Determinants of tuberculosis transmission and treatment abandonment in Fortaleza, Brazil

BACKGROUND: Tuberculosis (TB) remains a public health problem, despite recent achievements in reducing incidence and mortality rates. In Brazil, these achievements were above the worldwide average, but marked by large regional heterogeneities. In Fortaleza (5th largest city in Brazil), the tuberculosis cure rate has been declining and treatment abandonment has been increasing in the past decade, despite a reduction in incidence and an increase in directly observed therapy (DOT). These trends put efforts to eliminate tuberculosis at risk. We therefore sought to determine social and programmatic determinants of tuberculosis incidence and treatment abandonment in Fortaleza. METHODS: We analyzed sociodemographic and clinical data for all new tuberculosis cases notified in the Notifiable Diseases Information System (SINAN) from Fortaleza between 2007 and 2014. We calculated incidence rates for 117 neighborhoods in Fortaleza, assessed their spatial clustering, and used spatial regression models to quantify associations between neighborhood-level covariates and incidence rates. We used hierarchical logistic regression models to evaluate how individual- and neighborhood-level covariates predicted tuberculosis treatment abandonment. RESULTS: There were 12,338 new cases reported during the study period. Case rates across neighborhoods were significantly positively clustered in two low-income areas close to the city center. In an adjusted model, tuberculosis rates were significantly higher in neighborhoods with lower literacy, higher sewerage access and homicide rates, and a greater proportion of self-reported black residents. Treatment was abandoned in 1901 cases (15.4%), a rate that rose by 71% between 2007 and 2014. Abandonment was significantly associated with many individual sociodemographic and clinical factors. Notably, being recommended for DOT was protective for those who completed DOT, but associated with abandonment for those who did not. CONCLUSION: Low socioeconomic status areas have higher tuberculosis rates, and low socioeconomic individuals have higher risk of treatment abandonment, in Fortaleza. Treatment abandonment rates are growing despite the advent of universal DOT recommendations in Brazil. Proactive social policies, and active contact tracing to find missed cases, may help reduce the tuberculosis burden in this setting

Dissolved noble gases and stable isotopes as tracers of preferential fluid flow along faults in the Lower Rhine Embayment, Germany

Groundwater in shallow unconsolidated sedimentary aquifers close to the Bornheim fault in the Lower Rhine Embayment (LRE), Germany, has relatively low δ2H and δ18O values in comparison to regional modern groundwater recharge, and 4He concentrations up to 1.7 × 10−4 cm3 (STP) g–1 ± 2.2 % which is approximately four orders of magnitude higher than expected due to solubility equilibrium with the atmosphere. Groundwater age dating based on estimated in situ production and terrigenic flux of helium provides a groundwater residence time of ∼107 years. Although fluid exchange between the deep basal aquifer system and the upper aquifer layers is generally impeded by confining clay layers and lignite, this study’s geochemical data suggest, for the first time, that deep circulating fluids penetrate shallow aquifers in the locality of fault zones, implying  that sub-vertical fluid flow occurs along faults in the LRE. However, large hydraulic-head gradients observed across many faults suggest that they act as barriers to lateral groundwater flow. Therefore, the geochemical data reported here also substantiate a conduit-barrier model of fault-zone hydrogeology in unconsolidated sedimentary deposits, as well as corroborating the concept that faults in unconsolidated aquifer systems can act as loci for hydraulic connectivity between deep and shallow aquifers. The implications of fluid flow along faults in sedimentary basins worldwide are far reaching and of particular concern for carbon capture and storage (CCS) programmes, impacts of deep shale gas recovery for shallow groundwater aquifers, and nuclear waste storage sites where fault zones could act as potential leakage pathways for hazardous fluids

Modification of T lymphocytes with lentiviral vectors for expression of anti-CD19 chimeric antigen receptor (CAR)

