Safety Assessment of Streptococcus salivarius UBSS-01 in Rats and Double-Blind Placebo-Controlled Study in Healthy Individuals.

Streptococcus salivarius is a common, harmless, and prevalent member of the oral microbiota in humans. In the present study, the safety of S. salivarius UBSS-01 was evaluated using in silico methods and preclinical and clinical studies. In an acute toxicity study, rats were administered with 5 g/kg (500 × 109 CFU) S. salivarius UBSS-01. The changes in phenotypic behaviors and hematological, biochemical, electrolytes, and urine analyses were monitored. No toxicity was observed at 14 days post-treatment. The no observable effects limit (NOEL) of S. salivarius UBSS-01 was >5 g/kg in rats. In a 28-day repeat dose toxicity study, rats were administered S. salivarius UBSS-01 once daily at doses of 0.1, 0.5, and 1 g/kg (10, 50, and 100 billion CFU/kg, respectively) body weight. S. salivarius UBSS-01 did not influence any of the hematology parameters and clinical chemistry parameters in plasma and serum samples after 28-day repeated administration. No structural abnormality was observed in the histological examination of organs. Whole genome analysis revealed the absence of virulence factors or genes that may transmit antibiotic resistance. In the double-blind study with 60 human participants (aged 18-60 years), consumption of S. salivarius UBSS-01 for 30 days was found to be safe and results were comparable with placebo treatment These findings indicate that S. salivarius UBSS-01 may be safe for human consumption.

The Sociodemographic Characteristics of Indian Nursing Students and Their Intentions to Migrate Overseas for Work.

India being the second largest nurse exporter to the Organisation for Economic Cooperation and Development (OECD) countries, currently faces a shortage of 2.4 million nurses. The problem of nurse shortage has been aggravated by the COVID pandemic. The young age at which the Indian nurses migrate, suggests that the decision to work overseas is made probably at the time of pursuing the studies or probably one pursues nursing because it opens the opportunity for working overseas. The objective of this study was to assess the intensions of nursing students to pursue overseas career on completion of their studies. The study used a cross-sectional survey design to collect data from 1408 nursing students from across four states of India namely, Karnataka, Kerala, Maharashtra and Rajasthan using a google survey form. The major finding of the study was that 54% of the respondents intended to migrate overseas. Better career advancement opportunities, better working conditions, higher pay, better lifestyle, were the reasons cited by those who had an intension to migrate. Establishing norms for nurse-patient ratios, and scope of work along with pay scales for nurses with various qualifications and experience could be the most strategic moves that the policy makers can consider to control brain drain in nursing and control nurse migration.

Predicting the Safety of Ocular Iontophoresis Using Reconstructed Human Corneal Epithelial Cells.

We aimed to investigate eye damage caused by ocular iontophoresis (IP) based on an in vitro eye irritation test using a reconstructed human corneal cell. In this study, the LabCyte CORNEA-MODEL was selected as the reconstructed corneal cell. The test procedure was performed according to Test Guideline No.492 of the Organisation for Economic Co-operation and Development, which was partially revised for the IP. From the relationship between the cell viability of the cornea model and the electric field intensity [current density (mA/cm2) × application time (min)] of the IP, we predicted that the intensity values of 465 mA/cm2 × min and 930 mA/cm2 × min caused reversible eye irritation and irreversible eye damage, respectively. However, further studies are required to improve the accuracy and reproducibility of the prediction. This report provides essential knowledge on the clinical safety of ocular IP.

Assessment of Biological Activities, Acute and Sub-chronic Toxicity of Liang (Gnetum gnemon var. tenerum) Leaves Powder, a Natural Product.

