bluuebunny/crossref_metadata_2025 huggingface dataset:
Success Traps, Dynamic Capabilities and Firm Performance
Authors: Wang Catherine L. , Senaratne Chaminda , Rafiq Mohammed
Published: August 2014

Dynamic capabilities (DCs) are fundamental to the understanding of differential firm performance. However, the question remains why some firms are better at developing and applying DCs than others. In particular, successful firms have been warned against the tendency to fall into a success or competence trap, where success reinforces exploitation of existing competences and crowds out exploration of new competences, hindering the development of DCs. Therefore, this study examines the effects of success traps on DCs and consequently firm performance, taking into account firm strategy and market dynamism. To facilitate this, our study also identifies the commonalities of DCs across firms. Drawing on survey data from 113 UK high‐tech small and medium‐sized firms, we find that success traps have a significant, strong negative effect on DCs, which in turn have a weak positive effect on firm performance; DCs are manifested through absorptive and transformative capabilities as two common features across firms. We also find that the development and application of DCs is related to internal factors (such as success traps) rather than external factors (such as market dynamism).
Troponin Elevations Only Detected With a High‐sensitivity Assay: Clinical Correlations and Prognostic Significance
Authors: Korley Frederick K. , Schulman Steven P. , Sokoll Lori J. , DeFilippis Andrew P. , Stolbach Andrew I. , Bayram Jamil D. , Saheed Mustapha O. , Omron Rodney , Fernandez Christopher , Lwin Albert , Cai Stephen S. , Post Wendy S. , Jaffe Allan S.
Published: August 2014

Objectives

With clinical use of high‐sensitivity troponin I (hsTnI), more frequent troponin elevations will occur. However, the burden and implications of these elevations are not well understood. The authors quantified the prevalence of elevated hsTnI in patients presenting with possible acute coronary syndrome (ACS) who do not have elevated troponin with a current generation assay (cardiac troponin I [cTnI]) and determined the association of these newly detected elevations with a composite of all‐cause mortality and subsequent cardiac hospitalization.

Methods

This was a prospective observational study of 808 subjects evaluated for possible ACS and followed for up to 1 year. Troponin values were measured with hsTnI (Abbott Laboratories) and cTnI (Abbott and Beckman Coulter). Cardiac hospitalization was defined as hospitalization for ACS, revascularization, acute heart failure (AHF), or tachy/brady arrhythmia that occurred after the index emergency department (ED) visit or hospital discharge.

Results

Forty subjects (5%) were diagnosed with ACS (26 myocardial infarction and 14 unstable angina). On the initial sample, the prevalence of elevated hsTnI among subjects with nonelevated cTnI was 9.2% using a gender‐neutral cutoff (95% confidence interval [CI] = 7.1% to 11.4%) and 11.1% using a gender‐specific cutoff (95% CI = 8.8% to 13.4%). Adjudicated diagnoses for subjects whose initial samples had elevated hsTnI but nonelevated cTnI (gender‐neutral cutoff) were as follows: three (4.6%) ACS, 15 (23.1%) AHF, three (4.6%) volume overload etiology unclear/noncardiac, three (4.6%) cardiac (non‐ACS), and 41 (63.1%) other. Of the 65 patients whose initial samples had hsTnI but nonelevated cTnI, eight developed cTnI elevation on subsequent serial sampling. After traditional cardiovascular risk factors and renal function were adjusted for, subjects with elevated initial hsTnI but nonelevated cTnI (initial and serial sampling) had a higher risk of all‐cause mortality and subsequent cardiac hospitalization than subjects with both nonelevated hsTnI and nonelevated cTnI (hazard ratio [HR] = 1.91, 95% CI = 1.14 to 3.19).

Conclusions

On the initial sample, 9% to 11% of subjects without cTnI elevation had hsTnI elevation. Although the majority of the patients with these newly detected hsTnI elevations did not have ACS, they had a higher risk for all‐cause mortality and subsequent cardiac hospitalization.
Reflux pattern and role of impedance‐pH variables in predicting PPI response in patients with suspected GERD‐related chronic cough
Authors: Ribolsi M. , Savarino E. , De Bortoli N. , Balestrieri P. , Furnari M. , Martinucci I. , Casale M. , Greco F. , Salvinelli F. , Savarino V. , Marchi S. , Cicala M.
Published: August 2014

Background

Gastro‐oesophageal reflux disease (GERD) may contribute to the onset of chronic cough (CC); however, the multichannel intraluminal impedance‐pH (MII‐pH) monitoring is often within the normal range and the response to proton pump inhibitors (PPIs) unsatisfactory. The measure of impedance baseline (IB) increases the sensitivity of MII‐pH in patients with typical symptoms.

Aim

To evaluate the role of MII‐pH variables, including IB, in predicting PPI response and to define the characteristics of the reflux pattern in CC patients.

Methods

Prospectively selected CC patients suspected GERD‐related underwent MII‐pH monitoring and, therefore, received a double dose of PPIs for at least 6 weeks. Patients filled symptom scores before MII‐pH and after PPI therapy. MII‐pH data were compared with those obtained in 60 non‐erosive reflux disease patients with typical symptoms.

Results

A total of 156 CC patients entered the study: 68 (43.5%) responders and 88 (56.5%) nonresponders to PPIs. The number of reflux episodes was significantly higher in CC compared with that in typical symptoms patients. Nonresponder CC patients with a pathological acid exposure time (AET) and/or IB value were 43/88 (49%), while 15/88 (17%) presented only pathological AET (P < 0.001). CC patients with a pathological AET or IB, or with both a pathological AET and IB, showed a probability of PPI response twofold greater than patients with normal AET and IB.

