Conductance Spectroscopy of Exfoliated Thin Flakes of Nb xBi2Se3.

We study unconventional superconductivity in exfoliated single crystals of a promising three-dimensional (3D) topological superconductor candidate, Nb-doped Bi2Se3 through differential conductance spectroscopy and magneto-transport. The strong anisotropy of the critical field along the out-of-plane direction suggests that the thin exfoliated flakes are in the quasi-2D limit. Normal metal-superconductor (NS) contacts with either high or low transparencies made by depositing gold leads onto Nb-doped Bi2Se3 flakes both show significant enhancement in zero bias conductance and coherence dips at the superconducting energy gap. Such behavior is inconsistent with conventional Blonder-Tinkham-Klapwijk theory. Instead, we discuss how our results are consistent with p-wave pairing symmetry, supporting the possibility of topological superconductivity in Nb-doped Bi2Se3. Finally, we observe signatures of multiple superconducting energy gaps, which could originate from multiple Fermi surfaces reported earlier in bulk crystals.

Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.

Background: Invasive lobular carcinoma (ILC) as a disease entity distinct from invasive ductal carcinoma (IDC) has merited focused studies of the genomic landscape, but those to date are largely limited to the assessment of early-stage cancers. Given that genomic alterations develop as acquired resistance to endocrine therapy, studies on refractory ILC are needed. Patients and methods: Tissue from 336 primary-enriched, breast-biopsied ILC and 485 estrogen receptor (ER)-positive IDC and metastatic biopsy specimens from 180 ILC and 191 ER-positive IDC patients was assayed with hybrid-capture-based comprehensive genomic profiling for short variant, indel, copy number variants, and rearrangements in up to 395 cancer-related genes. Results: Whereas ESR1 alterations are enriched in the metastases of both ILC and IDC compared with breast specimens, NF1 alterations are enriched only in ILC metastases (mILC). NF1 alterations are predominantly under loss of heterozygosity (11/14, 79%), are mutually exclusive with ESR1 mutations [odds ratio = 0.24, P < 0.027] and are frequently polyclonal in ctDNA assays. Assessment of paired specimens shows that NF1 alterations arise in the setting of acquired resistance. An in vitro model of CDH1 mutated ER-positive breast cancer demonstrates that NF1 knockdown confers a growth advantage in the presence of 4-hydroxy tamoxifen. Our study further identified a significant increase in tumor mutational burden (TMB) in mILCs relative to breast ILCs or metastatic IDCs (8.9% >20 mutations/mb; P < 0.001). Most TMB-high mILCs harbor an APOBEC trinucleotide signature (14/16; 88%). Conclusions: This study identifies alteration of NF1 as enriched specifically in mILC. Mutual exclusivity with ESR1 alterations, polyclonality in relapsed ctDNA, and de novo acquisition suggest a role for NF1 loss in endocrine therapy resistance. Since NF1 loss leads to RAS/RAF kinase activation, patients may benefit from a matched inhibitor. Moreover, for an independent subset of mILC, TMB was elevated relative to breast ILC, suggesting possible benefit from immune checkpoint inhibitors.

Recurrent hyperactive ESR1 fusion proteins in endocrine therapy-resistant breast cancer.

