Shape-induced force fields in optical trapping

Advances in optical tweezers, coupled with the proliferation of two-photon polymerization systems, mean that it is now becoming routine to fabricate and trap non-spherical particles. The shaping of both light beams and particles allows fine control over the flow of momentum from the optical to mechanical regimes. However, understanding and predicting the behaviour of such systems is highly complex in comparison with the traditional optically trapped microsphere. In this Article, we present a conceptually new and simple approach based on the nature of the optical force density. We illustrate the method through the design and fabrication of a shaped particle capable of acting as a passive force clamp, and we demonstrate its use as an optically trapped probe for imaging surface topography. Further applications of the design rules highlighted here may lead to new sensors for probing biomolecule mechanics, as well as to the development of optically actuated micromachines

Transcriptomic Profiling Reveals Discrete Poststroke Dementia Neuronal and Gliovascular Signatures

\ua9 2022, The Author(s). Poststroke dementia (PSD) is associated with pathology in frontal brain regions, in particular dorsolateral prefrontal cortex (DLPFC) neurons and white matter, remote from the infarct. We hypothesised that PSD results from progressive DLPFC neuronal damage, associated with frontal white matter gliovascular unit (GVU) alterations. We investigated the transcriptomic profile of the neurons and white matter GVU cells previously implicated in pathology. Laser-capture microdissected neurons, astrocytes and endothelial cells were obtained from the Cognitive Function After Stroke cohort of control, PSD and poststroke non-dementia (PSND) human subjects. Gene expression was assessed using microarrays and pathway analysis to compare changes in PSD with controls and PSND. Neuronal findings were validated using NanoString technology and compared with those in the bilateral common carotid artery stenosis (BCAS) mouse model. Comparing changes in PSD compared to controls with changes in PSND compared to controls identified transcriptomic changes associated specifically with dementia. DLPFC neurons showed defects in energy production (tricarboxylic acid (TCA) cycle, adenosine triphosphate (ATP) binding and mitochondria), signalling and communication (MAPK signalling, Toll-like receptor signalling, endocytosis). Similar changes were identified in neurons isolated from BCAS mice. Neuronal findings accompanied by altered astrocyte communication and endothelium immune changes in the frontal white matter, suggesting GVU dysfunction. We propose a pathogenic model in PSD whereby neuronal changes are associated with frontal white matter GVU dysfunction leading to astrocyte failure in supporting neuronal circuits resulting in delayed cognitive decline associated with PSD. Therefore, targeting these processes could potentially ameliorate the dementia seen in PSD

REVIEW OF THE MOVIE DON JUAN DE MARCO

The Kaplan-Meier (K-M) method is currently the preferred approach to derive an efficacy estimate from anti-malarial trial data. In this approach event times are assumed to be continuous and estimates are generated on the assumption that there is only one cause of failure. In reality, failures are captured at pre-scheduled time points and patients can fail treatment due to a variety of causes other than the primary endpoint, commonly termed competing risk events. Ignoring these underlying assumptions can potentially distort the derived efficacy estimates and result in misleading conclusions. This review details the evolution of statistical methods used to derive anti-malarial efficacy for uncomplicated Plasmodium falciparum malaria and assesses the limitations of the current practices. Alternative approaches are explored and their implementation is discussed using example data from a large multi-site study

Projected effects on salt purchases following implementation of a national salt reduction policy in South Africa.

OBJECTIVE: To assess the contribution of different food groups to total salt purchases and to evaluate the estimated reduction in salt purchases if mandatory maximum salt limits in South African legislation were being complied with. DESIGN: This study conducted a cross-sectional analysis of purchasing data from Discovery Vitality members. Data were linked to the South African FoodSwitch database to determine the salt content of each food product purchased. Food category and total annual salt purchases were determined by summing salt content (kg) per each unit purchased across a whole year. Reductions in annual salt purchases were estimated by applying legislated maximum limits to product salt content. SETTING: South Africa. PARTICIPANTS: The study utilised purchasing data from 344 161 households, members of Discovery Vitality, collected for a whole year between January and December 2018. RESULTS: Vitality members purchased R12·8 billion worth of food products in 2018, representing 9562 products from which 264 583 kg of salt was purchased. The main contributors to salt purchases were bread and bakery products (23·3 %); meat and meat products (19 %); dairy (12·2 %); sauces, dressings, spreads and dips (11·8 %); and convenience foods (8·7 %). The projected total quantity of salt that would be purchased after implementation of the salt legislation was 250 346 kg, a reduction of 5·4 % from 2018 levels. CONCLUSIONS: A projected reduction in salt purchases of 5·4 % from 2018 levels suggests that meeting the mandatory maximum salt limits in South Africa will make a meaningful contribution to reducing salt purchases

Structure and Function of the α-Hydroxylation Bimodule of the Mupirocin Polyketide Synthase

