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Abstract Background Percutaneous cryoablation (PCA), having shown effectiveness in treating liver, lung, prostate, breast, and kidney tumors, is now gaining attention for the treatment of soft tissue tumors. PCA functions by freezing tissue, which induces ice crystal formation and cell death without damaging collagen structures. Technical considerations include the selection and handling of cryoprobes and cryogenic agents, procedural duration, and choice of image guidance for precision. This review aims to synthesize the mechanisms, applications, and technical aspects of PCA in the treatment of soft tissue tumors. Methods Adhering to PRISMA 2020 guidelines, a review was conducted of studies published prior to March 2024 that investigated PCA of soft tissue tumors. The review focused on technical and procedural aspects of cryoablation, cryobiological principles, cellular and tissue responses to extreme cold, intra- and post-procedure physiological mechanisms during and post-procedure, and main clinical applications. Results PCA is efficient in treating soft tissue tumors, including desmoid tumors, vascular malformations, and abdominal wall endometriosis. Several cryobiological mechanisms are involved, notably ice crystal formation, cellular dehydration, osmotic effects, and the inflammatory response, all of which contribute to its efficacy. Key technical aspects include the choice of cryoprobes, cryogenic agents (argon gas or liquid nitrogen), and the duration and control of freezing/thawing cycles. PCA also frequently outperformed traditional treatments like surgery and radiotherapy in terms of pain reduction, tumor size reduction, and patient outcomes. Moreover, its nerve sideration properties make it effective under local anesthesia. Conclusion Demonstrating substantial pain reduction, tumor size decrease, and high technical success rates, PCA offers a promising and minimally invasive alternative for soft tissue tumor treatment. Critical relevance statement Percutaneous cryoablation provides a minimally invasive, precise alternative for soft tissue tumor management, advancing clinical radiology by offering effective treatment with reduced patient risk and enhanced outcomes through image-guided procedures. Key Points Percutaneous cryoablation (PCA) offers a promising, minimally invasive alternative for managing soft tissue tumors. PCA employs image-guided techniques to accurately target and treat tumors, ensuring high precision and control. PCA preserves structures like collagen, reduces pain, decreases tumor size, and generally enhances patient outcomes. Graphical Abstract

Abstract Purpose To investigate over 10 years the safety and efficacy of percutaneous cryoablation for the treatment of abdominal wall endometriosis (AWE). Methods A systematic review was conducted of literature published between March 2014 and March 2024. Inclusion criteria focused on treatment efficacy studies, while exclusion criteria targeted case reports and studies lacking pertinent outcome data. Methodological quality was assessed using the Newcastle-Ottawa Scale for cohort studies. Results A total of eight studies were included. Local pain scores decreased from a median of 8/10 (interquartile range (IQR) 7–9) on the visual analog scale to 1/10 (IQR 0–2) at the last follow-up (p

In the current study, a 3D finite element study was performed to investigate the biomechanical response of an osteoporotic spine segment treated with a novel transpedicular implant (V-STRUT©, Hyprevention, France) made of PEEK (polyetheretherketone) material combined with either injections of 2, 3, 4, 5 and 6 cc of cement. The objective was to assess numerically the biomechanical performance of the implant in combination with different doses of the injected bone cement and to compare its performance with the gold standard vertebroplasty (VP) technique. A female (69 yo) was selected and a 3D finite element model of an osteoporotic spine segment was built based on a Computed Tomography (CT) scan performed from T12 to L2 with corresponding intervertebral discs and ligaments. A heterogeneous distribution of bone material properties was assigned to the bone using grey scale levels. Bilateral ellipsoid geometries of the inserted cement were retained for the V-STRUT and VP models based on experimental observation performed on different patients treated with the V-STRUT device. The current study demonstrated an optimal dose of 4 cc of bilaterally injected cement for the V-STRUT and VP techniques to restore the treated segment and confirmed that the V-STRUT device in combination with bone cement is superior to VP alone in establishing the normal stiffness and in reducing the applied stress to the immediately adjacent vertebral levels.

In our recent paper on the clinical pharmacology of tafenoquine (Watson et al., 2022), we used all available individual patient pharmacometric data from the tafenoquine pre-registration clinical efficacy trials to characterise the determinants of anti-relapse efficacy in tropical vivax malaria. We concluded that the currently recommended dose of tafenoquine (300 mg in adults, average dose of 5 mg/kg) is insufficient for cure in all adults, and a 50% increase to 450 mg (7.5 mg/kg) would halve the risk of vivax recurrence by four months. We recommended that clinical trials of higher doses should be carried out to assess their safety and tolerability. Sharma and colleagues at the pharmaceutical company GSK defend the currently recommended adult dose of 300 mg as the optimum balance between radical curative efficacy and haemolytic toxicity (Sharma et al., 2024). We contend that the relative haemolytic risks of the 300 mg and 450 mg doses have not been sufficiently well characterised to justify this opinion. In contrast, we provided evidence that the currently recommended 300 mg dose results in sub-maximal efficacy, and that prospective clinical trials of higher doses are warranted to assess their risks and benefits.

This article analyzes coastal and maritime frictions by examining the relationship between globalized maritime flows and maritime security. From the coast, local or regional players can influence global maritime exchanges that take place offshore. The case of the Bab el-Mandeb strait and its natural extensions (Southern Red Sea and Gulf of Aden) provides a good illustration of this : a major maritime traffic route, the strait is characterized by the presence of Somali piracy, mainly between 1995 and 2015, as well as by the extension at sea of the civil war in Yemen, which has turned into a regional conflict. This research, based on maritime data as well as an in-depth study of the regional context, seeks to identify the influences of acts of violence on the various trades of the Bab el-Mandeb strait. The impact of political contexts in coastal states on maritime flows in open seas seems to depend on the geographical scale, with a more significant effect at regional and local levels than at the global level. Nevertheless, the crucial factor lies in the ability of maritime actors to reduce the dissipation of energy resulting from these tensions.

Abstract The European flat oyster (Ostrea edulis L.) is a native bivalve of the European coasts. Harvest of this species has declined during the last decades because of the appearance of two parasites that have led to the collapse of the stocks and the loss of the natural oyster beds. O. edulis has been the subject of numerous studies in population genetics and on the detection of the parasites Bonamia ostreae and Marteilia refringens. These studies investigated immune responses to these parasites at the molecular and cellular levels. Several genetic improvement programs have been initiated especially for parasite resistance. Within the framework of a European project (PERLE 2) that aims to produce genetic lines of O. edulis with hardiness traits (growth, survival, resistance) for the purpose of repopulating natural oyster beds in Brittany and reviving the culture of this species in the foreshore, obtaining a reference genome becomes essential as done recently in many bivalve species of aquaculture interest. Here, we present a chromosome‐level genome assembly and annotation for the European flat oyster, generated by combining PacBio, Illumina, 10X linked, and Hi‐C sequencing. The finished assembly is 887.2 Mb with a scaffold‐N50 of 97.1 Mb scaffolded on the expected 10 pseudochromosomes. Annotation of the genome revealed the presence of 35,962 protein‐coding genes. We analyzed in detail the transposable element (TE) diversity in the flat oyster genome, highlighted some specificities in tRNA and miRNA composition, and provided the first insight into the molecular response of O. edulis to M. refringens. This genome provides a reference for genomic studies on O. edulis to better understand its basic physiology and as a useful resource for genetic breeding in support of aquaculture and natural reef restoration.