Conclusions

The presence of a pathological AET or pathological IB in CC patients is associated with a greater probability of PPI response. IB is a promising variable in patients with CC, as it increases the diagnostic yield of MII‐pH and allows confirmation of the GERD diagnosis in these patients.
Persistent inflammation and its relationship to leptin and insulin in phases of bipolar disorder from acute depression to full remission
Authors: Tsai Shang‐Ying , Chung Kuo‐Hsuan , Huang Shou‐Hung , Chen Pao‐Huan , Lee Hsin‐Chien , Kuo Chian‐Jue
Published: August 2014

Objective

A proinflammatory phase with various immunomodulatory mechanisms has been noted in bipolar mania and major depression. Weight gain and increased production of leptin may be associated with immunomodulation and insulin resistance in bipolar disorder. However, immunomodulation and its linkage with leptin and insulin in the depressive episode of bipolar disorder remain unclear. We investigated alterations in inflammatory markers and their relationship with leptin and insulin levels in patients with phases of bipolar disorder from acute depression to full remission.

Methods

Thirty‐two physically healthy bipolar I depressed patients aged <45 years and age‐ and sex‐matched healthy controls participated in this study. We measured their circulating levels of leptin, insulin, high‐sensitivity C‐reactive protein (hs‐CRP), soluble interleukin‐2 receptor (sIL‐2R), soluble interleukin‐6 receptor (sIL‐6R), soluble tumor necrosis factor receptor 1 (sTNF‐R1), and interleukin‐1 receptor antagonist (IL‐1Ra) in three phases, i.e., acute depression, subsequent partial remission, and full remission.

Results

In acute depression, subsequent partial remission, and full remission, patients with bipolar disorder had significantly higher mean levels of hs‐CRP, IL‐1Ra, sTNF‐R1, and sIL‐2R compared with control subjects. The IL‐1Ra and sTNF‐R1 levels in various affective phases were significantly correlated to body mass index, leptin level, circulating lipids, and medication status. The sIL‐2R levels in the three affective phases were all independent of other inflammatory markers and clinical and laboratory variables. Patients showed no alteration of sIL‐6R levels through the depressive episode.

Conclusions

Patients with bipolar disorder in depressive episodes may exhibit persistent inflammation with elevated levels of hs‐CRP, IL‐1Ra, sTNF‐R1, and sIL‐2R but not sIL‐6R from the acute phases to full remission. Only sIL‐2R production seems to be tightly linked with the pathophysiology of bipolar depression and is independent of insulin and leptin levels.
The genetic diversity of cystinuria in a UK population of patients
Authors: Wong Kathie A. , Mein Rachael , Wass Mark , Flinter Frances , Pardy Caroline , Bultitude Matthew , Thomas Kay
Published: August 2014

Objective

To examine the genetic mutations in the first UK cohort of patients with cystinuria with preliminary genotype/phenotype correlation.

Patients and Methods

DNA sequencing and multiplex ligation‐dependent probe amplification (MLPA) were used to identify the mutations in 74 patients in a specialist cystinuria clinic in the UK. Patients with type A cystinuria were classified into two groups: Group M patients had at least one missense mutation and Group N patients had two alleles of all other types of mutations including frameshift, splice site, nonsense, deletions and duplications. The levels of urinary dibasic amino acids, age at presentation of disease, number of stone episodes and interventions were compared between patients in the two groups using the Mann–Whitney U‐test.

Results

In all, 41 patients had type A cystinuria, including one patient with a variant of unknown significance and 23 patients had type B cystinuria, including six patients with variants of unknown significance. One patient had three sequence variants in SLC7A9; however, two are of unknown significance. Three patients had type AB cystinuria. Three had a single mutation in SLC7A9. No identified mutations were found in three patients in either gene. There were a total of 88 mutations in SLC3A1 and 55 mutations in SLC7A9. There were 23 pathogenic mutations identified in our UK cohort of patients not previously published. In patients with type A cystinuria, the presence of a missense mutation correlated to lower levels of urinary lysine (mean [se] 611.9 [22.65] vs 752.3 [46.39] millimoles per mole of creatinine [mm/MC]; P=0.02), arginine (194.8 [24.83] vs 397.7 [15.32] mm/MC; P<0.001) and ornithine (109.2 [7.40] vs 146.6 [12.7] mm/MC; P=0.02). There was no difference in the levels of urinary cystine (182.1 [8.89] vs 207.2 [19.23] mm/MC; P=0.23).

Conclusions

We have characterised the genetic diversity of cystinuria in a UK population including 23 pathogenic mutations not previously published. Patients with at least one missense mutation in SLC3A1 had significantly lower levels of lysine, arginine, and ornithine but not cystine than patients with all other combinations of mutations.
Cardiopulmonary reserve as determined by cardiopulmonary exercise testing correlates with length of stay and predicts complications after radical cystectomy
Authors: Tolchard Stephen , Angell Johanna , Pyke Mark , Lewis Simon , Dodds Nicholas , Darweish Alia , White Paul , Gillatt David
Published: August 2014

Objective

To investigate whether poor preoperative cardiopulmonary reserve and comorbid state dictate high‐risk status and can predict complications in patients undergoing radical cystectomy (RC).

