Modification to a testing assembly to enable strain-life measurements in pressurized hydrogen gas.

Strain-controlled fully reversed fatigue testing, or strain-life testing, provides critical information on material lifetime and damage response. Strain-life data in hydrogen gas environments is missing in the literature and could provide valuable insights into hydrogen effects on the mechanical response of metals such as steel. We adapted existing hydrogen-gas-environment mechanical-testing equipment, which had been designed only for tensile loads, to accommodate the large compressive loads needed to perform strain-life testing. The considerations of these adaptations are discussed. Successful strain-life testing data were acquired from a 4130 pressure vessel steel.

Cicatricial pemphigoid Brunsting-Perry variant masquerading as neutrophil-mediated cicatricial alopecia.

A 72-year-old male presented with scarring alopecia on the scalp vertex, multiple crusted plaques on the hairline, and a history of vesicular eruption on the face. The scalp showed crusted plaques with loss of follicular ostia. No follicular pustules or compound follicles were present. An initial transverse scalp biopsy showed perifollicular neutrophils, lymphocytes, and plasma cells along with dermal fibrosis. Focal epidermal/dermal and follicular/adventitial dermal clefts were apparent but were thought to be secondary to fibrosis, and the biopsy result was interpreted to represent a neutrophil-mediated cicatricial alopecia. Concurrently, direct immunofluorescence (DIF) analysis showed linear junctional deposition of IgG and C3. A repeat scalp biopsy revealed more prominent epidermal/dermal clefts, fibrosis, mixed infiltrate with neutrophils, lymphocytes, histiocytes, and plasma cells, as well as prominent follicular/adventitial dermal clefts with perifollicular neutrophils. Given the combination of clefts, perijunctional neutrophils, and positive DIF findings, it became clear that this eruption represented the Brunsting-Perry variant of cicatricial pemphigoid. Here, we illustrated that a neutrophil-rich form of cicatricial pemphigoid can masquerade as a neutrophil-mediated scarring alopecia. In evaluating a specimen suspected to be a neutrophil-mediated scarring alopecia, one should be alert to the presence of subepidermal and perifollicular clefting, and consider cicatricial pemphigoid.

Steroids to reduce the impact on delirium (STRIDE): a double-blind, randomised, placebo-controlled feasibility trial of pre-operative dexamethasone in people with hip fracture.

Neuro-inflammation may be important in the pathogenesis of postoperative delirium following hip fracture surgery. Studies have suggested a potential role for steroids in reducing postoperative delirium; however, the potential efficacy and safety of pre-operative high-dose dexamethasone in this specific population is largely unknown. Conducting such a study could be challenging, considering the multidisciplinary team involvement and the emergency nature of the surgery. The aim of this study was to assess feasibility and effectiveness of dexamethasone given as early as possible following hospital admission for hip fracture, to inform whether a full-scale trial is warranted. This single-centre, randomised, double-blind, placebo-controlled study randomly allocated 79 participants undergoing hip fracture surgery to dexamethasone 20 mg or placebo pre-operatively. Eligibility and recruitment rates, timing of the intervention and adverse events were recorded. Incidence and severity of postoperative delirium were assessed using the 4AT delirium screening tool and the Memorial Delirium Assessment Scale. Postoperative pain, length of stay and mortality were also assessed. The eligibility rate for inclusion was 178/527 (34%), and 57/178 (32%) of eligible patients presented to hospital when no researcher was available (e.g. after-hours, weekends, public holidays). Recruitment was limited mainly by ethical limitations (not including patients with impaired cognition) and lack of weekend staffing. Median (IQR [range]) time from emergency department admission to drug administration was 13.3 (5.9-17.6 [1.8-139.6]) hours. There was a significant difference in delirium severity scores, favouring the dexamethasone group: median (IQR [range]) 5 (3-6 [3-7]) vs. 9 (6-13 [5-14]) in the placebo group, with the probability of superiority effect size being 0.89, p = 0.010. Delirium incidence did not differ between groups: 6/40 (15%) in the dexamethasone group vs. 9/39 (23%) in the placebo group, relative risk (95%CI) 0.65 (0.22-1.65), p = 0.360). A larger randomised controlled trial is feasible and ideally this should include people with existing cognitive impairment, seven days-a-week cover and a multicentre design.

