bradycardia compared with other front-line antimalarials in adults and adolescents aged ≥12 years but not in children aged

To determine household and health-care provider costs associated withWe collected cost data alongside three multicentre clinical trials ofThe mean total household costs ranged from 8.7 United States dollars (US$; standard deviation, SD: 4.3) in Afghanistan to US$ 254.7 (SD: 148.4) in Colombia. Across all countries, productivity losses were the largest household cost component, resulting in mean indirect costs ranging from US$ 5.3 (SD: 3.0) to US$ 220.8 (SD: 158.40). The range of health-care provider costs for routine care was US$ 3.6-6.6. The cost of administering a glucose-6-phosphate-dehydrogenase rapid diagnostic test, ranged from US$ 0.9 to 13.5, consistently lower than the costs of the widely-used fluorescent spot test (US$ 6.3 to 17.4).An episode ofDéterminer les coûts, pour les ménages et les prestataires de soins, associés à l'infection parNous avons recueilli des données sur les coûts à l'occasion de trois essais cliniques multicentres relatifs au traitement contreLes coûts totaux moyens pour les ménages allaient de 8,7 dollars des États-Unis ($ US; écart type, ET: 4,3) en Afghanistan à 254,7 $ US (ET: 148,4) en Colombie. Tous pays confondus, les pertes de productivité étaient la principale composante des coûts pour les ménages, puisqu'elles entraînaient des coûts indirects moyens allant de 5,3 $ US (ET: 3,0) à 220,8 $ US (ET: 158,40). En ce qui concerne les prestataires de soins, le coût des soins courants allait de 3,6 à 6,6 $ US. Le coût de réalisation d'un test de diagnostic rapide basé sur le glucose-6-phosphate-déshydrogénase variait de 0,9 $ US à 13,5 $ US, un coût toujours inférieur à celui du très répandu test par fluorescence (6,3 $ US à 17,4 $ US).Un épisode de paludisme àDeterminar los costos del hogar y de los proveedores de atención de la salud asociados con la infección porSe recopilaron datos de costos junto con tres ensayos clínicos multicéntricos del tratamiento conLos costos totales promedio de los hogares oscilaron entre 8,7 dólares estadounidenses (USD; desviación estándar, DE: 4,3) en Afganistán y 254,7 USD (DE: 148,4) en Colombia. En todos los países, las pérdidas de productividad fueron el mayor componente del costo del hogar, lo que dio lugar a costos indirectos promedios que oscilaron entre 5,3 y 220,8 USD. El rango de los costos de los proveedores de atención de la salud para la atención de rutina fue de 3,6 a 6,6 USD. El costo por administrar una prueba de diagnóstico rápido de la glucosa-6-fosfato-deshidrogenasa, varió de 0,9 a 13,5 USD, consistentemente más bajo que los costos de la prueba de fluorescencia aleatoria ampliamente utilizada (6,3 a 17,4 USD).Un episodio de malaria porتحديد تكاليف مزود الرعاية الصحية والتكاليف الأسرية المرتبطة بعدوى بلازموديوم فيفاكس عبر مجموعة من الأوضاع الوبائية.قمنا بتجميع بيانات التكلفة إلى جانب ثلاث تجارب سريرية متعددة المراكز لعلاج بلازموديوم فيفاكس في كل من إثيوبيا وأفغانستان وإندونيسيا والبرازيل والفلبين وبيرو وتايلند وفييت نام وكولومبيا، تمت ما بين أبريل/نيسان 2014 إلى ديسمبر/كانون أول 2017. وحصلنا على التكاليف الأسرية من مسوح للمشاركين في التجربة تم إجراؤها عند التسجيل، ثم مرة أخرى بعد أسبوعين من تحديد تكاليف العلاج والنقل، وعدد الأيام التي لم يتمكن فيها المرضى ومقدمو الرعاية المنزلية من القيام بأنشطتهم المعتادة. قمنا بتحديد تكاليف الرعاية الروتينية من جانب مقدمي الرعاية الصحية عن طريق تقدير التكاليف الدقيقة للموارد المستخدمة لتشخيص وعلاج بلازموديوم فيفاكس في مواقع الدراسة. النتائج تراوح متوسط ​​إجمالي تكاليف الأسرة من 8.7 دولاراً أمريكياً (دولار أمريكي؛ الانحراف المعياري: 4.3) في أفغانستان إلى 254.7 دولاراً أمريكياً (الانحراف المعياري: 148.4) في كولومبيا. في كل البلدان، كانت خسائر الإنتاجية هي أكبر عنصر في التكلفة الأسرية، مما أسفر عن أن يتراوح متوسط التكاليف غير المباشرة من 5.3 دولار أمريكي (الانحراف المعياري: 3.0) إلى 220.8 دولاراً أمريكياً (الانحراف المعياري: 158.40). كان نطاق تكاليف مقدم الرعاية الصحية للرعاية الروتينية يتراوح بين 3.6 و6.6 دولاراً أمريكياً. تراوحت تكلفة إجراء الاختبار التشخيصي السريع للجلوكوز 6 فوسفات ديهيدروجينيز، ما بين 0.9 إلى 13.5 دولارًا أمريكيًا، وهي أقل بشكل متسق عن تكاليف اختبار بقعة الفلورسنت المستخدم بشكل شائع (6.3 دولار أمريكي إلى 17.4 دولاراً أمريكياً).تؤدي نوبة الإصابة بملاريا确定多个流行国家我们收集了从 2014 年 4 月至 2017 年 12 月在阿富汗、埃塞俄比亚、秘鲁、巴西、菲律宾、哥伦比亚、泰国、印度尼西亚和越南进行的三项各国的平均家庭总成本分别从阿富汗的 8.7 美元(美元;标准差:4.3)至哥伦比亚的 254.7 美元(标准差:148.4)不等。在所有国家中,生产力下降是家庭成本中最主要的部分,从而导致平均间接成本从 5.3 美元(标准差:3.0)至 220.8 美元(标准差:158.40)不等。医疗护理提供者进行一般性医疗的费用范围是 3.6–6.6 美元。进行葡萄糖-6-磷酸脱氢酶快速诊断测试的费用从 0.9 美元至 13.5 美元不等,比普遍使用的荧光点试验的费用(6.3 美元至 17.4 美元)要低。.Определение затрат поставщиков услуг в сфере здравоохранения и семей пациентов при всплесках малярии, вызваннойАвторы собрали данные по затратам для трех многоцентровых клинических исследований по лечению инфекцииСредняя общая величина затрат семьи находилась в диапазоне от 8,7 долл. США (среднеквадратичное отклонение, СО 4,3) в Афганистане до 254,7 долл. США (СО 148,4) в Колумбии. Во всех странах потеря трудоспособности составляла наибольший компонент затрат семьи, при этом средние косвенные затраты составляли от 5,3 долл. США (СО 3,0) до 220,8 долл. США (СО 158,4). Затраты медицинских учреждений на обеспечение стандартного набора медицинских услуг составляли от 3,6 до 6,6 долл. США. Затраты на проведение экспресс-теста для диагностики заболевания по глюкозо-6-фосфат-дегидрогеназе составляли от 0,9 до 13,5 долл. США, что было во всех случаях ниже затрат на широко используемый тест флуоресцентного пятна (от 6,3 до 17,4 долл. США).Вспышка заболеваемости малярией, вызванной