Gnetum gnemon var. tenerum (Gnetaceae) is a shrub plant native to South-East Asia. In Thailand, Liang leaves are commonly consumed in South of Thailand as vegetable. According to literature, they have an antihyperglycemic capacity because of their rich chlorophyll, fiber, and protein. However, there is need to assess the safety since natural food products are not completely devoid of toxicity. This study aimed to assess the biological activities as well as the acute and sub-chronic oral toxicity of Liang leaves powder (LLP). The evaluation of LLP for acute oral toxicity was performed at dose level 2000 mg/kg body weight in Wistar rats while the sub-chronic oral toxicity of LLP was performed at the effective dose (1.47 g/kg) for antihyperglycemic property according to Organisation for Economic Co-operation and Development (OECD)-425. The results showed that LLP demonstrated anti-inflammatory activities. It also showed no clinical signs of toxic effects and mortality in rats throughout 90 d. Thus, LLP could be classified in GHS category 5 which are of relatively low acute toxicity and then the lethal dose, 50% (LD50) cut off at 5000 mg/kg body weight to infinity (∞). Administration of LLP to the experimental rats significantly increased (p < 0.05) the concentration of triglyceride and increased concentration of creatinine as a result of kidney malfunction was also noticed in the experimental rats. Hematological alteration was not noticed in the treated female rats, but red blood cell, hemoglobin and hematocrit concentrations significantly increased in the treated male rats. The study concludes that sub-chronic administration of 1.47 g/kg LLP is relatively safe.

Fostering collective action through participation in natural resource and environmental management: An integrative and interpretative narrative review using the IAD, NAS and SES frameworks.

Solving humanity's social-environmental challenges calls for collective action by relevant actors. Hence, involving these actors in the policy process has been deemed both necessary and promising. But how and to what extent can participatory policy interventions (PIs) foster collective action for sustainable environmental and natural resource management? Lab and lab-in-the-field experiments on co-operation in the context of collective action challenges (i.e. social dilemmas) and case study research on participatory processes both offer insights into this question but have hitherto mainly remained unconnected. This article reviews insights from these two streams of literature in tandem, synthesising and analysing them using the institutional analysis and development (IAD) framework in combination with the network of action situations (NAS) framework and the social-ecological systems (SES) framework. We thus perform an integrative and interpretative narrative review to draw a richer and more nuanced picture of PIs: their potential impacts, their (institutional and behavioural) mechanisms and challenges, and caveats and recommendations for their design and implementation. Our review shows that PIs can indeed foster collective action by (a) helping the relevant actors craft suitable and legitimate institutional arrangements and (b) addressing and/or influencing actors' attributes of relevance to collective action, namely their individual and shared understandings, beliefs and preferences. To fulfil this potential, the organisers and sponsors of PIs must address and link to the broader context through soundly designed and implemented processes. Complementary follow-up, enforcement and conflict resolution mechanisms are necessary to nurture, reassure and sustain understandings, beliefs and preferences that undergird trust-building and collective action. The conceptual framework developed for the review can help researchers and practitioners further assess these insights, disentangle PIs' mechanisms and impacts, and integrate the research and practice of participatory governance and collective action.

Effects of transport-carbon intensity, transportation, and economic complexity on environmental and health expenditures.

Health and the environment are complex components of the countries, influenced by several factors, especially transport, and economics. Thus, this paper assesses the role of transportation and economic complexity in the environment and public health for the Organization for Economic Co-operation Development (OECD) countries from 2001 to 2020. This study also focuses on the relationship between transport and economic complexity with environmental and healthcare expenditures. Precisely, transport and economic activities stimulate healthcare expenditures through multiple channels. The current study employs the STIRPAT model to investigate the association with transportation, economic complexity, transport-carbon intensity, and healthcare expenditure. Besides, the current research confirms the plausible cross-sectional dependency across countries, and it adopts a second-generation technique. Analytical findings suggest that transportation-carbon intensity is positively and significantly associated with healthcare expenditures. Healthcare and transport-household expenditures increase transport-carbon intensity (TCI) by 75% and 45%, respectively, in the long run. In the contrast, TCI and transport-household expenditures have also a remarkable impact on healthcare expenditures and are estimated approximately 95% in the long run. Moreover, economic growth also upsurges TCI and healthcare expenditures through multiple economic activities. Besides, transport-household expenditures (THE) drastically impact transport-carbon intensity and healthcare expenditures (HEX) through passenger traffic (PTF). Diagnostic upshots unveil that the joint effect of THE and PTF increases TCI and HEX by 4 and 3%, respectively. Finally, findings recommend some policy implications and future research directions for the countries based on empirical outcomes. Countries should regulate economic activities to reduce transport carbon emissions.

Pre- and post-association barriers to host switching in sympatric mutualists.

