Underreporting or Failed Notification? Global Botulism Reporting, 2000-2022.

Botulism is a rare, potentially fatal illness caused by botulinum toxins produced by Clostridium bacteria. There are no coordinated worldwide reporting mechanisms for botulism cases and therefore few reliable case frequency estimates. This study aimed to establish an international benchmark for case frequency to determine estimated global rates of underreporting of botulism cases. To this end, a comprehensive, multilingual search of major global and national databases, including gray data and government sources, was performed. Data from case series were pooled, standardized against United Nations midyear population estimates, and analyzed using Kolmogorov-Smirnov tests to identify normally distributed data series. National incidence rates of normally distributed series were compared with that of the United States, which was considered the gold standard due to its extensive data reported for 2004-2018. A total of 6,932 botulism cases from 59 nations were identified in the literature, with a global case fatality rate of 1.37%. The national mean incidence rate ranged from 0.00 to 8.04 cases per million people, with an international mean incidence rate of 0.62 cases per million people. At the continent level, incidence rates tended toward normal distributions, although few countries outside of North America and Europe exhibited normal distributions. Based on comparisons with the US standard, an estimated 88.71% of botulism cases worldwide were unreported in 2016. Better awareness of botulism among healthcare professionals, coordinated global reporting mechanisms, and research on additional contributing factors to underreporting would enable better understanding of global case frequency, thereby potentially reducing the global incidence of botulism and improving outcomes.

Sustained delivery of salbutamol and beclometasone from spray-dried double emulsions.

The sustained delivery of multiple agents to the lung offers potential benefits to patients. This study explores the preparation of highly respirable dual-loaded spray-dried double emulsions. Spray-dried powders were produced from water-in-oil-in-water (w/o/w) double emulsions, containing salbutamol sulphate and/or beclometasone dipropionate in varying phases. The double emulsions contained the drug release modifier polylactide co-glycolide (PLGA 50 : 50) in the intermediate organic phase of the original micro-emulsion and low molecular weight chitosan (Mw<190 kDa: emulsion stabilizer) and leucine (aerosolization enhancer) in the tertiary aqueous phase. Following spray-drying resultant powders were physically characterized: with in vitro aerosolization performance and drug release investigated using a Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. Powders generated were of a respirable size exhibiting emitted doses of over 95% and fine particle fractions of up to 60% of the total loaded dose. Sustained drug release profiles were observed during dissolution for powders containing agents in the primary aqueous and secondary organic phases of the original micro-emulsion; the burst release of agents was witnessed from the tertiary aqueous phase. The novel spray-dried emulsions from this study would be expected to deposit and display sustained release character in the lung.

Chitosan-based spray-dried respirable powders for sustained delivery of terbutaline sulfate.

In this study, we describe the preparation of highly dispersible dry powders for pulmonary drug delivery that display sustained drug release characteristics. Powders were prepared by spray-drying 30% v/v aqueous ethanol formulations containing terbutaline sulfate as a model drug, chitosan as a drug release modifier and leucine as an aerosolisation enhancer. The influence of chitosan molecular weight on the drug release profile was investigated by using low, medium and high molecular weight chitosan or combinations thereof. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction, tapped density analysis, differential scanning calorimetry and thermogravitational analysis. The in vitro aerosolisation performance and drug release profile were investigated using Multi-Stage Liquid Impinger analysis and modified USP II dissolution apparatus, respectively. The powders generated were of a suitable aerodynamic size for inhalation, had low moisture content and were amorphous in nature. The powders were highly dispersible, with emitted doses of over 90% and fine particle fractions of up to 82% of the total loaded dose, and mass median aerodynamic diameters of less than 2.5microm. A sustained drug release profile was observed during dissolution testing; increasing the molecular weight of the chitosan in the formulation increased the duration of drug release.

Cholera: under diagnosis and differentiation from other diarrhoeal diseases.

