Interference of reversible redox compounds in enzyme catalysed assays - Electrochemical limitations.

BACKGROUND: Several commercial assay kits exist with limited explanation of the kit components and reagent constituents, which greatly increases potential incompatibility issues resulting in the loss of samples, time, and data. Herein we explore such issues via the redox ion [Fe(CN)6]3/4- in two commercial l-lactate and pyruvate assay kits. RESULTS: We clearly demonstrate significant interference from redox compounds with the l-lactate and pyruvate assays; a significance in signal inhibition/mechanism restriction, and false/mechanism exhaustion, respectively. Potential mechanisms are explored to explain interference. CONCLUSION: The need for transparency is crucial for consistency of assay kit performance from lab to lab. There is a need for suppliers to list the components of kits and/or list the potential for interference from specific agents to ensure that results obtained from these kits are reliable and reproducible.

Differential Cytokine Responses and the Clinical Severity of Adult and Pediatric Nephropathia Epidemica.

Nephropathia epidemica (NE), caused by the hantavirus infection, is endemic in Tatarstan Russia. The majority of patients are adults, with infection rarely diagnosed in children. This limited number of pediatric NE cases means there is an inadequate understanding of disease pathogenesis in this age category. Here, we have analyzed clinical and laboratory data in adults and children with NE to establish whether and how the disease severity differs between the two age groups. Serum cytokines were analyzed in samples collected from 11 children and 129 adult NE patients during an outbreak in 2019. A kidney toxicity panel was also used to analyze urine samples from these patients. Additionally, serum and urine samples were analyzed from 11 control children and 26 control adults. Analysis of clinical and laboratory data revealed that NE was milder in children than in adults. A variation in serum cytokine activation could explain the differences in clinical presentation. Cytokines associated with activation of Th1 lymphocytes were prominent in adults, while they were obscured in sera from pediatric NE patients. In addition, a prolonged activation of kidney injury markers was found in adults with NE, whilst only a short-lasting activation of these markers was observed in children with NE. These findings support previous observations of age differences in NE severity, which should be considered when diagnosing the disease in children.

Absence, loss-of-function, or inhibition of Escherichia coli AcrB does not increase expression of other efflux pump genes supporting the discovery of AcrB inhibitors as antibiotic adjuvants.

OBJECTIVES: To determine whether expression of efflux pumps and antibiotic susceptibility are altered in Escherichia coli in response to efflux inhibition. METHODS: The promoter regions of nine efflux pump genes (acrAB, acrD, acrEF, emrAB, macAB, cusCFBA, mdtK, mdtABC, mdfA) were fused to gfp in pMW82 and fluorescence from each reporter construct was used as a measure of the transcriptional response to conditions in which AcrB was inhibited, absent or made non-functional. Expression was also determined by RT-qPCR. Drug susceptibility of efflux pump mutants with missense mutations known or predicted to cause loss of function of the encoded efflux pump was investigated. RESULTS: Data from the GFP reporter constructs revealed that no increased expression of the tested efflux pump genes was observed when AcrB was absent, made non-functional, or inhibited by an efflux pump inhibitor/competitive substrate, such as PAßN or chlorpromazine. This was confirmed by RT-qPCR for PAßN and chlorpromazine; however, a small but significant increase in macB gene expression was seen when acrB is deleted. Efflux inhibitors only synergized with antibiotics in the presence of a functional AcrB. When AcrB was absent or non-functional, there was no impact on MICs when other efflux pumps were also made non-functional. CONCLUSIONS: Absence, loss-of-function, or inhibition of E. coli AcrB did not significantly increase expression of other efflux pump genes, which suggests there is no compensatory mechanism to overcome efflux inhibition and supports the discovery of inhibitors of AcrB as antibiotic adjuvants.

The mycolic acid reductase Rv2509 has distinct structural motifs and is essential for growth in slow-growing mycobacteria.

