Elucidating the effects of microbubble pinch-off dynamics on mammalian cell viability.

In the biotechnology industry, ensuring the health and viability of mammalian cells, especially Chinese Hamster Ovary (CHO) cells, plays a significant role in the successful production of therapeutic agents. These cells are typically cultivated in aerated bioreactors, where they encounter fluid stressors from rapidly deforming bubbles. These stressors can disrupt essential biological processes and potentially lead to cell death. However, the impact of these transient, elevated stressors on cell viability remains elusive. In this study, we first employ /cgqamicrofluidics to expose CHO cells near to bubbles undergoing pinch-off, subsequently collecting and assaying the cells to quantify the reduction in viability. Observing a significant impact, we set out to understand this phenomenon. We leverage computational fluid dynamics and numerical particle tracking to map the stressor field history surrounding a rapidly deforming bubble. Separately, we expose CHO cells to a known stressor level in a flow constriction device, collecting and assaying the cells to quantify the reduction in viability. By integrating the numerical data and results from the flow constriction device experiments, we develop a predictive model for cell viability reduction. We validate this model by comparing its predictions to the earlier microfluidic results, observing good agreement. Our findings provide critical insights into the relationship between bubble-induced fluid stressors and mammalian cell viability, with implications for bioreactor design and cell culture protocol optimization in the biotechnology sector.

Enrichment of Scavenged Particles in Jet Drops Determined by Bubble Size and Particle Position.

When small bubbles rupture in a contaminated water source, the resulting liquid jet breaks up into droplets that can aerosolize solid particulates such as bacteria, viruses, and microplastics. Particles collected on the bubble surface have the potential to become highly concentrated in the jet drops, dramatically increasing their impact. It has been assumed that only particles small enough to fit within a thin microlayer surrounding the bubble can be transported into its influential top jet drop. Yet here, we demonstrate that not only can larger particles be transported into this jet drop, but also that these particles can exceed previous enrichment measurements. Through experiments and simulations, we identify the prerupture location of the liquid that develops into the top jet drop and model how interfacial rearrangement combines with the bubble size, particle size, and the angular distribution of particles on the bubble surface to set the particle enrichment.

Using aeration to probe the flow characteristics associated with long-term marine macrofouling growth and suppression.

It is well-established that hydrodynamics affect the settlement of biofouling organisms. Laboratory studies have demonstrated a connection between larval attachment rates and the prevalence of time windows that satisfy certain instantaneous flow conditions. However, it is unclear whether a link exists between short-term hydrodynamics and long-term macrofouling survival and growth, or if it is applicable at an ecosystem-wide level. This study used single bubble stream aeration in field and laboratory experiments to find critical flow characteristics that correlate to long-term, multi-species fouling prevention. The research was accomplished by combining PIV-derived flow statistics with fouling severity measured over seven weeks in the field. Flows with a decreasing proportion of time windows defined by a flow speed < 15.1 mm s-1 for longer than 0.03 s correlated to decreased biofouling growth and survival. These results provide a potential framework for studying and comparing flow fields that successfully inhibit biofouling growth.

Heat exchange between a bouncing drop and a superhydrophobic substrate.

The ability to enhance or limit heat transfer between a surface and impacting drops is important in applications ranging from industrial spray cooling to the thermal regulation of animals in cold rain. When these surfaces are micro/nanotextured and hydrophobic, or superhydrophobic, an impacting drop can spread and recoil over trapped air pockets so quickly that it can completely bounce off the surface. It is expected that this short contact time limits heat transfer; however, the amount of heat exchanged and precise role of various parameters, such as the drop size, are unknown. Here, we demonstrate that the amount of heat exchanged between a millimeter-sized water drop and a superhydrophobic surface will be orders of magnitude less when the drop bounces than when it sticks. Through a combination of experiments and theory, we show that the heat transfer process on superhydrophobic surfaces is independent of the trapped gas. Instead, we find that, for a given spreading factor, the small fraction of heat transferred is controlled by two dimensionless groupings of physical parameters: one that relates the thermal properties of the drop and bulk substrate and the other that characterizes the relative thermal, inertial, and capillary dynamics of the drop.

Dental caries experience, care index and restorative index in children with learning disabilities and children without learning disabilities: a systematic review and meta-analysis.