Abstract Background The collection and utilization of surveillance data is essential in monitoring progress towards achieving malaria elimination, in the timely response to increases in malaria case numbers and in the assessment of programme functioning. This paper describes the surveillance activities used by the malaria elimination task force (METF) programme which operates in eastern Myanmar, and provides an analysis of data collected from weekly surveillance, case investigations, and monitoring and evaluation of programme performance. Methods This retrospective analysis was conducted using data collected from a network of 1250 malaria posts operational between 2014 and 2021. To investigate changes in data completeness, malaria post performance, malaria case numbers, and the demographic details of malaria cases, summary statistics were used to compare data collected over space and time. Results In the first 3 years of the METF programme, improvements in data transmission routes resulted in a 18.9% reduction in late reporting, allowing for near real-time analysis of data collected at the malaria posts. In 2020, travel restrictions were in place across Karen State in response to COVID-19, and from February 2021 the military coup in Myanmar resulted in widescale population displacement. However, over that period there has been no decline in malaria post attendance, and the majority of consultations continue to occur within 48 h of fever onset. Case investigations found that 43.8% of cases travelled away from their resident village in the 3 weeks prior to diagnosis and 36.3% reported never using a bed net whilst sleeping in their resident village, which increased to 72.2% when sleeping away from their resident village. Malaria post assessments performed in 82.3% of the METF malaria posts found malaria posts generally performed to a high standard. Conclusions Surveillance data collected by the METF programme demonstrate that despite significant changes in the context in which the programme operates, malaria posts have remained accessible and continue to provide early diagnosis and treatment contributing to an 89.3% decrease in Plasmodium falciparum incidence between 2014 and 2021.

Tafenoquine is a newly licensed antimalarial drug for the radical cure of Plasmodium vivax malaria. The mechanism of action and optimal dosing are uncertain. We pooled individual data from 1102 patients and 72 healthy volunteers studied in the pre-registration trials. We show that tafenoquine dose is the primary determinant of efficacy. Under an Emax model, we estimate the currently recommended 300 mg dose in a 60 kg adult (5 mg/kg) results in 70% of the maximal obtainable hypnozoiticidal effect. Increasing the dose to 7.5 mg/kg (i.e. 450 mg) would result in 90% reduction in the risk of P. vivax recurrence. After adjustment for dose, the tafenoquine terminal elimination half-life, and day 7 methaemoglobin concentration, but not the parent compound exposure, were also associated with recurrence. These results suggest that the production of oxidative metabolites is central to tafenoquine’s hypnozoiticidal efficacy. Clinical trials of higher tafenoquine doses are needed to characterise their efficacy, safety and tolerability.

Abstract Background Providing at-risk communities with uninterrupted access to early diagnosis and treatment is a key component in reducing malaria transmission and achieving elimination. As programmes approach malaria elimination targets it is critical that each case is tested and treated early, which may present a challenge when the burden of malaria is reduced. In this paper we investigate whether malaria testing rates decline over time and assess the impacts of integrating malaria and non-malaria services on testing rates in the malaria elimination task force (METF) programme in the Kayin state of Myanmar. Methods A retrospective analysis was conducted using weekly collected data on testing rates from a network of more than 1200 malaria posts during the period from 2014 to 2020. To determine whether monthly testing rates changed over the years of programme operations, and whether integrating malaria and non-malaria services impacted these testing rates, we fitted negative binomial mixed-effects regression models to aggregate monthly data, accounting for malaria seasonal variation. Results In the first year of malaria post operation, testing rates declined, correlating with a decline in attendance by people from outside the malaria post catchment area, but then remained fairly constant (the Rate Ratio (RR) for 2nd versus 1st year open ranged from 0.68 to 0.84 across the four townships included in the analysis, the RR for 3rd to 6th year versus 1st year open were similar, ranging from 0.59–0.78). The implementation of a training programme, which was intended to expand the role of the malaria post workers, had minimal impact on testing rates up to 24 months after training was delivered (RR for integrated versus malaria-only services ranged from 1.00 to 1.07 across METF townships). Conclusion Despite the decline in malaria incidence from 2014 to 2020, there has been no decline in the malaria testing rate in the METF programme after the establishment of the complete malaria post network in 2016. While the integration of malaria posts with other health services provides benefits to the population, our evaluation questions the necessity of integrated services in maintaining malaria testing rates in areas approaching elimination of malaria.

Drug and target discovery for advanced liver disease are hampered by a lack of suitable models for clinical translation. Here the authors present a human liver cell-based system modeling a clinical prognostic signature allowing to propose nizatidine for treatment of advanced liver fibrosis and hepatocellular carcinoma prevention.

Deep-sea mussels Bathymodiolus azoricus, from Azorean hydrothermal vents, house two types of symbionts in their fleshy gills: methane-oxidizing (MOX) and sulfide-oxidizing (SOX) Gamma-proteobacteria. As soon as the mussels are collected, their symbionts are deprived from their environmental nutrient flux, and cannot rely on their usual metabolism. Recent studies have shown that the gill cells undergo high rates of apoptosis, as well as regionalized cell proliferation. This study follows the fate of the symbionts and of the hosting bacteriocytes at the ultrastructural level, during an extended starvation period. Just upon collection, we evidenced an apico-basal journey of the symbionts in the bacteriocytes, starting with (1) apical single symbiont endocytosis, (2) symbiont division, (3) symbiont storage, (4) and symbiont digestion within lysosomes, above the basal lamina. After 4-9 days starvation, endocytosis occurred with (5) empty blebbing, (6) the lysosomes increased in size, and the bacteriocytes lost their apical membrane, resulting in (7) a baso-apical return of the symbiont-containing lysosomes outside the gills, while the nucleus showed condensed chromatin, characteristic of apoptosis/necroptosis (8). Between the bacteriocytes, narrow intercalary cells appear to divide (9). Our hypothesis is that intercalary cells are stem cells that replace lost bacteriocytes. After 61 days there was no symbiont left, and the epidermis resembled those of the non-symbiotic filter-feeding mussel Mytilus edulis.

Button-Simons et al. report on two different genetic crosses of Plasmodium falciparum derived from Asian and African origin parasites, and generate large numbers of recombinant progeny. These crosses are characterized and have the potential to map biologically important traits across parasite genomes.

