Microcirculation surrounding end-stage human chronic skin wounds is associated with endoglin/CD146/ALK-1 expression, endothelial cell proliferation and an absence of p16Ink4a.

Angiogenesis is an essential part of normal skin healing, re-establishing blood flow in developing granulation tissue. Non-healing skin wounds are associated with impaired angiogenesis and although the role of re-establishing macroscopic blood flow to limbs to prevent wound chronicity is well investigated, less is known about vascular alterations at the microcirculatory level. We hypothesised that significant phenotypic changes would be evident in blood vessels surrounding chronic skin wounds. Wound edge tissue, proximal to wound (2 cm from wound edge) and non-involved skin (>10 cm from wound edge) was harvested under informed consent from 20 patients undergoing elective amputation due to critical limb ischemia. To assess blood vessel structure and viability, tissue was prepared for histological analysis and labelled with antibodies specific for PECAM-1 (CD31), CD146, endoglin, ALK-1, ALK-5, and p16Ink4a as a marker of cellular senescence. Density of microvasculature was significantly increased in wound edge dermis, which was concomitant with increased labelling for endoglin and CD146. The number of CD31 positive vessel density was unchanged in wound edge tissue relative to non-involved tissue. Co-labelling of endoglin with the transforming growth factor receptor ALK-1, and to a lesser extent ALK-5, demonstrated activation of endothelial cells which correlated with PCNA labelling indicative of proliferation. Analysis of p16Ink4a staining showed a complete lack of immunoreactivity in the vasculature and dermis, although staining was evident in sub-populations of keratinocytes. We conclude that the endoglin-ALK-1-endothelial proliferation axis is active in the vasculature at the edge of chronic skin wounds and is not associated with p16Ink4a mediated senescence. This information could be further used to guide treatment of chronic skin wounds and optimise debridement protocols.

Screening of functionalized collagen membranes with a porcine periodontal regeneration model.

OBJECTIVES: Current methods for periodontal regeneration do not promote collagen fiber insertions into new bone and cementum. We used a pig wound model to screen different functionalized collagen membranes in promoting periodontal reattachment to root surfaces. METHODS: Treatment groups included (1) control with no membranes, (2) collagen-coated membranes, (3) membranes with insulin-like growth factor-1 (IGF-1), (4) membranes with amelotin, or (5) membranes attached with calcium phosphate cement (CPC), or with CPC combined with IGF-1. Flap procedures were performed on mandibular and maxillary premolars of each pig. RESULTS: Histomorphometric, micro-CT, and clinical measurements obtained at 4 and 12 weeks after surgery showed cementum formation on denuded roots and reformation of alveolar bone, indicating that the pig model can model healing responses in periodontal regeneration. Calcium phosphate cement simplified procedures by eliminating the need for sutures and improved regeneration of alveolar bone (p < 0.05) compared with other treatments. There was a reduction (p < 0.05) of PD only for the IGF group. Large observed variances between treatment groups indicated that a priori power analyses should be conducted to optimize statistical analysis. CONCLUSIONS: Pigs can model discrete elements of periodontal healing using collagen-based, functionalized membranes. Screening indicates that membrane anchorage with calcium phosphate cements improve regeneration of alveolar bone.

Pop-up COVID-19 vaccination clinics for vulnerable groups in the Midlands.

INTRODUCTION: Roma, travellers and the homeless suffer from a higher risk of both COVID-19 infection and severe disease relative to the general population. The purpose of this project was to ensure as many members as possible from vulnerable groups in the Midlands availed of COVID-19 vaccines. METHODS: Following on from successful testing of vulnerable populations in the Midlands of Ireland in March/April 2021, a collaboration of HSE Midland's Department of Public Health, Safetynet Primary Care and the HSE Midlands Traveller Health Unit (MTHU) operated pop-up vaccination clinics in June/July 2021, targeting the same populations. Clinics delivered the first dose of the Pfizer/BioNTech COVID-19 vaccine, registering clients for second doses in Community Vaccination Centres (CVCs). RESULTS: Thirteen clinics were hosted between 8 June 2021 and 20 July 2021, resulting in 890 first-dose Pfizer vaccinations delivered to vulnerable populations. DISCUSSION: Trust established months prior with our grassroots testing service resulted in strong vaccine uptake, with the quality service provided seeding further demand over time. This service integrated into the national system and allowed individuals to receive their second doses within the community.

