In vitro microvascular engineering approaches and strategies for interstitial tissue integration.

The increasing gap between clinical demand for tissue or organ transplants and the availability of donated tissue highlights the emerging opportunities for lab-grown or synthetically engineered tissue. While the field of tissue engineering has existed for nearly half a century, its clinical translation remains unrealised, in part, due to a limited ability to engineer sufficient vascular supply into fabricated tissue, which is necessary to enable nutrient and waste exchange, prevent cellular necrosis, and support tissue proliferation. Techniques to develop anatomically relevant, functional vascular networks in vitro have made significant progress in the last decade, however, the challenge now remains as to how best incorporate these throughout dense parenchymal tissue-like structures to address diffusion-limited development and allow for the fabrication of large-scale vascularised tissue. This review explores advances made in the laboratory engineering of vasculature structures and summarises recent attempts to integrate vascular networks together with sophisticated in vitro avascular tissue and organ-like structures. STATEMENT OF SIGNIFICANCE: The ability to grow full scale, functional tissue and organs in vitro is primarily limited by an inability to adequately diffuse oxygen and nutrients throughout developing cellularised structures, which generally results from the absence of perfusable vessel networks. Techniques to engineering both perfusable vascular networks and avascular miniaturised organ-like structures have recently increased in complexity, sophistication, and physiological relevance. However, integrating these two essential elements into a single functioning vascularised tissue structure represents a significant spatial and temporal engineering challenge which is yet to be surmounted. Here, we explore a range of vessel morphogenic phenomena essential for tissue-vascular co-development, as well as evaluate a range of recent noteworthy approaches for generating vascularised tissue products in vitro.

Meeting the long-term health needs of Ukrainian refugees.

OBJECTIVES: Since Russia's full-scale invasion of Ukraine on 24 February 2022, millions of people have fled the country. Most people have gone to the neighbouring countries of Poland, Slovakia, Hungary, Romania, and Moldova. This vulnerable population has significant healthcare needs. Among the most challenging to address will be chronic non-communicable diseases (NCDs), including mental disorders, as these require long-term, continuous care and access to medicines. Host country health systems are faced with the challenge of ensuring accessible and affordable care for NCDs and mental disorders to this population. Our objectives were to review host country health system experiences and identify priorities for research to inform sustainable health system responses to the health care needs of refugees from Ukraine. STUDY DESIGN: In-person conference workshop. METHODS: A workshop on this subject was held in November 2022 at the European Public Health Conference in Berlin. RESULTS: The workshop included participants from academia and non-governmental organisations, health practitioners, and World Health Organisation regional and country offices. This short communication reports the main conclusions from the workshop. CONCLUSION: Addressing the challenges and research priorities identified will require international solidarity and co-operation.

Larger-diameter trunnions and bolt-reinforced taper junctions are associated with less tribocorrosion in reverse total shoulder arthroplasty.

BACKGROUND: Morse taper junction tribocorrosion is recognized as an important failure mode in total hip arthroplasty. Although taper junctions are used in almost all shoulder arthroplasty systems currently available in the United States, with large variation in design, limited literature has described comparable analyses of taper damage in these implants. In this study, taper junction damage in retrieved reverse total shoulder arthroplasty (RTSA) implants was assessed and analyzed. METHODS: Fifty-seven retrieved RTSAs with paired baseplate and glenosphere components with Morse taper junctions were identified via database query; 19 of these also included paired humeral stems and trays or spacers with taper junctions. Components were graded for standard damage modes and for fretting and corrosion with a modified Goldberg-Cusick classification system. Medical records and preoperative radiographs were reviewed. Comparative analyses were performed assessing the impact of various implant, radiographic, and patient factors on taper damage. RESULTS: Standard damage modes were commonly found at the evaluated trunnion junctions, with scratching and edge deformation damage on 76% and 46% of all components, respectively. Fretting and corrosion damage was also common, observed on 86% and 72% of baseplates, respectively, and 23% and 40% of glenospheres, respectively. Baseplates showed greater moderate to severe (grade ≥ 3) fretting (43%) and corrosion (27%) damage than matched glenospheres (fretting, 9%; corrosion, 13%). Humeral stems showed moderate to severe fretting and corrosion on 28% and 30% of implants, respectively; matched humeral trays or spacers showed both less fretting (14%) and less corrosion (17%). On subgroup analysis, large-tapered implants had significantly lower summed fretting and corrosion grades than small-tapered implants (P < .001 for both) on glenospheres; paired baseplate corrosion grades were also significantly lower (P = .031) on large-tapered implants. Factorial analysis showed that bolt reinforcement of the taper junction was also associated with less fretting and corrosion damage on both baseplates and glenospheres. Summed fretting and corrosion grades on glenospheres with trunnions (male) were significantly greater than on glenospheres with bores (female) (P < .001 for both). CONCLUSIONS: Damage to the taper junction is commonly found in retrieved RTSAs and can occur after only months of being implanted. In this study, tribocorrosion predominantly occurred on the taper surface of the baseplate (vs. glenosphere) and on the humeral stem (vs. tray or spacer), which may relate to the flexural rigidity difference between the titanium and cobalt-chrome components. Bolt reinforcement and the use of large-diameter trunnions led to less tribocorrosion of the taper junction. The findings of this study provide evidence for the improved design of RTSA prostheses to decrease tribocorrosion.