The final step in mycolic acid biosynthesis in Mycobacterium tuberculosis is catalysed by mycolyl reductase encoded by the Rv2509 gene. Sequence analysis and homology modelling indicate that Rv2509 belongs to the short-chain fatty acid dehydrogenase/reductase (SDR) family, but with some distinct features that warrant its classification as belonging to a novel family of short-chain dehydrogenases. In particular, the predicted structure revealed a unique α-helical C-terminal region which we demonstrated to be essential for Rv2509 function, though this region did not seem to play any role in protein stabilisation or oligomerisation. We also show that unlike the M. smegmatis homologue which was not essential for growth, Rv2509 was an essential gene in slow-growing mycobacteria. A knockdown strain of the BCG2529 gene, the Rv2509 homologue in Mycobacterium bovis BCG, was unable to grow following the conditional depletion of BCG2529. This conditional depletion also led to a reduction of mature mycolic acid production and accumulation of intermediates derived from 3-oxo-mycolate precursors. Our studies demonstrate novel features of the mycolyl reductase Rv2509 and outline its role in mycobacterial growth, highlighting its potential as a new target for therapies.

Landscape-scale restoration minimizes tree growth vulnerability to 21st century drought in a dry forest.

Increasing aridity is a challenge for forest managers and reducing stand density to minimize competition is a recognized strategy to mitigate drought impacts on growth. In many dry forests, the most widespread and common forest management programs currently being implemented focus on restoration of historical stand structures, primarily to minimize fire risk and enhance watershed function. The implications of these restoration projects for drought vulnerability are not well understood. Here, we examined how planned restoration treatments in the Four Forests Restoration Initiative, the largest forest restoration project in the United States, would alter landscape-scale patterns of forest growth and drought vulnerability throughout the 21st century. Using drought-growth relationships developed within the landscape, we considered a suite of climate and treatment scenarios and estimated average forest growth and the proportion of years with extremely low growth as a measure of vulnerability to long-term decline. Climatic shifts projected for this landscape include higher temperatures and shifting seasonal precipitation that promotes lower soil moisture availability in the early growing season and greater hot-dry stress, conditions negatively associated with tree growth. However, drought severity and the magnitude of future growth declines were moderated by the thinning treatments. Compared to historical conditions, proportional growth in mid-century declines by ~40% if thinning ceases or continues at the status quo pace. By comparison, proportional growth declines by only 20% if the Four Forest Restoration Initiative treatments are fully implemented, and <10% if stands are thinned even more intensively than currently planned. Furthermore, restoration treatments resulted in dramatically fewer years with extremely low growth in the future, a recognized precursor to forest decline and eventual tree mortality. Benefits from density reduction for mitigating drought-induced growth declines are more apparent in mid-century and under RCP4.5 than under RCP8.5 at the end of the century. Future climate is inherently uncertain, and our results only reflect the climate projections from the representative suite of models examined. Nevertheless, these results indicate that forest restoration projects designed for other objectives also have substantial benefits for minimizing future drought vulnerability in dry forests and provide additional incentive to accelerate the pace of restoration.

Laparoscopic vs. open feeding jejunostomy insertion in oesophagogastric cancer.

BACKGROUND: Jejunal feeding is an invaluable method by which to improve the nutritional status of patients undergoing neoadjuvant and surgical treatment of oesophageal malignancies. However, the insertion of a feeding jejunostomy can cause significant postoperative morbidity. The aim of this study is to compare the outcomes of patients undergoing placement of feeding jejunostomy by conventional laparotomy with an alternative laparoscopic approach. METHODS: A retrospective review of data prospectively collected at the Oxford Oesophagogastric Centre between August 2017 and July 2019 was performed including consecutive patients undergoing feeding jejunostomy insertion. RESULTS: In the study period, 157 patients underwent jejunostomy insertion in the context of oesophageal cancer therapy, 126 (80%) by open technique and 31 (20%) laparoscopic. Pre-operative demographic and nutritional characteristics were broadly similar between groups. In the early postoperative period jejunostomy-associated complications were noted in 54 cases (34.4%) and were significantly more common among those undergoing open as compared with laparoscopic insertion (38.1% vs. 19.3%, P = 0.049). Furthermore, major complications were more common among those undergoing open insertion, whether as a stand-alone or at the time of staging laparoscopy (n = 11/71), as compared with insertion at the time of oesophagectomy (n = 3/86, P = 0.011). CONCLUSIONS: This report represents the largest to our knowledge single-centre comparison of open vs. laparoscopic jejunostomy insertion in patients undergoing oesophagectomy in the treatment of gastroesophageal malignancy. We conclude that the laparoscopic jejunostomy insertion technique described represents a safe and effective approach to enteral access which may offer superior outcomes to conventional open procedures.

