Evaluation of In-Hospital Management for Febrile Illness\ud in Northern Tanzania before and after 2010 World Health\ud Organization Guidelines for the Treatment of Malaria

In 2010, the World Health Organization (WHO) published updated guidelines emphasizing and expanding recommendations for a parasitological confirmation of malaria before treating with antimalarials. This study aimed to assess differences in historic (2007–2008) (cohort 1) and recent (2011–2012) (cohort 2) hospital cohorts in the diagnosis and treatment of febrile illness in a low malaria prevalence area of northern Tanzania. We analyzed data from two prospective cohort studies that enrolled febrile adolescents and adults aged $13 years. All patients received quality-controlled aerobic blood cultures and malaria smears. We compared patients’ discharge diagnoses, treatments, and outcomes to assess changes in the treatment of malaria and bacterial infections. In total, 595 febrile inpatients were enrolled from two referral hospitals in Moshi, Tanzania. Laboratory-confirmed malaria was detected in 13 (3.2%) of 402 patients in cohort 1 and 1 (0.5%) of 193 patients in cohort 2 (p = 0.041). Antimalarials were prescribed to 201 (51.7%) of 389 smear-negative patients in cohort 1 and 97 (50.5%) of 192 smearnegative patients in cohort 2 (p = 0.794). Bacteremia was diagnosed from standard blood culture in 58 (14.5%) of 401 patients in cohort 1 compared to 18 (9.5%) of 190 patients in cohort 2 (p = 0.091). In cohort 1, 40 (69.0%) of 58 patients with a positive blood culture received antibacterials compared to 16 (88.9%) of 18 patients in cohort 2 (p = 0.094). In cohort 1, 43 (10.8%) of the 399 patients with known outcomes died during hospitalization compared with 12 (6.2%) deaths among 193 patients in cohort 2 (p = 0.073). In a setting of low malaria transmission, a high proportion of smear-negative patients were diagnosed with malaria and treated with antimalarials despite updated WHO guidelines on malaria treatment. Improved laboratory diagnostics for non-malaria febrile illness might help to curb this practice.\u

An evaluation of the complement-regulating activities of human complement factor H (FH) variants associated with age-related macular degeneration

PURPOSE: Factor H (FH, encoded by CFH) prevents activation of the complement system's alternative pathway (AP) on host tissues. FH impedes C3 convertase (C3bBb) formation, accelerates C3bBb decay, and is a cofactor for factor I (FI)–catalyzed C3b cleavage. Numerous CFH variants are associated with age-related macular degeneration (AMD), but their functional consequences frequently remain undetermined. Here, we conduct functional comparisons between a control version of FH (not AMD linked) and 21 AMD-linked FH variants. METHODS: Recombinantly produced, untagged, full-length FH versions were assayed for binding to C3b and decay acceleration of C3bBb using surface-plasmon resonance, FI-cofactor activity using a fluorescent probe of C3b integrity, suppression of C5b-9 assembly on an AP-activating surface, and inhibition of human AP-mediated lysis of sheep erythrocytes. RESULTS: All versions were successfully purified despite below-average yields for Arg2Thr, Arg53Cys, Arg175Pro, Arg175Gln, Ile221Val, Tyr402His, Pro503Ala, Arg567Gly, Gly1194Asp, and Arg1210Cys. Compared to control FH, Arg2Thr, Leu3Val, Ser58Ala, Asp90Gly, Asp130Asn, Gln400Lys, Tyr402His, Gly650Val, Ser890Ile, and Thr965Met showed minimal functional differences. Arg1210C, Arg53His, Arg175Gln, Gly1194Asp, Pro503Ala, Arg53Cys, Arg576Gly, and Arg175Pro (in order of decreasing efficacy) underperformed, while Ile221Val, Arg303Gln, and Arg303Trp were “marginal.” We newly identified variants toward the center of the molecule, Pro503Ala and Arg567Gly, as potentially pathogenic. CONCLUSIONS: Our approach could be extended to other variants of uncertain significance and to assays for noncanonical FH activities, aiming to facilitate selection of cohorts most likely to benefit from therapeutic FH. This is timely as recombinant therapeutic FH is in development for intravitreal treatment of AMD in patients with reduced FH functionality