Patients and Methods

In all, 105 consecutive patients with transitional cell carcinoma (TCC; stage T1–T3) undergoing robot‐assisted (38 patients) or open (67) RC in a single UK centre underwent preoperative cardiopulmonary exercise testing (CPET). Prospective primary outcome variables were all‐cause complications and postoperative length of stay (LOS). Binary logistic regression analysis identified potential predictive factor(s) and the predictive accuracy of CPET for all‐cause complications was examined using receiver operator characteristic (ROC) curve analysis. Correlations analysis employed Spearman's rank correlation and group comparison, the Mann–Whitney U‐test and Fisher's exact test. Any relationships were confirmed using the Mantel–Haenszel common odds ratio estimate, Kaplan–Meier analysis and the chi‐squared test.

Results

The anaerobic threshold (AT) was negatively (r = −206, P = 0.035), and the ventilatory equivalent for carbon dioxide (VE/VCO2) positively (r = 0.324, P = 0.001) correlated with complications and LOS. Logistic regression analysis identified low AT (<11 mL/kg/min), high VE/VC02 (≥33) and hypertension as significant factors, such that, in their presence patients were 5.55‐times more likely to have complications at 90 days postoperatively [P = 0.001, 95% confidence interval (CI) 2.2–13.9]. ROC analysis showed a high significance (area under the curve 0.78, 95% CI 0.69–0.87; P < 0.001). In addition, based on CPET criteria >50% of patients presenting for RC had significant heart failure, whereas preoperatively only very few (2%) had this diagnosis. Analysis using the Mann–Whitney test showed that a VE/VCO2 ≥33 was the most significant determinant of LOS (P = 0.004). Kaplan–Meier analysis showed that patients in this group had an additional median LOS of 4 days (P = 0.008). Finally, patients with an American Society of Anesthesiologists grade of 3 (ASA 3) and those on long‐term β‐blocker therapy were found to be at particular risk of myocardial infarction (MI) and death after RC with odds ratios of 4.0 (95% CI 1.05–15.2; P = 0.042) and 6.3 (95% CI 1.60–24.8; P = 0.008).

Conclusion

Patients with poor cardiopulmonary reserve and hypertension are at higher risk of postoperative complications and have increased LOS after RC. Heart failure is known to be a significant determinant of perioperative death and is significantly under diagnosed in this patient group.
PROPIT: A PROspective comparative clinical study evaluating the efficacy and safety of PITavastatin in patients with metabolic syndrome
Authors: Choi Sung Hee , Lim Soo , Hong Eun Shil , Seo Ji A , Park Cheol‐Young , Noh Jung Hyun , Mok Ji Oh , Lee Ki Young , Park Jong Sook , Kim Dae Jung , Lee Chang Beom , Kim Sung Rae , Jang Hak Chul
Published: August 2014

Objective

Dyslipidaemia and central obesity are the major factors underlying the dramatic increase in metabolic syndrome (MS). We compared the effects of early combined therapy with pitavastatin and intensive lifestyle modification (LSM) on the amelioration of each component of MS with those of LSM only.

Design/Participants/Measurements

PROPIT (a PROspective comparative clinical study to evaluate the efficacy and safety of PITavastatin in patients with metabolic syndrome) was a prospective, randomized, multicenter open‐label 48‐week trial. We enrolled 187 patients with MS (central obesity and prediabetes) and randomized them into two treatment groups: 2 mg pitavastatin daily + intensive LSM or intensive LSM only. The primary outcome was the improvements in the components of MS and in the percentage of non‐MS converters.

Results

After 1 year treatment, the improvement of MS score was significantly higher in the pitavastatin + LSM group (P = 0·039). However, non‐MS converters (MS score ≤2) did not differ between the groups. The secondary outcomes, namely lipid profiles, the Apo B/A1 ratio, visceral fat/subcutaneous fat ratio and the Framingham risk score, were significantly improved in the pitavastatin group. There was no deterioration in glucose metabolism after treatment with pitavastatin for 1 year.

Conclusions

Early statin treatment can be an effective option in obese patients with MS, prediabetes and mild dyslipidaemia with further improvement of cardiovascular risk factors. We could not observe the increase rate of glucose intolerance in statin group. Future longitudinal studies are needed to test the benefits of early statin treatment compared with LSM.
Cell and molecular biology of intervertebral disc degeneration: current understanding and implications for potential therapeutic strategies
Authors: Wang SZ. , Rui YF. , Lu J. , Wang C.
Published: August 2014

Intervertebral disc degeneration (IDD) is a chronic, complex process associated with low back pain; mechanisms of its occurrence have not yet been fully elucidated. Its process is not only accompanied by morphological changes, but also by systematic changes in its histological and biochemical properties. Many cellular and molecular mechanisms have been reported to be related with IDD and to reverse degenerative trends, abnormal conditions of the living cells and altered cell phenotypes would need to be restored. Promising biological therapeutic strategies still rely on injection of active substances, gene therapy and cell transplantation. With advanced study of tissue engineering protocols based on cell therapy, combined use of seeding cells, bio‐active substances and bio‐compatible materials, are promising for IDD regeneration. Recently reported progenitor cells within discs themselves also hold prospects for future IDD studies. This article describes the background of IDD, current understanding and implications of potential therapeutic strategies.
Attenuated improvements in adiponectin and fat loss characterize type 2 diabetes non‐remission status after bariatric surgery
Authors: Malin S. K. , Bena J. , Abood B. , Pothier C. E. , Bhatt D. L. , Nissen S. , Brethauer S. A. , Schauer P. R. , Kirwan J. P. , Kashyap S. R.
Published: August 2014

Aim

To identify the metabolic determinants of type 2 diabetes non‐remission status after bariatric surgery at 12 and 24 months.

