Delay in diagnosis of pulmonary tuberculosis in low-and middle-income settings: systematic review and meta-analysis

Background

Assessment of delays in seeking care and diagnosis of tuberculosis is essential to evaluate effectiveness of tuberculosis control programs, and identify programmatic impediments. Thus, this review of studies aimed to examine the extent of patient, health system, and total delays in diagnosis of pulmonary tuberculosis in low- and middle- income countries.

Methods

It was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Electronic databases were searched to retrieve studies published from 2007 to 2015 including Pubmed central, Springer link, Hinari and Google scholar. Searching terms were pulmonary tuberculosis, health care seeking, health care seeking behavior, patient delay, diagnostic delay, health system delay, provider delay, and doctor delay. Retrieved studies were systematically reviewed and summarized using Comprehensive Meta-analysis software.

Results

Forty studies involving 18,975 patients qualified for systematic review, and 14 of them qualified for meta-analysis. The median diagnostic delay ranged from 30 to 366.5 days [IQR?=?44–77.8], with a 4–199 days [IQR?=?15–50] and 2–128.5 days [IQR?=?12–34] due to patient and health system delays, respectively. The meta-analysis showed 42% of pulmonary tuberculosis patients delayed seeking care by a month or more; uneducated patients [pooled OR?=?1.5, 95%CI?=?1.1–1.9] and those who sought initial care from informal providers [pooled OR?=?3, 95%CI?=?2.3–3.9] had higher odds of patient delay.

Conclusion

Delay in diagnosis is still a major challenge of tuberculosis control and prevention programs in low- and middle- income settings. Efforts to develop new strategies for better case-finding using the existing systems and improving patients’ care seeking behavior need to be intensified.

     

Low Cd concentration-activated morphogenic defence responses are inhibited by high Cd concentration-induced toxic superoxide generation in barley root tip

Exposure of roots to low Cd concentration induced morphogenic responses including the inhibition of root growth and the radial swelling of root tip. High Cd concentrations within a few minutes caused a robust induction of superoxide generation leading to the cell death and root growth arrest. This toxic superoxide generation blocked the development of low Cd concentration-activated morphogenic responses. While the morphogenic responses of roots to low Cd concentration are induced very rapidly and probably due to the interaction of Cd with the apoplast of root tissue, high Cd concentration-induced superoxide production required the entry of Cd into the symplast. Auxin signaling is involved in the activation of Cd-induced morphogenic defence responses but not in the Cd-induced toxic superoxide generation. These results suggest that oxidative stress is not a primary cause for the Cd-induced morphogenic responses such as growth reduction and radial cell expansion in barley root tips.     

Combining Multi-Element Analysis with Statistical Modeling for Tracing the Origin of Green Coffee Beans from Amhara Region,Ethiopia

Biological Trace Element Research - Characterization of coffee terroirs is important to determine authenticity and provide confidence for consumers to select the right product. In this regard,...     

Functional plasticity in the substrate binding site of beta-secretase

The aspartic protease beta-secretase (BACE) cleaves the amyloid precursor protein into a 42 residue beta-peptide, which is the principal biochemical marker of Alzheimer's disease. Multiple explicit-water molecular dynamics simulations of the apo and inhibitor bound structures of BACE indicate that both open- and closed-flap conformations are accessible at room temperature and should be taken into account for inhibitor design. Correlated motion is observed within each of the two lobes of BACE, as well as for the interfacial region. A self-inhibited conformation with the side chain of Tyr71 occupying the S(1) pocket is present in some of the unbound simulations. The reversible loss of the side chain hydrogen bond between the catalytic Asp32 and Ser35, due to the concomitant reorientation of the Ser35 hydroxyl group and a water molecule conserved in pepsin-like enzymes, provides further evidence for the suggestion that Ser35 assists in proton acceptance and release by Asp32 during catalysis.     