Abstract Single Encounter Radical Cure and Prophylaxis (SERCAP) describes an ideal anti-malarial drug that cures all malaria in a single dose. This target product profile has dominated anti-malarial drug discovery and development over the past decade. The operational advantage of a single encounter has to be balanced against the need for a high dose, reliable absorption, little variability in pharmacokinetic properties, slow elimination (to ensure curative drug exposures in all patients) and a very low rate of vomiting. The demanding aspirational target may have hindered anti-malarial drug development. Aiming for three-day regimens, as in current anti-malarial treatments, would be better.

Abstract Background Tracking and understanding artemisinin resistance is key for preventing global setbacks in malaria eradication efforts. The ring-stage survival assay (RSA) is the current gold standard for in vitro artemisinin resistance phenotyping. However, the RSA has several drawbacks: it is relatively low throughput, has high variance due to microscopy readout, and correlates poorly with the current benchmark for in vivo resistance, patient clearance half-life post-artemisinin treatment. Here a modified RSA is presented, the extended Recovery Ring-stage Survival Assay (eRRSA), using 15 cloned patient isolates from Southeast Asia with a range of patient clearance half-lives, including parasite isolates with and without kelch13 mutations. Methods Plasmodium falciparum cultures were synchronized with single layer Percoll during the schizont stage of the intraerythrocytic development cycle. Cultures were left to reinvade to early ring-stage and parasitaemia was quantified using flow cytometry. Cultures were diluted to 2% haematocrit and 0.5% parasitaemia in a 96-well plate to start the assay, allowing for increased throughput and decreased variability between biological replicates. Parasites were treated with 700 nM of dihydroartemisinin or 0.02% dimethyl sulfoxide (DMSO) for 6 h, washed three times in drug-free media, and incubated for 66 or 114 h, when samples were collected and frozen for PCR amplification. A SYBR Green-based quantitative PCR method was used to quantify the fold-change between treated and untreated samples. Results 15 cloned patient isolates from Southeast Asia with a range of patient clearance half-lives were assayed using the eRRSA. Due to the large number of pyknotic and dying parasites at 66 h post-exposure (72 h sample), parasites were grown for an additional cell cycle (114 h post-exposure, 120 h sample), which drastically improved correlation with patient clearance half-life compared to the 66 h post-exposure sample. A Spearman correlation of − 0.8393 between fold change and patient clearance half-life was identified in these 15 isolates from Southeast Asia, which is the strongest correlation reported to date. Conclusions eRRSA drastically increases the efficiency and accuracy of in vitro artemisinin resistance phenotyping compared to the traditional RSA, which paves the way for extensive in vitro phenotyping of hundreds of artemisinin resistant parasites.

Abstract Background Competitive outcomes between co-infecting malaria parasite lines can reveal fitness disparities in blood stage growth. Blood stage fitness costs often accompany the evolution of drug resistance, with the expectation that relatively fitter parasites will be more likely to spread in populations. With the recent emergence of artemisinin resistance, it is important to understand the relative competitive fitness of the metabolically active asexual blood stage parasites. Genetically distinct drug resistant parasite clones with independently evolved sets of mutations are likely to vary in asexual proliferation rate, contributing to their chance of transmission to the mosquito vector. Methods An optimized in vitro 96-well plate-based protocol was used to quantitatively measure-head-to-head competitive fitness during blood stage development between seven genetically distinct field isolates from a hotspot of emerging artemisinin resistance and the laboratory strain, NF54. These field isolates were isolated from patients in Southeast Asia carrying different alleles of kelch13 and included both artemisinin-sensitive and artemisinin-resistant isolates. Fluorescent labeled microsatellite markers were used to track the relative densities of each parasite throughout the co-growth period of 14–60 days. All-on-all competitions were conducted for the panel of eight parasite lines (28 pairwise competitions) to determine their quantitative competitive fitness relationships. Results Twenty-eight pairwise competitive growth outcomes allowed for an unambiguous ranking among a set of seven genetically distinct parasite lines isolated from patients in Southeast Asia displaying a range of both kelch13 alleles and clinical clearance times and a laboratory strain, NF54. This comprehensive series of assays established the growth relationships among the eight parasite lines. Interestingly, a clinically artemisinin resistant parasite line that carries the wild-type form of kelch13 outcompeted all other parasites in this study. Furthermore, a kelch13 mutant line (E252Q) was competitively more fit without drug than lines with other resistance-associated kelch13 alleles, including the C580Y allele that has expanded to high frequencies under drug pressure in Southeast Asian resistant populations. Conclusions This optimized competitive growth assay can be employed for assessment of relative growth as an index of fitness during the asexual blood stage growth between natural lines carrying different genetic variants associated with artemisinin resistance. Improved understanding of the fitness costs of different parasites proliferating in human blood and the role different resistance mutations play in the context of specific genetic backgrounds will contribute to an understanding of the potential for specific mutations to spread in populations, with the potential to inform targeted strategies for malaria therapy.

Abstract Background Improving access to early diagnosis and treatment (EDT) has increasingly proven to be a major contributor to decreasing malaria incidence in low-transmission settings. The Malaria Elimination Task Force (METF) has deployed malaria posts set up in Eastern Myanmar, providing free uninterrupted community-based access to EDT in more than 1200 villages. Ensuring high quality services are provided by these malaria posts is essential to reaching elimination targets. The present study aimed to determine the functionality of the malaria posts in the METF programme. Methods This report analysed routinely collected data (weekly reports, individual consultation, diagnostic test quality control) and data collected specifically during monitoring and evaluation visits using descriptive statistics and univariate logistic regression. The presence of major dysfunctions (stock-outs and reported closing; likely to impair the ability of the population to access EDT) or minor dysfunctions (no formal METF training, lack of regular salary, forms and manual not on-site, and low frequency of supervisor visits) and the ability to anticipate dysfunctions through analysis of weekly reports were assessed. Results A total of 65% of malaria posts had no major dysfunction identified during monitoring and evaluation visits, while 86% of malaria posts were fully stocked with tests and medicines used for treatment. Diagnosis was correctly conducted with few false positives and rare mis-speciation of results. Malaria post worker knowledge of malaria treatments showed few gaps, mostly in the treatment of more complex presentations. Malaria posts were well utilized in the population, with 94% of consultations occurring within the first 3 days of fever. In the regression analysis, reported stock-outs and delayed weekly reports were associated with observed major and minor dysfunctions in monitoring and evaluation visits, emphasizing the need to reinforce support to malaria post supervisors, who were responsible for the local logistics of supply and data transmission and day-to-day supervision. Conclusion The malaria posts operating under the METF programme perform to a high standard, with the majority offering uninterrupted access to diagnosis and treatment, and high service uptake in the villages serviced by the programme. However, programme operations can be strengthened by increasing malaria post supervisor visits and re-training malaria post workers.

