Harmonization of criteria and terminology in fetal rat skeletal evaluations.

BACKGROUND: A survey of laboratories in North American and Europe that routinely conduct fetal skeletal examinations was performed with the purpose of (1) understanding current terminology used for classifying skeletal findings in developmental toxicity (DT) studies and (2) understanding the criteria used to identify relatively common findings that sufficiently deviate from normal. The goal was to promote terminology harmonization and improve interlaboratory consistency in the criteria used to identify developmental anomalies. METHODS: The survey, designed based on terminology for developmental anomalies recommended by an international collaboration (Makris et al., Congenital Anomalies, 2009;49(3):123-246), was conducted by a subgroup (authors of this publication) of the Royal Society of Biology's International Register of Fetal Morphologists (IRFM). RESULTS: Individual and summarized anonymized responses are provided here. The authors, who are expert fetal morphologists with experience performing fetal examinations, reviewed the responses and generated recommendations on preferred terminology and criteria for determining when morphological variations deviate from normal and warrant recording of the findings for skeletal observations in Sprague Dawley (SD) fetal rats. The objective of these recommendations is to complement Makris et al. (Congenital Anomalies, 2009;49(3):123-246). CONCLUSION: The broad application will improve interlaboratory harmonization of recording fetal skeleton findings in developmental toxicity studies intended for regulatory submissions, including SEND (Standard for Exchange of Nonclinical Data).

Dairy cow hoof impact and slide measurements for common Ontario dairy farm floorings.

In the context of understanding lameness and injury from slipping, our objective was to characterize hoof impact and slide of 5 cows walking on 6 flooring surfaces commonly used in Ontario dairy farms: diamond-grooved concrete (DC), sanded epoxy-covered concrete (EC), grooved rubber mat (GR), high-profile rubber mat (HR), low-profile rubber mat (LR), and turf grass (TG; Kentucky bluegrass/fescue mix). Surface hardness was measured on each surface using a Clegg Impact Soil Tester. Five trained lactating Holstein cows were each walked over all 6 surfaces sequentially in a randomized order. Walking speeds were determined from 60-fps videos. A 3-axis accelerometer attached to the lateral claw of each hindfoot captured continuous horizontal (aH), vertical (aV), lateral (aTLat), and medial (aTMed) accelerations at 2,500 Hz during each trial, from which peak values were identified. Data from 45°-rosette strain gauges glued to the dorsal surface of both medial and lateral hooves allowed for the calculation of principal strains (ε1 and ε2). From continuous data, several data points were extracted from 3 to 6 stances/trial: peak values of aH, aV, and aT for the impact phase of the stance; midstance values of ε1 and ε2 as proxies for force on the foot; magnitudes of normal (i.e., consistent and repeatable) sliding on the surface during the support phase; and 3 timing events to capture the cadence of the motion. All aH and aV signals were inspected onscreen to identify irregularities between the end of impact and beginning of breakover that indicated hoof slipping, which was observed on all surfaces. The effects on all measured variables of surface, cow, speed, and hoof (and all significant higher-order factors) were assessed by ANOVA in SAS 9.4 (SAS Institute Inc.), after verifying data normality. Values of aHmax, indicating grip on the surface from highest to lowest, ranked the surfaces in this order: LR, DC, HR, GR, EC, and TG. Ranking on aVmax, indicating most to least cushioning of the hoof on impact, ranked the surfaces in this order: DC, HR, GR, EC, LR, and TG. Differences in ranking among these and other significant impact variables indicate that future studies of lameness on different surfaces need to include all significant variables identified here. We detected no surface and strain interactions in either the ε1 or ε2 strain, indicating that the surfaces do not affect the overall loads on the foot at midstance. Additionally, lateral and medial hooves may have different roles in a stance. The results highlight the capacity to evaluate flooring types with this technology, and the study provides a tool for future work to examine the role of flooring types in the causation of lameness.

Suppressors of Break-Induced Replication in Human Cells.