Defining renal phenotype in Alström syndrome.

BACKGROUND: Alström syndrome (AS) is a rare autosomal recessive ciliopathy with a wide spectrum of clinical features, including cone-rod retinal dystrophy, neuronal deafness, severe insulin resistance and major organ failure. The characteristics of renal disease in the syndrome have not been systematically described. The aim of this study is to define the onset and progression of renal disease in AS. METHOD: Prospective observational cohort study. SETTING AND PARTICIPANTS: Thirty-two adult subjects from a national specialist clinic in UK and 86 subjects from an international AS registry were studied. OUTCOMES: First, an international registry cross-sectional study across all age groups to determine change in kidney function was performed. Secondly, a detailed assessment was carried out of adult AS patients with serial follow-up to determine incidence, aetiology and progression of renal disease. ANALYTICAL APPROACH: Generalized estimating equations were used to evaluate the relationship between age and estimated glomerular filtration rate (eGFR). Associations between patient factors and eGFR levels were then assessed in the adult AS cohort. RESULTS: The international registry study of the renal function of 118 subjects with AS (median age 21 years) showed a rapid decline with age, at an average of -16.7 and -10.9 mL/min/1.73 m2 per decade in males and females, respectively. In a UK national cohort of 32 patients with AS (median age 22 years), 20/32 (63%) had chronic kidney disease (CKD) Stage 3 or above based on eGFR <60 mL/min/1.73 m2 or evidence of albuminuria. Hyperuricaemia was noted in 25/32 (79%). Structural abnormalities such as nephrocalcinosis without hypercalcaemia and cysts were observed in 20/32 (63%) subjects. Lower urinary tract symptoms were frequent in 17/19 (70%) of AS patients. Histological evidence showed mixed tubulo-interstitial and glomerular disease. CONCLUSIONS: This is the first study to demonstrate that renal disease is the hallmark of AS, which starts early and progresses with age, leading to a high prevalence of advanced CKD at young age. AS should be considered in the differential diagnosis of rare genetic renal diseases.

Enhancing Patient Activation and Self-Management Activities in Patients With Type 2 Diabetes Using the US Department of Defense Mobile Health Care Environment: Feasibility Study.

