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Abstract Hybrid ion capacitors (HICs) have aroused extreme interest due to their combined characteristics of energy and power densities. The performance of HICs lies hidden in the electrode materials used for the construction of battery and supercapacitor components. The hunt is always on to locate the best material in terms of cost‐effectiveness and overall optimized performance characteristics. Functionalized biomass‐derived porous carbons (FBPCs) possess exquisite features including easy synthesis, wide availability, high surface area, large pore volume, tunable pore size, surface functional groups, a wide range of morphologies, and high thermal and chemical stability. FBPCs have found immense use as cathode, anode and dual electrode materials for HICs in the recent literature. The current review is designed around two main concepts which include the synthesis and properties of FBPCs followed by their utilization in various types of HICs. Among monovalent HICs, lithium, sodium, and potassium, are given comprehensive attention, whereas zinc is the only multivalent HIC that is focused upon due to corresponding literature availability. Special attention is also provided to the critical factors that govern the performance of HICs. The review concludes by providing feasible directions for future research in various aspects of FBPCs and their utilization in HICs.

Abstract Background Physical activity has a range of health benefits for older people. The aim of this study was to determine physical activity prevalence and attitudes amongst respondents to a trial screening survey. Methods A cross-sectional survey was conducted. Subjects were community dwelling older people aged ≥ 65 years, recruited via general practices in Victoria, Australia. Participants completed a mailed screening tool containing the Geriatric Depression Scale, the Active Australia survey and the Physical Activity Readiness Questionnaire. Results Of 330 participants, 20% were ≥ 80 years. Activity levels were similar to those reported in population studies. The proportion of participants reporting physical activity was greatest for the walking category, but decreased across categories of physical activity intensity. The oldest-old were represented at all physical activity intensity levels. Over half reported exercising at levels that, according to national criteria are, 'sufficient to attain health benefit'. A greater proportion of participants aged 85 years and older were unaware of key physical activity messages, compared to participants aged less than 85 years. Conclusion Most population surveys do not provide details of older people across age categories. This survey provided information on the physical activity of people up to 91 years old. Physical activity promotion strategies should be tailored according to the individual's needs. A better understanding of the determinants of physical activity behaviour amongst older sub-groups is needed to tailor and target physical activity promotion strategies and programs to maximise physical activity related health outcomes for older people.

Abstract Background Depression is a disabling, prevalent condition. Physical activity programs may assist depression management in older people, ameliorate co-morbid conditions and reduce the need for antidepressants. The UPLIFT pilot study assessed the feasibility of older depressed people attending a community-based progressive resistance training (PRT) program. The study also aimed to determine whether PRT improves depressive status in older depressed patients. Methods A randomised controlled trial was conducted. People aged ≥ 65 years with depressive symptoms were recruited via general practices. Following baseline assessment, subjects were randomly allocated to attend a local PRT program three times per week for 10 weeks or a brief advice control group. Follow-up assessment of depressive status, physical and psychological health, functional and quality of life status occurred post intervention and at six months. Results Three hundred and forty six people responded to the study invitation, of whom 22% had depressive symptoms (Geriatric Depression Scale, GDS-30 score ≥ 11). Thirty two people entered the trial. There were no significant group differences on the GDS at follow-up. At six months there was a trend for the PRT intervention group to have lower GDS scores than the comparison group, but this finding did not reach significance (p = 0.08). More of the PRT group (57%) had a reduction in depressive symptoms post program, compared to 44% of the control group. It was not possible to discern which specific components of the program influenced its impact, but in post hoc analyses, improvement in depressive status appeared to be associated with the number of exercise sessions completed (r = -0.8, p < 0.01). Conclusion The UPLIFT pilot study confirmed that older people with depression can be successfully recruited to a community based PRT program. The program can be offered by existing community-based facilities, enabling its ongoing implementation for the potential benefit of other older people.

Factory-treated permethrin uniforms are the primary method used by the US Army to prevent arthropod bites and transmission of arthropod-borne diseases. In this study previously worn uniforms were collected from cadets at the United States Military Academy in West Point, NY to determine the amount of permethrin remaining after prolonged wear and subsequent effects on ticks. Six trousers were collected from cadets in the sophomore, junior, and senior classes. A new, unwashed uniform served as a positive control and an untreated maternity uniform served as a negative control. Fabric samples were removed from each trouser and used in bioassays with laboratory-reared Ixodes scapularis Say nymphs. Contact irritancy bioassays measured the nymphs' ability to remain in contact with fabric for a period of 5 min. Toxicity bioassays measured tick survival at 1 and 24 h after contacting uniform samples. liquid chromatography-mass spectrometry was used to quantify the permethrin content (mg/cm2) in each uniform after the bioassays were complete. The results showed significant amounts of permethrin were lost after extended wear and it was related to the cadet year group. The contact irritancy assays found uniforms with less permethrin did not irritate ticks and cause them to dislodge. Mortality was also affected by permethrin levels, with less ticks dying at 24 h on older uniforms. The results from this study show older uniforms lose most of their permethrin and no longer provide the same levels of protection., (Published by Oxford University Press on behalf of Entomological Society of America 2024.)

Objective: Intensive rehabilitation aims to improve and maintain functioning in young people who experience disability due to illness or injury. Day rehabilitation may have advantages for families and healthcare systems over inpatient models of rehabilitation., Methods: This study evaluated the goals and outcomes of a cohort of young people in Western Australia who attended a specialist intensive day rehabilitation programme ("iRehab") at Perth Children's Hospital. Analysis of the iRehab service database was performed. Rehabilitation goals and outcomes were recorded as per the Canadian Occupational Performance Measure (COPM), Children's Functional Independence Measure (WeeFIM), and Goal Attainment Scale (GAS)., Results: There were 586 iRehab admissions between August 11, 2011, and December 31, 2018. Admissions were divided by diagnosis: Cerebral Palsy (228, 38.5%), Acquired Brain Injury (125, 21.3%), Spinal Cord Disorders (91, 15.5%), and Other (141, 24.2%). Mean COPM Performance increased by 2.78 points from admission to discharge (95% CI 2.58 to 2.98, p < 0.001). Mean COPM Satisfaction was 3.29 points higher at discharge than admission (95% CI 3.07 to 3.51, p < 0.001). Mean total WeeFIM score improved by 6.51 points between admission and discharge (95% CI 5.56 to 7.45, p < 0.001), and by 3.33 additional points by six months post discharge (95% CI 2.14 to 4.53, p < 0.001). Mean GAS T-scores increased by 27.85 (95% CI 26.73 to 28.97, p < 0.001) from admission to discharge, and by 29.64 (95% CI 28.26 to 31.02, p < 0.001) from admission to six months post discharge, representing improvement consistent with team expectations., Conclusion: This study describes a model by which intensive rehabilitation can be delivered in a day rehabilitation setting. A diverse population of young people who experienced disability achieved significant improvements in occupational performance, independence, and goal attainment after accessing intensive day rehabilitation. Improvements were measured in all diagnostic subgroups and were maintained six months after discharge.

