bluuebunny/crossref_metadata_2025 huggingface dataset:
A standardized workflow for surveying recombinases expands bacterial genome‐editing capabilities
Authors: Ricaurte Deirdre E. , Martínez‐García Esteban , Nyerges Ákos , Pál Csaba , de Lorenzo Víctor , Aparicio Tomás
Published: November 2017

Bacterial recombineering typically relies on genomic incorporation of synthetic oligonucleotides as mediated by Escherichia coli λ phage recombinase β – an occurrence largely limited to enterobacterial strains. While a handful of similar recombinases have been documented, recombineering efficiencies usually fall short of expectations for practical use. In this work, we aimed to find an efficient Recβ homologue demonstrating activity in model soil bacterium Pseudomonas putida EM42. To this end, a genus‐wide protein survey was conducted to identify putative recombinase candidates for study. Selected novel proteins were assayed in a standardized test to reveal their ability to introduce the K43T substitution into the rpsL gene of P. putida. An ERF superfamily protein, here termed Rec2, exhibited activity eightfold greater than that of the previous leading recombinase. To bolster these results, we demonstrated Rec2 ability to enter a range of mutations into the pyrF gene of P. putida at similar frequencies. Our results not only confirm the utility of Rec2 as a Recβ functional analogue within the P. putida model system, but also set a complete workflow for deploying recombineering in other bacterial strains/species. Implications range from genome editing of P. putida for metabolic engineering to extended applications within other Pseudomonads – and beyond.
Growing the biphasic framework: Techniques and recommendations for fitting emerging growth models
Authors: Wilson Kyle L. , Honsey Andrew E. , Moe Brian , Venturelli Paul
Published: November 2017

Several new growth models have been proposed to account for the life‐history trade‐offs that occur when indeterminately growing species allocate energy between somatic growth and reproduction. These models can improve the understanding of lifetime growth and life history, but can be more difficult to fit than conventional growth models. Increased data demands, multiple growth phases and increased parameterization all serve as barriers to the adoption and proper use of these new models.

We review and comment on confounding issues during model fitting for several of these models, and provide advice on surmounting such issues. We then simulation‐test an example model, the Lester biphasic growth model, using several common fitting approaches. We highlight the biases and precision of each approach and provide guiding documents using r and jags code.

The Bayesian Markov chain Monte Carlo and likelihood profiling approaches generally provided the best fits. Simpler approaches can be unbiased and precise if sampled data are of relatively high quality (e.g. moderate sample sizes for juvenile and adult phases) and model assumptions are met. Bayesian hierarchical approaches can accommodate more complicated data scenarios (e.g. unbalanced design across multiple populations); we provide an example of such an approach by recovering growth trajectories and inferring growth‐associated trait variation and environmental effects across multiple populations.

Conventional growth models provide limited inference on life history. Many biphasic growth models can provide direct inference on multiple life‐history traits, but can be difficult to fit. The recommended approaches herein provide a path forward for fitting biphasic growth models in a variety of scenarios, allowing for wider application and tests of life history and ecological theory.
Prospective study on long‐term outcome after abdominal surgery
Authors: Brynjarsdottir E. D. , Sigurdsson M. I. , Sigmundsdottir E. , Möller P. H. , Sigurdsson G. H.
Published: November 2017

Background

Complications following major abdominal surgery are common and an important cause of morbidity and mortality. The aim of this study was to describe 1‐year mortality and identify factors that influence adverse outcomes after abdominal surgery.

Methods

This prospective observational cohort study was performed in Landspitali University Hospital and included all adult patients undergoing abdominal surgery requiring > 24‐h hospital admission over 13 months. The follow‐up period was 60 days for complications and 24 months for mortality.

Results

Data were available for 1113 (99.5%) of the 1119 patients who fulfilled inclusion criteria. A total of 23% of patients had at least one underlying co‐morbidity. Non‐elective surgeries were 48% and 13% of the patients were admitted to ICU post‐operatively. A total of 20% of patients developed complications. Mortality at 30 days, 1 and 2 years was 1.8%, 5.6%, and 8.3% respectively. One‐year mortality for those admitted to ICU was 18%. The long‐term survival of the individuals surviving 30 days was significantly worse than for an age‐ and gender‐matched population control group. Independent predictors for 1‐year mortality were age, pre‐operative acute kidney injury and intermediate‐ or major surgery.

Conclusion

Post‐operative complication rates and mortality following abdominal surgery in Iceland were comparable or in the lower range of previously published outcomes, validating the utility of offering a full host of abdominal surgical services in geographically isolated region with a relatively small referral base.
Amyloid Beta monomers regulate cyclic adenosine monophosphate response element binding protein functions by activating type‐1 insulin‐like growth factor receptors in neuronal cells
Authors: Zimbone Stefania , Monaco Irene , Gianì Fiorenza , Pandini Giuseppe , Copani Agata G. , Giuffrida Maria Laura , Rizzarelli Enrico
Published: November 2017