Coevolution between mutualists can lead to reciprocal specialization, potentially causing barriers to host switching. Here, we conducted assays to identify pre- and post-association barriers to host switching by endosymbiotic bacteria, both within and between two sympatric nematode clades. In nature, Steinernema nematodes and Xenorhabdus bacteria form an obligate mutualism. Free-living juvenile nematodes carry Xenorhabdus in a specialized intestinal receptacle. When nematodes enter an insect, they release the bacteria into the insect hemocoel. The bacteria aid in killing the insect and facilitate nematode reproduction. Prior to dispersing from the insect, juvenile nematodes must form an association with their symbionts; the bacteria must adhere to the intestinal receptacle. We tested for pre-association barriers by comparing the effects of bacterial strains on native versus non-native nematodes via their virulence towards, nutritional support of, and ability to associate with different nematode species. We then assessed post-association barriers by measuring the relative fitness of nematodes carrying each strain of bacteria. We found evidence for both pre- and post-association barriers between nematode clades. Specifically, some bacteria were highly virulent to non-native hosts, and some nematode hosts carried fewer cells of non-native bacteria, creating pre-association barriers. In addition, reduced infection success and lower nematode reproduction were identified as post-association barriers. No barriers to symbiont switching were detected between nematode species within the same clade. Overall, our study suggests a framework that could be used to generate predictions for the evolution of barriers to host switching in this and other systems.

Improving primary health care quality for refugees and asylum seekers: A systematic review of interventional approaches.

BACKGROUND: It has been widely acknowledged that refugees are at risk of poorer health outcomes, spanning mental health and general well-being. A common point of access to health care for the migrant population is via the primary health care network in the country of resettlement. This review aims to synthesize the evidence of primary health care interventions to improve the quality of health care provided to refugees and asylum seekers. METHODS: A systematic review was undertaken, and 55 articles were included in the final review. The Preferred Reporting Items for Systematic Reviews was used to guide the reporting of the review, and articles were managed using a reference-management software (Covidence). The findings were analysed using a narrative empirical synthesis. A quality assessment was conducted for all the studies included. RESULTS: The interventions within the broad primary care setting could be organized into four categories, that is, those that focused on developing the skills of individual refugees/asylum seekers and their families; skills of primary health care workers; system and/or service integration models and structures; and lastly, interventions enhancing communication services. Promoting effective health care delivery for refugees, asylum seekers and their families is a complex challenge faced by primary care professionals, the patients themselves and the communication between them. CONCLUSION: This review highlights the innovative interventions in primary care promoting refugee health. Primary care interventions mostly focused on upskilling doctors, with a paucity of research exploring the involvement of other health care members. Further research can explore the involvement of interprofessional team members in providing effective refugee/migrant health. PATIENT OR PUBLIC CONTRIBUTION: Patient and public involvement was explored in terms of interventions designed to improve health care delivery for the humanitarian migrant population, that is, specifically refugees and asylum seekers.

Facilitators and barriers of intersectoral co-operation to promote healthier and more environmentally friendly behaviour: a qualitative evaluation through focus groups for the INHERIT project.

BACKGROUND: Tackling challenges related to health, environmental sustainability and equity requires many sectors to work together. This "intersectoral co-operation" can pose a challenge on its own. Research commonly focuses on one field or is conducted within one region or country. The aim of this study was to investigate facilitators and barriers regarding intersectoral co-operative behaviour as experienced in twelve distinct case studies in ten European countries. The COM-B behavioural system was applied to investigate which capabilities, opportunities and motivational elements appear necessary for co-operative behaviour. METHOD: Twelve focus groups were conducted between October 2018 and March 2019, with a total of 76 participants (policymakers, case study coordinators, governmental institutes and/or non-governmental organisations representing citizens or citizens). Focus groups were organised locally and held in the native language using a common protocol and handbook. One central organisation coordinated the focus groups and analysed the results. Translated data were analysed using deductive thematic analysis, applying previous intersectoral co-operation frameworks and the COM-B behavioural system. RESULTS: Amongst the main facilitators experienced were having highly motivated partners who find common goals and see mutual benefits, with good personal relationships and trust (Motivation). In addition, having supportive environments that provide opportunities to co-operate in terms of support and resources facilitated co-operation (Opportunity), along with motivated co-operation partners who have long-term visions, create good external visibility and who have clear agreements and clarity on roles from early on (Capability). Barriers included not having necessary and/or structural resources or enough time, and negative attitudes from specific stakeholders. CONCLUSIONS: This study on facilitators and barriers to intersectoral co-operation in ten European countries confirms findings of earlier studies. This study also demonstrates that the COM-B model can serve as a relatively simple tool to understand co-operative behaviour in terms of the capability, opportunity and motivation required amongst co-operation partners from different sectors. Results can support co-operators' and policymakers' understanding of necessary elements of intersectoral co-operation. It can help them in developing more successful intersectoral co-operation when dealing with challenges of health, environmental sustainability and equity.