Methods

A total of 40 adults [mean ± sd body mass index 36 ± 3 kg/m2, age 48 ± 9 years, glycated haemoglobin (HbA1c) 9.7 ± 2%) undergoing bariatric surgery [Roux‐en‐Y gastric bypass (RYGB) or sleeve gastrectomy (SG)] were enrolled in the present study, the Surgical Treatment and Medication Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial. Type 2 diabetes remission was defined as HbA1c <6.5% and fasting glucose <126 mg/dl (i.e. <7 mmol/l) without antidiabetic medication. Indices of insulin secretion and sensitivity were calculated from plasma glucose, insulin and C‐peptide values during a 120‐min mixed‐meal tolerance test. Body fat, incretins (glucagon‐like polypeptide‐1, gastric inhibitory peptide, ghrelin) and adipokines [adiponectin, leptin, tumour necrosis factor‐α, high‐sensitivity C‐reactive protein (hs‐CRP)] were also assessed.

Results

At 24 months, 37 patients had available follow‐up data (RYGB, n = 18; SG, n = 19). Bariatric surgery induced type 2 diabetes remission rates of 40 and 27% at 12 and 24 months, respectively. Total fat/abdominal fat loss, insulin secretion, insulin sensitivity and β‐cell function (C‐peptide0–120/glucose0–120 × Matsuda index) improved more in those with remission at 12 and 24 months than in those without remission. Incretin levels were unrelated to type 2 diabetes remission, but, compared with those without remission, hs‐CRP decreased and adiponectin increased more in those with remission. Only baseline adiponectin level predicted lower HbA1c levels at 12 and 24 months, and elevated adiponectin correlated with enhanced β‐cell function, lower triglyceride levels and fat loss.

Conclusions

Smaller rises in adiponectin level, a mediator of insulin action and adipose mass, characterize type 2 diabetes non‐remission up to 2 years after bariatric surgery. Adjunctive strategies promoting greater fat loss and/or raising adiponectin may be key to achieving higher type 2 diabetes remission rates after bariatric surgery.
Dipeptidyl‐peptidase‐4 inhibitors and pancreatic cancer: a cohort study
Authors: Gokhale M. , Buse J. B. , Gray C. L. , Pate V. , Marquis M. A. , Stürmer T.
Published: August 2014

Aim

To compare pancreatic cancer incidence and diagnostic evaluation among patients initiating dipeptidyl‐peptidase‐4 (DPP‐4) inhibitor treatment with those initiating sulfonylureas (SU) and thiazolidinediones (TZD).

Methods

Medicare claims data were examined in a new‐user active‐comparator cohort study. Patients >65 years with no prescriptions for DPP‐4 inhibitors, SU or TZD at baseline were included if they had at least two claims for the same drug within 180 days. Using an as‐treated approach and propensity score‐adjusted Cox models, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) for pancreatic cancer. Diagnostic evaluations were compared using risk ratios.

Results

In the DPP‐4 inhibitor versus SU comparison, there were 18 179 patients who initiated treatment with DPP‐4 inhibitors, of whom 26 developed pancreatic cancer (interquartile range follow‐up 5–18 months). In the DPP‐4 inhibitor versus TZD comparison there were 29 366 people initiating DPP‐4 inhibitor treatment and 52 of these developed pancreatic cancer. The risk of pancreatic cancer with DPP‐4 inhibitor treatment was lower relative to SU treatment (HR: 0.6, CI: 0.4–0.9) and similar to TZD treatment (HR: 1.0, 95% CI: 0.7–1.4). After the first 6 months of follow‐up were excluded to reduce the potential for reverse causality, the results were not altered. The probability of diagnostic evaluation after commencing DPP‐4 inhibitor treatment (79.3%) was similar to that for TZD (74.1%, risk ratio 1.06, 95% CI: 1.05–1.07) and SU (74.6%) (risk ratio 1.06, 95% CI: 1.05–1.07). The probability of diagnostic evaluation before the index date (date of initiating treatment) was ∼80% for all cohorts.

Conclusion

Although the present study was limited by sample size and the observed duration of treatment in the USA, our well‐controlled population‐based study suggests there is no higher short‐term pancreatic cancer risk with DPP‐4 inhibitor treatment relative to SU or TZD treatment.
Understanding the Impact of Mobile Phones on Livelihoods in Developing Countries
Authors: Duncombe Richard A.
Published: August 2014

Mobile phones are spreading rapidly in developing countries, but research conceptualisations have been lagging behind practice, particularly those that link mobile phones to livelihoods. This article seeks to fill this gap in two ways. First, by means of a literature review which analyses how they impact upon assets – through facilitating asset substitution, enhancement, combination, exchange and forms of disembodiment. On this basis key roles for mobile phones are defined within livelihood strategies. Secondly, the analysis demonstrates the shortcomings of the livelihoods framework for understanding technological innovation; its agriculture‐oriented understanding of assets; its silence on the developmental role of information and on user appropriation of technology; and its narrow categorisation of impact. Ways of addressing these shortcomings are suggested, pointing towards areas of future research and application.
Relatedness Does not Affect Competitive Behavior of Rival Males or Offspring Growth in Multiply Sired Litters of Bank Voles (Myodes glareolus)
Authors: Klemme Ines , Ala‐Honkola Outi
Published: August 2014