Primaquine is the only drug available to prevent relapse in vivax malaria. The main adverse effect of primaquine is erythrocyte age and dose-dependent acute haemolytic anaemia in individuals with glucose-6-phosphate dehydrogenase deficiency (G6PDd). As testing for G6PDd is often unavailable, this limits the use of primaquine for radical cure. A compartmental model of the dynamics of red blood cell production and destruction was designed to characterise primaquine-induced haemolysis using a holistic Bayesian analysis of all published data and was used to predict a safer alternative to the currently recommended once weekly 0.75 mg/kg regimen for G6PDd. The model suggests that a step-wise increase in daily administered primaquine dose would be relatively safe in G6PDd. If this is confirmed, then were this regimen to be recommended for radical cure patients would not require testing for G6PDd in areas where G6PDd Viangchan or milder variants are prevalent. DOI: http://dx.doi.org/10.7554/eLife.23061.001, eLife digest Malaria is the most important parasitic disease that affects humans. Over half of the malaria cases in Asia and South America are caused by a species of malaria parasite called Plasmodium vivax (known as vivax malaria). This form of malaria results in repeated illness because dormant parasites in the liver wake at intervals to infect the blood. The only available drug that can stop these relapses is a drug called primaquine, which was developed seventy years ago. Unfortunately, primaquine causes dangerous side effects in certain individuals who are deficient in an enzyme called G6PD, which helps defend red blood cells against stresses. Primaquine damages these cells so that they burst, leading to anaemia. This is a major problem because G6PD deficiency is common in regions where malaria is present: in some areas up to 30% of the population may be G6PD deficient. Since G6PD testing is not widely available, doctors often avoid prescribing primaquine to treat malaria, which results in more cases of disease relapse. Failing to prevent vivax relapses causes extensive illness and hinders efforts to eliminate malaria. Is there a way to give this drug to patients that would be safer for people with G6PD deficiency? Primaquine destroys older rather than younger red blood cells. Watson et al. used mathematical modelling to see whether it is possible to develop a primaquine treatment strategy that would allow a gradual destruction of older red blood cells in individuals with G6PD deficiency, which would be safer. The mathematical model incorporates data from previous studies in malaria patients and healthy volunteers with G6PD deficiency and combines this with knowledge of how red blood cells are produced and destroyed. Watson et al. predicted that giving primaquine over 20 days in a steadily increasing dose was safer than current recommendations. Mathematical models are simplifications of real world processes. The only way to test these findings properly will be to run a clinical trial that gives healthy volunteers who are G6PD deficient a course of primaquine treatment with a steadily increasing dose. DOI: http://dx.doi.org/10.7554/eLife.23061.002

