Application of pulsed electric field technology to skin engineering.

Tissue engineering encompasses a range of techniques that direct the growth of cells into a living tissue construct for regenerative medicine applications, disease models, drug discovery, and safety testing. These techniques have been implemented to alleviate the clinical burdens of impaired healing of skin, bone, and other tissues. Construct development requires the integration of tissue-specific cells and/or an extracellular matrix-mimicking biomaterial for structural support. Production of such constructs is generally expensive and environmentally costly, thus eco-sustainable approaches should be explored. Pulsed electric field (PEF) technology is a nonthermal physical processing method commonly used in food production and biomedical applications. In this review, the key principles of PEF and the application of PEF technology for skin engineering will be discussed, with an emphasis on how PEF can be applied to skin cells to modify their behaviour, and to biomaterials to assist in their isolation or sterilisation, or to modify their physical properties. The findings indicate that the success of PEF in tissue engineering will be reliant on systematic evaluation of key parameters, such as electric field strength, and their impact on different skin cell and biomaterial types. Linking tangible input parameters to biological responses critical to healing will assist with the development of PEF as a sustainable tool for skin repair and other tissue engineering applications.

Unravelling the origin of isoprene in the human body-a forty year Odyssey.

In the breath research community's search for volatile organic compounds that can act as non-invasive biomarkers for various diseases, hundreds of endogenous volatiles have been discovered. Whilst these systemic chemicals result from normal and abnormal metabolic activities or pathological disorders, to date very few are of any use for the development of clinical breath tests that could be used for disease diagnosis or to monitor therapeutic treatments. The reasons for this lack of application are manifold and complex, and these complications either limit or ultimately inhibit the analytical application of endogenous volatiles for use in the medical sciences. One such complication is a lack of knowledge on the biological origins of the endogenous volatiles. A major exception to this is isoprene. Since 1984, i.e. for 40 years, it has been generally accepted that the pathway to the production of human isoprene, and hence the origin of isoprene in exhaled breath, is through cholesterol biosynthesis via the mevalonate (MVA) pathway within the liver. However, various studies between 2001 and 2012 provide compelling evidence that human isoprene is produced in skeletal muscle tissue. A recent multi-omic investigation of genes and metabolites has revealed that this proposal is correct by showing that human isoprene predominantly results from muscular lipolytic cholesterol metabolism. Despite the overwhelming proof for a muscular pathway to isoprene production in the human body, breath research papers still reference the hepatic MVA pathway. The major aim of this perspective is to review the evidence that leads to a correct interpretation for the origins of human isoprene, so that the major pathway to human isoprene production is understood and appropriately disseminated. This is important, because an accurate attribution to the endogenous origins of isoprene is needed if exhaled isoprene levels are to be correctly interpreted and for assessing isoprene as a clinical biomarker.

Art therapy masks reflect emotional changes in military personnel with PTSS.

Among disabling post-traumatic stress symptoms (PTSS) are irritability, aggressive behavior, distressing memories and general impaired cognition and negative mood. Art therapy interventions, including mask-making, can potentially alleviate these symptoms. We tested the hypothesis that art conveys emotions and predicted that blinded viewers would be able to perceive changes in theoretically derived emotional profiles expressed in art made by military personnel with PTSS from the onset to the end of therapy. Five service members and veterans exhibiting PTSS were enrolled in an 8-session art therapy protocol, during which they artistically transformed papier-mâché masks at the beginning and end of the protocol. We found that blinded viewers without knowledge of the masks' creation stage (onset or end of therapy) read initial masks as conveying more negative emotions (e.g., angry, upset, and challenged) and later masks as conveying more positive emotions (calm and pleasure). Based on the assessments from the blinded evaluators, we infer the emotional transition experienced by the participants was expressed in the masks. In an exploratory arm of the study, we also found that viewers were better able to empathize with the negative emotions experienced by participants with PTSS when asked to explicitly take their perspective.

Avialan-like brain morphology in Sinovenator (Troodontidae, Theropoda).