Peptidergic modulation of a multi-functional central pattern generator in the pulmonate snail.

Egg laying in pulmonate snails is a well-orchestrated process that involves a period of reduced locomotion, followed by substrate cleaning with rhythmic rasping of the surface to make tiny grooves, into which eggs are deposited. Although the neurohormonal control of initiating egg laying has been well established, the signals that modulate the buccal central pattern generator to substrate cleaning during egg laying are not known. Neuropeptides of the invertebrate gonadotropin-releasing hormone/corazonin family (invGnRH/CRZ) have been shown to be involved in reproduction and allied behaviors in many vertebrates and invertebrates. Here, we show that the buccal motor pattern underlying substrate cleaning during egg laying is altered by a vertebrate GnRH agonist. Signals from the intestinal nerve innervating reproductive structures, previously shown to be both necessary and sufficient for egg-laying behaviors, are blocked by a vertebrate GnRH antagonist. Further, the vertebrate GnRH-triggered response elicits rhythmic, phase 2 and non-phase 2 activity in the buccal motor pattern, with a shutdown of phase 3, indicative of repetitive rasping without accompanied swallowing behavior. Using immunohistochemistry, intracellular electrophysiology and extracellular nerve stimulation, we show that a member of the invGnRH/CRZ family of neuropeptides could be the signal that contextually switches the multifunctional buccal CPG to a biphasic rasping rhythm that underlies substrate cleaning behavior during egg laying in the pulmonate snail Planorbella (Helisoma) trivolvis.

Characterization of a 1D-imaging high-energy x-ray backlighter driven by the National Ignition Facility Advanced Radiographic Capability laser.

Plastic deformation of samples compressed to Mbar pressures at high strain rates at the National Ignition Facility (NIF) forms the basis of ongoing material strength experiments in conditions relevant to meteor impacts, geophysics, armor development, and inertial confinement fusion. Hard x-ray radiography is the primary means of measuring the evolution of these samples, typically employing a slit-collimated high-Z microdot driven by the NIF laser to generate >40 keV x rays [E. Gumbrell et al., Rev. Sci. Instrum. 89, 10G118 (2018) and C. M. Huntington et al., Rev. Sci. Instrum. 89, 10G121 (2018)]. Alternatively, a dysprosium "micro-flag" target driven by the Advanced Radiographic Capability laser (∼2 kJ, 10 ps) can deliver significantly higher spatiotemporal resolution [M. P. Hill et al., Rev. Sci. Instrum. 92, 033535 (2021)], especially in high-opacity samples. Initial experiments revealed problematic brightness and spectral gradients from this source, but by radiographing a set of diamond-turned, 105 µm-thick Pb test objects and supported by simulations using the 3D Monte Carlo code GEANT4, these geometry-dependent gradients across the field of view are quantified and mitigation strategies are assessed. In addition to significantly enhancing the modulation transfer function compared to the existing system, image stacking from multiple layers of image plate is shown to almost double the signal to noise ratio that will reduce uncertainties in future dynamic strength experiments.

