Comparison of patients with severe COVID-19 admitted to an intensive care unit in South Africa during the first and second wave of the COVID-19 pandemic.

Background: The second wave of coronavirus disease 2019 (COVID-19), dominated by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Beta variant, has been reported to be associated with increased severity in South Africa (SA). Objectives: To describe and compare clinical characteristics, management and outcomes of COVID-19 patients admitted to an intensive care unit (ICU) in SA during the first and second waves. Methods: In a prospective, single-centre, descriptive study, we compared all patients with severe COVID-19 admitted to ICU during the first and second waves. The primary outcomes assessed were ICU mortality and ICU length of stay (LOS). Results: In 490 patients with comparable ages and comorbidities, no difference in mortality was demonstrated during the second compared with the first wave (65.9% v. 62.5%, p=0.57). ICU LOS was longer in the second wave (10 v. 6 days, p<0.001). More female admissions (67.1% v. 44.6%, p<0.001) and a greater proportion of patients were managed with invasive mechanical ventilation than with non-invasive respiratory support (39.0% v. 14%, p<0.001) in the second wave. Conclusion: While clinical characteristics were comparable between the two waves, a higher proportion of patients was invasively ventilated and ICU stay was longer in the second. ICU mortality was unchanged.

Full-Genome Sequences of Two Newcastle Disease Virus Strains Isolated in West Java, Indonesia.

The full-genome sequences of strains chicken/Indonesia/Cilebut/010WJ/2015 and chicken/Indonesia/ITA/012WJ/1951, isolated in West Java, Indonesia, in 2015 and 1951, respectively, were examined. Chicken/Indonesia/Cilebut/010WJ/2015 (genotype VII) caused a 2015 disease outbreak in Indonesia, and chicken/Indonesia/ITA/012WJ/1951 (genotype VI) is used as a standard strain for challenge in Newcastle disease virus (NDV) vaccine trials.

Six years of progress in the oral biopharmaceutics area - A summary from the IMI OrBiTo project.

OrBiTo was a precompetitive collaboration focused on the development of the next generation of Oral Biopharmaceutics Tools. The consortium included world leading scientists from nine universities, one regulatory agency, one non-profit research organisation, three small/medium sized specialist technology companies together with thirteen pharmaceutical companies. The goal of the OrBiTo project was to deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This goal was achieved through novel prospective investigations to define new methodologies or refinement of existing tools. Extensive validation has been performed of novel and existing biopharmaceutics tools using historical datasets supplied by industry partners as well as laboratory ring studies. A combination of high quality in vitro and in vivo characterizations of active drugs and formulations have been integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of gastrointestinal drug absorption and some of the best practices has been highlighted. This approach has given an unparalleled opportunity to deliver transformational change in European industrial research and development towards model based pharmaceutical product development in accordance with the vision of model-informed drug development.

Oesophageal sarcocystosis observed at slaughter provides a reliable and efficient proximate measure of Toxoplasma gondii seroprevalence in sheep.

OBJECTIVE: Successful disease management requires effective surveillance. Slaughterhouse inspections provide opportunities to efficiently collect regular disease data from many animals across large areas. Toxoplasma is a cat-borne parasite that causes reproduction failure in sheep, although it is not visually detectable at slaughterhouses. Macroscopic sarcocystosis is a disease of sheep that is visually detectable at slaughter and is caused by parasites that share a similar biology with Toxoplasma. We investigated if sarcocystosis could act as a proximate measure for Toxoplasma exposure in sheep to facilitate its efficient surveillance at large scales. DESIGN/METHODS: We compared the presence of macroscopic sarcocystosis to Toxoplasma serostatus at the animal and farm levels. RESULTS: At the animal level, we found a weak association between Toxoplasma seropositivity and sarcocysts in the oesophagus (OR = 1.76 [95% CI: 1.17, 2.65; McFadden's R2 = 0.01]) but no association between Toxoplasma seropositivity and sarcocysts in skeletal muscles. At the farm level, the seroprevalence of Toxoplasma was strongly associated with oesophageal sarcocystosis prevalence (OR = 28.59 [95% CI: 13.07, 62.57; McFadden's R2 = 0.34]) but less strongly associated with sarcocystosis prevalence in skeletal muscles (OR = 7.91 [95% CI: 1.24, 50.39; McFadden's R2 = 0.02]). CONCLUSIONS: For Toxoplasma surveillance in sheep at the farm level, routine slaughter inspection and recording of macroscopic oesophageal sarcocystosis could be are liable and efficient proximate measure. The monitoring of oesophageal sarcocystosis may be a useful passive Toxoplasma surveillance tool for guiding the timing and location of other Toxoplasma detection methods to facilitate the management of Toxoplasma impacts within the sheep industry.