Objectives: To report on knowledge translation strategies and outcomes from the implementation of the early detection guidelines for cerebral palsy (CP) in a state-wide tertiary early intervention (EI) service and investigate the impact of social determinants on clinical services., Design: Retrospective longitudinal cohort study., Setting: The Western Australia tertiary paediatric EI service., Participants: EI clinicians, consumers and children using the EI service., Outcome Measures: Knowledge translation strategies including consumer perspectives, clinician training and Communities of Practice (CoP) guided implementation. We measured changes in referral number and age, delivery of early detection and intervention following the implementation of the guidelines. Exposure to adverse childhood experiences (ACEs), appointment non-attendance (DNA) rates, remoteness and socioeconomic quintiles were used to measure social determinants of health using negative binomial (Incidence Rate Ratios, IRR) and logistic regression (Odds Ratios, ORs)., Results: Ten consumers participated in Focus Groups, 100 clinicians were trained and 22 clinicians established a monthly CoP. Referrals increased fourfold to 511 children. Corrected gestational age at referral decreased from a median of 16.1 to 5.1 months (p<0.001) and at first appointment from 18.8 to 6.8 months (p<0.001). Children living in social disadvantage had the highest DNA risk (quintile 1 vs 5: IRR 2.2, 95% CI 1.1 to 4.6, p=0.037). Children exposed to ACEs had higher odds of living in social disadvantage (quintile 1 vs 5, OR=3.8, 95% CI 1.4 to 10.0, p=0.007). No significant association was found between remoteness and DNA rate or ACE score., Conclusions: Implementation strategies reduced referral age and improved the delivery of early detection assessments. Further investigation of the association between social disadvantage, DNA risk and ACE score is required in the development of a state-wide early detection network., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The Army uses permethrin-treated uniforms as the primary method to protect soldiers from tick-borne diseases. Permethrin binds strongly to fabric and provides long-term protection against many blood-feeding arthropods. However, protection decreases if the uniforms are not washed and cared for according to label instructions. This study was conducted among cadets at the United States Military Academy (USMA) at West Point, NY, to determine what the cadets know about permethrin and how they care for and wear their uniforms. West Point is in an area with high rates of tick-borne disease transmission. A survey was developed to determine what cadets know about the threat of tick-borne diseases and if they wear and maintain their uniforms in a manner that effectively maintains permethrin levels., Materials and Methods: A 16-question survey was developed and submitted to the local review board for approval. The study was classified as human subjects research according to 32CFR219 and met the requirements for exempt status under 32CFR219.104(d)(2)(i). After receiving approval, a hard copy survey was distributed among cadets with efforts to sample at least 50 members from each cadet class., Results: A total of 319 cadets provided responses to the survey questions, representing more than 7% of the cadet population at the USMA. The results showed most cadets knew their uniforms were treated with permethrin, but less than half knew there are specific instructions attached to their uniforms describing how the uniforms should be laundered. From the cadets who knew there were instructions, most admittedly did not follow the instructions. Sixteen percent of cadets said they had dry-cleaned their uniforms. This is a process known to remove most of the permethrin. The majority of cadets viewed the risk of tick-borne disease at West Point to be moderate or lower., Conclusions: This study provides a basic understanding of the wear patterns of permethrin-treated uniforms among cadets at the USMA. It is also one of the few studies to measure knowledge and uniform-wearing behavior among service members since the Army switched to factory-treated uniforms in 2013. The results indicate that compliance with uniform laundry and care instructions is low. This information is useful to develop training plans and educate cadets how they can wear and take care of their permethrin-treated uniforms to better protect themselves from tick-borne diseases., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2022. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

There are eight Anopheles spp. present in the Republic of Korea (ROK), including five members of the Anopheles Hyrcanus Group that cannot be identified using current morphological methods. The vector competence of only Anopheles sinensis s.s., An. lesteri, and An. kleini have been investigated. As the geographical distribution of Anopheles spp. varies in the ROK, determining the relative vector competence of the Anopheles spp. provides a basis for delineating malaria risks to Korean populations and U.S. military/civilian populations deployed to the ROK. Anopheles belenrae and An. pullus, collected from a malaria high-risk area in the ROK, were evaluated for vector competence of P. vivax. A total of 1,000 each of An. dirus (Thai strain), and Korean strains of An. pullus and An. belenrae were fed on P. vivax infected blood collected from Thai patients via artificial membrane feeding. The overall oocyst infection rates for An. dirus, An. pullus, and An. belenrae dissected on days 8-9 postfeed were 64.1, 12.0, and 11.6%, respectively. The overall sporozoite infection rates for those species dissected on days 14-15 postfeed were 84.5, 3.4, and 5.1% respectively. The salivary gland sporozoite indices for positive females with +4 (>1,000 sporozoites) were observed in An. dirus (72.8%), but not observed for either An. pullus or An. belenrae. Most sporozoite-positive An. pullus (83.3%) and An. belenrae (71.4%) females were observed with only +1 (1-10 sporozoites) salivary glands. These data indicate that both An. belenrae and An. pullus are very poor vectors of P. vivax., (Published by Oxford University Press on behalf of Entomological Society of America 2022.)

Environmental adaptation and species divergence often involve suites of co-evolving traits. Pigmentation in insects presents a variable, adaptive, and well-characterized class of phenotypes for which correlations with multiple other traits have been demonstrated. In Drosophila , the pigmentation genes ebony and tan have pleiotropic effects on flies' response to light, creating the potential for correlated evolution of pigmentation and vision. Here, we investigate differences in light preference within and between two sister species, Drosophila americana and D. novamexicana , which differ in pigmentation in part because of evolution at ebony and tan and occupy environments that differ in many variables including solar radiation. We hypothesized that lighter pigmentation would be correlated with a greater preference for environmental light and tested this hypothesis using a habitat choice experiment. In a first set of experiments, using males of D. novamexicana line N14 and D. americana line A00, the light-bodied D. novamexicana was found slightly but significantly more often than D. americana in the light habitat. A second experiment, which included additional lines and females as well as males, failed to find any significant difference between D. novamexicana -N14 and D. americana -A00. Additionally, the other dark line of D. americana (A04) was found in the light habitat more often than the light-bodied D. novamexicana -N14, in contrast to our predictions. However, the lightest line of D. americana , A01, was found substantially and significantly more often in the light habitat than the two darker lines of D. americana , thus providing partial support for our hypothesis. Finally, across all four lines, females were found more often in the light habitat than their more darkly pigmented male counterparts. Additional replication is needed to corroborate these findings and evaluate conflicting results, with the consistent effect of sex within and between species providing an especially intriguing avenue for further research., Competing Interests: None declared., (© 2021 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Several light trap devices have been invented and developed to assess the abundance of sand flies. Traps available in the market have different designs and attractant combinations to catch sand fly vectors. We evaluated the efficacy of four commercial light traps and determined the effect of trap placement and carbon dioxide (CO 2 ) on sand fly collection in northern Thailand. Trap evaluations were conducted at two natural caves located in Chiang Rai province, Thailand. In the first part of the study, the efficacies of four trap types including the Centers for Disease Control miniature light trap (CDC LT), Encephalitis Vector Survey trap (EVS), CDC Updraft Blacklight trap (CDC UB), and Laika trap (LK) were evaluated and compared using a Latin square experimental design. The second half of the study evaluated the influence of trap placement and CO 2 on sand fly collection. Additionally, CDC LT were placed inside, outside, and at the entrance of caves to compare the number of sand flies collected. For the trap efficacy experiment, a total of 11,876 phlebotomine sand flies were collected over 32 trap-nights. Results demonstrated that CDC LT, CDC UB, and LK collected significantly more sand flies than EVS (P > 0.05). However, there were no significant differences between the numbers of sand flies collected by CDC LT, CDC UB, and LK. A total of 6,698 sand flies were collected from the trap placement and CO 2 experiment over 72 trap-nights. Results showed that CO 2 did not influence the numbers of sand flies captured (P < 0.05), whereas trap placement at the entrance of the caves resulted in collection of significantly more sand flies than traps placed inside and outside of the caves. We found the CDC LT, CDC UB, and LK without CO 2 captured the greatest amount of sand flies. This was particularly observed when traps were placed at the entrance of a cave, perhaps because of the greater passage of stimuli caused by wind flow at the entrance of the cave. The light traps in this study can be used effectively to collect sand fly vectors in northern Thailand., (Published by Elsevier B.V.)

Background: Ivermectin mass drug administration (MDA) could accelerate malaria elimination in the Greater Mekong Subregion. This study was performed to characterize the bionomics of Anopheles in Surat Thani province, Thailand., Methods: Mosquitoes were collected via human landing collections between February and October 2019. Anopheles mosquitoes were morphologically identified to species. Primary Anopheles malaria vectors were dissected to assess parity status, and a subset were evaluated for molecular identification and Plasmodium detection., Results: A total of 17,348 mosquitoes were collected during the study period; of these, 5777 were Anopheles mosquitoes. Morphological studies identified 15 Anopheles species, of which the most abundant were Anopheles minimus (s.l.) (87.16%, n = 5035), An. dirus s.l. (7.05%, n = 407) and An. barbirostris s.l. (2.86%, n = 165). Molecular identification confirmed that of the An. minimus s.l. mosquitoes collected, 99.80% were An. minimus (s.s.) (n = 484) and 0.2% were An. aconitus (n = 1), of the An. dirus (s.l.) collected, 100% were An. baimaii (n = 348), and of the An. maculatus (s.l.) collected, 93.62% were An. maculatus (s.s.) (n = 44) and 6.38% were An. sawadwongporni (n = 3). No Anopheles mosquito tested was Plasmodium positive (0/879). An average of 11.46 Anopheles were captured per collector per night. There were differences between species in hour of collection (Kruskal-Wallis H-test: χ 2  =  80.89, P < 0.0001, n = 5666), with more An. barbirostris (s.l.) and An. maculatus (s.l.) caught earlier compared to An. minimus (s.l.) (P = 0.0001 and P < 0.0001, respectively) and An. dirus (s.l.) (P = 0.0082 and P < 0.001, respectively). The proportion of parous An. minimus (s.l.) captured by hour increased throughout the night (Wald Chi-square: χ 2  = 17.31, P = 0.000, odds ratio = 1.0535, 95% confidence interval 1.0279-1.0796, n = 3400). Overall, An. minimus (s.l.) parity was 67.68% (2375/3509) with an intra-cluster correlation of 0.0378. A power calculation determined that an An. minimus (s.l.) parity reduction treatment effect size = 34%, with four clusters per treatment arm and a minimum of 300 mosquitoes dissected per cluster, at an α = 0.05, will provide 82% power to detect a significant difference following ivermectin MDA., Conclusions: The study area in Surat Thani province is an ideal location to evaluate the impact of ivermectin MDA on An. minimus parity., (© 2021. The Author(s).)