The pig as a model system for investigating the recruitment and contribution of myofibroblasts in skin healing.

In the skin-healing field, porcine models are regarded as a useful analogue for human skin due to their numerous anatomical and physiological similarities. Despite the widespread use of porcine models in skin healing studies, the initial origin, recruitment and transition of fibroblasts to matrix-secreting contractile myofibroblasts are not well defined for this model. In this review, we discuss the merit of the pig as an animal for studying myofibroblast origin, as well as the challenges associated with assessing their contributions to skin healing. Although a variety of wound types (incisional, partial thickness, full thickness, burns) have been investigated in pigs in attempts to mimic diverse injuries in humans, direct comparison of human healing profiles with regards to myofibroblasts shows evident differences. Following injury in porcine models, which often employ juvenile animals, myofibroblasts are described in the developing granulation tissue at 4 days, peaking at Days 7-14, and persisting at 60 days post-wounding, although variations are evident depending on the specific pig breed. In human wounds, the presence of myofibroblasts is variable and does not correlate with the age of the wound or clinical contraction. Our comparison of porcine myofibroblast-mediated healing processes with those in humans suggests that further validation of the pig model is essential. Moreover, we identify several limitations evident in experimental design that need to be better controlled, and standardisation of methodologies would be beneficial for the comparison and interpretation of results. In particular, we discuss anatomical location of the wounds, their size and depth, as well as the healing microenvironment (wet vs. moist vs. dry) in pigs and how this could influence myofibroblast recruitment. In summary, although a widespread model used in the skin healing field, further research is required to validate pigs as a useful analogue for human healing with regards to myofibroblasts.

The rapid formation of Sputnik Planitia early in Pluto's history.

Pluto's Sputnik Planitia is a bright, roughly circular feature that resembles a polar ice cap. It is approximately 1,000 kilometres across and is centred on a latitude of 25 degrees north and a longitude of 175 degrees, almost directly opposite the side of Pluto that always faces Charon as a result of tidal locking. One explanation for its location includes the formation of a basin in a giant impact, with subsequent upwelling of a dense interior ocean. Once the basin was established, ice would naturally have accumulated there. Then, provided that the basin was a positive gravity anomaly (with or without the ocean), true polar wander could have moved the feature towards the Pluto-Charon tidal axis, on the far side of Pluto from Charon. Here we report modelling that shows that ice quickly accumulates on Pluto near latitudes of 30 degrees north and south, even in the absence of a basin, because, averaged over its orbital period, those are Pluto's coldest regions. Within a million years of Charon's formation, ice deposits on Pluto concentrate into a single cap centred near a latitude of 30 degrees, owing to the runaway albedo effect. This accumulation of ice causes a positive gravity signature that locks, as Pluto's rotation slows, to a longitude directly opposite Charon. Once locked, Charon raises a permanent tidal bulge on Pluto, which greatly enhances the gravity signature of the ice cap. Meanwhile, the weight of the ice in Sputnik Planitia causes the crust under it to slump, creating its own basin (as has happened on Earth in Greenland). Even if the feature is now a modest negative gravity anomaly, it remains locked in place because of the permanent tidal bulge raised by Charon. Any movement of the feature away from 30 degrees latitude is countered by the preferential recondensation of ices near the coldest extremities of the cap. Therefore, our modelling suggests that Sputnik Planitia formed shortly after Charon did and has been stable, albeit gradually losing volume, over the age of the Solar System.

Tidal evolution of the Moon from a high-obliquity, high-angular-momentum Earth.

In the giant-impact hypothesis for lunar origin, the Moon accreted from an equatorial circum-terrestrial disk; however, the current lunar orbital inclination of five degrees requires a subsequent dynamical process that is still unclear. In addition, the giant-impact theory has been challenged by the Moon's unexpectedly Earth-like isotopic composition. Here we show that tidal dissipation due to lunar obliquity was an important effect during the Moon's tidal evolution, and the lunar inclination in the past must have been very large, defying theoretical explanations. We present a tidal evolution model starting with the Moon in an equatorial orbit around an initially fast-spinning, high-obliquity Earth, which is a probable outcome of giant impacts. Using numerical modelling, we show that the solar perturbations on the Moon's orbit naturally induce a large lunar inclination and remove angular momentum from the Earth-Moon system. Our tidal evolution model supports recent high-angular-momentum, giant-impact scenarios to explain the Moon's isotopic composition and provides a new pathway to reach Earth's climatically favourable low obliquity.

