Evidence-based de-implementation for contradicted, unproven, and aspiring healthcare practices

Abandoning ineffective medical practices and mitigating the risks of untested practices are important for improving patient health and containing healthcare costs. Historically, this process has relied on the evidence base, societal values, cultural tensions, and political sway, but not necessarily in that order. We propose a conceptual framework to guide and prioritize this process, shifting emphasis toward the principles of evidence-based medicine, acknowledging that evidence may still be misinterpreted or distorted by recalcitrant proponents of entrenched practices and other biases.     

Infectious disease in consumer populations: dynamic consequences of resource-mediated transmission and infectiousness

Nonhost species can strongly affect the timing and progression of epidemics. One central interaction—between hosts, their resources, and parasites—remains surprisingly underdeveloped from a theoretical perspective. Furthermore, key epidemiological traits that govern disease spread are known to depend on resource density. We tackle both issues here using models that fuse consumer–resource and epidemiological theory. Motivated by recent studies of a phytoplankton–zooplankton–fungus system, we derive and analyze a family of dynamic models for parasite spread among consumers in which transmission depends on consumer (host) and resource densities. These models yield four key insights. First, host–resource cycling can lower mean host density and inhibit parasite invasion. Second, host–resource cycling can create Allee effects (bistability) if parasites increase mean host density by reducing the amplitude of host–resource cycles. Third, parasites can stabilize host–resource cycles; however, host–resource cycling can also cause disease cycling. Fourth, resource dependence of epidemiological traits helps to govern the relative dominance of these different behaviors. However, these resource dependencies largely have quantitative rather than qualitative effects on these three-species dynamics. Given the extent of these results, host–resource–parasite interactions should become more fundamental components of the burgeoning theory for the community ecology of infectious diseases.     

Compositional shifts in Costa Rican forests due to climate‐driven species migrations

Species are predicted to shift their distributions upslope or poleward in response to global warming. This prediction is supported by a growing number of studies documenting species migrations in temperate systems but remains poorly tested for tropical species, and especially for tropical plant species. We analyzed changes in tree species composition in a network of 10 annually censused 1‐ha plots spanning an altitudinal gradient of 70–2800 m elevation in Costa Rica. Specifically, we combined plot data with herbarium records (accessed through GBIF) to test if the plots' community temperature scores (CTS, average thermal mean of constituent species weighted by basal area) have increased over the past decade as is predicted by climate‐driven species migrations. In addition, we quantified the contributions of stem growth, recruitment, and mortality to the observed patterns. Supporting our a priori hypothesis of upward species migrations, we found that there have been consistent directional shifts in the composition of the plots, such that the relative abundance of lowland species, and hence CTS, increased in 90% of plots. The rate of the observed compositional shifts corresponds to a mean thermal migration rate (TMR) of 0.0065 °C yr^?1 (95% CI = 0.0005–0.0132 °C yr^?1). While the overall TMR is slower than predicted based on concurrent regional warming of 0.0167 °C yr^?1, migrations were on pace with warming in 4 of the 10 plots. The observed shifts in composition were driven primarily by mortality events (i.e., the disproportionate death of highland vs. lowland species), suggesting that individuals of many tropical tree species will not be able to tolerate future warming and thus their persistence in the face of climate change will depend on successful migrations. Unfortunately, in Costa Rica and elsewhere, land area inevitably decreases at higher elevations; hence, even species that are able to migrate successfully will face heightened risks of extinction.     

Associations between COPD related manifestations: a cross-sectional study

Background

Cardiovascular disease, osteoporosis and emphysema are associated with COPD. Associations between these factors and whether they predict all-cause mortality in COPD patients are not well understood. Therefore, we examined associations between markers of cardiovascular disease (coronary artery calcification [CAC], thoracic aortic calcification [TAC] and arterial stiffness), bone density (bone attenuation of the thoracic vertebrae), emphysema (PI-950 and 15th percentile) and all-cause mortality in a COPD cohort.

Methods

We assessed CAC, TAC, bone attenuation of the thoracic vertebrae, PI-950 and 15th percentile on low-dose chest computed tomography in COPD subjects. We measured arterial stiffness as carotid-radial pulse wave velocity (PWV), and identified deaths from the national register.

Results

We studied 119 COPD subjects; aged 67.8 ±7.3, 66% were males and mean FEV₁% predicted was 46.0 ±17.5. Subjects were classified into three pre-specificed groups: CAC = 0 (n = 14), 0 < CAC ≤ 400 (n = 41) and CAC > 400 (n = 64). Subjects with higher CAC were more likely to be older (p < 0.001) and male (p = 0.03), and more likely to have higher systolic blood pressure (p = 0.001) and a history of hypertension (p = 0.002) or ischemic heart disease (p = 0.003). Higher CAC was associated with higher PWV (OR 1.62, p = 0.04) and lower bone attenuation (OR 0.32, p = 0.02), but not with 15th percentile, after adjustment for age, sex and pack-years of smoking. In a Cox proportional hazards model, CAC, TAC and 15th percentile predicted all-cause mortality (HR 2.01, 2.09 and 0.66, respectively).

Conclusions

Increased CAC was associated with increased arterial stiffness and lower bone density in a COPD cohort. In addition, CAC, TAC and extent of emphysema predicted all-cause mortality.

