Successful Formulation Window for the design of pharmaceutical tablets with required mechanical properties.

Pharmaceutical tablet formulations combine the active ingredient with processing aids and functional components. This paper evaluates compressibility based predictive models for binary and ternary formulations to establish an acceptable range of tablet compression parameters that satisfy prescribed quality target criteria for tablets including minimum tablet strength and processing constraints such as maximum ejection stress and maximum compaction pressure. The concept of Successful Formulation Window (SFW) is introduced. A methodology is proposed to determine the SFW for a given formulation based on compaction simulator data collected for individual formulation components. The methodology is validated for binary and ternary mixtures and lubricated formulations. The SFW analysis was developed to support tablet formulation design to meet mechanical requirements.

Complete Genome Sequence and Methylome Analysis of Micrococcus luteus SA211, a Halophilic, Lithium-Tolerant Actinobacterium from Argentina.

Micrococcus luteus has been found in a wide range of habitats. We report the complete genome sequence and methylome analysis of strain SA211 isolated from a hypersaline, lithium-rich, high-altitude salt flat in Argentina with single-molecule real-time sequencing.

Methodology to estimate the break force of pharmaceutical tablets with curved faces under diametrical compression.

This paper develops a methodology to estimate the break force of curved faced tablets under diametrical compression. Common excipients used in pharmaceutical tablet formulations, including microcrystalline cellulose, calcium phosphate and mannitol as well as their mixtures were characterised. Compacts of different densities were manufactured and their compressive and tensile strength was measured. The break force of curved face tablets having a comprehensive range of face curvatures and thickness was measured using the diametrical compression method ("hardness" test). Equation σd=FπD2atD+bWD-1 introduced by Shang et al. (2013) was used to relate the break force (F) to tablet geometry (D, t, W) and material tensile strength (σd). Here, we propose a method to estimate the parameters a and b using data for flat faced tablets. The method was validated for four mixtures. The errors were analysed and compared with the USP29 method σd=10FπD2(2.84(t/D)-0.126t/W+3.15(W/D)+0.01)-1. The proposed method has better accuracy, however, requires additional characterisation of the compressive strength of the material.

Occupational vaccination of health care workers: uptake, attitudes and potential solutions.

OBJECTIVES: Occupational vaccination of health care workers is strongly recommended to prevent health care associated transmission but coverage in general remains suboptimal. The aim of this survey was to: 1. Estimate levels vaccination coverage for annual flu and MMR vaccines among hospital-based health care workers; 2. Explore the reasons behind low vaccination rates; and 3. Identify potential practical and policy solutions. STUDY DESIGN: A cross-sectional study. METHODS: An opportunistic survey was used to estimate MMR and flu vaccination coverage, and review attitudes and explore solutions. Staff from eight randomly selected wards, stratified by ward-level patient susceptibility, were invited to participate. RESULTS: In total 133 staff responded, an approximate response rate of 68%. Seventy one percent had ever received an MMR and 42% had received the most recent flu vaccination. Actively declining vaccination was more common for flu than MMR (29% and 7% respectively). Side-effects, insufficient knowledge and vaccine ineffectiveness were popular justifications for declining flu vaccination but not MMR. Not seeing vaccination as a professional responsibility was associated with declining flu vaccination (P < 0.001). Improving vaccination coverage with booster vaccines for new staff and immunity testing received strong support from staff working with vulnerable groups (82% and 74% respectively); 70% of this staff group also supported compulsory vaccination. CONCLUSIONS: Improving staff education may increase coverage. Clarification of the benefits of vaccination in specific staff groups may also improve uptake. Routine booster vaccinations and immunity testing were generally acceptable and compulsory vaccination of certain staff groups warrants further investigation.

Lake Malawi cichlid evolution along a benthic/limnetic axis.

