Socio-economic and ethnic disparities in childhood cancer survival, Yorkshire, UK.

BACKGROUND: Establishing the existence of health inequalities remains a high research and policy agenda item in the United Kingdom. We describe ethnic and socio-economic differences in paediatric cancer survival, focusing specifically on the extent to which disparities have changed over a 20-year period. METHODS: Cancer registration data for 2674 children (0-14 years) in Yorkshire were analysed. Five-year survival estimates by ethnic group (south Asian/non-south Asian) and Townsend deprivation fifths (I-V) were compared over time (1997-2016) for leukaemia, lymphoma, central nervous system (CNS) and other solid tumours. Hazard ratios (HR: 95% CI) from adjusted Cox models quantified the joint effect of ethnicity and deprivation on mortality risk over time, framed through causal interpretation of the deprivation coefficient. RESULTS: Increasing deprivation was associated with significantly higher risk of death for children with leukaemia (1.11 (1.03-1.20)) and all cancers between 1997 and 2001. While we observed a trend towards reducing differences in survival over time in this group, a contrasting trend was observed for CNS tumours whereby sizeable variation in outcome remained for cases diagnosed until 2012. South Asian children with lymphoma had a 15% reduced chance of surviving at least 5 years compared to non-south Asian, across the study period. DISCUSSION: Even in the United Kingdom, with a universally accessible healthcare system, socio-economic and ethnic disparities in childhood cancer survival exist. Findings should inform where resources should be directed to provide all children with an equitable survival outcome following a cancer diagnosis.

Comparison of a novel form of zinc with zinc oxide bolus licensed for prevention of facial eczema, and interaction with copper oxide in sheep.

To evaluate a novel elemental zinc bolus compared with a registered positive control zinc oxide bolus and assess serum zinc concentrations following concomitant treatment with a capsule containing copper oxide needles. Forty Romney-cross ewes were randomly allocated in a 2 × 2 factorial design study. On Day 0, 20 ewes received novel boluses containing elemental zinc (Investigational Veterinary Product, IVP) while 20 received a zinc oxide bolus (control; CP). Half the animals in each zinc treatment group (n = 10) were treated with a copper oxide needle capsule [Copasure® - Ewe]. Weekly, from Day -7 to 56, all ewes were assessed for signs of photosensitization, and for 10 ewes from each zinc treatment groups, samples were collected for analysis of serum GGT activity, serum zinc concentrations, faecal zinc concentrations and on Days -7 and 56, liver copper concentrations. Multivariable random-effects models assessed the effects of zinc treatment, copper treatment, treatment interactions and time on all analytes. Regression models examined associations between serum and faecal zinc concentrations and GGT activity. Low spore numbers indicated low Pithomyces chartarum challenge. Serum zinc levels were significantly higher in the IVP than in the CP group [p < 0.0001] and varied by time [p < 0.001] and positively associated with faecal zinc concentration [p < 0.001]. Copper treatment did not affect serum zinc [p = 0.82] or faecal zinc [p = 0.92] concentrations. Liver copper concentrations did not differ between zinc treatment groups on Day -7 [p = 0.6] or Day 56 [p = 0.95]. Only the CP/no copper group had no increase in liver copper concentrations.

Specimen Collection for Translational Studies in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by painful nodules, sinus tracts, and scars occurring predominantly in intertriginous regions. The prevalence of HS is currently 0.053-4%, with a predominance in African-American women and has been linked to low socioeconomic status. The majority of the reported literature is  retrospective, population based, epidemiologic studies. In this regard, there is a need to establish a repository of biospecimens, which represent appropriate gender and racial demographics amongst HS patients. These efforts will diminish knowledge gaps in understanding the disease pathophysiology. Hence, we sought to outline a step-by-step protocol detailing how we established our HS biobank to facilitate the formation of other HS tissue banks. Equipping researchers with carefully detailed processes for collection of HS specimens would accelerate the accumulation of well-organized human biological material. Over time, the scientific community will have access to a broad range of HS tissue biospecimens, ultimately leading to more rigorous basic and translational research. Moreover, an improved understanding of the pathophysiology is necessary for the discovery of novel therapies for this debilitating disease. We aim to provide high impact translational research methodology for cutaneous biology research and foster multidisciplinary collaboration and advancement of our understanding of cutaneous diseases.