African biomass burning is a substantial source of phosphorus deposition to the Amazon, Tropical Atlantic Ocean, and Southern Ocean.

The deposition of phosphorus (P) from African dust is believed to play an important role in bolstering primary productivity in the Amazon Basin and Tropical Atlantic Ocean (TAO), leading to sequestration of carbon dioxide. However, there are few measurements of African dust in South America that can robustly test this hypothesis and even fewer measurements of soluble P, which is readily available for stimulating primary production in the ocean. To test this hypothesis, we measured total and soluble P in long-range transported aerosols collected in Cayenne, French Guiana, a TAO coastal site located at the northeastern edge of the Amazon. Our measurements confirm that in boreal spring when African dust transport is greatest, dust supplies the majority of P, of which 5% is soluble. In boreal fall, when dust transport is at an annual minimum, we measured unexpectedly high concentrations of soluble P, which we show is associated with the transport of biomass burning (BB) from southern Africa. Integrating our results into a chemical transport model, we show that African BB supplies up to half of the P deposited annually to the Amazon from transported African aerosol. This observational study links P-rich BB aerosols from Africa to enhanced P deposition in the Amazon. Contrary to current thought, we also show that African BB is a more important source of soluble P than dust to the TAO and oceans in the Southern Hemisphere and may be more important for marine productivity, particularly in boreal summer and fall.

Climate-driven oscillation of phosphorus and iron limitation in the North Pacific Subtropical Gyre.

The supply of nutrients is a fundamental regulator of ocean productivity and carbon sequestration. Nutrient sources, sinks, residence times, and elemental ratios vary over broad scales, including those resulting from climate-driven changes in upper water column stratification, advection, and the deposition of atmospheric dust. These changes can alter the proximate elemental control of ecosystem productivity with cascading ecological effects and impacts on carbon sequestration. Here, we report multidecadal observations revealing that the ecosystem in the eastern region of the North Pacific Subtropical Gyre (NPSG) oscillates on subdecadal scales between inorganic phosphorus (P i ) sufficiency and limitation, when P i concentration in surface waters decreases below 50-60 nmol⋅kg-1 In situ observations and model simulations suggest that sea-level pressure changes over the northwest Pacific may induce basin-scale variations in the atmospheric transport and deposition of Asian dust-associated iron (Fe), causing the eastern portion of the NPSG ecosystem to shift between states of Fe and P i limitation. Our results highlight the critical need to include both atmospheric and ocean circulation variability when modeling the response of open ocean pelagic ecosystems under future climate change scenarios.

Small particles dominate Saturn's Phoebe ring to surprisingly large distances.

Saturn's faint outermost ring, discovered in 2009 (ref. 1), is probably formed by particles ejected from the distant moon Phoebe. The ring was detected between distances of 128 and 207 Saturn radii (RS = 60,330 kilometres) from the planet, with a full vertical extent of 40RS, making it well over ten times larger than Saturn's hitherto largest known ring, the E ring. The total radial extent of the Phoebe ring could not, however, be determined at that time, nor could particle sizes be significantly constrained. Here we report infrared imaging of the entire ring, which extends from 100RS out to a surprisingly distant 270RS. We model the orbital dynamics of ring particles launched from Phoebe, and construct theoretical power-law profiles of the particle size distribution. We find that very steep profiles fit the data best, and that elevated grain temperatures, arising because of the radiative inefficiency of the smallest grains, probably contribute to the steepness. By converting our constraint on particle sizes into a form that is independent of the uncertain size distribution, we determine that particles with radii greater than ten centimetres, whose orbits do not decay appreciably inward over 4.5 billion years, contribute at most about ten per cent to the cross-sectional area of the ring's dusty component.

Wound healing and fibrosis: a contrasting role for periostin in skin and the oral mucosa.