BACKGROUND: Globally 1.4 billion people are at risk from cholera in countries where the disease is endemic, with an estimated 2.8 million cases annually. The disease is significantly under reported due to economic, social and political disincentives as well as poor laboratory resources and epidemiological surveillance in those regions. In addition, identification of cholera from other diarrhoeal causes is often difficult due to shared pathology and symptoms with few reported cases in travellers from Northern Europe. METHODS: A search of PubMed and Ovid Medline for publications on cholera diagnosis from 2010 through 2017 was conducted. Search terms included were cholera, Rapid Diagnostic Test (RDT), multiplex PCR and diagnosis of diarrhoea. Studies were included if they are published in English, French or Spanish. RESULTS: An increase of RDT study publications for diarrhoeal disease and attempted test validations were seen over the publication period. RDTs were noted as having varied selectivity and specificity, as well as associated costs and local resource requirements that can prohibit their use. CONCLUSIONS: Despite opportunities to employ RDTs with high selectivity and specificity in epidemic areas, or in remote locations without access to health services, such tests are limited to surveillance use. This may represent a missed opportunity to discover the true global presence of Vibrio cholerae and its role in all cause diarrhoeal disease in underdeveloped countries and in travellers to those areas. The wider applicability of RDTs may also represent an opportunity in the wider management of traveller's diarrhoea.

Japanese encephalitis: the vectors, ecology and potential for expansion.

BACKGROUND: Japanese encephalitis (JE) is a viral disease predominantly located in South East Asia and commonly associated with transmission between amplifying hosts, such as pigs, and the mosquito Culex tritaeniorhynchus, where human infection represents a dead end in the life cycle of the virus. The expansion of JE beyond an Asiatic confine is dependent on a multitude of complex factors that stem back to genetic subtype variation. A complex interplay of the genetic variation and vector competencies combine with variables such as geography, climate change and urbanization. METHODS: Our understanding of JE is still at an early stage with long-term longitudinal vector surveillance necessary to better understand the dynamics of JE transmission and to characterize the role of potential secondary vectors such as Cx. pipiens and Cx. bitaeniorhynchus. The authors review the vectors indicated in transmission and the ecological, genetic and anthropological factors that affect the disease's range and epidemiology. CONCLUSION: Monitoring for the presence of JE virus in mosquitoes in general can be used to estimate levels of potential JE exposure, intensity of viral activity and genetic variation of JEV throughout surveyed areas. Increased surveillance and diagnosis of viral encephalitis caused by genotype 5 JE virus is required in particular, with the expansion in epidemiology and disease prevalence in new geographic areas an issue of great concern. Additional studies that measure the impact of vectors (e.g. bionomics and vector competence) in the transmission of JEV and that incorporate environmental factors (e.g. weekly rainfall) are needed to define the roles of Culex species in the viral pathogenesis during outbreak and non-outbreak years.

Spray-dried powders for pulmonary drug delivery.

Powders for inhalation are traditionally prepared using a destructive micronization process such as jet milling to reduce the particle size of the drug to 2-5 mum. The resultant particles are typically highly cohesive and display poor aerosolization properties, necessitating the addition of a coarse carrier particle to the micronized drug to improve powder flowability. Spray-drying technology offers an alternative, constructive particle production technique to the traditional destructive approach, which may be particularly useful when processing biotechnology products that could be adversely affected by high-energy micronization processes. Advantages of spray drying include the ability to incorporate a wide range of excipients into the spray-drying feedstock, which could modify the aerosolization and stability characterizations of the resultant powders, as well as modify the drug release and absorption profiles following inhalation. This review discusses some of the reasons why pulmonary drug delivery is becoming an increasingly popular route of administration and describes the various investigations that have been undertaken in the preparation of spray-dried powders for pulmonary drug delivery.

Sustained delivery by leucine-modified chitosan spray-dried respirable powders.

The controlled co-delivery of multiple agents to the lung offers potential benefits to patients. This study investigated the preparation and characterisation of highly respirable spray-dried powders displaying the sustained release of two chemically distinct therapeutic agents. Spray-dried powders were produced from 30% (v/v) aqueous ethanol formulations that contained hydrophilic (terbutaline sulphate) and hydrophobic (beclometasone dipropionate) model drugs, chitosan (as a drug release modifier) and leucine (aerosolisation enhancer). The influence of chitosan molecular weight on spray-drying thermal efficiency, aerosol performance and drug release profile was investigated. Resultant powders were physically characterised: with in vitro aerosolisation performance and drug release profile investigated by the Multi-Stage Liquid Impinger and modified USP II dissolution apparatus, respectively. It was found that increased chitosan molecular weight gave increased spray-drying thermal efficiency. The powders generated were of a suitable size for inhalation-with emitted doses over 90% and fine particle fractions up to 72% of the loaded dose. Sustained drug release profiles were observed in dissolution tests for both agents: increased chitosan molecular weight associated with increased duration of drug release. The controlled co-delivery of hydrophilic and hydrophobic entities underlines the capability of spray drying to produce respirable particles with sustained release for delivery to the lung.