Non-treatment of children with community health worker-diagnosed fast-breathing pneumonia in rural Malawi: exploratory subanalysis of a prospective cohort study

BACKGROUND: Despite recent progress, pneumonia remains the largest infectious killer of children globally. This paper describes outcomes of not treating community-diagnosed fast-breathing pneumonia on patient recovery. METHODS: We conducted an exploratory subanalysis of an observational prospective cohort study in Malawi. We recruited children (2-59 months) diagnosed by community health workers with fast-breathing pneumonia using WHO integrated community case management (iCCM) guidelines. Children were followed at days 5 and 14 with a clinical assessment of recovery. We conducted bivariate and multivariable logistic regression for the association between treatment of fast-breathing pneumonia and recovery, adjusting for potential confounders. RESULTS: We followed up 847 children, of whom 78 (9%) had not been given antibiotics (non-treatment). Non-treatment cases had higher baseline rates of diarrhoea, non-severe hypoxaemia and fever. Non-recovery (persistence or worsening of symptoms) was 13% and 23% at day 5 in those who did receive and those who did not receive co-trimoxazole. Non-recovery, when defined as worsening of symptoms only, at day 5 was 7% in treatment and 10% in non-treatment cases. For both definitions, combined co-trimoxazole and lumefantrine-artemether (LA) treatment trended towards protection (adjusted OR (aOR) 0.28; 95% CI 0.12 to 0.68/aOR 0.29; 95% CI 0.08 to 1.01). CONCLUSION: We found that children who did not receive co-trimoxazole treatment had worse clinical outcomes; malaria co-diagnosis and treatment also play a significant role in non-recovery. Further research into non-treatment of fast-breathing pneumonia, using a pragmatic approach with consideration for malaria co-diagnosis and HIV status is needed to guide refinement of community treatment algorithms in this region

Molecular and cellular mechanisms underlying the evolution of form and function in the amniote jaw.

The amniote jaw complex is a remarkable amalgamation of derivatives from distinct embryonic cell lineages. During development, the cells in these lineages experience concerted movements, migrations, and signaling interactions that take them from their initial origins to their final destinations and imbue their derivatives with aspects of form including their axial orientation, anatomical identity, size, and shape. Perturbations along the way can produce defects and disease, but also generate the variation necessary for jaw evolution and adaptation. We focus on molecular and cellular mechanisms that regulate form in the amniote jaw complex, and that enable structural and functional integration. Special emphasis is placed on the role of cranial neural crest mesenchyme (NCM) during the species-specific patterning of bone, cartilage, tendon, muscle, and other jaw tissues. We also address the effects of biomechanical forces during jaw development and discuss ways in which certain molecular and cellular responses add adaptive and evolutionary plasticity to jaw morphology. Overall, we highlight how variation in molecular and cellular programs can promote the phenomenal diversity and functional morphology achieved during amniote jaw evolution or lead to the range of jaw defects and disease that affect the human condition

Sports teams as complex adaptive systems: manipulating player numbers shapes behaviours during football small-sided games

Small-sided and conditioned games (SSCGs) in sport have been modelled as complex adaptive systems. Research has shown that the relative space per player (RSP) formulated in SSCGs can impact on emergent tactical behaviours. In this study we adopted a systems orientation to analyse how different RSP values, obtained through manipulations of player numbers, influenced four measures of interpersonal coordination observed during performance in SSCGs. For this purpose we calculated positional data (GPS 15 Hz) from ten U-15 football players performing in three SSCGs varying in player numbers (3v3, 4v4 and 5v5). Key measures of SSCG system behaviours included values of (1) players’ dispersion, (2) teams’ separateness, (3) coupling strength and time delays between participants’ emerging movements, respectively. Results showed that values of participants’ dispersion increased, but the teams’ separateness remained identical across treatments. Coupling strength and time delay also showed consistent values across SSCGs. These results exemplified how complex adaptive systems, like football teams, can harness inherent degeneracy to maintain similar team spatial–temporal relations with opponents through changes in inter-individual coordination modes (i.e., players’ dispersion). The results imply that different team behaviours might emerge at different ratios of field dimension/player numbers. Therefore, sport pedagogists should carefully evaluate the effects of changing RSP in SSCGs as a way of promoting increased or decreased pressure on players