Both skin and oral mucosa are characterized by the presence of keratinized epithelium in direct apposition to an underlying collagen-dense connective tissue. Despite significant overlap in structure and physiological function, skin and the oral mucosa exhibit significantly different healing profiles in response to injury. The oral mucosa has a propensity for rapid restoration of barrier function with minimal underlying fibrosis, but in contrast, skin is associated with slower healing and scar formation. Modulators of cell function, matricellular proteins have been shown to play significant roles in cutaneous healing, but their role in restoration of the oral mucosa is poorly defined. As will be discussed in this review, over the last 12 years our research group has been actively investigating the role of the profibrotic matricellular protein periostin in tissue homeostasis and fibrosis, as well as healing, in both skin and gingiva. In the skin, periostin is highly expressed in fibrotic scars and is upregulated during cutaneous wound repair, where it facilitates myofibroblast differentiation. In contrast, in gingival healing, periostin regulates extracellular matrix synthesis but does not appear to be associated with the transition of mesenchymal cells to a contractile phenotype. The significance of these findings will be discussed, with a focus on periostin as a potential therapeutic to augment healing of soft tissues or suppress fibrosis.

Impact of Prolonged Spaceflight on Orthostatic Tolerance During Ambulation and Blood Pressure Profiles in Astronauts.

BACKGROUND: Astronauts returning to earth usually demonstrate reduced orthostatic tolerance when assessed on a tilt table or quiet standing, but no studies have evaluated postflight orthostatic tolerance during activities of daily living, when it is most clinically relevant. Ambulatory blood pressure (BP) variability also is associated with orthostatic intolerance in certain patient populations and can capture clinically significant orthostatic hypotension during activities of daily living, especially when measured on a beat-to-beat basis. We evaluated the impact of prolonged spaceflight on orthostatic tolerance and BP profiles in astronauts. METHODS: Ambulatory beat-to-beat BP was recorded using a portable device for multiple 24-hour time periods before, during, and after 6 months of spaceflight in 12 astronauts (4 women; age 48±5 [mean±SD] years). BP variability in the time domain was calculated as the SD. Systolic BP distribution during activities of daily living was characterized by skewness and kurtosis. RESULTS: In contrast with results from previous studies that used tilt tables or stand tests, no astronaut experienced orthostatic intolerance/hypotension during activities of daily living before or after spaceflight. Also, 24-hour systolic BP decreased in space (120±10 mm Hg before spaceflight versus 106±9 mm Hg during spaceflight; P<0.01), but it returned to normal upon landing (122±13 mm Hg). Diastolic BP was unchanged during and after spaceflight. Systolic and diastolic BP variability remained the same before, during, and after spaceflight (both P>0.05). The skewness of systolic BP increased in space (0.74±0.51 versus 1.43±1.00; P=0.001), indicating that signal fluctuations became asymmetrical; however, it returned to preflight levels after landing (0.51±0.42). The kurtosis increased in space (5.01±7.67 versus 11.10±11.79; P=0.010), suggesting that fluctuations concentrated around the mean with a narrow distribution; however, it also returned to preflight levels (2.21±2.56) after return to earth. CONCLUSIONS: Given current countermeasures including in-flight exercise training and volume resuscitation on return, no astronauts experienced orthostatic hypotension or intolerance during routine (for landing day) activities in the initial 24 hours after landing following 6 months in space. Prolonged exposure to spaceflight had little impact on systolic BP variability and its distribution, although the latter showed a transient change in space (accompanied by mild relative hypotension), all of which returned to preflight values after return to earth.

Do we have the guts to go? The abdominal compartment, intra-abdominal hypertension, the human microbiome and exploration class space missions.

