Doses per vaccine vial container: An understated and underestimated driver of performance that needs more evidence

The widespread use of multidose vaccine containers in low and middle income countries’ immunization programs is assumed to have multiple benefits and efficiencies for health systems, yet the broader impacts on immunization coverage, costs, and safety are not well understood. To document what is known on this topic, how it has been studied, and confirm the gaps in evidence that allow us to assess the complex system interactions, the authors undertook a review of published literature that explored the relationship between doses per container and immunization systems. The relationships examined in this study are organized within a systems framework consisting of operational costs, timely coverage, safety, product costs/wastage, and policy/correct use, with the idea that a change in dose per container affects all of them, and the optimal solution will depend on what is prioritized and used to measure performance.Studies on this topic are limited and largely rely on modeling to assess the relationship between doses per container and other aspects of immunization systems. Very few studies attempt to look at how a change in doses per container affects vaccination coverage rates and other systems components simultaneously. This article summarizes the published knowledge on this topic to date and suggests areas of current and future research to ultimately improve decision making around vaccine doses per container and increase understanding of how this decision relates to other program goals.     

Plasma fractionation

The first plasma fractionation process was developed in the 1940s by Cohn and co-workers to prepare albumin and immunoglobulins. It relies on sequential precipitation steps at negative temperatures, different ethanol concentrations and various pH to segregate bulk plasma proteins. The ‘Cohn procedure’ has been modified over the years but largely remains the core fractionation process in use up to now. The introduction of cryoprecipitation (thawing of plasma at 2–4°C), as the first plasma fractionation step, to isolate a crude factor-VIII fraction, and the integration of chromatographic steps to extract labile plasma or trace plasma proteins, have eventually shaped the modern fractionation technologies into complex procedures. Viral inactivation and removal treatments are performed to prevent the risks of transmission of enveloped and non-enveloped viruses. Viral inactivation steps are applied most often on pre-purified fractions, the downstream steps being used to remove protein contaminants and viral inactivation agents. Depending upon products and protein stability, treatments include incubations with combinations of solvent (TnBP) and detergent (e.g. Tween 80 or Triton X-100) (S/D), pasteurization (heat-treatment in the liquid state at 60°C for 10 h in the presence of stabilizers), as well as low pH or caprylic acid treatments (these last two treatments are restricted to immunoglobulins). Nanofiltration, to capture viruses on nm-membranes, is typically performed on the final purified protein fractions prior to sterile filtration and aseptic filling. Terminal dry-heat treatment at 80–100°C is used for some coagulation factor preparations. Modern plasma protein products have an unprecedented level of quality and safety when there is careful process control and monitoring together with sensitive test methods to detect potentially harmful contaminants, such as procoagulant impurities. Since the implementation of validated robust viral reduction treatments, plasma products have a high viral safety profile including against emerging agents (WNV, Dengue virus, Chikungunya virus). Experimental spiking studies suggest that several fractionation steps are capable of removing prions causing variant Creutzfeldt-Jakob disease. Alternative fractionation processes based exclusively on chromatography have been developed at pilot scale and need further validations to demonstrate the quality, safety and consistency of resulting plasma products. A mini-pool viral inactivation and fractionation process relying on single-use equipment is also being developed to facilitate the access to safer plasma components, including plasma for transfusion, cryoprecipitate, prothrombin complex, immunoglobulins and fibrin sealant, in particular in developing countries.     

Evaluation of exposure–response relationships for health effects of microbial bioaerosols – A systematic review

Studies suggest adverse health effects following exposure to bioaerosols in the environment and in particular at workplaces. However, there is still a lack of health-related exposure limits based on toxicological or epidemiological studies from environmental health or from the working environment. The aim of this study was to derive health-based exposure limits for bioaerosols that can protect the general population as group “at risk” via environmental exposure using analysis of peer-reviewed studies related to occupational medicine, indoor air and environmental health. The derivation of exposure limits should be conducted by the members of a bioaerosol expert panel according to established toxicological criteria. A systematic review was performed in Medline (PubMed) including studies containing both data on exposure measurements and observed health outcomes. In addition, literature recommended by the experts was considered. A comprehensive search strategy was generated and resulted in a total of n = 1569 studies in combination with the literature recommendations. Subsequently, abstracts were screened using defined exclusion criteria yielding a final number of n = 44 studies. A standardized extraction sheet was used to combine data on health effects and exposure to different bioaerosols. After full-text screening and extraction according to the defined exclusion criteria n = 20 studies were selected all related to occupational exposures comprising the working areas wood processing, farming, waste processing and others. These studies were analyzed in collaboration with the bioaerosol expert network in terms of suitability for derivation of health-related exposure limits. The bioaerosol expert network concluded that none of the analyzed studies provided suitable dose–response relationships for derivation of exposure limits. The main reasons were: (1) lack of studies with valid dose–response data; (2) diversity of employed measuring methods for microorganisms and bioaerosol-emitting facilities; (3) heterogeneity of health effects; (4) insufficient exposure assessment. However, several indicator parameters and exposure concentrations could be identified for different bioaerosol-emitting facilities. Nevertheless, health-related exposure limits are urgently needed especially in approval procedures of facilities like composting plants or livestock farms emitting bioaerosols in the neighbourhood of residents. In the regulatory toxicology framework, it is common to use animal experimental studies for derivation of general exposure limits if appropriate environmental epidemiological studies on harmful substances are lacking. This might be another possibility to obtain health-related exposure limits for specific bioaerosol parameters. Furthermore, we recommend to use suitable measurable outcome parameters related to bioaerosols; to measure bioaerosols according to a protocol representative for exposure pattern and duration at the particular work place; to develop standardized detection methods for indicator parameters; to combine different detection methods to compensate for the limitations of each method; to apply new analysis methods to identify the real risk potential.     