Energetics of sequence-specific protein-DNA association: computational analysis of integrase Tn916 binding to its target DNA

The N-terminal domain of the bacterial integrase Tn916 specifically recognizes the 11 bp DNA target site by positioning the face of a three-stranded beta-sheet into the major groove. Binding is linked to structural adaptation. We have characterized INT-DBD binding to DNA in detail by calorimetry [Milev, S., Gorfe, A., Karshikoff, A., Clubb, R. T., Bosshard, H. R., and Jelesarov, I. (2003) Biochemistry 42, 3481-3491]. Our thermodynamic analysis has indicated that the major driving force of association is the hydrophobic effect while polar interactions contribute less. To gain more comprehensive information about the binding process, we performed a computational analysis of the binding free energy and report here the results. A hybrid molecular mechanics/continuum approach was followed. The total binding free energy is predicted with reasonable accuracy. The calculations confirm that nonpolar effects stabilize the protein-DNA complex while electrostatics opposes binding. Structural changes optimizing surface complementarity are costly in terms of energy. The energetic consequences from the replacement of nine DNA-contacting residues by alanine were investigated. The calculations correctly predict the binding affinity decrease of eight mutations and the destabilizing effect of one wild-type residue. Bulky side chains stabilize the wild-type complex through packing interactions and favorable nonpolar dehydration, but the net nonpolar energy changes do not correlate with the relative affinity loss upon mutation. Discrete protein-DNA electrostatic interactions may be net stabilizing or net destabilizing depending on the local environment. In contrast to nonpolar energy changes, the magnitude of the electrostatic free energy ranks the mutations according to the experimentally measured DeltaDeltaG. Free energy decomposition analysis from a structural perspective leads to detailed information about the thermodynamic strategy used by INT-DBD for sequence-specific DNA binding.     

Aconitase activity and expression during the development of lemon fruit

Citrus fruits are characterized by the accumulation of high levels of citric acid in the juice sac cells and a decline in acid level toward maturation. It has been suggested that changes in mitochondrial aconitase (EC 4.2.1.3) activity affect fruit acidity. Recently, a cytosolic aconitase (cyt-Aco) homologous to mammalian iron-regulated proteins was identified in plants, leading us to re-evaluate the role of aconitase in acid accumulation. Aconitase activity was studied in 2 contrasting citrus varieties, sweet lime ( Citrus limettioides Tan., low acid) and sour lemon ( Citrus limon var. Eureka, high acid). Two aconitase isozymes were detected. One declined early in sour lemon fruit development, but was constant throughout sweet lime fruit development. Its reduction in sour lemon was associated with a decrease in aconitase activity in the mitochondrial fraction. Another isozyme was detected in sour lemon toward maturation, and was associated with an increase in aconitase activity in the soluble fraction, suggesting a cytosolic localization. The cyt-Aco was cloned from lemon juice sac cells, but in contrast to the changes in isozyme activity, its expression was constant during fruit development. We present a model, which suggests that reduction of the mitochondrial aconitase activity plays a role in acid accumulation, while an increase in the cyt-Aco activity reduces acid level toward fruit maturation.     

Short- and long-term outcomes in infective endocarditis patients: a systematic review and meta-analysis

Background

Despite advances in medical knowledge, technology and antimicrobial therapy, infective endocarditis (IE) is still associated with devastating outcomes. No reviews have yet assessed the outcomes of IE patients undergoing short- and long-term outcome evaluation, such as all-cause mortality and IE-related complications. We conducted a systematic review and meta-analysis to examine the short- and long-term mortality, as well as IE-related complications in patients with definite IE.

Methods

A computerized systematic literature search was carried out in PubMed, Scopus and Google Scholar from 2000 to August, 2016. Included studies were published studies in English that assessed short-and long-term mortality for adult IE patients. Pooled estimations with 95% confidence interval (CI) were calculated with DerSimonian-Laird (DL) random-effects model. Sensitivity and subgroup analyses were also performed. Publication bias was evaluated using inspection of funnel plots and statistical tests.

Results

Twenty five observational studies (retrospective, 14; prospective, 11) including 22,382 patients were identified. The overall pooled mortality estimates for IE patients who underwent short- and long-term follow-up were 20% (95% CI: 18.0–23.0, P?<?0.01) and 37% (95% CI: 27.0–48.0, P?<?0.01), respectively. The pooled prevalence of cardiac complications in patients with IE was found to be 39% (95%CI: 32.0–46.0) while septic embolism and renal complications accounted for 25% (95% CI: 20.0–31) and 19% (95% CI: 14.0–25.0) (all P?<?0.01), respectively.

Conclusion

Irrespective of the follow-up period, a significantly higher mortality rate was reported in IE patients, and the burden of IE-related complications were immense. Further research is needed to assess the determinants of overall mortality in IE patients, as well as well-designed observational studies to conform our results.