Objective To investigate the validity of recommendations in treatment guidelines to use higher than approved doses of oseltamivir in patients with severe influenza. Design Double blind randomised trial. Setting Thirteen hospitals in Indonesia, Singapore, Thailand, and Vietnam. Participants Patients aged ≥1 year admitted to hospital with confirmed severe influenza. Interventions Oral oseltamivir at double dose (150 mg twice a day/paediatric equivalent) versus standard dose (75 mg twice a day/paediatric equivalent). Main outcome measure Viral status according to reverse transcriptase polymerase chain reaction (RT-PCR) for influenza RNA in nasal and throat swabs on day five. Results Of 326 patients (including 246 (75.5%) children aged

Information on forest use and dependence on tree hollows was collated for vertebrates in the Top End of the Northern Territory. The proportion of the total fauna that used hollows was 40% for mamma...

Bird communities in montane wet forest at three sites (altitudes 700,750 and 880 m) on the Central Plateau of Tasmania were surveyed over a 12-month period between December 1991 and November 1992. Monthly transect counts were carried out at each site. Snowf:,lls are common at all three sites during winter and snow can remain at the highest site for several weeks. Bird communities at the study sites showed significant differences in densities and seasonal patterns even though species composition was similar. These differences were influenced by the variation in habitats and the environments at the sites. Butlers Road, the lowest site with the mildest winters and greatest proportion of drier habitat, had the highest bird densities, while D'Arcys Bluff, at the highest altitude, had the lowest. The degree of seasonal changes of birds was similar to mainland montane wet forests, with over half the species moving either locally or to the mainland, However, there was variation in seasonal occurrences between the study sites, with proportionally more species moving from the highest site during the winter, Within the study sites, the wet forest habitats with a diverse shrub and/or fern understorey supported higher bird populations than did mixed forest and damp forest. Species richness is lower at these sites compared with equivalent montane forests on mainland southeastern Australia.

