RTS,S/AS01E malaria vaccine induces IgA responses against CSP and vaccine-unrelated antigens in African children in the phase 3 trial

BackgroundThe evaluation of immune responses to RTS,S/AS01 has traditionally focused on immunoglobulin (Ig) G antibodies that are only moderately associated with protection. The role of other antibody isotypes that could also contribute to vaccine efficacy remains unclear. Here we investigated whether RTS,S/AS01_E elicits antigen-specific serum IgA antibodies to the vaccine and other malaria antigens, and we explored their association with protection.MethodsNinety-five children (age 5–17 months old at first vaccination) from the RTS,S/AS01_E phase 3 clinical trial who received 3 doses of RTS,S/AS01_E or a comparator vaccine were selected for IgA quantification 1 month post primary immunization. Two sites with different malaria transmission intensities (MTI) and clinical malaria cases and controls, were included. Measurements of IgA against different constructs of the circumsporozoite protein (CSP) vaccine antigen and 16 vaccine-unrelated Plasmodium falciparum antigens were performed using a quantitative suspension array assay.ResultsRTS,S vaccination induced a 1.2 to 2-fold increase in levels of serum/plasma IgA antibodies to all CSP constructs, which was not observed upon immunization with a comparator vaccine. The IgA response against 13 out of 16 vaccine-unrelated P. falciparum antigens also increased after vaccination, and levels were higher in recipients of RTS,S than in comparators. IgA levels to malaria antigens before vaccination were more elevated in the high MTI than the low MTI site. No statistically significant association of IgA with protection was found in exploratory analyses.ConclusionsRTS,S/AS01_E induces IgA responses in peripheral blood against CSP vaccine antigens and other P. falciparum vaccine-unrelated antigens, similar to what we previously showed for IgG responses. Collectively, data warrant further investigation of the potential contribution of vaccine-induced IgA responses to efficacy and any possible interplay, either synergistic or antagonistic, with protective IgG, as identifying mediators of protection by RTS,S/AS01_E immunization is necessary for the design of improved second-generation vaccines.Clinical trial registration: ClinicalTrials.gov: NCT008666191.     

Alcohol-related acute-on-chronic liver failure—Comparison of various prognostic scores in predicting outcome

Background and Aims

Various prognostic scores are available for predicting outcome in acute-on-chronic liver failure (ACLF). We compared the available prognostic models as predictors of outcome in alcohol-related ACLF patients.

Methods

All consecutive patients with alcohol-related ACLF were included. At admission, prognostic indices-acute physiology and chronic health evaluation score (APACHE II), model for end-stage liver disease (MELD), MELD-Na, Maddrey’s discriminant function (DF), age-bilirubin-INR-creatinine (ABIC), and Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C ACLF) score were calculated. Receiver operator characteristic (ROC) curves were plotted for all prognostic scores with in-hospital, 90-day, and 1-year mortality as outcome.

Results

Of the 171 patients, 170 were males, and grade 1 ACLF in 20 (11.7%), grade 2 in 52 (30.4%), and grade 3 in 99 (57.9%) patients. One hundred and nineteen (69.6%) died in-hospital. The median (IQR) Maddrey’s score, MELD, MELD-Na, ABIC, APACHE II, and CLIF-C ACLF were 87.8 (66.5–123.0), 33.1 (27.6–40.0), 34.4 (29.5–40.0), 8.5 (7.3–9.6), 15 (12–21), and 51.1 (44.1–56.4), respectively. On multivariate Cox regression analysis, independent predictors of in-hospital outcome were presence of hepatic encephalopathy (early HR, 2.078; 95%CI, 1.173–3.682, p?=?0.012 and advanced, HR, 2.330; 95% CI, 1.270–4.276, p?=?0.006), elevated serum creatinine (HR, 1.140; 95% CI, 1.023–1.270, p?=?0.018), and infection at admission (HR, 1.874; 95% CI, 1.160–23.029, p?=?0.010). On comparison of ROC curves, APACHE II and CLIF-C ACLF AUROC were significantly higher than MELD, MELD-Na, DF, and ABIC (p?<?0.05) for predicting in-hospital, 90-day, and 1-year mortality. The AUROC was highest for APACHE II followed by CLIF-C ACLF (Hanley and McNeil, p?=?0.660).

Conclusions

Alcohol-related ACLF has high in-hospital mortality. Among the available prognostic scores, CLIF-C ACLF and APACHE II perform best.