The construction and implementation of a clinical decision-making algorithm reduces the cost of adult fracture clinic visits by up to £104,800 per year: a quality improvement study.

INTRODUCTION Inappropriate referrals to the new patient fracture clinic unnecessarily consume hospital resources and many hospitals lack clear guidelines as to what should be referred. Many of these injuries can be definitively managed by the emergency department. Our aim was to construct and disseminate a clinical decision-making algorithm to reduce the frequency of inappropriate referrals to fracture clinics at our institution, to improve the management of patients with minor injuries and save the hospital and the patient the cost of unnecessary visits. MATERIALS AND METHODS Data were prospectively collected for all new fracture clinic referrals over two separate 1-week cycles with cohorts of 94 and 74 patients, respectively. After the first cycle, the referral algorithm was disseminated both electronically (intranet) and orally (presentations to emergency department staff). The results of this intervention were examined in the second cycle, which took place 6 months after the first cycle. RESULTS The introduction of this algorithm significantly reduced inappropriate referrals by almost 20% (P = 0.0445). DISCUSSION This simple intervention highlighted a potential annual cost saving of up to £104,000. We advocate the use of this concise algorithm in improving the efficiency of the referral system to fracture clinics.

Epidermal aquaporin-3 is increased in the cutaneous burn wound.

INTRODUCTION: Aquaporins (AQP) are a family of transmembrane proteins that transport water and small solutes such as glycerol across cell membranes. It is a mediator of transcellular water flow and plays an important role in maintaining intra/extracellular fluid homeostasis by facilitating water transport in response to changing osmotic gradients. In the skin, AQPs permit rapid, regulated, and selective water permeability and have been demonstrated to play a role in skin hydration, cell proliferation, migration, immunity, and wound healing. However, the expression of AQP-3 in the cutaneous burn wound has never been elucidated. We sought to assess the expression of AQP-3 in patients with burn wounds. METHODS: A fresh full thickness biopsy sample was taken from the center of the burn wound, the burn wound edge, and the graft donor site in 7 patients (n=21), approximately 3-7 days post injury. Fixed, paraffin embedded sections were stained using AQP-3 specific antibody and examined by immunofluorescence. Fresh samples were processed to quantify AQP-3 protein expression with Western blot analysis. RESULTS: The central portion of the burn wound revealed destruction of the epidermis and dermis with no AQP-3 present. Along the burn wound edge where the epidermal architecture was disrupted, there was robust AQP-3 staining. Western blot analysis demonstrated deeper staining along the burn wound edge compared to unburned skin (control). Quantification of the protein shows a significant amount of AQP-3 expression along the burn wound edge (3.6±0.34) compared to unburned skin (2.1±0.28, N=7, *p<0.05). There is no AQP-3 expression in the burn wound center. CONCLUSION: AQP-3 expression is increased in the burn wound following injury. While its role in wound healing has been defined, we report for the first time the effect of cutaneous burns on AQP-3 expression. Our data provides the first step in determining its functional role in burn wounds. We hypothesize that development of AQP3 targeted therapies may improve burn wound healing.

Severe hyperkalaemia: demographics and outcome.