Abstract Background Colonization of deep-sea hydrothermal vents by most invertebrates was made efficient through their adaptation to a symbiotic lifestyle with chemosynthetic bacteria, the primary producers in these ecosystems. Anatomical adaptations such as the establishment of specialized cells or organs have been evidenced in numerous deep-sea invertebrates. However, very few studies detailed global inter-dependencies between host and symbionts in these ecosystems. In this study, we proposed to describe, using a proteo-transcriptomic approach, the effects of symbionts loss on the deep-sea mussel Bathymodiolus azoricus’ molecular biology. We induced an in situ depletion of symbionts and compared the proteo-transcriptome of the gills of mussels in three conditions: symbiotic mussels (natural population), symbiont-depleted mussels and aposymbiotic mussels. Results Global proteomic and transcriptomic results evidenced a global disruption of host machinery in aposymbiotic organisms. We observed that the total number of proteins identified decreased from 1118 in symbiotic mussels to 790 in partially depleted mussels and 761 in aposymbiotic mussels. Using microarrays we identified 4300 transcripts differentially expressed between symbiont-depleted and symbiotic mussels. Among these transcripts, 799 were found differentially expressed in aposymbiotic mussels and almost twice as many in symbiont-depleted mussels as compared to symbiotic mussels. Regarding apoptotic and immune system processes – known to be largely involved in symbiotic interactions – an overall up-regulation of associated proteins and transcripts was observed in symbiont-depleted mussels. Conclusion Overall, our study showed a global impairment of host machinery and an activation of both the immune and apoptotic system following symbiont-depletion. One of the main assumptions is the involvement of symbiotic bacteria in the inhibition and regulation of immune and apoptotic systems. As such, symbiotic bacteria may increase their lifespan in gill cells while managing the defense of the holobiont against putative pathogens.

Introduction To examine the interactions between short maternal stature, body mass index (BMI) and gestational weight gain (GWG) among appropriate for gestational age (AGA) term newborns in a population of refugees and migrants in Southeast Asia.Methods This is a retrospective cohort study from 2004 to 2016, including women delivering term, singleton newborns, with first trimester height, weight and gestation dated by ultrasound and a last body weight measured within 4 weeks of birth. AGA newborns were those not classified as small for gestational age or large for gestational age by either INTERGROWTH-21st or Gestation Related Optimal Weight standards. The influence of maternal stature on GWG in delivering an AGA newborn was analysed, with GWG compared with existing National Academy of Medicine (NAM) recommendations.Results 4340 women delivered AGA newborns. Mean maternal height (SD) was 151.5 cm (5.13), with 58.5% of women considered too short by INTERGROWTH-21st standards. Only one in four women (26.5%, 1150/4340) had GWG within NAM recommendations. Women of shorter stature had a significantly lower mean GWG compared with taller women in underweight and normal BMI categories (p

Host-microbe interactions play crucial roles in marine ecosystems. However, we still have very little understanding of the mechanisms that govern these relationships, the evolutionary processes that shape them, and their ecological consequences. The holobiont concept is a renewed paradigm in biology that can help to describe and understand these complex systems. It posits that a host and its associated microbiota with which it interacts, form a holobiont, and have to be studied together as a coherent biological and functional unit to understand its biology, ecology, and evolution. Here we discuss critical concepts and opportunities in marine holobiont research and identify key challenges in the field. We highlight the potential economic, sociological, and environmental impacts of the holobiont concept in marine biological, evolutionary, and environmental sciences. Given the connectivity and the unexplored biodiversity specific to marine ecosystems, a deeper understanding of such complex systems requires further technological and conceptual advances, e.g., the development of controlled experimental model systems for holobionts from all major lineages and the modeling of (info)chemical-mediated interactions between organisms. Here we propose that one significant challenge is to bridge cross-disciplinary research on tractable model systems in order to address key ecological and evolutionary questions. This first step is crucial to decipher the main drivers of the dynamics and evolution of holobionts and to account for the holobiont concept in applied areas, such as the conservation, management, and exploitation of marine ecosystems and resources, where practical solutions to predict and mitigate the impact of human activities are more important than ever.

Four in five neonatal deaths of preterm births occur in low and middle income countries and placental histopathology examination can help clarify the pathogenesis. Infection is known to play a significant role in preterm birth. The aim of this systematic review is to explore the association between placental histopathological abnormality and preterm birth in the presence of confirmed infection. PubMed/Medline, Scopus, Web of Science and Embase were searched using the keywords related to preterm birth, placental histopathology and infection. Titles and abstracts were screened and the full texts of eligible articles were reviewed to extract and summarise data. Of 1529 articles, only 23 studies (13 bacterial, 6 viral and 4 parasitic) were included, and they used 7 different gestational age windows, and 20 different histopathological classification systems, precluding data pooling. Despite this, histopathological chorioamnionitis, and funisitis (when examined) were commonly observed in preterm birth complicated by confirmed bacterial or viral, but not parasitic, infection. The presence of malaria parasites but not pigment in placenta was reported to increase the risk of PTB, but this finding was inconclusive. One in three studies were conducted in low and middle income countries. An array of: definitions of preterm birth subgroups, histological classification systems, histopathologic abnormalities and diagnostic methods to identify infections were reported in this systematic review. Commitment to using standardised terminology and classification of histopathological abnormalities associated with infections is needed to identify causality and potential treatment of preterm birth. Studies on preterm birth needs to occur in high burden countries and control for clinical characteristics (maternal, fetal, labor, and placental) that may have an impact on placental histopathological abnormalities.

BackgroundElectrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.Methods and findingsWe conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.ConclusionsAdjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

The optimized design of a photonic platform based on a nanowire light emitting diode (LED) and a nanowire photodetector connected with a waveguide is proposed. The light coupling efficiency from the LED to the detector is optimized as a function of the geometrical parameters of the system using the finite difference time domain simulation tool Lumerical. Starting from a design reported in the literature with a coupling efficiency of only 8.7%, we propose an optimized photonic platform with efficiency reaching 65.5%.

Purpose: To evaluate the morbidity and efficacy of percutaneous radiofrequency ablation (RFA) performed before surgical resection for multiple residual lung metastases of germ cell tumors with negative tumor markers. Materials and Methods: This Review Board-approved retrospective study was carried out on five consecutive patients (mean age: 31 years, range: 22–41) treated successively with percutaneous RFA and surgery for multiple lung metastases of germ cell tumors. Mean number of lung metastases before treatment was 9.4. Staged procedures were performed on an average of 7.2 months (range: 1–16) after the primitive tumor resection. Results: The median clinical and imaging follow-up was 26 months (range: 24–36). Percutaneous RFA was technically feasible in one session under general anesthesia and CT guidance in all cases. On average, 2.8 tumors were ablated per patient (range: 1–6), and three of five procedures were bilateral. Three patients developed pneumothorax requiring drainage, but no severe complications were reported. Mean time between RFA and surgical resection of residual tumors was 2.5 months (range: 1–5). No local recurrences were noted, but one patient died due to metastatic evolution. Conclusion: Staged percutaneous RFA and surgical resection could be efficient with low morbidity for the management of multiple lung metastases of germ cell tumors.