Background: Estrogen receptor-positive (ER-positive) metastatic breast cancer is often intractable due to endocrine therapy resistance. Although ESR1 promoter switching events have been associated with endocrine-therapy resistance, recurrent ESR1 fusion proteins have yet to be identified in advanced breast cancer. Patients and methods: To identify genomic structural rearrangements (REs) including gene fusions in acquired resistance, we undertook a multimodal sequencing effort in three breast cancer patient cohorts: (i) mate-pair and/or RNAseq in 6 patient-matched primary-metastatic tumors and 51 metastases, (ii) high coverage (>500×) comprehensive genomic profiling of 287-395 cancer-related genes across 9542 solid tumors (5216 from metastatic disease), and (iii) ultra-high coverage (>5000×) genomic profiling of 62 cancer-related genes in 254 ctDNA samples. In addition to traditional gene fusion detection methods (i.e. discordant reads, split reads), ESR1 REs were detected from targeted sequencing data by applying a novel algorithm (copyshift) that identifies major copy number shifts at rearrangement hotspots. Results: We identify 88 ESR1 REs across 83 unique patients with direct confirmation of 9 ESR1 fusion proteins (including 2 via immunoblot). ESR1 REs are highly enriched in ER-positive, metastatic disease and co-occur with known ESR1 missense alterations, suggestive of polyclonal resistance. Importantly, all fusions result from a breakpoint in or near ESR1 intron 6 and therefore lack an intact ligand binding domain (LBD). In vitro characterization of three fusions reveals ligand-independence and hyperactivity dependent upon the 3' partner gene. Our lower-bound estimate of ESR1 fusions is at least 1% of metastatic solid breast cancers, the prevalence in ctDNA is at least 10× enriched. We postulate this enrichment may represent secondary resistance to more aggressive endocrine therapies applied to patients with ESR1 LBD missense alterations. Conclusions: Collectively, these data indicate that N-terminal ESR1 fusions involving exons 6-7 are a recurrent driver of endocrine therapy resistance and are impervious to ER-targeted therapies.

Translational Pharmacokinetic-Pharmacodynamic Modeling and Simulation: Optimizing 5-Fluorouracil Dosing in Children With Pediatric Ependymoma.

We previously investigated novel therapies for pediatric ependymoma and found 5-fluorouracil (5-FU) i.v. bolus increased survival in a representative mouse model. However, without a quantitative framework to derive clinical dosing recommendations, we devised a translational pharmacokinetic-pharmacodynamic (PK-PD) modeling and simulation approach. Results from our preclinical PK-PD model suggested tumor concentrations exceeded the 1-hour target exposure (in vitro IC90), leading to tumor growth delay and increased survival. Using an adult population PK model, we scaled our preclinical PK-PD model to children. To select a 5-FU dosage for our clinical trial in children with ependymoma, we simulated various 5-FU dosages for tumor exposures and tumor growth inhibition, as well as considering tolerability to bolus 5-FU administration. We developed a pediatric population PK model of bolus 5-FU and simulated tumor exposures for our patients. Simulations for tumor concentrations indicated that all patients would be above the 1-hour target exposure for antitumor effect.

Development and validation of a new bariatric-specific health-related quality of life instrument ''bariatric and obesity-specific survey (BOSS)''.

BACKGROUND: There is a lack of a psychometrically robust bariatric-specific health-related quality of life (HRQOL) tool. AIM: A single centre, prospective study to develop and validate a new bariatric-specific 81-item self-report HRQOL instrument called the Bariatric and Obesity-Specific Survey (BOSS). MATERIALS AND METHODS: Data were collected from 236 participants. Of these 83 patients were under consideration for bariatric surgery (Group 1) 68 patients had undergone a bariatric procedure (Group 2) and 85 normal healthy participants (Group 3). At baseline, participants were asked to complete the Short Form Health survey (SF-36), Hospital Anxiety and Depression (HADS) scale, Moorehead-Ardelt Quality of life Questionnaire (M-A QoLQ II), and a demographic data sheet. Two weeks following the completion of these five questionnaires, participants were asked to complete BOSS once more along with a feedback sheet. RESULTS: Exploratory factor analysis revealed a multidimensional instrument consisting of 42 items distributed over six domains that addressed various HRQOL aspects and dimensions pertinent to bariatric surgery, and relevant to morbidly obese patients. Further psychometric analysis showed that BOSS has adequate internal consistency reliability (Cronbach α = 0.970), test re-test reliability (ICC = 0.926), construct validity, criterion validity, face validity and acceptability. CONCLUSION: BOSS thus appears to be a valid and reliable multidimensional instrument that provides a clinically useful and relevant measure to assess HRQOL in patients undergoing bariatric surgery.