     

Investigation of crystal structure,microstructure and low temperature magnetic behavior of Ce4+ and Zn2+ co-doped barium hexaferrites (BaFe12O19)

Ce⁴⁺ and Zn²⁺ co-doped barium hexaferrites (BFO) have been synthesized via a citrate-nitrate autocombustion route. Phase purity has been confirmed by high resolution (HR) powder X-ray diffraction analysis. Rietveld refinement on HR-XRD data has been carried out to reveal the crystal structure, bond angles and bond lengths. High-resolution scanning electron microscope (HR-SEM) has been used to study the effect of Ce⁴⁺ and Zn²⁺ on microstructure. Magnetic behavior of co-doped barium hexaferrites in the low temperature regime, 2–300 K has been studied. Further, it has been explained on the basis of superexchange interactions and formation of Bloch walls due to the presence of imperfections in the doped samples. It has been found that BFO changes hard to soft magnetic behavior when the temperature is decreased from 300 K to 2 K. Moreover, doping of Ce⁴⁺ and Zn²⁺ at Fe³⁺ site also brings similar effects which strengthens with decreasing temperature.

Preparation of Ce–Zn substituted barium hexaferrites and investigation of their magnetic behavior in low temperature regime (2–300 K).     

A Review on Joint Carotid Intima-Media Thickness and Plaque Area Measurement in Ultrasound for Cardiovascular/Stroke Risk Monitoring: Artificial Intelligence Framework

Journal of Digital Imaging - Cardiovascular diseases (CVDs) are the top ten leading causes of death worldwide. Atherosclerosis disease in the arteries is the main cause of the CVD, leading to...     

Long‐term follow‐up and second malignancies in 487 patients with hairy cell leukaemia

A large, multicentre, retrospective survey of patients with hairy cell leukaemia (HCL) was conducted in France to determine the frequency of second malignancies and to analyse the long‐term effects of the established purine nucleoside analogues (PNAs), cladribine and pentostatin. The survey retrospectively reviewed the medical history of patients and their immediate family, clinical and biological presentation at the time of HCL diagnosis, treatment choice, response to treatment, time to relapse and cause of death. Data were collected for 487 patients with HCL. Of the patients included in the survey, 18% (88/487) had a familial history of cancers, 8% (41/487) presented with malignancies before HCL diagnosis and 10% (48/487) developed second malignancies after HCL was diagnosed. An excess incidence of second malignancies was observed, with a standardized incidence ratio (SIR) of 1·86 (95% confidence interval (CI): 1·34–2·51), with no significant difference between PNAs. For second haematological malignancies alone, the SIR was markedly increased at 5·32 (95% CI: 2·90–8·92). This study highlights the high frequency of cancers in HCL patients and their family members. The frequency of second malignancies is notably increased, particularly for haematological malignancies. The respective role of pentostatin and cladribine in the development of second malignancies is debatable.     

Carcinosarcoma of esophagus—a case report and review of literature

Carcinosarcoma of esophagus contains both the carcinomatous and sarcomatous elements. These are rare polypoidal malignancies of esophagus. One such case is presented and available literature is reviewed.     

Antiangiogenic Effect of Docetaxel and Everolimus as Individual and Dual-Drug-Loaded Micellar Nanocarriers

Purpose

The in vitro inhibitory effect of Docetaxel (DTX) and Everolimus (EVR) alone and together in poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-b-PLA) nanocarriers on angiogenic processes and acute toxicity in mice was evaluated.

Methods

PEG-b-PLA DTX and/or EVR nanocarriers were characterized for size, drug loading, stability, and drug release. Cell proliferation, tubule formation, and migration studies were performed in Human Umbilical Vein Endothelial Cells (HUVEC) and Maximum Tolerated Doses (MTD) studies were in mice.

Results

DTX and EVR loading was 1.93 and 2.00 mg/mL respectively with similar solubilities for dual-drug micelles. All micelles were below 30 nm with diffusion controlled drug release. The IC₅₀ for DTX, EVR micelles were, 6.80?±?0.67, 18.57?±?2.86 and 0.65?±?0.11 nM respectively with a synergistic inhibitory effect for dual-drug nanocarriers. Significant inhibition of tube formation occurred upon treatment with dual-drug nanocarriers as compared to individual micelles. EVR presence in dual-drug nanocarriers was able to significantly increase the inhibition of the migration of HUVEC by DTX. The MTDs for EVR, DTX and dual-drug micelles were 50, 30 and 20 mg/kg for each respectively.

Conclusions

DTX-EVR dual-drug nanocarriers have antiangiogenic effects in vitro mediated through cellular angiogenic process and possess clinically relevant MTD.