Borrelia is a genus of spirochetal bacteria with several species known to cause disease in humans. The distribution of Borrelia has rarely been studied in Thailand. In this study, a retrospective survey of Borrelia was conducted in ticks and wild rodents to better characterize the prevalence, diversity, and distribution of Borrelia across Thailand. Several pools of DNA from tick samples were positive for Borrelia spp. (36/258, 13.9%). Borrelia theileri/B. lonestari was found in 17 tick samples (16 pools of Haemaphysalis bandicota and 1 pool of Rhipicephalus sp.), and Borrelia yangtzensis was found in 8 tick samples (2 pools of H. bandicota and 6 pools of Ixodes granulatus). Borrelia spp. were detected at low prevalence levels in rodent tissue samples (24/2001, 1.2%), with 19 identified as B. theileri or B. lonestari and 5 identified as B. miyamotoi. Several geographic and species-specific infection trends were apparent, with Ixodes ticks infected with B. yangtzensis and Haemaphysalis and Rhipicephalus ticks infected with both B. yangtzensis and B. theileri/B. lonestari. Notably, B. yangtzensis showed a similar geographic distribution to B. miyamotoi, which was identified in new areas of Thailand in this study. The flagellin gene sequence from B. miyamotoi was more similar to European (99.3-99.9%) than Japanese (96.9-97.6%) genotypes. This study greatly expands the knowledge of Borrelia in Thailand and identified several Borrelia species for the first time. It also found several ticks and rodents infected with the pathogen that were not previously known to carry Borrelia., (Published by Oxford University Press on behalf of Entomological Society of America 2020.)

Introduction: The current diagnostic pathways for cognitive impairment rarely identify babies at risk before 2 years of age. Very early detection and timely targeted intervention has potential to improve outcomes for these children and support them to reach their full life potential. Early Moves aims to identify early biomarkers, including general movements (GMs), for babies at risk of cognitive impairment, allowing early intervention within critical developmental windows to enable these children to have the best possible start to life., Method and Analysis: Early Moves is a double-masked prospective cohort study that will recruit 3000 term and preterm babies from a secondary care setting. Early Moves will determine the diagnostic value of abnormal GMs (at writhing and fidgety age) for mild, moderate and severe cognitive delay at 2 years measured by the Bayley-4. Parents will use the Baby Moves smartphone application to video their babies' GMs. Trained GMs assessors will be masked to any risk factors and assessors of the primary outcome will be masked to the GMs result. Automated scoring of GMs will be developed through applying machine-based learning to the data and the predictive value for an abnormal GM will be investigated. Screening algorithms for identification of children at risk of cognitive impairment, using the GM assessment (GMA), and routinely collected social and environmental profile data will be developed to allow more accurate prediction of cognitive outcome at 2 years. A cost evaluation for GMA implementation in preparation for national implementation will be undertaken including exploring the relationship between cognitive status and healthcare utilisation, medical costs, health-related quality of life and caregiver burden., Ethics and Dissemination: Ethics approval has been granted by the Medical Research Ethics Committee of Joondalup Health Services and the Health Service Human Research Ethics Committee (1902) of Curtin University (HRE2019-0739)., Trial Registration Number: ACTRN12619001422112., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This audit aimed to increase understanding of the long-term outcomes of evidence-based medical and surgical interventions to improve gross motor function in children and adolescents with Cerebral Palsy., Methods: Retrospective audit of a birth cohort (2000-2009) attending a tertiary service in Western Australia., Results: The cohort comprises 771 patients aged 8 to 17 years. Percentage of children receiving no Botulinum Toxin treatments in each Gross Motor Functional Classification System level was: I: 40%, II: 26%, III: 33%, IV: 28% and V: 46%. Of the total cohort, 53% of children received 4 or less Botulinum Toxin treatments and 3.7% received more than 20 treatments. Statistically significant difference in the rate of use of Botulinum Toxin pre and post-surgery ( p  < 0.001) was documented. Children levels IV and V had 5 times the odds of surgery compared to children levels I-III (Odds Ratio 5.2, 95% Confidence Interval 3.5 to 7.8, p  < 0.001). For 578 (75%) of participants the last recorded level was the same as the first., Conclusion: This audit documents medical intervention by age and Gross Motor Functional Classification System level in a large cohort of children with cerebral palsy over time and confirms stability of the level in the majority.IMPLICATIONS FOR REHABILITATIONThe information from this audit may be of use in discussions with families regarding the timing and use of Botulinum toxin and surgical intervention for motor function in children and adolescents with Cerebral Palsy.Long term use of Botulinum Toxin within an integrated evidence-based clinical program is not associated with loss of gross motor function in the long term as evidenced by the maintenance of Gross Motor Functional Classification System stability.

Background: Scrub typhus is a largely ignored tropical disease and a leading cause of undifferentiated febrile illness in the areas of tsutsugamushi triangle caused by Orientia tsutsugamushi. It is frequently diagnosed in South Asian countries, although clear epidemiological information is not available from Nepal. After the 2015 earthquake in Nepal, a sudden upsurge in scrub typhus cases was reported. The objective of this study was to investigate epidemiology of scrub typhus and its causative agents in humans, animals, and chigger mites to understand the ongoing transmission ecology., Methods: Scrub typhus cases with confirmed diagnosis throughout the country were included in the analysis. Studies were concentrated in the Chitwan district, the site of a major outbreak in 2016. Additional nation-wide data from 2015 to 2017 available from the government database included to analyse the disease distribution by geographical mapping., Results: From 2015 to 2017, 1239 scrub typhus cases were confirmed with the largest outbreak occurring in 2016 with 831 (67.1%) cases. The case fatality rate was 5.7% in 2015 which declined to 1.1% in 2017. A nationwide outbreak of scrub typhus was declared as the cases were detected in 52 out of the 75 districts of Nepal. Seasonal trend was observed with a peak during August and September. In addition to the human cases, the presence of O. tsutsugamushi was also confirmed in animals (rodents) and chigger mites (Leptotrombidium imphalum) from the outbreak areas of southern Nepal., Conclusion: The detection of O. tsutsugamushi in humans, animals, and chigger mites from outbreak locations and wide-spread reports of scrub typhus throughout the country consecutively for 3 years confirms the ongoing transmission of O. tsutsugamushi with a firmly established ecology in Nepal. The country's health system needs to be strengthened for systematic surveillance, early outbreak detection, and immediate actions including treatment and preventive measures.

Entomological surveillance for arthropod-borne viruses is vital for monitoring vector-borne diseases and informing vector control programs. In this study, we conducted entomological surveillance in Zika virus endemic areas. In Thailand, it is standard protocol to perform mosquito control within 24 h of a reported dengue case. Aedes females were collected within 72 h of case reports from villages with recent Zika-human cases in Kamphaeng Phet Province, Thailand in 2017 and 2018. Mosquitoes were bisected into head-thorax and abdomen and then screened for Zika (ZIKV) and dengue (DENV) viruses using real-time RT-PCR. ZIKV RNA was detected in three samples from two female Ae. aegypti (1.4%). A partial envelope sequence analysis revealed that the ZIKV sequences were the Asian lineage identical to sequences from ZIKV-infected cases reported in Thailand during 2016 and 2017. Dengue virus-1 (DENV-1) and dengue virus-4 (DENV-4) were found in four Ae. aegypti females (2.8%), and partial capsid sequences were nearly identical with DENV-1 and DENV-4 from Thai human cases reported in 2017. Findings in the current study demonstrate the importance of entomological surveillance programs to public health mosquito-borne disease prevention measures and control.