Divergence along a benthic to limnetic habitat axis is ubiquitous in aquatic systems. However, this type of habitat divergence has largely been examined in low diversity, high latitude lake systems. In this study, we examined the importance of benthic and limnetic divergence within the incredibly species-rich radiation of Lake Malawi cichlid fishes. Using novel phylogenetic reconstructions, we provided a series of hypotheses regarding the evolutionary relationships among 24 benthic and limnetic species that suggests divergence along this axis has occurred multiple times within Lake Malawi cichlids. Because pectoral fin morphology is often associated with divergence along this habitat axis in other fish groups, we investigated divergence in pectoral fin muscles in these benthic and limnetic cichlid species. We showed that the eight pectoral fin muscles and fin area generally tended to evolve in a tightly correlated manner in the Lake Malawi cichlids. Additionally, we found that larger pectoral fin muscles are strongly associated with the independent evolution of the benthic feeding habit across this group of fish. Evolutionary specialization along a benthic/limnetic axis has occurred multiple times within this tropical lake radiation and has produced repeated convergent matching between exploitation of water column habitats and locomotory morphology.

Enhancement of Hsp70 synthesis protects common carp, Cyprinus carpio L., against lethal ammonia toxicity.

Exposure to TEX-OE®, a patented extract of the prickly pear cactus (Opuntia ficus indica) containing chaperone-stimulating factor, was shown to protect common carp, Cyprinus carpio L., fingerlings against acute ammonia stress. Survival was enhanced twofold from 50% to 95% after exposure to 5.92 mg L(-1) NH(3) , a level determined in the ammonia challenge bioassay as the 1-h LD50 concentration for this species. Survival of TEX-OE®-pre-exposed fish was enhanced by 20% over non-exposed controls during lethal ammonia challenge (14.21 mg L(-1) NH(3) ). Increase in the levels of gill and muscle Hsp70 was evident in TEX-OE®-pre-exposed fish but not in the unexposed controls, indicating that application of TEX-OE® accelerated carp endogenous Hsp70 synthesis during ammonia perturbation. Protection against ammonia was correlated with Hsp70 accretion.

Cold machine perfusion versus static cold storage of kidneys donated after cardiac death: a UK multicenter randomized controlled trial.

One third of deceased donor kidneys for transplantation in the UK are donated following cardiac death (DCD). Such kidneys have a high rate of delayed graft function (DGF) following transplantation. We conducted a multicenter, randomized controlled trial to determine whether kidney preservation using cold, pulsatile machine perfusion (MP) was superior to simple cold storage (CS) for DCD kidneys. One kidney from each DCD donor was randomly allocated to CS, the other to MP. A sequential trial design was used with the primary endpoint being DGF, defined as the necessity for dialysis within the first 7 days following transplant. The trial was stopped when data were available for 45 pairs of kidneys. There was no difference in the incidence of DGF between kidneys assigned to MP or CS (58% vs. 56%, respectively), in the context of an asystolic period of 15 min and median cold ischemic times of 13.9 h for MP and 14.3 h for CS kidneys. Renal function at 3 and 12 months was similar between groups, as was graft and patient survival. For kidneys from controlled DCD donors (with mean cold ischemic times around 14 h), MP offers no advantage over CS, which is cheaper and more straightforward.

Heat shock proteins (chaperones) in fish and shellfish and their potential role in relation to fish health: a review.

Heat shock proteins (HSPs), also known as stress proteins and extrinsic chaperones, are a suite of highly conserved proteins of varying molecular weight (c. 16-100 kDa) produced in all cellular organisms when they are exposed to stress. They develop following up-regulation of specific genes, whose transcription is mediated by the interaction of heat shock factors with heat shock elements in gene promoter regions. HSPs function as helper molecules or chaperones for all protein and lipid metabolic activities of the cell, and it is now recognized that the up-regulation in response to stress is universal to all cells and not restricted to heat stress. Thus, other stressors such as anoxia, ischaemia, toxins, protein degradation, hypoxia, acidosis and microbial damage will also lead to their up-regulation. They play a fundamental role in the regulation of normal protein synthesis within the cell. HSP families, such as HSP90 and HSP70, are critical to the folding and assembly of other cellular proteins and are also involved in regulation of kinetic partitioning between folding, translocation and aggregation within the cell. HSPs also have a wider role in relation to the function of the immune system, apoptosis and various facets of the inflammatory process. In aquatic animals, they have been shown to play an important role in health, in relation to the host response to environmental pollutants, to food toxins and in particular in the development of inflammation and the specific and non-specific immune responses to bacterial and viral infections in both finfish and shrimp. With the recent development of non-traumatic methods for enhancing HSP levels in fish and shrimp populations via heat, via provision of exogenous HSPs or by oral or water administration of HSP stimulants, they have also, in addition to the health effects, been demonstrated to be valuable in contributing to reducing trauma and physical stress in relation to husbandry events such as transportation and vaccination.