Activity patterns of geometrid moths were compared in two areas, one in wet eucalypt forest at high altitude and the other in mainly dry forest at low altitude in Tasmania. One hundred and twenty-six species were able to be grouped into six distinct groups (i.e. spring, spring and summer, summer, autumn, autumn and winter, all year) in terms of their patterns of seasonal occurrence. Three of the 16 species common to the two sites differed in their seasonality of occurrence, with their length of occurrence being extended at Old Chum Dam compared with Central Plateau. Moth numbers strongly reflected monthly changes in minimum temperature, with moth activity being greater at the high altitude site than at the low altitude site for an equivalent temperature. However, a given change in minimum temperature led to an equivalent change in the magnitude of moth numbers at both sites. These seasonal patterns of occurrence must be considered in the planning of biodiversity surveys.

Searches for a scalar top quark and a scalar bottom quark have been performed using a data sample of 438 pb-1 at centre-of-mass energies of sqrt(s) = 192 - 209 GeV collected with the OPAL detector at LEP. No evidence for a signal was found. The 95% confidence level lower limit on the scalar top quark mass is 97.6 GeV if the mixing angle between the supersymmetric partners of the left- and right-handed states of the top quark is zero. When the scalar top quark decouples from the Z0 boson, the lower limit is 95.7 GeV. These limits were obtained assuming that the scalar top quark decays into a charm quark and the lightest neutralino, and that the mass difference between the scalar top quark and the lightest neutralino is larger than 10 GeV. The complementary decay mode of the scalar top quark decaying into a bottom quark, a charged lepton and a scalar neutrino has also been studied. The lower limit on the scalar top quark mass is 93.0 GeV for this decay mode, if the mass difference between the scalar top quark and the scalar neutrino is greater than 10 GeV and if the mixing angle of the scalar top quark is zero. From a search for the scalar bottom quark, a mass limit of 96.6 GeV was obtained if the mass difference between the scalar bottom quark and the lightest neutralino is larger than 10 GeV., Comment: 19 pages, 5 figures

Millipedes were sampled by hand-collecting from plots and by pitfall trapping at three forest sites in central Tasmania. Seven days of pitfall trapping each month over one year was less efficient than four weeks of hand-collecting in autumn, yielding fewer species and fewer specimens per working day in the field. Hand-collecting is likely to provide more accurate data on species diversity and relative abundance for a range of litter invertebrates.

Composition of the amphipod fauna and seasonal changes in captures in pitfall traps were compared at a lowland forest in northeastern Tasmania and three sites in highland forest in central Tasmania. The number of species at the highland sites (five) was greater than for the lowland area (two), possibly due to the greater development of the litter habitat and the moister, more humid conditions at the highland sites. Capture rates were correlated with temperature, but not rainfall, at both the lowland and highland areas. However, minium temperature was most significant for the highland sites, and maximum temperature was most significant at the lowland area. Captures at the highland sites were proportionally greater in autumn and lower in summer and showed a peak in October which was not present at the lowland area. Capture rates are most likely influenced by both activity levels and population size, as determined by seasonal reproductive patterns. It is, therefore, possible that the differences in the seasonality of captures at the highland and lowland areas may be related to different patterns of reproductive activity at the different altitudes.

A survey of small terrestrial mammals and bats was undertaken in two areas of southwestern Tasmania: around Melaleuca, in sedgeland, scrub and woodland communities, and at Claytons in mixed forest. The density of bats was extremely low in comparison with populations in eastern Tasmania. The densities of Rattus lutreolusand Antechinus minimuswere greatest in sedgeland/scrub with a dense undergrowth. Pseudomys higginsi was only captured in mixed forest but is also present around Deny King's garden. Dasyurus viverrinus was most abundant in young sedgeland. Cercartetus nanus was present at both Clay tons and Melaleuca. No introduced rodents were trapped, but an outbreak of Rattus rattus had occurred previous to our study. No Mastacomys fuscus were trapped but they have been recorded in a previous study. Fire has an important influence on the composition and structure of the vegetation which, in turn, influences the composition and density of the mammal community.