Multi-constituent synergism is responsible for anti-inflammatory effect of Azadirachta indica leaf extract

Context: Azadirachta indica A. Juss. (Meliaceaes) leaves have been used traditionally to treat swelling and rheumatism in Indian cultures.

Objective: To fractionate A. indica leaf extracts using bioactivity guided manner for identification of the active anti-inflammatory principles.

Materials and methods: Polarity-gradient sequential extracts (petroleum ether, chloroform, methanol, and water) of A. indica leaves were screened for their anti-inflammatory potential using the carrageenan-induced rat paw edema model (1?g/kg). The chloroform extract was sequentially fractionated to obtain n-hexane (F-1), n-hexane-chloroform (F-2), and chloroform (F-3) fractions and their inhibitory effect on rat paw edema was evaluated (500?mg/kg). Inhibitory effect of F-2 on granuloma formation, plasma interleukin (IL-1), and tumor necrosis factor (TNF-α) was assessed at the doses of 100, 200, and 400?mg/kg using the cotton pellet assay in rats. Three sub-fractions (SF-1, SF-2, and SF-3) were obtained upon chromatography of F-2, and their inhibitory effect on cyclooxygenase was assessed at 200?µg/mL concentration. The sub-fractions were subjected to gas chromatography–mass spectrometry (GC-MS).

Results: All the extracts showed significant anti-inflammatory effect; however, chloroform extract was the most effective against paw edema (53.25% inhibition). The three fractions of chloroform extract showed significant effect, while F-2 being the most potent (51.02%). F-2 demonstrated dose-dependent inhibition of granuloma and cytokines. Interestingly, all the sub-fractions of F-2 inhibited COX-1 and COX-2 with almost equal potential. GC-MS revealed that chemically the sub-fractions were totally different from each other.

Discussion and conclusion: Anti-inflammatory effect of A. indica is a result of cumulative and synergistic effects of diversified constituents with varying polarities that collectively exert the effect via suppression of cyclo-oxygenases and cytokines (IL-1 and TNF-α).     

Plasma fractionation in Asia–Pacific: challenges and perspectives

Patients in every country should have access to quality blood products. National health authorities play a critical role in ensuring that patients’ needs are met with safe and cost-effective products. Fractionated plasma products, as other blood products, are essential therapeutics used in the prevention, management, and treatment of life-threatening conditions resulting from trauma, metabolic congenital deficiencies, immunological disorders or infections. A few high development index (HDI) countries in the region have sufficient access to a broad portfolio of plasma products (coagulation factors, immunoglobulin, albumin) through domestic (e.g. Australia, Japan, Korea) or contract (e.g. Singapore, New Zealand) plasma fractionation programmes. China is gradually establishing a modern plasma fractionation industry. Other countries face plasma product shortages leading to inappropriate clinical use of plasma for transfusion and of non-virally inactivated cryoprecipitate, and ultimately to inappropriate treatment of patients. The volume of plasma fractionated in the region is too low to meet the needs. The volume (about 6 million l) represents 20% of the total volume fractionated worldwide for 60% of the world population. There is a rationale to encourage plasma contract fractionation programmes or operation of domestic facilities (when justified) to use local resources. However, many challenges are being faced as national plasma fractionation programmes require a mature blood collection infrastructure. Unfortunately, several LDI countries lack a mature national blood programme and a legislative framework on national policies and legislation on blood donations. They lack a safe blood donor base and a well-organized, nationally coordinated blood transfusion services; their blood collection system is scattered among different entities, resulting in non-uniform screening and testing procedures. Financial and human resources are lacking. Still, a few countries (e.g. Hong Kong, Malaysia, Singapore, Taiwan) have strengthened the national blood programmes, national blood policies have been implemented and the management of the blood transfusion service improved, allowing to implement contract plasma fractionation programme with established fractionators. Others are considering initiating (Indonesia and Malaysia) or enhancing (Thailand) domestic fractionation. Plasma fractionation programmes require good awareness and understanding by national regulatory authorities on quality criteria of plasma products. Local plasma product market and potential trends should be evaluated to determine plasma needs and the capacity to implement collection of plasma by apheresis from volunteer dedicated donors to supplement recovered plasma as a source material for fractionation. Appropriate choice of a contract fractionation partner should be made and contract terms discussed carefully. The fractionation technology and product portfolio should be evaluated to make sure that intended products can meet domestic needs (e.g. range, potency and formulation). A reimbursement policy (in particular for IVIG) for a range of proven indications should be established, as approved in the marketing authorization dossier. Confidence of clinicians and patients in the quality and safety of domestic vs. imported products should be built. With the economical development of the region and the ageing population trends, the needs for plasma products are expected to increase, justifying efforts to fractionate domestic plasma (e.g. initially through contract fractionation) and increase guarantee of supply in quality plasma products.     