Prediction of contrast induced acute kidney injury using novel biomarkers following contrast coronary angiography.

BACKGROUND/INTRODUCTION: Chronic kidney disease (CKD) is a risk factor for contrast induced acute kidney injury (CI-AKI). Contrast angiography in CKD patients is a common procedure. Creatinine is a delayed marker of CI-AKI and delays diagnosis which results in significant morbidity and mortality. AIM: Early diagnosis of CI-AKI requires validated novel biomarkers. DESIGN: A prospective observation study of 301 consecutive CKD patients undergoing coronary angiography was performed. METHODS: Samples for plasma neutrophil gelatinase-associated lipocalin (NGAL), serum liver fatty acid-binding protein (L-FABP), serum kidney injury marker 1, serum interleukin 18 and serum creatinine were taken at 0, 1, 2, 4, 6 and 48 h post-contrast. Urinary NGAL and urinary cystatin C were collected at 0, 6 and 48 h. Incidence of major adverse clinical events (MACE) was recorded at 1 year. CI-AKI was defined as an absolute delta rise in creatinine of ≥26.5 µmol/l or a 50% relative rise from baseline at 48 h following contrast. RESULTS: CI-AKI occurred in 28 (9.3%) patients. Plasma NGAL was most predictive of CI-AKI at 6 h. L-FABP performed best at 4 h. A combination of Mehran score > 10, 4 h L-FABP and 6 h NGAL improved specificity to 96.7%. MACE was statistically higher at 1 year in CI-AKI patients (25.0 vs. 6.2% in non-CI-AKI patients). DISCUSSION/CONCLUSION: Mehran risk score, 4 h serum L-FAPB and 6 h plasma NGAL performed best at early CI-AKI prediction. CI-AKI patients were four times more likely to develop MACE and had a trebling of mortality risk at 1 year.

Hidradenitis Suppurativa and Crohn's Disease: A Case Series.

Hidradenitis Suppurativa (HS) is characterized by chronic recurrent abscesses, nodules and draining sinus tracts with scar formation. Cutaneous Crohn's Disease (CD) may also present similarly. We wished to identify and describe an Irish cohort with combined HS and CD, with a view to a better recognition of clinical manifestations and understanding of the pathophysiology underlying these two overlapping conditions. Cases were identified using the HIPE Code at Tallaght Hospital from 1990-2014 and retrospective review was performed. Seven patients with both HS and CD were identified, 5(71%) female. The median age of diagnosis with both conditions was 37 years. In all cases, CD had preceded the diagnosis of HS. All patients smoked. Six had an increased BMI and 43% had additional autoimmune conditions. All patients required treatment with a TNF-alpha inhibitor for HS with 5 of 6 subjects having reduced frequency of flare ups and clinically less active HS on follow up.

Spectrum of Immune-Related Conditions Associated with Risk of Keratinocyte Cancers among Elderly Adults in the United States.

Background: Elevated keratinocyte carcinoma risk is present with several immune-related conditions, e.g., solid organ transplantation and non-Hodgkin lymphoma. Because many immune-related conditions are rare, their relationships with keratinocyte carcinoma have not been studied.Methods: We used Medicare claims to identify cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) cases in 2012, and controls matched on sex and age. All subjects were aged 65 to 95 years, of white race, and had attended ≥1 dermatologist visit in 2010-2011. Immune-related conditions were identified during 1999-2011 using Medicare claims. Associations were estimated with logistic regression, with statistical significance determined after Bonferroni correction for multiple comparisons.Results: We included 258,683 SCC and 304,903 BCC cases. Of 47 immune-related conditions, 21 and 9 were associated with increased SCC and BCC risk, respectively. We identified strongly elevated keratinocyte carcinoma risk with solid organ transplantation (SCC OR = 5.35; BCC OR = 1.94) and non-Hodgkin lymphoma (SCC OR = 1.62; BCC OR = 1.25). We identified associations with common conditions, e.g., rheumatoid arthritis [SCC OR = 1.06, 95% confidence interval (95% CI), 1.04-1.09] and Crohn's disease (SCC OR = 1.33, 95% CI, 1.27-1.39; BCC OR = 1.10, 95% CI, 1.05-1.15), and rare or poorly characterized conditions, e.g., granulomatosis with polyangiitis (SCC OR = 1.88; 95% CI, 1.61-2.19), autoimmune hepatitis (SCC OR = 1.81; 95% CI, 1.52-2.16), and deficiency of humoral immunity (SCC OR = 1.51, 95% CI, 1.41-1.61; BCC OR = 1.22, 95% CI, 1.14-1.31). Most conditions were more positively associated with SCC than BCC. Associations were generally consistent regardless of prior keratinocyte carcinoma history.Conclusions: Many immune-related conditions are associated with elevated keratinocyte carcinoma risk and appear more tightly linked to SCC.Impact: Immunosuppression or immunosuppressive treatment may increase keratinocyte carcinoma risk, particularly SCC. Cancer Epidemiol Biomarkers Prev; 26(7); 998-1007. ©2017 AACR.