Short tandem DNA repeats are drivers of genome instability. To identify suppressors of break-induced mutagenesis human cells, unbiased genetic screens were conducted using a lentiviral shRNA library. The recipient cells possessed fragile non-B DNA that could induce DNA double-strand breaks (DSBs), integrated at an ectopic chromosomal site adjacent to a thymidine kinase marker gene. Mutagenesis of the thymidine kinase gene rendered cells resistant to the nucleoside analog ganciclovir (GCV). The screen identified genes that have established roles in DNA replication and repair, chromatin modification, responses to ionizing radiation, and genes encoding proteins enriched at replication forks. Novel loci implicated in BIR included olfactory receptors, the G0S2 oncogene/tumor suppressor axis, the EIF3H-METTL3 translational regulator, and the SUDS3 subunit of the Sin3A corepressor. Consistent with a role in suppressing BIR, siRNA knockdown of selected candidates increased the frequency of the GCVr phenotype and increased DNA rearrangements near the ectopic non-B DNA. Inverse PCR and DNA sequence analyses showed that hits identified in the screen increased genome instability. Further analysis quantitated repeat-induced hypermutagenesis at the ectopic site and showed that knockdown of a primary hit, COPS2, induced mutagenic hotspots, remodeled the replication fork, and increased nonallelic chromosome template switches.

Work-related injuries and attendance at a Canadian regional emergency department.

BACKGROUND: Monitoring trends in the burden of illness and injury attributable to work is key in assessing occupational health hazards; however, New Brunswick does not participate in the Canadian National Ambulatory Care Reporting System which itself does not collect details of occupation and industry. AIMS: We set out to determine the proportion of emergency department attendances that were attributable to a work-related cause. We also wanted to evaluate the recording of occupation in the electronic health record system, and to describe the characteristics of patients with a work-related presentation. METHODS: A retrospective observational study over a 1-year period was conducted using an administrative database obtained from Canadian Emergency Department Information System. Descriptive statistics are used to present the analysis of categorical and continuous data. RESULTS: A total of 49 365 patients were included for analysis. Two per cent of patients presented with a self-reported work-related condition. Health care and social assistance, construction, retail trade and manufacturing were the most common industries reported by patients. CONCLUSIONS: This study found the rate of work-related medical conditions to be substantially less than expected, and that occupation was not captured for any patients presenting to the emergency department with a work-related condition, despite a field being available in the electronic health record registration system. We were able to analyse the industry sectors for work-related presentations. The recording and coding of occupation and industry would significantly benefit occupational epidemiology in emergency medicine as well as potentially improving patient outcomes and health system efficiencies.

Stable G-quadruplex DNA structures promote replication-dependent genome instability.

G-quadruplex (G4)-prone structures are abundant in mammalian genomes, where they have been shown to influence DNA replication, transcription, and genome stability. In this article, we constructed cells with a single ectopic homopurine/homopyrimidine repeat tract derived from the polycystic kidney disease type 1 (PKD1) locus, which is capable of forming triplex (H3) and G4 DNA structures. We show that ligand stabilization of these G4 structures results in deletions of the G4 consensus sequence, as well as kilobase deletions spanning the G4 and ectopic sites. Furthermore, we show that DNA double-strand breaks at the ectopic site are dependent on the nuclease Mus81. Hypermutagenesis during sister chromatid repair extends several kilobases from the G4 site and breaks at the G4 site resulting in microhomology-mediated translocations. To determine whether H3 or G4 structures are responsible for homopurine/homopyrimidine tract instability, we derived constructs and cell lines from the PKD1 repeat, which can only form H3 or G4 structures. Under normal growth conditions, we found that G4 cell lines lost the G4 consensus sequence early during clonal outgrowth, whereas H3 cells showed DNA instability early during outgrowth but only lost reporter gene expression after prolonged growth. Thus, both the H3 and G4 non-B conformation DNAs exhibit genomic instability, but they respond differently to endogenous replication stress. Our results show that the outcomes of replication-dependent double-strand breaks at non-B-DNAs model the instability observed in microhomology-mediated break-induced replication (BIR). Marked variability in the frequency of mutagenesis during BIR suggests possible dynamic heterogeneity in the BIR replisome.

Operationalising coastal resilience to flood and erosion hazard: A demonstration for England.