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with synaptic dysfunction, pathological accumulation of β‐amyloid (Aβ), and neuronal loss. The self‐association of Aβ monomers into soluble oligomers seems to be crucial for the development of neurotoxicity (J. Neurochem., 00, 2007 and 1172). Aβ oligomers have been suggested to compromise neuronal functions in AD by reducing the expression levels of the CREB target gene and brain‐derived neurotrophic factor (BDNF) (J. Neurosci., 27, 2007 and 2628; Neurobiol. Aging, 36, 2015 and 20406 Mol. Neurodegener., 6, 2011 and 60). We previously reported a broad neuroprotective activity of physiological Aβ monomers, involving the activation of type‐1 insulin‐like growth factor receptors (IGF‐IRs) (J. Neurosci., 29, 2009 and 10582, Front Cell Neurosci., 9, 2015 and 297). We now provide evidence that Aβ monomers, by activating the IGF‐IR‐stimulated PI3‐K/AKT pathway, induce the activation of CREB in neurons and sustain BDNF transcription and release.
Mu opioid receptors in GABAergic neurons of the forebrain promote alcohol reward and drinking
Authors: Ben Hamida Sami , Boulos Laura‐Joy , McNicholas Michael , Charbogne Pauline , Kieffer Brigitte Lina
Published: November 2017

Mu opioid receptors (MORs) are widely distributed throughout brain reward circuits and their role in drug and social reward is well established. Substantial evidence has implicated MOR and the endogenous opioid system in alcohol reward, but circuit mechanisms of MOR‐mediated alcohol reward and intake behavior remain elusive, and have not been investigated by genetic approaches. We recently created conditional knockout (KO) mice targeting the Oprm1 gene in GABAergic forebrain neurons. These mice (Dlx‐MOR KO) show a major MOR deletion in the striatum, whereas receptors in midbrain (including the Ventral Tegmental Area or VTA) and hindbrain are intact. Here, we compared alcohol‐drinking behavior and rewarding effects in total (MOR KO) and conditional KO mice. Concordant with our previous work, MOR KO mice drank less alcohol in continuous and intermittent two‐bottle choice protocols. Remarkably, Dlx‐MOR KO mice showed reduced drinking similar to MOR KO mice, demonstrating that MOR in the forebrain is responsible for the observed phenotype. Further, alcohol‐induced conditioned place preference was detected in control but not MOR KO mice, indicating that MOR is essential for alcohol reward and again, Dlx‐MOR KO recapitulated the MOR KO phenotype. Taste preference and blood alcohol levels were otherwise unchanged in mutant lines. Together, our data demonstrate that MOR expressed in forebrain GABAergic neurons is essential for alcohol reward‐driven behaviors, including drinking and place conditioning. Challenging the prevailing VTA‐centric hypothesis, this study reveals another mechanism of MOR‐mediated alcohol reward and consumption, which does not necessarily require local VTA MORs but rather engages striatal MOR‐dependent mechanisms.
Influence of shaded systems on Xylosandrus compactus infestation in Robusta coffee along a rainfall gradient in Uganda
Authors: Bukomeko Hannington , Jassogne Laurence , Kagezi Godfrey H. , Mukasa David , Vaast Philippe
Published: November 2017

We investigated the relationship between characteristics of coffee shade systems and coffee pest infestation by the black coffee twig borer Xylosandrus compactus Eichhoff. The pest deprives Uganda of $40 millions annually, yet its control remains inadequate.

The present study considered three rainfall zones in Central Uganda and 50 coffee plots that were randomly selected from each rainfall zone. Data were collected on X. compactus infestation and key shade indicators: canopy cover, tree‐species densities, diameter at breast height (DBH) and ratio of coffee to banana.

Cluster analysis revealed two coffee shade systems: a matured shade tree (MST) system and a young poly‐culture (YPC) system. Xylosandrus compactus infestations were significantly less in the MST system than in the YPC system and significantly less in the low rainfall zone than in the high rainfall zone. An increase in the density of Carica papaya and Albizia chinensis significantly reduced and increased X. compactus infestation, respectively. A higher average DBH of individual trees and a higher density of trees that exude sap significantly lowered X. compactus infestation.

Suppressing X. compactus infestation requires bigger trees, a high density of sap‐exuding trees and no Albizia chinensis. Further research should aim to investigate X. compactus flight activity and microclimate influencing X. compactus population dynamics.
The impact of safety nets on technology adoption: a difference‐in‐differences analysis
Authors: Alem Yonas , Broussard Nzinga H.
Published: November 2017

This article contributes to a growing body of empirical literature relating credit constraints and incomplete insurance to investment decisions. We use panel data from rural Ethiopia to investigate whether participation in a safety net program enhances fertilizer adoption. Using a difference‐in‐differences estimator and inverse propensity score weighting, we find that participation in Ethiopia's food‐for‐work (FFW) program increased fertilizer adoption in the short run, but not in the long run. Results also indicate that the intensity of fertilizer usage increased with livestock holdings for FFW‐participant households, providing some evidence that the intervention helped asset‐rich farm households more than asset‐poor households. We find no significant effects of free distribution on fertilizer adoption or intensification. Our results are consistent with the hypothesis that safety nets can be viewed as mechanisms that allow households to take on more risk to pursue higher profits. The results highlight the importance of safety net programs, their effectiveness in ensuring farmers that they will be protected against uninsured shocks, and how that assurance can translate into productivity‐enhancing behavior.
Heterogeneity of commercialization gains in the rural economy
Authors: Radchenko Natalia , Corral Paul , Winters Paul
Published: November 2017