BACKGROUND: Past mobile health (mHealth) efforts to empower type 2 diabetes (T2D) self-management include portals, text messaging, collection of biometric data, electronic coaching, email, and collection of lifestyle information. OBJECTIVE: The primary objective was to enhance patient activation and self-management of T2D using the US Department of Defense's Mobile Health Care Environment (MHCE) in a patient-centered medical home setting. METHODS: A multisite study, including a user-centered design and a controlled trial, was conducted within the US Military Health System. Phase I assessed preferences regarding the enhancement of the enabling technology. Phase II was a single-blinded 12-month feasibility study that randomly assigned 240 patients to either the intervention (n=123, received mHealth technology and behavioral messages tailored to Patient Activation Measure [PAM] level at baseline) or the control group (n=117, received equipment but not messaging. The primary outcome measure was PAM scores. Secondary outcome measures included Summary of Diabetes Self-Care Activities (SDSCA) scores and cardiometabolic outcomes. We used generalized estimating equations to estimate changes in outcomes. RESULTS: The final sample consisted of 229 patients. Participants were 61.6% (141/229) male, had a mean age of 62.9 years, mean glycated hemoglobin (HbA1c) of 7.5%, mean BMI of 32.7, and a mean duration of T2D diagnosis of 9.8 years. At month 12, the control group showed significantly greater improvements compared with the intervention group in PAM scores (control mean 7.49, intervention mean 1.77; P=.007), HbA1c (control mean -0.53, intervention mean -0.11; P=.006), and low-density lipoprotein cholesterol (control mean -7.14, intervention mean 4.38; P=.01). Both groups showed significant improvement in SDSCA, BMI, waist size, and diastolic blood pressure; between-group differences were not statistically significant. Except for patients with the highest level of activation (PAM level 4), intervention group patients exhibited significant improvements in PAM scores. For patients with the lowest level of activation (PAM level 1), the intervention group showed significantly greater improvement compared with the control group in HbA1c (control mean -0.09, intervention mean -0.52; P=.04), BMI (control mean 0.58, intervention mean -1.22; P=.01), and high-density lipoprotein cholesterol levels (control mean -4.86, intervention mean 3.56; P<.001). Significant improvements were seen in AM scores, SDSCA, and waist size for both groups and in diastolic and systolic blood pressure for the control group; the between-group differences were not statistically significant. The percentage of participants who were engaged with MHCE for ≥50% of days period was 60.7% (68/112; months 0-3), 57.4% (62/108; months 3-6), 49.5% (51/103; months 6-9), and 43% (42/98; months 9-12). CONCLUSIONS: Our study produced mixed results with improvement in PAM scores and outcomes in both the intervention and control groups. Structural design issues may have hampered the influence of tailored behavioral messaging within the intervention group. TRIAL REGISTRATION: ClinicalTrials.gov NCT02949037; https://clinicaltrials.gov/ct2/show/NCT02949037. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/resprot.6993.

Large-scale forest restoration stabilizes carbon under climate change in Southwest United States.

Higher tree density, more fuels, and a warmer, drier climate have caused an increase in the frequency, size, and severity of wildfires in western U.S. forests. There is an urgent need to restore forests across the western United States. To address this need, the U.S. Forest Service began the Four Forest Restoration Initiative (4FRI) to restore four national forests in Arizona. The objective of this study was to evaluate how restoration of ~400,000 ha under the 4FRI program and projected climate change would influence carbon dynamics and wildfire severity from 2010 to 2099. Specifically, we estimated forest carbon fluxes, carbon pools and wildfire severity under a moderate and fast 4FRI implementation schedule and compared those to status quo and no-harvest scenarios using the LANDIS-II simulation model and climate change projections. We found that the fast-4FRI scenario showed early decreases in ecosystem carbon due to initial thinning/prescribed fire treatments, but total ecosystem carbon increased by 9-18% over no harvest by the end of the simulation. This increased carbon storage by 6.3-12.7 million metric tons, depending on the climate model, equating to removal of carbon emissions from 55,000 to 110,000 passenger vehicles per year until the end of the century. Nearly half of the additional carbon was stored in more stable soil pools. However, climate models with the largest predicted temperature increases showed declines by late century in ecosystem carbon despite restoration. Our study uses data from a real-world, large-scale restoration project and indicates that restoration is likely to stabilize carbon and the benefits are greater when the pace of restoration is faster.

Variable priming of a docked synaptic vesicle.

The priming of a docked synaptic vesicle determines the probability of its membrane (VM) fusing with the presynaptic membrane (PM) when a nerve impulse arrives. To gain insight into the nature of priming, we searched by electron tomography for structural relationships correlated with fusion probability at active zones of axon terminals at frog neuromuscular junctions. For terminals fixed at rest, the contact area between the VM of docked vesicles and PM varied >10-fold with a normal distribution. There was no merging of the membranes. For terminals fixed during repetitive evoked synaptic transmission, the normal distribution of contact areas was shifted to the left, due in part to a decreased number of large contact areas, and there was a subpopulation of large contact areas where the membranes were hemifused, an intermediate preceding complete fusion. Thus, fusion probability of a docked vesicle is related to the extent of its VM-PM contact area. For terminals fixed 1 h after activity, the distribution of contact areas recovered to that at rest, indicating the extent of a VM-PM contact area is dynamic and in equilibrium. The extent of VM-PM contact areas in resting terminals correlated with eccentricity in vesicle shape caused by force toward the PM and with shortness of active zone material macromolecules linking vesicles to PM components, some thought to include Ca(2+) channels. We propose that priming is a variable continuum of events imposing variable fusion probability on each vesicle and is regulated by force-generating shortening of active zone material macromolecules in dynamic equilibrium.