Resilience is widely seen as an important attribute of coastal systems and, as a concept, is increasingly prominent in policy documents. However, there are conflicting ideas on what constitutes resilience and its operationalisation as an overarching principle of coastal management remains limited. In this paper, we show how resilience to coastal flood and erosion hazard could be measured and applied within policy processes, using England as a case study. We define resilience pragmatically, integrating what is presently a disparate set of policy objectives for coastal areas. Our definition uses the concepts of resistance, recovery and adaptation, to consider how the economic, social and environmental dimensions of coastal systems respond to change. We develop a set of composite indicators for each dimension, grounded empirically with reference to national geospatial datasets. A prototype Coastal Resilience Model (CRM) has been developed, which combines the dimensions and generates a quantitative resilience index. We apply it to England's coastal hazard zone, capturing a range of different stakeholder perspectives using relative indicator weightings. The illustrative results demonstrate the practicality of formalising and quantifying resilience. To re-focus national policy around the stated desire of enhancing resilience to coastal flooding and erosion would require firm commitment from government to monitor progress towards resilience, requiring extension of the present risk-based approach, and a consensus methodology in which multiple (and sometimes conflicting) stakeholder values are explicitly considered. Such a transition may also challenge existing governance arrangements at national and local levels, requiring incentives for coastal managers to engage with and apply this new approach, more departmental integration and inter-agency cooperation. The proposed Coastal Resilience Model, with the tools to support planning and measure progress, has the potential to help enable this transition.

Replication stress at microsatellites causes DNA double-strand breaks and break-induced replication.

Short tandemly repeated DNA sequences, termed microsatellites, are abundant in the human genome. These microsatellites exhibit length instability and susceptibility to DNA double-strand breaks (DSBs) due to their tendency to form stable non-B DNA structures. Replication-dependent microsatellite DSBs are linked to genome instability signatures in human developmental diseases and cancers. To probe the causes and consequences of microsatellite DSBs, we designed a dual-fluorescence reporter system to detect DSBs at expanded (CTG/CAG) n and polypurine/polypyrimidine (Pu/Py) mirror repeat structures alongside the c-myc replication origin integrated at a single ectopic chromosomal site. Restriction cleavage near the (CTG/CAG)100 microsatellite leads to homology-directed single-strand annealing between flanking AluY elements and reporter gene deletion that can be detected by flow cytometry. However, in the absence of restriction cleavage, endogenous and exogenous replication stressors induce DSBs at the (CTG/CAG)100 and Pu/Py microsatellites. DSBs map to a narrow region at the downstream edge of the (CTG)100 lagging-strand template. (CTG/CAG) n chromosome fragility is repeat length-dependent, whereas instability at the (Pu/Py) microsatellites depends on replication polarity. Strikingly, restriction-generated DSBs and replication-dependent DSBs are not repaired by the same mechanism. Knockdown of DNA damage response proteins increases (Rad18, polymerase (Pol) η, Pol κ) or decreases (Mus81) the sensitivity of the (CTG/CAG)100 microsatellites to replication stress. Replication stress and DSBs at the ectopic (CTG/CAG)100 microsatellite lead to break-induced replication and high-frequency mutagenesis at a flanking thymidine kinase gene. Our results show that non-B structure-prone microsatellites are susceptible to replication-dependent DSBs that cause genome instability.

The Role of Noncoding Variants in Heritable Disease.

The genetic basis of disease has largely focused on coding regions. However, it has become clear that a large proportion of the noncoding genome is functional and harbors genetic variants that contribute to disease etiology. Here, we review recent examples of inherited noncoding alterations that are responsible for Mendelian disorders or act to influence complex traits. We explore both rare and common genetic variants and discuss the wide range of mechanisms by which they affect gene regulation to promote disease. We also debate the challenges and progress associated with identifying and interpreting the functional and clinical significance of genetic variation in the context of the noncoding regulatory landscape.

Conceptualising, evaluating and communicating uncertainty in forensic science: Identifying commonly used tools through an interdisciplinary configurative review.