Farmers in low‐income rural economies often fail to switch to cash crops from staple production despite the positive income effects of commercialization expected by policy makers. The literature suggests that market failures prevent households from cash crop adoption but remains inconclusive regarding farmers' motives and the effects of commercialization. This article contributes to the debate by offering an original approach to the analysis of commercialization outcomes and farmers' decisions. It consists of applying a model with essential heterogeneity and a semiparametric estimation technique to analyzing harvest value returns to cash cropping. Using Malawian data, we show considerable heterogeneity in harvest value returns to cash cropping both within and between groups of farmers choosing different crop portfolios. Importantly, the results imply rational choices based on comparative advantage considerations of farming households: farmers self‐select into the activity where they expect higher gains and adopt cash crops when facing weaker market barriers.
Dermoscopic ‘Chaos and Clues’ in the diagnosis of melanomain situ
Authors: Ramji Rajan , Valdes‐Gonzalez Guillermo , Oakley Amanda , Rademaker Marius
Published: November 2017

Background/Objective

To describe the dermoscopic features of melanomain situusing theChaos and Cluesmethod.

Method

Histologically proven primary melanomain situ(MIS) diagnosed through a specialist teledermoscopy clinic were reviewed by three dermatologists. By consensus they agreed on the global dermoscopic pattern, colours, presence of chaos (asymmetry of colour and structure and more than one pattern), and each of the nine clues described for malignancy.

Results

One hundredMISin 92 patients of European ethnicity (45 males) were assessed. Mean age was 67.3 years (range 20–95). The mean dimensions of the lesions were 11.1 × 12.0 mm (range 2.5–31.3 × 2.3–32.3 mm). Using pattern analysis, 82% of the lesions had three or more patterns (multicomponent) and the rest had 2 patterns. Colours included light brown (100%), dark brown (98%) and grey (75%). AllMISdemonstrated chaos. The most prevalent clues were thick lines (88%), eccentric structureless areas (88%), and grey or blue structures (75%).

Conclusion

Dermoscopy can be very helpful in the early diagnosis of melanoma andMIS. TheChaos and Cluesmethod is simple to use. Its unambiguous descriptors can be successfully used to describeMIS. The presence of chaos and clues to malignancy (including thick lines, eccentric structureless areas, and blue/grey structures) should raise a red flag and lead to referral or excision.
Antenatal haemoglobin A1c centiles: does one size fit all?
Authors: Hughes Ruth C. E. , Williman Jonathan A. , Gullam Joanna E.
Published: November 2017

Background

In New Zealand, haemoglobin A1c measurements are routinely offered at booking, preferably before 20 weeks gestation, to detect pre‐existing hyperglycaemia. A haemoglobin A1c <5.9% (41 mmol/mol) is considered normal based on the reference range for the non‐pregnant population.

Aims

To determine pregnancy‐specific haemoglobin A1c centiles by gestation and ethnicity.

Materials and Methods

This is a population‐based observational study of pregnancies uncomplicated by diabetes (pre‐existing or gestational) with ≥1 haemoglobin A1c measurement. Haemoglobin A1c centiles were calculated from data extracted from electronic laboratory and clinical records for pregnancies during 2008–2010.

Results

Included were 6800 pregnancies, European 80% (5462), Māori 6% (415), Pacific Islander 3% (196) and 11% (727) ‘Others’ (mostly Asian). Haemoglobin A1c levels fell with increasing gestation, reaching a nadir at 24 weeks, a trend verified by longitudinal data from 112 women. The 97.5th centile for haemoglobin A1c in European women was 5.76% (39.5 mmol/mol) at 8+0 weeks, 5.70% (38.8 mmol/mol) at 16+0 weeks, and 5.65% (38.3 mmol/mol) at 24+0 weeks. Non‐European women had both higher plasma glucose levels (although within the range considered normal) and higher mean haemoglobin A1c levels compared with Europeans; mean (SD) difference in haemoglobin A1c in Māori +0.13% (0.05) (+1.4 mmol/mol (0.5)), Pacific +0.20% (0.03) (+2.2 mmol/mol (0.3)), ‘Others’ +0.10% (0.03) (+1.1 mmol/mol (0.3)).

Conclusions

The New Zealand haemoglobin A1c cut‐point ≥5.9% (41 mmol/mol) for identifying hyperglycaemia in early pregnancy is greater than the 97.5th centile in European and ‘Other’ women. Utilising population haemoglobin A1c centiles adjusted by gestation may thus better guide management decisions.
Effect of inter‐twin delivery interval on umbilical artery pH and Apgar score in the second twin
Authors: Tal Alon , Peretz Hadar , Garmi Gali , Zafran Noah , Romano Shabtai , Salim Raed
Published: November 2017

Background

To examine the effect of inter‐twin delivery interval on umbilical artery pH and Apgar score of the second twin after vaginal delivery of the first twin.

Methods

Retrospective study conducted at a single teaching hospital. All pregnant women with twin gestation who delivered the first twin vaginally at more than 24 weeks between 1995 and 2015 were included. Major malformations and intrauterine deaths of one or both twins were excluded. Women were divided into those who had an inter‐twin delivery interval of less than 30 minutes (group 1) or 30 minutes or more (group 2). Primary outcome was umbilical artery pH less than 7.1 and/or Apgar score less than 7 at 5 minutes of the second twin. Generalized linear regression with log was performed to evaluate the association with delivery interval.