The evaluation of nurse navigators in chronic and complex care.

AIM: With increasing age and chronicity in populations, the need to reduce the costs of care while enhancing quality and hospital avoidance, is important. Nurse-led co-ordination is one such model of care that supports this approach. The aim of this research was to assess the impact that newly appointed Navigators have on service provision; social and economic impact; nurses' professional quality of life and compassion fatigue; and analysis of the change that has occurred to models of care and service delivery. DESIGN: A concurrent mixed-method approach was selected to address the research aims. METHODS: The research project was funded in July 2018 and will conclude in December 2020. Several cohorts will be studied including; patients assigned to a navigator, patients not assigned to a navigator, family members of patients assigned a navigator; and a sample sized estimated at 140 navigators. DISCUSSION: This study provides a comprehensive international longitudinal and mixed method framework for evaluating the impact of nurse navigators on quality of care outcomes for patients with chronic conditions. IMPACT-WHAT PROBLEM WILL THE STUDY ADDRESS?: Even with specialty focused co-ordinated care, patients get lost in the system, increasing the incidence of non-compliance and exacerbation of condition. Navigators work with patients across service boundaries allowing for care that is patient responsive, and permitting variables in clinical, social and practical elements of care to be addressed in a timely manner. This novel nurse-led approach, supports hospital avoidance and patient self-management, while encouraging expansion and opportunity for the nursing and midwifery workforce.

Sharpin Controls Osteogenic Differentiation of Mesenchymal Bone Marrow Cells.

The cytosolic protein Sharpin is a component of the linear ubiquitin chain assembly complex, which regulates NF-κB signaling in response to specific ligands, such as TNF-α. Its inactivating mutation in chronic proliferative dermatitis mutation (Cpdm) mice causes multiorgan inflammation, yet this phenotype is not transferable into wild-type mice by hematopoietic stem cell transfer. Recent evidence demonstrated that Cpdm mice additionally display low bone mass, and that this osteopenia is corrected by Tnf deletion. Because the cellular mechanism underlying this pathology, however, was still undefined, we performed a thorough skeletal phenotyping of Cpdm mice on the basis of nondecalcified histology and cellular and dynamic histomorphometry. We show that the trabecular and cortical osteopenia in Cpdm mice is solely explained by impaired bone formation, whereas osteoclastogenesis is unaffected. Consistently, Cpdm primary calvarial cells display reduced osteogenic capacity ex vivo, and the same was observed with CD11b(-) bone marrow cells. Unexpectedly, short-term treatment of these cultures with TNF-α did not reveal an impaired molecular response in the absence of Sharpin. Instead, genome-wide and gene-specific expression analyses revealed that Cpdm mesenchymal cells display increased responsiveness toward TNF-α-induced expression of specific cytokines, such as CXCL5, IL-1ß, and IL-6. Therefore, our data not only demonstrate that the skeletal defects of Cpdm mice are specifically caused by impaired differentiation of osteoprogenitor cells, they also suggest that increased cytokine expression in mesenchymal bone marrow cells contributes to the inflammatory phenotype of Cpdm mice.

How the European eel (Anguilla anguilla) loses its skeletal framework across lifetime.

