Complexities related to the amorphous content of lactose carriers

Although the amount of amorphous content in lactose is low, its impact on the performance of a dry powder inhalation formulation might be high. Many formulators and regulatory agencies believe that the levels of amorphous content should be controlled once there is a relationship with the final product performance. This is however not an easy task. The current paper elaborates on multiple challenges and complexities that are related to the control of the amorphous content in lactose. The definition and quantification methods of amorphous lactose are reviewed, as well as challenges related to thermodynamic instability. Additionally, current monographs and recent position papers considering this parameter are discussed to provide an overview of the regulatory landscape. Development of a control strategy is recommended, provided that the amorphous content at a specific moment in the process has shown to have an impact on the performance of the dry powder inhaler

Complexities related to the amorphous content of lactose carriers

Although the amount of amorphous content in lactose is low, its impact on the performance of a dry powder inhalation formulation might be high. Many formulators and regulatory agencies believe that the levels of amorphous content should be controlled once there is a relationship with the final product performance. This is however not an easy task. The current paper elaborates on multiple challenges and complexities that are related to the control of the amorphous content in lactose. The definition and quantification methods of amorphous lactose are reviewed, as well as challenges related to thermodynamic instability. Additionally, current monographs and recent position papers considering this parameter are discussed to provide an overview of the regulatory landscape. Development of a control strategy is recommended, provided that the amorphous content at a specific moment in the process has shown to have an impact on the performance of the dry powder inhaler

Complexities related to the amorphous content of lactose carriers

Although the amount of amorphous content in lactose is low, its impact on the performance of a dry powder inhalation formulation might be high. Many formulators and regulatory agencies believe that the levels of amorphous content should be controlled once there is a relationship with the final product performance. This is however not an easy task. The current paper elaborates on multiple challenges and complexities that are related to the control of the amorphous content in lactose. The definition and quantification methods of amorphous lactose are reviewed, as well as challenges related to thermodynamic instability. Additionally, current monographs and recent position papers considering this parameter are discussed to provide an overview of the regulatory landscape. Development of a control strategy is recommended, provided that the amorphous content at a specific moment in the process has shown to have an impact on the performance of the dry powder inhaler

Serum antibodies to Vibrio vulnificus biotype 3 lipopolysaccharide and susceptibility to disease caused by the homologous V. vulnificus biotype

In 1996 an outbreak of severe soft tissue infections caused by Vibrio vulnificus unexpectedly erupted in fish consumers in Israel with relatively little morbidity in fish farmers. To test the hypothesis that recurrent exposure of fishermen to the virulent strain may have provided protection against severe or symptomatic disease, we investigated the association between the immune response to V. vulnificus biotype 3 lipopolysaccharide (BT3 LPS) and disease susceptibility in fish farmers and fish consumers. Serum samples were tested for IgA and IgG of anti-BT3 LPS in fishermen and fish consumers who suffered from V. vulnificus BT3 infections and their matched controls. Pre-existing levels of IgG (IgG0) of anti-BT3 LPS were significantly lower in diseased fishermen who developed disease associated with the homologous biotype, compared to controls. In multivariate analysis, levels of IgG0 anti-BT3 LPS remained the only variable significantly associated with disease occurrence in fishermen. Higher levels of pre-existing IgG anti-BT 3 LPS antibodies may be associated with protection against severe or symptomatic disease with the homologous biotype in fishermen but not in subjects from the general public

Genome-Wide SNP-genotyping array to study the evolution of the human pathogen Vibrio vulnificus Biotype 3

Vibrio vulnificus is an aquatic bacterium and an important human pathogen. Strains Of V. vulnificus are classified into three different biotypes. The newly emerged biotype 3 has been found to be clonal and restricted to Israel. In the family Vibrionaceae , horizontal gene transfer is the main mechanism responsible for the emergence of new pathogen groups. To better understand the evolution of the bacterium, and in particular to trace the evolution of biotype 3, we performed genome-wide SNP genotyping of 254 clinical and environmental V. vulnificus isolates with worldwide distribution recovered over a 30-year period, representing all phylogeny groups. A custom single-nucleotide polymorphism (SNP) array implemented on the Illumina GoldenGate platform was developed based on 570 SNPs randomly distributed throughout the genome. In general, the genotyping results divided the V. vulnificus species into three main phylogenetic lineages and an additional subgroup, clade B, consisting of environmental and clinical isolates from Israel. Data analysis suggested that 69% of biotype 3 SNPs are similar to SNPs from clade B, indicating that biotype 3 and clade B have a common ancestor. The rest of the biotype 3 SNPs were scattered along the biotype 3 genome, probably representing multiple chromosomal segments that may have been horizontally inserted into the clade B recipient core genome from other phylogroups or bacterial species sharing the same ecological niche. Results emphasize the continuous evolution of V. vulnificus and support the emergence of new pathogenic groups within this species as a recurrent phenomenon. Our findings contribute to a broader understanding of the evolution of this human pathogen

Characterization of invasive and colonizing isolates of Streptococcus agalactiae in East African adults

Ninety-five colonizing isolates and 74 invasive isolates of Streptococcus agalactiae from Kenyan adults were characterized by using capsular serotyping and multilocus sequence typing. Twenty-two sequence types clustering into five clonal complexes were found. Data support the view that S. agalactiae isolates belonging to a limited number of clonal complexes are invasive in adults worldwide

Diversity of Prophage DNA Regions of Streptococcus agalactiae Clonal Lineages from Adults and Neonates with Invasive Infectious Disease