This study provides a set of tools for conceptualising, evaluating and communicating uncertainty in forensic science. Given that the concept of uncertainty is one that transcends disciplinary boundaries, an interdisciplinary configurative review was carried out incorporating the disciplines of medicine, environmental science and economics, in order to identify common themes which could have valuable applications to the discipline of forensic science. Critical Interpretive Synthesis was used to develop sub-synthetic and synthetic constructs which interpreted and synthesised the underlying evidence and codes. This study provides three toolkits, one each for conceptualisation, evaluation and communication. The study identified an underlying theme concerning the obstacles that would need to be overcome for the effective application of these toolkits and achieving effective conceptualisation, evaluation and communication of uncertainty in forensic science to lay-stakeholders. These toolkits offer a starting point for developing the conversation for achieving greater transparency in the communication of uncertainty. They also have the potential to offer stakeholders enhanced understanding of the nuances and limitations of forensic science evidence and enable more transparent evaluation and scrutiny of the reliability, relevance and probative value of forensic materials in a crime reconstruction.

Consensus guidelines for interventional cardiology services delivery during covid-19 pandemic in Australia and new Zealand.

The global coronavirus disease (COVID-19) pandemic poses an unprecedented stress on healthcare systems internationally. These Health system-wide demands call for efficient utilisation of resources at this time in a fair, consistent, ethical and efficient manner would improve our ability to treat patients. Excellent co-operation between hospital units (especially intensive care unit [ICU], emergency department [ED] and cardiology) is critical in ensuring optimal patient outcomes. The purpose of this document is to provide practical guidelines for the effective use of interventional cardiology services in Australia and New Zealand. The document will be updated regularly as new evidence and knowledge is gained with time. Goals Considerations.

Prospective assessment of resection margin status following pancreaticoduodenectomy for pancreatic ductal adenocarcinoma after standardisation of margin definitions.

BACKGROUND: Surgical resection remains the only curative treatment for pancreatic ductal adenocarcinoma (PDAC). The prognostic value of resection margin status following pancreatoduodenectomy (PD) remains controversial. Standardised pathological assessment increases positive margins but limited data is available on the significance of involved margins. We investigated the impact of resection margin status in PDAC on patient outcome. METHOD: We identified all patients with PD for PDAC at one pancreatic cancer centre between August 2008 and December 2014. Demographic, operative, adjuvant therapeutic and survival data was obtained. Pathology data including resection margin status of specific anatomic margins was collected and analysed. RESULTS: 107 patients were included, all pathologically staged as T3 with 102 N1. 87.9% of patients were R1 of which 53.3% showed direct extension to the resection margin. Median survival for R0 patients versus R1<1 mm and R1 = 0 mm was 28.4 versus 15.4 and 25.1 versus 13.4 months. R1 = 0 mm status remained a predictor of poor outcome on multivariate analysis. Evaluation of individual margins (R1<1 mm) showed the SMV and SMA margins were associated with poorer overall survival. Multiple involved margins impacted negatively on outcome. SMA margin patient outcome with R1 = 1-1.9 mm was similar to R1=>2 mm. CONCLUSION: Using an R1 definition of <1 mm and standardised pathology we demonstrate that R1 rates in PDAC can approach 90%. R1 = 0 mm remained an independent prognostic factor for overall survival. Using R1<1 mm we have shown that involvement of medial margins and multiple margins has significant negative impact on overall survival. We conclude that not all margin positivity has the same prognostic significance.

Network meta-analysis comparing techniques and outcomes of stump closure after distal pancreatectomy.

BACKGROUND: The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy remains high, and different pancreatic stump closure techniques have been used to reduce the incidence. A network meta-analysis was undertaken to compare the most frequently performed pancreatic stump closure techniques after distal pancreatectomy and determine the technique associated with the lowest POPF rate. METHODS: A systematic search of the Scopus, PubMed, MEDLINE and Embase databases was conducted to identify eligible RCTs. The primary outcome was the occurrence of clinically relevant POPF. Secondary outcomes were duration of operation, blood loss, intrabdominal collections, postoperative complications and 30-day mortality. RESULTS: Sixteen RCTs including 1984 patients and eight different pancreatic stump closure techniques were included in the network meta-analysis. Patch coverage of the pancreatic stump (round ligament or seromuscular patch) after stapler or suture closure ranked best, with the lowest rates of clinically relevant POPF, lowest volume of intraoperative blood loss, fewer intra-abdominal abscesses, and lower rates of overall complications and 30-day mortality. Round ligament patch closure outperformed seromuscular patch closure in preventing clinically relevant POPF with a significantly larger cohort for comparative analysis. Pancreaticoenteric anastomotic closure consistently ranked poorly for most reported postoperative outcomes. CONCLUSION: Patch coverage after stapler or suture closure has the lowest POPF rate and best outcomes among stump closure techniques after distal pancreatectomy.