European eels (Anguilla anguilla) undertake an impressive 5 000 km long migration from European fresh waters through the North Atlantic Ocean to the Sargasso Sea. Along with sexual maturation, the eel skeleton undergoes a remarkable morphological transformation during migration, where a hitherto completely obscure bone loss phenomenon occurs. To unravel mechanisms of the maturation-related decay of the skeleton, we performed a multiscale assessment of eels' bones at different life-cycle stages. Accordingly, the skeleton reflects extensive bone loss that is mediated via multinucleated bone-resorbing osteoclasts, while other resorption mechanisms such as osteocytic osteolysis or matrix demineralization were not observed. Preserving mechanical stability and releasing minerals for energy metabolism are two mutually exclusive functions of the skeleton that are orchestrated in eels through the presence of two spatially segregated hard tissues: cellular bone and acellular notochord. The cellular bone serves as a source of mineral release following osteoclastic resorption, whereas the mineralized notochord sheath, which is inaccessible for resorption processes due to an unmineralized cover layer, ensures sufficient mechanical stability as a part of the notochord sheath. Clearly, an eel's skeleton is structurally optimized to meet the metabolic challenge of fasting and simultaneous sexual development during an exhausting journey to spawning areas, while the function of the vertebral column is maintained to achieve this goal.

Endoscopic mucosal resection of early oesophageal neoplasia in patients requiring anticoagulation: is it safe?

BACKGROUND AND AIM: Endoscopic mucosal resection (EMR) has become the standard treatment for early oesophageal neoplasia. The mucosal defect caused by EMR usually takes several weeks to heal. Despite guidelines on high-risk endoscopic procedures in patients on anticoagulation, evidence is lacking whether EMR is safe in such patients. We investigated the immediate and delayed bleeding risk in patients undergoing diagnostic or therapeutic oesophageal EMR comparing patients requiring warfarin anticoagulation with a control group. METHODS: Warfarin was stopped 5 days before the planned EMR and restarted on the evening following the procedure. Patients with high-risk conditions, such as recent pulmonary thromboemboli, received bridging with low molecular weight heparin. All EMRs were performed when the INR was <1.5. Bleeding events on the day of the EMR and within 3 months post-procedure were documented. RESULTS: One hundred and seventeen consecutive patients with early oesophageal neoplasia were included. Sixty-eight EMRs were performed in 15 patients requiring anticoagulation. One patient on warfarin was readmitted 10 days after EMR with haematemesis and melaena. Out of 400 EMRs in 102 controls, 26 immediate bleeding events occurred requiring endoscopic intervention. One delayed bleeding event (melaena) occurred in the control group. The number of bleeding events did not differ between groups [p = 0.99; odds ratio 1.01 (0.30-3.44)], neither for acute (p = 0.76) nor delayed bleeding (p = 0.24). CONCLUSION: EMR of early oesophageal neoplasia can be safely performed in patients requiring anticoagulation when warfarin is discontinued 5 days before the endoscopic intervention and reinstituted on the evening of the procedure day.

Multichannel tunable imager architecture for hyperspectral imaging in relevant spectral domains.

In this paper, we present a technique for dimensionality reduction in hyperspectral imaging during the data collection process. A four-channel hyperspectral imager using liquid crystal Fabry-Perot etalons has been built and used to verify this method for four applications: auroral imaging, plant study, landscape classification, and anomaly detection. This imager is capable of making measurements simultaneously in four wavelength ranges while being tunable within those ranges, and thus can be used to measure narrow contiguous bands in four spectral domains. In this paper, we describe the design, concept of operation, and deployment of this instrument. The results from preliminary testing of this instrument are discussed and are promising and demonstrate this instrument as a good candidate for hyperspectral imaging.

Characterization of mutations in the PAS domain of the EvgS sensor kinase selected by laboratory evolution for acid resistance in Escherichia coli.

Laboratory-based evolution and whole-genome sequencing can link genotype and phenotype. We used evolution of acid resistance in exponential phase Escherichia coli to study resistance to a lethal stress. Iterative selection at pH 2.5 generated five populations that were resistant to low pH in early exponential phase. Genome sequencing revealed multiple mutations, but the only gene mutated in all strains was evgS, part of a two-component system that has already been implicated in acid resistance. All these mutations were in the cytoplasmic PAS domain of EvgS, and were shown to be solely responsible for the resistant phenotype, causing strong upregulation at neutral pH of genes normally induced by low pH. Resistance to pH 2.5 in these strains did not require the transporter GadC, or the sigma factor RpoS. We found that EvgS-dependent constitutive acid resistance to pH 2.5 was retained in the absence of the regulators GadE or YdeO, but was lost if the oxidoreductase YdeP was also absent. A deletion in the periplasmic domain of EvgS abolished the response to low pH, but not the activity of the constitutive mutants. On the basis of these results we propose a model for how EvgS may become activated by low pH.