Data sources MEDLINE, PubMed, Scopus and Web of Science.Study selection Two reviewers independently selected observational studies which compared caries experience between children with learning disabilities (CLD) and children with no learning disabilities (CNLD). Data extraction and synthesis DMFT/dmft, Care Index (CI) and Restorative Index (RI) data was extracted from each study. Meta analyses were conducted on the overall data and then on the following subgroups: Down's syndrome, autism and mixed learning disabilities. An adapted Newcastle-Ottawa Scale (NOS) was used to assess bias. Results Twenty five comparative cross sectional studies from eighteen countries were included in the review. The standardised mean difference in DMFT between CLD and CNLD was 0.43 (95% CI; 0.91 to 0.05 I² >95%) and for dmft was 0.41 (95% CI; 0.14 to 0.96 I² >95%). The only significant difference revealed by sub group analyses of the three main disability groups was lower caries experience in the permanent dentition of children with Down's syndrome (SMD = 0.73; 95% CI; 1.28 to 0.18). There was a larger difference between mean CI and mean RI for CLD than for CNLD, however, the standard deviations were large and no variance data was provided so meta-analyses could not be completed.Conclusions Overall there was no difference in caries experience between CLD and CNLD. However, sub group analysis showed that children with Down's syndrome had lower levels of caries than CNLD but this may be due to the delayed eruption of the permanent teeth commonly seen with Down's syndrome. There was limited data suggesting that caries in permanent teeth was more commonly treated by extraction in CLD than in CNLD, however, this was based on only eight studies.

Shooting Rubber Bands: Two Self-Similar Retractions for a Stretched Elastic Wedge.

Stretching and shooting rubber bands is a familiar experience for both children and adults, yet the initial dynamics are so quick that they are generally missed. When a cut elastic strip is stretched from its end and suddenly released, the dynamics depend on a balance of stretching and inertia. However, when a rubber band is stretched, a region of high curvature is created and it is unclear how this curvature affects the dynamics. Here, we demonstrate that during the retraction of a circular rubber band, a wavelength develops at the rear which increases in size as time progresses. Through a combination of experiments and modeling, we investigate the speed at which the back of the elastic retracts and observe a self-similar shape that depends on stretching, inertia, and bending. These retraction dynamics illuminate how a rubber band can pass by a thumb when discharged without hitting it.

Reducing the contact time of a bouncing drop.

Surfaces designed so that drops do not adhere to them but instead bounce off have received substantial attention because of their ability to stay dry, self-clean and resist icing. A drop striking a non-wetting surface of this type will spread out to a maximum diameter and then recoil to such an extent that it completely rebounds and leaves the solid material. The amount of time that the drop is in contact with the solid--the 'contact time'--depends on the inertia and capillarity of the drop, internal dissipation and surface-liquid interactions. And because contact time controls the extent to which mass, momentum and energy are exchanged between drop and surface, it is often advantageous to minimize it. The conventional approach has been to minimize surface-liquid interactions that can lead to contact line pinning; but even in the absence of any surface interactions, drop hydrodynamics imposes a minimum contact time that was conventionally assumed to be attained with axisymmetrically spreading and recoiling drops. Here we demonstrate that it is possible to reduce the contact time below this theoretical limit by using superhydrophobic surfaces with a morphology that redistributes the liquid mass and thereby alters the drop hydrodynamics. We show theoretically and experimentally that this approach allows us to reduce the overall contact time between a bouncing drop and a surface below what was previously thought possible.

Capillary induced twisting of Janus cylinders.

At the appropriate length scales, capillary forces exerted by a liquid in contact with a compliant solid can cause the solid's deformation. Capillary forces are also able to align particles with discrete wettabilities - or Janus particles - at liquid interfaces. Their amphiphilic properties enable Janus particles to orient themselves at liquid interfaces such that both of their surfaces are facing their preferred fluid. However, it is unclear how to spontaneously obtain varying degrees of rotational alignment. Here we extend ideas of elasto-capillarity to modulate rotational alignment by connecting amphiphilic Janus cylinders in an antisymmetric configuration. As the Janus cylinders rotate they cause a twisting deformation of rod. We develop both a mathematical model and a physical macroscale setup to relate the angle of twist to the elastic and interfacial properties, which can be used to tune the extent of alignment of Janus particles at air-water interfaces. We additionally extend our analysis to calculate the twist profile on a compliant element with a distributed capillary torque.

Measuring a critical stress for continuous prevention of marine biofouling accumulation with aeration.

When cleaning the hull of a ship, significant shear stresses are needed to remove established biofouling organisms. Given that there exists a link between the amount of time that fouling accumulates and the stress required to remove it, it is not surprising that more frequent grooming requires less shear stress. Yet, it is unclear if there is a minimum stress needed to prevent the growth of macrofouling in the limit of continuous grooming. This manuscript shows that single bubble stream aeration provides continuous grooming and prevents biofouling accumulation in regions where the average wall stress exceeds ~0.01 Pa. This value was found by comparing observations of biofouling growth from field studies with complementary laboratory measurements that probe the associated flow fields. These results suggest that aeration and other continuous grooming systems must exceed a wall stress of 0.01 Pa to prevent macrofouling accumulation.