The use of immunotherapy with modified T lymphocytes with chimeric antigen receptor (CAR) has been proven effective in the treatment of leukemias and lymphomas resistant to chemotherapy. CAR possess an extracellular domain derived from variable regions of antibodies and costimulation intracellular domains of T lymphocytes. CD19 protein has been shown to be an ideal target because it is expressed on most B-cell tumors as well as normal B cells, but not in other types of cells. Recent clinical studies involving anti-CD19 CAR T-cells have shown excellent responses in a variety of B-cell tumors, even in patients with relapse after high-dose chemotherapy. This study aimed to produce CD4+ lymphocyte lineage Jurkat (ATCC® TIB-152 ™) modified with a second generation anti-CD19 CAR with 4-1BB as intracellular costimulation domain. Lentiviral vectors were produced in HEK293T (ATCC® CRL-3216 ™) transiently transfected with plasmids containing the coding sequence of the CAR, viral envelope VSV-G, and viral capsid. The viral titer was calculated by real time PCR after transduction of HEK293T cells, resulting in 1.65 x 105 IU/mL. The literature indicates an MOI (multiplicity of infection) from 5 to 10 IU/cell for transduction of lymphocytes. A new batch of virus was produced, and the supernatant was ultracentrifuged at 19200 rpm (Beckman Coulter, SW28 rotor) in order to concentrate the viral particles. The viral titer of the concentrated batch was 1.26 x 108 IU/mL. This new titer is compatible with the necessary to infect 107 cells, amount of pre-expansion cells necessary to obtain the number of cells suitable for infusion into patients (2.5 x 109 to 5 x 109 cells). Then, the infection of Jurkat was performed in a 6-well plate with RPMI 1640 supplemented with 10% fetal bovine serum (FBS), 2 µg/mL Polybrene®, and centrifugation at 1000 rpm for 20 minutes at room temperature. After 16 hours of incubation (37°C, 5% CO2 and 85% humidity), the medium was exchanged for fresh RPMI 1640 10% FBS. After additional 48 hours of incubation under the same conditions, the cells were collected and was their DNA was extracted. We obtained by real-time PCR that the number of integrated viral copies per genome was 35.3 ± 4.5 (mean ± standard deviation) for transduction with MOI of 5 IU/cell. While for MOI of 10 IU/cell, it was obtained 42.6 ± 0.1 copies per genome. It was observed that there was not a significant increase in viral copies when the MOI increased from 5 to 10. This may occur because cell’s surface receptors have been saturated by the large number of viruses. The lentiviral vector used by us has been shown to transduce T lymphocyte satisfactorily. The next steps of the study are the transduction of T lymphocytes from healthy donors and verification of the CAR receptor effectiveness to bind to CD19 of cell B lymphocyte lineages. Grant #2016/08374-5, São Paulo Research Foundation (FAPESP)

Analysis of drugs returned by inpatient services after unit dose distribution in a portuguese public hospital

Unit-dose has been considered the most effective dispensing system in hospital pharmacy, however not all drugs are administered, are then returned to the pharmacy. The analysis of non-administered drugs might provide important data regarding pharmacotherapeutic follow-up, but also regarding pharmacy management decisions. The present study aims at depicting the drugs returned to the pharmacy following their previous unit-dose dispensing. Methods: During a period of 45 days, the unused returned drugs of five different inpatient clinical services were analyzed regarding the state of conservation, justification for return, inpatient clinical service provenance, and dosage regimen. Of a total of 65280 unit-dose dispensed drugs, 25.2% were returned (n=16431) and 74.9% of SOS (i.e. medications prescribed as needed) drugs (n=6583) were unused. Excluding SOS drugs, more than a half of the returned drugs (52.4%, n=4967), were probably returned due to unintended omission of administration, after excluding patients that were not physically on the unit and patients whose treatments were modified. The large majority of returned drugs (98.6%, n=16201) were suitable for reintroduction in the medication circuit. In order to accomplish the basic principles of unit-dose dispensing genesis, the returned drugs must be kept to a minimum. Therefore, the suspension of dispensing SOS drugs by unit-dose should be considered. Additionally, the careful analysis of returned drugs should be promoted, in order to avoid, as much as possible, the omission of administration.info:eu-repo/semantics/publishedVersio

Oral tolerance to cancer can be abrogated by T regulatory cell inhibition

Oral administration of tumour cells induces an immune hypo-responsiveness known as oral tolerance. We have previously shown that oral tolerance to a cancer is tumour antigen specific, non-cross-reactive and confers a tumour growth advantage. We investigated the utilisation of regulatory T cell (Treg) depletion on oral tolerance to a cancer and its ability to control tumour growth. Balb/C mice were gavage fed homogenised tumour tissue – JBS fibrosarcoma (to induce oral tolerance to a cancer), or PBS as control. Growth of subcutaneous JBS tumours were measured; splenic tissue excised and flow cytometry used to quantify and compare systemic Tregs and T effector (Teff) cell populations. Prior to and/or following tumour feeding, mice were intraperitoneally administered anti-CD25, to inactivate systemic Tregs, or given isotype antibody as a control. Mice which were orally tolerised prior to subcutaneous tumour induction, displayed significantly higher systemic Treg levels (14% vs 6%) and faster tumour growth rates than controls (p<0.05). Complete regression of tumours were only seen after Treg inactivation and occurred in all groups - this was not inhibited by tumour feeding. The cure rates for Treg inactivation were 60% during tolerisation, 75% during tumour growth and 100% during inactivation for both tolerisation and tumour growth. Depletion of Tregs gave rise to an increased number of Teff cells. Treg depletion post-tolerisation and post-tumour induction led to the complete regression of all tumours on tumour bearing mice. Oral administration of tumour tissue, confers a tumour growth advantage and is accompanied by an increase in systemic Treg levels. The administration of anti-CD25 Ab decreased Treg numbers and caused an increase in Teffs. Most notably Treg cell inhibition overcame established oral tolerance with consequent tumor regression, especially relevant to foregut cancers where oral tolerance is likely to be induced by the shedding of tumour tissue into the gut