\ua9 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.Mupirocin is a clinically important antibiotic produced by a trans-AT Type I polyketide synthase (PKS) in Pseudomonas fluorescens. The major bioactive metabolite, pseudomonic acid A (PA−A), is assembled on a tetrasubstituted tetrahydropyran (THP) core incorporating a 6-hydroxy group proposed to be introduced by α-hydroxylation of the thioester of the acyl carrier protein (ACP) bound polyketide chain. Herein, we describe an in vitro approach combining purified enzyme components, chemical synthesis, isotopic labelling, mass spectrometry and NMR in conjunction with in vivo studies leading to the first characterisation of the α-hydroxylation bimodule of the mupirocin biosynthetic pathway. These studies reveal the precise timing of hydroxylation by MupA, substrate specificity and the ACP dependency of the enzyme components that comprise this α-hydroxylation bimodule. Furthermore, using purified enzyme, it is shown that the MmpA KS0 shows relaxed substrate specificity, suggesting precise spatiotemporal control of in trans MupA recruitment in the context of the PKS. Finally, the detection of multiple intermodular MupA/ACP interactions suggests these bimodules may integrate MupA into their assembly

Population pharmacokinetics of intravenous artesunate: a pooled analysis of individual data from patients with severe malaria.

There are ~660,000 deaths from severe malaria each year. Intravenous artesunate (i.v. ARS) is the first-line treatment in adults and children. To optimize the dosing regimen of i.v. ARS, the largest pooled population pharmacokinetic study to date of the active metabolite dihydroartemisinin (DHA) was performed. The pooled dataset consisted of 71 adults and 195 children with severe malaria, with a mixture of sparse and rich sampling within the first 12 h after drug administration. A one-compartment model described the population pharmacokinetics of DHA adequately. Body weight had the greatest impact on DHA pharmacokinetics, resulting in lower DHA exposure for smaller children (6-10 kg) than adults. Post hoc estimates of DHA exposure were not significantly associated with parasitological outcomes. Comparable DHA exposure in smaller children and adults after i.v. ARS was achieved under a dose modification for intramuscular ARS proposed in a separate analysis of children

A telephone survey of cancer awareness among frontline staff: informing training needs

Background: Studies have shown limited awareness about cancer risk factors among hospital-based staff. Less is known about general cancer awareness among community frontline National Health Service and social care staff. Methods: A cross-sectional computer-assisted telephone survey of 4664 frontline community-based health and social care staff in North West England. Results: A total of 671 out of 4664 (14.4%) potentially eligible subjects agreed to take part. Over 92% of staff recognised most warning signs, except an unexplained pain (88.8%, n=596), cough or hoarseness (86.9%, n=583) and a sore that does not heal (77.3%, n=519). The bowel cancer-screening programme was recognised by 61.8% (n=415) of staff. Most staff agreed that smoking and passive smoking ‘increased the chance of getting cancer.’ Fewer agreed about getting sunburnt more than once as a child (78.0%, n=523), being overweight (73.5%, n=493), drinking more than one unit of alcohol per day (50.2%, n=337) or doing less than 30 min of moderate physical exercise five times a week (41.1%, n=276). Conclusion: Cancer awareness is generally good among frontline staff, but important gaps exist, which might be improved by targeted education and training and through developing clearer messages about cancer risk factors

Development and Evolution of a Model Interprofessional Education Program in Parkinson’s disease: A Ten-year Experience

OBJECTIVE This paper describes development, evolution and learner reactions in a model interprofessional education program for medical, nursing, physician assistant, occupational therapy, physical therapy, music therapy, social work and speech-language pathology practitioners. Sponsored by the National Parkinson Foundation (NPF) (currently Parkinson’s Foundation), Allied Team Training for Parkinson (ATTP) is a U.S.-based multi-day interprofessional education program in best practices for integrated, interprofessional team-based Parkinson’s disease (PD) care. NPF sponsored 26 ATTP trainings from 2003 to 2013. METHODS This mixed methods evaluation uses case study document review and observation to outline ATTP curriculum development, evolution, and implementation challenges. Learner-perceived effectiveness ratings, knowledge change, pre-post ratings on the Team Skills Scale, confidence in working with people with PD and caregivers, and trainee-reported practice changes at 6-month follow-up were collected. RESULTS Qualitative results identified multiple factors in building an effective interprofessional education program, including interprofessional team practice opportunities through case-based learning, engaging care networks and continuous feedback loops for program improvement. Quantitative results showed that trainees across professions, geographic regions and work settings rated the overall program and curriculum effectiveness, amount of new knowledge and knowledge change very highly. ATTP resulted in significant post-training improvement in team skills, confidence in working with PD, and post-training self-reported practice changes. CONCLUSION Findings suggest that ATTP is an effective interprofessional education program that could be replicated or adapted to other settings and neurodegenerative or chronic illnesses. The model of combining interprofessional team training with disease-specific curriculum content appears to be an effective “next practice” in continuing professional development