Alternatives to Laboratory Animals: Trends in Replacement and the Three Rs.

The significance of contributions in volumes 11-46 (1983 to 2018) of Alternatives to Laboratory Animals in relation to the reduction, refinement and replacement of animal experimentation in biomedical research and testing is reviewed and discussed by the journal's former editor-in-chief, with particular emphasis on the development and production of the journal itself, FRAME, the European Centre for the Validation of Alternative Methods and other organisations. The role of the journal in promoting the principles of humane research (as spelled out by William Russell and Rex Burch) and highlighting a range of important issues and focus topics is explored. These include: botulinum toxin potency testing; ethical issues; the use of human volunteers, and human cells and tissues; the use of non-human primates (especially chimpanzees) and dogs as laboratory animals; toxicity testing in relation to cosmetics, pharmaceuticals and chemicals; UK and EU politics and legislation; and test validation and invalidation. The review concludes by identifying some of the issues that still need to be discussed and some of the questions that urgently need to be addressed.

Analyses of Transcriptomics Cell Signalling for Pre-Screening Applications in the Integrated Approach for Testing and Assessment of Non-Genotoxic Carcinogens.

With recent rapid advancement of methodological tools, mechanistic understanding of biological processes leading to carcinogenesis is expanding. New approach methodologies such as transcriptomics can inform on non-genotoxic mechanisms of chemical carcinogens and can be developed for regulatory applications. The Organisation for the Economic Cooperation and Development (OECD) expert group developing an Integrated Approach to the Testing and Assessment (IATA) of Non-Genotoxic Carcinogens (NGTxC) is reviewing the possible assays to be integrated therein. In this context, we review the application of transcriptomics approaches suitable for pre-screening gene expression changes associated with phenotypic alterations that underlie the carcinogenic processes for subsequent prioritisation of downstream test methods appropriate to specific key events of non-genotoxic carcinogenesis. Using case studies, we evaluate the potential of gene expression analyses especially in relation to breast cancer, to identify the most relevant approaches that could be utilised as (pre-) screening tools, for example Gene Set Enrichment Analysis (GSEA). We also consider how to address the challenges to integrate gene panels and transcriptomic assays into the IATA, highlighting the pivotal omics markers identified for assay measurement in the IATA key events of inflammation, immune response, mitogenic signalling and cell injury.

Patients' perception on generating medication plans in an interprofessional medication management program: a mixed-methods study.

A medication plan (MP) provides an overview of a patient's entire medication. In the interprofessional medication management program ARMIN (ARzneiMittelINitiative Sachsen-Thueringen), MPs are jointly generated by general practitioners (GPs) and community pharmacists (CPs). We aimed to assess patients' initial acceptance of the service, how they use the printed MP, and whether they perceived a benefit from it. This was evaluated with mixed-methods: a cross sectional written (quantitative) survey followed by semi-structured (qualitative) interviews. The data were analysed separately and compared. Qualitative data were analysed by thematic analysis. For the survey, 103 patients (mean 73 years) were involved. Benefits indicated were: improved communication between GPs and CPs, safer handling of the medication, and increased knowledge on dosages and indications. Ninety-six percent of the patients used their MP, 51% regularly. Regular use was significantly associated with older age, higher number of drugs, and need for assistance with the medication. Ten patients were interviewed. Results from interviews agreed with the results from the survey but revealed some additional aspects (e.g., patients reported an increased feeling of safety). Health-care professionals should consider providing MPs for their patients. This interprofessional cooperation also meets patient's need for safety in health issues.

Identification of potent aldose reductase inhibitors as antidiabetic (Anti-hyperglycemic) agents using QSAR based virtual Screening, molecular Docking, MD simulation and MMGBSA approaches.