A thematic literature review of innovative strategies to prepare nursing students for aged-care.

BACKGROUND: The exponential rise in people living longer but requiring residential care is adding pressure to already overstretched aged care nurses. Consequently, a person-centred care culture in residential care remains aspirational, rather than a reality. For nursing students in Australia and elsewhere, clinical placements in aged care facilities are under-utilised due to negative perceptions about the likelihood for learning. Creative strategies to engage students to safely challenge ageist thinking and to inspire enthusiasm for learning in this context are needed. OBJECTIVES: The purpose of this thematic review of the literature is to better understand challenges related to learning in aged care settings and identify innovative strategies to enhance nursing student learning experiences in residential aged care placements. REVIEW METHODS: A literature review was undertaken in 2019 using CINAHL, PUBMED, Elsevier, Medline, ProQuest and Google Scholar. The search was limited to papers that were peer reviewed, in English, and published between 2001 and the date of review (mid-2019) in order to situate the review in the new millennium. RESULTS: 47 articles and books were included in the review that introduce solutions and innovative strategies that could be used to improve students' attitudes to learning in aged care and from older people. The literature review was categorized into three main themes, including: barriers to working with older people; the need for pedagogical change to foster empathy; and innovative strategies to address barriers. CONCLUSION: These themes are useful to consider in designing engaging learning and teaching for nursing students to be effective in working in aged care.

No Evidence of Toxoplasma Gondii Exposure in South Australian Koalas (Phascolarctos cinereus).

Infection with the cat-borne parasite Toxoplasma gondii has been detected in numerous Australian marsupials and can lead to severe disease (toxoplasmosis) in some cases. The seroprevalence of Toxoplasma on Kangaroo Island, South Australia has been reported to be higher than the South Australian mainland in macropods, cats, and sheep, suggesting an increased risk of infection on this island. However, Toxoplasma seroprevalence in small- and medium-sized terrestrial mammals was almost zero on the island and did not differ from that on the mainland. We surveyed Toxoplasma seroprevalence in koala (Phascolarctos cinereus) populations on the island and on the mainland and assessed their risk of infection and their role in the life cycle of Toxoplasma. All screened koalas from the island (n = 94) and the mainland (n = 63) were seronegative. This represents the largest Toxoplasma seroprevalence survey in this species and provided sufficient evidence to confidently demonstrate freedom from parasite exposure in both island and mainland populations at the time of the survey. Because koalas are extensively arboreal and predominately consume tree foliage, they appear to be at negligible risk of Toxoplasma infection. Furthermore, as koalas are rarely consumed by cats, we suggest that they have a minor role in the parasite's life cycle.

Introduction to the OrBiTo decision tree to select the most appropriate in vitro methodology for release testing of solid oral dosage forms during development.

The EU research initiative OrBiTo (oral biopharmaceutics tools) involving partners from academia, pharmaceutical industry, small medium enterprises and a regulatory agency was launched with the goal of improving tools to predict the absorption of drugs in humans and thereby accelerating the formulation development process. The OrBiTo project was divided into four work packages (WP), with WP2 focusing on characterization of drug formulations. The present work introduces the OrBiTo WP2 Decision Tree, which is designed to assist the investigator in choosing the most appropriate in vitro methods for optimizing the oral formulation design and development process. The WP2 Decision Tree consists of four stages to guide the investigator. At the first stage, the investigator is asked to choose the formulation type of interest. At the second stage, the investigator is asked to identify which type of equipment (compendial/modified/noncompendial) is preferred/available. At the third stage, characteristics of the active pharmaceutical ingredient (API) are evaluated and in the fourth stage of the decision tree, suitable experimental protocols are recommended. A link to the living Decision Tree document is provided, and we now invite the pharmaceutical sciences community to apply it to current research and development projects and offer suggestions for improvement and expansion.