ANTECEDENTES: La incidencia de fístula pancreática (postoperative pancreatic fistula, POPF) tras una pancreatectomía distal sigue siendo alta y se han utilizado diferentes técnicas para el cierre del muñón pancreático con la intención de reducir su incidencia. Se realizó un metaanálisis en red para comparar las técnicas de cierre del muñón pancreático realizadas con más frecuencia después de la pancreatectomía distal y determinar qué técnica se asocia a una menor tasa de POPF. MÉTODOS: Se realizó una búsqueda sistemática en las bases de datos Scopus, PubMed, Medline y EMBASE de los RCTs que podían ser incluidos en estudio. La variable principal fue la aparición de POPF clínicamente relevante. Las variables secundarias fueron el tiempo operatorio, la pérdida de sangre, las colecciones intraabdominales, las complicaciones postoperatorias y la mortalidad a los 30 días. RESULTADOS: En el metaanálisis se incluyeron 16 RCTs con 1.984 pacientes y 8 técnicas diferentes de cierre del muñón pancreático. Los mejores resultados (menor tasa de POPF clínicamente relevante, menor pérdida sanguínea intraoperatoria, menor número de abscesos intraabdominales, menor tasa de complicaciones generales y menor mortalidad a los 30 días) se obtuvieron con el refuerzo del muñón pancreático con parches (de ligamento redondo o seromuscular), seguidos del grapado quirúrgico o la sutura simple. El cierre con parche del ligamento redondo fue superior al parche seromuscular en la prevención de POPF clínicamente relevante en una cohorte suficiente para el análisis estadístico comparativo. Los peores resultados en la mayoría de las variables postoperatorias se obtuvieron con el cierre simple. CONCLUSIÓN: En la pancreatectomía distal, la menor tasa de POPF y los mejores resultados perioperatorios se obtuvieron con el refuerzo con parches, seguidos del grapado quirúrgico o la sutura simple.

Multicentre observational cohort study of implementation and outcomes of laparoscopic distal pancreatectomy.

BACKGROUND: Laparoscopic distal pancreatectomy (LDP) is increasingly being performed as an alternative to open surgery. Whether the implementation and corresponding learning curve of LDP have an impact on patient outcome is unknown. The aim was to investigate the temporal trends in practice across UK centres. METHODS: This was a retrospective multicentre observational cohort study of LDP in 11 tertiary referral centres in the UK between 2006 and 2016. The learning curve was analysed by pooling data for the first 15 consecutive patients who had LDP and examining trends in surgical outcomes in subsequent patients. RESULTS: In total, 570 patients underwent LDP, whereas 888 underwent open resection. For LDP the median duration of operation was 240 min, with 200 ml blood loss. The conversion rate was 12·1 per cent. Neuroendocrine tumours (26·7 per cent) and mucinous cystic neoplasms (19·7 per cent) were commonest indications. The proportion of LDPs increased from 24·4 per cent in 2006-2009 (P1) to 46·0 per cent in 2014-2016 (P3) (P < 0·001). LDP was increasingly performed for patients aged 70 years or more (16 per cent in P1 versus 34·4 per cent in P3; P = 0·002), pancreatic ductal adenocarcinoma (6 versus 19·1 per cent; P = 0·005) and advanced malignant tumours (27 versus 52 per cent; P = 0·016). With increasing experience, there was a trend for a decrease in blood transfusion rate (14·1 per cent for procedures 1-15 to 3·5 per cent for procedures 46-75; P = 0·008), ICU admissions (32·7 to 19·2 per cent; P = 0·021) and median duration of hospital stay (7 (i.q.r. 5-9) to 6 (4-7) days; P = 0·002). After 30 procedures, a decrease was noted in rates of both overall morbidity (57·7 versus 42·2 per cent for procedures 16-30 versus 46-75 respectively; P = 0·009) and severe morbidity (18·8 versus 9·7 per cent; P = 0·031). CONCLUSION: LDP has increased as a treatment option for lesions of the distal pancreas as indications for the procedure have expanded. Perioperative outcomes improved with the number of procedures performed.