The phylogenetic position and prophage DNA content of the genomes of 142 S. agalactiae (group-B streptococcus, GBS) isolates responsible for bacteremia and meningitis in adults and neonates were studied and compared. The distribution of the invasive isolates between the various serotypes, sequence types (STs) and clonal complexes (CCs) differed significantly between adult and neonatal isolates. Use of the neighbor-net algorithm with the PHI test revealed evidence for recombination in the population studied (PHI, P = 2.01×10−6), and the recombination-mutation ratio (R/M) was 6∶7. Nevertheless, the estimated R/M ratio differed between CCs. Analysis of the prophage DNA regions of the genomes of the isolates assigned 90% of the isolates to five major prophage DNA groups: A to E. The mean number of prophage DNA fragments amplified per isolate varied from 2.6 for the isolates of prophage DNA group E to 4.0 for the isolates of prophage DNA group C. The isolates from adults and neonates with invasive diseases were distributed differently between the various prophage DNA groups (P<0.00001). Group C prophage DNA fragments were found in 52% of adult invasive isolates, whereas 74% of neonatal invasive isolates had prophage DNA fragments of groups A and B. Differences in prophage DNA content were also found between serotypes, STs and CCs (P<0.00001). All the ST-1 and CC1 isolates, mostly of serotype V, belonged to the prophage DNA group C, whereas 84% of the ST-17 and CC17 isolates, all of serotype III, belonged to prophage DNA groups A and B. These data indicate that the transduction mechanisms, i.e., gene transfer from one bacterium to another by a bacteriophage, underlying genetic recombination in S. agalactiae species, are specific to each intraspecies lineage and population of strains responsible for invasive diseases in adults and neonates

Public reaction to Chikungunya outbreaks in Italy—Insights from an extensive novel data streams-based structural equation modeling analysis

The recent outbreak of Chikungunya virus in Italy represents a serious public health concern, which is attracting media coverage and generating public interest in terms of Internet searches and social media interactions. Here, we sought to assess the Chikungunya-related digital behavior and the interplay between epidemiological figures and novel data streams traffic. Reaction to the recent outbreak was analyzed in terms of Google Trends, Google News and Twitter traffic, Wikipedia visits and edits, and PubMed articles, exploiting structural modelling equations. A total of 233,678 page-views and 150 edits on the Italian Wikipedia page, 3,702 tweets, 149 scholarly articles, and 3,073 news articles were retrieved. The relationship between overall Chikungunya cases, as well as autochthonous cases, and tweets production was found to be fully mediated by Chikungunya-related web searches. However, in the allochthonous/imported cases model, tweet production was not found to be significantly mediated by epidemiological figures, with web searches still significantly mediating tweet production. Inconsistent relationships were detected in mediation models involving Wikipedia usage as a mediator variable. Similarly, the effect between news consumption and tweets production was suppressed by the Wikipedia usage. A further inconsistent mediation was found in the case of the effect between Wikipedia usage and tweets production, with web searches as a mediator variable. When adjusting for the Internet penetration index, similar findings could be obtained, with the important exception that in the adjusted model the relationship between GN and Twitter was found to be partially mediated by Wikipedia usage. Furthermore, the link between Wikipedia usage and PubMed/MEDLINE was fully mediated by GN, differently from what was found in the unadjusted model. In conclusion—a significant public reaction to the current Chikungunya outbreak was documented. Health authorities should be aware of this, recognizing the role of new technologies for collecting public concerns and replying to them, disseminating awareness and avoid misleading information

The One-State as a Demand of International Law: Jus Cogens

This article provides the initial contours of an argument that uses International Law to challenge the validity of Israeli apartheid. It challenges the conventional discourse of legal debates on Israel’s actions and bordersand seeks to link the illegalities of these actions to the validity of an inbuilt Israeli apartheid. The argument also connects the deontological doctrine of peremptory norms of International Law (jus cogens), the right of self-determination and the International Crime of Apartheid to the doctrine of state recognition. It applies these to the State of Israel and the vision of a single democratic state in historic Palestine

Population gene introgression and high genome plasticity for the zoonotic pathogen Streptococcus agalactiae

The influence that bacterial adaptation (or niche partitioning) within species has on gene spillover and transmission among bacteria populations occupying different niches is not well understood. Streptococcus agalactiae is an important bacterial pathogen that has a taxonomically diverse host range making it an excellent model system to study these processes. Here we analyze a global set of 901 genome sequences from nine diverse host species to advance our understanding of these processes. Bayesian clustering analysis delineated twelve major populations that closely aligned with niches. Comparative genomics revealed extensive gene gain/loss among populations and a large pan-genome of 9,527 genes, which remained open and was strongly partitioned among niches. As a result, the biochemical characteristics of eleven populations were highly distinctive (significantly enriched). Positive selection was detected and biochemical characteristics of the dispensable genes under selection were enriched in ten populations. Despite the strong gene partitioning, phylogenomics detected gene spillover. In particular, tetracycline resistance (which likely evolved in the human-associated population) from humans to bovine, canines, seals, and fish, demonstrating how a gene selected in one host can ultimately be transmitted into another, and biased transmission from humans to bovines was confirmed with a Bayesian migration analysis. Our findings show high bacterial genome plasticity acting in balance with selection pressure from distinct functional requirements of niches that is associated with an extensive and highly partitioned dispensable genome, likely facilitating continued and expansive adaptation