Kin selection operates through the fitness of an organism's relatives. In the polyandry context, kin selection may be observable on the one hand in competition between rival males and, on the other hand, in competition between litter mates. Sperm competition theory predicts that males should invest less into mating when competing for fertilizations against a close relative as compared to an unrelated male. We tested this hypothesis with bank voles (Myodes glareolus) by mating each focal male to two females: one of which had previously mated with a full sibling of the focal male and the other one with a male unrelated to the focal male. However, we found no effect of rival male relatedness on mating behavior or proportion of offspring sired by the 2nd male to mate. Possibly, the probability of successive mating of related males with the same female is too low in natural bank vole populations for selection to have fine‐tuned mating behavior in relation to rival male relatedness. Further, polyandry often results in litters sired by multiple males. Litter mates of such litters have a reduced relatedness and are thus expected to be less cooperative during gestation and lactation, which may impair growth. Following double matings with either two full‐sibling males or two unrelated males, we compared offspring growth at birth and during lactation. Against our prediction, there was no difference in growth between litters sired either by two full‐sibling males or by two unrelated males. Either the conflict was not severe enough to be visible with our sample size (N = 16) or it may have been resolved by maternal control of offspring provisioning.
Mpdz expression in the caudolateral substantia nigra pars reticulata is crucially involved in alcohol withdrawal
Authors: Kruse L. C. , Walter N. A. R. , Buck K. J.
Published: August 2014

Association studies implicate the multiple PDZ domain protein (MUPP1/MPDZ) gene in risk for alcoholism in humans and alcohol withdrawal in mice. Although manipulation of the Mpdz gene by homologous recombination and bacterial artificial chromosome transgenesis has suggested that its expression affects alcohol withdrawal risk, the potential confounding effects of linked genes and developmental compensation currently limit interpretation. Here, using RNA interference (RNAi), we directly test the impact of Mpdz expression on alcohol withdrawal severity and provide brain regional mechanistic information. Lentiviral‐mediated delivery of Mpdz short hairpin RNA (shRNA) to the caudolateral substantia nigra pars reticulata (clSNr) significantly reduces Mpdz expression and exacerbates alcohol withdrawal convulsions compared with control mice that delivered a scrambled shRNA. Neither baseline nor pentylenetetrazol‐enhanced convulsions differed between Mpdz shRNA and control animals, indicating Mpdz expression in the clSNr does not generally affect seizure susceptibility. To our knowledge, these represent the first in vivo Mpdz RNAi analyses, and provide the first direct evidence that Mpdz expression impacts behavior. Our results confirm that Mpdz is a quantitative trait gene for alcohol withdrawal and demonstrate that its expression in the clSNr is crucially involved in risk for alcohol withdrawal.
A comprehensive immunohistochemistry algorithm for the histological subtyping of small biopsies obtained from non‐small cell lung cancers
Authors: Koh Jaemoon , Go Heounjeong , Kim Moon‐Young , Jeon Yoon Kyung , Chung Jin‐Haeng , Chung Doo Hyun
Published: August 2014

Aims

Need for accurate histologic subtyping of non‐small cell lung carcinomas (NSCLCs) is growing. IHC patterns may be ambiguous in some cases, rendering it difficult to determine subtypes.

Methods and results

Tissue microarrays composed of 184 resected NSCLCs were stained for TTF‐1, Napsin A, CK7, p40, p63, CK5/6, and mucicarmine. TTF‐1 and Napsin A were chosen as the most accurate adenocarcinoma (ADC) marker (ACM), and p40 as squamous cell carcinoma (SCC) marker (SCM). We then prospectively performed IHC using these markers (TTF‐1, Napsin A, and p40) in a cohort of small NSCLC biopsies (n = 186) with ambiguous morphology. Of these biopsies, 82.8% (154/186) were classifiable into either ADC or SCC by applying ‘3‐marker IHC panel’. Additional CK7, p63, and CK5/6 were applied in 30 biopsies with equivocal IHC patterns, including 18 ACM−/SCM− (double‐negative) and 12 ACM+/SCM+ (double‐positive) cases. Decision tree and support vector machine models revealed that TTF‐1 was a critical single marker for ADC in double‐positive cases (91.7% accuracy), whereas p63 and/or CK5/6 helped to subtype double‐negative cases (72.2% accuracy).

Conclusions

We propose a novel comprehensive algorithm for subtyping NSCLCs using a 3‐marker IHC panel and additional p63 and CK5/6 that would be useful for subtyping small NSCLC biopsies.
Improvements in phenotype studies of hemoglobin disorders brought by advances in reversed‐phase chromatography of globin chains
Authors: Riou J. , Pissard S. , Goossens M. , Wajcman H.
Published: August 2014

Introduction

Phenotype studies still occupy a key position in the diagnosis of hemoglobin (Hb) disorders.

Material and Methods

In addition to the conventional methods for diagnosis of Hb disorders which are mostly based on differences in charge of the Hb molecules, some progresses have been brought by studying other properties of the globin chains. Among those, difference in hydrophobicity that may be investigated by reversed‐phase HPLC (RP‐HPLC) discriminates between variants displaying identical charges.

Results

In this study, we show how an update of this method allows to recognize an α‐chain variant from a γ‐chain variant, a problem frequently during neonatal screening. We illustrate that RP‐HPLC may also unravel unclear phenotypes which are modified by the presence of an additional variant not detected by the conventional methods, and help to characterize rare mutants. Also we show that it allows a clear distinction between variants with identical electrophoretical charges as exemplified by Hb Lepore Boston–Washington and Lepore Baltimore.