ALMACAL. XI. Over-densities as signposts to proto-clusters? A cautionary tale

It may be unsurprising that the most common approach to finding proto-clusters is to search for over-densities of galaxies. Upgrades to submillimetre (submm) interferometers and the advent of the James Webb Space Telescope will soon offer the opportunity to find more distant candidate proto-clusters in deep sky surveys without any spectroscopic confirmation. In this letter, we report the serendipitous discovery of an extremely dense region centred on the blazar, J0217-0820, at z=0.6 in the ALMACAL sky survey. Its density is eight times higher than that predicted by blind submm surveys. Among the seven submm-bright galaxies, three are as bright as conventional single-dish submm galaxies, with S_870um > 3mJy. The over-density is thus comparable to the densest known and confirmed proto-cluster cores. However, their spectra betray a wide range of redshifts. We investigate the likelihood of line-of-sight projection effects using light cones from cosmological simulations, finding that the deeper we search, the higher the chance that we will suffer from such projection effects. The extreme over-density around J0217-0820 demonstrates the strong cosmic variance we may encounter in the deep submm surveys. Thus, we should also question the fidelity of galaxy proto-cluster candidates selected via over-densities of galaxies, where the negative K correction eases the detection of dusty galaxies along an extraordinarily extended line of sight.Comment: 7 pages, 5 figures, update with the accepted versio

Temporal dynamics of aquatic communities and implications for pond conservation

Conservation through the protection of particular habitats is predicated on the assumption that the conservation value of those habitats is stable. We test this assumption for ponds by investigating temporal variation in macroinvertebrate and macrophyte communities over a 10-year period in northwest England. We surveyed 51 ponds in northern England in 1995/6 and again in 2006, identifying all macrophytes (167 species) and all macroinvertebrates (221 species, excluding Diptera) to species. The alpha-diversity, beta-diversity and conservation value of these ponds were compared between surveys. We find that invertebrate species richness increased from an average of 29. 5 species to 39. 8 species between surveys. Invertebrate gamma-diversity also increased between the two surveys from 181 species to 201 species. However, this increase in diversity was accompanied by a decrease in beta-diversity. Plant alpha-, beta and gamma-diversity remained approximately constant between the two periods. However, increased proportions of grass species and a complete loss of charophytes suggests that the communities are undergoing succession. Conservation value was not correlated between sampling periods in either plants or invertebrates. This was confirmed by comparing ponds that had been disturbed with those that had no history of disturbance to demonstrate that levels of correlation between surveys were approximately equal in each group of ponds. This study has three important conservation implications: (i) a pond with high diversity or high conservation value may not remain that way and so it is unwise to base pond conservation measures upon protecting currently-speciose habitats; (ii) maximising pond gamma-diversity requires a combination of late and early succession ponds, especially for invertebrates; and (iii) invertebrate and plant communities in ponds may require different management strategies if succession occurs at varying rates in the two groups