Mass administration of antimalarial drugs and ivermectin are being considered as potential accelerators of malaria elimination. The safety, tolerability, pharmacokinetics, and mosquito-lethal effects of combinations of ivermectin, dihydroartemisinin-piperaquine, and primaquine were evaluated. Coadministration of ivermectin and dihydroartemisinin-piperaquine resulted in increased ivermectin concentrations with corresponding increases in mosquito-lethal effect across all subjects. Exposure to piperaquine was also increased when coadministered with ivermectin, but electrocardiograph QT-interval prolongation was not increased. One subject had transiently impaired liver function. Ivermectin mosquito-lethal effect was greater than predicted previously against the major Southeast Asian malaria vectors. Both Anopheles dirus and Anopheles minimus mosquito mortality was increased substantially (20-fold and 35-fold increase, respectively) when feeding on volunteer blood after ivermectin administration compared with in vitro ivermectin-spiked blood. This suggests the presence of ivermectin metabolites that impart mosquito-lethal effects. Further studies of this combined approach to accelerate malaria elimination are warranted., (© 2019 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: The aim of this study is to contribute to the knowledge base on the long-term outcomes of evidence-based medical interventions used to improve gross motor function in children and adolescents with Cerebral Palsy., Method: Prospective cohort study of children with Cerebral Palsy in the birth years 2000-2009 attending a tertiary level service for children with Cerebral Palsy who's first recorded Gross Motor Function Classification System level was II., Results: A total of 40 children were eligible for the study, of whom 28 (72.7%) enrolled. The Botulinum toxin A treatment for this cohort, (median and interquartile ranges) were: total number of lower limb Botulinum toxin A injections 11 (6.7, 5.5); total dose of Botulinum Toxin A per lower limb treatment 6.95 u/kg (4.5, 11); and dose of Botulinum Toxin u/kg/muscle 2.95 (2.2, 4). For all 28 subjects there was a median of 15 (8.5 to 22) Gross Motor Function Classification System level recordings: six of the 28 children (21.4%) improved from level II to level I, the remaining 22 children remained stable at level II (78.6%). In this highly treated population, the average 66 item Gross Motor Function Measure score for the 22 children in level II was 72.55, which is consistent with the mean of 68.5 reported in the original Ontario cohort., Conclusion: This cohort study has confirmed that children with Cerebral Palsy, Gross Motor Function level II treated at a young age with repeated doses of Botulinum Toxin A within an integrated comprehensive service, maintain or improve their functional motor level at a later age.

Background: Secondary surgical cytoreduction in women with platinum-sensitive, recurrent epithelial ovarian, primary peritoneal, or fallopian-tube ("ovarian") cancer is widely practiced but has not been evaluated in phase 3 investigation., Methods: We randomly assigned patients with recurrent ovarian cancer who had received one previous therapy, had an interval during which no platinum-based chemotherapy was used (platinum-free interval) of 6 months or more, and had investigator-determined resectable disease (to no macroscopic residual disease) to undergo secondary surgical cytoreduction and then receive platinum-based chemotherapy or to receive platinum-based chemotherapy alone. Adjuvant chemotherapy (paclitaxel-carboplatin or gemcitabine-carboplatin) and use of bevacizumab were at the discretion of the investigator. The primary end point was overall survival., Results: A total of 485 patients underwent randomization, 240 to secondary cytoreduction before chemotherapy and 245 to chemotherapy alone. The median follow-up was 48.1 months. Complete gross resection was achieved in 67% of the patients assigned to surgery who underwent the procedure. Platinum-based chemotherapy with bevacizumab followed by bevacizumab maintenance was administered to 84% of the patients overall and was equally distributed between the two groups. The hazard ratio for death (surgery vs. no surgery) was 1.29 (95% confidence interval [CI], 0.97 to 1.72; P = 0.08), which corresponded to a median overall survival of 50.6 months and 64.7 months, respectively. Adjustment for platinum-free interval and chemotherapy choice did not alter the effect. The hazard ratio for disease progression or death (surgery vs. no surgery) was 0.82 (95% CI, 0.66 to 1.01; median progression-free survival, 18.9 months and 16.2 months, respectively). Surgical morbidity at 30 days was 9%; 1 patient (0.4%) died from postoperative complications. Patient-reported quality of life decreased significantly after surgery but did not differ significantly between the two groups after recovery., Conclusions: In this trial involving patients with platinum-sensitive, recurrent ovarian cancer, secondary surgical cytoreduction followed by chemotherapy did not result in longer overall survival than chemotherapy alone. (Funded by the National Cancer Institute and others; GOG-0213 ClinicalTrials.gov number, NCT00565851.)., (Copyright © 2019 Massachusetts Medical Society.)

Purpose: To evaluate the impact of two different intraperitoneal (IP) chemotherapy regimens on progression-free survival (PFS) among women with newly diagnosed advanced ovarian carcinoma., Methods: Eligible patients were randomly assigned to six cycles of IV paclitaxel 80 mg/m 2 once per week with intravenous (IV) carboplatin area under the curve 6 (IV carboplatin) versus IV paclitaxel 80 mg/m 2 once per week with IP carboplatin area under the curve 6 (IP carboplatin) versus once every 3 weeks IV paclitaxel 135 mg/m 2 over 3 hours day 1, IP cisplatin 75 mg/m 2 day 2, and IP paclitaxel 60 mg/m 2 day 8 (IP cisplatin). All participants received bevacizumab 15 mg/kg IV every 3 weeks in cycles 2 to 22., Results: A total of 1,560 participants were enrolled and had 84.8 months of follow-up. The median PFS duration was 24.9 months in the IV carboplatin arm, 27.4 months in the IP carboplatin arm, and 26.2 months in the IP cisplatin arm. For the subgroup of 1,380 patients with stage II/III and residual disease of 1 cm or less, median PFS was 26.9 (IV-carboplatin), 28.7 (IP-carboplatin), and 27.8 months (IP cisplatin), respectively. Median PFS for patients with stage II/III and no residual disease was 35.9, 38.8, and 35.5 months, respectively. Median overall survival for all enrolled was 75.5, 78.9, and 72.9 months, respectively, and median overall survival for stage II/III with no gross residual disease was 98.8 months, 104.8 months, and not reached. Mean patient-reported Functional Assessment of Cancer Therapy neurotoxicity scores (Gynecologic Oncology Group) were similar for all arms, but the mean Trial Outcome Index of the Functional Assessment of Cancer Therapy-Ovary scores during chemotherapy were statistically worse in the IP cisplatin arm., Conclusion: Compared with the IV carboplatin reference arm, the duration of PFS was not significantly increased with either IP regimen when combined with bevacizumab and was better tolerated than IP cisplatin.

In this study, we used a metagenomic approach to analyze bacterial communities from diverse populations (humans, animals, and vectors) to investigate the role of these microorganisms as causative agents of disease in human and animal populations. Wild rodents and ectoparasites were collected from 2014 to 2018 in Nan province, Thailand where scrub typhus is highly endemic. Samples from undifferentiated febrile illness (UFI) patients were obtained from a local hospital. A total of 200 UFI patient samples were obtained and 309 rodents and 420 pools of ectoparasites were collected from rodents ( n = 285) and domestic animals ( n = 135). The bacterial 16S rRNA gene was amplified and sequenced with the Illumina. Real-time PCR and Sanger sequencing were used to confirm the next-generation sequencing (NGS) results and to characterize pathogen species. Several pathogens were detected by NGS in all populations studied and the most common pathogens identified included Bartonella spp., Rickettsia spp., Leptospira spp., and Orientia tsutsugamushi . Interestingly, Anaplasma spp. was detected in patient, rodent and tick populations, although they were not previously known to cause human disease from this region. Candidatus Neoehrlichia, Neorickettsia spp., Borrelia spp., and Ehrlichia spp. were detected in rodents and their associated ectoparasites. The same O. tsutsugamushi genotypes were shared among UFI patients, rodents, and chiggers in a single district indicating that the chiggers found on rodents were also likely responsible for transmitting to people. Serological testing using immunofluorescence assays in UFI samples showed high prevalence (IgM/IgG) of Rickettsia and Orientia pathogens, most notably among samples collected during September-November. Additionally, a higher number of seropositive samples belonged to patients in the working age population (20-60 years old). The results presented in this study demonstrate that the increased risk of human infection or exposure to chiggers and their associated pathogen ( O. tsutsugamushi ) resulted in part from two important factors; working age group and seasons for rice cultivation and harvesting. Evidence of pathogen exposure was shown to occur as there was seropositivity (IgG) in UFI patients for bartonellosis as well as for anaplasmosis. Using a metagenomic approach, this study demonstrated the circulation and transmission of several pathogens in the environment, some of which are known causative agents of illness in human populations.

Purpose: To describe the medical complexity of traumatic spinal cord injury (TSCI) in paediatric patients in Western Australia (WA). Secondly, to determine if Princess Margaret Hospital (PMH) for Children (the tertiary paediatric centre in WA where all TSCI patients are managed) is meeting the requirements of the Australasian Rehabilitation Outcomes Centre (AROC) paediatric rehabilitation minimum data set gathered on each patient., Methods: Retrospective cohort study of patients seen at PMH between 1996-2016. The AROC minimum dataset information data were gathered on each patient. Functional status and rehabilitation outcomes were assessed using Functional Independence Measure for Children (weeFIM), Canadian Occupational Performance Measure (COPM), and Goal Attainment Scaling (GAS). Patient complexity was captured by documenting the specialty teams involved, the number of readmissions, and the International Statistical Classification of Disease and Related Health Problems Z codes., Results: Data from 19 patients (13 males, age range 6 months-15 years; 6 females, age range 4 years-13 years) were available. There were 10 cervical TSCIs with a median length of stay of 213 days and 9 thoracic TSCIs with a median length of stay of 49 days. Patients had between zero and six comorbidities prior to their TSCI., Conclusions: Children with medical complexity are responsive to rehabilitation but have a high burden of care, requiring multiple-specialty care and hospital re-admissions. AROC has set a minimum data set recommendation for the collection and examination of patient data. PMH meets the AROC guidelines for patient data collection and descriptive analyses.