Conclusions

In view of our results, RP‐HPLC is a technique that needs to be used as a second step in the general strategy for a correct characterization of Hb variants.
Repeatability and Reproducibility of Measurements of Femoral and Tibial Alignment Using Computed Tomography Multiplanar Reconstructions
Authors: Barnes Duncan M. , Anderson Angus A. , Frost Chris , Barnes Josephine
Published: August 2014

Objectives

(1) To describe a protocol for measurement of the anatomic lateral distal femoral angle (aLDFA), angle of anteversion (AA), mechanical medial proximal tibial angle (mMPTA), tibial tuberosity displacement (TTD), and crural torsion angle (CTA) from computed tomography (CT) multiplanar reconstructions of canine hindlimbs. (2) To test the intra‐observer variability (repeatability) and inter‐observer variability (reproducibility) of the protocol. (3) To assess the proportion of variance in the measurement of each parameter explained by dog, observer, body mass, and medial patellar luxation (MPL).

Study design

Anatomic study.

Animals

Twenty client‐owned dogs.

Methods

A protocol for the measurement of aLDFA, AA, mMPTA, TTD, and CTA was performed by 3 observers, and performed 3 times by 1 observer, on CT multiplanar reconstructions of 20 canine hindlimbs. Intraclass correlation coefficients (ICC) were calculated for each parameter to examine intra‐observer variability (repeatability) and inter‐observer variability (reproducibility). The proportion of variance in the measurement of each parameter explained by dog, observer, body mass, and MPL was assessed using mixed effect, linear models.

Results

Intra‐observer and inter‐observer ICC were >0.8 for all parameters indicating good repeatability and reproducibility. Most of the variance in the measurement of each parameter was attributable to dog.

Conclusions

The CT protocol, as described, was repeatable and reproducible for assessing the femoral and tibial alignment of dogs.
Mass Fractions of S, Cu, Se, Mo, Ag, Cd, In, Te, Ba, Sm, W, Tl and Bi in Geological Reference Materials and Selected Carbonaceous Chondrites Determined by Isotope Dilution ICP‐MS
Authors: Wang Zaicong , Becker Harry , Wombacher Frank
Published: August 2014

Mass fractions of S, Cu, Se, Mo, Ag, Cd, In, Te, Ba, Sm, W and Tl were determined by isotope dilution sector field ICP‐MS in the same sample aliquot of reference materials using HF‐HNO3 digestion in PFA beakers in pressure bombs and glassy carbon vessels in a high‐pressure asher (HPA‐S) for comparison. Additionally, Bi was determined by internal standardisation relative to Tl. Because isobaric and oxide interferences pose problems for many of these elements, efficient chromatographic separation methods in combination with an Aridus desolvator were employed to minimise interference effects. Repeated digestion and measurement of geological reference materials (BHVO‐1, BHVO‐2, SCo‐1, MAG‐1, MRG‐1 and UB‐N) gave results with < 5% relative intermediate precision (1s) for most elements, except Bi. Replicates of NIST SRM 612 glass digested on a hot plate were analysed by the same methods, and the results agree with reference values mostly within 2% relative deviation. Data for the carbonaceous chondrites Allende, Murchison, Orgueil and Ivuna are also reported. Digestion in a HPA‐S was as efficient as in pressure bombs, but some elements displayed higher blank levels following HPA‐S treatment. Pressure bomb digestion yielded precise data for volatile S, Se and Te, but may result in high blanks for W.
Concept analysis of family homeostasis
Authors: Kim Heejung , Rose Karen M.
Published: August 2014

Aim

To report a concept analysis of family homeostasis.

Background

As family members are a majority of informal caregivers, negative consequences from caregiving duty create a vicious cycle in the family unit resulting in ongoing health crises and care challenges.

Design

Concept analysis.

Data Sources

Forty empirical studies published from 1956–2012 were selected by searching five electronic bibliographical databases and by a manual search conducted from 2012–2013. Search terms included ‘family homeostasis’, ‘homeostasis in family’, ‘homeostatic care’ and ‘family equilibrium’. Clinical experiences in nursing practice were used for constructing cases and clinical implications.

Methods

Walker and Avant's method guided this analysis.

Results

Family homeostasis is defined as the capacity and mechanisms by which equilibrium is re‐established in the family after a change occurs. Five critical attributes are identified: (1) predetermined setpoint; (2) self‐appraised antecedents; (3) interdependence; (4) tendency to stability; and (5) feedback mechanisms. Antecedents include any type of causative change beyond the tolerable limit, while consequences encompass intermediate and long‐term outcomes as well as equilibrium itself.

Conclusion

Family homeostasis provides a conceptual rationale of family caregiving. While care recipients remain the primary beneficiaries of healthcare provision, homeostatic mechanisms are required to support the family caregiver's valuable contribution in the caring process to enhance family well‐being. Further study should expand the definition and settings of family to reflect healthcare needs of diverse types of families and from the perspectives of different healthcare providers.
Provocation of Atrial Fibrillation Triggers During Ablation: Does the Use of General Anesthesia Affect Inducibility?
Authors: MOUNTANTONAKIS STAVROS E. , ELKASSABANY NABIL , KONDAPALLI LAVANYA , MARCHLINSKI FRANCIS E. , MANDEL JEFF E. , HUTCHINSON MATHEW D.
Published: August 2014

AF Triggers During General Anesthesia

Introduction

The autonomic nervous system exerts important effects upon atrial fibrillation (AF) initiation. The strategy of anesthesia used during AF ablation may impact the provocation of AF triggers. We hypothesized that the use of general anesthesia (GA) would reduce the incidence of provokable AF triggers in patients undergoing AF ablation compared to patients studied while receiving only conscious sedation (CS).