Multi-criteria decision analysis (MCDA): testing a proposed MCDA framework for orphan drugs.

BACKGROUND: Since the introduction of the orphan drugs legislation in Europe, it has been suggested that the general method of assessing drugs for reimbursement is not necessarily suitable for orphan drugs. The National Institute for Health and Clinical Excellence indicated that several criteria other than cost and efficacy could be considered in reimbursement decisions for orphan drugs. This study sought to explore the multi-criteria decision analysis (MCDA) framework proposed by (Orphanet J Rare Dis 7:74, 2012) to a range of orphan drugs, with a view to comparing the aggregate scores to the average annual cost per patient for each product, and thus establishing the merit of MCDA as a tool for assessing the value of orphan drugs in relation to their pricings. METHODS: An MCDA framework was developed using the nine criteria proposed by (Orphanet J Rare Dis 7:74, 2012) for the evaluation of orphan drugs, using the suggested numerical scoring system on a scale of 1 to 3 for each criterion. Correlations between the average annual cost of the drugs and aggregate MCDA scores were tested and plotted graphically. Different weightings for each of the attributes were also tested. A further analysis was conducted to test the impact of including the drug cost as an attribute in the aggregate index scores. RESULTS: In the drugs studied, the R 2, that statistically measures how close the data are to the fitted regression line was 0.79 suggesting a strong correlation between the drug scores and the average annual cost per patient. CONCLUSION: Despite several limitations of the proposed model, this quantitative study provided insight into using MCDA and its relationship to the average annual costs of the products.

Postoperative exercise training is associated with reduced respiratory infection rates and early discharge: A case-control study.

INTRODUCTION: Pulmonary complications are a significant cause of morbidity, mortality and increased hospital stay following complex abdominal surgery. We investigated whether postoperative early aerobic activity with a pedal exerciser reduced respiratory morbidity and length of stay and improved pulmonary function. METHODS: A prospective case-control study on 30 cases and 30 case matched controls aged 18 years or more who underwent major surgery was conducted. Controls were case-mix matched prospectively from a similar general surgical service not utilising postoperative exercising. Thirty consecutive cases were started on a twice-daily aerobic exercise program with pedal exerciser post-operatively day 2 or from when sitting independently. Primary outcome measures were respiratory tract infection (RTI), deep vein thrombosis (DVT) or pulmonary embolus (PE). Secondary outcome measure was subjective breathlessness and Length of Stay (LOS) postoperatively. RESULTS: The rate of RTI was only 16.6% in the exercise group and 43.3% in the control group (P = 0.024). None of the cases or controls suffered from a DVT or PE. Median postoperative length of stay in the control group was 11 ± 7.5 days whereas in the cases it was 8.5 ± 5.00 days (P = 0.049). The Borg subjective breathlessness score in the cases group showed a decline in the subjective breathlessness on postoperative day 4 (P = 0.002). CONCLUSIONS: Early aerobic activity with a pedal exerciser halves the rate of postoperative RTI and postoperative hospital stay after complex abdominal surgery. Subjective breathlessness was also reduced with the use of pedal exerciser, signifying potential to improve exercise endurance in the postoperative patient.

Updates in adult-onset Still disease: Atypical cutaneous manifestations and associations with delayed malignancy.