BACKGROUND: Few studies have evaluated the prevalence of severe hyperkalaemia in unselected patient populations. We identified all episodes of severe hyperkalaemia occurring in 1 year, and described patient demographics, clinical response and outcome. We also assessed junior doctor knowledge of its causes and significance. MATERIALS AND METHODS: A retrospective interrogation of the database of the regional biochemical laboratory identified all episodes of severe hyperkalaemia (K≥ 6.5 mmol/L) occurring in 2011. The understanding of trainee doctors of the importance, causes and treatment of severe hyperkalaemia was assessed by structured questionnaire. RESULTS: Severe hyperkalaemia was recorded in 433 samples (365 patients) giving a prevalence of 0.11%. Thirty-six per cent of episodes occurred in patients under the care of a nephrologist, who were significantly younger than those not under the care of a nephrologist. In the nephrology cohort, 86% occurred in patients with chronic kidney disease (CKD), the majority of which had CKD Stage 5. In the non-nephrology cohort, only 65% occurred in the context of CKD, which was equally distributed between Stages 3 and 5 CKD. In both patient groups, roughly 50% of episodes occurred in association with acute kidney injury (AKI). Acute mortality (death within 48 h of documented severe hyperkalaemia) was higher in the non-nephrology compared with the nephrology cohort. Time to repeat serum potassium was influenced by the clinical setting with shorter time to repeat for acute care compared with ward settings. Assessment of trainee doctor's knowledge suggested significant deficiencies in relation to severe hyperkalaemia. CONCLUSIONS: The prevalence of severe hyperkalaemia was low and occurred predominantly in the context of CKD and/or AKI. The majority of episodes occurred in patients not under the care of a nephrologist. Variability in time to repeat serum potassium levels suggested deficiencies in care, and assessment of trainee doctor's knowledge suggests the need for further educational initiatives to highlight its importance.

Combination of HIF-1α gene transfection and HIF-1-activated bone marrow-derived angiogenic cell infusion improves burn wound healing in aged mice.

Impaired burn wound healing in the elderly represents a major clinical problem. Hypoxia-inducible factor-1 (HIF-1) is a transcriptional activator that orchestrates the cellular response to hypoxia. Its actions in dermal wounds promote angiogenesis and improve healing. In a murine burn wound model, aged mice had impaired wound healing associated with reduced levels of HIF-1. When gene therapy with HIF-1 alone did not correct these deficits, we explored the potential benefit of HIF-1 gene therapy combined with the intravenous infusion of bone marrow-derived angiogenic cells (BMDACs) cultured with dimethyloxalylglycine (DMOG). DMOG is known to reduce oxidative degradation of HIF-1. The mice treated with a plasmid DNA construct expressing a stabilized mutant form of HIF-1α (CA5-HIF-1α)+BMDACs had more rapid wound closure. By day 17, there were more mice with completely closed wounds in the treated group (χ(2), P=0.05). The dermal blood flow measured by laser Doppler showed significantly increased wound perfusion on day 11. Homing of BMDACs to the burn wound was dramatically enhanced by CA5-HIF-1α gene therapy. HIF-1α mRNA expression in the burn wound was increased after transfection with CA5-HIF-1α plasmid. Our findings offer insight into the pathophysiology of burns in the elderly and point to potential targets for developing new therapeutic strategies.

Plantar fasciitis and the calcaneal spur: Fact or fiction?

BACKGROUND: Plantar fasciitis is a common diagnosis in patients presenting with heel pain. The presence of co-existing calcaneal spurs has often been reported but confusion exists as to whether it is a casual or significant association. METHODS: The lateral heel radiographs of nineteen patients with a diagnosis of plantar fasciitis and nineteen comparison subjects with a lateral ankle ligament sprain matched for age and sex, were reviewed independently by two observers. Objective measurements of calcaneal spur length and a subjective grading of spur size were recorded. RESULTS: There was a significantly higher prevalence of calcaneal spurs in the cases than the comparison group (89% versus 32%; McNemar chi-square=9.09, df=2, p=0.00257). There was good inter- and intra-observer agreement. CONCLUSION: The current study has demonstrated a significant association between plantar fasciitis and calcaneal spur formation. Further research is warranted to assess whether the association is causal.