Conclusions: These differences in the exposure to artesunate, dihydroartemisinin and mefloquine are unlikely to be of clinical relevance based on in vitro and clinical data. However, the results of this study do emphasise the importance of evaluating the bioavailability and bioequivalence of new formulations, particularly in specific patient groups. Purpose: The current World Health Organization recommendation for the treatment of uncomplicated Plasmodium falciparum malaria is with artemisinin-based combination therapy. Artesunate and mefloquine combination therapy has achieved consistently high efficacy rates and reduced malaria morbidity; however, the current standard treatment regimen is complex and may be difficult to comply with outside of a research setting. Consequently, an artesunate mefloquine fixed dose oral co-formulation has been developed and is now registered in Brazil. This study was conducted in order to assess the pharmacokinetics and comparative bioavailabilities of artesunate and mefloquine administered as separate products and the new co-formulated product. Methods: The pharmacokinetics of artesunate, dihydroartemisinin, the artesunate metabolite and predominant species and mefloquine were assessed in a single-dose, randomised, crossover design study in healthy volunteers and in a multiple-dose, randomised, parallel group study in patients with uncomplicated falciparum malaria. Results: For artesunate/dihydroartemisinin the lower bound of the 90% confidence intervals for the comparison between co-formulated and separate products extended below the 80% bioequivalence limit; area under the curve and Cmax values were 15-25% and 25-40% lower than those observed after administration of the separate products. The two formulations were bioequivalent in terms of mefloquine pharmacokinetics in uncomplicated falciparum malaria patients; the 90% confidence intervals for dose-normalised area under the curve (AUClast and AUCinf) and maximum observed concentration (Cmax) were within the 80 - 125% limits. In contrast, mefloquine area under the curve and Cmax values were 15% and 30% lower for the co-formulated products compared to the separate products in healthy volunteers. Refereed/Peer-reviewed

Background Artesunate and amodiaquine (AS&AQ) is at present the world's second most widely used artemisinin-based combination therapy (ACT). It was necessary to evaluate the efficacy of ACT, recently adopted by the World Health Organization (WHO) and deployed over 80 countries, in order to make an evidence-based drug policy. Methods An individual patient data (IPD) analysis was conducted on efficacy outcomes in 26 clinical studies in sub-Saharan Africa using the WHO protocol with similar primary and secondary endpoints. Results A total of 11,700 patients (75% under 5 years old), from 33 different sites in 16 countries were followed for 28 days. Loss to follow-up was 4.9% (575/11,700). AS&AQ was given to 5,897 patients. Of these, 82% (4,826/5,897) were included in randomized comparative trials with polymerase chain reaction (PCR) genotyping results and compared to 5,413 patients (half receiving an ACT). AS&AQ and other ACT comparators resulted in rapid clearance of fever and parasitaemia, superior to non-ACT. Using survival analysis on a modified intent-to-treat population, the Day 28 PCR-adjusted efficacy of AS&AQ was greater than 90% (the WHO cut-off) in 11/16 countries. In randomized comparative trials (n = 22), the crude efficacy of AS&AQ was 75.9% (95% CI 74.6–77.1) and the PCR-adjusted efficacy was 93.9% (95% CI 93.2–94.5). The risk (weighted by site) of failure PCR-adjusted of AS&AQ was significantly inferior to non-ACT, superior to dihydroartemisinin-piperaquine (DP, in one Ugandan site), and not different from AS+SP or AL (artemether-lumefantrine). The risk of gametocyte appearance and the carriage rate of AS&AQ was only greater in one Ugandan site compared to AL and DP, and lower compared to non-ACT (p = 0.001, for all comparisons). Anaemia recovery was not different than comparator groups, except in one site in Rwanda where the patients in the DP group had a slower recovery. Conclusion AS&AQ compares well to other treatments and meets the WHO efficacy criteria for use against falciparum malaria in many, but not all, the sub-Saharan African countries where it was studied. Efficacy varies between and within countries. An IPD analysis can inform general and local treatment policies. Ongoing monitoring evaluation is required.

Frequently, planning and authorization processes for a variety of management programs require estimates of size of the area or the potential number of animals that might be exposed to, or influenced by, the program(s) under consideration. A mathematical model, using animal density and average movement patterns as inputs, was developed and applied using coyote data from southern Texas. On the basis of this model, it appears that when the area encompassed by the management program is small relative to the average movements of the animals, animals in an area 10 to 50 times larger than the "application zone" may be affected. Even when the application zone is 40 times larger than the average home range, animals in an area 1.7 times larger than the management zone could be exposed. Ramifications and aspects for enhancing the reality of the model are discussed.