The aldose reductase (AR) enzyme is an important target enzyme in the development of therapeutics against hyperglycaemia induced health complications such as retinopathy, etc. In the present study, a quantitative structure activity relationship (QSAR) evaluation of a dataset of 226 reported AR inhibitor (ARi) molecules is performed using a genetic algorithm - multi linear regression (GA-MLR) technique. Multi-criteria decision making (MCDM) analysis furnished two five variables based QSAR models with acceptably high performance reflected in various statistical parameters such as, R2 = 0.79-0.80, Q2 LOO = 0.78-0.79, Q2 LMO = 0.78-0.79. The QSAR model analysis revealed some of the molecular features that play crucial role in deciding inhibitory potency of the molecule against AR such as; hydrophobic Nitrogen within 2 Å of the center of mass of the molecule, non-ring Carbon separated by three and four bonds from hydrogen bond donor atoms, number of sp2 hybridized Oxygen separated by four bonds from sp2 hybridized Carbon atoms, etc. 14 in silico generated hits, using a compound 18 (a most potent ARi from present dataset with pIC50 = 8.04 M) as a template, on QSAR based virtual screening (QSAR-VS) furnished a scaffold 5 with better ARi activity (pIC50 = 8.05 M) than template compound 18. Furthermore, molecular docking of compound 18 (Docking Score = -7.91 kcal/mol) and scaffold 5 (Docking Score = -8.08 kcal/mol) against AR, divulged that they both occupy the specific pocket(s) in AR receptor binding sites through hydrogen bonding and hydrophobic interactions. Molecular dynamic simulation (MDS) and MMGBSA studies right back the docking results by revealing the fact that binding site residues interact with scaffold 5 and compound 18 to produce a stable complex similar to co-crystallized ligand's conformation. The QSAR analysis, molecular docking, and MDS results are all in agreement and complementary. QSAR-VS successfully identified a more potent novel ARi and can be used in the development of therapeutic agents to treat diabetes.

Realistic genetic architecture enables organismal adaptation as predicted under the folk definition of inclusive fitness.

A fundamental task of evolutionary biology is to explain the pervasive impression of organismal design in nature, including traits benefiting kin. Inclusive fitness is considered by many to be a crucial piece in this puzzle, despite ongoing discussion about its scope and limitations. Here, we use individual-based simulations to study what quantity (if any) individual organisms become adapted to maximize when genetic architectures are more or less suitable for the presumed main driver of biological adaptation, namely cumulative multi-locus evolution. As an expository device, we focus on a hypothetical situation called Charlesworth's paradox, in which altruism is seemingly predicted to evolve, yet altruists immediately perish along with their altruistic genes. Our results support a recently proposed re-definition of inclusive fitness, which is concerned with the adaptive design of whole organisms as shaped by multi-locus evolution, rather than with selection for any focal gene. They also illustrate how our conceptual understanding of adaptation at the phenotypic level should inform our choice of genetic assumptions in abstract simplified models.

Getting into sync: Data-driven analyses reveal patterns of neural coupling that distinguish among different social exchanges.

In social interactions, each individual's brain drives an action that, in turn, elicits systematic neural responses in their partner that drive a reaction. Consequently, the brain responses of both interactants become temporally contingent upon one another through the actions they generate, and different interaction dynamics will be underpinned by distinct forms of between-brain coupling. In this study, we investigated this by "performing functional magnetic resonance imaging on two individuals simultaneously (dual-fMRI) while they competed or cooperated with one another in a turn-based or concurrent fashion." To assess whether distinct patterns of neural coupling were associated with these different interactions, we combined two data-driven, model-free analytical techniques: group-independent component analysis and inter-subject correlation. This revealed four distinct patterns of brain responses that were temporally aligned between interactants: one emerged during co-operative exchanges and encompassed brain regions involved in social cognitive processing, such as the temporo-parietal cortex. The other three were associated with competitive exchanges and comprised brain systems implicated in visuo-motor processing and social decision-making, including the cerebellum and anterior cingulate cortex. Interestingly, neural coupling was significantly stronger in concurrent relative to turn-based exchanges. These results demonstrate the utility of data-driven approaches applied to "dual-fMRI" data in elucidating the interpersonal neural processes that give rise to the two-in-one dynamic characterizing social interaction.

Stronger regional biosecurity is essential to prevent hundreds of harmful biological invasions.