Pan-steatitis in farmed northern bluefin tuna, Thunnus thynnus (L.), in the eastern Adriatic.

Clinical, gross and histopathological investigations were carried out into large-scale mortalities on eastern Mediterranean bluefin tuna, Thunnus thynnus (L.), farms. Fish showed only nervous signs and darkened colour. At post-mortem the liver was bronze coloured and the pyloric area waxy in consistency. There was no evidence of any other gross pathology. Histopathology showed severe hepatic necrosis and lipidosis. Peri-pancreatic lipoid tissue was heavily infiltrated with an inflammatory round cell infiltrate. Fish on all three farms had been fed on a North African pilchard diet rather than traditional local or Baltic species. Once the diet was modified, losses ceased. A diagnosis of pan-steatitis as seen in other farmed fish species, as well as in terrestrial animals, on particular fish-based diets was made, although the actual factor within the diet which induced the inflammatory effect is not known.

The aetiology of spinal deformity in Atlantic salmon, Salmo salar L.: influence of genetic factors on the frequency and severity in freshwater stages.

A radiographic study was carried out on 2-year groups of pre-smolt parr to detect the comparative frequency of vertebral change in a range of defined pedigreed families of high growth rate of Atlantic salmon, Salmo salar L., reared under identical conditions. The observed frequency of deformity was related to the observed deformity level in the seawater parental generation, and to a potentially uncontrolled environmental determinant, i.e. stripping date. High and low parental deformity groups of families were found to produce offspring that had very similar levels of radiographically detectable spinal deformities in the pre-smolt parr, suggesting no genetic link. With regard to stripping date, the overall incidence was nearly half that seen in the preceding year (8.7% cf 16.6%). However, a non-significant trend to fewer radiographic spinal deformities was seen in the later stripping period.

Spinal deformation in commercially cultured Atlantic salmon, Salmo salar L.: a clinical and radiological study.

A clinical and radiographic study was carried out on 2016 randomly selected Atlantic salmon parr from six farms, which weighed between 55 and 100 g. In addition, 86 fish from six marine farms were similarly studied. Radiographically detectable vertebral lesions were found in 3.8-8.8% of the parr. The changes ranged from a single vertebra showing features, such as demineralization, increased density and slight loss of structure, to fish with multiple vertebrae affected by collapse, fusion and change in intervertebral space that could give rise to lordosis or kyphosis or abnormal vertebrae at several locations. The predominant location was the vertebral region V21-27, and rarely V44 caudad. The radiographic changes in seawater salmon mirrored those found in parr, but vertebrae V35 caudad were more frequently involved. Very few parr were found to have abnormal vertebrae in the peduncle area which suggests that the development of lesions at this location occurs de novo in the seawater phase, given that 'stumpy' fish are most frequent reported deformity at slaughter. It was concluded that minor vertebral change could be detected radiographically in many parr with no observable effect on external morphology. Whether such minor radiographic alteration would proceed to observable morphological change at slaughter weight is open to question.

The aetiology of spinal deformity in Atlantic salmon, Salmo salar L.: influence of different commercial diets on the incidence and severity of the preclinical condition in salmon parr under two contrasting husbandry regimes.

