Effectiveness of unsupervised primaquine regimen for preventing Plasmodium vivax malaria relapses in northeast Myanmar, a single-arm non-randomized observational study.

BACKGROUND: Plasmodium vivax presents a significant challenge for malaria elimination in the Greater Mekong Subregion (GMS). We evaluated the effectiveness of primaquine (PQ) for reducing relapses of vivax malaria. METHODS: Patients with uncomplicated P. vivax malaria from eastern Myanmar received chloroquine (CQ, 25 mg base/kg given in 3 days) plus unsupervised PQ (0.25 mg/kg/day for 14 days) without screening for glucose-6-phosphate dehydrogenase deficiency and were followed for a year. RESULTS: Totally 556 patients were enrolled to receive the CQ/PQ treatment from February 2012 to August 2013. During the follow-up, 38 recurrences were detected, presenting a cumulative rate of recurrence of 9.1% (95% confidence interval, 4.1-14.1%). Genotyping at the pvmsp1 and pvmsp3α loci by Amplicon deep sequencing and model prediction indicated that 13 of the 27 recurrences with genotyping data were likely due to relapses. Notably, all confirmed relapses occurred within the first six months. CONCLUSIONS: The unsupervised standard dose of PQ was highly effective as a radical cure for P. vivax malaria in eastern Myanmar. The high presumed effectiveness might have benefited from the health messages delivered during the enrollment and follow-up activities. Six-month follow-ups in the GMS are sufficient for detecting most relapses.

Employee organizational commitment and hospital performance.

BACKGROUND: There is widespread evidence of the purported benefits of employee organizational commitment (EOC) and its impact on both individual and organizational performance. This study contributes to this literature by providing a unique insight into this relationship, focusing on the interrelationship between EOC with hospital performance and the role of the provision of adequate facilities in eliciting EOC. PURPOSE: The aim of this study was to introduce and empirically examine a new theoretical model in which it is argued that the performance of hospitals with regard to the provision of adequate facilities (medical facilities, support facilities, and staff resources) influences the level of EOC, which in turn influences hospital performance with regard to patient care and operational effectiveness. METHODOLOGY/APPROACH: To examine the interrelationships between the provision of adequate facilities, EOC, and hospital performance, the study utilizes a survey of hospital managers. RESULTS: The findings support the theoretical model, with the provision of support facilities and staff resources positively indirectly associated with both patient care and operational effectiveness through their impact on EOC. CONCLUSION: The findings highlight the importance of providing adequate facilities and EOC within hospitals and suggest that CEOs and general managers should try to enhance the provision of such resources in an attempt to elicit EOC within their hospitals. PRACTICE IMPLICATIONS: The findings suggest that managers should try to enhance their provision of adequate facilities in order to elicit EOC and enhance hospital performance. With regard to medical facilities, they should consider and incorporate the latest technology and up-to-date equipment. They should also provide adequate staff resources, including appropriate numbers of beds, nurses, and doctors, to prevent "fatigue" (West, 2001, p. 41) and provide adequate support facilities.

Confirmed Plasmodium vivax Resistance to Chloroquine in Central Vietnam.

