Persistent p55TNFR expression impairs T cell responses during chronic tuberculosis and promotes reactivation

Acknowledgements We thank Lizette Fick for her contribution to histopathology. We thank Faried Abbass for technical support. We thank the support staff of the Division of Immunology and the Research Animal Facility at the University of Cape Town for their contribution to animal care and technical support. The study was supported by the University of Cape Town, National Research Foundation (South Africa), South African Medical Research Council (SAMRC) National Health Laboratory Service (South Africa), The European Union (contract number: 028190), FP6 NEST project N°028190 “TB REACT”. Research carried out within the scope of the Franco/South African Laboratory “TB Immunity” (Associated International Laboratory ‘AIL’).Peer reviewedPublisher PD

Expressions 2001

https://openspace.dmacc.edu/expressions/1020/thumbnail.jp

Neutralizing and non-neutralizing monoclonal antibodies against dengue virus E protein derived from a naturally infected patient

<p>Abstract</p> <p>Background</p> <p>Antibodies produced in response to infection with any of the four serotypes of dengue virus generally provide homotypic immunity. However, prior infection or circulating maternal antibodies can also mediate a non-protective antibody response that can enhance the course of disease in a subsequent heterotypic infection. Naturally occurring human monoclonal antibodies can help us understand the protective and pathogenic roles of the humoral immune system in dengue virus infection.</p> <p>Results</p> <p>Epstein-Barr Virus (EBV) transformation of B cells isolated from the peripheral blood of a human subject with previous dengue infection was performed. B cell cultures were screened by ELISA for antibodies to dengue (DENV) envelope (E) protein. ELISA positive cultures were cloned by limiting dilution. Three IgG1 human monoclonal antibodies (HMAbs) were purified and their binding specificity to E protein was verified by ELISA and biolayer interferometry. Neutralization and enhancement assays were conducted in epithelial and macrophage-like cell lines, respectively. All three HMAbs bound to E from at least two of the four DENV serotypes, one of the HMAbs was neutralizing, and all were able to enhance DENV infection.</p> <p>Conclusions</p> <p>HMAbs against DENV can be successfully generated by EBV transformation of B cells from patients at least two years after naturally acquired DENV infections. These antibodies show different patterns of cross-reactivity, neutralizing, and enhancement activity.</p

Reactivation of M. tuberculosis Infection in Trans-Membrane Tumour Necrosis Factor Mice

Of those individuals who are infected with M. tuberculosis, 90% do not develop active disease and represents a large reservoir of M. tuberculosis with the potential for reactivation of infection. Sustained TNF expression is required for containment of persistent infection and TNF neutralization leads to tuberculosis reactivation. In this study, we investigated the contribution of soluble TNF (solTNF) and transmembrane TNF (Tm-TNF) in immune responses generated against reactivating tuberculosis. In a chemotherapy induced tuberculosis reactivation model, mice were challenged by aerosol inhalation infection with low dose M. tuberculosis for three weeks to establish infection followed chemotherapeutic treatment for six weeks, after which therapy was terminated and tuberculosis reactivation investigated. We demonstrate that complete absence of TNF results in host susceptibility to M. tuberculosis reactivation in the presence of established mycobacteria-specific adaptive immunity with mice displaying unrestricted bacilli growth and diffused granuloma structures compared to WT control mice. Interestingly, bacterial re-emergence is contained in Tm-TNF mice during the initial phases of tuberculosis reactivation, indicating that Tm-TNF sustains immune pressure as in WT mice. However, Tm-TNF mice show susceptibility to long term M. tuberculosis reactivation associated with uncontrolled influx of leukocytes in the lungs and reduced IL-12p70, IFNγ and IL-10, enlarged granuloma structures, and failure to contain mycobacterial replication relative to WT mice. In conclusion, we demonstrate that both solTNF and Tm-TNF are required for maintaining immune pressure to contain reactivating M. tuberculosis bacilli even after mycobacteria-specific immunity has been established

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie

Multidimensional signals and analytic flexibility: Estimating degrees of freedom in human speech analyses