Identification of risk factors associated with acute kidney injury in patients admitted to acute medical units.

In 2009, the National Confidential Enquiry into Patient Outcome and Death (NCEPOD) report identified significant deficiencies in the management of acute kidney injury (AKI) in hospitals in the UK. Many errors arose from failure to recognise patients with AKI and those at risk of developing AKI. Currently, there is no universally accepted risk factor assessment for identifying such patients on admission to acute medical units (AMUs). A multicentre prospective observational study was performed in the AMUs of 10 hospitals in England and Scotland to define the risk factors associated with AKI and to assess quality of care. Data were collected on consecutive acute medical admissions over two separate 24-h periods. Acute kidney injury was present in 55/316 (17.7%) patients, with sepsis, hypovolaemia, chronic kidney disease (CKD) and diabetes mellitus identified as the major risk factors. Deficiencies in patient care were identified, reinforcing the continuing need to improve the management of AKI.

An inhibitor of thrombin activated fibrinolysis inhibitor (TAFI) can reduce extracellular matrix accumulation in an in vitro model of glucose induced ECM expansion.

Chronic kidney disease (CKD) is characterised by the pathological accumulation of extracellular matrix (ECM) proteins leading to progressive kidney scarring via glomerular and tubular basement membrane expansion. Increased ECM synthesis and deposition, coupled with reduced ECM breakdown contribute to the elevated ECM level in CKD. Previous pre-clinical studies have demonstrated that increased plasmin activity has a beneficial effect in the protein overload model of CKD. As plasmin activation is downregulated by the action of the thrombin activated fibrinolytic inhibitor (TAFI), we tested the hypothesis that inhibition of TAFI might increase plasmin activity and reduce ECM accumulation in an in vitro model of glucose induced ECM expansion. Treatment of NRK52E tubular epithelial cells with increasing concentrations of glucose resulted in a 40% increase in TAFI activity, a 38% reduction in plasmin activity and a subsequent increase in ECM accumulation. In this model system, application of the previously reported TAFI inhibitor UK-396082 [(2S)-5-amino-2-[(1-n-propyl-1H-imidazol-4-yl)methyl]pentanoic acid] caused a reduction in TAFI activity, increased plasmin activity and induced a parallel decrease in ECM levels. In contrast, RNAi knockdown of plasmin resulted in an increase in ECM levels. The data presented here indicate that high glucose induces TAFI activity, inhibiting plasmin activation which results in elevated ECM levels in tubular epithelial cells. The results support the hypothesis that UK-396082 is able to reduce TAFI activity, normalising plasmin activity and preventing excess ECM accumulation suggesting that TAFI inhibition may have potential as an anti-scarring strategy in CKD.

Improving the efficiency of selection to Core Medical Training: a study of the use of multiple assessment stations.

PURPOSE: To compare three separate assessment stations used for selection to Core Medical Training (CMT) and to determine the effect of reducing the number from three to two. METHODS: Quantitative analysis of candidates' assessment station scores, financial analysis of costs of the selection process and quantitative and qualitative surveys of candidates and assessors. RESULTS: The assessment stations used for selection to CMT were reliable and valid for assessing suitability for employment as a CMT trainee. There was no significant difference in candidate ranking if only two assessment stations were used rather than three, i.e. there was no change in the likelihood of receiving a job offer. All of the assessment stations were perceived to have face validity by candidates and assessors. The efficiency of the selection process could be improved without loss of quality if two stations were used rather than three. CONCLUSIONS: Using two assessment stations rather than three would appear to improve the efficiency and maintain the quality of the CMT selection process while reducing costs.

Management of acute ischaemic stroke in the acute medical unit.

Ischaemic stroke is a major cause of death and disability which costs the NHS £2.8 billion/year. Acute stroke care is developing rapidly in line with an increasing evidence base. Intravenous thrombolysis is now recommended by NICE. For this guidance to be effectively implemented stroke must be viewed as a medical emergency by both the public and professionals. Emergency medical services must work in partnership with stroke services to establish systems and protocols which offer high quality acute stroke care. This provides challenges, both in systems design and delivery of clinical care.