Background : Natural Wolbachia infections in malaria mosquitoes were recently reported in Africa, and negatively correlated with the development of Plasmodium falciparum in the vectors. The occurrence and effects of Wolbachia infections outside Africa have not been described and may have been underestimated. Methods : Mosquitoes were collected by human-landing catch during May and June 2017 in ten villages in Kayin state, Myanmar. Closely related species of malaria vectors were identified with molecular assays. 16S rRNA Wolbachia DNA sequences were detected with quantitative real-time PCR. Results: Low titer of Wolbachia DNA was detected in 13/370 samples in six malaria vector species. Sequences were diverse and different from those described in the African malaria mosquitoes. Conclusion: The detection of Wolbachia DNA in malaria mosquitoes from Kayin state warrants further investigations to understand better the ecology and biology of Anopheles-Wolbachia interactions in Southeast Asia.

Background: The Thailand-Myanmar borderland is an area endemic for malaria where transmission is low, seasonal and unstable. The epidemiology has been described but there is relatively few data on the entomological determinants of malaria transmission. Methods: Entomological investigations were conducted during 24 months in four villages located in Kayin state, on the Myanmar side of the Thailand-Myanmar border. Anopheles mosquitoes were identified by morphology, and molecular assays were used in order to discriminate between closely related sibling species of malaria vectors. Plasmodium infection rate was determined using quantitative real-time PCR. Results: The diversity of Anopheles mosquitoes was very high and multiple species were identified as malaria vectors. The intensity of human-vector contact (mean human-biting rate= 369 bites/person/month) compensates for the low infection rate in naturally infected populations of malaria vectors (mean sporozoite index= 0.04 and 0.17 % for P. falciparum and P. vivax respectively), yielding intermediary level of transmission intensity (mean entomological inoculation rate= 0.13 and 0.64 infective bites/person/month for P. falciparum and P. vivax, respectively). Only 36% of the infected mosquitoes were collected indoors between 09:00 pm and 05:00 am, suggesting that mosquito bed-nets would fail to prevent most of the infective bites in the study area. Conclusion: This study provided a unique opportunity to describe the entomology of malaria in low transmission settings of Southeast Asia. Our data are important in the context of malaria elimination in the Greater Mekong Subregion.

Background: The Thailand-Myanmar borderland is an area endemic for malaria where transmission is low, seasonal and unstable. The epidemiology has been described but there is relatively few data on the entomological determinants of malaria transmission. Methods: Entomological investigations were conducted during 24 months in four villages located in Kayin state, on the Myanmar side of the Thailand-Myanmar border. Anopheles mosquitoes were identified by morphology, and molecular assays were used in order to discriminate between closely related sibling species of malaria vectors. Plasmodium infection rate was determined using quantitative real-time PCR. Results: The diversity of Anopheles mosquitoes was very high and multiple species were identified as malaria vectors. The intensity of human-vector contact (mean human-biting rate= 369 bites/person/month) compensates for the low infection rate in naturally infected populations of malaria vectors (mean sporozoite index= 0.04 and 0.17 % for P. falciparum and P. vivax respectively), yielding intermediary level of transmission intensity (mean entomological inoculation rate= 0.13 and 0.64 infective bites/person/month for P. falciparum and P. vivax, respectively). Only 36% of the infected mosquitoes were collected indoors between 09:00 pm and 05:00 am, suggesting that mosquito bed-nets would fail to prevent most of the infective bites in the study area. Conclusion: This study provided a unique opportunity to describe the entomology of malaria in low transmission settings of Southeast Asia. Our data are important in the context of malaria elimination in the Greater Mekong Subregion.

Background and objectives: Hip fracture is a major public health issue. Those fractures lead to high costs and a decrease in quality of life. A national French survey was conducted, with the objectives to firstly assess the current management of hip fracture and its prevention, both in the osteoporotic and cancer settings, and secondly to evaluate the opinions of physicians on the potential use of minimally invasive implantable devices to prevent hip fracture in alternative of surgery. Materials and methods: This national survey was conducted in France between April and July 2017. Questionnaires were sent to orthopedic surgeons, interventional radiologists, oncologists, and rheumatologists. Completed questionnaires were analyzed and compared according to two indications: orthopedics-traumatology and oncology. Factors associated with these responses were assessed using univariable analyses, based on chi-square tests or an exact Fisher test, as appropriate. Results: A total of 182 questionnaires were completed and further analyzed. Physicians have highlighted the need for a low re-fracture rate and to improve life expectancy for more than 1 year (50% for responders of the orthopedics-traumatology questionnaire and 80% for the responders interested in both indications), as well as quality of life (12.5% and 31%, respectively), but with no significant differences in the oncologic indication. Most of the experts were willing to use or prescribe implantable devices for prevention (63% in orthopedics-traumatology and 93% in oncology), although limited clinical experience (54 and 58%) and surgical risk (around 30% in each indication) were considered as limits. Conclusions: Prevention of hip fracture remains a concern for physicians. More clinical experience with implantable devices, in particular in cancer patients, is needed, but implemented in a strategy to maximize patient recovery while reducing costs.

Symbiosis between Bathymodiolus and Gammaproteobacteria allows these deep-sea mussels to live in toxic environments such as hydrothermal vents and cold seeps. The quantity of endosymbionts within the gill-bacteriocytes appears to vary according to the hosts environment; however, the mechanisms of endosymbiont population size regulation remain obscure. We investigated the possibility of a control of endosymbiont density by apoptosis, a programmed cell death, in three mussel species. Fluorometric TUNEL and active Caspase-3-targeting antibodies were used to visualize and quantify apoptotic cells in mussel gills. To control for potential artefacts due to depressurization upon specimen recovery from the deep-sea, the apoptotic rates between mussels recovered unpressurised, versus mussels recovered in a pressure-maintaining device, were compared in two species from hydrothermal vents on the Mid-Atlantic Ridge: Bathymodiolus azoricus and B. puteoserpentis. Results show that pressurized recovery had no significant effect on the apoptotic rate in the gill filaments. Apoptotic levels were highest in the ciliated zone and in the circulating hemocytes, compared to the bacteriocyte zone. Apoptotic gill-cells in B. aff. boomerang from cold seeps off the Gulf of Guinea show similar distribution patterns. Deep-sea symbiotic mussels have much higher rates of apoptosis in their gills than the coastal mussel Mytilus edulis, which lacks chemolithoautotrophic symbionts. We discuss how apoptosis might be one of the mechanisms that contribute to the adaptation of deep-sea mussels to toxic environments and/or to symbiosis.

