Intranasal immunization with pneumococcal polysaccharide conjugate vaccines protects mice against invasive pneumococcal infections.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links fieldHost defenses against Streptococcus pneumoniae depend largely on opsonophagocytosis mediated by antibodies and complement. Since pneumococcus is a respiratory pathogen, mucosal immune responses may play a significant role in the defense against pneumococcal infections. Thus, mucosal vaccination may be an alternative approach to current immunization strategies, but effective adjuvants are required. Protein antigens induce significant mucosal immunoglobulin A (IgA) and systemic IgG responses when administered intranasally (i. n.) with the glyceride-polysorbate based adjuvant RhinoVax (RV) both in experimental animals and humans. The immunogenicity and efficacy of pneumococcal polysaccharide conjugate vaccines (PNC) of serotypes 1 and 3 was studied in mice after i.n. immunization with RV. Antibodies were measured in serum (IgM, IgG, and IgA) and saliva (IgA) and compared to antibody titers induced by parenteral immunization. The PNCs induced significant systemic IgG and IgA antibodies after i.n. immunization only when given with RV and, for serotype 1, serum IgG titers were comparable to titers induced by subcutaneous immunization. In addition, i.n. immunization with PNC-1 in RV elicited detectable mucosal IgA. These results demonstrate that RV is a potent mucosal adjuvant for polysaccharides conjugated to proteins. A majority of the PNC-1-immunized mice were protected against both bacteremia and pneumonia after i.n. challenge with a lethal dose of serotype 1 pneumococci, and protection correlated significantly with the serum IgG titers. Similarly, the survival of mice immunized i.n. with PNC-3 in RV was significantly prolonged. These results indicate that mucosal vaccination with PNC and adjuvants may be an alternative strategy for prevention against pneumococcal infections

Impact of changes to reimbursement of fixed combinations of inhaled corticosteroids and long-acting β₂ -agonists in obstructive lung diseases: a population-based, observational study.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access.In 2010, the Icelandic government introduced a new cost-saving policy that limited reimbursement of fixed inhaled corticosteroid/long-acting β₂ -agonist (ICS/LABA) combinations.This population-based, retrospective, observational study assessed the effects of this policy change by linking specialist/primary care medical records with data from the Icelandic Pharmaceutical Database. The policy change took effect on 1 January 2010 (index date); data for the year preceding and following this date were analysed in 8241 patients with controlled/partly controlled asthma and/or chronic obstructive pulmonary disease (COPD) who had been dispensed an ICS/LABA during 2009. Oral corticosteroid (OCS) and short-acting β₂ -agonist (SABA) use, and healthcare visits, were assessed pre- and post-index.The ICS/LABA reimbursement policy change led to 47.8% fewer fixed ICS/LABA combinations being dispensed during the post-index period among patients whose asthma and/or COPD was controlled/partly controlled during the pre-index period. Fewer ICS monocomponents were also dispensed. A total of 48.6% of patients were no longer receiving any respiratory medications after the policy change. This was associated with reduced disease control, as demonstrated by more healthcare visits (44.0%), and more OCS (76.3%) and SABA (51.2%) dispensations.Overall, these findings demonstrate that changes in healthcare policy and medication reimbursement can directly impact medication use and, consequently, clinical outcomes and should, therefore, be made cautiously.AstraZenec

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageCurrent conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts.Ablation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs.By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique

Path towards efficient paediatric formulation development based on partnering with clinical pharmacologists and clinicians, a c4c expert group White paper

Improved global access to novel age-appropriate formulations for paediatric subsets, either of new chemical entities or existing drugs, is a priority to ensure that medicines meet the needs of these patients. However, despite regulatory incentives, the introduction to the market of paediatric formulations still lags behind adult products. This is mainly caused by additional complexities associated with the development of acceptable age-appropriate paediatric medicines. This position paper recommends the use of a paediatric Quality Target Product Profile as an efficient tool to facilitate early planning and decision making across all teams involved in paediatric formulation development during the children-centric formulation design for new chemical entities, or to repurpose/reformulate off-patent drugs. Essential key attributes of a paediatric formulation are suggested and described. Moreover, greater collaboration between formulation experts and clinical colleagues, including healthcare professionals, is advocated to lead to safe and effective, age-appropriate medicinal products. Acceptability testing should be a secondary endpoint in paediatric clinical trials to ensure postmarketing adherence is not compromised by a lack of acceptability. Not knowing the indications and the related age groups and potential dosing regimens early enough is still a major hurdle for efficient paediatric formulation development; however, the proposed paediatric Quality Target Product Profile could be a valuable collaborative tool for planning and decision making to expedite paediatric product development, particularly for those with limited experience in developing a paediatric product

Bioequivalence study of lumefantrine rectal enema and the commercially available generic oral suspension. A pilot study