NLRP3 as a potentially novel biomarker for the management of osteoarthritis.

Osteoarthritis (OA) was previously thought of as 'wear and tear' as humans age, however there is increasing evidence to support an inflammatory theory. The nucleotide-binding and oligomerization domain-like receptor containing protein 3 (NLRP3) inflammasome has been implicated in the pathogenesis of a number of arthritic disorders, producing proinflammatory cytokines and degradative enzymes such as Interleukin-1 beta (IL-1ß), Tumour necrosis factor alpha (TNF-α) and Matrix metalloproteinase-3 (MMP-3) which drive cartilage degeneration and synovial inflammation. This review aims to summarise the evidence of NLRP3 involvement in OA. Currently, treatment options focus on management of the disease and to date there is no cure. The development of novel biomarkers for OA could improve diagnosis, treatment and management. Importantly, this review provides detail on the involvement of the NLRP3 inflammasome in OA pathology and how its members could act as potential biomarkers to assist clinical decisions.

Wave directional spreading from point field measurements.

Ocean waves have multidirectional components. Most wave measurements are taken at a single point, and so fail to capture information about the relative directions of the wave components directly. Conventional means of directional estimation require a minimum of three concurrent time series of measurements at different spatial locations in order to derive information on local directional wave spreading. Here, the relationship between wave nonlinearity and directionality is utilized to estimate local spreading without the need for multiple concurrent measurements, following Adcock & Taylor (Adcock & Taylor 2009 Proc. R. Soc. A465, 3361-3381. (doi:10.1098/rspa.2009.0031)), with the assumption that directional spreading is frequency independent. The method is applied to measurements recorded at the North Alwyn platform in the northern North Sea, and the results compared against estimates of wave spreading by conventional measurement methods and hindcast data. Records containing freak waves were excluded. It is found that the method provides accurate estimates of wave spreading over a range of conditions experienced at North Alwyn, despite the noisy chaotic signals that characterize such ocean wave data. The results provide further confirmation that Adcock and Taylor's method is applicable to metocean data and has considerable future promise as a technique to recover estimates of wave spreading from single point wave measurement devices.

In Vivo Predictive Dissolution (IPD) and Biopharmaceutical Modeling and Simulation: Future Use of Modern Approaches and Methodologies in a Regulatory Context.

The overall objective of OrBiTo, a project within Innovative Medicines Initiative (IMI), is to streamline and optimize the development of orally administered drug products through the creation and efficient application of biopharmaceutics tools. This toolkit will include both experimental and computational models developed on improved understanding of the highly dynamic gastrointestinal (GI) physiology relevant to the GI absorption of drug products in both fasted and fed states. A part of the annual OrBiTo meeting in 2015 was dedicated to the presentation of the most recent progress in the development of the regulatory use of PBPK in silico modeling, in vivo predictive dissolution (IPD) tests, and their application to biowaivers. There are still several areas for improvement of in vitro dissolution testing by means of generating results relevant for the intraluminal conditions in the GI tract. The major opportunity is probably in combining IPD testing and physiologically based in silico models where the in vitro data provide input to the absorption predictions. The OrBiTo project and other current research projects include definition of test media representative for the more distal parts of the GI tract, models capturing supersaturation and precipitation phenomena, and influence of motility waves on shear and other forces of hydrodynamic origin, addressing the interindividual variability in composition and characteristics of GI fluids, food effects, definition of biorelevant buffer systems, and intestinal water volumes. In conclusion, there is currently a mismatch between the extensive industrial usage of modern in vivo predictive tools and very limited inclusion of such data in regulatory files. However, there is a great interest among all stakeholders to introduce recent progresses in prediction of in vivo GI drug absorption into regulatory context.

Standards for the Reporting of Genetic Counseling Interventions in Research and Other Studies (GCIRS): an NSGC Task Force Report.