Current Insights into the role of HIF-1 in cutaneous wound healing.

Hypoxia Inducible Factor-1 (HIF-1) is considered the major coordinator of the cellular adaptive response to hypoxia. Over recent years, its activity in the context of wound healing has been the object of increasing investigation. On the molecular level, HIF-1 transcriptional target products have been shown to regulate the process of endothelial cell survival, migration and proliferation (VEGF, ANGPT-1, ANGPT-2, ANGPT-4, FGF-2, PlGF, PDGF-B, RGC-32), vascular smooth muscle cell migration and proliferation (FGF-2, EGF, PDGF, thrombospondin) and mobilization of Circulating Angiogenic Cells to the periphery (SFD-1/CXCR4). Studies on the effect of HIF-1 on the expression and activity of extracellular cell matrix modifying enzymes, such as MMPs and prolidase, have been conducted in the context of tumor angiogenesis and metastasis, and have resulted in controversial findings. A growing body of evidence suggests that HIF-1 also affects reepithelialization of the wound bed, through increasing keratinocyte migration, but decreasing their proliferation. Diminished HIF-1 levels and activity have been documented in conditions of impaired wound healing, such as wound healing in aged and in diabetic mice. The increasing number of studies on the role of HIF-1 in wound healing, apart from answering certain questions, has also raised an equal number, if not more. Clarifying the topics that still remain unclear could introduce a new era of HIF-1 targeted management of a wide range of problematic wounds.

The impact of digital mammography on screening a young cohort of women for breast cancer in an urban specialist breast unit.

OBJECTIVE: To compare the diagnostic performance of full-field digital mammography (FFDM) with screen-film mammography (SFM) in a corporate screening programme including younger women. METHODS: Data were available on 14,946 screening episodes, 5010 FFDM and 9936 SFM. Formal analysis was by logistic regression, adjusting for age and calendar year. FFDM is compared with SFM with reference to cancer detection rates, cancers presenting as clustering microcalcifications, recall rates and PPV of recall. RESULTS: Overall detection rates were 6.4 cancers per thousand screens for FFDM and 2.8 per thousand for SFM (p < 0.001). In women aged 50+ cancer detection was significantly higher for FFDM at 8.6 per thousand vs. 4.0 per thousand, (p = 0.002). In women <50, cancer detection was also significantly higher for FFDM at 4.3 per thousand vs. 1.4 per thousand, (p = 0.02). Cancers detected as clustering microcalcifications increased from 0.4 per thousand with SFM to 2.0 per thousand with FFDM. Rates of assessment recall were higher for FFDM (7.3% vs. 5.0%, p < 0.001). FFDM provided a higher PPV for assessment recall, (32 cancers/364 recalls, 8.8%) than SFM, (28 cancers/493 recalls, 5.7%). CONCLUSIONS: Cancer detection rates were significantly higher for FFDM than for SFM, especially for women <50, and cancers detected as clustering microcalcifications.

From cholera to burns: a role for oral rehydration therapy.

According to the practice guidelines of the American Bum Association on burn shock resuscitation, intravenous (i.v.) fluid therapy is the standard of care for the replacement of fluid and electrolyte losses in burn injury of > or = 20% of the total body surface area. However, in mass burn casualties, i.v. fluid resuscitation may be delayed or unavailable. Oral rehydration therapy (ORT), which has been shown to be highly effective in the treatment of dehydration in epidemics of cholera, could be an alternate way to replace fluid losses in burns. A prospective case series of three patients was carried out as an initial step to establish whether oral Ceralyte 90 could replace fluid losses requiring i.v. fluid therapy in thermal injury. The requirement of the continuing i.v. fluid therapy was reduced by an average of 58% in the first 24 hours after the injury (range 37-78%). ORT may be a feasible alternative to i.v. fluid therapy in the resuscitation of burns. It could also potentially save many lives in mass casualty situations or in resource-poor settings where i.v. fluid therapy is not immediately available. Further studies are needed to assess the efficacy of this treatment and to determine whether the present formulations of ORT for cholera need modification.