A list of colcopteran, large collembolan, centipede, miilipede and molluscan specics associated with rotting logs was compiled for an old-growth Eucalyptus obliqua wet sclerophyll forest and adjacent 19- year-old regeneration in southern Tasmania. A total of 67 species were found, 40 occurring in both areas, 53 in old-growth forest and 54 in the regenerated area. Of the species found in only one of the areas, nearly all occured in one or two samples only, so no conclusion about their absence from the other area can be made. Two rarely collected species of beetles were recorded only in the old growth forest. Conservation of log-dwelling invertebrates in production forests is discussed.

The early detection of allograft rejection remains elusive after solitary pancreas transplantation (PTX). We have previously described a modified technique of cystoscopic transduodenal PTX biopsy using the Biopty gun under ultrasound guidance. During the last 2 years, we performed 24 solitary PTXs with prospective protocol biopsy monitoring as well as biopsies performed whenever clinically indicated. The study group included 17 pancreas transplants alone, 6 sequential pancreas after kidney transplants, and 1 sequential pancreas after liver transplant. Five patients received pancreas retransplants. A total of 92 cystoscopically directed core PTX biopsies were performed, including 50 protocol biopsies (mean 2.1 per patient). Protocol biopsies were performed at 1 month (19), 2 months (3), 3 months (20), 6 months (7), and 12 months (1) after PTX. Adequate PTX tissue for histopathologic examination was obtained in 49 cases (98%). Biopsy findings included no rejection (34), mild rejection (13), pancreatitis (1), and cytomegalovirus infection (1). Overall, 15 of the 49 evaluable biopsies (31%) had significant histopathologic findings. All but 1 of the cases of mild rejection were treated with bolus steroids. Eight of these patients subsequently developed recurrent biopsy-proven rejection within 2 months; 5 grafts were subsequently lost to rejection between 3 and 13 months after PTX. Three biopsy complications occurred: 1 hematoma, 1 pancreatitis, and 1 ileus. Patient survival is 96% and PTX graft survival (complete insulin independence) is 75% after a mean follow-up of 15 months. In the remaining 42 clinically indicated biopsies, 3 were insufficient, 8 showed no rejection, and 31 (79%) had rejection. In half of these cases, the rejection was graded as moderate to severe. In conclusion, prospective monitoring with protocol PTX biopsies may result in the earlier detection of allograft rejection and have a direct effect on improving results after solitary PTX.

Background The clinical presentation of malaria, considered as the result of a complex interaction between parasite and human genetics, is described to be different between rural and urban areas. The analysis of the Plasmodium falciparum genetic diversity in children with uncomplicated malaria, living in these two different areas, may help to understand the effect of urbanization on the distribution of P. falciparum genotypes. Methods Isolates collected from 75 and 89 children with uncomplicated malaria infection living in a rural and an urban area of Burkina Faso, respectively, were analysed by a nested PCR amplification of msp1 and msp2 genes to compare P. falciparum diversity. Results The K1 allelic family was widespread in children living in the two sites, compared to other msp1 allelic families (frequency >90%). The MAD 20 allelic family of msp1 was more prevalent (p = 0.0001) in the urban (85.3%) than the rural area (63.2%). In the urban area, the 3D7 alleles of msp2 were more prevalent compared to FC27 alleles, with a high frequency for the 3D7 300bp allele (>30%). The multiplicity of infection was in the range of one to six in the urban area and of one to seven in the rural area. There was no difference in the frequency of multiple infections (p = 0.6): 96.0% (95% C.I: 91.6–100) in urban versus 93.1% (95%C.I: 87.6–98.6) in rural areas. The complexity of infection increased with age [p = 0.04 (rural area), p = 0.06 (urban area)]. Conclusion Urban-rural area differences were observed in some allelic families (MAD20, FC27, 3D7), suggesting a probable impact of urbanization on genetic variability of P. falciparum. This should be taken into account in the implementation of malaria control measures.