Many modifications to the skull and brain anatomy occurred along the lineage encompassing non-avialan theropod dinosaurs and modern birds. Anatomical changes to the endocranium include an enlarged endocranial cavity, relatively larger optic lobes that imply elevated visual acuity, and proportionately smaller olfactory bulbs that suggest reduced olfactory capacity. Here, we use micro-computed tomographic (µCT) imaging to reconstruct the endocranium and its neuroanatomical features from an exceptionally well-preserved skull of Sinovenator changii (Troodontidae, Theropoda). While its overall morphology resembles the typical endocranium of other troodontids, Sinovenator also exhibits unique endocranial features that are similar to other paravian taxa and non-maniraptoran theropods. Landmark-based geometric morphometric analysis on endocranial shape of non-avialan and avialan dinosaurs points to the overall brain morphology of Sinovenator most closely resembling that of Archaeopteryx, thus indicating acquisition of avialan-grade brain morphology in troodontids and wide existence of such architecture in Maniraptora.

Sleep in people with and without intellectual disabilities: a systematic review and meta-analysis.

BACKGROUND: Sleep problems are regularly reported in people with intellectual disabilities. Recent years have seen a substantial increase in studies comparing sleep in people with intellectual disabilities to control participants, with an increase in the use of validated, objective measures. Emerging patterns of differences in sleep time and sleep quality warrant pooled investigation. METHODS: A systematic search was conducted across three databases (Ovid Embase, PsycInfo and Medline) and returned all papers comparing sleep in people with intellectual disabilities to a control group, published since the last meta-analysis on the topic. A quality framework was employed to rate the risk of bias across studies. Separate meta-analyses of sleep duration and sleep quality were conducted. Subgrouping compared findings for those studies with participants with genetic syndromes or neurodevelopmental conditions and those with heterogeneous intellectual disability. RESULTS: Thirteen new papers were identified and combined with those from the previous meta-analysis to provide 34 papers in total. Quality of studies was generally rated highly, though sampling provided risk of bias and adaptive functioning was rarely measured. People with intellectual disability associated with genetic syndromes or neurodevelopmental conditions sleep for shorter time periods (standardised mean difference = .26) and experience worse sleep quality (standardised mean difference = .68) than their peers. People with intellectual disability of heterogeneous origin show no difference in sleep time but have poorer sleep quality. There was some evidence that age moderated these effects. CONCLUSIONS: People with intellectual disability have poorer sleep than those without. Subtle patterns suggest that aetiology of intellectual disability moderates the topography of these difficulties, with further work needed to differentiate common and distinct mechanisms across groups.

Flexible tape-drive target system for secondary high-intensity laser-driven sources.

We present the development of a flexible tape-drive target system to generate and control secondary high-intensity laser-plasma sources. Its adjustable design permits the generation of relativistic MeV particles and x rays at high-intensity (i.e., ≥1 × 1018 W cm-2) laser facilities, at high repetition rates (>1 Hz). The compact and robust structure shows good mechanical stability and a high target placement accuracy (<4 µm RMS). Its compact and flexible design allows for mounting in both the horizontal and vertical planes, which makes it practical for use in cluttered laser-plasma experimental setups. The design permits ∼170° of access on the laser-driver side and 120° of diagnostic access at the rear. A range of adapted apertures have been designed and tested to be easily implemented to the targetry system. The design and performance testing of the tape-drive system in the context of two experiments performed at the COMET laser facility at the Lawrence Livermore National Laboratory and at the Advanced Lasers and Extreme Photonics (ALEPH) facility at Colorado State University are discussed. Experimental data showing that the designed prototype is also able to both generate and focus high-intensity laser-driven protons at high repetition rates are also presented.

Emergency Department Visit Rates by Selected Characteristics: United States, 2021.

In 2021, 140 million emergency department (ED) visits occurred in the United States (1). During that year, about 4% of children had two or more ED visits in the past 12 months, and 18% of adults had visited the ED in the past 12 months (2,3). This report presents characteristics of ED visits by age group, sex, race and ethnicity, insurance, and mentions of COVID-19, using data from the 2021 National Hospital Ambulatory Medical Care Survey (NHAMCS) (4).

Energetic Electron Precipitation Driven by Electromagnetic Ion Cyclotron Waves from ELFIN's Low Altitude Perspective.