Hydrofiber dressing with silver for the management of split-thickness donor sites: a randomized evaluation of two protocols of care.

BACKGROUND: This randomized, open-label study evaluated Aquacel Ag Hydrofiber dressing with silver (HDS; ConvaTec, Skillman, NJ, USA) with an adherent or gelled protocol in the management of split-thickness donor sites. METHODS: HDS was the primary dressing in the adherent group (gauze as secondary covering) and gelled group (transparent film as secondary covering). Dressings were changed on study day 1 or 2 and study days 5 (optional), 10 (optional), and 14. The primary outcome was healing (>or=90% re-epithelialization) at study day 14. RESULTS: Seventy subjects were treated (36 adherent, 34 gelled). By study day 14, 77% of donor sites had healed (67% adherent, 88% gelled). Pain scores decreased over time in both treatment groups. Investigators were "very satisfied" or "satisfied" with (adherent, gelled) time required to manage dressing change (89%, 79% of subjects), minimization of donor-site pain (64%, 82%), ease of application (97%, 94%), management of drainage (92%, 82%), ease of removal (77%, 85%), and ability of dressing to remain in place (69%, 76%). Thirty-nine (56%) subjects had adverse events, most commonly non-donor-site infection (11%) and gastrointestinal events (11%). CONCLUSION: In this randomized, open-label study, HDS was well-tolerated, versatile, and effective in the management of split-thickness donor sites.

Mammographic breast density by area of residence: possible evidence of higher density in urban areas.

OBJECTIVES: A comparison of mammographic breast densities of women living in London with those of women living in rural and suburban areas. DESIGN AND METHODS: Using the standard four American College of Radiology Breast Imaging Reporting and Data System (BIRADS) categories of mammographic density, 318 mammograms of women from London and 654 mammograms of women from outside the capital aged 27-87 years who had received mammography at the Princess Grace Hospital, London, were assessed for density. The association between having any dense tissue and area of residence was assessed using both ordered and standard logistic regression, giving odds ratio estimates of relative risk of dense tissue adjusting for age. RESULTS: Adjusting for age, London residents had significantly higher levels of density (OR = 1.32, 95% CI 1.04-1.70, p = 0.02). The major difference occurred in the age group 45-54 years and was most strongly manifested as a higher rate in London for density of 25% or more (BIRADS categories 2-4) as compared to almost entirely fatty (BIRADS 1) (OR = 2.22, 95% CI 1.05-4.68, p = 0.035). CONCLUSION: The higher density is likely to be due to a different prevalence of risk factors in the London population. This study cannot ascertain the reason for the higher density in this urban population, but the result is a cause for concern given that screening uptake is lower in London. Increased attention to screening in urban areas and attention to screening quality for dense breast tissue might be prudent.

Inducibility of HBD-2 in acute burns and chronic conditions of the lung.

The respiratory tract produces a number of molecules that act in the first line of host defense to protect against pathogenic colonization and tissue invasion. Most of the innate antimicrobial activity can be attributed to airway fluid proteins, such as lysozyme, lactoferrin, and secretory leukoproteinase inhibitor, and peptides, such as defensins. Human beta-defensins are cationic antimicrobial peptides with broad and potent microbicidal activity that have been shown to play a role in protecting the healthy lung from infection. To determine the effect of thermal injury on the production of the inducible beta-defensin, human beta-defensin-2 (HBD-2), we measured the concentration of HBD-2 by Western blot analysis in bronchoalveolar lavage samples from the lungs of burned patients with and without inhalation injury. Our data demonstrates an increased amount of HBD-2 in the pulmonary airways with thermal injury compared to normal lung. A further substantial increase in levels was noted in chronic lung conditions.

'Fit for purpose' health impact assessment: a realistic way forward.