Capillary Displacement of Viscous Liquids.

When a capillary tube is brought into contact with a wetting liquid, surface tension forces overcome gravity and the liquid spontaneously rises into the tube until an equilibrium height is reached. The early viscous dynamics of the rise typically follow the well-known Lucas-Washburn law, which is independent of gravity and neglects the displaced fluid. Here we explore the early viscous dynamics when the properties of displaced fluid are significant. Using a combination of experiments and theory, we show how the characteristic behavior of the Lucas-Washburn law is modified when the viscosity of the displaced fluid is comparable to or exceeds the wetting fluid. Additionally, we find that the effects of gravity reshape the dynamics of the capillary rise not only in the late viscous regime but also in the early viscous regime.

Daughter bubble cascades produced by folding of ruptured thin films.

Thin liquid films, such as soap bubbles, have been studied extensively for over a century because they are easily formed and mediate a wide range of transport processes in physics, chemistry and engineering. When a bubble on a liquid-gas or solid-gas interface (referred to herein as an interfacial bubble) ruptures, the general expectation is that the bubble vanishes. More precisely, the ruptured thin film is expected to retract rapidly until it becomes part of the interface, an event that typically occurs within milliseconds. The assumption that ruptured bubbles vanish is central to theories on foam evolution and relevant to health and climate because bubble rupture is a source for aerosol droplets. Here we show that for a large range of fluid parameters, interfacial bubbles can create numerous small bubbles when they rupture, rather than vanishing. We demonstrate, both experimentally and numerically, that the curved film of the ruptured bubble can fold and entrap air as it retracts. The resulting toroidal geometry of the trapped air is unstable, leading to the creation of a ring of smaller bubbles. The higher pressure associated with the higher curvature of the smaller bubbles increases the absorption of gas into the liquid, and increases the efficiency of rupture-induced aerosol dispersal.

Experiences of dental behaviour support techniques: A qualitative systematic review.

BACKGROUND: Little is known about patients' or carers' reported experiences of dental care provided using dental behaviour support (DBS) techniques. Qualitative literature can provide unique insight into these experiences. AIM: To explore and synthesize qualitative literature related to patient experience of dental behaviour support. METHODS: A PROSPERO-registered systematic review of qualitative articles was undertaken. Studies were identified through MEDLINE, Embase and PsycINFO. Abstracts were screened by two reviewers and data were extracted to summarize the qualitative findings included within them. A thematic summary approach was used to synthesize the qualitative data identified. RESULTS: Twenty-three studies were included. Studies primarily explored experiences of dental care of children by speaking to their parents (n = 16), particularly regarding paediatric dental general anaesthesia (DGA) (n = 8). Studies of adults' experiences of DBS (n = 7) covered a range of techniques. Nine studies explored broader dental care experiences and did not study specific DBS approaches. A thematic synthesis identified five themes applicable across the studies identified: Trust and the therapeutic alliance supporting effective care delivery; considered information sharing often alleviated anticipatory anxiety; control and autonomy-reduced anxieties; variations in the perceived treatment successes and failures of DBS techniques; and DBS techniques produced longer positive and negative impacts on patients beyond direct care provision. CONCLUSION: Qualitative research has been under-utilized in research on DBS techniques. Care experiences of most DBS techniques outside of paediatric DGA are poorly understood. Building trust with patients and enabling autonomy appear to support positive patient-reported experiences of care.

A scoping review of interventions and outcome measures in trials of dental behavior support.