Results

Of 88 145 deliveries during this period, 1955 (2.2%) were twins. Overall, 713 twin pregnancies, 596 (83.6%) in group 1 and 117 (16.4%) in group 2, were eligible and included. Mean inter‐delivery interval was 11.0 ± 6.5 and 52.5 ± 31.5 minutes in groups 1 and 2, respectively. After adjusting for variables found significantly different between the groups in univariate analysis, inter‐delivery interval of less than 30 minutes or 30 minutes or more was not a significant risk factor for pH less than 7.1 and/or Apgar less than 7 (P = .91). The cesarean rate for delivery of the second twin after vaginal delivery of the first twin was 4.3% overall, with a higher rate among group 2 compared with group 1 (18.2% and 3.2%, respectively; P = .001).

Conclusions

The second twin's Apgar score and cord artery pH are probably not affected when the inter‐twin delivery interval exceeds 30 minutes.
Birth plans—Impact on mode of delivery, obstetrical interventions, and birth experience satisfaction: A prospective cohort study
Authors: Afshar Yalda , Mei Jenny Y. , Gregory Kimberly D. , Kilpatrick Sarah J. , Esakoff Tania F.
Published: November 2017

Objective

To examine whether the presence of a birth plan was associated with mode of delivery, obstetrical interventions, and patient satisfaction.

Methods

This was a prospective cohort study of singleton pregnancies greater than 34 weeks’ gestation powered to evaluate a difference in mode of delivery. Maternal characteristics, antenatal factors, neonatal characteristics, and patient satisfaction measures were compared between groups. Differences between groups were analyzed using chi‐squared for categorical variables, Fisher exact test for dichotomous variables, and Wilcoxon rank sum test for continuous or ordinal variables.

Results

Three hundred women were recruited: 143 (48%) had a birth plan. There was no significant difference in the risk of cesarean delivery for women with a birth plan compared with those without a birth plan (21% vs 16%, adjusted odds ratio [adjOR] 1.11 [95% confidence interval (CI) 0.61‐2.04]). Women with a birth plan were 28% less likely to receive oxytocin (P < .01), 29% less likely to undergo artificial rupture of membranes (P < .01), and 31% less likely to have an epidural (P < .01). There was no difference in the length of labor (P = .12). Women with a birth plan were less satisfied (P < .01) and felt less in control (P < .01) of their birth experience than those without a birth plan.

Conclusion

Women with and without a birth plan had similar odds of cesarean delivery. Though they had fewer obstetrical interventions, they were less satisfied with their birth experience, compared with women without birth plans. Further research is needed to understand how to improve childbirth‐related patient satisfaction.
Quantitative mass spectrometry of human reticulocytes reveal proteome‐wide modifications during maturation
Authors: Chu Trang T. T. , Sinha Ameya , Malleret Benoit , Suwanarusk Rossarin , Park Jung E. , Naidu Renugah , Das Rupambika , Dutta Bamaprasad , Ong Seow Theng , Verma Navin K. , Chan Jerry K. , Nosten François , Rénia Laurent , Sze Siu K. , Russell Bruce , Chandramohanadas Rajesh
Published: November 2017

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi‐lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re‐arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome‐wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub‐fractionation into triton‐extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin‐1/2 and ß‐Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)‐based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.
Transplant results in adults with Fanconi anaemia
Authors: Bierings Marc , Bonfim Carmem , Peffault De Latour Regis , Aljurf Mahmoud , Mehta Parinda A. , Knol Cora , Boulad Farid , Tbakhi Abdelghani , Esquirol Albert , McQuaker Grant , Sucak Gulsan A. , Othman Tarek B. , Halkes Constantijn J. M. , Carpenter Ben , Niederwieser Dietger , Zecca Marco , Kröger Nicolaus , Michallet Mauricette , Risitano Antonio M. , Ehninger Gerhard , Porcher Raphael , Dufour Carlo ,   EBMT SAA WP
Published: November 2017

The outcomes of adult patients transplanted for Fanconi anaemia (FA) have not been well described. We retrospectively analysed 199 adult patients with FA transplanted between 1991 and 2014. Patients were a median of 16 years of age when diagnosed with FA, and underwent transplantation at a median age of 23 years. Time between diagnosis and transplant was shortest (median 2 years) in those patients who had a human leucocyte antigen identical sibling donor. Fifty four percent of patients had bone marrow (BM) failure at transplantation and 46% had clonal disease (34% myelodysplasia, 12% acute leukaemia). BM was the main stem cell source, the conditioning regimen included cyclophosphamide in 96% of cases and fludarabine in 64%. Engraftment occurred in 82% (95% confidence interval [CI] 76–87%), acute graft‐versus‐host disease (GvHD) grade II–IV in 22% (95% CI 16–28%) and the incidence of chronic GvHD at 96 months was 26% (95% CI 20–33). Non‐relapse mortality at 96 months was 56% with an overall survival of 34%, which improved with more recent transplants. Median follow‐up was 58 months. Patients transplanted after 2000 had improved survival (84% at 36 months), using BM from an identical sibling and fludarabine in the conditioning regimen. Factors associated with improved outcome in multivariate analysis were use of fludarabine and an identical sibling or matched non‐sibling donor. Main causes of death were infection (37%), GvHD (24%) and organ failure (12%). The presence of clonal disease at transplant did not significant impact on survival. Secondary malignancies were reported in 15 of 131 evaluable patients.
Vitamin D and calcium supplementation, skeletal muscle strength and serum testosterone in young healthy adult males: Randomized control trial
Authors: Saha Soma , Goswami Ravinder , Ramakrishnan Lakshmy , Vishnubhatla Sreenivas , Mahtab Samrina , Kar Parmita , Srinivasan Sunita , Singh Namrata , Singh Upinderpal
Published: November 2017