Humans are destined to explore space, yet critical illness and injury may be catastrophically limiting for extraterrestrial travel. Humans are superorganisms living in symbiosis with their microbiomes, whose genetic diversity dwarfs that of humans. Symbiosis is critical and imbalances are associated with disease, occurring within hours of serious illness and injury. There are many characteristics of space flight that negatively influence the microbiome, especially deep space itself, with its increased radiation and absence of gravity. Prolonged weightlessness causes many physiologic changes that are detrimental; some resemble aging and will adversely affect the ability to tolerate critical illness or injury and subsequent treatment. Critical illness-induced intra-abdominal hypertension (IAH) may induce malperfusion of both the viscera and microbiome, with potentially catastrophic effects. Evidence from animal models confirms profound IAH effects on the gut, namely ischemia and disruption of barrier function, mechanistically linking IAH to resultant organ dysfunction. Therefore, a pathologic dysbiome, space-induced immune dysfunction and a diminished cardiorespiratory reserve with exacerbated susceptibility to IAH, imply that a space-deconditioned astronaut will be vulnerable to IAH-induced gut malperfusion. This sets the stage for severe gut ischemia and massive biomediator generation in an astronaut with reduced cardiorespiratory/immunological capacity. Fortunately, experiments in weightless analogue environments suggest that IAH may be ameliorated by conformational abdominal wall changes and a resetting of thoracoabdominal mechanics. Thus, review of the interactions of physiologic changes with prolonged weightlessness and IAH is required to identify appropriate questions for planning exploration class space surgical care.

L'humanité est à l'aube d'une nouvelle ère d'exploration spatiale, mais le risque de maladies et blessures graves pourrait restreindre de manière catastrophique le potentiel des voyages dans l'espace. L'être humain est un superorganisme vivant en symbiose avec son microbiote, dont la diversité génétique éclipse celle de l'hôte. Cette symbiose est essentielle : tout déséquilibre est associé à une dégradation de l'état de santé dans les heures suivant l'occurrence d'une blessure ou d'une maladie grave. Bon nombre de caractéristiques propres au vol spatial ont des répercussions négatives sur le microbiote; l'espace lointain présente des dangers particuliers en raison de l'exposition accrue au rayonnement et de l'absence de gravité. L'exposition prolongée à l'apesanteur cause une myriade de changements physiologiques nuisant à la santé. Certains ressemblent à des processus de vieillissement et réduiront la capacité à tolérer une blessure ou une maladie grave et son traitement. L'hypertension intra-abdominale (HIA) causée par une maladie grave peut réduire la perfusion des viscères et du microbiote, ce qui peut avoir des conséquences catastrophiques. Des études sur modèle animal ont confirmé les effets profondément délétères de l'HIA sur les intestins par l'apparition d'une ischémie et une altération de la barrière intestinale; cette découverte permettrait d'établir un lien mécanistique entre l'HIA et la défaillance d'organes résultante. Par conséquent, une dysbiose pathologique, associée à un dysfonctionnement immunitaire en apesanteur et à une réduction de la réserve cardiorespiratoire accompagnée d'une exacerbation de la susceptibilité à l'HIA, pourrait signifier qu'un astronaute exposé à l'effet déconditionnant de l'apesanteur serait vulnérable aux problèmes de perfusion de l'intestin découlant de l'HIA. Ce problème pourrait à son tour mener à une ischémie intestinale grave et à une production massive de biomédiateurs chez un astronaute présentant déjà une capacité cardiorespiratoire et immunitaire réduite. Heureusement, des expériences dans des environnements simulant l'apesanteur semblent indiquer que les effets de l'HIA pourraient être contrés par des changements conformationnels de la paroi abdominale et un rétablissement de la mécanique thoracoabdominale. Par conséquent, un examen des interactions des changements physiologiques associés à un état d'apesanteur prolongé et à l'HIA est requis pour déterminer les questions à poser afin de planifier adéquatement les soins chirurgicaux en contexte d'exploration spatiale.

JNK Signaling as a Key Modulator of Soft Connective Tissue Physiology, Pathology, and Healing.

In healthy individuals, the healing of soft tissues such as skin after pathological insult or post injury follows a relatively predictable and defined series of cell and molecular processes to restore tissue architecture and function(s). Healing progresses through the phases of hemostasis, inflammation, proliferation, remodeling, and concomitant with re-epithelialization restores barrier function. Soft tissue healing is achieved through the spatiotemporal interplay of multiple different cell types including neutrophils, monocytes/macrophages, fibroblasts, endothelial cells/pericytes, and keratinocytes. Expressed in most cell types, c-Jun N-terminal kinases (JNK) are signaling molecules associated with the regulation of several cellular processes involved in soft tissue wound healing and in response to cellular stress. A member of the mitogen-activated protein kinase family (MAPK), JNKs have been implicated in the regulation of inflammatory cell phenotype, as well as fibroblast, stem/progenitor cell, and epithelial cell biology. In this review, we discuss our understanding of JNKs in the regulation of cell behaviors related to tissue injury, pathology, and wound healing of soft tissues. Using models as diverse as Drosophila, mice, rats, as well as human tissues, research is now defining important, but sometimes conflicting roles for JNKs in the regulation of multiple molecular processes in multiple different cell types central to wound healing processes. In this review, we focus specifically on the role of JNKs in the regulation of cell behavior in the healing of skin, cornea, tendon, gingiva, and dental pulp tissues. We conclude that while parallels can be drawn between some JNK activities and the control of cell behavior in healing, the roles of JNK can also be very specific modes of action depending on the tissue and the phase of healing.