Biological invasions often transcend political boundaries, but the capacity of countries to prevent invasions varies. How this variation in biosecurity affects the invasion risks posed to the countries involved is unclear. We aimed to improve the understanding of how the biosecurity of a country influences that of its neighbours. We developed six scenarios that describe biological invasions in regions with contiguous countries. Using data from alien species databases, socio-economic and biodiversity data and species distribution models, we determined where 86 of 100 of the world's worst invasive species are likely to invade and have a negative impact in the future. Information on the capacity of countries to prevent invasions was used to determine whether such invasions could be avoided. For the selected species, we predicted 2,523 discrete invasions, most of which would have significant negative impacts and are unlikely to be prevented. Of these invasions, approximately a third were predicted to spread from the country in which the species first establishes to neighbouring countries where they would cause significant negative impacts. Most of these invasions are unlikely to be prevented as the country of first establishment has a low capacity to prevent invasions or has little incentive to do so as there will be no impact in that country. Regional biosecurity is therefore essential to prevent future harmful biological invasions. In consequence, we propose that the need for increased regional co-operation to combat biological invasions be incorporated in global biodiversity targets.

Evolution of specialized microbial cooperation in dynamic fluids.

Here, we study the evolution of specialization using realistic computer simulations of bacteria that secrete two public goods in a dynamic fluid. Through this first-principles approach, we find physical factors such as diffusion, flow patterns and decay rates are as influential as fitness economics in governing the evolution of community structure, to the extent that when mechanical factors are taken into account, (a) generalist communities can resist becoming specialists despite the invasion fitness of specialization; (b) generalist and specialists can both resist cheaters despite the invasion fitness of free-riding; and (c) multiple community structures can coexist despite the opposing force of competitive exclusion. Our results emphasize the role of spatial assortment and physical forces on niche partitioning and the evolution of diverse community structures.

Structure features of peptide-type SARS-CoV main protease inhibitors: Quantitative structure activity relationship study.

In the present work, an extensive QSAR (Quantitative Structure Activity Relationships) analysis of a series of peptide-type SARS-CoV main protease (MPro) inhibitors following the OECD guidelines has been accomplished. The analysis was aimed to identify salient and concealed structural features that govern the MPro inhibitory activity of peptide-type compounds. The QSAR analysis is based on a dataset of sixty-two peptide-type compounds which resulted in the generation of statistically robust and highly predictive multiple models. All the developed models were validated extensively and satisfy the threshold values for many statistical parameters (for e.g. R2 â€‹= â€‹0.80-0.82, Q2 loo â€‹= â€‹0.74-0.77, Q 2 LMO  â€‹= â€‹0.66-0.67). The developed QSAR models identified number of sp2 hybridized Oxygen atoms within seven bonds from aromatic Carbon atoms, the presence of Carbon and Nitrogen atoms at a topological distance of 3 and other interrelations of atom pairs as important pharmacophoric features. Hence, the present QSAR models have a good balance of Qualitative (Descriptive QSARs) and Quantitative (Predictive QSARs) approaches, therefore useful for future modifications of peptide-type compounds for anti- SARS-CoV activity.

Inclusive early childhood education and care: a longitudinal study into the growth of interprofessional collaboration.

Inclusive early childhood education and care (ECEC) requires interprofessional collaboration between professionals with diverse professional backgrounds. Following developments in human services, there is a growing interest in the role of interprofessional teams in community-based settings for young children. In a three-year longitudinal study, we investigated interprofessional collaboration (IPC) between staff from childcare, education and youth care. At the individual level, a survey was used for the analysis of IPC competences. At the network level, we investigated professional relationships between individuals using social network analysis. Results of a multilevel mixed linear model showed an increase in interdependence and reflection on process of individual staff, followed by the progressive development of perceived team performance. Smaller networks with higher density and professionals' centrality predicted more positive perceptions of inclusive ECEC. We discuss our findings in the context of growing interest in interprofessional teams in ECEC.

Morgagni and Boerhaave in 1719 : The European academic network in the 18th century demonstrated by a letter from Giovanni Battista Morgagni.

The European academic network in 18th century Europe and the interaction between two eminent 18th century scientists is illustrated by a recently recovered letter from 25.IX.1719 by Giovanni Battista Morgagni (1682-1771). It appears from this letter that Morgagni was interested in the latest edition of Boerhaave's Institutiones Medicae exactly in the same year that Boerhaave tried in vain to persuade him to transfer from the University of Padua to the University of Leiden.