Undertaking a face-to-face objective structured clinical examination for medical students during the COVID-19 pandemic.

INTRODUCTION AND AIMS: Objective structured clinical examinations (OSCEs) play a pivotal role in medical education assessment. The Advanced Clinical Skills (ACS) OSCE examines clinical skills in psychiatry, general practice, obstetrics and gynaecology and paediatrics. This study examined if the 2020 ACS OSCE for fourth year medical students attending the National University of Ireland, Galway, was associated with any significant result differences compared to the equivalent 2019 OSCE. Additionally, we assessed students' satisfaction and explored any organisational difficulties in conducting a face-to-face OSCE during the COVID-19 pandemic. MATERIALS AND METHODS: This study compared anonymised data between the 2019 and 2020 ACS OSCEs and analysed anonymised student feedback pertaining to the modified 2020 OSCE. RESULTS: The mean total ACS OSCE result achieved in 2020 was statistically higher compared to the 2019 OSCE [62.95% (SD = 6.21) v. 59.35% (SD = 5.54), t = 6.092, p < 0.01], with higher marks noted in psychiatry (p = 0.001), paediatrics (p = 0.001) and general practice (p < 0.001) with more students attaining honours grades (χ2 = 27.257, df = 3, p < 0.001). No difference in failure rates were found. Students reported feeling safe performing the 2020 OSCE (89.2%), but some expressed face-mask wearing impeded their communication skills (47.8%). CONCLUSION: This study demonstrates that conducting a face-to-face OSCE during the pandemic is feasible and associated with positive student feedback. Exam validity has been demonstrated as there was no difference in the overall pass rate.

Radiative Capture on Nuclear Isomers: Direct Measurement of the

We present the first direct measurement of an astrophysical reaction using a radioactive beam of isomeric nuclei. In particular, we have measured the strength of the key 447-keV resonance in the ^{26m}Al(p,γ)^{27}Si reaction to be 432_{-226}^{+146} meV and find that this resonance dominates the thermally averaged reaction rate for temperatures between 0.3 and 2.5 GK. This work represents a critical development in resolving one of the longest standing issues in nuclear astrophysics research, relating to the measurement of proton capture reactions on excited quantum levels, and offers unique insight into the destruction of isomeric ^{26}Al in astrophysical plasmas.

RNA-seq analysis of murine peyer's patches at 6 and 18 h post infection with Fasciola hepatica metacecariae.

Fasciola hepatica is a zoonotic parasite that not only economically burdens the agribusiness sector, but also infects up to 1 million people worldwide, with no commercial vaccine yet available. An ideal vaccine would induce protection in the gut, curtailing the extensive tissue damage associated with parasite's migration from the gut to the bile ducts. The design of such a vaccine requires greater knowledge of gut mucosal responses during the early stage of infection. We examined total mRNA expression of the peyer's patches at 6 and 18 h post F. hepatica infection using RNA sequencing. Differential expression analysis revealed 1341 genes upregulated and 61 genes downregulated at 6 h post infection, while 1562 genes were upregulated and 10 genes downregulated after 18 h. Gene-set enrichment analysis demonstrated that immune specific biological processes were amongst the most downregulated. The Toll-like receptor pathway in particular was significantly affected, the suppression of which is a well-documented immune evasive strategy employed by F. hepatica. In general, the genes identified were associated with suppression of inflammatory responses, helminth induced immune responses and tissue repair/homeostasis. This study provides a rich catalogue of the genes expressed in the early stages of F. hepatica infection, adding to the understanding of early host-parasite interactions and assisting in the design of future studies that look to advance the development of a novel F. hepatica vaccine.

Advancement of Photospheric Radius Expansion and Clocked Type-I X-Ray Burst Models with the New

We report the first (in)elastic scattering measurement of ^{25}Al+p with the capability to select and measure in a broad energy range the proton resonances in ^{26}Si contributing to the ^{22}Mg(α,p) reaction at type I x-ray burst energies. We measured spin-parities of four resonances above the α threshold of ^{26}Si that are found to strongly impact the ^{22}Mg(α,p) rate. The new rate advances a state-of-the-art model to remarkably reproduce light curves of the GS 1826-24 clocked burster with mean deviation <9% and permits us to discover a strong correlation between the He abundance in the accreting envelope of the photospheric radius expansion burster and the dominance of ^{22}Mg(α,p) branch.