Background

Cholecalciferol and/or calcium supplementation might increase skeletal muscle strength and serum testosterone in young adult males.

Objective

We performed a randomized control trial assessing the effect of cholecalciferol/calcium on skeletal muscle strength and serum testosterone in vitamin D deficient young males.

Design

Two‐by‐two factorial RCT.

Subject and Intervention

Two‐hundred and twenty‐eight young males were block‐randomized to (i) double‐placebo, (ii) calcium/placebo, (iii) cholecalciferol/placebo and (iv) cholecalciferol/calcium. Doses for cholecalciferol were 60 000 IU/wk for 8 weeks followed by 60 000 IU/fortnightly, and doses for elemental calcium were 500 mg/twice daily for 6 months. A total of 180 subjects completed the study protocol. Their  ean age, body mass index and baseline 25(OH)D were 20.2 ± 2.2 years, 23.0 ± 3.6 kg/m2 and 21.5 ± 9.5 nmol/L, respectively.

Measurements

Handgrip (primary outcome), pinch‐grip strength, distance walked in 6 minutes, dyspnoea‐score, quality of life by Short Form 36, serum 25(OH)D, 1,25(OH)2D, iPTH, total testosterone and free androgen index (FAI).

Results

After intervention, mean serum 25(OH)D was >75.0 nmol/L in cholecalciferol groups. However, the handgrip strength (29.7 ± 4.4, 29.3 ± 4.6, 30.6 ± 5.0 and 28.8 ± 4.3 kg, P = .28) was comparable in the 4 groups. Subgroups analysis among subjects with baseline serum 25OH)D < 25.0 and <12.0 nmol/L showed similar results. The mean serum testosterone decreased significantly at 6 months; however, delta change was similar in 4 groups. Change in handgrip strength and other outcomes was similar in 4 groups with and without adjustment for delta testosterone and FAI.

Conclusions

Six months of cholecalciferol/calcium supplementation had no significant effect on skeletal muscle strength and serum testosterone in young adult males.
Clinical guidance for radioiodine refractory differentiated thyroid cancer
Authors: Gild Matti L. , Topliss Duncan J. , Learoyd Diana , Parnis Francis , Tie Jeanne , Hughes Brett , Walsh John P. , McLeod Donald S.A. , Clifton‐Bligh Roderick J. , Robinson Bruce G.
Published: November 2017

Prognosis from differentiated thyroid cancer is worse when the disease becomes refractory to radioiodine. Until recently, treatment options have been limited to local therapies such as surgery and radiotherapy, but the recent availability of systemic therapies now provides some potential for disease control. Multitargeted kinase inhibitors (TKIs) including lenvatinib and sorafenib have been shown to improve progression‐free survival in phase III clinical trials, but are also associated with a spectrum of adverse effects. Other TKIs have been utilized as “redifferentiation” agents, increasing sodium iodide symporter expression in metastases and thus restoring radioiodine avidity. Some patients whose disease progresses on initial TKI therapy will still respond to a different TKI and clinical trials currently in progress will clarify the best options for such patients. As these drugs are not inexpensive, care needs to be taken to minimize not only biological but also financial toxicity. In this review, we examine the basic biology of radioiodine refractory disease and discuss optimal treatment approaches, with specific focus on choice and timing of TKI treatment. This clinical field remains fluid, and directions for future research include exploring biomarkers and considering adjuvant TKI use in certain patient groups.
Homozygous mutation in ELMO2 may cause Ramon syndrome
Authors: Mehawej C. , Hoischen A. , Farah R.A. , Marey I. , David M. , Stora S. , Lachlan K. , Brunner H.G. , Mégarbané A.
Published: November 2017

We report on a girl, born to first cousin Lebanese parents, with intellectual disability, seizures, repeated gingivorrhagia, enlarged lower and upper jaws, overgrowth of the gums, high arched and narrow palate, crowded teeth, hirsutism of the back, large abdomen and a small umbilical hernia. Cysts of the mandible, fibrous dysplasia of bones, and enlarged adenoids causing around 60% narrowing of the nasopharyngeal airways were noted at radiographic examination. Her brother presented with the same features in addition to a short stature, an ostium secundum, and more pronounced intellectual disability. He died at the age of 8 years from a severe pulmonary infection and repeated bleeding episodes. A clinical diagnosis of Ramon syndrome was made.