Recent empirical studies have highlighted the large degree of analytic flexibility in data analysis which can lead to substantially different conclusions based on the same data set. Thus, researchers have expressed their concerns that these researcher degrees of freedom might facilitate bias and can lead to claims that do not stand the test of time. Even greater flexibility is to be expected in fields in which the primary data lend themselves to a variety of possible operationalizations. The multidimensional, temporally extended nature of speech constitutes an ideal testing ground for assessing the variability in analytic approaches, which derives not only from aspects of statistical modeling, but also from decisions regarding the quantification of the measured behavior. In the present study, we gave the same speech production data set to 46 teams of researchers and asked them to answer the same research question, resulting insubstantial variability in reported effect sizes and their interpretation. Using Bayesian meta-analytic tools, we further find little to no evidence that the observed variability can be explained by analysts’ prior beliefs, expertise or the perceived quality of their analyses. In light of this idiosyncratic variability, we recommend that researchers more transparently share details of their analysis, strengthen the link between theoretical construct and quantitative system and calibrate their (un)certainty in their conclusions

Development and pilot testing of a decision aid for navigating breast cancer survivorship care

BackgroundThe predominant oncologist-led model in many countries is unsustainable to meet the needs of a growing cohort of breast cancer survivors (BCS). Despite available alternative models, adoption rates have been poor. To help BCS navigate survivorship care, we aimed to systematically develop a decision aid (DA) to guide their choice of follow-up care model and evaluate its acceptability and usability among BCS and health care providers (HCPs).MethodsWe recruited BCS aged ≥ 21&nbsp;years who have completed primary treatment and understand English. BCS receiving palliative care or with cognitive impairment were excluded. HCPs who routinely discussed post-treatment care with BCS were purposively sampled based on disciplines. Each participant reviewed the DA during a semi-structured interview using the 'think aloud' approach and completed an acceptability questionnaire. Descriptive statistics and directed content analysis were used.ResultsWe conducted three rounds of alpha testing with 15 BCS and 8 HCPs. All BCS found the final DA prototype easy to navigate with sufficient interactivity. The information imbalance favouring the shared care option perceived by 60% of BCS in early rounds was rectified. The length of DA was optimized to be 'just right'. Key revisions made included (1) presenting care options side-by-side to improve perceived information balance, (2) creating dedicated sections explaining HCPs' care roles to address gaps in health system contextual knowledge, and (3) employing a multicriteria decision analysis method for preference clarification exercise to reflect the user's openness towards shared care. Most BCS (73%) found the DA useful for decision-making, and 93% were willing to discuss the DA with their HCPs. Most HCPs (88%) agreed that the DA was a reliable tool and would be easily integrated into routine care.ConclusionsOur experience highlighted the need to provide contextual information on the health care system for decisions related to care delivery. Developers should address potential variability within the care model and clarify inherent biases, such as low confidence levels in primary care. Future work could expand on the developed DA's informational structure to apply to other care models and leverage artificial intelligence to optimize information delivery

Are Phthalate Exposure Related to Oxidative Stress in Children and Adolescents with Asthma? A Cumulative Risk Assessment Approach

Childhood asthma has become one of the most common chronic diseases in children and adolescents. However, few case–control studies investigating the relationship between phthalate exposure and asthma in children and adolescents have been conducted, especially in Asia. Therefore, we assessed the potential associations between phthalate exposure and asthma among children and adolescents in Taiwan. Because various demographic and environmental variables may influence the incidence and prognosis of asthma, we performed a case–control study with propensity score matching. Out of 615 Childhood Environment and Allergic Diseases Study participants, we conditionally matched 41 children with clinically diagnosed asthma with 111 controls. We then analyzed 11 phthalate metabolites by using liquid chromatography with tandem mass spectrometry. Compared with the control group, the median urinary phthalate levels for most phthalate metabolites in the case group were slightly increased, including monomethyl phthalate, mono-n-butyl phthalate, monobenzyl phthalate, monoethylhexyl phthalate, mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate, and mono-(2-carboxymethylhexyl) phthalate. Hence, our results suggest that phthalate exposure may be associated with the development of asthma. In addition, prenatal environmental factors, such as active or passive smoking during pregnancy, may increase the risk of asthma