Sheldon Spectrum and the Plankton Paradox: Two Sides of the Same Coin : A trait-based plankton size-spectrum model

The Sheldon spectrum describes a remarkable regularity in aquatic ecosystems: the biomass density as a function of logarithmic body mass is approximately constant over many orders of magnitude. While size-spectrum models have explained this phenomenon for assemblages of multicellular organisms, this paper introduces a species-resolved size-spectrum model to explain the phenomenon in unicellular plankton. A Sheldon spectrum spanning the cell-size range of unicellular plankton necessarily consists of a large number of coexisting species covering a wide range of characteristic sizes. The coexistence of many phytoplankton species feeding on a small number of resources is known as the Paradox of the Plankton. Our model resolves the paradox by showing that coexistence is facilitated by the allometric scaling of four physiological rates. Two of the allometries have empirical support, the remaining two emerge from predator-prey interactions exactly when the abundances follow a Sheldon spectrum. Our plankton model is a scale-invariant trait-based size-spectrum model: it describes the abundance of phyto- and zooplankton cells as a function of both size and species trait (the maximal size before cell division). It incorporates growth due to resource consumption and predation on smaller cells, death due to predation, and a flexible cell division process. We give analytic solutions at steady state for both the within-species size distributions and the relative abundances across species

Meta-analysis of binary outcomes via generalized linear mixed models: a simulation study

Background: Systematic reviews and meta-analyses of binary outcomes are widespread in all areas of application. The odds ratio, in particular, is by far the most popular effect measure. However, the standard meta-analysis of odds ratios using a random-effects model has a number of potential problems. An attractive alternative approach for the meta-analysis of binary outcomes uses a class of generalized linear mixed models (GLMMs). GLMMs are believed to overcome the problems of the standard random-effects model because they use a correct binomial-normal likelihood. However, this belief is based on theoretical considerations, and no sufficient simulations have assessed the performance of GLMMs in meta-analysis. This gap may be due to the computational complexity of these models and the resulting considerable time requirements. Methods: The present study is the first to provide extensive simulations on the performance of four GLMM methods (models with fixed and random study effects and two conditional methods) for meta-analysis of odds ratios in comparison to the standard random effects model. Results: In our simulations, the hypergeometric-normal model provided less biased estimation of the heterogeneity variance than the standard random-effects meta-analysis using the restricted maximum likelihood (REML) estimation when the data were sparse, but the REML method performed similarly for the point estimation of the odds ratio, and better for the interval estimation. Conclusions: It is difficult to recommend the use of GLMMs in the practice of meta-analysis. The problem of finding uniformly good methods of the meta-analysis for binary outcomes is still open

A Key Marine Diazotroph in a Changing Ocean: The Interacting Effects of Temperature, CO2 and Light on the Growth of Trichodesmium erythraeum IMS101

Trichodesmium is a globally important marine diazotroph that accounts for approximately 60-80% of marine biological N2 fixation and as such plays a key role in marine N and C cycles. We undertook a comprehensive assessment of how the growth rate of Trichodesmium erythraeum IMS101 was directly affected by the combined interactions of temperature, pCO2 and light intensity. Our key findings were: low pCO2 affected the lower temperature tolerance limit (Tmin) but had no effect on the optimum temperature (Topt) at which growth was maximal or the maximum temperature tolerance limit (Tmax); low pCO2 had a greater effect on the thermal niche width than low-light; the effect of pCO2 on growth rate was more pronounced at suboptimal temperatures than at supraoptimal temperatures; temperature and light had a stronger effect on the photosynthetic efficiency (Fv/Fm) than did CO2; and at Topt, the maximum growth rate increased with increasing CO2, but the initial slope of the growth-irradiance curve was not affected by CO2. In the context of environmental change, our results suggest that the (i) nutrient replete growth rate of Trichodesmium IMS101 would have been severely limited by low pCO2 at the last glacial maximum (LGM), (ii) future increases in pCO2 will increase growth rates in areas where temperature ranges between Tmin to Topt, but will have negligible effect at temperatures between Topt and Tmax, (iii) areal increase of warm surface waters (> 18°C) has allowed the geographic range to increase significantly from the LGM to present and that the range will continue to expand to higher latitudes with continued warming, but (iv) continued global warming may exclude Trichodesmium spp. from some tropical regions by 2100 where temperature exceeds Topt