A large-scale trial of the effect of different commercial diets on the incidence of preclinical spinal deformation, as assessed by radiography, and the influence of two contrasting rearing systems was carried out. Two sets of three populations of Atlantic salmon, each of 20 000 first feeding fry of identical hatchery origin, created from equal numbers of eggs from 15 different families, were reared under commercial conditions on two different farms. Three commercial (closed formula) extruded fish meal-based diets were used in this study (diets A, B & C). Each diet was fed to one population of 20 000 fish at each site. Fish were fed a percentage of their body weight per day, with feeding rates set at commercial levels, based on water temperature, day length and fish biomass. Additional hand feeding was used to ensure satiation in all tanks. Fish in each tank were bulk-weighed and counted at the beginning and at 2-week intervals throughout the study. The fish were grown for 30 weeks. In addition, phosphorus (P) digestibility was evaluated by in-feed absorption testing in rainbow trout. The morphology of the radiographic lesions conformed to those described previously. Statistical analysis using multivariate regression analysis showed that date of sampling, site and diet were all statistically significant (P < 0.001) on univariable analysis. Farm A had significantly more affected fish than farm B (P < 0.001), which may have been attributable to variation in dissolved oxygen levels. The available dietary P levels were low in each diet. The number of fish affected in the group of fish being fed diet B was significantly lower than in the groups being fed diets A or C (P < 0.001). It appears most likely that the occurrence of preclinical radiographically apparent defects in parr which are believed to lead to the condition known as 'spinal deformity' is predominantly caused by a deficiency of available dietary P in first-feeding fry. The availability of dietary P may also vary considerably between diets formulated using different ingredients. Phytate-P associated with plant ingredients may affect the availability of P as well as other essential dietary nutrients. Additionally, diets for the production of salmonids in fresh water are currently formulated to keep P effluent to a minimum compatible with healthy spinal development. These various factors combine to make it crucial that small Atlantic salmon, especially first-feeding fry, are provided with carefully formulated diets fortified to an adequate level with a high quality source of available P.

Needle-stick injuries in primary care in Wales.

BACKGROUND: Accidental needle-stick injuries (NSIs) are a hazard for health-care workers and for the general public. OBJECTIVES: To estimate the presentation rate of NSIs to general medical practices, their relation to practice characteristics, and review practice policies for managing NSIs. METHOD: Descriptive study using logistic regression analysis. RESULTS: Annual rates of 2.73 (95% CI 2.08, 3.50) occupational NSIs per 100 clinical practice staff and 2.14 (95% CI 1.39, 3.13) non-occupational NSIs per 100,000 practice population were recorded. Stepwise logistic regressions showed that chance of a practice reporting at least one occupational NSI in previous five years was best predicted by being a single-handed practice (decreased odds). In contrast, the chance of a practice reporting at least one non-occupational NSI was best predicted by being a rural practice (increased odds). About one in five practices possessed no written policy on managing NSIs. Stepwise logistic regressions showed that the chance of a practice owning a NSI policy was best predicted by being located in an LHB area with a coastline (increased odds). CONCLUSION: NSIs are an important public health issue in Wales. We have tried to address the lack of guidance by developing new guidelines in Wales.

Analysis of the incidence of infectious pancreatic necrosis mortality in pedigreed Atlantic salmon, Salmo salar L., populations.

A total of 77,124 Atlantic salmon post-smolts, representing 197 full-sib families produced by 149 males and 197 females, experienced a field challenge from infectious pancreatic necrosis virus (IPNV), following transfer to three separate seawater sites. The first IPN mortality was observed 45 days after transfer, and the duration of the epidemic varied between 37 and 92 days among sites. Mortalities were traced to their parental families by PIT (Passive Integrated Transpondes) tag records and DNA genotyping. Full-sib family mean incidence of mortality was calculated for each family on each site. Heritabilities were estimated based on the heterogeneity of chi-square using incidence within half-sib families and the variance in incidence among full-sib families, both on the observed and underlying liability scale. The observed correlation among families across sites was used to estimate genetic correlations. The overall mortality rate was 10.8%, with only small differences between sites, ranging from 10.3% to 11.9%. Heritabilities on the liability scale were found to be moderate to strong, and ranged between 0.24 and 0.81, with a pooled estimate of 0.43, greater than is typically associated with disease traits. Genetic correlations among sites were all substantial, between 0.71 and 0.78, and indicated that a substantial component of the genetic variation displayed within sites was common to all. The results show that field challenges can yield very good genetic information on family differences in resistance, especially when replicated over sites, which may then be developed for use in selection for breeding strains of Atlantic salmon with greater resistance to IPN.