Plasmodium vivax resistance to chloroquine (CQ) is currently reported in almost all countries where P. vivax is endemic. In Vietnam, despite a first report on P. vivax resistance to chloroquine published in the early 2000s, P. vivax was still considered sensitive to CQ. Between May 2009 and December 2011, a 2-year cohort study was conducted in central Vietnam to assess the recommended radical cure regimen based on a 10-day course of primaquine (0.5 mg/kg/day) together with 3 days of CQ (25 mg/kg). Here we report the results of the first 28-day follow-up estimating the cumulative risk of P. vivax recurrences together with the corresponding CQ blood concentrations, among other endpoints. Out of 260 recruited P. vivax patients, 240 completed treatment and were followed up to day 28 according to the WHO guidelines. Eight patients (3.45%) had a recurrent P. vivax infection, at day 14 (n = 2), day 21 (n = 1), and day 28 (n = 5). Chloroquine blood concentrations, available for 3/8 recurrent infections (days 14, 21, and 28), were above the MIC (>100 ng/ml whole blood) in all of these cases. Fever and parasitemia (both sexual and asexual stages) were cleared by day 3. Anemia was common at day 0 (35.8%), especially in children under 10 years (50%), and hemoglobin (Hb) recovery at day 28 was substantial among anemic patients (median change from day 0 to 28, +1.7 g/dl; interquartile range [IQR], +0.7 to +3.2). This report, based on CQ blood levels measured at the time of recurrences, confirms for the first time P. vivax CQ resistance in central Vietnam and calls for further studies using standardized protocols for accurately monitoring the extent and evolution of P. vivax resistance to chloroquine in Vietnam. These results, together with the mounting evidence of artemisinin resistance in central Vietnam, further highlight the increasing threat of antimalarial drug resistance to malaria elimination in Vietnam.

The comprehensiveness of environmental management systems: The influence of institutional pressures and the impact on environmental performance.

This study contributes to the EMS literature by providing a more detailed insight into the comprehensiveness of environmental management systems (EMSs) by focusing on the intensity of use of environmental management practices. In addition, the study examines the influence of institutional pressures (coercive, mimetic and normative) on the comprehensiveness of environmental management systems (EMSs), and the impact of EMS comprehensiveness on environmental performance. A mail survey questionnaire was used to collect data from a random sample of Australian senior managers across various industries. Both coercive and normative pressures were found to influence the comprehensiveness of EMSs. Specifically, the pressure exerted by the government, through the creation of appropriate regulatory pressures and public incentives, and by employees, customers, professional groups, the media, and community, influenced the comprehensiveness of the EMS. In addition, organisations with more comprehensive EMSs were found to experience higher levels of environmental performance. With more than 300,000 organisations worldwide adopting EMSs (ISO, 2013), the findings provide an important insight into the relevance of EMSs. In particular, it is suggested that organisations should endeavour to implement a more comprehensive EMS and be conscious of the role that coercive and normative pressures play in influencing the comprehensiveness of their EMSs.

The relationship between organisational factors and the effectiveness of environmental management.

This paper examines the relationship between specific organisational factors (top management support, training, employee participation, teamwork and the link of performance to rewards) with the effectiveness of environmental management. The effectiveness of environmental management is measured in respect of the effectiveness of environmental management processes and environmental performance. Data were collected by mail survey questionnaire from a random sample of 899 senior financial officers in Australian manufacturing organisations. The findings highlight the significance of the effectiveness of environmental management processes as an antecedent of environmental performance and a mediator of the relationship between organisational factors and environmental performance. The findings provide managers with an insight into the specific organisational factors that they need to focus on to enhance the effectiveness of environmental management.

A description of lineage 1 Mycobacterium tuberculosis from papua, Indonesia.

Indonesia has the third highest number of tuberculosis (TB) patients infected with Mycobacterium tuberculosis (MTB) Lineage 1 (L1). Most of these MTB L1 cases can be found in Indonesia's remote easternmost province of Papua, one of Indonesia's most underdeveloped provinces with a particularly high burden for TB. In this study, we sequenced and described 42 MTB L1 isolates from a well-characterized cohort of patients. We found a genetically diverse MTB L1 population with no association between pathogen genetic relatedness and place of residence or pathogen genetic relatedness and patient ethnicity, which could reflect mixing between different locales and ethnicities or our low sampling fraction. Only a small number showed genetic variants associated with drug resistance (5/42, 11.9 %), probably due to a lack of effective treatment programs. The Papuan isolates showed similarities to other Island Southeast Asian Countries due to the high proportion of L1.2.1.2.1 (30/42, 71.4 %), especially East Timor and the Philippines. This study fills a research gap of MTB L1 in Indonesian Papua and should serve as a stepping stone for further research in the region.

Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens: a workshop report.

The diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency is a crucial aspect in the current phases of malaria control and elimination, which will require the wider use of 8-aminoquinolines for both reducing Plasmodium falciparum transmission and achieving the radical cure of Plasmodium vivax. 8-aminoquinolines, such as primaquine, can induce severe haemolysis in G6PD-deficient individuals, potentially creating significant morbidity and undermining confidence in 8-aminoquinoline prescription. On the other hand, erring on the side of safety and excluding large numbers of people with unconfirmed G6PD deficiency from treatment with 8-aminoquinolines will diminish the impact of these drugs. Estimating the remaining G6PD enzyme activity is the most direct, accessible, and reliable assessment of the phenotype and remains the gold standard for the diagnosis of patients who could be harmed by the administration of primaquine. Genotyping seems an unambiguous technique, but its use is limited by cost and the large range of recognized G6PD genotypes. A number of enzyme activity assays diagnose G6PD deficiency, but they require a cold chain, specialized equipment, and laboratory skills. These assays are impractical for care delivery where most patients with malaria live. Improvements to the diagnosis of G6PD deficiency are required for the broader and safer use of 8-aminoquinolines to kill hypnozoites, while lower doses of primaquine may be safely used to kill gametocytes without testing. The discussions and conclusions of a workshop conducted in Incheon, Korea in May 2012 to review key knowledge gaps in G6PD deficiency are reported here.

G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests.

Malaria elimination will be possible only with serious attempts to address asymptomatic infection and chronic infection by both Plasmodium falciparum and Plasmodium vivax. Currently available drugs that can completely clear a human of P. vivax (known as "radical cure"), and that can reduce transmission of malaria parasites, are those in the 8-aminoquinoline drug family, such as primaquine. Unfortunately, people with glucose-6-phosphate dehydrogenase (G6PD) deficiency risk having severe adverse reactions if exposed to these drugs at certain doses. G6PD deficiency is the most common human enzyme defect, affecting approximately 400 million people worldwide.Scaling up radical cure regimens will require testing for G6PD deficiency, at two levels: 1) the individual level to ensure safe case management, and 2) the population level to understand the risk in the local population to guide Plasmodium vivax treatment policy. Several technical and operational knowledge gaps must be addressed to expand access to G6PD deficiency testing and to ensure that a patient's G6PD status is known before deciding to administer an 8-aminoquinoline-based drug.In this report from a stakeholder meeting held in Thailand on October 4 and 5, 2012, G6PD testing in support of radical cure is discussed in detail. The focus is on challenges to the development and evaluation of G6PD diagnostic tests, and on challenges related to the operational aspects of implementing G6PD testing in support of radical cure. The report also describes recommendations for evaluation of diagnostic tests for G6PD deficiency in support of radical cure.

Reducing the risk of Plasmodium vivax after falciparum infections in co-endemic areas-a randomized controlled trial (PRIMA).

BACKGROUND: Plasmodium vivax forms dormant liver stages that can reactivate weeks or months following an acute infection. Recurrent infections are often associated with a febrile illness and can cause a cumulative risk of severe anaemia, direct and indirect mortality, and onward transmission of the parasite. There is an increased risk of P. vivax parasitaemia following falciparum malaria suggesting a rationale for universal use of radically curative treatment in patients with P. falciparum malaria even in the absence of detectable P. vivax parasitaemia in areas that are co-endemic for both species. METHODS: This is a multicentre, health care facility-based, randomized, controlled, open-label trial in Bangladesh, Indonesia and Ethiopia. Patients with uncomplicated falciparum malaria, G6PD activity of ≥70% of the adjusted male median (AMM) and haemoglobin levels ≥8g/dl are recruited into the study and randomized to either receive standard schizonticidal treatment plus 7-day high dose primaquine (total dose 7mg/kg) or standard care in a 1:1 ratio. Patients are followed up weekly until day 63. The primary endpoint is the incidence risk of any P. vivax parasitemia on day 63. Secondary endpoints include incidence risk on day 63 of symptomatic P. vivax malaria and the risk of any P. falciparum parasitaemia. Secondary safety outcomes include the proportion of adverse events and serious adverse events, the incidence risk of severe anaemia (Hb<5g/dl and <7g/dl) and/or the risk for blood transfusion, the incidence risk of ≥ 25% fall in haemoglobin with and without haemoglobinuria, and the incidence risk of ≥ 25% fall in haemoglobin to under 7g/dl with and without haemoglobinuria. DISCUSSION: This study evaluates the potential benefit of a universal radical cure for both P. vivax and P. falciparum in different endemic locations. If found safe and effective universal radical cure could represent a cost-effective approach to clear otherwise unrecognised P. vivax infections and hence accelerate P. vivax elimination. TRIAL REGISTRATION: NCT03916003 . Registered on 12 April 2019.