Scrub typhus is a mites-borne rickettsiosis caused by the obligate intracellular Gram-negative bacterium Orientia tsutsugamushi. The disease is potentially life threatening and is prevalent in tropical Asia, islands of the western Pacific Ocean and northern Australia where an estimated one million cases occur annually. Orientia tsutsugamushi is transmitted by the bite of larval mites in the genus Leptotrombidium. In the present study, the composition of the microbiome in larvae, deutonymphs and adult males and females from laboratory colonies of L. imphalum that were infected as well as uninfected with O. tsutsugamushi were investigated by high-throughput sequencing of the bacterial 16S rRNA gene. Notably, the bacterial microbiomes of infected adult females were dominated by sequences of O. tsutsugamushi and an unidentified species of Amoebophilaceae, which together comprised 98.2% of bacterial sequences. To improve the taxonomic resolution of the Amoebophilaceae OTU a nearly full length sequence of the 16S rRNA gene was amplified, cloned, and Sanger sequenced. Infected female mites had 89 to 92% nucleotide identity with the Amoebophilaceae family, indicating that the bacterium was likely to be a species of a novel genus. The species composition of bacterial communities varied between mite life stages regardless of their infection status. Uninfected adults exhibited greater species diversity than adults infected with O. tsutsugamushi. In the infected colony, the rate of filial infection with Orientia was less than 100%. Larval and male mites that were PCR-negative for Orientia contained low numbers of sequences of Amoebophilaceae (0.01 and 0.06%, respectively) in their taxonomic profiles, suggesting that a mutualistic relationship exists between the novel species of Amoebophilaceae and O. tsutsugamushi. Our study findings provide the basis for further research to determine the influence of the novel Amoebophilaceae species on the bacterial microbiome and on vector susceptibility to and transovarial transmission of O. tsutsugamushi., Competing Interests: The authors have declared that no competing interests exist.

The Anopheles Hyrcanus Group in the Republic of Korea (ROK) consists of 5 morphologically indistinct species that can only be identified with certainty by polymerase chain reaction (PCR). A total of 86 bloodfed Anopheles spp. were collected from a cow barn located in the village of Tongilchon near the demilitarized zone in the ROK on June 13, 2016, and sent to the Armed Forces Research Institute of Medical Sciences in Bangkok, Thailand, where they were identified to species by PCR. The 1st shipment contained 15 An. belenrae and 37 An. pullus females that were used to start the colonies. Parent females that oviposited were identified by PCR for colonization. A higher proportion of F 1 -F 4 females of An. belenrae than An. pullus bloodfed when provided both blood meals on human arms and using a membrane feeding system with human blood. Following blood meals, the females were forced mated for colony maintenance. The mean numbers of eggs oviposited per female for An. belenrae was 127.7 ± 19.3 and for An. pullus was 136 ± 23.6. On average, at 25°C (±2°C) An. belenrae and An. pullus took 15.1 and 16.1 days to develop from egg to adult, respectively. A 2nd group of bloodfed Anopheles spp. was collected at the same location in the ROK on June 24, 2017. This group contained 13 An. belenrae and 27 An. pullus . Similarly, eggs were obtained and adults identified by PCR and then reared to adults and subsequent generations forced mated to members of each of the existing colonies to increase genetic diversity. The colonies were established to evaluate their susceptibility to vector vivax malaria, which is essential to better understand the epidemiology of malaria transmission in Korea. This is the 1st report of colonization of both An. belenrae and An. pullus .

Rodents are well-known reservoirs and vectors of many emerging and re-emerging infectious diseases, but little is known about their role in zoonotic disease transmission in Bhutan. In this study, a cross-sectional investigation of zoonotic disease pathogens in rodents was performed in Chukha district, Bhutan, where a high incidence of scrub typhus and cases of acute undifferentiated febrile illness had been reported in people during the preceding 4-6 months. Twelve rodents were trapped alive using wire-mesh traps. Following euthanasia, liver and kidney tissues were removed and tested using PCR for Orientia tsutsugamushi and other bacterial and rickettsial pathogens causing bartonellosis, borreliosis, human monocytic ehrlichiosis, human granulocytic anaplasmosis, leptospirosis, and rickettsiosis. A phylogenetic analysis was performed on all rodent species captured and pathogens detected. Four out of the 12 rodents (33.3%) tested positive by PCR for zoonotic pathogens. Anaplasma phagocytophilum, Bartonella grahamii, and B. queenslandensis were identified for the first time in Bhutan. Leptospira interrogans was also detected for the first time from rodents in Bhutan. The findings demonstrate the presence of these zoonotic pathogens in rodents in Bhutan, which may pose a risk of disease transmission to humans.

Trombiculid mites are the vectors of scrub typhus, with infected larval mites (chiggers) transmitting the causative agent, Orientia tsutsugamushi, during feeding. Co-existence of multiple O. tsutsugamushi strains within infected mites has previously been reported in naturally infected, laboratory-reared mite lines using molecular methods to characterize the 56-kDa type-specific antigen (TSA) gene. In the current study, more advanced next-generation sequencing technology was used to reveal the heterogeneity of O. tsutsugamushi genotypes in field-collected trombiculid mites from rodents and small mammals in scrub typhus-endemic areas of Thailand. Twenty-eight trombiculid mites collected from 10 small mammals were positive for O. tsutsugamushi, corresponding to a prevalence rate of 0.7% within the mite population. Twenty-four of the infected mites were Leptotrombidium spp., indicating that this genus is the main vector for O. tsutsugamushi transmission in Thailand. In addition, O. tsutsugamushi was detected in the mite genera Ascoschoengastia, Blankaartia, Gahrliepia, and Lorillatum. Of the 10 infested small animal hosts, six had 2-10 infected mites feeding at the time of collection. Deep sequencing was used to characterize mixed infections (two to three O. tsutsugamushi genotypes within an individual mite), and 5 of the 28 infected mites (17.9%) contained mixed infections. Additionally, 56-kDa TSA gene sequence analysis revealed identical bacterial genotypes among co-feeding mites with single or mixed infections. These results suggest that co-feeding transmission may occur during the feeding process, and could explain the occurrence of mixed infections in individual mites, as well as the recovery of multiple infected mites from the same host. This study also revealed highly diverse within-host O. tsutsugamushi genotypes. The occurrence of multiple O. tsutsugamushi genotypes within individual mites has important implications, and could provide a mechanism for pathogen evolution/diversification in the mite vector., Competing Interests: The authors have declared that no competing interests exist.

A total of 6,255 ticks belonging to three genera and six species (Haemaphysalis flava Neumann, Haemaphysalis longicornis Neumann, Haemaphysalis phasiana Saito, Ixodes nipponensis Kitaoka & Saito, Ixodes persulcatus Schulze, and Amblyomma testudinarium Koch) collected from May-August, 2013, at four southwestern provinces in the Republic of Korea (ROK) were submitted to the Armed Forces Research Institute of Medical Sciences and assayed for selected tick-borne pathogens. One pool each of H. flava and H. phasiana was positive by PCR and sequencing for a Francisella-like endosymbiont, while all pools were negative for Francisella tularensis, the causative agent of tularemia., (Published by Oxford University Press on behalf of Entomological Society of America 2017. This work is written by US Government employees and is in the public domain in the US.)

Successful mating by male mosquitoes is dependent on several factors, with sugar feeding being particularly important. The effect of ingested vitamins on adult male mosquitoes is poorly understood. This laboratory study used 3 anopheline species, Anopheles campestris, An. dirus, and An. sawadwongporni, to study the effect of sugar and vitamins on male longevity, copulation, and fecundity. Males were fed 1 of 5 diets containing different combinations of sugar and vitamins: 10% glucose, 10% sucrose, 10% multivitamin syrup, 10% multivitamin syrup + 10% glucose, and 10% multivitamin syrup + 10% sucrose. The longevity of males was measured for a period of 15 days. Forced mating was used to simulate copulation, and fecundity was measured by counting the number of eggs oviposited and the hatch rate of larvae. The longevity of An. campestris and An. dirus was greatest when fed a diet of 10% multivitamin syrup + 10% glucose, and the longevity of An. sawadwongporni was greatest when fed a diet of 10% multivitamin syrup + 10% sucrose. The 1st mating routinely produced the most viable eggs when males were mated with several females. The diet of 10% multivitamin syrup + 10% sucrose produced numerically greater egg production and larval emergence for all 3 species, although this was not always statistically significant due to variability and small sample size. These results indicate that the addition of multivitamin syrup to sucrose may produce healthier and more fit male anophelines. This has potential implications for increasing insectary operations and improving the fitness of laboratory-reared male mosquitoes that will be released for mosquito and disease-pathogen control studies.