Background : No universal demarcation of gestational age distinguishes miscarriage and stillbirth or extreme preterm birth (exPTB). This study provides a synopsis of outcome between 22 to

Background: Myanmar has one of the largest malaria burdens in the Greater Mekong Subregion (GMS). Throughout the GMS, Plasmodium falciparum parasites are increasingly resistant to artemisinin combination therapies. Given that there are no current alternative treatment therapies, one proposed solution to the threat of untreatable P. falciparum malaria is to eliminate the parasite from the region. Several small-scale elimination projects have been piloted in the GMS, including along the Myanmar-Thailand border. Following the success of the pilot elimination project along the Myanmar-Thailand border, there was a scale up to a broad area of Eastern Kayin State, Myanmar. Here we describe the establishment of the scale up elimination project in Easter Kayin State. Methods: The scale up relied on geographic reconnaissance and a geographic information system, community engagement, generalized access to community-based early diagnosis and treatment, near real-time epidemiological surveillance, cross sectional malaria prevalence surveys and targeted mass drug administration in villages with high prevalence of P. falciparum malaria. Molecular markers of drug resistance were also monitored in individuals with symptomatic and asymptomatic infections. Discussion: This protocol illustrates the establishment of an elimination project and operational research in a remote, rural area encompassing several armed groups, multiple political organizations and a near-absent health care infrastructure. The establishment of the project relied on a strong rapport with the target community, on-the-ground knowledge (through geographic surveys and community engagement), rapid decision making and an approach that was flexible enough to quickly adapt to a complex landscape. The elimination project is ongoing, now over three years in operation, and assessment of the impact of this operational research will follow. This project has relevance not only for other malaria elimination projects but also for operational research aimed at eliminating other diseases.

Background: Myanmar has one of the largest malaria burdens in Southeast Asia. Along the border with Thailand, Plasmodium falciparum parasites are increasingly showing reduced sensitivity to artemisinin combination therapies. Given that there are no current alternative treatment therapies, one proposed solution to the threat of untreatable P. falciparum malaria is to eliminate the parasite from the region. Several small-scale elimination projects have been piloted along the Myanmar-Thailand border. Following their success, this operational research aimed to scale up the elimination to a broad area of Eastern Kayin State, Myanmar. Methods: The project relied on geographic reconnaissance and a geographic information system, community engagement, generalized access to community-based early diagnosis and treatment, near real-time epidemiological surveillance, cross sectional malaria prevalence surveys and targeted mass drug administration in villages with high prevalence of P. falciparum malaria. Molecular markers of drug resistance were also monitored in individuals with symptomatic and asymptomatic infections. Discussion: This project illustrates the establishment of an elimination project and operational research in a remote, rural area encompassing several armed groups, multiple political organizations and a near-absent health care infrastructure. The establishment of the project relied on a strong rapport with the target community, on-the-ground knowledge (through geographic surveys and community engagement), rapid decision making and an approach that was flexible enough to quickly adapt to a complex landscape. The elimination project is ongoing, now over three years in operation, and assessment of the impact of this operational research will follow. This project has relevance not only for other malaria elimination projects but also for operational research aimed at eliminating other diseases.

Background: Artemisinin and partner drug-resistant falciparum malaria is expanding over the Greater Mekong Sub-region (GMS). Eliminating falciparum malaria in the GMS while drugs still retain enough efficacy could prevent global spread of antimalarial resistance. Eliminating malaria rapidly requires targeting the reservoir of asymptomatic parasite carriers. This pilot trial aimed to evaluate the acceptability, safety, feasibility and effectiveness of mass-drug administration (MDA) in reducing malaria in four villages in Eastern Myanmar. Methods: Villages with ≥30% malaria prevalence were selected. Long-lasting insecticidal bednets (LLINs) and access to malaria early diagnosis and treatment (EDT) were provided. Two villages received MDA immediately and two were followed for nine months pre-MDA. MDA consisted of a 3-day supervised course of dihydroartemisinin-piperaquine and single low-dose primaquine administered monthly for three months. Adverse events (AE) were monitored by interviews and consultations. Malaria prevalence was assessed by ultrasensitive PCR quarterly for 24 months. Symptomatic malaria incidence,entomological indices, and antimalarial resistance markers were monitored. Results: MDA was well tolerated. There were no serious AE and mild to moderate AE were reported in 5.6%(212/3931) interviews. In the smaller villages, participation to three MDA courses was 61% and 57%, compared to 28% and 29% in the larger villages. Baseline prevalence was higher in intervention than in control villages (18.7% (95%CI=16.1-21.6) versus 6.8%(5.2-8.7), p

This review aimed to identify the potential role of integrative medicine in interventional oncology. The music therapy; stress management techniques; guided imagery, including virtual reality; clinical hypnosis; and digital sedation may all be efficient on anxiety and pain during procedures performed in interventional oncology. Beyond pharmacological sedation, the implementation of integrative medicine to interventional oncology may, therefore, improve the support and care of cancer patients, which may further create a virtuous alliance.

Background and objectives: Patients suffering from bone metastasis are at high risk for pathological fractures and especially hip fractures. Osteolytic metastases can induce a high morbidity rate (i.e., pain, facture risk, mobility impairment), and operation on them can be difficult in this frail population having a reduced life expectancy. Several medical devices have been investigated for the prevention of these pathological hip fractures. Materials and Methods: To investigate these solutions, a literature review and a meta-analysis of primary studies was performed. Data sources included electronic databases (PubMed, CENTRAL and ClinicalTrials.gov) from 1990 until 1 January 2019. Titles, abstracts and full-text articles were reviewed in order to select only studies evaluating the performance of the studied solution to prevent osteoporotic and/or pathological hip fracture. The main outcomes were the occurrence of hip fracture, pain evaluation (VAS score) and adverse events occurrence (including severe adverse events and deaths). All randomised controlled trials (RCTs) and cohort studies were considered. A Bayesian cumulative meta-analysis was undertaken on the primary studies conducted in patients with bone metastasis. Results: A total of 12 primary studies were identified, all were cohort studies without a control group, and one compared two devices, and were thereafter considered separately. In those 12 samples, 255 patients were included, mean age 61.7 years. After implantation, the cumulative risk of fracture was 5.5% (95% confidence interval, 3.0% to 8.6%), and adverse event occurrence was 17.4% (95%CI, 12.6 to 22.8%), with a median follow-up of 10 months. The posterior probability of a fracture rate below 5% was 40.3%. Conclusions: The literature about medical devices evaluation for preventing hip fractures in metastatic patients is poor and mostly based on studies with a limited level of evidence. However, this systematic review shows promising results in terms of efficacy and tolerance of these devices in patients with bone metastases. This treatment strategy requires further investigations.

We report on the systematic study of two main scattering mechanisms on intersubband transitions, namely ionized impurity scattering and interface roughness scattering. The former mechanism has been investigated as a function of the dopants position within a multiple GaAs/AlGaAs quantum well structure and compared to the transition of an undoped sample. The study on the latter scattering mechanism has been conducted using the growth interruption technique. We report an improvement of the intersubband (ISB) transition linewidth up to 11% by interrupting growth at GaAs-on-AlGaAs interfaces. As a result, the lifetime of intersubband polaritons could be improved up to 9%. This leads to a reduction of 17% of the theoretical threshold intensity for polaritonic coherent emission. This work brings a useful contribution towards the realization of polariton-based devices.