ANTECEDENTES: Cada día se utiliza más la pancreatectomía distal laparoscópica (laparoscopic distal pancreatectomy, LDP) como una alternativa a la cirugía abierta. Se desconoce si la implementación y la correspondiente curva de aprendizaje de la LDP tienen impacto en los resultados. El objetivo fue investigar las tendencias relacionadas con su implementación en los centros del Reino Unido a los largo del tiempo. MÉTODOS: Se realizó el estudio observacional retrospectivo y multicéntrico de una cohorte de LDP en once centros de referencia terciarios del Reino Unido entre 2006-2016. Se analizó la curva de aprendizaje agrupando los 15 primeros pacientes consecutivos de LDP y se compararon los resultados quirúrgicos con los obtenidos en los pacientes subsiguientes. RESULTADOS: En total, se incluyeron 570 pacientes con LDP y 888 con resección abierta. Para el LDP, la mediana de tiempo operatorio fue de 240 minutos con 200 ml de pérdida de sangre. La tasa de conversión fue del 12,2%. Las indicaciones más frecuentes fueron los tumores neuroendocrinos (26,7%) y las neoplasias quísticas mucinosas (19,7%). La proporción de LDP aumentó del 24% al 46% (de 2006-2009 a 2014-2016; P < 0,001). La LDP se realizó cada vez con mayor frecuencia en pacientes de ≥ 70 años (15,8% versus 34,4%, P = 0,002), en pacientes con adenocarcinoma ductal pancreático (6,5% versus 19,1%, P = 0,005) y en pacientes con tumores malignos avanzados (27,3% versus 51,85%, P = 0,016). Con el aumento de la experiencia, disminuyeron las tendencias de la tasa de transfusión sanguínea (14,1% al 3,5%, P = 0,008), los ingresos en la UCI (32,7% a 19,2%, P = 0.021) y la mediana de la duración de la estancia hospitalaria (7 (rango intercuartílico 5-9) a 6 (rango intercuartilico 4-7) días, P = 0,002). Tras 30 procedimientos, disminuyeron tanto la morbilidad global (57,7% versus 42,2%, P = 0,009) como las tasas de morbilidad grave (21,5% versus 14,6%, P = 0,022). CONCLUSIÓN: La pancreatectomía distal laparoscópica se ha incrementado como una opción de tratamiento para las lesiones del páncreas distal a medida que se han ido ampliando las indicaciones del procedimiento. Los resultados perioperatorios mejoran con el número de procedimientos realizados.

Under-vaccinated groups in Europe and their beliefs, attitudes and reasons for non-vaccination; two systematic reviews.