We review comprehensive observations of electromagnetic ion cyclotron (EMIC) wave-driven energetic electron precipitation using data collected by the energetic electron detector on the Electron Losses and Fields InvestigatioN (ELFIN) mission, two polar-orbiting low-altitude spinning CubeSats, measuring 50-5000 keV electrons with good pitch-angle and energy resolution. EMIC wave-driven precipitation exhibits a distinct signature in energy-spectrograms of the precipitating-to-trapped flux ratio: peaks at >0.5 MeV which are abrupt (bursty) (lasting ∼17 s, or ΔL∼0.56) with significant substructure (occasionally down to sub-second timescale). We attribute the bursty nature of the precipitation to the spatial extent and structuredness of the wave field at the equator. Multiple ELFIN passes over the same MLT sector allow us to study the spatial and temporal evolution of the EMIC wave - electron interaction region. Case studies employing conjugate ground-based or equatorial observations of the EMIC waves reveal that the energy of moderate and strong precipitation at ELFIN approximately agrees with theoretical expectations for cyclotron resonant interactions in a cold plasma. Using multiple years of ELFIN data uniformly distributed in local time, we assemble a statistical database of ∼50 events of strong EMIC wave-driven precipitation. Most reside at L∼5-7 at dusk, while a smaller subset exists at L∼8-12 at post-midnight. The energies of the peak-precipitation ratio and of the half-peak precipitation ratio (our proxy for the minimum resonance energy) exhibit an L-shell dependence in good agreement with theoretical estimates based on prior statistical observations of EMIC wave power spectra. The precipitation ratio's spectral shape for the most intense events has an exponential falloff away from the peak (i.e., on either side of ∼1.45 MeV). It too agrees well with quasi-linear diffusion theory based on prior statistics of wave spectra. It should be noted though that this diffusive treatment likely includes effects from nonlinear resonant interactions (especially at high energies) and nonresonant effects from sharp wave packet edges (at low energies). Sub-MeV electron precipitation observed concurrently with strong EMIC wave-driven >1 MeV precipitation has a spectral shape that is consistent with efficient pitch-angle scattering down to ∼ 200-300 keV by much less intense higher frequency EMIC waves at dusk (where such waves are most frequent). At ∼100 keV, whistler-mode chorus may be implicated in concurrent precipitation. These results confirm the critical role of EMIC waves in driving relativistic electron losses. Nonlinear effects may abound and require further investigation.

Fiber reinforced hydrated networks recapitulate the poroelastic mechanics of articular cartilage.

The role of poroelasticity on the functional performance of articular cartilage has been established in the scientific literature since the 1960s. Despite the extensive knowledge on this topic there remain few attempts to design for poroelasticity and to our knowledge no demonstration of an engineered poroelastic material that approaches the physiological performance. In this paper, we report on the development of an engineered material that begins to approach physiological poroelasticity. We quantify poroelasticity using the fluid load fraction, apply mixture theory to model the material system, and determine cytocompatibility using primary human mesenchymal stem cells. The design approach is based on a fiber reinforced hydrated network and uses routine fabrication methods (electrohydrodynamic deposition) and materials (poly[ɛ-caprolactone] and gelatin) to develop the engineered poroelastic material. This composite material achieved a mean peak fluid load fraction of 68%, displayed consistency with mixture theory, and demonstrated cytocompatibility. This work creates a foundation for designing poroelastic cartilage implants and developing scaffold systems to study chondrocyte mechanobiology and tissue engineering. STATEMENT OF SIGNIFICANCE: Poroelasticity drives the functional mechanics of articular cartilage (load bearing and lubrication). In this work we develop the design rationale and approach to produce a poroelastic material, known as a fiber reinforced hydrated network (FiHy™), that begins to approach the native performance of articular cartilage. This is the first engineered material system capable of exceeding isotropic linear poroelastic theory. The framework developed here enables fundamental studies of poroelasticity and the development of translational materials for cartilage repair.

Losing a part of life: experiences of cancer survivors accessing treatment and sheltering in place during the COVID-19 pandemic.

PURPOSE: To explore experiences of sheltering in place and accessing treatment during the initial stages of the COVID-19 pandemic among survivors with cancer receiving tyrosine kinase inhibitor (TKI) therapy. METHODS: Participants from two pilot studies evaluating TKI therapy use in the Southeastern United States during the start of the COVID-19 pandemic (March 2020) were interviewed. Identical interview guides were used across both studies to assess participants' experiences accessing cancer treatment, sheltering in place, and coping during the COVID-19 pandemic. Digitally recorded sessions were transcribed professionally and checked for accuracy. Descriptive statistics were used to summarize participant sociodemographics, and a six-step thematic approach was used to analyze interview data and identify salient themes. Dedoose qualitative research software was used to manage and organize qualitative codes, themes, and memos. RESULTS: Participants (n = 15) ranged from 43 to 84 years of age, and were mostly female (53.3%), married (60%), and survivors with hematologic malignancies (86.7%). The research team identified five salient themes: Participants followed pandemic guidelines, Variable impact on well-being, Common feelings of fear, anxiety and anger, No barriers to accessing therapy and medical care, and Faith and God as powerful forces for coping. CONCLUSIONS: The conclusions of the study provide several implications for survivorship programs or clinics for supporting survivors who are taking chronic TKI therapy during COVID-19, including enhancement of current psychosocial support efforts for cancer survivors or development of new programs tailored to the unique needs of a survivor during a pandemic, such as focused coping strategies, modified physical activity programs, family/professional role changes, and access to safe public spaces.