Distribution records and details of habitat are provided for Helicarion rubicundus, a land snail. This was known from one location. It was found to occur through much of the wet forest on Forestier Peninsula but to be rare within suitable habitat on Tasman Peninsula.

The effect of glyphosate on seedhead development of bent grass (Agrostis castellana) was evaluated in an experiment at 2 sites in south-western Victoria.Application of glyphosate at 0.1350.225 kg a.i./ha on 7 November and 7 December 1993 prevented the formation of seedheads and stimulated the plant into renewed vegetative growth in response to following summer rain. The treatment with 0.135 kg a.i./ha of glyphosate, applied on 7 November, increased digestible dry matter of the regrowth by 20% and protein content by 70% compared with the unsprayed control which was dominated by seedheads. These results reflect the amount of new growth in treated plots and thus should not be confused with either the 'spraytopping' technique which aims to sterilise seeds after seedhead emergence or 'hay freezing' which and aims to preserve the feed value of existing vegetation by 'chemically curing' standing hay. We conclude that application of glyphosate at 0.135 kg a.i./ha in early November has the potential to reduce the dominance of bent grass, creating an opportunity for follow up fertiliser and management techniques to maintain productive pastures.

A new test method has been adopted to evaluate the flammability of electrical wire insulation materials. In this test, wire insulation is exposed to an external ignition source while the electrical conductor is internally heated by an electric current. The repeatability of the test and the effects of wire gage and insulation thickness, internal wire temperature, and sample orientation on the wire insulation flammability were evaluated. Experimental results showed that the new test is a practical and repeatable method for evaluating flammability of wire insulation materials.

The distributions of 34 species of terrestrial mammals native to Tasmania are presented as presence/ absence records on 10 x 10 km grid maps. All native species and the possibly introduced Petaurus breviceps are included except Thylacinus cynocephalus, which is probably extinct. The distribution maps were prepared from approximately 10 000 recent (1967-89) mammal records held on computer, selected literature records and other sources. Twenty-six species are widely distributed across the State. Five species have more limited distributions confined to the east or west of the State, depending upon the occurrence of their habitats. The three remaining species are bats that are little-recorded and their distributions are unclear. Notes on the ease of recording species and their habitats are provided to supplement and assist the interpretation of their distributions. Further records of all species are needed, especially from islands.

Photographs of the hair structure of the five species of Tasmanian mammals (Sarcophilus harrisii, Thylacinus cynocephalus, Bettongia gaimardi, Cercartetus lepidus and Pseudomys higginsi) which have not been described by Brunner & Coman (1974) are presented. A key to the hair of forty Tasmanian mammals is provided to allow the identification of unknown samples. The key can be used in mammal surveys and in carnivore dietary studies.

All four of Tasmania's large mammalian carnivores (Sarcophilus harrisii, Dasyurus maculatus, D. viverrinus, Felis catus) occur in the Upper Henty River region~ in western Tasmania. A short-term study was undertaken to compare the diet of these species when in sympatry. No data were obtained for D. maculatus. The other species overlapped in their use of small mammals. However each species had a major component of the diet (S. harrisii, large mammals; D. viverrinus, invertebrates and plant material; F. catus,birds)which was not utilized by the other species and hence substantial competition between them is unlikely. The diet reported others for D. maculatus is similar to that found for F. catus. These two species had similar habit preferences and hence it is possible that competition could occur between the native D. maculatus and the introduced F. catus.

A review of the natural history of bats in Tasmania is presented along with data collected in recent surveys. Recent taxonomic changes affecting the Tasmanian bat species are discussed and a key is provided to allow the identification of Tasmanian bats. The appearance of each species is described and body measurements given. Tasmanian populations do not show a uniform trend of increased size compared with southeast Australian populations. Distribution records are presented along with data on habitat preferences and abundance. The diet, activity patterns, roosting requirements, reproductive cycles and conservation status of the species are also discussed.