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL. Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls. Results: Specificity for ultrasound referral was 92% versus 90% ( P = 0.0001), and PPV was 4.6% versus 10% ( P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent = 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years). Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation. Clin Cancer Res; 23(14); 3628-37. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: Novel vector control methods that can directly target outdoor malaria transmission are urgently needed in the Greater Mekong Subregion (GMS) to accelerate malaria elimination and artemisinin resistance containment efforts. Ivermectin mass drug administration (MDA) to humans has been shown to effectively kill wild Anopheles and suppress malaria transmission in West Africa. Preliminary laboratory investigations were performed to determine ivermectin susceptibility and sporontocidal effect in GMS Anopheles malaria vectors coupled with pharmacokinetic models of ivermectin at escalating doses., Methods: A population-based pharmacokinetic model of ivermectin was developed using pre-existing data from a clinical trial conducted in Thai volunteers at the 200 µg/kg dose. To assess ivermectin susceptibility, various concentrations of ivermectin compound were mixed in human blood meals and blood-fed to Anopheles dirus, Anopheles minimus, Anopheles sawadwongporni, and Anopheles campestris. Mosquito survival was monitored daily for 7 days and a non-linear mixed effects model with probit analyses was used to calculate concentrations of ivermectin that killed 50% (LC 50 ) of mosquitoes for each species. Blood samples were collected from Plasmodium vivax positive patients and offered to mosquitoes with or without ivermectin at the ivermectin LC 25 or LC 5 for An. dirus and An. minimus., Results: The GMS Anopheles displayed a range of susceptibility to ivermectin with species listed from most to least susceptible being An. minimus (LC 50  = 16.3 ng/ml) > An. campestris (LC 50  = 26.4 ng/ml) = An. sawadwongporni (LC 50  = 26.9 ng/ml) > An. dirus (LC 50  = 55.6 ng/ml). Mosquito survivorship results, the pharmacokinetic model, and extensive safety data indicated that ivermectin 400 µg/kg is the ideal minimal dose for MDA in the GMS for malaria parasite transmission control. Ivermectin compound was sporontocidal to P. vivax in both An. dirus and An. minimus at the LC 25 and LC 5 concentrations., Conclusions: Ivermectin is lethal to dominant GMS Anopheles malaria vectors and inhibits sporogony of P. vivax at safe human relevant concentrations. The data suggest that ivermectin MDA has potential in the GMS as a vector and transmission blocking control tool to aid malaria elimination efforts.

Background: Platinum-based chemotherapy doublets are a standard of care for women with ovarian cancer recurring 6 months after completion of initial therapy. In this study, we aimed to explore the roles of secondary surgical cytoreduction and bevacizumab in this population, and report the results of the bevacizumab component here., Methods: The multicentre, open-label, randomised phase 3 GOG-0213 trial was done in 67 predominantly academic centres in the USA (65 centres), Japan (one centre), and South Korea (one centre). Eligible patients were adult women (aged ≥18 years) with recurrent measurable or evaluable epithelial ovarian, primary peritoneal, or fallopian tube cancer, and a clinical complete response to primary platinum-based chemotherapy, who had been disease-free for at least 6 months following last infused cycle of platinum. Patients were randomly assigned (1:1) to standard chemotherapy (six 3-weekly cycles of paclitaxel [175 mg/m 2 of body surface area] and carboplatin [area under the curve 5]) or the same chemotherapy regimen plus bevacizumab (15 mg/kg of bodyweight) every 3 weeks and continued as maintenance every 3 weeks until disease progression or unacceptable toxicity. Individuals who participated in both the bevacizumab objective and surgical objective (which is ongoing) were randomly assigned (1:1:1:1) to receive either of these two chemotherapy regimens with or without prior secondary cytoreductive surgery. Randomisation for the bevacizumab objective was stratified by treatment-free interval and participation in the surgical objective. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00565851., Findings: Between Dec 10, 2007, and Aug 26, 2011, 674 women were enrolled and randomly assigned to standard chemotherapy (n=337) or chemotherapy plus bevacizumab (n=377). Median follow-up at the end of the trial on Nov 5, 2014, was 49·6 months in each treatment group (IQR 41·5-62·2 for chemotherapy plus bevacizumab; IQR 40·8-59·3 for chemotherapy), at which point 415 patients had died (214 in the chemotherapy group and 201 in the chemotherapy plus bevacizumab group). Based on pretreatment stratification data, median overall survival in the chemotherapy plus bevacizumab group was 42·2 months (95% CI 37·7-46·2) versus 37·3 months (32·6-39·7) in the chemotherapy group (hazard ratio [HR] 0·829; 95% CI 0·683-1·005; p=0·056). We identified incorrect treatment-free interval stratification data for 45 (7%) patients (equally balanced between treatment groups); a sensitivity analysis of overall survival based on the audited treatment-free interval stratification data gave an adjusted HR of 0·823 (95% CI 0·680-0·996; p=0·0447). In the safety population (all patients who initiated treatment), 317 (96%) of 325 patients in the chemotherapy plus bevacizumab group had at least one grade 3 or worse adverse event compared with 282 (86%) of 332 in the chemotherapy group; the most frequently reported of these in the chemotherapy plus bevacizumab group compared with the chemotherapy group were hypertension (39 [12%] vs two [1%]), fatigue (27 [8%] vs eight [2%]), and proteinuria (27 [8%] vs none). Two (1%) treatment-related deaths occurred in the chemotherapy group (infection [n=1] and myelodysplastic syndrome [n=1]) compared with nine (3%) in the chemotherapy plus bevacizumab group (infection [n=1], febrile neutropenia [n=1], myelodysplastic syndrome [n=1], secondary malignancy [n=1]; deaths not classified with CTCAE terms: disease progression [n=3], sudden death [n=1], and not specified [n=1])., Interpretation: The addition of bevacizumab to standard chemotherapy, followed by maintenance therapy until progression, improved the median overall survival in patients with platinum-sensitive recurrent ovarian cancer. Although the intention-to-treat analysis for overall survival was not significant, our sensitivity analysis based on corrected treatment-free interval stratification indicates that this strategy might be an important addition to the therapeutic armamentarium in these patients., Funding: National Cancer Institute and Genentech., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Flaviviruses comprise a large and diverse group of positive-stranded RNA viruses, including tick-, mosquito- and unknown-vector-borne flaviviruses. A novel flavivirus was detected in pools of Aedes vexans nipponii (n=1) and Aedes esoensis (n=3) collected in 2012 and 2013 near the demilitarized zone (DMZ), Republic of Korea (ROK). Phylogenetic analyses of the NS5, E gene and complete polyprotein coding sequence (CDS) showed that the novel virus fell within the Aedes-borne flaviviruses (ABFVs), with nucleotide identity ranging from 57.8-75.1 %, 46.1-74.2 % and 51.1-76.2 %, respectively. While the novel ABFV was distant from other flaviviruses within the group, it formed a clade with Ilomantsi virus (ILOV). Sequence alignments of the partial NS5 gene, full-length E gene and polyprotein CDS between the novel virus and ILOV showed approximately 76.2 % nucleotide identity and 90 % amino acid identity, respectively. The ABFV identified in Aedes mosquitoes from the ROK is a novel ABFV based on the sequence analyses and is designated as Panmunjeom flavivirus (PANFV).

Objective: Sexual dysfunction can be a long-term issue for women with gynecologic cancer. This study assesses the extent of sexual and marital dysfunction women face following treatment of a gynecologic cancer., Methods: A cross-sectional study of women with gynecologic cancer was conducted using a 181-item survey. Sexual dysfunction was measured by change in the Female Sexual Function Index score; marital dysfunction was measured by change in Intimate Bond Measure from prediagnosis to posttreatment. Paired t tests and Fisher exact test were used to compare women with dysfunction to those without dysfunction., Results: Three hundred twenty women were enrolled (mean age, 56.0 [SD, 12.0] years). Among all women, sexual function declined from a score of 21.3 (SD, 10.4) prior to 15.3 (SD, 10.2) (P < 0.001), and sexual activity decreased from 6.1 (SD, 6.8) to 2.6 (SD, 4.9) times per month following treatment (P < 0.001). Among the 208 women who were sexually active at the time of study, sexual dysfunction after treatment was associated with younger age (50.9 [SD, 11.7] years to 57.3 [SD, 12.3] years), ovarian (40.7% vs 30.7%) or cervical (21.0% vs 10.2%) cancer diagnosis, chemotherapy treatment (72.8% vs 50.4%), and being in a relationship (97.3% vs 82.7%). Among women in relationships, 27% experienced marital dysfunction., Conclusions: Women who are younger, have an ovarian or cervical cancer diagnosis, receive chemotherapy, or are in a committed relationship are at particularly high risk of sexual dysfunction. These women should be provided information about the risks associated with their cancer treatment.