BACKGROUND: Dental behavior support (DBS) describes all techniques used by dental professionals to ensure that dental care is safe, effective, and acceptable. There is a need to standardize outcome measures across DBS techniques to reduce heterogeneity, limit selective reporting, promote consistency, and optimize outcomes across DBS research. A comprehensive review of existing measures is a prerequisite to understanding potential outcomes related to the area of interest. AIM: This review had three aims: first, to identify the outcome measures (OMs) reported in trials of dental behavior support; second, to categorize the component DBS techniques reported within interventions according to emerging agreed terminology; and, third, to map outcome measures to intervention type. METHODS: A scoping review of trials evaluating DBS techniques was undertaken from 2012 to 2022. The review was prospectively registered. Studies were identified through Medline, Embase, and PsycINFO. Study abstracts were screened by two reviewers. Data were extracted by single selector. Outcome measures were sorted according to measurement domains (physiological, behavioral, psychological, and treatment). Responses were assimilated and summed to produce a refined list of distinguishable outcome measures. Intervention types were categorized according to accepted descriptors. Frequencies were presented; associations between outcome domain and DBS type were also reported (Chi-square test of independence). RESULTS: A total of 344 trials were included in the review from an initial 14,793 titles / title and abstracts screened. Most involved children (n = 215), most were from India (n = 104), involving basic dental care (n = 117). The median number of outcome measures per trial was four (range = 1-12); 1,317 individual outcomes were reported, categorized as: psychological (n = 501, 38.0%); physiological (n = 491, 37.3%), behavioral (n = 123, 9.3%) or, treatment-related (n = 202, 15.3%). DBS interventions were split between 239 (45.7%) pharmacological and 283 (54.1%) non-pharmacological; 96.6% of interventions mapped to accepted descriptors. A significant relationship was noted between the type of intervention and the outcome domain reported. CONCLUSION: The findings demonstrate massive variation in outcome measures of DBS interventions that likely lead to unnecessary heterogeneity, selective reporting, and questionable relevance in the literature. A large range of DBS interventions were mapped according to BeSiDe list. There is a need for consensus on a core outcome set across the spectrum of DBS techniques.

Raising the barcode: improving medication safety behaviours through a behavioural science-informed feedback intervention. A quality improvement project and difference-in-difference analysis.

Barcode medication administration (BCMA) technology can improve patient safety by using scanning technology to ensure the right drug and dose are given to the right patient. Implementation can be challenging, requiring adoption of different workflows by nursing staff. In one London National Health Service trust scanning rates were lower than desired at around 0-20% of doses per ward. Our objective was to encourage patient safety behaviours in the form of medication scanning through implementation of a feedback intervention. This was informed by behavioural science, codesigned with nurses and informed by known barriers to use. Five wards were selected to trial the intervention over an 18-week period beginning August 2021. The remaining 14 hospital wards acted as controls. Intervention wards had varying uptake of BCMA at baseline and represented a range of specialties. A bespoke feedback intervention comprising three behavioural science constructs (gamification, the messenger effect and framing) was delivered to each intervention ward each week. A linear difference-in-difference analysis was used to evaluate the impact of our intervention on scan rates, both for the overall 18-week period and at two weekly intervals within this timeframe. We identified a 23.1 percentage point increase in medication scan rates (from an average baseline of 15.0% to 38.1%) on the intervention wards compared with control (p<0.001) following implementation of the intervention. Feedback had most impact in the first 6 weeks, with an initial percentage point increase of 26.3 (p<0.001), which subsequently plateaued. Neither clinical specialty nor number of beds on each ward were significant factors in our models. Our study demonstrated that a feedback intervention, codesigned with end users and incorporating behavioural science constructs, can lead to a significant increase in the adoption of BCMA scanning.

Insights from a single centre implementation of a digitally-enabled atrial fibrillation virtual ward.

Atrial fibrillation (AF) is the most prevalent cardiac arrhythmia and poses a significant public health burden. Virtual wards are a novel approach utilising digital solutions to provide hospital-level care remotely; their rollout has become a key priority for the UK National Health Service to expand acute care capacity. We devised and implemented a digitally-enabled AF virtual ward to monitor patients being established onto medical therapy following an AF diagnosis or an AF-related hospitalisation. Patients were onboarded either as outpatients to avoid admission or on discharge after an acute AF hospitalisation. Remote monitoring was undertaken using a clinically validated photoplethysmography-based smartphone app. Over a 1-2 week period, patients performed twice daily measurements of heart rate and rhythm and provided corresponding symptoms. A traffic light system guided frequency of telephone assessments by specialist practitioners. Red flag symptoms or abnormal heart rate parameters prompted an urgent care escalation. We report our experience of the first 73 patients onboarded to the AF virtual ward from October 2022 to June 2023 (mean age 65 years, median 68 years, IQR range 27-101 years; 33 females). Thirty-nine (53%) patients had red flag features requiring care escalation, of whom 9 (23%) were advised to attend ED (emergency department) for urgent assessment, 10 (26%) attended for expedited review and 14 (36%) required medication changes. By 3 months post-monitoring, only 3 patients (4%) had re-attended ED with an arrhythmia-related presentation. Virtual ward patients had an average 3-day shorter inpatient stay (mean duration 4 days) compared with AF patients hospitalised prior to virtual ward implementation (mean duration 7 days). Overall, 22 arrhythmia-related readmissions were prevented via the virtual ward model. In this study, we present a novel implementation of a digitally-enabled virtual ward for the acute management of patients with newly diagnosed or poorly controlled AF. Our pilot data indicate that this model is feasible and is potentially cost-effective. Further longitudinal study is needed to definitively evaluate long-term clinical utility and safety.