Gauss-Bonnet Black Holes and Heavy Fermion Metals

We consider charged black holes in Einstein-Gauss-Bonnet Gravity with Lifshitz boundary conditions. We find that this class of models can reproduce the anomalous specific heat of condensed matter systems exhibiting non-Fermi-liquid behaviour at low temperatures. We find that the temperature dependence of the Sommerfeld ratio is sensitive to the choice of Gauss-Bonnet coupling parameter for a given value of the Lifshitz scaling parameter. We propose that this class of models is dual to a class of models of non-Fermi-liquid systems proposed by Castro-Neto et.al.Comment: 17 pages, 6 figures, pdfLatex; small corrections to figure 10 in this versio

Daily sperm production and evaluation of morphological reproductive parameters of Murrah buffaloes in an extensive breeding system

The development of male sexual maturity varies among buffaloes. The Murrah buffalo is considered the most important and efficient milk and fat producer, but aspects of its reproductive biology are still unknown. The present study aimed to evaluate the daily sperm production (DSP) and spermatogenesis in developing Murrah buffalo bulls by evaluation of the seminiferous tubules, testicular morphometry and using light microscopy and scanning electron microscopy. The testes of Murrah buffalo bulls at 18 mo was immature and at 24 mo could still be considered an average-efficiency breed based on their DSP. At 24 mo, the DSP rate was 0.97 billion sperm per testis and 13 million sperm per gram of testis. However, the animals had superior morphometric parameters compared with those of other livestock animals, except for the seminiferous tubule volume and diameter, which were inferior. In conclusion, our data support former views that the testes of the Murrah breed does not reach sexual maturity before 2 y of age and that important developmental steps occur later than Murrah crossbreeds from Brazil

Ureterolithiasis after Cohen re-implantation – case report

BACKGROUND: In the past decades, the widespread use of cross-trigonal ureteral reimplants for the treatment of children with vesicoureteral reflux has resulted in a large population of patients with transversely lying ureters. As this population gets older they will consequently be entering an age group at higher risk for stone and urothelial cancer formation. If ureteroscopy becomes necessary, the transverse position of the ureter makes ureteric access often impossible. CASE PRESENTATION: We present the case of a young man who not only suffered from urolithiasis due to hyperparathyroidism, but also further jeopardized his treatment by omitting the fact that as a child he underwent Cohen reimplantation of the right ureter. CONCLUSIONS: This case illustrates the particular difficulties the endoscopist may face in this group of patients. Patients with difficult ureteric access, abnormal anatomy, or those with known cross-trigonal ureteric reimplantations should be managed in a specialised endourology unit

Evolutionary plasticity determination by orthologous groups distribution

<p>Abstract</p> <p>Background</p> <p>Genetic plasticity may be understood as the ability of a functional gene network to tolerate alterations in its components or structure. Usually, the studies involving gene modifications in the course of the evolution are concerned to nucleotide sequence alterations in closely related species. However, the analysis of large scale data about the distribution of gene families in non-exclusively closely related species can provide insights on how plastic or how conserved a given gene family is. Here, we analyze the abundance and diversity of all Eukaryotic Clusters of Orthologous Groups (KOG) present in STRING database, resulting in a total of 4,850 KOGs. This dataset comprises 481,421 proteins distributed among 55 eukaryotes.</p> <p>Results</p> <p>We propose an index to evaluate the evolutionary plasticity and conservation of an orthologous group based on its abundance and diversity across eukaryotes. To further KOG plasticity analysis, we estimate the evolutionary distance average among all proteins which take part in the same orthologous group. As a result, we found a strong correlation between the evolutionary distance average and the proposed evolutionary plasticity index. Additionally, we found low evolutionary plasticity in <it>Saccharomyces cerevisiae </it>genes associated with inviability and <it>Mus musculus </it>genes associated with early lethality. At last, we plot the evolutionary plasticity value in different gene networks from yeast and humans. As a result, it was possible to discriminate among higher and lower plastic areas of the gene networks analyzed.</p> <p>Conclusions</p> <p>The distribution of gene families brings valuable information on evolutionary plasticity which might be related with genetic plasticity. Accordingly, it is possible to discriminate among conserved and plastic orthologous groups by evaluating their abundance and diversity across eukaryotes.</p> <p>Reviewers</p> <p>This article was reviewed by Prof Manyuan Long, Hiroyuki Toh, and Sebastien Halary.</p