Methods and Results

We performed a prospective, case control study comparing the incidence of provokable AF triggers in a consecutive series of patients undergoing AF ablation under GA using a standard trigger induction protocol. We compared the frequency and distribution of AF triggers to a second cohort of historical controls (matched for age, gender, left atrial dimension, and AF phenotype) who underwent ablation while receiving CS. We calculated that 44 total subjects (22 patients in each group) were required to detect a 50% reduction in the incidence of AF triggers in the GA cohort. There was no difference between the 2 groups in the rate of AF trigger inducibility (77% vs. 68%, P = 0.26) or the number of triggers provoked per patient (1.2 ± 0.8 vs. 1.3 ± 0.8, P = 0.38). Patients ablated under GA required higher doses of phenylephrine during the trigger induction protocol (408.3 mg [52–600] vs. 158.3 mg [0–75]; P = 0.003), and tended to require higher doses of isoproterenol to initiate triggers (92.8 mg [20–111] vs. 63.6 mg [6–103]; P = 0.25).

Conclusion

AF trigger induction during GA is both safe and efficacious.
Fibrillar β‐amyloid 1‐42 alters cytokine secretion, cholinergic signalling and neuronal differentiation
Authors: Malmsten Linn , Vijayaraghavan Swetha , Hovatta Outi , Marutle Amelia , Darreh‐Shori Taher
Published: August 2014

Adult neurogenesis is impaired by inflammatory processes, which are linked to altered cholinergic signalling and cognitive decline in Alzheimer's disease. In this study, we investigated how amyloid beta (Aβ)‐evoked inflammatory responses affect the generation of new neurons from human embryonic stem (hES) cells and the role of cholinergic signalling in regulating this process. The hES were cultured as neurospheres and exposed to fibrillar and oligomeric Aβ1‐42 (Aβf, AβO) or to conditioned medium from human primary microglia activated with either Aβ1‐42 or lipopolysaccharide. The neurospheres were differentiated for 29 days in vitro and the resulting neuronal or glial phenotypes were thereafter assessed. Secretion of cytokines and the enzymes acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and choline acetyltransferase (ChAT) involved in cholinergic signalling was measured in medium throughout the differentiation. We report that differentiating neurospheres released various cytokines, and exposure to Aβf, but not AβO, increased the secretion of IL‐6, IL‐1β and IL‐2. Aβf also influenced the levels of AChE, BuChE and ChAT in favour of a low level of acetylcholine. These changes were linked to an altered secretion pattern of cytokines. A different pattern was observed in microglia activated by Aβf, demonstrating decreased secretion of TNF‐α, IL‐1β and IL‐2 relative to untreated cells. Subsequent exposure of differentiating neurospheres to Aβf or to microglia‐conditioned medium decreased neuronal differentiation and increased glial differentiation. We suggest that a basal physiological secretion of cytokines is involved in shaping the differentiation of neurospheres and that Aβf decreases neurogenesis by promoting a microenvironment favouring hypo‐cholinergic signalling and gliogenesis.
Reducing risk of overdose with midazolam injection in adults: an evaluation of change in clinical practice to improve patient safety in England
Authors: Flood Chris , Matthew Linda , Marsh Rachel , Patel Bhavesh , Mansaray Mariama , Lamont Tara
Published: August 2014

Rationale aims and objectives

This study sought to evaluate potential reductions in risk associated with midazolam injection, a sedating medication, following a UK National Patient Safety Alert. This alert, ‘Reducing risk of overdose with midazolam injection in adults’, was sent to all National Health Service organizations as a Rapid Response Report detailing actions services should take to minimize risks.

Method

To evaluate any potential changes arising from this alert, a number of data sources were explored including reported incidents to a national reporting system for health care error, clinician survey and audit data, pharmaceutical purchasing patterns and feedback from National Health Service managers.

Results

Prior to the Rapid Response Report, 498 incidents were received by the National Patient Safety Agency including three deaths. Post‐implementation of the Rapid Response Report (June 2009), no incidents resulting in death or severe harm had been received. All organizations reported having completed the Rapid Response Report actions. Purchase and use of risk‐prone, high‐strength sedating midazolam by health care organizations decreased significantly as did the increased use of safer, lower strength doses (as recommended in the Rapid Response Report).

Conclusions

Organizations can achieve safer medication practices, better knowledge, awareness and implementation of national safer practice recommendations. Risks from inadvertent overdose of midazolam injection were reduced post‐implementation of national recommendations. Ongoing monitoring of this particular adverse event will be required with a sustained patient safety message to health services to maintain awareness of the issue and reduction in the number of midazolam‐related errors.
The Development of a Physician Vitality Program: A Brief Report
Authors: Hernandez Barbara Couden , Thomas Tamara L.
Published: August 2014

We describe the development of an innovative program to support physician vitality. We provide the context and process of program delivery which includes a number of experimental support programs. We discuss a model for intervention and methods used to enhance physician resilience, support work‐life balance, and change the culture to one that explicitly addresses the physician's biopsychosocial‐spiritual needs. Recommendations are given for marriage and family therapists (MFTs) who wish to develop similar support programs for healthcare providers.