As the demand for evidence to support the value of genetic counseling increases, it is critical that reporting of genetic counseling interventions in research and other types of studies (e.g. process improvement or service evaluation studies) adopt greater rigor. As in other areas of healthcare, the appraisal, synthesis, and translation of research findings into genetic counseling practice are likely to be improved if clear specifications of genetic counseling interventions are reported when studies involving genetic counseling are published. To help improve reporting practices, the National Society of Genetic Counselors (NSGC) convened a task force in 2015 to develop consensus standards for the reporting of genetic counseling interventions. Following review by the NSGC Board of Directors, the NSGC Practice Guidelines Committee and the editorial board of the Journal of Genetic Counseling, 23 items across 8 domains were proposed as standards for the reporting of genetic counseling interventions in the published literature (GCIRS: Genetic Counseling Intervention Reporting Standards). The authors recommend adoption of these standards by authors and journals when reporting studies involving genetic counseling interventions.

A survey on IVIVC/IVIVR development in the pharmaceutical industry - Past experience and current perspectives.

The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Exogenous Carbohydrate Reduces Cortisol Response from Combined Mental and Physical Stress.

Combined mental and physical stress is associated with exacerbated cortisol production which may increase risk for the progression of cardiovascular disease in individuals working in high-stress occupations (e.g., firefighters, military personnel, etc.). Carbohydrate (CHO) ingestion prior to physical stress may attenuate cortisol concentrations. This project was the first to investigate the effect of CHO ingestion on cortisol response from combined mental and physical stress. 16 men 21-30 years old were randomly assigned a 6.6% CHO beverage or non-CHO control 15 min prior to performing a dual-concurrent-stress challenge. This consisted of physical stress (i.e., steady state exercise) combined with computerized mental challenges. Blood was sampled 70, 40, and 15 min before exercise, immediately at onset of exercise, 10, 20, 30, 35 min during exercise, and 15, 30, 45, and 60 min after exercise. There was a significant main effect for treatment regarding mean cortisol concentrations (F=5.30, P=0.0219). The total area under curve for cortisol was less when CHO was ingested (T7=4.07, P=0.0048). These findings suggest that CHO ingestion immediately prior to combined mental and physical stress may attenuate cortisol responses.

Unusual presentation of neosporosis in a neonatal puppy from a litter of bulldogs.

CASE REPORT: A 17-day-old Bulldog puppy died soon after presentation for weakness and tachypnoea. Gross lesions included diffuse pulmonary oedema and a region of myocardial pallor that resembled an infarct. Inflammation was observed histopathologically in many organs, with numerous clusters of intracellular protozoa that stained positively using Neospora caninum immunohistochemistry. Myocarditis was severe and had associated necrosis of individual myocytes, but the tissue was not infarcted. The bitch had an antibody titre of 1 : 1600 for N. caninum. All six littermates were sold and reported to be healthy at 6 months of age. CONCLUSION: Unusual aspects of this case include the occurrence of clinical disease in only 1 of 7 neonatal puppies, widespread dissemination of the organism in multiple tissues, and regional pallor associated with myocarditis that gave a false gross appearance of infarction. This report also adds Bulldogs to the list of dog breeds shown to be susceptible to clinical neosporosis.

Identifying variation in models of care for the genomic-based diagnosis of inherited retinal dystrophies in the United Kingdom.

PurposeAdvances in genomic technologies are prompting a realignment of diagnostic and management pathways for rare inherited disease. New models of care are being developed as genomic-based diagnostic testing becomes increasingly relevant within more and more aspects of medicine. This study describes current care models for the provision of a genomic-based diagnosis for patients with inherited retinal dystrophy (IRD) in UK clinical practice.MethodsA structured telephone survey, conducted (in 2014) with all 23 UK Regional Genetics Centres and a sample of specialist ophthalmology centres (n=4), was used to describe models of service delivery and current levels of genomic-based diagnostic testing. Quantitative data were summarised using descriptive statistics. Responses to open-ended questions were summarised using thematic analysis.ResultsOf the 27 centres 10 of them saw IRD patients in 'generic' clinics and 17 centres offered ophthalmic-specific clinics. Extensive regional variation was observed in numbers of patients seen and in how care for the diagnosis and management of IRD was provided.ConclusionsUnderstanding current practice is a necessary first step in the development and evaluation of complex interventions, such as care models for the genomic-based diagnosis of inherited eye conditions. Presented findings here relating to disparities in care provision are potentially linked to previously reported evidence of perceived unmet needs and expectations of IRD service users. This work provides a foundation for the integration of new care models in mainstream medicine.

Missing voices: Profile and extent of acquired communication disorders in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia using linked administrative records.