Adult-onset Still disease (AOSD) is a systemic inflammatory disorder that is clinically characterized by a heterogeneous constellation of symptoms and signs. Though an evanescent eruption is the classic cutaneous finding, recent literature has highlighted atypical rashes associated with Still disease. A second emerging concept in presentations of AOSD is its association with malignancy. This review focuses on these concepts: the clinical spectrum of atypical skin manifestations and AOSD as a paraneoplastic phenomenon. PubMed-MEDLINE was screened for peer-reviewed articles describing atypical presentations of AOSD and cases associated with malignancy. Erythematous, brown or violaceous, persistent papules and plaques were the most common cutaneous finding (28/30 [93%]). Linear configurations were also rarely described. Of these patients, 81% concurrently had the typical evanescent skin eruption. There were 31 patients with associated malignancies, most commonly breast cancer and lymphoma. The diagnosis of malignancy did not precede or immediately follow a clinical presentation otherwise consistent with AOSD in a considerable subset of patients (42%). Understanding the cutaneous spectrum of AOSD and heightened awareness for its delayed association with malignancy may lead to improved recognition of cutaneous variants and reinforce the need for diagnostic evaluation and long-term follow-up for malignancy in patients with this clinical presentation.

Novel Biomarkers of Acute Kidney Injury After Contrast Coronary Angiography.

Acute kidney injury (AKI), defined as a rise in serum creatinine of greater than 25% from baseline measured at 48 hours after renal insult, may follow iodinated contrast coronary angiography. Termed contrast-induced nephropathy, it can result in considerable morbidity and mortality. Measurement of serum creatinine as a functional biomarker of glomerular filtration rate is widely used for detection of AKI, but it lacks sensitivity for the early diagnosis of AKI (typically rising 24 hours after functional loss) and, as a solely functional marker of glomerular filtration rate, is unable to differentiate among the various causes of AKI. These intrinsic limitations to creatinine measurement and the recognition that improved clinical outcomes are linked to a more timely diagnosis of AKI, has led investigators to search for novel biomarkers of "early" kidney injury. Several studies have investigated the utility of renal injury biomarkers in a variety of clinical settings including angiography/percutaneous coronary intervention, coronary artery bypass graft surgery, sepsis in intensive care patients, and pediatric cardiac surgery. In this article, we discuss the use of iodinated contrast for coronary procedures and the risk factors for contrast-induced nephropathy, followed by a review the potential diagnostic utility of several novel biomarkers of early AKI in the clinical settings of coronary angiography/percutaneous coronary intervention. In particular, we discuss neutrophil gelatinase associated lipocalin in depth. If validated, such biomarkers would facilitate earlier AKI diagnosis and improve clinical outcomes.

A TGFbeta-responsive gene signature is associated with a subset of diffuse scleroderma with increased disease severity.

Systemic sclerosis is a complex disease with widespread skin fibrosis and variable visceral organ involvement. Since transforming growth factor-beta (TGFbeta) has been implicated in driving fibrosis in systemic sclerosis, a mechanism-derived gene expression signature was used to assay TGFbeta-responsive gene expression in the skin of patients with systemic sclerosis (SSc). Primary dermal fibroblasts from patients with diffuse SSc (dSSc) and healthy controls were treated with TGFbeta, and the genome-wide gene expression was measured on DNA microarrays over a time course of 24 hours. Eight hundred and ninety-four probes representing 674 uniquely annotated genes were identified as TGFbeta responsive. Expression of the TGFbeta-responsive signature was examined in skin biopsies from 17 dSSc, seven limited SSc (lSSc), three morphea patients, and six healthy controls. The TGFbeta-responsive signature was expressed in 10 out of 17 dSSc skin biopsies, but was not found in lSSc, morphea, or healthy control biopsies. Expression of dSSC the TGFbeta-responsive signature stratifies patients into two major groups, one of which corresponds to the "diffuse-proliferation" intrinsic subset that showed higher modified Rodnan skin score and a higher likelihood of scleroderma lung disease. The TGFbeta-responsive signature is found in only a subset of dSSc patients who could be targeted by specific therapies.

Incidence of acquired demyelination of the CNS in Canadian children.