A review on isoprene in human breath.

We summarize the history and review the literature on isoprene in exhaled breath and discuss the current evidence and models that describe its endogenous origin and consequence for understanding isoprene levels and their variations in exhaled breath.

Emergency Department Visit Rates by Selected Characteristics: United States, 2020.

In 2020, an estimated 131 million emergency department (ED) visits occurred in the United States, with 19.0% of adults reporting a visit and 4.7% of children reporting two or more visits in the past 12 months (1-3). In that time, over 20 million cases of COVID-19 caused a disruption in access to and use of care (4). This report presents characteristics of ED visits, including those with mentions of COVID-19, by age group, sex, race and ethnicity, and primary expected source of payment, using data from the 2020 National Hospital Ambulatory Medical Care Survey (NHAMCS)(5).

The Use of Palliative Radiotherapy in the Treatment of Lung Cancer.

There have been significant advances in the systemic treatment of stage IV lung cancer, which is now recommended first line in patients with adequate fitness. This includes some patients with brain metastases due to the increased understanding of the central nervous system penetration of targeted therapies. The trials evidence base for palliative radiotherapy pre-dated this routine use of systemic therapy in our practice, which means that the sequence and role of palliative radiotherapy are not currently well defined in the first-line treatment setting. However, due to its efficacy in symptom control, radiotherapy remains a core component in the palliative management of lung cancer, particularly in the second-line setting and those unsuited to primary systemic treatment. This overview focuses on the evidence behind palliative radiotherapy to the thorax and brain for non-small cell and small cell lung cancer and the potential for future studies, including the TOURIST Trial Platform, to guide the future direction of these treatments.

Mode of delivery following obstetric anal sphincter injury: a 7-year retrospective review and follow-up cohort survey.

INTRODUCTION AND HYPOTHESIS: Limited evidence exists regarding long-term outcomes following birth after prior obstetric anal sphincter injury (OASI). This article set out to describe outcomes following birth after OASI by reviewing the grades of tear, endoanal ultrasound (EAUS) findings, subsequent delivery outcomes and long-term symptoms. METHODS: This study was conducted in two parts. The first involved a retrospective review of all OASI at a tertiary hospital in Australia over 7 years (2013-2019 inclusive) where the patient underwent a subsequent delivery. Following this, a retrospective cohort survey of this group was performed. RESULTS: There were 27,284 vaginal births and 828 OASIs (3.03%); 247 (29.8%) had at least one subsequent birth by January 2021. Vaginal delivery occurred in 68%; recurrence of OASI was 5.4%. There were 90 responses (36.4%) to the follow-up survey. EAUS had been performed in 87.5%; none demonstrated a defect. Vaginal birth was the preferred mode for 77.8%; this occurred in 64%. The majority had high levels of satisfaction, this related to communication rather than the mode of delivery itself. Ongoing faecal or flatal incontinence was reported by 12%. There was no statistically significant difference in St Mark's incontinence scores between modes of birth. CONCLUSIONS: In our unit most women who sustain OASI will have a subsequent vaginal delivery in future pregnancies. The majority remain asymptomatic at long-term follow-up with no statistically significant difference in incontinence scores regardless of mode of delivery. The rate of recurrent OASI was 5.4%.

A Multicentre Retrospective Study of Fulvestrant Use and Efficacy in Advanced/Metastatic Breast Cancer.