BACKGROUND: Despite effective national immunisation programmes in Europe, some groups remain incompletely or un-vaccinated ('under-vaccinated'), with underserved minorities and certain religious/ideological groups repeatedly being involved in outbreaks of vaccine preventable diseases (VPD). Gaining insight into factors regarding acceptance of vaccination of 'under-vaccinated groups' (UVGs) might give opportunities to communicate with them in a trusty and reliable manner that respects their belief system and that, maybe, increase vaccination uptake. We aimed to identify and describe UVGs in Europe and to describe beliefs, attitudes and reasons for non-vaccination in the identified UVGs. METHODS: We defined a UVG as a group of persons who share the same beliefs and/or live in socially close-knit communities in Europe and who have/had historically low vaccination coverage and/or experienced outbreaks of VPDs since 1950. We searched MEDLINE, EMBASE and PsycINFO databases using specific search term combinations. For the first systematic review, studies that described a group in Europe with an outbreak or low vaccination coverage for a VPD were selected and for the second systematic review, studies that described possible factors that are associated with non-vaccination in these groups were selected. RESULTS: We selected 48 articles out of 606 and 13 articles out of 406 from the first and second search, respectively. Five UVGs were identified in the literature: Orthodox Protestant communities, Anthroposophists, Roma, Irish Travellers, and Orthodox Jewish communities. The main reported factors regarding vaccination were perceived non-severity of traditional "childhood" diseases, fear of vaccine side-effects, and need for more information about for example risk of vaccination. CONCLUSIONS: Within each UVG identified, there are a variety of health beliefs and objections to vaccination. In addition, similar factors are shared by several of these groups. Communication strategies regarding these similar factors such as educating people about the risks associated with being vaccinated versus not being vaccinated, addressing their concerns, and countering vaccination myths present among members of a specific UVG through a trusted source, can establish a reliable relationship with these groups and increase their vaccination uptake. Furthermore, other interventions such as improving access to health care could certainly increase vaccination uptake in Roma and Irish travellers.

Patient reported outcomes of autologous fat grafting after breast cancer surgery.

INTRODUCTION: Autologous fat grafting (AFG) can be used as an adjunct in breast cancer surgery to improve contour defects. Few previous studies have assessed patient reported outcomes (PROs) for AFG. This study analysed AFG use and assessed PROs in terms of physical and psychosocial well-being. MATERIALS AND METHODS: All patients undergoing AFG were identified from a prospective database and asked to complete the validated BREAST-Q questionnaire and a tool to assess patient-perceived change after AFG (5-point Likert-type scale). Descriptive statistics were computed for all BREAST-Q and perceived change subscales. Independent sample t-tests were conducted to compare scores on each of the BREAST-Q and perceived change subscales by type of breast cancer surgery and radiotherapy status. RESULTS: 156 AFG sessions were performed over 4 years on 119 breasts in 88 patients. Fifty-seven patients received AFG after reconstruction and 19 after breast conserving surgery. Forty-six patients (52%) completed the questionnaire. BREAST-Q scores (out of 100) and patient-perceived change after AFG (out of 5) were respectively: 54 and 4.0 for Breast satisfaction, 69 and 3.3 for Physical well-being and 60 and 3.6 for Psychosocial well-being. Radiotherapy status and type of surgery made little difference. Number of AFG procedures positively correlated with perceived improvement. DISCUSSION: Autologous fat grafting was associated with improved patient satisfaction despite small volumes transferred. BREAST-Q scores were comparable with previously published series on reconstructive breast surgery. Perceived change after AFG was no different in patients receiving radiotherapy.

Implementation of a 3D ocean model to understand upland lake wind-driven circulation.

A community numerical ocean model is used to extend the understanding of wind-driven circulation in small upland lakes. A 3D model of a case study lake (Llyn Conwy, Wales, UK) is calibrated against measured velocity profiles via adjustment of the bottom roughness coefficient. Validation against a separate set of measured velocity profiles confirms the ability of the model to resolve key features of the flow field. Sensitivity analysis shows that the velocity field responds rapidly to changes in the wind forcing. Analysis of the gross circulation using Empirical Orthogonal Functions reveals a persistent two-gyre circulation pattern in the upper half layer of the water column driven by the interaction of wind and bathymetry. At the bottom, the flow is characterised by locally strong currents and analysis of vertical circulation over short time scales shows strong currents in the deepest parts of the lake basin and the responsiveness of the water column to changes in wind speed and direction. Even in small lakes, the assumption of uniform wind stress across the water surface is not always justified and topographic sheltering or other catchment roughness effects give rise to heterogeneity in the wind field. An idealized experiment for the case study lake shows that differences in circulation emerge if the wind stress is allowed to vary across the lake. Energetic wind forcing in upland areas can drive an energetic lake circulation that has important implications for mixing and sediment dynamics. 3D numerical modelling of wind-driven circulation should be more widely used to provide insights into physical limnology to support a wide range of ecological, biogeochemical and palaeoenvironmental studies.

Body image and psychological distress in nipple-sparing mastectomy: the roles of self-compassion and appearance investment.