BACKGROUND: The incidence of acquired demyelination of the CNS (acquired demyelinating syndromes [ADS]) in children is unknown. It is important that physicians recognize the features of ADS to facilitate care and to appreciate the future risk of multiple sclerosis (MS). OBJECTIVE: To determine the incidence, clinical features, familial autoimmune history, and acute management of Canadian children with ADS. METHODS: Incidence and case-specific data were obtained through the Canadian Pediatric Surveillance Program from April 1, 2004, to March 31, 2007. Before study initiation, a survey was sent to all pediatric health care providers to determine awareness of MS as a potential outcome of ADS in children. RESULTS: Two hundred nineteen children with ADS (mean age 10.5 years, range 0.66-18.0 years; female to male ratio 1.09:1) were reported. The most common presentations were optic neuritis (ON; n = 51, 23%), acute disseminated encephalomyelitis (ADEM; n = 49, 22%), and transverse myelitis (TM; n = 48, 22%). Children with ADEM were more likely to be younger than 10 years, whereas children with monolesional ADS (ON, TM, other) were more likely to be older than 10 years (p < 0.001). There were 73 incident cases per year, leading to an annual incidence of 0.9 per 100,000 Canadian children. A family history of MS was reported in 8%. Before study initiation, 65% of physicians indicated that they considered MS as a possible outcome of ADS in children. This increased to 74% in year 1, 81% in year 2, and 87% in year 3. CONCLUSION: The incidence of pediatric acquired demyelinating syndromes (ADS) is 0.9 per 100,000 Canadian children. ADS presentations are influenced by age.

Molecular framework for response to imatinib mesylate in systemic sclerosis.

Systemic sclerosis (SSc) is an autoimmune disease in which the tyrosine kinases platelet-derived growth factor receptor (PDGFR) and Abl are hypothesized to contribute to the fibrosis and vasculopathy of the skin and internal organs. Herein we describe 2 patients with early diffuse cutaneous SSc (dcSSc) who experienced reductions in cutaneous sclerosis in response to therapy with the tyrosine kinase inhibitor imatinib mesylate. Immunohistochemical analyses of skin biopsy specimens demonstrated reductions of phosphorylated PDGFRbeta and Abl with imatinib therapy. By gene expression profiling, an imatinib-responsive signature specific to dcSSc was identified (P < 10(-8)). The response of these patients and the findings of the analyses suggest that PDGFRbeta and Abl play critical, synergistic roles in the pathogenesis of SSc, and that imatinib targets a gene expression program that is frequently dysregulated in dcSSc.

Single-stage sacral coccygectomy and repair using human acellular dermal matrix (AlloDerm) with bilateral gluteus maximus flaps for hernia prophylaxis.

Sacrococcygectomy is often necessary for the ablation of malignancies involving the sacrum and coccyx, and can result in deep posterior peritoneal defects with disruption of the pelvic floor. Such a radical procedure is frequently associated with significant morbidity, including sacral herniation. Numerous techniques for the closure of the surgical defect have been described, with varying degrees of success in avoiding future herniation. We report the first single-stage coccygectomy and partial sacrectomy with closure utilizing human acellular dermal matrix (HADM) (AlloDerm; LifeCell Corporation, Branchburg, NJ) and bilateral gluteus maximus transposition flaps.

The stiff skin syndrome: case series, differential diagnosis of the stiff skin phenotype, and review of the literature.

BACKGROUND: Stiff skin syndrome is a sclerodermalike disorder that presents in infancy or early childhood with rock-hard skin, limited joint mobility, and mild hypertrichosis in the absence of visceral or muscle involvement, immunologic abnormalities, or vascular hyperreactivity. OBSERVATIONS: We describe 6 children who fit criteria for stiff skin syndrome. A review of the clinical range of this disorder and discussion of the differential diagnosis is presented. The age at onset in our cases ranged from infancy to 6 years of age. Stony-hard skin was noted mostly on the thighs, buttocks, and lower back with shoulder and arm involvement in 2 cases. There was associated hypertrichosis in 3 of 6 cases. Extracutaneous manifestations consisted primarily of joint restriction, and several patients had resulting postural and thoracic wall irregularities. Histopathologically, our cases showed areas of fascial sclerosis or showed increased fibroblast cellularity with thickened, sclerotic, horizontally oriented collagen bundles in the deep reticular dermis and/or subcutaneous septa without associated inflammation. CONCLUSIONS: Stiff skin syndrome is characterized by an early, insidious onset of stony-hard skin, often with associated contracturelike joint restriction, hypertrichosis, and postural and thoracic wall abnormalities. Supportive histopathologic findings consisting of either fascial sclerosis or increased fibroblast cellularity with sclerotic collagen bundles in the deep reticular dermis and/or subcutaneous septa may help to confirm this diagnosis.