AIMS: Fulvestrant is a selective oestrogen receptor (ER) degrader used in postmenopausal women with hormone receptor-positive advanced breast cancer. The study aim was to analyse demographics and outcomes of UK patients treated with fulvestrant monotherapy at nine representative centres. MATERIALS AND METHODS: Medical records of 459 patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer treated with fulvestrant between August 2011 and November 2018 at nine UK centres were reviewed. Data were collated on demographics, progression-free survival, overall survival and disease response at first radiological assessment following fulvestrant initiation. Patients still alive by December 2018 were censored. RESULTS: Data from 429 of the 459 patients identified were eligible for inclusion in the analysis. The median age was 69 (range 21-95) and 64% (n = 275) had Eastern Cooperative Oncology Group performance status 0-1. Bone was the most commonly involved metastatic site (72%, n = 306). However, 295 (69%) patients had visceral involvement. Patients had received a median 2 (range 0-5) prior lines of endocrine therapy and median 0 (range 0-6) prior chemotherapies. Fulvestrant was first-line therapy in 43 patients (10%). The median duration of treatment was 5 months (range 1-88). The median progression-free survival was 5.5 months. In 51% of 350 patients radiologically assessed, there was evidence of disease response to fulvestrant. Fifteen per cent of these had a complete/partial response. Fulvestrant was discontinued predominantly due to disease progression, with 3% discontinued solely due to adverse events. The median overall survival for the whole cohort was 22.5 months (range 0-88). CONCLUSIONS: This is one of the largest studied cohorts of breast cancer patients treated with fulvestrant. This heavily endocrine-pretreated population reflects real-life use in the UK. Within this context, our retrospective data show that patients can experience maintained disease response when treated with fulvestrant, supporting the importance of equitable availability for all UK patients.

CFTR modulator therapies - Effect on life expectancy in people with cystic fibrosis.

CFTR modulators have dramatically changed the clinical course of CF in those fortunate enough to receive them. Inevitably, randomised controlled trials during the development of these drugs are too short to use mortality as an outcome. Evidence for their effect on life expectancy are best gained from real world registry studies specifically looking at mortality, but these are only available for ivacaftor to date. Therefore, indirect evidence must be obtained by looking at outcomes known to affect mortality and seeing the effect of these drugs on those outcomes.

Telemedicine and cystic fibrosis: Do we still need face-to-face clinics?

There has been growing interest in telemedicine for cystic fibrosis over recent years based largely on convenience for patients and/or increasing the frequency of surveillance and early detection which, it is assumed, could improve treatment outcomes. During 2020, the covid-19 pandemic catalysed the pace of development of this field, as CF patients were presumed to be at high risk of infection. Most clinics adapted to digital platforms with provision of lung function monitoring and sample collection systems. Here, we present the views of multidisciplinary team members at a large paediatric CF centre on what has worked well and what requires further optimisation in the future. In response to the question posed, 'Do we still need face to face clinics?' our answer is 'Yes, but not every time, and not for everyone'.

Consensus on safe implementation of vaginal natural orifice transluminal endoscopic surgery (vNOTES).

STUDY OBJECTIVE: The first ever report of vaginal natural orifice transluminal endoscopic surgery (vNOTES) for benign gynaecological was reported in 2012. There has been an exponential uptake of the number of surgeons performing such procedures worldwide with no official guidance to ensure the safe implementation of this technique into gynaecological practice due its recency. The objective of this study is to report an international consensus-based statement to help guide a basis for adopting vNOTES into clinical practice. STUDY DESIGN: The consensus-based statement was developed amongst 39 international experts using the Delphi methodology over three successive rounds. Consensus was pre-defined as an agreement of 80% or more by the experts. Consensus sought over eight key concepts pertaining to vNOTES including patient selection, perioperative management, surgical technique, instruments, anatomy, training, registries and trials and definition of the surgical technique. Recommendations from an expert anaesthetist and urogynaecologist were also sought to give a broader perspective with respect to the implementation of vNOTES. RESULTS: Fifty nine international surgeons were invited to participate and 39 (66%) agreed to participate based on being involved in a minimum of 20 vNOTES procedures. They were from 13 countries across 5 continents (Europe, North America, South America, Australia and Asia). Participation was 100% on all three rounds. Overall, consensus was reached in 50 of the 56 questions (89%) with the remaining 6 questions where consensus was not reached pertaining to the domain of patient selection. CONCLUSION: An international expert based vNOTES statement is presented here to help guide adoption of vNOTES based on the experience of early adopters. Consensus was achieved on most components of this consensus statement. Given the recency of this technique, until high-level evidence becomes available, this statement provides an appropriate guidance to the safe implementation of vNOTES into gynaecological practice.