Borderline personality disorder: resource utilisation costs in Ireland.

OBJECTIVES: Borderline personality disorder (BPD) is characterised by recurring crises, hospitalisations, self-harm, suicide attempts, addictions, episodes of depression, anxiety and aggression and lost productivity. The objective of this study is to determine the use of direct health care resources by persons with BPD in Ireland and the corresponding costs. METHODS: This prevalence-based micro-costing study was undertaken on a sample of 196 individuals with BPD attending publicly funded mental health services in Ireland. All health care costs were assessed using a resource utilisation questionnaire completed by mental health practitioners. A probabilistic sensitivity analysis, using a Monte Carlo simulation, was performed to examine uncertainty. RESULTS: Total direct healthcare cost per individual was €10 844 annually (ranging from 5228 to 20 609). Based on a prevalence of 1% and an adult population (18-65 years) of 2.87 million, we derived that there were 28 725 individuals with BPD in Ireland. Total yearly cost of illness was calculated to be up to €311.5 million. CONCLUSIONS: There is a dearth of data on health care resource use and costs of community mental health services in Ireland. The absence of this data is a considerable constraint to research and decision-making in the area of community mental health services. This paper contributes to the limited literature on resource use and costs in community mental health services in Ireland. The absence of productivity loss data (e.g. absenteeism and presenteeism), non-health care costs (e.g. addiction treatment), and indirect costs (e.g. informal care) from study participants is a limitation of this study.

Current management of adults receiving oral anti-cancer medications: A scoping review.

PURPOSE: Oral anti-cancer medication (OAM) has revolutionised oncology care. Due to their potential toxicities and associated safety challenges ongoing assessment and monitoring is essential; currently generally performed in acute care settings. Internationally there exists a transformative vision to shift patient care from acute to primary care. A nurse-led integrated model of care could be developed for OAM patient management in primary care. The aim of this study was to examine international literature regarding current clinical management practices for assessment and monitoring of patients receiving OAM. METHODS: Following PRISMA-ScR guidelines, databases MEDLINE, CINAHL and Web of Science were searched for English studies published between 2010 and 2020 using keywords: assessment, cancer, care, management, oral anticancer medications. Articles were screened and assessed for eligibility. From eligible studies, data were extracted to summarize, collate and make a narrative account of the findings. RESULTS: 2261 papers were reviewed, 14 met inclusion criteria. Three phases of management are reported: 1. Patient treatment plan development; 2. Patient education; 3. Patient monitoring. Within these phases seven specific stages of care were identified broadly representing the patient's journey: (1) treatment decision, (2) prescribing of OAM, (3) OAM dispensing and administration, (4) maximising patient safety (5) ongoing patient assessment (6) patient support (7) communication with other health-care professionals. CONCLUSIONS: Despite a paucity of international literature, a dedicated OAM clinic was endorsed as a means to achieve improved care. Nurses and pharmacists were identified as being of particular importance especially in education and ongoing management of patients receiving OAMs.

Timing of adjuvant chemotherapy after laparotomy for Wilms tumor and neuroblastoma.

PURPOSE: To describe the timing of chemotherapy initiation after surgery for Wilms tumor (WT) and neuroblastoma within a dedicated children's cancer center. METHODS: A single-institution retrospective cohort study identified patients that underwent resection of unilateral WT or high-risk neuroblastoma and received adjuvant chemotherapy treatment. Adjuvant chemotherapy initiation and postoperative complications were recorded. RESULTS: Among 47 WT patients, the median time to chemotherapy initiation was 11 days [interquartile range IQR 7-14]. 3 WT patients had post-operative complications, but all preceded chemotherapy. Among 83 patients treated for high-risk neuroblastoma, the median time to chemotherapy was 11 days [IQR 9-14]. High-risk neuroblastoma patients with 30-day postoperative complications had a significantly longer time to initiation of adjuvant chemotherapy (odds ratio 1.13; p = 0.008). Many of these complications preceded and delayed the initiation of post-operative chemotherapy. No complications occurred in the group of 12 (25%) WT patients or 16 (19.3%) neuroblastoma patients who started chemotherapy ≤ 7 days after surgery. CONCLUSION: There is no association between early initiation of adjuvant chemotherapy and post-operative complications including wound healing. Early initiation of chemotherapy (≤ 7 days) is feasible in unilateral WT or high-risk neuroblastoma patients who are otherwise doing well without resulting in a preponderance of wound healing complications.