The genetic basis and evolution of red blood cell sickling in deer

Crescent-shaped red blood cells, the hallmark of sickle-cell disease, present a striking departure from the biconcave disc shape normally found in mammals. Characterized by increased mechanical fragility, sickled cells promote haemolytic anaemia and vaso-occlusions and contribute directly to disease in humans. Remarkably, a similar sickle-shaped morphology has been observed in erythrocytes from several deer species, without obvious pathological consequences. The genetic basis of erythrocyte sickling in deer, however, remains unknown. Here, we determine the sequences of human β-globin orthologues in 15 deer species and use protein structural modelling to identify a sickling mechanism distinct from the human disease, coordinated by a derived valine (E22V) that is unique to sickling deer. Evidence for long-term maintenance of a trans-species sickling/non-sickling polymorphism suggests that sickling in deer is adaptive. Our results have implications for understanding the ecological regimes and molecular architectures that have promoted convergent evolution of sickling erythrocytes across vertebrates

Allosteric Modulation of the HIV-1 gp120-gp41 Association Site by Adjacent gp120 Variable Region 1 (V1) N-Glycans Linked to Neutralization Sensitivity

The HIV-1 gp120-gp41 complex, which mediates viral fusion and cellular entry, undergoes rapid evolution within its external glycan shield to enable escape from neutralizing antibody (NAb). Understanding how conserved protein determinants retain functionality in the context of such evolution is important for their evaluation and exploitation as potential drug and/ or vaccine targets. In this study, we examined how the conserved gp120-gp41 association site, formed by the N- and Cterminal segments of gp120 and the disulfide-bonded region (DSR) of gp41, adapts to glycan changes that are linked to neutralization sensitivity. To this end, a DSR mutant virus (K601D) with defective gp120-association was sequentially passaged in peripheral blood mononuclear cells to select suppressor mutations. We reasoned that the locations of suppressors point to structural elements that are functionally linked to the gp120-gp41 association site. In culture 1, gp120 association and viral replication was restored by loss of the conserved glycan at Asn136 in V1 (T138N mutation) inconjunction with the L494I substitution in C5 within the association site. In culture 2, replication was restored with deletion of the N139INN sequence, which ablates the overlapping Asn141-Asn142-Ser-Ser potential N-linked glycosylation sequons inV1, in conjunction with D601N in the DSR. The 136 and 142 glycan mutations appeared to exert their suppressive effects by altering the dependence of gp120-gp41 interactions on the DSR residues, Leu593, Trp596 and Lys601. The 136 and/or 142glycan mutations increased the sensitivity of HIV-1 pseudovirions to the glycan-dependent NAbs 2G12 and PG16, and also pooled IgG obtained from HIV-1-infected individuals. Thus adjacent V1 glycans allosterically modulate the distal gp120-gp41 association site. We propose that this represents a mechanism for functional adaptation of the gp120-gp41 association site to an evolving glycan shield in a setting of NAb selection

Automated Detection of Infectious Disease Outbreaks in Hospitals: A Retrospective Cohort Study

Susan Huang and colleagues describe an automated statistical software, WHONET-SaTScan, its application in a hospital, and the potential it has to identify hospital infection clusters that had escaped routine detection