Exposure to school children as a risk factor in a community outbreak of hepatitis A in young adults: a case control study.

To investigate risk factors during a community outbreak of hepatitis A we carried out a case- control study of 35 cases and 49 matched controls using an interviewer-administered questionnaire on clinical history, travel, household details including domestic toilet facilities, infectious contacts, and food history. Of 99 cases notified in the city during the outbreak year, 50 (51%) were young adults age 15-34 years. Hepatitis A infection was independently associated with household contact with a case (P=0.0005), and sharing a household with children in primary school (OR 3.4, 95% CI 1.2-9.5, P=0.008) with risk increasing with number of primary-school pupils in the household (chi(2) for linear trend 6.47, P=0.01). We concluded that in a population with a low prevalence of hepatitis A, adults who live in the same household as primary-school-age children are at increased risk of acquiring the infection during community outbreaks.

Maternal age in pregnancy and offspring blood pressure in childhood in the Avon Longitudinal Study of Parents and Children (ALSPAC).

Associations between maternal age in pregnancy and offspring blood pressure (BP) at age 7(1/2) were investigated in 7623 singletons from the Avon Longitudinal Study of Parents and Children (ALSPAC). In models adjusted for age and sex there was an inverse relationship between maternal age and BP in children: beta = -0.06 mmHg per year of maternal age (95% CI -0.10 to -0.01, P = 0.02) for systolic BP and beta = -0.04 (95% CI -0.07 to -0.01, P = 0.02) for diastolic BP. However, this association disappeared after adjustment for confounding factors: beta = -0.02 mmHg per year of maternal age (95% CI -0.07 to 0.04, P = 0.5) for systolic BP and beta = -0.03 (95% CI -0.07 to 0.01, P = 0.2) for diastolic BP. We conclude that there is no evidence of a relationship between maternal age in pregnancy and childhood BP in this contemporary birth cohort.

Infectious pancreatic necrosis in Atlantic salmon, Salmo salar L.

A clinical and histopathological review was carried out of 21 outbreaks of acute infectious pancreatic necrosis (IPN) in Scottish Atlantic salmon, Salmo salar L., farms (13 marine and eight fresh water) during 1991-2004. A distinctive syndrome was evident in both post-smolts in sea water and fry in fresh water, where liver lesions, which had not previously been associated with IPN, became a consistent finding in addition to the more typical pancreatic and intestinal changes. Initial cases were described in post-smolts in Shetland, but by the end of the period of investigation this type of pathology had extended down the West coast of Scotland and into Ireland. Limited viral strain analysis suggested that similar strains were involved in both fresh water and sea water and that these differed from earlier isolates from rainbow trout, Oncorhynchus mykiss (Walbaum). In fresh water, recovered fish frequently developed a greatly distended intestine associated with accumulation of undigested food. In sea water, after the initial, often significant (50% or more), losses, there were many fish which failed to grow and became chronically emaciated and prone to sea louse infection. Although use of transfer diets containing immune enhancers and the selection of IPN resistant broodstock has reduced losses the disease remains a serious cause of economic loss.

The pathology of phosphorus deficiency in fish--a review.

Phosphorus (P) is an essential component of fish diets. Its deficiency affects not only hard tissues, where it is responsible for rickets, leading to skeletal malformation, but also influences various aspects of intermediary metabolism, and thus growth and feed conversion. Therefore, optimizing the dietary inclusion level is critical at all times. As the aquaculture industry has expanded, so the effects of P in farm effluents, derived from metabolic and uneaten food sources, have also become recognized. Diets are increasingly formulated on a basis that will not only provide adequate P for fish needs, but also endeavour to ensure minimal acceptable P levels in effluents at the same time. Many variables influence P requirements and P availability in fish diets, so it is inadvisable to feed diets formulated to an assumed minimum dietary requirement level, irrespective of the advantages that such a formulation may provide to environmental impact.