Assessing Taper Geometry, Head Size, Head Material, and Their Interactions in Taper Fretting Corrosion of Retrieved Total Hip Arthroplasty Implants.

BACKGROUND: Decreased fretting and corrosion damage at the taper interface of retrieved ceramic-on-polyethylene total hip arthroplasty (THA) implants has been consistently reported; however, resultant fretting corrosion as a function of femoral head size and taper geometry has not been definitively explained. METHODS: Eight cohorts were defined from 157 retrieved THA implants based on femoral head composition (n = 95, zirconia-toughened alumina, ZTA vs n = 62, cobalt-chromium alloy, CoCr), head size (n = 56, 32mm vs n = 101, 36mm), and taper geometry (n = 84, 12/14 vs n = 73, V40). THA implants were evaluated and graded for taper fretting and corrosion. Data were statistically analyzed, including via a 23 factorial modeling. RESULTS: Factorial-based analysis indicated the significant factors related to both resultant (summed) fretting and corrosion damage were head material and taper geometry; head material-taper geometry interaction was also a significant factor in resultant corrosion damage. Lower rates of moderate-to-severe fretting and corrosion damage were exhibited on ZTA heads (ZTA = 13%, CoCr = 38%), smaller heads (32mm = 18%, 36mm = 26%), and 12/14 tapers (12/14 = 13%, V40 = 35%). ZTA+32mm heads demonstrated the lowest rates of moderate-to-severe fretting and corrosion damage (12/14 = 2%, V40 = 7%), whereas CoCr heads with V40 tapers demonstrated the greatest rates of moderate-to-severe damage (32mm = 47%, 36mm = 59%). CONCLUSION: In this series, retrieved implants with ZTA, 32-mm heads paired with 12/14 tapers exhibited lower rates of moderate-to-severe damage. Factorial analysis showed head material, taper geometry, and their interactions were the most significant factors associated with resultant damage grades. Isolating implant features may provide additional information regarding factors leading to fretting and corrosion damage in THA. LEVEL OF EVIDENCE: IV (case series).

Changes in peripheral HCN2 channels during persistent inflammation.

Nociceptor sensitization following nerve injury or inflammation leads to chronic pain. An increase in the nociceptor hyperpolarization-activated current, Ih, is observed in many models of pathological pain. Pharmacological blockade of Ih prevents the mechanical and thermal hypersensitivity that occurs during pathological pain. Alterations in the Hyperpolarization-activated Cyclic Nucleotide-gated ion channel 2 (HCN2) mediate Ih-dependent thermal and mechanical hyperalgesia. Limited knowledge exists regarding the nature of these changes during chronic inflammatory pain. Modifications in HCN2 expression and post-translational SUMOylation have been observed in the Complete Freund's Adjuvant (CFA) model of chronic inflammatory pain. Intra-plantar injection of CFA into the rat hindpaw induces unilateral hyperalgesia that is sustained for up to 14 days following injection. The hindpaw is innervated by primary afferents in lumbar DRG, L4-6. Adjustments in HCN2 expression and SUMOylation have been well-documented for L5 DRG during the first 7 days of CFA-induced inflammation. Here, we examine bilateral L4 and L6 DRG at day 1 and day 3 post-CFA. Using L4 and L6 DRG cryosections, HCN2 expression and SUMOylation were measured with immunohistochemistry and proximity ligation assays, respectively. Our findings indicate that intra-plantar injection of CFA elicited a bilateral increase in HCN2 expression in L4 and L6 DRG at day 1, but not day 3, and enhanced HCN2 SUMOylation in ipsilateral L6 DRG at day 1 and day 3. Changes in HCN2 expression and SUMOylation were transient over this time course. Our study suggests that HCN2 is regulated by multiple mechanisms during CFA-induced inflammation.