Trial registration

Lothian NHS Board, Lothian Research Ethics Committee, LREC/2003/8/28.     

Aggressive Regimens for Multidrug-Resistant Tuberculosis Decrease All-Cause Mortality

Rationale

A better understanding of the composition of optimal treatment regimens for multidrug-resistant tuberculosis (MDR-TB) is essential for expanding universal access to effective treatment and for developing new therapies for MDR-TB. Analysis of observational data may inform the definition of an optimized regimen.

Objectives

This study assessed the impact of an aggressive regimen–one containing at least five likely effective drugs, including a fluoroquinolone and injectable–on treatment outcomes in a large MDR-TB patient cohort.

Methods

This was a retrospective cohort study of patients treated in a national outpatient program in Peru between 1999 and 2002. We examined the association between receiving an aggressive regimen and the rate of death.

Measurements and Main Results

In total, 669 patients were treated with individualized regimens for laboratory-confirmed MDR-TB. Isolates were resistant to a mean of 5.4 (SD 1.7) drugs. Cure or completion was achieved in 66.1% (442) of patients; death occurred in 20.8% (139). Patients who received an aggressive regimen were less likely to die (crude hazard ratio [HR]: 0.62; 95% CI: 0.44,0.89), compared to those who did not receive such a regimen. This association held in analyses adjusted for comorbidities and indicators of severity (adjusted HR: 0.63; 95% CI: 0.43,0.93).

Conclusions

The aggressive regimen is a robust predictor of MDR-TB treatment outcome. TB policy makers and program directors should consider this standard as they design and implement regimens for patients with drug-resistant disease. Furthermore, the aggressive regimen should be considered the standard background regimen when designing randomized trials of treatment for drug-resistant TB.     

Genetic and structural validation of Aspergillus fumigatus UDP‐N‐acetylglucosamine pyrophosphorylase as an antifungal target

The sugar nucleotide UDP‐N‐acetylglucosamine (UDP‐GlcNAc) is an essential metabolite in both prokaryotes and eukaryotes. In fungi, it is the precursor for the synthesis of chitin, an essential component of the fungal cell wall. U DP‐N‐a cetylglucosamine p yrophosphorylase (UAP) is the final enzyme in eukaryotic UDP‐GlcNAc biosynthesis, converting UTP and N‐acetylglucosamine‐1‐phosphate (GlcNAc‐1P) to UDP‐GlcNAc. As such, this enzyme may provide an attractive target against pathogenic fungi. Here, we demonstrate that the fungal pathogen Aspergillus fumigatus possesses an active UAP (AfUAP1) that shows selectivity for GlcNAc‐1P as the phosphosugar substrate. A conditional mutant, constructed by replacing the native promoter of the A. fumigatus uap1 gene with the Aspergillus nidulans alcA promoter, revealed that uap1 is essential for cell survival and important for cell wall synthesis and morphogenesis. The crystal structure of AfUAP1 was determined and revealed exploitable differences in the active site compared with the human enzyme. Thus AfUAP1 could represent a novel antifungal target and this work will assist the future discovery of small molecule inhibitors against this enzyme.     

Systems biological approach to investigate the lack of familial link between Down's Syndrome & Neural Tube Disorders

Systems Biology involves the study of the interactions of biological systems and ultimately their functions. Down''s syndrome (DS) is one of the most common genetic disorders which are caused by complete, or occasionally partial, triplication of chromosome 21, characterized by cognitive and language dysfunction coupled with sensory and neuromotor deficits. Neural Tube Disorders (NTDs) are a group of congenital malformations of the central nervous system and neighboring structures related to defective neural tube closure during the first trimester of pregnancy usually occurring between days 18-29 of gestation. Several studies in the past have provided considerable evidence that abnormal folate and methyl metabolism are associated with onset of DS & NTDs. There is a possible common etiological pathway for both NTDs and Down''s syndrome. But, various research studies over the years have indicated very little evidence for familial link between the two disorders. Our research aimed at the gene expression profiling of microarray datasets pertaining to the two disorders to identify genes whose expression levels are significantly altered in these conditions. The genes which were 1.5 fold unregulated and having a p-value <0.05 were filtered out and gene interaction network were constructed for both NTDs and DS. The top ranked dense clique for both the disorders were recognized and over representation analysis was carried out for each of the constituent genes. The comprehensive manual analysis of these genes yields a hypothetical understanding of the lack of familial link between DS and NTDs. There were no genes involved with folic acid present in the dense cliques. Only – CBL, EGFR genes were commonly present, which makes the allelic variants of these genes – good candidates for future studies regarding the familial link between DS and NTDs.

Abbreviations

NTD - Neural Tube Disorders, DS - Down''s Syndrome, MTHFR - Methylenetetrahydrofolate reductase, MTRR– 5 - methyltetrahydrofolate-homocysteine methyltransferase reductase.     

Four-year evaluation of the effect of vaccination against Coxiella burnetii on reduction of animal infection and environmental contamination in a naturally infected dairy sheep flock

Vaccination is considered one of the best options for controlling Coxiella burnetii infection in livestock. The efficacy of a phase I vaccine was investigated over 4 years in a sheep flock with confirmed C. burnetii infection. Shedding was not detected in ewes and yearlings in the last 2 years, but C. burnetii still persisted in the environment.