In total, 1,300 each of Anopheles kleini Rueda and Anopheles sinensis Wiedemann sensu stricto (s.s.) females (colonized from the Republic of Korea) and Anopheles dirus Peyton & Harrison (Thai strain) were allowed to feed on blood from Thai malaria patients naturally infected with Plasmodium vivax The overall oocyst infection rates for An. dirus, An. kleini, and An. sinensis s.s. were 77.4, 46.1, and 45.9%, respectively. The mean number of oocysts was significantly higher for An. dirus (82.7) compared with An. kleini (6.1) and An. sinensis s.s. (8.6), whereas the mean number of oocysts for An. kleini and An. sinensis s.s. was similar. The overall sporozoite infection rates for An. dirus, An. kleini, and An. sinensis s.s. dissected on days 14-15, 21, and 28 days post-feed were significantly higher for An. dirus (90.0%) than An. kleini (5.4%), whereas An. kleini sporozoite rates were significantly higher than An. sinensis s.s. (<0.1%). The overall sporozoite indices for positive females with +3 (100-1,000 sporozoites) and +4 (>1,000 sporozoites) salivary gland indices were significantly higher for An. dirus (85.7%), compared with An. kleini (47.1%). Only one An. sinensis s.s. had sporozoites (+2; >10-100 sporozoites). These results indicate that An. kleini is a competent vector of vivax malaria. Although An. sinensis s.s. develops relatively high numbers of oocysts, it is considered a very poor vector of vivax malaria due to a salivary gland barrier., (Published by Oxford University Press on behalf of Entomological Society of America 2016. This work is written by US Government employees and is in the public domain in the US.)

Background: Three full doses of RTS,S/AS01 malaria vaccine provides partial protection against controlled human malaria parasite infection (CHMI) and natural exposure. Immunization regimens, including a delayed fractional third dose, were assessed for potential increased protection against malaria and immunologic responses., Methods: In a phase 2a, controlled, open-label, study of healthy malaria-naive adults, 16 subjects vaccinated with a 0-, 1-, and 2-month full-dose regimen (012M) and 30 subjects who received a 0-, 1-, and 7-month regimen, including a fractional third dose (Fx017M), underwent CHMI 3 weeks after the last dose. Plasmablast heavy and light chain immunoglobulin messenger RNA sequencing and antibody avidity were evaluated. Protection against repeat CHMI was evaluated after 8 months., Results: A total of 26 of 30 subjects in the Fx017M group (vaccine efficacy [VE], 86.7% [95% confidence interval [CI], 66.8%-94.6%]; P < .0001) and 10 of 16 in the 012M group (VE, 62.5% [95% CI, 29.4%-80.1%]; P = .0009) were protected against infection, and protection differed between schedules (P = .040, by the log rank test). The fractional dose boosting increased antibody somatic hypermutation and avidity and sustained high protection upon rechallenge., Discussions: A delayed third fractional vaccine dose improved immunogenicity and protection against infection. Optimization of the RTS,S/AS01 immunization regimen may lead to improved approaches against malaria., Clinical Trials Registration: NCT01857869., (Published by Oxford University Press on behalf of the Infectious Diseases Society of America, 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10(5) PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks. To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-γ-producing CD8 T cells were present at ∼100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

Importance: Germline mutations in BRCA1 and BRCA2 are relatively common in women with ovarian, fallopian tube, and peritoneal carcinoma (OC) causing a greatly increased lifetime risk of these cancers, but the frequency and relevance of inherited mutations in other genes is less well characterized., Objective: To determine the frequency and importance of germline mutations in cancer-associated genes in OC., Design, Setting, and Participants: A study population of 1915 woman with OC and available germline DNA were identified from the University of Washington (UW) gynecologic tissue bank (n = 570) and from Gynecologic Oncology Group (GOG) phase III clinical trials 218 (n = 788) and 262 (n = 557). Patients were enrolled at diagnosis and were not selected for age or family history. Germline DNA was sequenced from women with OC using a targeted capture and multiplex sequencing assay., Main Outcomes and Measures: Mutation frequencies in OC were compared with the National Heart, Lung, and Blood Institute GO Exome Sequencing Project (ESP) and the Exome Aggregation Consortium (ExAC). Clinical characteristics and survival were assessed by mutation status., Results: Overall, the median (range) age at diagnosis was 60 (28-91) years in patients recruited from UW and 61 (23-87) years in patients recruited from the GOG trials. A higher number of black women were recruited from the GOG trials (4.3% vs 1.4%; P = .009); but in patients recruited from UW, there was a higher proportion of fallopian tube carcinomas (13.3% vs 5.7%; P < .001); stage I and II disease (14.6% vs 0% [GOG trials were restricted to advanced-stage cancer]); and nonserous carcinomas (29.9% vs 13.1%, P < .001). Of 1915 patients, 280 (15%) had mutations in BRCA1 (n = 182), or BRCA2 (n = 98), and 8 (0.4%) had mutations in DNA mismatch repair genes. Mutations in BRIP1 (n = 26), RAD51C (n = 11), RAD51D (n = 11), PALB2 (n = 12), and BARD1 (n = 4) were significantly more common in patients with OC than in the ESP or ExAC, present in 3.3%. Race, histologic subtype, and disease site were not predictive of mutation frequency. Patients with a BRCA2 mutation from the GOG trials had longer progression-free survival (hazard ratio [HR], 0.60; 95% CI, 0.45-0.79; P < .001) and overall survival (HR, 0.39; 95% CI, 0.25-0.60; P < .001) compared with those without mutations., Conclusions and Relevance: Of 1915 patients with OC, 347 (18%) carried pathogenic germline mutations in genes associated with OC risk. PALB2 and BARD1 are suspected OC genes and together with established OC genes (BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH2, MLH1, PMS2, and MSH6) bring the total number of genes suspected to cause hereditary OC to 11.

Background: This study sought to determine the association between preoperative chemotherapy and postoperative morbidity and mortality in ovarian cancer patients., Methods: The American College of Surgeons National Surgical Quality Improvement Program was used to identify women who underwent surgery for ovarian cancer between 2005 and 2012. The women were divided into two groups based on whether they had received chemotherapy within 30 days before surgery or not. Preoperative variables, intraoperative measures, and postoperative morbidity and mortality were compared using χ(2) and Student's t test. Multivariable analyses using logistic regression modeling were used to correct for potential confounding variables., Results: Of 1807 patients, 1612 (89.2%) underwent primary surgery, and 195 (10.8%) received preoperative chemotherapy. The chemotherapy group had a lower preoperative platelet count (317,640 vs 249,740 plt/μL; P < 0.001), hematocrit (36.9 vs 33.1%; P < 0.001), and white blood cell (WBC) count (7970 vs 6060 WBC/μL; P < 0.001). Postoperatively, the chemotherapy group had a higher rate of organ/space infection (2.2 vs 4.6%; P = 0.04; odds ratio [OR], 2.12; 95% confidence interval [CI], 1.01-4.47) and a higher blood transfusion rate (17.1 vs 32.3%; P < 0.001; OR, 2.31; 95% CI, 1.67-3.20). A subanalysis of only those with disseminated cancer showed myelosuppression and an increased blood transfusion rate in the chemotherapy group. In multivariable analyses, preoperative chemotherapy, hematocrit, and ascites were independent predictors of postoperative blood transfusion in the entire cohort, whereas preoperative chemotherapy was the only independent predictor of postoperative blood transfusion in the disseminated cancer group., Conclusions: Preoperative chemotherapy for the treatment of ovarian cancer is associated with myelosuppression and an increased risk of postoperative blood transfusion.