We describe the epidemiology of influenza virus infections in refugees in a camp in rural Southeast Asia during May–October 2009, the first 6 months after identification of pandemic (H1N1) 2009 in Thailand. Influenza A viruses were detected in 20% of patients who had influenza-like illness and in 23% of those who had clinical pneumonia. Seasonal influenza A (H1N1) was the predominant virus circulating during weeks 26–33 (June 25–August 29) and was subsequently replaced by the pandemic strain. A review of passive surveillance for acute respiratory infection did not show an increase in acute respiratory tract infection incidence associated with the arrival of pandemic (H1N1) 2009 in the camp.

Neurological examination, including visual fixation and tracking of a target, is routinely performed in the Shoklo Malaria Research Unit postnatal care units on the Thailand-Myanmar border. We aimed to evaluate a simple visual newborn test developed in Italy and performed by non-specialized personnel working in neonatal care units. An intensive training of local health staff in Thailand was conducted prior to performing assessments at 24, 48 and 72 hours of life in healthy, low-risk term singletons. The 48 and 72 hours results were then compared to values obtained to those from Italy. Parents and staff administering the test reported on acceptability. One hundred and seventy nine newborns, between June 2011 and October 2012, participated in the study. The test was rapidly completed if the infant remained in an optimal behavioral stage (7 ± 2 minutes) but the test duration increased significantly (12 ± 4 minutes, p < 0.001) if its behavior changed. Infants were able to fix a target and to discriminate a colored face at 24 hours of life. Horizontal tracking of a target was achieved by 96% (152/159) of the infants at 48 hours. Circular tracking, stripe discrimination and attention to distance significantly improved between each 24-hour test period. The test was easily performed by non-specialized local staff and well accepted by the parents. Healthy term singletons in this limited-resource setting have a visual response similar to that obtained to gestational age matched newborns in Italy. It is possible to use these results as a reference set of values for the visual assessment in Karen and Burmese infants in the first 72 hours of life. The utility of the 24 hours test should be pursued.

The aim of this study was first to identify lysozymes paralogs in the deep sea mussel Bathymodiolus azoricus then to measure their relative expression or activity in different tissue or conditions. B. azoricus is a bivalve that lives close to hydrothermal chimney in the Mid-Atlantic Ridge (MAR). They harbour in specialized gill cells two types of endosymbiont (gram-bacteria): sulphide oxidizing bacteria (SOX) and methanotrophic bacteria (MOX). This association is thought to be ruled by specific mechanism or actors of regulation to deal with the presence of symbiont but these mechanisms are still poorly understood. Here, we focused on the implication of lysozyme, a bactericidal enzyme, in this endosymbiosis. The relative expression of Ba-lysozymes paralogs and the global anti-microbial activity, were measured in natural population (Lucky Strike--1700 m, Mid-Atlantic Ridge), and in in situ experimental conditions. B. azoricus individuals were moved away from the hydrothermal fluid to induce a loss of symbiont. Then after 6 days some mussels were brought back to the mussel bed to induce a re-acquisition of symbiotic bacteria. Results show the presence of 6 paralogs in B. azoricus. In absence of symbionts, 3 paralogs are up-regulated while others are not differentially expressed. Moreover the global activity of lysozyme is increasing with the loss of symbiont. All together these results suggest that lysozyme may play a crucial role in symbiont regulation.

Malaria vaccine development has largely focused on Plasmodium falciparum; however a reawakening to the importance of P. vivax has spurred efforts to develop vaccines against this difficult to treat and at times severe form of relapsing malaria, which constitutes a significant proportion of human malaria cases worldwide. The almost complete dependence of P. vivax red blood cell invasion on the interaction of the P. vivax Duffy-binding protein region II (PvDBP_RII) with the human Duffy antigen receptor for chemokines (DARC), makes this antigen an attractive vaccine candidate against blood-stage P. vivax. Here, we generated both preclinical and clinically-compatible adenoviral and poxviral vectored vaccine candidates expressing the Salvador I allele of PvDBP_RII – including human adenovirus serotype 5 (HAdV5), chimpanzee adenovirus serotype 63 (ChAd63) and modified vaccinia virus Ankara (MVA) vectors. We report on the antibody and T cell immunogenicity of these vaccines in mice or rabbits, either used alone in a viral vectored prime-boost regime, or in ‘mixed-modality’ adenovirus prime – protein-in-adjuvant boost regimes (using a recombinant protein PvDBP_RII protein antigen formulated in Montanide®ISA720 or Abisco®100 adjuvants). Antibodies induced by these regimes were found to bind to native parasite antigen from P. vivax infected Thai patients and were capable of inhibiting the binding of PvDBP_RII to its receptor DARC using an in vitro binding inhibition assay. In recent years, recombinant ChAd63 and MVA vectors have been quickly translated into human clinical trials for numerous antigens from P. falciparum as well as a growing number of other pathogens. The vectors reported here are immunogenic in small animals, elicit antibodies against PvDBP_RII and have recently entered clinical trials which will provide the first assessment of the safety and immunogenicity of the PvDBP_RII antigen in humans.

BackgroundThe collection and utilization of surveillance data is essential in monitoring progress towards achieving malaria elimination, in the timely response to increases in malaria case numbers and in the assessment of programme functioning. This paper describes the surveillance activities used by the malaria elimination task force (METF) programme which operates in eastern Myanmar, and provides an analysis of data collected from weekly surveillance, case investigations, and monitoring and evaluation of programme performance.MethodsThis retrospective analysis was conducted using data collected from a network of 1250 malaria posts operational between 2014 and 2021. To investigate changes in data completeness, malaria post performance, malaria case numbers, and the demographic details of malaria cases, summary statistics were used to compare data collected over space and time.ResultsIn the first 3 years of the METF programme, improvements in data transmission routes resulted in a 18.9% reduction in late reporting, allowing for near real-time analysis of data collected at the malaria posts. In 2020, travel restrictions were in place across Karen State in response to COVID-19, and from February 2021 the military coup in Myanmar resulted in widescale population displacement. However, over that period there has been no decline in malaria post attendance, and the majority of consultations continue to occur within 48 h of fever onset. Case investigations found that 43.8% of cases travelled away from their resident village in the 3 weeks prior to diagnosis and 36.3% reported never using a bed net whilst sleeping in their resident village, which increased to 72.2% when sleeping away from their resident village. Malaria post assessments performed in 82.3% of the METF malaria posts found malaria posts generally performed to a high standard.ConclusionsSurveillance data collected by the METF programme demonstrate that despite significant changes in the context in which the programme operates, malaria posts have remained accessible and continue to provide early diagnosis and treatment contributing to an 89.3% decrease in Plasmodium falciparum incidence between 2014 and 2021.