Whole exome sequencing studies performed on the family revealed the presence of a novel homozygous missense mutation in ELMO2 gene, p.I606S in the affected individuals. Loss of function mutations in ELMO2 have been recently described in another clinically distinct condition: primary intraosseous vascular malformation or intraosseous hemangioma, called VMOS. Review of the literature and differential diagnoses are discussed.
Black swans, cognition, and the power of learning from failure
Authors: Catalano Allison S. , Redford Kent , Margoluis Richard , Knight Andrew T.
Published: November 2017

Failure carries undeniable stigma and is difficult to confront for individuals, teams, and organizations. Disciplines such as commercial and military aviation, medicine, and business have long histories of grappling with it, beginning with the recognition that failure is inevitable in every human endeavor. Although conservation may arguably be more complex, conservation professionals can draw on the research and experience of these other disciplines to institutionalize activities and attitudes that foster learning from failure, whether they are minor setbacks or major disasters. Understanding the role of individual cognitive biases, team psychological safety, and organizational willingness to support critical self‐examination all contribute to creating a cultural shift in conservation to one that is open to the learning opportunity that failure provides. This new approach to managing failure is a necessary next step in the evolution of conservation effectiveness.
A Model‐Based Approach to the Wisdom of the Crowd in Category Learning
Authors: Danileiko Irina , Lee Michael D.
Published: November 2017

We apply the “wisdom of the crowd” idea to human category learning, using a simple approach that combines people's categorization decisions by taking the majority decision. We first show that the aggregated crowd category learning behavior found by this method performs well, learning categories more quickly than most or all individuals for 28 previously collected datasets. We then extend the approach so that it does not require people to categorize every stimulus. We do this using a model‐based method that predicts the categorization behavior people would produce for new stimuli, based on their behavior with observed stimuli, and uses the majority of these predicted decisions. We demonstrate and evaluate the model‐based approach in two case studies. In the first, we use the general recognition theory decision‐bound model of categorization (Ashby & Townsend, ) to infer each person's decision boundary for two categories of perceptual stimuli, and we use these inferences to make aggregated predictions about new stimuli. In the second, we use the generalized context model exemplar model of categorization (Nosofsky, ) to infer each person's selective attention for face stimuli, and we use these inferences to make aggregated predictions about withheld stimuli. In both case studies, we show that our method successfully predicts the category of unobserved stimuli, and we emphasize that the aggregated crowd decisions arise from psychologically interpretable processes and parameters. We conclude by discussing extensions and potential real‐world applications of the approach.
Autophagic compound database: A resource connecting autophagy‐modulating compounds, their potential targets and relevant diseases
Authors: Deng Yiqi , Zhu Lingjuan , Cai Haoyang , Wang Guan , Liu Bo
Published: November 2017

Objectives

Autophagy, a highly conserved lysosomal degradation process in eukaryotic cells, can digest long‐lived proteins and damaged organelles through vesicular trafficking pathways. Nowadays, mechanisms of autophagy have been gradually elucidated and thus the discovery of small‐molecule drugs targeting autophagy has always been drawing much attention. So far, some autophagy‐related web servers have been available online to facilitate scientists to obtain the information relevant to autophagy conveniently, such as HADb, CTLPScanner, iLIR server and ncRDeathDB. However, to the best of our knowledge, there is not any web server available about the autophagy‐modulating compounds.

Methods

According to published articles, all the compounds and their relations with autophagy were anatomized. Subsequently, an online Autophagic Compound Database (ACDB) (http://www.acdbliulab.com/) was constructed, which contained information of 357 compounds with 164 corresponding signalling pathways and potential targets in different diseases.

Results

We achieved a great deal of information of autophagy‐modulating compounds, including compounds, targets/pathways and diseases. ACDB is a valuable resource for users to access to more than 300 curated small‐molecule compounds correlated with autophagy.

Conclusions

Autophagic compound database will facilitate to the discovery of more novel therapeutic drugs in the near future.
Indolent, waxing and waning cutaneous presentation of HTLV‐1‐associated adult T‐cell leukemia/lymphoma in an HIV‐1‐positive patient
Authors: Richey Justin D. , Chen Benjamin J. , Deng April C.
Published: November 2017

We present an unusual case of human T‐cell leukemia‐lymphoma virus type 1 (HTLV‐1)‐associated adult T‐cell leukemia/lymphoma in an human immunodeficiency virus (HIV) patient who presented with non‐diffuse, papular, waxing and waning cutaneous eruptions. The patient is a 61‐year‐old Haitian male with history of HIV on highly active antiretroviral therapy (HAART) who presented with multiple painful pink papules on his distal fingers and back for more than a year with a waxing and waning course. Skin biopsy demonstrated a CD4+, CD25+, CD8− lymphocytic proliferation with a clonal T‐cell receptor gene rearrangement. Peripheral blood demonstrated lymphocytosis with a CD4:CD8 ratio greater than 20:1 and an identical T‐cell receptor (TCR) clone as that in the biopsy. HTLV‐1 antibodies and PCR testing for HTLV virus were positive. Retrospective review of CBCs during the past 8 years demonstrated chronic lymphocytosis with a sharp increase in absolute CD4 counts corresponding to the onset of rash. The patient lacked systemic symptoms after 6 months follow‐up.
FNA diagnosis of poorly differentiated thyroid carcinoma. A review of the recent literature
Authors: Saglietti C. , Onenerk A. M. , Faquin W. C. , Sykiotis G. P. , Ziadi S. , Bongiovanni M.
Published: November 2017