A practical composite risk score for the development of Haemolytic Uraemic Syndrome from Shiga toxin-producing Escherichia coli.

BACKGROUND: Haemolytic Uraemic Syndrome (HUS) is a serious complication of Shiga toxin-producing Escherichia coli (STEC) infection and the key reason why intensive health protection against STEC is required. However, although many potential risk factors have been identified, accurate estimation of risk of HUS from STEC remains challenging. Therefore, we aimed to develop a practical composite score to promptly estimate the risk of developing HUS from STEC. METHODS: This was a retrospective cohort study where data for all confirmed STEC infections in Ireland during 2013-15 were subjected to statistical analysis with respect to predicting HUS. Multivariable logistic regression was used to develop a composite risk score, segregating risk of HUS into 'very low risk' (0-0.4%), 'low risk' (0.5-0.9%), 'medium risk' (1.0-4.4%), 'high risk' (4.5-9.9%) and 'very high risk' (10.0% and over). RESULTS: There were 1397 STEC notifications with complete information regarding HUS, of whom 5.1% developed HUS. Young age, vomiting, bloody diarrhoea, Shiga toxin 2, infection during April to November, and infection in Eastern and North-Eastern regions of Ireland, were all statistically significant independent predictors of HUS. Demonstration of a risk gradient provided internal validity to the risk score: 0.2% in the cohort with 'very low risk' (1/430), 1.1% with 'low risk' (2/182), 2.3% with 'medium risk' (8/345), 3.1% with 'high risk' (3/98) and 22.2% with 'very high risk' (43/194) scores, respectively, developed HUS. CONCLUSION: We have developed a composite risk score which may be of practical value, once externally validated, in prompt estimation of risk of HUS from STEC infection.

CDC Safety Training Course for Ebola Virus Disease Healthcare Workers.

Response to sudden epidemic infectious disease emergencies can demand intensive and specialized training, as demonstrated in 2014 when Ebola virus disease (EVD) rapidly spread throughout West Africa. The medical community quickly became overwhelmed because of limited staff, supplies, and Ebola treatment units (ETUs). Because a mechanism to rapidly increase trained healthcare workers was needed, the US Centers for Disease Control and Prevention developed and implemented an introductory EVD safety training course to prepare US healthcare workers to work in West Africa ETUs. The goal was to teach principles and practices of safely providing patient care and was delivered through lectures, small-group breakout sessions, and practical exercises. During September 2014-March 2015, a total of 570 participants were trained during 16 course sessions. This course quickly increased the number of clinicians who could provide care in West Africa ETUs, showing the feasibility of rapidly developing and implementing training in response to a public health emergency.

Occurrence of pristine aerosol environments on a polluted planet.

Natural aerosols define a preindustrial baseline state from which the magnitude of anthropogenic aerosol effects on climate are calculated and are a major component of the large uncertainty in anthropogenic aerosol-cloud radiative forcing. This uncertainty would be reduced if aerosol environments unperturbed by air pollution could be studied in the present--day atmosphere, but the pervasiveness of air pollution makes identification of unperturbed regions difficult. Here, we use global model simulations to define unperturbed aerosol regions in terms of two measures that compare 1750 and 2000 conditions-the number of days with similar aerosol concentrations and the similarity of the aerosol response to perturbations in model processes and emissions. The analysis shows that the aerosol system in many present-day environments looks and behaves like it did in the preindustrial era. On a global annual mean, unperturbed aerosol regions cover 12% of the Earth (16% of the ocean surface and 2% of the land surface). There is a strong seasonal variation in unperturbed regions of between 4% in August and 27% in January, with the most persistent conditions occurring over the equatorial Pacific. About 90% of unperturbed regions occur in the Southern Hemisphere, but in the Northern Hemisphere, unperturbed conditions are transient and spatially patchy. In cloudy regions with a radiative forcing relative to 1750, model results suggest that unperturbed aerosol conditions could still occur on a small number of days per month. However, these environments are mostly in the Southern Hemisphere, potentially limiting the usefulness in reducing Northern Hemisphere forcing uncertainty.