MUSE-ALMA Haloes IX: Morphologies and Stellar Properties of Gas-rich Galaxies

Understanding how galaxies interact with the circumgalactic medium (CGM) requires determining how galaxies morphological and stellar properties correlate with their CGM properties. We report an analysis of 66 well-imaged galaxies detected in HST and VLT MUSE observations and determined to be within $\pm$500 km s$^{-1}$ of the redshifts of strong intervening quasar absorbers at $0.2 \lesssim z \lesssim 1.4$ with H I column densities $N_{\rm H I}$ $>$ $10^{18}$ $\rm cm^{-2}$. We present the geometrical properties (S\'ersic indices, effective radii, axis ratios, and position angles) of these galaxies determined using GALFIT. Using these properties along with star formation rates (SFRs, estimated using the H$\alpha$ or [O II] luminosity) and stellar masses ($M_{*}$ estimated from spectral energy distribution fits), we examine correlations among various stellar and CGM properties. Our main findings are as follows: (1) SFR correlates well with $M_{*}$, and most absorption-selected galaxies are consistent with the star formation main sequence (SFMS) of the global population. (2) More massive absorber counterparts are more centrally concentrated and are larger in size. (3) Galaxy sizes and normalized impact parameters correlate negatively with $N_{\rm H I}$, consistent with higher $N_{\rm H I}$ absorption arising in smaller galaxies, and closer to galaxy centers. (4) Absorption and emission metallicities correlate with $M_{*}$ and sSFR, implying metal-poor absorbers arise in galaxies with low past star formation and faster current gas consumption rates. (5) SFR surface densities of absorption-selected galaxies are higher than predicted by the Kennicutt-Schmidt relation for local galaxies, suggesting a higher star formation efficiency in the absorption-selected galaxies.Comment: Accepted for publication in MNRAS, 25 pages, 19 figure

Targeted genetic testing for familial hypercholesterolaemia using next generation sequencing:a population-based study

Background<p></p> Familial hypercholesterolaemia (FH) is a common Mendelian condition which, untreated, results in premature coronary heart disease. An estimated 88% of FH cases are undiagnosed in the UK. We previously validated a method for FH mutation detection in a lipid clinic population using next generation sequencing (NGS), but this did not address the challenge of identifying index cases in primary care where most undiagnosed patients receive healthcare. Here, we evaluate the targeted use of NGS as a potential route to diagnosis of FH in a primary care population subset selected for hypercholesterolaemia.<p></p> Methods<p></p> We used microfluidics-based PCR amplification coupled with NGS and multiplex ligation-dependent probe amplification (MLPA) to detect mutations in LDLR, APOB and PCSK9 in three phenotypic groups within the Generation Scotland: Scottish Family Health Study including 193 individuals with high total cholesterol, 232 with moderately high total cholesterol despite cholesterol-lowering therapy, and 192 normocholesterolaemic controls.<p></p> Results<p></p> Pathogenic mutations were found in 2.1% of hypercholesterolaemic individuals, in 2.2% of subjects on cholesterol-lowering therapy and in 42% of their available first-degree relatives. In addition, variants of uncertain clinical significance (VUCS) were detected in 1.4% of the hypercholesterolaemic and cholesterol-lowering therapy groups. No pathogenic variants or VUCS were detected in controls.<p></p> Conclusions<p></p> We demonstrated that population-based genetic testing using these protocols is able to deliver definitive molecular diagnoses of FH in individuals with high cholesterol or on cholesterol-lowering therapy. The lower cost and labour associated with NGS-based testing may increase the attractiveness of a population-based approach to FH detection compared to genetic testing with conventional sequencing. This could provide one route to increasing the present low percentage of FH cases with a genetic diagnosis

New Agendas for Agricultural Research in Developing Countries: Policy Analysis and Institutional Implications

This article argues that the goals of agricultural research in poor countries have changed substantially over the last four decades. In particular they have broadened from the early (and narrow) emphasis on food production to a much wider agenda that includes poverty alleviation, environmental degradation, and social inclusion. Conversely, agricultural research systems have proved remarkably resistant to the concomitant need for changes in research focus. As a result many, at both the national and international level, are under great strain. In terms of public policy the article goes on to suggest that shortcomings of existing conceptual approaches to technology development could be supplemented by adopting analytical principles that view innovation in systemic terms. An approach where flows of knowledge between institutional nodes is a key to innovative performance (the “National Systems of Innovation” approach) is suggested as one such conceptual framework that might help supplement conventional policy analysis. An earlier version of this paper was presented at a workshop “New Policy Agendas for Agricultural Research: Implications for Institutional Arrangements” held on 28 March 2000 at the International Crops Research Institute for the Semi-Arid Tropics (ICRISAT), Patancheru, India. The workshop was supported by the UK Department of International Development (DFID) Crop Post-Harvest Programme as an output of the project “Optimising Institutional Arrangements.