Adjunctive dexamethasone for the treatment of HIV-infected adults with tuberculous meningitis (ACT HIV): Study protocol for a randomised controlled trial.

Background: Tuberculous meningitis (TBM) is the most severe form of tuberculosis. Co-infection with HIV increases the risk of developing TBM, complicates treatment, and substantially worsens outcome. Whether corticosteroids confer a survival benefit in HIV-infected patients with TBM remains uncertain. Hepatitis is the most common drug-induced serious adverse event associated with anti-tuberculosis treatment, occurring in 20% of HIV-infected patients. The suggested concentration thresholds for stopping anti-tuberculosis drugs are not evidence-based. This study aims to determine whether dexamethasone is a safe and effective addition to the first 6-8 weeks of anti-tuberculosis treatment of TBM in patients with HIV, and investigate alternative management strategies in a subset of patients who develop drug induced liver injury (DILI) that will enable the safe continuation of rifampicin and isoniazid therapy.  Methods: We will perform a parallel group, randomised (1:1), double blind, placebo-controlled multi-centre Phase III trial, comparing the effect of dexamethasone versus placebo on overall survival in HIV-infected patients with TBM, in addition to standard anti-tuberculosis and antiretroviral treatment. The trial will be set in two hospitals in Ho Chi Minh City, Vietnam, and two hospitals in Jakarta, Indonesia. The trial will enrol 520 HIV-infected adults. An ancillary study will perform a randomised comparison of three DILI management strategies with the aim of demonstrating which strategy results in the least interruption in rifampicin and isoniazid treatment. An identical ancillary study will also be performed in the linked randomised controlled trial of dexamethasone in HIV-uninfected adults with TBM stratified by LTA4H genotype (LAST ACT).  Discussion: Whether corticosteroids confer a survival benefit in HIV-infected patients remains uncertain, and the current evidence base for using corticosteroids in this context is limited. Interruptions in anti-tuberculosis chemotherapy is a risk factor for death from TBM. Alternative management strategies in DILI may allow the safe continuation of rifampicin and isoniazid therapy.

Origins and implications of neglect of G6PD deficiency and primaquine toxicity in Plasmodium vivax malaria.

Most of the tens of millions of clinical attacks caused by Plasmodium vivax each year likely originate from dormant liver forms called hypnozoites. We do not systematically attack that reservoir because the only drug available, primaquine, is poorly suited to doing so. Primaquine was licenced for anti-relapse therapy in 1952 and became available despite threatening patients having an inborn deficiency of glucose-6-phosphate dehydrogenase (G6PD) with acute haemolytic anaemia. The standard method for screening G6PD deficiency, the fluorescent spot test, has proved impractical where most malaria patients live. The blind administration of daily primaquine is dangerous, but so too are the relapses invited by withholding treatment. Absent G6PD screening, providers must choose between risking harm by the parasite or its treatment. How did this dilemma escape redress in science, clinical medicine and public health? This review offers critical historic reflection on the neglect of this serious problem in the chemotherapy of P. vivax.

The effects of probe length on Fitts' law.