A mammal survey was conducted in the Upper Henty River Region in western Tasmania. The area had been subject to much disturbance from mining, forestry and frequent fires and was covered by a maze of roads and tracks. Nineteen native species (including bats) were recorded. Four of the species listed in 1983 as occurring in the Lower Gordon Region, 80 km south ofthe present study area, were not recorded during our survey. It is considered that three of these species would probably have been found in the area with further searching. The fourth species, Mastacomysfuscus, is thought not to be present due to increased fire frequency in the sedgeland areas compared with the Lower Gordon Region. Potorous tridactylus is recorded for the first time from rainforest. Microhabitat selection by Rattus lutreolus and Pseudomys higginsi differed from that previously reported. Disturbance from road construction led to the creation ofa new food source for Thylogale billardierii. The abundance of tracks in the area increased ease of movement for carnivorous mammals. Only one introduced species Felis catus, which is also known to occur in the Lower Gordon, was recorded. Disturbance had thus not led to an invasion of exotics.

An epidemiological study of atrophic rhinitis was carried out in four pig herds. Observations were made of (i) infection with Bordetella bronchiseptica and Pasteurella multocida, (ii) the presence of brachygnathia superior (BS score), (iii) the extent (grade) of turbinate atrophy and pneumonia at slaughter and (iv) growth rates from two to 16 weeks of age and average daily weight gains to slaughter. In two of the herds with no history of atrophic rhinitis, B bronchiseptica and non-toxigenic strains of P multocida were isolated; only one of 47 pigs (2 per cent) had a BS score greater than +10 mm and the most severe turbinate atrophy observed in 21 pigs at slaughter was grade 3. In contrast, from two herds with atrophic rhinitis, toxigenic strains of P multocida were isolated as well as B bronchiseptica and non-toxigenic P multocida. BS scores of greater than +10 mm were present in six of 47 pigs (13 per cent) of which five were infected with toxigenic P multocida and had severe turbinate atrophy of grade 4 or 5. There was no significant reduction in growth rates in the affected compared with the unaffected herds nor in the affected compared with the unaffected pigs in the same herd. Neither was there a correlation between progressive disease and the extent of pneumonia found at slaughter. It was concluded that in field cases of the disease, high BS scores plus severe turbinate atrophy were associated with infection by toxigenic type-D strains of P multocida.

In summary, we believe that combined PKT can be performed safely and effectively in the absence of uremia, thereby providing the potential for arresting the progression of diabetic complications prior to the development of ESRD. Furthermore, performing solitary PTx prior to the need for a kidney transplant can be accomplished with morbidity and results comparable to PKT. Rehabilitation potential tends to favor patients undergoing either solitary PTx or preemptive PKT. In selected IDDM patients without end-stage diabetic nephropathy, we believe that solitary PTx or PKT are effective treatment options and need not be considered as preemptive, especially in view of increasing waiting times and the variable progressive nature of diabetic complications. As results continue to improve, solitary PTx may offer a potential solution to the growing number of IDDM patients awaiting kidney transplantation in the United States. Ultimately, the role of solitary PTx in the treatment of IDDM will be determined by long-term studies documenting the prevention or arrest of secondary diabetic complications. In the short-term, improvement in quality of life and rehabilitation potential makes preemptive PKT or solitary PTx important therapeutic alternatives for consideration.

To determine patterns of dental services provided to a cohort of the insured population 18 years and over, in private general practice in New South Wales, Australia.A cohort study using the person-years method and Poisson regression for analysis.Data were derived from claims records submitted by members of a health insurance fund (Government Employees Health Fund-GEHF) for rebates during the study period 1 January 1992-31 December 1995.There were 133,467 members aged 18 years and over from New South Wales.To determine, by age group, for those members who used private general practice and made a claim (referred to as 'patients') the annual number of visits, total number of services received per year and number of services received at a visit.The mean number of visits per patient was 2.4 per year with patients under 45 years making fewer visits than the 45-54 age group reference category. Mean number of services utilised per patient-year was 5.9, with services provided increasing from 3.5 for the 18-24-year-old group, reaching a plateau of approximately 6.2 for those aged 45 years or more. The number of services received per visit was 2.4 and there were no differences by age. Service mix was dominated by restorative (35%), diagnostic (27%), and preventive services (18%); with age specific variations observed.Age was found to be an important determinant in the use of dental services, independent of membership duration and gender.