Tumour endoproteases: the cutting edge of cancer drug delivery?

Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal' cells and a lack of tumour selective targeting, resulting in a therapeutic index which is modest at best. Consequently, the development of more tumour selective cancer treatments, with better discrimination between tumour and normal cells is unequivocally an important goal for cancer drug discovery. One such strategy is to exploit the tumour phenotype as a mechanism for tumour-selective delivery of potent therapeutics. An exciting approach in this area is to develop anticancer therapeutics as prodrugs, which are non-toxic until activated by enzymes localized specifically in the tumour. Enzymes suitable for tumour-activated prodrug development must have increased activity in the tumour relative to non-diseased tissue and an ability to activate the prodrug to its active form. One class of enzyme satisfying these criteria are the tumour endoproteases, particularly the serine- and metallo-proteases. These proteolytic enzymes are essential for tumour angiogenesis, invasion and metastasis, the major defining features of malignancy. This review describes the concept behind development of tumour-endoprotease activated prodrugs and discusses the various studies to date that have demonstrated the huge potential of this approach for improvement of cancer therapy.

Membrane type matrix metalloproteinases (MMPs) show differential expression in non-small cell lung cancer (NSCLC) compared to normal lung: correlation of MMP-14 mRNA expression and proteolytic activity.

Improved understanding of the involvement of matrix metalloproteinases (MMPs), including membrane-type MMPs (MT-MMPs), in human tumours has potential diagnostic, prognostic and therapeutic implications. We assessed the relationship between MT-MMP expression and clinicopathological parameters in human non-small cell lung cancer (NSCLC) and histologically normal lung tissue by quantitative Real Time PCR (qRT-PCR). All MT-MMPs (MMPs 14-17, 24 and 25) were detected by qRT-PCR with significantly higher MMP-14, -15 and -17 expression observed in tumour relative to normal lung specimens. MMP-16 was undetectable in normal lung but expressed in 8% tumours. MMP-15 demonstrated significant overexpression in adenocarcinomas relative to squamous cell carcinomas and normal lung tissue. MMP-14 mRNA expression strongly correlated to MMP-14 proteolytic activity in preclinical tumour models, indicating that qRT-PCR may predict MMP-14 activity levels in NSCLC. These data suggest that MMP-14, -15 and -17 may be good markers of disease, or therapeutic targets for treatment of human NSCLC.

Randomised trial of personalised computer based information for patients with schizophrenia.

OBJECTIVES: To compare use, effect, and cost of personalised computer education with community psychiatric nurse education for patients with schizophrenia. DESIGN: Randomised trial of three interventions. Modelling of costs of alternatives. PARTICIPANTS: 112 patients with schizophrenia in contact with community services; 67 completed the intervention. INTERVENTIONS: Three interventions of five educational sessions: (a) computer intervention combining information from patient's medical record with general information about schizophrenia; (b) sessions with a community psychiatric nurse; (c) "combination" (first and last sessions with nurse and remainder with computer). MAIN OUTCOME MEASURES: Patients' attendance, opinions, change in knowledge, and psychological state; costs of interventions and patients' use of NHS community services; modelling of costs for these three, and alternative, interventions. RESULTS: Rates of completion of intervention did not differ significantly (71% for combination intervention, 61% for computer only, 46% for nurse only). Computer sessions were shorter than sessions with nurse (14 minutes v 60 minutes). More patients given nurse based education thought the information relevant. Of 20 patients in combination group, 13 preferred the sessions with the nurse and seven preferred the computer. There were no significant differences between groups in psychological outcomes. Because of the need to transport patients to the computer for their sessions, there was no difference between interventions in costs, but computer sessions combined with other patient contacts would be substantially cheaper. CONCLUSIONS: The computer based patient education offered no advantage over sessions with a community psychiatric nurse. Investigation of computer use combined with other health service contacts would be worth while.