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey.

Alström syndrome (ALMS) is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to have a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with ALMS. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of the common ALMS1 mutations were subjected to direct DNA sequencing or next-generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, eight of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most of the alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. In addition, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. ALMS has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

LiCHI - Liquid Crystal Hyperspectral Imager for simultaneous multispectral imaging in aeronomy.

A four channel hyperspectral imager using Liquid Crystal Fabry-Perot (LCFP) etalons has been built and tested. This imager is capable of making measurements simultaneously in four wavelength ranges in the visible spectrum. The instrument was designed to make measurements of natural airglow and auroral emissions in the upper atmosphere of the Earth and was installed and tested at the Poker Flat Research Range in Fairbanks, Alaska from February to April 2014. The results demonstrate the capabilities and challenges this instrument presents as a sensor for aeronomical studies.

Whistleblowing in medicine and in Homer's Iliad.

'Thinking with Homer', or drawing creatively on themes and scenes from Homer's Iliad and Odyssey, can help us to better understand medical culture and practice. One current, pressing, issue is the role of the whistleblower, who recognises and exposes perceived poor practice or ethical transgressions that compromise patient care and safety. Once, whistleblowers were ostracised where medical culture closed ranks. However, in a new era of public accountability, medicine looks to formally embrace whistleblowing to the point that not reporting transgressions can now constitute a transgression of professionalism. Where medical students identify with the history and traditions of medical culture, they inevitably find themselves in situations of conflicting loyalties if they encounter senior clinicians behaving unprofessionally. What are the implications of facing these dilemmas for students in terms of role modelling and shaping of character as a doctor, and how might a study of Homer help with such dilemmas? We suggest that a close reading of an opening scene in Homer's the Iliad can help us to better appreciate such ethical dilemmas. We link this with the early Greek tradition of parrhesia or 'truth telling', where frankly speaking out against perceived injustice is encouraged as resistance to power and inappropriate use of authority. We encourage medical educators to openly discuss perceived ethical dilemmas with medical students, and medicine as a culture to examine its conscience in a transition from an authoritarian to an 'open' society, where whistleblowing becomes as acceptable and necessary as good hygiene on the wards.

Enhanced recovery for esophagectomy: a systematic review and evidence-based guidelines.

OBJECTIVE: This article aims to provide the first systematic review of enhanced recovery after surgery (ERAS) programs for esophagectomy and generate guidelines. BACKGROUND: ERAS programs use multimodal approaches to reduce complications and accelerate recovery. Although ERAS is well established in colorectal surgery, experience after esophagectomy has been minimal. However, esophagectomy remains an extremely high-risk operation, commonly performed in patients with significant comorbidities. Consequently, ERAS may have a significant role to play in improving outcomes. No guidelines or reviews have been published in esophagectomy. METHODS: We undertook a systematic review of the PubMed, EMBASE, and the Cochrane databases in July 2012. The literature was searched for descriptions of ERAS in esophagectomy. Components of successful ERAS programs were determined, and when not directly available for esophagectomy, extrapolation from related evidence was made. Graded recommendations for each component were then generated. RESULTS: Six retrospective studies have assessed ERAS for esophagectomy, demonstrating favorable morbidity, mortality, and length of stay. Methodological quality is, however, low. Overall, there is little direct evidence for components of ERAS, with much derived from nonesophageal thoracoabdominal surgery. CONCLUSIONS: ERAS in principle seems logical and safe for esophagectomy. However, the underlying evidence is poor and lacking. Despite this, a number of recommendations for practice and research can be made.