The UK government is committed to health impact assessment (HIA) as a means of ensuring that health will be a key consideration in policy formulation and other public decision making. However there has been some debate about whether current HIA practice can reliably inform decision making. In particular consultation with stakeholders and literature reviewing, key tools used in HIA, are said to suffer from a number of conceptual and methodological problems, which can undermine the validity of the assessment. In this paper, we argue that the philosophical nature of HIA, its purpose and its contribution to the promotion of public health is still being established. We outline our own HIA practice, which is based on a broad philosophy of 'fit for purpose' i.e. what is this HIA for and what is its spatial, temporal, social and political context. We suggest that it is important to guard against unrealistic expectations and illusions of total objectivity and precision in the HIA process. HIA 'screening' is capable of delivering benefits by making policies, programmes and projects, more health conscious. Once we move beyond this basic expectation and wish to be able to make judgements about the relative health benefits of alternative courses of action, the potential resource intensiveness of the process increases considerably. Even at a high level of resource usage any conclusions reached through the HIA process will always be, in part, subjective and therefore likely to be contested. We must decide what we want, what we are prepared to legislate for and what we are prepared to pay for in the HIA process.

Long-term outcome after tibial shaft fracture: is malunion important?

BACKGROUND: Fractures of the shaft of the tibia often heal with some angulation. Although there is biomechanical evidence that such angulation alters load transmission through the joints of the lower limb, it is not clear whether it can eventually lead to osteoarthritis. METHODS: One hundred and sixty-four individuals who had sustained a tibial shaft fracture were assessed in a research clinic thirty to forty-three years after the injury. The subjects were evaluated with regard to self-reported lower limb joint pain, stiffness, and disability (assessed with the Western Ontario and McMaster Universities [WOMAC] osteoarthritis questionnaire); clinical signs of osteoarthritis; and radiographic evidence of osteophytes and joint-space narrowing in the knees, ankles, and subtalar joints. RESULTS: Twenty-two (15%) of the 151 subjects who reported no other knee injury reported at least moderate knee pain, and eight (6%) of the 145 subjects who reported no other ankle injury reported at least moderate ankle pain. Seventeen (13%) of the 135 subjects who reported no other knee or ankle injury reported at least moderate disability. The ipsilateral side demonstrated a higher prevalence than the contralateral side in terms of pain with passive ankle movement (nineteen versus nine subjects, p = 0.02), pain with passive subtalar movement (fifteen versus four subjects, p = 0.01), and radiographic signs of ankle joint space narrowing (twelve subjects versus one subject, p = 0.0055). Knee osteoarthritis was frequently bilateral. Forty-seven fractures (29%) healed with coronal angulation of > or = 5 degrees. Apart from an association between shortening of > or = 10 mm and self-reported knee pain (p = 0.016), there were no significant univariate associations between these malunions and the development of osteoarthritis. Seventeen (15%) of 114 eligible subjects had overall malalignment of the lower limb, defined as a hip-knee-ankle angle outside the normal range of 6.25 degrees of varus to 4.75 degrees of valgus. This malalignment was due to the fracture malunion in nine subjects and predated the fracture in eight. In limbs with varus or valgus malalignment, there was an excess of subtalar stiffness (p = 0.04) and a nonsignificant trend toward more frequent knee pain. In limbs with varus malalignment, there was a nonsignificant trend toward more frequent radiographic evidence of osteoarthritis in the medial compartment of the knee joint. Most of the subjects in whom osteoarthritis was observed had normal overall alignment of the lower limb. CONCLUSIONS: The thirty-year outcome after a tibial shaft fracture is usually good, although mild osteoarthritis is common. Fracture malunion is not the cause of the higher prevalence of symptomatic ankle and subtalar osteoarthritis on the side of the fracture. Although varus malalignment of the lower limb occurs occasionally and may cause osteoarthritis in the medial compartment of the knee, other factors are more important in causing osteoarthritis after a tibial shaft fracture.