Children under five years of age, with severe or cerebral malaria, cannot consume oral medication especially if they are vomiting or are unconscious. In such situations they are given an injectable drug until they can tolerate oral medication. The situation is bad in Sub-Saharan Africa, especially in rural areas as children are sometimes referred to the closest referral health care facility for proper management. The aim of this study was therefore to conduct a pilot study to estimate the bioavailability of lumefantrine (LF) when administered as a rectal enema, and compare it with a commercially available oral suspension, in rabbits. The study was conducted on six healthy rabbits in an open randomized, crossover three sequence, single dose study, where each rabbit received rectal and oral formulations. The oral formulation was administered under fed and fasted conditions. A two-week washout period was allowed between the experiments. LF was quantified in rabbit plasma using ultraperformance liquid chromatography tandem mass spectrometry (UPLC MS/MS). Results showed that the relative bioavailability of rectal LF was about four times higher than oral. The observed data suggest that a significant adjustment in the dose will be required when LF is administered via the rectal route. The data provide important information for the next step in finding a method to provide a rescue treatment for children with severe or cerebral malaria

Extracellular, cell-permeable survivin inhibits apoptosis while promoting proliferative and metastatic potential

The tumour microenvironment is believed to be involved in development, growth, metastasis, and therapy resistance of many cancers. Here we show survivin, a member of the inhibitor of apoptosis protein (IAP) family, implicated in apoptosis inhibition and the regulation of mitosis in cancer cells, exists in a novel extracellular pool in tumour cells. Furthermore, we have constructed stable cell lines that provide the extracellular pool with either wild-type survivin (Surv-WT) or the previously described dominant-negative mutant survivin (Surv-T34A), which has proven pro-apoptotic effects in cancer cells but not in normal proliferating cells. Cancer cells grown in conditioned medium (CM) taken from Surv-WT cells absorbed survivin and experienced enhanced protection against genotoxic stresses. These cells also exhibited an increased replicative and metastatic potential, suggesting that survivin in the tumour microenvironment may be directly associated with malignant progression, further supporting survivin's function in tumourigenesis. Alternatively, cancer cells grown in CM taken from the Surv-T34A cells began to apoptose through a caspase-2- and caspase-9-dependent pathway that was further enhanced by the addition of other chemo- and radiotherapeutic modalities. Together our findings suggest a novel microenvironmental function for survivin in the control of cancer aggressiveness and spread, and should result in the genesis of additional cancer treatment modalities

Arrhythmia care in ESC member countries: The 2025 ESC-EHRA atlas on heart rhythm disorders

The ESC-EHRA Atlas on Heart Rhythm Disorders was developed to comprehensively map arrhythmia care across the European Society of Cardiology (ESC) member countries. A survey of National Cardiac Societies, Working Groups, and other EHRA partners in ESC member countries was conducted to gather data from 2023 or the most recently available year on arrhythmia care organization and delivery. In total, 51 ESC member countries actively participated in the study, with a survey completeness rate of 91%. The median number of hospitals performing EP or CIED procedures was 3.3 per million people. The annual median numbers of ablation procedures for heart rhythm disorders, atrial fibrillation, and supraventricular tachycardia per million people were 432, 151, and 136, respectively. The annual median numbers of pacemakers, implantable cardioverter-defibrillators (ICD), and cardiac resynchronization therapy cardioverter-defibrillator (CRT-D) implantations per million people were 739, 195, and 54, respectively. The median number of hospitals performing remote monitoring of CIEDs per million people was 0.5, though this service was unavailable in 15 countries. Two main universal issues emerged among the obstacles to guideline implementation: a lack of heart rhythm allied professionals and general dissatisfaction with the country's reimbursement system. The first edition of the ESC-EHRA Atlas presents up-to-date information on arrhythmia care organization and delivery among ESC member countries and highlights significant discrepancies in patients' access to ESC-guideline-recommended therapies

Comparability of Raman Spectroscopic Configurations: A Large Scale Cross-Laboratory Study

This is the final version. Available on open access from the American Chemical Society via the DOI in this recordThe variable configuration of Raman spectroscopic platforms is one of the major obstacles in establishing Raman spectroscopy as a valuable physicochemical method within real-world scenarios such as clinical diagnostics. For such real world applications like diagnostic classification, the models should ideally be usable to predict data from different setups. Whether it is done by training a rugged model with data from many setups or by a primary-replica strategy where models are developed on a 'primary' setup and the test data are generated on 'replicate' setups, this is only possible if the Raman spectra from different setups are consistent, reproducible, and comparable. However, Raman spectra can be highly sensitive to the measurement conditions, and they change from setup to setup even if the same samples are measured. Although increasingly recognized as an issue, the dependence of the Raman spectra on the instrumental configuration is far from being fully understood and great effort is needed to address the resulting spectral variations and to correct for them. To make the severity of the situation clear, we present a round robin experiment investigating the comparability of 35 Raman spectroscopic devices with different configurations in 15 institutes within seven European countries from the COST (European Cooperation in Science and Technology) action Raman4clinics. The experiment was developed in a fashion that allows various instrumental configurations ranging from highly confocal setups to fibre-optic based systems with different excitation wavelengths. We illustrate the spectral variations caused by the instrumental configurations from the perspectives of peak shifts, intensity variations, peak widths, and noise levels. We conclude this contribution with recommendations that may help to improve the inter-laboratory studies.COST (European Cooperation in Science and Technology)Portuguese Foundation for Science and TechnologyNational Research Fund of Luxembourg (FNR)China Scholarship Council (CSC)BOKU Core Facilities Multiscale ImagingDeutsche Forschungsgemeinschaft (DFG, German Research Foundation