Poorly differentiated thyroid carcinoma (PDTC) is a follicular cell‐derived tumour that was recognised as a distinct entity by the World Health Organisation in 2004. The natural history and pathological features of PDTC are reported to be intermediate between those of well‐differentiated and undifferentiated (anaplastic) thyroid carcinomas. Preoperative identification of PDTC could facilitate better initial patient management in many cases, namely more extensive surgery, without any delay. However, according to some experts, a diagnosis of PDTC can only be rendered on histologic specimens based on criteria recommended in the Turin proposal. Although high‐grade features (namely necrosis and mitoses) can be recognised in FNA material, other cytomorphological features have limited value for the preoperative diagnosis of PDTC and specific features for a definitive diagnosis of PDTC have not yet been clearly defined. Here, we review the current status and future prospects for cytological recognition of PDTC; we emphasise the features that should raise suspicion of this rare condition in FNA cytology and provide an update on molecular features and management of PDTC. Despite proposed histological criteria for the diagnosis of PDTC, its recognition on routine thyroid cytology presents a notable challenge. Current and future advances in molecular testing could contribute to the cytological diagnosis of PDTC.
A risk score including body mass index, glycated haemoglobin and triglycerides predicts future glycaemic control in people with type 2 diabetes
Authors: Hertroijs Dorijn F. L. , Elissen Arianne M. J. , Brouwers Martijn C. G. J. , Schaper Nicolaas C. , Köhler Sebastian , Popa Mirela C. , Asteriadis Stylianos , Hendriks Steven H. , Bilo Henk J. , Ruwaard Dirk
Published: November 2017

Aim

To identify, predict and validate distinct glycaemic trajectories among patients with newly diagnosed type 2 diabetes treated in primary care, as a first step towards more effective patient‐centred care.

Methods

We conducted a retrospective study in two cohorts, using routinely collected individual patient data from primary care practices obtained from two large Dutch diabetes patient registries. Participants included adult patients newly diagnosed with type 2 diabetes between January 2006 and December 2014 (development cohort, n = 10 528; validation cohort, n = 3777). Latent growth mixture modelling identified distinct glycaemic 5‐year trajectories. Machine learning models were built to predict the trajectories using easily obtainable patient characteristics in daily clinical practice.

Results

Three different glycaemic trajectories were identified: (1) stable, adequate glycaemic control (76.5% of patients); (2) improved glycaemic control (21.3% of patients); and (3) deteriorated glycaemic control (2.2% of patients). Similar trajectories could be discerned in the validation cohort. Body mass index and glycated haemoglobin and triglyceride levels were the most important predictors of trajectory membership. The predictive model, trained on the development cohort, had a receiver‐operating characteristic area under the curve of 0.96 in the validation cohort, indicating excellent accuracy.

Conclusions

The developed model can effectively explain heterogeneity in future glycaemic response of patients with type 2 diabetes. It can therefore be used in clinical practice as a quick and easy tool to provide tailored diabetes care.
MEASURING THE INTERDEPENDENCE OF MULTINATIONAL FIRMS' FOREIGN INVESTMENTS
Authors: Bösenberg Simon , Egger Peter H. , Merlo Valeria , Wamser Georg
Published: November 2017

Earlier work found evidence for geographic linkages of aggregate foreign direct investment across countries and country‐pairs. From a theoretical point of view, such linkages at the macroeconomic level may root in between‐firm as well as within‐firm linkages and originate from information spillovers across or within firms in exploring unknown markets, and vertical linkages between production plants across different locations within the firm. We use data on the universe of German multinational enterprises (MNEs) to empirically explore how marginal investments at one foreign affiliate depend on investments at other affiliates within the same MNE. The empirical approach employs two channels or modes of cross‐affiliate interdependence: mere geography (capturing horizontal linkages through correlated learning and horizontal competition within the firm) and input–output relationships within or across industries (which capture vertical linkages). Adding to earlier findings at the aggregate level, we find evidence of a significant interdependence of investments within the firm. In the firm‐level data at hand, vertical linkages appear to be more important than horizontal ones. Investments at one location tend to stimulate investments at other locations of the same MNE, particularly if input linkages are strong. The opposite seems to be true for output linkages. Beyond vertical linkages, mere geographic proximity matters only to a minor extent. This suggests that evidence of linkages through geographic closeness at aggregate data levels accrue mainly to reasons of vertical linkages within networks of affiliates. (JEL C31, D22, F21, F23, F68, G31, H32)
Coping strategies in individuals at ultra‐high risk of psychosis: A systematic review
Authors: Mian Louise , Lattanzi Guido Maria , Tognin Stefania
Published: November 2017

Aim

The impact of dysfunctional coping strategies during the prodromal phase of psychosis has recently been explored by several studies. What has yet to be clarified is whether maladaptive coping is evident in the prodromal phase and the impact that this might have on symptomatic and functional outcomes. The aim of this study was to review the findings on coping in individuals at ultra‐high risk of psychosis (UHR) in relation to symptoms and level of functioning.

Methods

Original articles were identified by searching 7 databases using the terms “prodrom*,” “ultra high risk,” “clinical high risk,” “at‐risk mental state,” “coping style*,” “coping strategies,” “cope,” “coping” and “psychosis”. We included original articles that: (1) reported a measure of coping and (2) evaluated UHR individuals.

