Epidemiological and Entomological Evaluations after Six Years or More of Mass Drug Administration for Lymphatic Filariasis Elimination in Nigeria

The current strategy for interrupting transmission of lymphatic filariasis (LF) is annual mass drug administration (MDA), at good coverage, for 6 or more years. We describe our programmatic experience delivering the MDA combination of ivermectin and albendazole in Plateau and Nasarawa states in central Nigeria, where LF is caused by anopheline transmitted Wuchereria bancrofti. Baseline LF mapping using rapid blood antigen detection tests showed mean local government area (LGA) prevalence of 23% (range 4–62%). MDA was launched in 2000 and by 2003 had been scaled up to full geographic coverage in all 30 LGAs in the two states; over 26 million cumulative directly observed treatments were provided by community drug distributors over the intervention period. Reported treatment coverage for each round was ≥85% of the treatment eligible population of 3.7 million, although a population-based coverage survey in 2003 showed lower coverage (72.2%; 95% CI 65.5–79.0%). To determine impact on transmission, we monitored three LF infection parameters (microfilaremia, antigenemia, and mosquito infection) in 10 sentinel villages (SVs) serially. The last monitoring was done in 2009, when SVs had been treated for 7–10 years. Microfilaremia in 2009 decreased by 83% from baseline (from 4.9% to 0.8%); antigenemia by 67% (from 21.6% to 7.2%); mosquito infection rate (all larval stages) by 86% (from 3.1% to 0.4%); and mosquito infectivity rate (L3 stages) by 76% (from 1.3% to 0.3%). All changes were statistically significant. Results suggest that LF transmission has been interrupted in 5 of the 10 SVs, based on 2009 finding of microfilaremia ≥1% and/or L3 stages in mosquitoes. Four of the five SVs where transmission persists had baseline antigenemia prevalence of >25%. Longer or additional interventions (e.g., more frequent MDA treatments, insecticidal bed nets) should be considered for ‘hot spots’ where transmission is ongoing

In Search of a Trade Mark: Search Practices and Bureaucratic Poetics

Trade marks have been understood as quintessential ‘bureaucratic properties’. This article suggests that the making of trade marks has been historically influenced by bureaucratic practices of search and classification, which in turn were affected by the possibilities and limits of spatial organisation and technological means of access and storage. It shows how the organisation of access and retrieval did not only condition the possibility of conceiving new trade marks, but also served to delineate their intangible proprietary boundaries. Thereby they framed the very meaning of a trade mark. By advancing a historical analysis that is sensitive to shifts, both in actual materiality and in the administrative routines of trade mark law, the article highlights the legal form of trade mark as inherently social and materially shaped. We propose a historical understanding of trade mark law that regards legal practice and bureaucratic routines as being co-constitutive of the very legal object itself

The Transcription Factor Ultraspiracle Influences Honey Bee Social Behavior and Behavior-Related Gene Expression

Behavior is among the most dynamic animal phenotypes, modulated by a variety of internal and external stimuli. Behavioral differences are associated with large-scale changes in gene expression, but little is known about how these changes are regulated. Here we show how a transcription factor (TF), ultraspiracle (usp; the insect homolog of the Retinoid X Receptor), working in complex transcriptional networks, can regulate behavioral plasticity and associated changes in gene expression. We first show that RNAi knockdown of USP in honey bee abdominal fat bodies delayed the transition from working in the hive (primarily “nursing” brood) to foraging outside. We then demonstrate through transcriptomics experiments that USP induced many maturation-related transcriptional changes in the fat bodies by mediating transcriptional responses to juvenile hormone. These maturation-related transcriptional responses to USP occurred without changes in USP's genomic binding sites, as revealed by ChIP–chip. Instead, behaviorally related gene expression is likely determined by combinatorial interactions between USP and other TFs whose cis-regulatory motifs were enriched at USP's binding sites. Many modules of JH– and maturation-related genes were co-regulated in both the fat body and brain, predicting that usp and cofactors influence shared transcriptional networks in both of these maturation-related tissues. Our findings demonstrate how “single gene effects” on behavioral plasticity can involve complex transcriptional networks, in both brain and peripheral tissues

Transcriptional Responses of Cultured Rat Sympathetic Neurons during BMP-7-Induced Dendritic Growth