Discovery and Characterization of a Bicyclic Peptide (Bicycle) Binder to Thymic Stromal Lymphopoietin.

Thymic stromal lymphopoietin (TSLP) is an epithelial-derived pro-inflammatory cytokine involved in the development of asthma and other atopic diseases. We used Bicycle Therapeutics' proprietary phage display platform to identify bicyclic peptides (Bicycles) with high affinity for TSLP, a target that is difficult to drug with conventional small molecules due to the extended protein-protein interactions it forms with both receptors. The hit series was shown to bind to TSLP in a hotspot, that is also used by IL-7Rα. Guided by the first X-ray crystal structure of a small peptide binding to TSLP and the identification of key metabolites, we were able to improve the proteolytic stability of this series in lung S9 fractions without sacrificing binding affinity. This resulted in the potent Bicycle 46 with nanomolar affinity to TSLP (KD = 13 nM), low plasma clearance of 6.4 mL/min/kg, and an effective half-life of 46 min after intravenous dosing to rats.

Predicting metabolic clearance for drugs that are actively transported into hepatocytes: incubational binding as a consequence of in vitro hepatocyte concentration is a key factor.

Incubational binding or the fraction of drug unbound in an in vitro incubation, fuinc, is an important parameter to predict or measure in the pursuit of accurate clearance predictions from in vitro data. Here we describe a method for fuinc determination directly in the hepatocyte intrinsic clearance (CLint) assay with emphasis on compounds that are actively transported into hepatocytes, hypothesizing that for such compounds the typical protocol of 1 million hepatocytes/ml systematically underestimates the maximum attainable unbound intracellular drug concentration. Using the transporter substrate atorvastatin as a test compound, incubations were performed and a mathematical model applied to describe metabolism, distribution, and binding at different hepatocyte concentrations. From these investigations it was evident that, since binding is more extensive intracellularly than in the medium, increased partitioning into the cellular volume, due to active uptake, increases the total amount of atorvastatin bound in the incubation. Consequently, a significant lowering of the hepatocyte concentration impacts the free drug concentration in the incubation and increases the observed rate of metabolism and therefore observed CLint (that is, when viewed from the media drug concentration). The applicability of the findings was tested for a series of 11 actively transported zwitterions for which standard rat hepatocyte metabolic CLint data (1 million cells/ml incubation) poorly predicted in vivo clearance (average fold error of 5.4). Using metabolic CLint determined at a lower hepatocyte concentration (0.125 million cells/ml) considerably improved clearance predictions (average fold error of 2.3).

A novel matrix for the short-term storage of cells: utility in drug metabolism and drug transporter studies with rat, dog and human hepatocytes.

1. The SureTran matrix is a novel method facilitating short-term maintenance of fresh primary hepatocyte cellular function and offers the potential use of primary cells "as fresh" for several days post isolation. In the study presented, the maintenance of several key phase I and II drug metabolizing enzyme and drug transporter activities is demonstrated with rat and dog hepatocytes preserved for up to 7 days after cell isolation. 2. Intrinsic clearance values were determined for 60 new chemical entities using rat hepatocytes freshly isolated at AstraZeneca and rat hepatocytes prepared at the facilities of Abcellute Ltd (SureTran purveyors), stored and incubated 24 hours after isolation. A very good correspondence in the intrinsic clearance values underlines the utility of the cell maintenance matrix. 3. For human hepatocytes many of the enzyme activities assayed were well maintained for 7 days of storage but some declined to below 50% of initial values between day 4 and 7 of storage. Human OATP1B1 activity was only determined with one batch and declined to 51% of the initial test value by day 4 and further down to 35% by day 7.

Universal non-monotonic drainage in large bare viscous bubbles.

Bubbles will rest at the surface of a liquid bath until their spherical cap drains sufficiently to spontaneously rupture. For large film caps, the memory of initial conditions is believed to be erased due to a visco-gravitational flow, whose velocity increases from the top of the bubble to its base. Consequently, the film thickness has been calculated to be relatively uniform as it thins, regardless of whether the drainage is regulated by shear or elongation. Here, we demonstrate that for large bare bubbles, the film thickness is highly nonuniform throughout drainage, spanning orders of magnitude from top to base. We link the film thickness profile to a universal non-monotonic drainage flow that depends on the bubble thinning rate. These results highlight an unexpected coupling between drainage velocity and bubble thickness profiles and provide critical insight needed to understand the retraction and breakup dynamics of these bubbles upon rupture.