Experiments were aimed at determining the effect of a human using an extended probe when making movements that required accuracy at the completion of the movement. Ten subjects performed 64 conditions of varying amplitude of movement, final accuracy and probe length. Movement time increased with probe lengths from 100 to 400mm for all conditions of amplitude and required accuracy. The effect of probe length was included in a mathematical description of the data through a multiplicative term on Fitts' index of difficulty (ID), possibly arising from tremor of the hand probe system in controlling approach to the target. Probe length had the greatest effect at high ID, where a probe of 400 mm length increased movement time by about 25% over that for a 100mm probe. The model developed has application for accurate movements with long tools such as screwdrivers or crowbars, head-mounted devices for the disabled, or other tasks where the work interface is at the end of an extended probe.

Diagnosis and treatment of Plasmodium vivax malaria.

Infection by Plasmodium vivax poses unique challenges for diagnosis and treatment. Relatively low numbers of parasites in peripheral circulation may be difficult to confirm, and patients infected by dormant liver stages cannot be diagnosed before activation and the ensuing relapse. Radical cure thus requires therapy aimed at both the blood stages of the parasite (blood schizontocidal) and prevention of subsequent relapses (hypnozoitocidal). Chloroquine and primaquine have been the companion therapies of choice for the treatment of vivax malaria since the 1950s. Confirmed resistance to chloroquine occurs in much of the vivax endemic world and demands the investigation of alternative blood schizontocidal companions in radical cure. Such a shift in practice necessitates investigation of the safety and efficacy of primaquine when administered with those therapies, and the toxicity profile of such combination treatments, particularly in patients with glucose-6-phosphate dehydrogenase deficiency. These clinical studies are confounded by the frequency and timing of relapse among strains of P. vivax, and potentially by differing susceptibilities to primaquine. The inability to maintain this parasite in continuous in vitro culture greatly hinders new drug discovery. Development of safe and effective chemotherapies for vivax malaria for the coming decades requires overcoming these challenges.

The global public health significance of Plasmodium vivax.

Plasmodium vivax occurs globally and thrives in both temperate and tropical climates. Here, we review the evidence of the biological limits of its contemporary distribution and the global population at risk (PAR) of the disease within endemic countries. We also review the most recent evidence for the endemic level of transmission within its range and discuss the implications for burden of disease assessments. Finally, the evidence-base for defining the contemporary distribution and PAR of P. vivax are discussed alongside a description of the vectors of human malaria within the limits of risk. This information along with recent data documenting the severe morbid and fatal consequences of P. vivax infection indicates that the public health significance of P. vivax is likely to have been seriously underestimated.

The treatment of established non-union of the proximal humerus using the Polarus locking intramedullary nail.

INTRODUCTION: Non-union following fracture of the proximal humerus is not uncommon, particularly in the elderly. This can be associated with significant morbidity due to pain, instability and functional impairment. The Polarus device (Acumed) is a locked, antegrade intramedullary nail designed to stabilize displaced 2-, 3- and 4-part fractures of the proximal humerus. We report our experience with the Polarus nail for the treatment of established non-union of the proximal humerus. MATERIALS AND METHODS: A total of 7 Polarus nails were inserted for the treatment of non-union of the proximal humerus between June 2000 and July 2007. Each fracture site was opened, debrided, stabilized with a Polarus nail and then grafted with autologous cancellous iliac crest bone. The time between injury and surgery ranged from 6 to 102 months. One patient had undergone previous fixation of her fracture using Rush intramedullary rods. All patients were females, and mean age at surgery was 63.6 years (range, 49-78 years). A retrospective review of notes and radiographs was carried out. Patients were reviewed at varying intervals postoperatively (range, 13-68 months) and assessed using the Constant shoulder-scoring system. RESULTS: All un-united fractures progressed to union. There were no wound complications and no postoperative nerve palsies. Functional outcome was good, even in those cases with a long interval between injury and surgery. The mean Constant score was 63 (range, 54-81). Migration of a single proximal locking screw was seen in 2 patients, and these screws required removal at 5 and 12 months, respectively, postoperatively. CONCLUSION: In our experience, a locked proximal humeral nail used in conjunction with autologous bone grafting is an excellent device for the treatment of proximal humerus non-unions.