The influence of hydrodynamic environment on the nucleation mechanism of a chiral crystallization

This thesis presents the results and discussions of an investigation into nucleation mechanisms in a cooling crystallization of sodium chlorate in both a stirred tank crystallizer (STC) and an oscillatory baffled crystallizer (OBC) under various crystallizer configurations and operational conditions. The key question to be addressed was why nucleation took place in an OBC without seeds, while seeds were essential in an STC for the same chemistry and at the same process conditions. Various hypotheses have been initiated, tested and verified in both primary and secondary nucleation experiments, and new scientific insights and better understanding have been achieved on the parameters that have influenced the nucleation mechanisms and some explanations as to why seeds were not necessary in the OBC are put forward. For the seeded nucleation, the fluid dynamic environment and mixing mechanics were responsible for dictating the nature of the nucleation mechanism. The unique scraping action of the baffles against the crystallizer wall in the OBC enabled a different enantiomorphism of the product crystals compared to the seed crystal. Removing such a motion in the OBC provided product crystals similar to that seen in the STC. The degree and the means of mixing near the single seed crystal also affected the crystal handedness. For the primary nucleation experiments, it was found that the handedness of the product crystals in the STC was strongly orientated towards a single enantiomorph, while both enantiomorphs were formed in the OBC. The results were suggestive of a lower free energy barrier in the OBC, in turn resulting in primary nucleation being favoured in the OBC as opposed to rapid secondary nucleation being dominant in the STC

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie

Challenge Demcare: management of challenging behaviour in dementia at home and in care homes:Development, evaluation and implementation of an online individualised intervention for care homes; and a cohort study of specialist community mental health care for families

Background: Dementia with challenging behaviour (CB) causes significant distress for caregivers and the person with dementia. It is associated with breakdown of care at home and disruption in care homes. Challenge Demcare aimed to assist care home staff and mental health practitioners who support families at home to respond effectively to CB. Objectives: To study the management of CB in care homes (ResCare) and in family care (FamCare). Following a conceptual overview, two systematic reviews and scrutiny of clinical guidelines, we (1) developed and tested a computerised intervention; (2) conducted a cluster randomised trial (CRT) of the intervention for dementia with CB in care homes; (3) conducted a process evaluation of implementation of the intervention; and (4) conducted a longitudinal observational cohort study of the management of people with dementia with CB living at home, and their carers. Review methods: Cochrane review of randomised controlled trials; systematic meta-ethnographic review of quantitative and qualitative studies. Design: ResCare – survey, CRT, process evaluation and stakeholder consultations. FamCare – survey, longitudinal cohort study, participatory development design process and stakeholder consultations. Comparative examination of baseline levels of CB in the ResCare trial and the FamCare study participants. Settings: ResCare – 63 care homes in Yorkshire. FamCare – 33 community mental health teams for older people (CMHTsOP) in seven NHS organisations across England. Participants: ResCare – 2386 residents and 861 staff screened for eligibility; 555 residents with dementia and CB; 277 ‘other’ residents; 632 care staff; and 92 staff champions. FamCare – every new referral (n = 5360) reviewed for eligibility; 157 patients with dementia and CB, with their carer; and 26 mental health practitioners. Stakeholder consultations – initial workshops with 83 practitioners and managers from participating organisations; and 70 additional stakeholders using eight group discussions and nine individual interviews. Intervention: An online application for case-specific action plans to reduce CB in dementia, consisting of e-learning and bespoke decision support care home and family care e-tools. Main outcome measures: ResCare – survey with the Challenging Behaviour Scale; measurement of CB with the Neuropsychiatric Inventory (NPI) and medications taken from prescriptions; implementation with thematic views from participants and stakeholders. FamCare – case identification from all referrals to CMHTsOP; measurement of CB with the Revised Memory and Behaviour Problems Checklist and NPI; medications taken from prescriptions; and thematic views from stakeholders. Costs of care calculated for both settings. Comparison of the ResCare trial and FamCare study participants used the NPI, Clinical Dementia Rating and prescribed medications. Results: ResCare – training with group discussion and decision support for individualised interventions did not change practice enough to have an impact on CB in dementia. Worksite e-learning opportunities were not readily taken up by care home staff. Smaller homes with a less hierarchical management appear more ready than others to engage in innovation. FamCare – home-dwelling people with dementia and CB are referred to specialist NHS services, but treatment over 6 months, averaging nine contacts per family, had no overall impact on CB. Over 60% of people with CB had mild dementia. Families bear the majority of the care costs of dementia with CB. A care gap in the delivery of post-diagnostic help for families supporting relatives with dementia and significant CB at home has emerged. Higher levels of CB were recorded in family settings; and prescribing practices were suboptimal in both care home and family settings. Limitations: Functionality of the software was unreliable, resulting in delays. This compromised the feasibility studies and undermined delivery of the intervention in care homes. A planned FamCare CRT could not proceed because of insufficient referrals. Conclusions: A Cochrane review of individualised functional analysis-based interventions suggests that these show promise, although delivery requires a trained dementia care workforce. Like many staff training interventions, our interactive e-learning course was well received by staff when delivered in groups with facilitated discussion. Our e-learning and decision support e-tool intervention in care homes, in its current form, without ongoing review of implementation of recommended action plans, is not effective at reducing CB when compared with usual care. This may also be true for staff training in general. A shift in priorities from early diagnosis to early recognition of dementia with clinically significant CB could bridge the emerging gap and inequities of care to families. Formalised service improvements in the NHS, to co-ordinate such interventions, may stimulate better opportunities for practice models and pathways. Separate services for care homes and family care may enhance the efficiency of delivery and the quality of research on implementation into routine care. Future work: There is scope for extending functional analysis-based interventions with communication and interaction training for carers. Our clinical workbooks, video material of real-life episodes of CB and process evaluation tool resources require further testing. There is an urgent need for evaluation of interventions for home-dwelling people with dementia with clinically significant CB, delivered by trained dementia practitioners. Realist evaluation designs may illuminate how the intervention might work, and for whom, within varying service contexts

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570