OBJECTIVE: Women with breast cancer face threats to body image following surgery. Nipple-sparing mastectomy with immediate breast reconstruction (NSM + IBR) may minimise body image disturbance as this preserves the woman's skin and areola complex. We assessed levels of body image disturbance and psychological distress in women undergoing NSM + IBR. To further understand the body image-distress relationship, we investigated the potential moderating effect of self-compassion and appearance investment on this relationship. METHODS: Women diagnosed with breast cancer (N = 75) who had undergone NSM + IBR completed online questionnaires including the Body Image Scale, general (Depression, Anxiety and Stress Scales) and cancer-specific (Impact of Event Scale) psychological distress and Self-Compassion Scale and Appearance Schemas Inventory - Revised. RESULTS: Mean general and cancer-specific psychological distress scores were within normal ranges, and body image disturbance was moderately low. Body image was positively correlated with depression, stress, Impact of Event Scale scores and appearance investment and negatively correlated with self-compassion. MANCOVA analyses indicated a significant moderating effect of self-compassion and appearance investment on the body image disturbance-distress relationship (for depression, stress and intrusion), such that participants with high self-compassion and low appearance investment experienced lower distress than individuals with low self-compassion and high appearance investment. CONCLUSIONS: Moderately low levels of psychological distress and body image disturbance suggest NSM + IBR may minimise adverse psychological impacts of mastectomy. Increased body image disturbance was associated with psychological distress and moderated by self-compassion and appearance investment, suggesting a potential role for these characteristics as the focus of psychological interventions to minimise the negative impacts of mastectomy. Copyright © 2016 John Wiley & Sons, Ltd.

Correlation of Ki-67 indices from biopsy and resection specimens of neuroendocrine tumours.

INTRODUCTION Neuroendocrine tumours (NETs) are a heterogeneous group of tumours with a highly variable presentation and prognosis. Management decisions are complex. Ki-67 levels in tissue samples are a key indicator used to grade tumours and guide treatment. This study assessed whether the Ki-67 index and tumour grade generated from tissue samples correlated with that assessed in resection specimens. METHODS This was a retrospective cohort analysis of all patients who had both a tissue sample and a resection specimen analysed in our trust, a tertiary referral centre, during 2012 and 2013. RESULTS Data from 36 patients were reviewed. Ki-67 indices from tissue samples and resection specimens showed strong correlation (r=0.95, p<0.001). Tumour grading was the same in the tissue sample and resection specimens for 22 patients (61.1%). In four patients (11.1%), the tissue sample overestimated the grade while in ten (27.8%), the sample underestimated the grade. CONCLUSIONS In most cases, the Ki-67 index and tumour grade from the tissue sample matched that of the resection specimen. However, in nearly 40% of cases, the tissue sample grading did not match the resection tumour grading. In the majority of these, the tissue sample underestimated disease activity. A low Ki-67 index in a tissue sample should therefore be taken as provisional and should not, in isolation, persuade clinicians to choose a more conservative treatment approach if there is clinical, biochemical or radiological evidence suggestive of a more aggressive disease pathology.

Animal-to-Human Dose Translation of Obiltoxaximab for Treatment of Inhalational Anthrax Under the US FDA Animal Rule.

Obiltoxaximab, a monoclonal antibody against protective antigen (PA), is approved for treatment of inhalational anthrax under the US Food and Drug Administration's (FDA) Animal Rule. The human dose was selected and justified by comparing observed obiltoxaximab exposures in healthy and infected New Zealand White rabbits and cynomolgus macaques to observed exposures in healthy humans, to simulated exposures in healthy and infected humans, and to serum PA levels in infected animals. In humans, at 16 mg/kg intravenous, obiltoxaximab AUC was >2 times that in animals, while maximum serum concentrations were comparable to those in animals and were maintained in excess of the concentration required for PA neutralization in infected animals for 2-3 weeks. Obiltoxaximab 16 mg/kg in humans provided exposure beyond that of 16 mg/kg in animals, ensuring a sufficient duration of PA neutralization to allow for adaptive immunity development. Our approach to dose translation may be applicable to other agents being developed under the Animal Rule.