Video Abstract
Oestradiol Modulates the Effects of Leptin on Energy Homeostasis by Corticotrophin‐Releasing Factor Type 2 Receptor
Authors: Marangon P. B. , Silva L. E. C. M. , Rorato R. , Gomiero Alves P. , Antunes‐Rodrigues J. , Elias L. L. K.
Published: August 2014

In addition to its action in the control of the hypothalamic‐pituitary‐adrenal axis, corticotrophin‐releasing factor (CRF) has been described as an anorexigenic neuropeptide, modulating food intake and energy expenditure. CRF synthesis is influenced by leptin, which would act to increase CRF neurone activation in the paraventricular nucleus (PVN). Gonadal hormones also participate in the regulation of energy homeostasis. The reduction of food intake and body weight gain in ovariectomised (OVX) rats treated with oestradiol is associated with an increase in CRF mRNA expression in the PVN. The present study aimed to investigate the role of CRF as a mediator of leptin responsiveness in the presence of oestradiol. Wistar female rats were bilaterally OVX and divided into three groups: OVX, OVX+E (i.e. treated with oestradiol) and OVX+PF (i.e. OVX pairfed with OVX+E). The rats received daily s.c. injections of either oestradiol cypionate or vehicle for 8 days. To evaluate the role of CRF on the effects of leptin, we performed an i.c.v. leptin injection (10 μg/5 μl) with or without previous i.c.v. treatment with an CRF‐R2 antagonist. We observed that oestradiol replacement in OVX rats reduced body weight gain and food intake. The effects of exogenous leptin administration with respect to decreasing food intake and body weight, and increasing uncoupling protein‐1 expression in the brown adipose tissue and neuronal activation in the arcuate nucleus, were reversed by previous administration of a CRF‐R2 antagonist only in oestradiol‐treated OVX rats. These effects appear to be mediated by CRF‐2 receptor because the antagonist of this receptor reversed the action of oestradiol on the effects of leptin.
Investment‐Based Corporate Bond Pricing
Authors: KUEHN LARS‐ALEXANDER , SCHMID LUKAS
Published: August 2014

A standard assumption of structural models of default is that firms' assets evolve exogenously. In this paper, we examine the importance of accounting for investment options in models of credit risk. In the presence of financing and investment frictions, firm‐level variables that proxy for asset composition are significant determinants of credit spreads beyond leverage and asset volatility, because they capture the systematic risk of firms' assets. Cross‐sectional studies of credit spreads that fail to control for the interdependence of leverage and investment decisions are unlikely to be very informative. Such frictions also give rise to a realistic term structure of credit spreads in a production economy.
Repo Runs: Evidence from the Tri‐Party Repo Market
Authors: COPELAND ADAM , MARTIN ANTOINE , WALKER MICHAEL
Published: August 2014

The repo market has been viewed as a potential source of financial instability since the 2007 to 2009 financial crisis, based in part on findings that margins increased sharply in a segment of this market. This paper provides evidence suggesting that there was no system‐wide run on repo. Using confidential data on tri‐party repo, a major segment of this market, we show that, the level of margins and the amount of funding were surprisingly stable for most borrowers during the crisis. However, we also document a sharp decline in the tri‐party repo funding of Lehman in September 2008.
Effects of salpingectomy and antituberculosis treatments on fertility results in patients with genital tuberculosis
Authors: Caliskan Eray , Cakiroglu Yigit , Sofuoglu Kenan , Doger Emek , Akar Munire E. , Ozkan Sabiha O.
Published: August 2014

Aim

The aim of this study was to demonstrate the effects of tubal surgery and antituberculosis treatments in patients with genital tuberculosis.

Material and Methods

A total of 38 infertile women who had been diagnosed with pelvic tuberculosis and who had had laparoscopy and hysteroscopy were recruited into the study. All women with female genital tuberculosis were divided into two groups: group 1 (salpingectomized, n = 21) and group 2 (not salpingectomized, n = 15). Both of the groups were treated with antitubercular therapy for 6–12 months.

Results

There was no significant difference in level of gonadotrophins used, estradiol levels on human chorionic gonadotrophin day, mean and mature oocytes retrieved, mean embryos transferred, or cancellation and fertilization rates. Only the number of days of stimulation was statistically significantly higher in group 1 compared to group 2 (10.4 ± 2.3 vs 9.2 ± 1.8; P = 0.048). Although it did not reach the statistically significant level, clinical pregnancy rate was higher in group 1 (37.5%, 12/32 vs 23.8%, 5/21; P = 0.306). Although not statistically significant, number of ongoing pregnancies per embryo transfer, spontaneous abortion rates before 20 weeks of gestation and take‐home baby rates were higher in group 1 compared to group 2 (15.5%, 12/77 vs 6.6%, 3/45; P = 0.150; 28.1%, 9 vs 23.8%, 5; P = 0.600; 9%, 3 vs 0; P = 0.160, respectively).

Conclusion

Salpingectomy is an option for treatment in patients diagnosed with pelvic tuberculosis and infertility to improve both clinical pregnancy rates and take‐home baby rates in patients treated with antituberculosis therapy for 12 months.
Case of radioactive iodine exposure during pregnancy
Authors: Sadakata Hisanobu , Shinozaki Hiromitsu , Higuchi Tetsuya , Minegishi Takashi
Published: August 2014

A 43‐year‐old woman (gravida 0, para 0) was diagnosed with thyroid carcinoma and had been receiving radioactive iodine for remnant ablation. Eventually, her pregnant status became apparent; during radiation, she was at 5 gestational weeks. She decided to continue the pregnancy and delivered a boy of 2362 g at 37 gestational weeks. The infant did not present thyroid dysfunction or developmental abnormalities at 2 months of age. The patient was in the early pregnancy stage during radiation, so the fetus did not develop radiation‐related damage of the thyroid gland because at this stage, the fetal thyroid does not concentrate iodine. Although the mother had received radioactive iodine during the critical organogenesis period, the fetus did not develop teratogenicity because the radiation was administered at the borderline threshold for teratogenicity. This case suggests the importance of iodine thyroid absorption when considering radiation‐related damage to the fetal thyroid gland during early pregnancy.