Dendrites are the primary site of synapse formation in the vertebrate nervous system; however, relatively little is known about the molecular mechanisms that regulate the initial formation of primary dendrites. Embryonic rat sympathetic neurons cultured under defined conditions extend a single functional axon, but fail to form dendrites. Addition of bone morphogenetic proteins (BMPs) triggers these neurons to extend multiple dendrites without altering axonal growth or cell survival. We used this culture system to examine differential gene expression patterns in naïve vs. BMP-treated sympathetic neurons in order to identify candidate genes involved in regulation of primary dendritogenesis.To determine the critical transcriptional window during BMP-induced dendritic growth, morphometric analysis of microtubule-associated protein (MAP-2)-immunopositive processes was used to quantify dendritic growth in cultures exposed to the transcription inhibitor actinomycin-D added at varying times after addition of BMP-7. BMP-7-induced dendritic growth was blocked when transcription was inhibited within the first 24 hr after adding exogenous BMP-7. Thus, total RNA was isolated from sympathetic neurons exposed to three different experimental conditions: (1) no BMP-7 treatment; (2) treatment with BMP-7 for 6 hr; and (3) treatment with BMP-7 for 24 hr. Affymetrix oligonucleotide microarrays were used to identify differential gene expression under these three culture conditions. BMP-7 significantly regulated 56 unique genes at 6 hr and 185 unique genes at 24 hr. Bioinformatic analyses implicate both established and novel genes and signaling pathways in primary dendritogenesis.This study provides a unique dataset that will be useful in generating testable hypotheses regarding transcriptional control of the initial stages of dendritic growth. Since BMPs selectively promote dendritic growth in central neurons as well, these findings may be generally applicable to dendritic growth in other neuronal cell types

Match-Play and Performance Test Responses of Soccer Goalkeepers: A Review of Current Literature.

Goalkeepers are typically the last defensive line for soccer teams aiming to minimise goals being conceded, with match rules permitting ball handling within a specific area. Goalkeepers are also involved in initiating some offensive plays, and typically remain in close proximity to the goal line while covering ~ 50% of the match distances of outfield players; hence, the competitive and training demands of goalkeepers are unique to their specialised position. Indeed, isolated performance tests differentiate goalkeepers from outfield players in multiple variables. With a view to informing future research, this review summarised currently available literature reporting goalkeeper responses to: (1) match play (movement and skilled/technical demands) and (2) isolated performance assessments (strength, power, speed, aerobic capacity, joint range of motion). Literature searching and screening processes yielded 26 eligible records and highlighted that goalkeepers covered ~ 4-6 km on match day whilst spending ~ 98% of time at low-movement intensities. The most decisive moments are the 2-10 saves·match-1 performed, which often involve explosive actions (e.g. dives, jumps). Whilst no between-half performance decrements have been observed in professional goalkeepers, possible transient changes over shorter match epochs remain unclear. Isolated performance tests confirm divergent profiles between goalkeepers and outfield players (i.e. superior jump performance, reduced [Formula: see text]2max values, slower sprint times), and the training of soccer goalkeepers is typically completed separately from outfield positions with a focus primarily on technical or explosive drills performed within confined spaces. Additional work is needed to examine the physiological responses to goalkeeper-specific training and match activities to determine the efficacy of current preparatory strategies

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]), is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Somatotypes of South Australian Male Athletes

Heath-Carter somatotypes were determined on 206 male members of South Australian representative squads in 17 sports. Complete state squads were tested in the following sports: badminton, basketball, cycling, field hockey, field lacrosse, gymnastics, speed roller skating, squash, swimming and volleyball. Thirty-six percent of the subjects had either represented their country in international competition or, in the case of Australian Rules football, received All-Australian recognition. The overall somatotype of 2.3-5.3-2.8 (balanced mesomorph) was significantly (p \u3c 0.05) less endomorphic, more mesomorphic and more ectomorphic than baseline data in the literature. The sportsmen are therefore better equipped for physical activity in that they have to displace less relative fat mass yet have a greater relative muscle mass with which to initiate and sustain movement. Ten of the group means were in the ectomorphic mesomorph category, 5 were balanced mesomorphs and 2 were in the endomorphic mesomorph grouping. A one-way MANOVA, which used Wilks’ lambda as the test statistic, was employed to determine whether there were any statistically significant differences between the group somatotype means. This analysis was significant beyond the 0.05 level. Subsequent pairwise comparisons by means of Hotelling’s T2 with a Bonferroni adjusted alpha level of 0.00048 indicated that there were significant differences between the following: the field lacrosse players (2.9-5.4-2.5) and both the gymnasts (1.9-6.1-2.5) and Australian Rules footballers (2.1-5.7-2.5); the rugby union footballers (2.7-6.0-2.0) and swimmers (1.9-4.7-3.6); and the gymnasts (1.9-6.1-2.5) and track and field athletes (2.0-4.7-3.4)