Results

A total of 9 original articles of 335 that examined coping in individuals at high risk of psychosis were included. UHR subjects were more likely to use maladaptive coping strategies than healthy controls and were more likely to use emotion‐focussed than task‐oriented coping. Maladaptive coping was associated with higher levels of negative symptoms, whereas positive coping was associated with fewer negative symptoms. The coping style employed by UHR individuals was found to negatively influence their psychosocial functioning.

Conclusions

It is still unclear whether coping heightens or reduces the likelihood of transition to psychosis in relation to other factors, including environment. Longitudinal studies could clarify whether coping styles remain stable after the onset of psychosis or whether the emerging psychotic symptoms influence the coping strategies.
Longitudinal changes in LIC and other parameters in patients receiving different chelation regimens: Data from LICNET
Authors: Vitrano Angela , Sacco Massimiliano , Rosso Rosamaria , Quota Alessandra , Fiorino Daniela , Oliva Esther , Gerardi Calogera , Roccamo Gaetano , Spadola Vincenzo , Filosa Aldo , Tesé Lorenzo , Calvaruso Giuseppina , Pitrolo Lorella , Mistretta Laura , Cassarà Filippo , Di Maggio Rosario , Maggio Aurelio
Published: November 2017

Objectives

The liver remains the primary site of iron storage, with liver iron concentration (LIC) being a strong surrogate of total body iron. MRI‐R2 can accurately measure LIC. The LICNET (Liver Iron Cutino Network) was established to diagnostics of liver iron overload by MRI‐R2 subjects with hemochromatosis in hematological disorders. The aims of the study were to look at variation in LIC measurements during time across different chelation regimens.

Methods

This was a cross‐sectional study of 130 patients attending 9 Italian centers participating in the LICNET. LIC comparisons over time (T0 and T1) were made using t test and/or Wilcoxon test.

Results

LIC significantly decreased from MRI1 to MRI2 although at high variance (median change −0.8 mg Fe/g dw, range: −29.0 to 33.0; P = .011) and 7.7% of patients shifted from LIC values of high risk (>15 mg Fe/g dw) to an intermediate‐risk category (7‐15 mg Fe/g dw). Median change in LIC and correlation with serum ferritin levels (SF), during different chelation regimens, is reported.

Conclusions

These findings suggest as longitudinal variation in the LIC is possible, across all chelation regimens. It confirms as SF levels not always can be used for estimating changes in LIC.
Distracter suppression dominates attentional modulation of responses to multiple stimuli inside the receptive fields of middle temporal neurons
Authors: Malek Nour , Treue Stefan , Khayat Paul , Martinez‐Trujillo Julio
Published: November 2017

Single‐cell studies in macaques have shown that attending to one of two stimuli, positioned inside a visual neuron's receptive field (RF), modulates the neuron's response to reflect the features of the attended stimulus. Such a modulation has been described as a ‘push–pull’ effect relative to a reference response: a neuron's response increases when attention is directed to a preferred stimulus, and decreases when attention is directed to a non‐preferred stimulus. It has been further suggested that the response increase when attending to a preferred stimulus is the predominant effect. Here, we show that the observed attentional modulation depends on the reference response. We recorded neuronal responses in motion processing area middle temporal (MT) of macaques to two moving random dot patterns positioned inside neurons’ RF. One pattern always moved in the neuron's antipreferred direction (null pattern), while the other moved in one of 12 directions (tuning pattern). At the beginning of a trial, a cue indicated the location and direction of the target. The animal was required to release a lever when a change in the target direction occurred, and to ignore changes in the distracter. Relative to neurons’ initial responses to the dual stimuli (when attention was less likely to modulate responses), attending to the tuning pattern did not significantly modulate responses over time. However, attending to the null pattern progressively decreased responses over time. These results were quantitatively described by filter and input gain models, characterising a predominant response suppression relative to a reference response, rather than response enhancement.
MAP6 interacts with Tctex1 and Cav2.2/N‐type calcium channels to regulate calcium signalling in neurons
Authors: Brocard Jacques , Dufour Fabrice , Gory‐Fauré Sylvie , Arnoult Christophe , Bosc Christophe , Denarier Eric , Peris Leticia , Saoudi Yasmina , De Waard Michel , Andrieux Annie
Published: November 2017

MAP6 proteins were first described as microtubule‐stabilizing agents, whose properties were thought to be essential for neuronal development and maintenance of complex neuronal networks. However, deletion of all MAP6 isoforms in MAP6 KO mice does not lead to dramatic morphological aberrations of the brain but rather to alterations in multiple neurotransmissions and severe behavioural impairments. A search for protein partners of MAP6 proteins identified Tctex1 – a dynein light chain with multiple non‐microtubule‐related functions. The involvement of Tctex1 in calcium signalling led to investigate it in MAP6 KO neurons. In this study, we show that functional Cav2.2/N‐type calcium channels are deficient in MAP6 KO neurons, due to improper location. We also show that MAP6 proteins interact directly with both Tctex1 and the C‐terminus of Cav2.2/N‐type calcium channels. A balance of these two interactions seems to be crucial for MAP6 to modulate calcium signalling in neurons.