Background: A dose-dense weekly schedule of paclitaxel (resulting in a greater frequency of drug delivery) plus carboplatin every 3 weeks or the addition of bevacizumab to paclitaxel and carboplatin administered every 3 weeks has shown efficacy in ovarian cancer. We proposed to determine whether dose-dense weekly paclitaxel and carboplatin would prolong progression-free survival as compared with paclitaxel and carboplatin administered every 3 weeks among patients receiving and those not receiving bevacizumab., Methods: We prospectively stratified patients according to whether they elected to receive bevacizumab and then randomly assigned them to receive either paclitaxel, administered intravenously at a dose of 175 mg per square meter of body-surface area every 3 weeks, plus carboplatin (dose equivalent to an area under the curve [AUC] of 6) for six cycles or paclitaxel, administered weekly at a dose of 80 mg per square meter, plus carboplatin (AUC, 6) for six cycles. The primary end point was progression-free survival., Results: A total of 692 patients were enrolled, 84% of whom opted to receive bevacizumab. In the intention-to-treat analysis, weekly paclitaxel was not associated with longer progression-free survival than paclitaxel administered every 3 weeks (14.7 months and 14.0 months, respectively; hazard ratio for disease progression or death, 0.89; 95% confidence interval [CI], 0.74 to 1.06; P=0.18). Among patients who did not receive bevacizumab, weekly paclitaxel was associated with progression-free survival that was 3.9 months longer than that observed with paclitaxel administered every 3 weeks (14.2 vs. 10.3 months; hazard ratio, 0.62; 95% CI, 0.40 to 0.95; P=0.03). However, among patients who received bevacizumab, weekly paclitaxel did not significantly prolong progression-free survival, as compared with paclitaxel administered every 3 weeks (14.9 months and 14.7 months, respectively; hazard ratio, 0.99; 95% CI, 0.83 to 1.20; P=0.60). A test for interaction that assessed homogeneity of the treatment effect showed a significant difference between treatment with bevacizumab and without bevacizumab (P=0.047). Patients who received weekly paclitaxel had a higher rate of grade 3 or 4 anemia than did those who received paclitaxel every 3 weeks (36% vs. 16%), as well as a higher rate of grade 2 to 4 sensory neuropathy (26% vs. 18%); however, they had a lower rate of grade 3 or 4 neutropenia (72% vs. 83%)., Conclusions: Overall, weekly paclitaxel, as compared with paclitaxel administered every 3 weeks, did not prolong progression-free survival among patients with ovarian cancer. (Funded by the National Cancer Institute and Genentech; GOG-0262 ClinicalTrials.gov number, NCT01167712.).

Mosquito blood meals taken from humans and animals potentially represent a useful source of blood for the detection of blood-borne pathogens. In this feasibility study, Anopheles stephensi mosquitoes were fed with blood meals spiked with dengue virus type 2 (DENV-2) and harvested at serial time points. These mosquitoes are not competent vectors, and the virus is not expected to replicate. Ingested blood was spotted on Whatman FTA cards and stored at room temperature. Mosquito abdomens were removed and stored at -80°C. Control blood meal aliquots were stored in vials or applied onto FTA cards. After 4 weeks of storage, the samples were extracted using beadbeating and QIAamp Viral RNA kit (Qiagen Sciences, Germantown, MD). Recovered viral RNA was analyzed by DENV-2 TaqMan RT-PCR assay and next-generation sequencing (NGS). Overall viral RNA recovery efficiency was 15% from the directly applied dried blood spots and approximately 20% or higher for dried blood spots made by blotting mosquito midgut on FTA cards. Viral RNA in mosquito-ingested blood decreases over time, but remains detectable 24 hours after blood feeding. The viral sequences in FTA-stored specimens can be maintained at room temperature. The strategy has the potential utility in expedited zoonotic virus discovery and blood-borne pathogen surveillance., (© The American Society of Tropical Medicine and Hygiene.)

Objectives: Changes in cognitive function have been identified in and reported by many cancer survivors. These changes have the potential to impact patient quality of life and functional ability. This prospective longitudinal study was designed to quantify the incidence of change in cognitive function in newly diagnosed ovarian cancer patients throughout and following primary chemotherapy., Methods: Eligible patients had newly diagnosed, untreated ovarian cancer and had planned to receive chemotherapy. Web-based and patient reported cognitive assessments and quality of life questionnaires were conducted prior to chemotherapy, prior to cycle four, after cycle six, and six months after completion of primary therapy., Results: Two-hundred-thirty-one evaluable patients entered this study between May 2010 and October 2011. At the cycle 4 time point, 25.2% (55/218) of patients exhibited cognitive impairment in at least one domain. At the post-cycle 6 and 6-month follow up time points, 21.1% (44/208) and 17.8% (30/169) of patients, respectively, demonstrated impairment in at least one domain of cognitive function. There were statistically significant, but clinically small, improvements in processing speed (p<0.001) and attention (p<0.001) but not in motor response time (p=0.066), from baseline through the six-month follow up time period., Conclusions: This was a large, prospective study designed to measure cognitive function in ovarian cancer. A subset of patients had evidence of cognitive decline from baseline during chemotherapy treatment in this study as measured by the web-based assessment; however, changes were generally limited to no more than one domain., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Small mammals have difficulty maintaining body temperature under anesthesia. This hypothermia is a potential detriment not only to the health and comfort of the animal but also to the integrity of any treatment given or data gathered during the anesthetic period. Using an external warming device to assist with temperature regulation can mitigate these effects. In this study, we investigated the ability of an advanced warming device that uses far-infrared (FIR) heating and responds to real-time core temperature monitoring to maintain a normothermic core temperature in guinea pigs. Body temperatures were measured during 30 min of ketamine-xylazine general anesthesia with and without application of the heating device. The loss of core body heat from anesthetized guinea pigs under typical (unwarmed) conditions was significant, and this loss was almost completely mitigated by application of the FIR heating pad. The significant difference between the temperatures of the actively warmed guinea pigs as compared with the control group began as early as 14 min after anesthetic administration, leading to a 2.6 °C difference at 30 min. Loss of core body temperature was not correlated with animals' body weight; however, weight influences the efficiency of FIR warming slightly. These study results show that the FIR heating device accurately controls core body temperature in guinea pigs, therefore potentially alleviating the effects of body heat loss on animal physiology.

Background: This study aimed to assess the safety of robotic surgery for older women undergoing surgery for endometrial cancer., Methods: A retrospective chart review of women undergoing surgery for endometrial cancer between October 2010 and December 2012 was conducted at the authors' institution. This cohort was divided by age (≥65 vs <65 years) and surgical approach (laparotomy vs robotic surgery). Postoperative morbidity and mortality were compared using standard statistical analysis., Results: Of 228 patients identified, 73 (32 %) were 65 years old or older, and 98 (43 %) had undergone robotic surgery. Among the robotic surgery patients, women 65 years old or older had a higher Charlson comorbidity score (7.6 vs 4.9; p < 0.01) and were more likely to undergo pelvic lymphadenectomy (73 vs 39 %; p < 0.01). The complication rates did not differ between the groups except for increased urinary retention in the older group (15 % vs 3 %; p = 0.04). Older patients had a longer hospital stay (2.2 vs 1.3 days; p < 0.01) and a similar rate of discharge home (100 vs 96 %; p = 0.09). For the patients 65 years old or older, robotic surgery was associated with less blood loss (131 vs 235 ml; p = 0.03), a lower rate of ileus (0 vs 15 %; p = 0.04), a lower perioperative surgical complication rate (4 vs 30 %; p = 0.01), a shorter hospital stay (2.2 vs 4.4 days; p < 0.01), and a similar rate of discharge home (96 vs 91 %; p = 0.45) compared with laparotomy., Conclusion: Robotic surgery appears to be associated with less postoperative morbidity than laparotomy for endometrial cancer staging in women 65 years old or older. The complication rates after robotic surgery were similar between the two age groups.

Insecticide treated nets (ITNs) are a potential tool to help control sand flies and prevent Leishmaniasis. However, little is currently known about the response of Leishmania infected sand flies to ITNs. In this study, Phlebotomus duboscqi sand flies were infected with the parasite Leishmania major. Infected and noninfected sand flies were then evaluated against permethrin treated and untreated bed nets in a laboratory assay that required sand flies to pass through suspended netting material to feed on a mouse serving as an attractive host. The number of sand flies passing through the nets and blood feeding was recorded. There was not a significant difference in the ability of infected or noninfected sand flies to move through treated or untreated nets. Fewer sand flies entered the permethrin treated nets compared to the untreated nets, indicating that permethrin creates an effective barrier. The results show that in addition to reducing the nuisance bites of noninfected sand flies, ITNs also protect against Leishmania infected sand flies and therefore can play in key role in reducing the rates of Leishmaniasis. This study is important to the Department of Defense as it continues to develop and field new bed nets to protect service members.

Thirty years ago, the Entomology Branch at the Walter Reed Army Institute of Research (WRAIR) performed the first controlled human malaria infection, in which lab-reared mosquitoes were infected with lab-cultured malaria parasites and allowed to feed on human volunteers. The development of this model was a turning point for pre-erythrocytic malaria vaccine research and, through decades of refinement, has supported 30 years of efficacy testing of a suite of antimalarial vaccines and drugs. In this article, we present a historical overview of the research that enabled the first challenge to occur and the modifications made to the challenge over time, a summary of the 104 challenges performed by WRAIR from the first into 2015, and a prospective look at what the next generation of challenges might entail.