BACKGROUND: Limited data exist on the extent of specific functional sequelae, including acquired communication disorder, among Aboriginal stroke survivors, making planning of multidisciplinary services difficult. AIMS: To obtain estimates of the extent and profile of acquired communication disorder in Aboriginal and non-Aboriginal adult stroke survivors in Western Australia and investigate potential disparities in receiving in-hospital speech pathology services among survivors with acquired communication disorder. METHODS: Stroke cases surviving their first stroke episode during 2002-2011 were identified using Western Australia-wide person-based linked hospital and mortality data, and their five-year comorbidity profiles determined. The mid-year prevalence of stroke cases with acquired communication disorder was estimated for 2011. Regression methods were used to investigate determinants of receiving speech pathology services among acquired communication disorder cases. RESULTS: Of 14,757 stroke survivors aged 15-79 years admitted in 2002-2011, 33% had acquired communication disorder (22% aphasia/dysphasia) and 777 (5.3%) were Aboriginal. Aboriginal patients were more likely to be younger, live remotely, and have comorbidities. A diagnosis of aphasia was more common in Aboriginal than non-Aboriginal patients 15-44 years (p = 0.003). A minimum of 107 Aboriginal and 2324 non-Aboriginal stroke patients with acquired communication disorder lived in Western Australia in 2011. Aboriginal status was not associated with receiving in-hospital speech services among acquired communication disorder patients in unadjusted or adjusted models. CONCLUSIONS: The relative youth, geographical distribution, high comorbidity prevalence, and cultural needs of Aboriginal stroke patients with acquired communication disorder should inform appropriate service design for speech pathology and rehabilitation. Innovative models are required to address workforce issues, given low patient volumes.

A Comparison of Antiserum and Protein A as Secondary Reagents to Assess Toxoplasma gondii Antibody Titers in Cats and Spotted Hyenas.

Toxoplasma gondii is a protozoal parasite with worldwide distribution that is able to infect a wide variety of mammals and birds. Our main goal was to screen for T. gondii antibody titers in a previously untested species, the spotted hyena ( Crocuta crocuta); however, this goal first required us to investigate serological procedures that could be suitable for hyenas. Cats are the closest domestic relations of hyenas, so T. gondii antibody titers were first compared in 26 feral cats with specific or nonspecific fluorophore-labeled secondary reagents, i.e., anti-cat IgG or protein A. Substitution of anti-cat IgG with protein A caused a statistically significant drop in titer measurements in cats (P = 0.01) with a reduction of the geometric mean titer equivalent to 1 doubling-dilution. The same procedures were then applied to captive spotted hyenas. Titers measured in 9 of 10 hyenas were identical whether anti-cat IgG or protein A was used as the secondary reagent: 5 had titers <1:16, 2 had titers of 1:16, and 2 had titers of 1:32. One hyena had maximum titers of 1:64 or 1:32 when anti-cat IgG or protein A was used, respectively. The use of protein A as the secondary reagent in serologic assays can be applied to a range of mammalian species and seems unlikely to affect test specificity; however, the use of protein A may reduce test sensitivity, as suggested in the present study using cats. Despite a control program, some exposure to T. gondii had occurred in the Zoo's spotted hyenas.

Patient reported outcomes and patient empowerment in clinical genetics services.

Evaluation of clinical genetics services (CGS), including genetic counseling and genetic testing, has been problematic. Patient mortality and morbidity are unlikely to be directly improved by interventions offered in CGS. Patient-reported outcomes (PROs) are not routinely measured in CGS evaluation, but this may change as patient-reported outcome measures (PROMs) become a key part of how healthcare services are managed and funded across the world. However, there is no clear consensus about which PROMs are most useful for CGS evaluation. This review summarizes the published research on how PROs from CGS have been measured and how patients may benefit from using those services, with a focus on patient empowerment. Many patient benefits (PROs) identified repeatedly in the research literature can be re-interpreted within a patient empowerment framework. Other important PROs identified include family functioning, social functioning, altruism, sense of purpose, enabling development of future research and treatment/participating in research. Well-validated measures are available to capture (dimensions of) patient empowerment. Although generic measures of family functioning are available, suitable measures capturing social functioning, development of future treatments, and altruism were not identified in this review. Patient empowerment provides one useful approach to measuring PROs from CGS.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.