Tropical pathogens often cause febrile illnesses in humans and are responsible for considerable morbidity and mortality. The similarities in clinical symptoms provoked by these pathogens make diagnosis difficult. Thus, early, rapid and accurate diagnosis will be crucial in patient management and in the control of these diseases. In this study, a microfluidic lab-on-chip integrating multiplex molecular amplification and DNA microarray hybridization was developed for simultaneous detection and species differentiation of 26 globally important tropical pathogens. The analytical performance of the lab-on-chip for each pathogen ranged from 102 to 103 DNA or RNA copies. Assay performance was further verified with human whole blood spiked with Plasmodium falciparum and Chikungunya virus that yielded a range of detection from 200 to 4×105 parasites, and from 250 to 4×107 PFU respectively. This lab-on-chip was subsequently assessed and evaluated using 170 retrospective patient specimens in Singapore and Thailand. The lab-on-chip had a detection sensitivity of 83.1% and a specificity of 100% for P. falciparum; a sensitivity of 91.3% and a specificity of 99.3% for P. vivax; a positive 90.0% agreement and a specificity of 100% for Chikungunya virus; and a positive 85.0% agreement and a specificity of 100% for Dengue virus serotype 3 with reference methods conducted on the samples. Results suggested the practicality of an amplification microarray-based approach in a field setting for high-throughput detection and identification of tropical pathogens.

Mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene result in red blood cells with increased susceptibility to oxidative damage. Significant haemolysis can be caused by primaquine and other 8-aminoquinoline antimalarials used for the radical treatment of Plasmodium vivax malaria. The distribution and phenotypes of mutations causing G6PD deficiency in the male population of migrants and refugees in a malaria endemic region on the Thailand-Myanmar border were characterized. Blood samples for G6PD fluorescent spot test (FST), G6PD genotyping, and malaria testing were taken from 504 unrelated males of Karen and Burman ethnicities presenting to the outpatient clinics. The overall frequency of G6PD deficiency by the FST was 13.7%. Among the deficient subjects, almost 90% had the Mahidol variant (487G>A) genotype. The remaining subjects had Chinese-4 (392G>T), Viangchan (871G>A), Açores (595A>G), Seattle (844G>C) and Mediterranean (563C>T) variants. Quantification of G6PD activity was performed using a modification of the standard spectrophotometric assay on a subset of 24 samples with Mahidol, Viangchan, Seattle and Chinese-4 mutations; all samples showed a residual enzymatic activity below 10% of normal and were diagnosed correctly by the FST. Further studies are needed to characterise the haemolytic risk of using 8-aminoquinolines in patients with these genotypes.

Chloroquine was a cheap, extremely effective drug against Plasmodium falciparum until resistance arose. One approach to reversing resistance is the inhibition of chloroquine efflux from its site of action, the parasite digestive vacuole. Chloroquine accumulation studies have traditionally relied on radiolabelled chloroquine, which poses several challenges. There is a need for development of a safe and biologically relevant substitute. We report here a commercially-available green fluorescent chloroquine-BODIPY conjugate, LynxTag-CQGREEN, as a proxy for chloroquine accumulation. This compound localized to the digestive vacuole of the parasite as observed under confocal microscopy, and inhibited growth of chloroquine-sensitive strain 3D7 more extensively than in the resistant strains 7G8 and K1. Microplate reader measurements indicated suppression of LynxTag-CQGREEN efflux after pretreatment of parasites with known reversal agents. Microsomes carrying either sensitive- or resistant-type PfCRT were assayed for uptake; resistant-type PfCRT exhibited increased accumulation of LynxTag-CQGREEN, which was suppressed by pretreatment with known chemosensitizers. Eight laboratory strains and twelve clinical isolates were sequenced for PfCRT and Pgh1 haplotypes previously reported to contribute to drug resistance, and pfmdr1 copy number and chloroquine IC50s were determined. These data were compared with LynxTag-CQGREEN uptake/fluorescence by multiple linear regression to identify genetic correlates of uptake. Uptake of the compound correlated with the logIC50 of chloroquine and, more weakly, a mutation in Pgh1, F1226Y.

Comparative phylogeography of deep-sea hydrothermal vent species has uncovered several genetic breaks between populations inhabiting northern and southern latitudes of the East Pacific Rise. However, the geographic width and position of genetic clines are variable among species. In this report, we further characterize the position and strength of barriers to gene flow between populations of the deep-sea vent mussel Bathymodiolus thermophilus. Eight allozyme loci and DNA sequences of four nuclear genes were added to previously published sequences of the cytochrome c oxidase subunit I gene. Our data confirm the presence of two barriers to gene flow, one located at the Easter Microplate (between 21°33'S and 31°S) recently described as a hybrid zone, and the second positioned between 7°25'S and 14°S with each affecting different loci. Coalescence analysis indicates a single vicariant event at the origin of divergence between clades for all nuclear loci, although the clines are now spatially discordant. We thus hypothesize that the Easter Microplate barrier has recently been relaxed after a long period of isolation and that some genetic clines have escaped the barrier and moved northward where they have subsequently been trapped by a reinforcing barrier to gene flow between 7°25'S and 14°S.

BACKGROUND:Several studies have shown a prolonged or increased susceptibility to malaria in the post-partum period. A matched cohort study was conducted to evaluate prospectively the susceptibility to malaria of post-partum women in an area where P.falciparum and P.vivax are prevalent. METHODS:In an area of low seasonal malaria transmission on the Thai-Myanmar border pregnant women attending antenatal clinics were matched to a non-pregnant, non-post-partum control and followed up prospectively until 12 weeks after delivery. RESULTS:Post-partum women (n = 744) experienced significantly less P.falciparum episodes than controls (hazard ratio (HR) 0.39 (95%CI 0.21-0.72) p = 0.003) but significantly more P.vivax (HR 1.34 (1.05-1.72) p = 0.018). The reduced risk of falciparum malaria was accounted for by reduced exposure, whereas a history of P.vivax infection during pregnancy was a strong risk factor for P.vivax in post-partum women (HR 13.98 (9.13-21.41), p

IntroductionMaternal mortality is high in developing countries, but there are few data in high-risk groups such as migrants and refugees in malaria-endemic areas. Trends in maternal mortality were followed over 25 years in antenatal clinics prospectively established in an area with low seasonal transmission on the north-western border of Thailand.Methods and findingsAll medical records from women who attended the Shoklo Malaria Research Unit antenatal clinics from 12(th) May 1986 to 31(st) December 2010 were reviewed, and maternal death records were analyzed for causality. There were 71 pregnancy-related deaths recorded amongst 50,981 women who attended antenatal care at least once. Three were suicide and excluded from the analysis as incidental deaths. The estimated maternal mortality ratio (MMR) overall was 184 (95%CI 150-230) per 100,000 live births. In camps for displaced persons there has been a six-fold decline in the MMR from 499 (95%CI 200-780) in 1986-90 to 79 (40-170) in 2006-10, pConclusionsFrequent antenatal clinic screening allows early detection and treatment of falciparum malaria and substantially reduces maternal mortality from P. falciparum malaria. No significant decline has been observed in deaths from sepsis or other causes in refugee and migrant women on the Thai-Myanmar border.