Ablation of Complex Fractionated Atrial Electrograms in Catheter Ablation for AF; Where have we been and where are we going?

Catheter ablation for persistent AF remains a challenge to the ablator as the disease is now outside the veins and cannot be tackled by pulmonary vein isolation alone. In this article we describe targeting complex fractionated atrial electrograms (CFAE) as a method to guide atrial substrate modification.     

Diphenhydramine dose–response: a novel approach to determine triage thresholds

Context. It is unclear how much diphenhydramine (DPH) is toxic in humans. Previous dose–response studies have had conflicting results. Objective. We sought to evaluate DPH dose–response using a unique method that utilizes acetaminophen (APAP) serum concentrations to estimate DPH doses in patients ingesting APAP/DPH in a fixed-combination product. Methods. We retrospectively analyzed APAP/DPH-only exposures in patients 2–80 years of age using case data from 15 U.S. poison centers. DPH dose was extrapolated from measured serum APAP concentrations. A clinically significant response (CSR) was predefined in terms of eight specific manifestations (e.g., coma) that would warrant emergency department intervention. Nominal logistic regression was used to model the probability of each recorded manifestation across DPH dose ranges examining fits for mg, mg/kg, log10 mg, and log10 mg/kg DPH doses. The threshold value where patients reliably became symptomatic was determined by further examining receiver operating characteristic curves. Results. There were 509 cases that met inclusion criteria. Forty-five patients (9%) developed CSRs. A higher percentage of patients developed CSR at ≥ 7.5 mg/kg DPH and ≥1 g total DPH cutoff points (p < 0.05, Fisher's exact test). The best model for predicting the probability of CSR was a logistic fit of log₁₀ mg/kg dose (p < 0.05). By this model, for every 1 log₁₀ unit increase of mg/kg DPH dose, the odds of developing a CSR increased 47-fold (95% CI 17, 154). Receiver operating characteristic analyses showed a dose-related progression of symptoms. The cut-point with greatest sensitivity (98%) versus 1-specificity (57%) corresponded to an extrapolated mg/kg DPH dose of 8.2 mg/kg (95% CI 5.6, 10.5). Conclusion. Our findings support the current American Association of Poison Control Centers' guideline recommendation to refer patients to the hospital for evaluation if they have ingested greater than or equal to 7.5 mg/kg of DPH.     

Investigating perceptions of ‘dose creep’ amongst student radiographers: A grounded theory study

IntroductionThe dose creep phenomenon is now a widely recognized concept in diagnostic radiography in light of recent technological advancements transnationally. However, this still remains underexplored amongst radiography students preparing to enter the radiography profession. In response, this study explores the perceptions of dose creep amongst undergraduate student radiographers.MethodsThe methodological approach utilized in this research study was grounded theory. The qualitative approach aimed to uncover findings from a higher education institution in Australia. Six students were recruited and took part in semi-structured interviews. This enabled the exploration of previously uncovered data, leading to the construction of original theory within the clinical and academic environment. The data analysis employed was constant comparative analysis (CCA).ResultsA number of insights emerged from the qualitative data set. For instance, the radiography students understanding of the term ‘dose creep’ and decision making leading to dose creep in the clinical environment is captured. This is further supported with assessment of image evaluation determining appropriate exposure factor selection and future impact upon graduation as diagnostic radiographers. The findings identify some important learning needs and actions for both clinical and academic settings which may help foster good use of X-ray exposures.ConclusionThis paper concludes by affirming some challenges surrounding optimal exposure selection and the known phenomenon, dose creep. Further, this study identifies the importance of learning and teaching in the clinical environment whereby learned behaviour leads to suboptimum practices.Implications for practiceThis study advances the existing evidence base by providing a unique lens into the knowledge and understanding of dose creep amongst radiography students in both academic and clinical contexts. It is anticipated this paper will help practitioners and educators better understand potential instances of dose creep within the clinical environment.