Periostin as a multifunctional modulator of the wound healing response.

During tissue healing, the dynamic and temporal alterations required for effective repair occur in the structure and composition of the extracellular matrix (ECM). Matricellular proteins (MPs) are a group of diverse non-structural ECM components that bind cell surface receptors mediating interactions between the cell and its microenviroment, effectively regulating adhesion, migration, proliferation, signaling, and cell phenotype. Periostin (Postn), a pro-fibrogenic secreted glycoprotein, is defined as an MP based on its expression pattern and regulatory roles during development and healing and in disease processes. Postn consists of a typical signal sequence, an EMI domain responsible for binding to fibronectin, four tandem fasciclin-like domains that are responsible for integrin binding, and a C-terminal region in which multiple splice variants originate. This review focuses specifically on the role of Postn in wound healing and remodeling, an area of intense research during the last 10 years, particularly as related to skin healing and myocardium post-infarction. Postn interacts with cells through various integrin pairs and is an essential downstream effector of transforming growth factor-ß superfamily signaling. Across various tissues, Postn is associated with the pro-fibrogenic process: specifically, the transition of fibroblasts to myofibroblasts, collagen fibrillogenesis, and ECM synthesis. Although the complexity of Postn as a modulator of cell behavior in tissue healing is only beginning to be elucidated, its expression is clearly a defining event in moving wound healing through the proliferative and remodeling phases.

A Pooled Analysis Evaluating Renal Safety in Placebo- and Active Comparator-Controlled Phase III Trials of Multiple-Dose Injectable HPßCD-Diclofenac in Subjects with Acute Postoperative Pain.

OBJECTIVE : While injectable nonsteroidal anti-inflammatory drugs (NSAIDs) are a key component of postoperative multimodal analgesia, renal safety concerns may limit use in some patients. This study examined the renal safety of injectable HPßCD-diclofenac when given for ≤ 5 days following orthopedic or abdominal/pelvic surgery. METHODS : Pooled analysis of data from two randomized, placebo- and active comparator-controlled phase III trials in 608 total patients was conducted. Renal safety was assessed by examining treatment-emergent adverse events (AEs) and postoperative blood urea nitrogen (BUN) and serum creatinine shifts. RESULTS : There were three renal AEs each in the HPßCD-diclofenac (n = 318 patients) and placebo (n = 148 patients) groups, and two renal AEs in the ketorolac group (n = 142 patients). No significant difference in renal AE risk was detected for patients receiving HPßCD-diclofenac (RR: 1.40 [0.15,13.3]; P = 0.75) or ketorolac (RR: 2.08 [0.19,22.7]; P = 0.56) versus placebo. All renal AEs were mild or moderate in severity, and a single renal AE (acute renal failure in a patient receiving HPßCD-diclofenac) was treatment-related. One incidence of postoperative shift to high (> upper limit of normal) serum creatinine occurred in the HPßCD-diclofenac group (n = 2 in the ketorolac group). Mean changes in serum creatinine or BUN did not differ significantly between patients receiving HPßCD-diclofenac and placebo. CONCLUSIONS : While this analysis examined relatively brief exposure typical for parenterally administered analgesics in the postoperative setting in patients with largely normal renal function, the results suggest that HPßCD-diclofenac use for acute postoperative pain may not be associated with added renal safety risks over placebo in this patient population.

An ongoing measles outbreak linked to a suspected imported case, Ireland, April to June 2016.

We report an outbreak of measles which started in April 2016 and which, by 13 June, has resulted in 22 confirmed and five probable measles cases occurring in four regions of Ireland. Genotype B3 was identified. We describe the identification, ongoing investigation and control measures being implemented. This outbreak occurs during a period of very low measles transmission in Ireland, with only one confirmed case (imported) notified in 2016 before this event.