Training nurses to support carers of relatives with schizophrenia.

Carers have an enormous amount of responsibility for the welfare and management of people with a mental illness in Britain, and many require help if they are to continue caring. Mental health nurses may be in a key position to offer support, but they are often unclear of what is required and how it should be delivered. Existing UK nurse-led psychosocial interventions for families often focus on the needs of the patient rather than the carer. This article describes a needs-led support service that has been designed for carers whose relatives are diagnosed with schizophrenia. It recognizes the importance of a collaborative partnership between carers and nurses. In 2000, 10 mental health nurses were trained to deliver this support to carers. An evaluation is currently underway. This article outlines the principles of the training programme and how it might enable nurses to meet the carers' needs.

Randomised trial of personalised computer based information for cancer patients.

OBJECTIVE: To compare the use and effect of a computer based information system for cancer patients that is personalised using each patient's medical record with a system providing only general information and with information provided in booklets. DESIGN: Randomised trial with three groups. Data collected at start of radiotherapy, one week later (when information provided), three weeks later, and three months later. PARTICIPANTS: 525 patients started radical radiotherapy; 438 completed follow up. INTERVENTIONS: Two groups were offered information via computer (personalised or general information, or both) with open access to computer thereafter; the third group was offered a selection of information booklets. OUTCOMES: Patients' views and preferences, use of computer and information, and psychological status; doctors' perceptions; cost of interventions. RESULTS: More patients offered the personalised information said that they had learnt something new, thought the information was relevant, used the computer again, and showed their computer printouts to others. There were no major differences in doctors' perceptions of patients. More of the general computer group were anxious at three months. With an electronic patient record system, in the long run the personalised information system would cost no more than the general system. Full access to booklets cost twice as much as the general system. CONCLUSIONS: Patients preferred computer systems that provided information from their medical records to systems that just provided general information. This has implications for the design and implementation of electronic patient record systems and reliance on general sources of patient information.

The impact of education groups for people with schizophrenia on social functioning and quality of life.

BACKGROUND: Education groups for people with schizophrenia have tended to concentrate on compliance with medication. This study examines impact on social behaviour and quality of life. METHOD: A catchment-wide service was set up for community-based patients. Patients who indicated an interest in education groups were randomly allocated to either an education group or a waiting list control group. Those who attended groups were compared with the control group. RESULTS: About one-quarter of community-based patients showed interest in attending education groups. Those who attended showed no change in mental state or compliance with medication (already high) but significant gains in quality of life, social functioning and social networks. CONCLUSIONS: For patients who choose to attend education groups significant gains in social functioning and quality of life are possible without specific skills training.

Orthognathic surgery: patient expectations; psychological profile and satisfaction with outcome.

61 orthognathic surgery patients were studied (39% male, 61% female). It confirms that the group of patients we see in the West of Scotland are well adjusted psychologically and that the majority seek orthognathic surgery for aesthetic reasons. The degree of satisfaction is high (87%). Dissatisfaction is not related to sex, age or procedure. Patients who were dissatisfied tend to have higher neuroticism scores on the Eysenck Personality Inventory and those patients who had had unreal expectations of post surgical pain, numbness and swelling, were likely to express dissatisfaction with the outcome in the early stages. Several patients initially expressed some dissatisfaction with the outcome after 3 months then went on to increase their score and by 12 months became satisfied with the procedure. The authors outline the importance of adequate patient preparation prior to surgery and the use of printed literature is recommended.

The patient as sufferer.

The use of the term sufferer to replace patient has become increasingly common. This paper examines the varied meanings implicit in the word sufferer from the Judaeo-Christian perspective. This includes the biblical themes of suffering as human nature, as punishment, as a test, as atonement and as liberation and deliverance. The consequences of these themes for the sufferer's role are examined, particularly the sufferer as accepting and the sufferer as victim. It is argued that replacing the medical model, implied by 'patient' with a theological model, implied by 'sufferer' does not free the person from the constraints of a damaging label.