bluuebunny/crossref_metadata_2025 huggingface dataset:
Revisiting the reduction of stochastic models of genetic feedback loops with fast promoter switching
Authors: Holehouse J. , Grima R.
Published: June 2019

Propensity functions of the Hill-type are commonly used to model transcriptional regulation in stochastic models of gene expression. This leads to an effective reduced master equation for the mRNA and protein dynamics only. Based on deterministic considerations, it is often stated or tacitly assumed that such models are valid in the limit of rapid promoter switching. Here, starting from the chemical master equation describing promoter-protein interactions, mRNA transcription, protein translation and decay, we prove that in the limit of fast promoter switching, the distribution of protein numbers is different than that given by standard stochastic models with Hill-type propensities. We show the differences are pronounced whenever the protein-DNA binding rate is much larger than the unbinding rate, a special case of fast promoter switching. Furthermore we show using both theory and simulations that use of the standard stochastic models leads to drastically incorrect predictions for the switching properties of positive feedback loops and that these differences decrease with increasing mean protein burst size. Our results confirm that commonly used stochastic models of gene regulatory networks are only accurate in a subset of the parameter space consistent with rapid promoter switching.

Statement of Significance

A large number of models of gene regulatory networks in the literature assume that since promoter switching is fast then transcriptional regulation can be effectively modeled using Hill functions. While this approach can be rigorously justified for deterministic models, it is presently unclear if it is also the case for stochastic models. In this article we prove that this is not the case, i.e. stochastic models of gene regulatory systems, namely those with feedback loops, describing transcriptional regulation using Hill functions are only valid in a subset of parameter conditions consistent with fast promoter switching. We identify parameter regimes where these models are correct and where their predictions cannot be trusted.
Pervasive off-target and double-stranded DNA nicking by CRISPR-Cas12a
Authors: Murugan Karthik , Seetharam Arun S. , Severin Andrew J. , Sashital Dipali G.
Published: June 2019

Cas12a (formerly Cpf1) is an RNA-guided endonuclease in the CRISPR-Cas immune system that can be easily programmed for genome editing. Cas12a can bind and cut dsDNA targets with high specificity in vivo, making it an ideal candidate for precise genome editing applications. This specificity is contradictory to the natural role of Cas12a as an immune effector against rapidly evolving phages. However, the native cleavage specificity and activity remains to be fully understood. We employed high-throughput in vitro cleavage assays to determine and compare the native specificities of three Cas12a orthologs. Surprisingly, we observed pervasive nicking of randomized target libraries, with strong nicking activity observed against targets with up to four mismatches. Nicking and cleavage activities are dependent on mismatch type and position, and vary depending on the Cas12a ortholog and crRNA sequence. Our high-throughput and biochemical analysis further reveal that Cas12a has robust activated non-specific nicking and weak non-specific dsDNA degradation activity in trans. Together, our findings reveal Cas12a cleavage activities that could be beneficial in the context of bacterial CRISPR-Cas immunity but may be detrimental for genome editing technology.
Minimum epistasis interpolation for sequence-function relationships
Authors: Zhou Juannan , McCandlish David M.
Published: June 2019

Massively parallel phenotyping assays have provided unprecedented insight into how multiple mutations combine to determine biological function. While these assays can measure phenotypes for thousands to millions of genotypes in a single experiment, in practice these measurements are not exhaustive, so that there is a need for techniques to impute values for genotypes whose phenotypes are not directly assayed. Here we present a method based on the idea of inferring the least epistatic possible sequence-function relationship compatible with the data. In particular, we infer the reconstruction in which mutational effects change as little as possible across adjacent genetic backgrounds. Although this method is highly conservative and has no tunable parameters, it also makes no assumptions about the form that genetic interactions take, resulting in predictions that can behave in a very complicated manner where the data require it but which are nearly additive where data is sparse or absent. We apply this method to analyze a fitness landscape for protein G, showing that our technique can provide a substantially less epistatic fit to the landscape than standard methods with little loss in predictive power. Moreover, our analysis reveals that the complex structure of epistasis observed in this dataset can be well-understood in terms of a simple qualitative model consisting of three fitness peaks where the landscape is locally additive in the vicinity of each peak.
Lifetime marijuana use in relation to insulin resistance in lean, overweight, and obese US adults
Authors: Ngueta Gerard , Ndjaboue Ruth
Published: June 2019

Background

Obese individuals are more likely to show insulin resistance (IR). However, limited population studies on marijuana use with markers of IR have yielded mixed results. The aim of this study was to examine the association of marijuana use with IR in US adults with different body mass index (BMI) status.

Methods

Data from the 2009 to 2016 National Health and Nutrition Examination Survey (NHANES) were abstracted. Minimal lifetime marijuana use was estimated using the duration of regular exposure and frequency of use. The association of marijuana use with both fasting insulin (FINS) and homeostasis model assessment of insulin resistance (HOMA‐IR) was determined in lean, overweight, and obese individuals separately using generalized linear models. Interview weight years of data were used to account for the unequal probability of sampling and non‐response.

Results

Of all 129 509 adults aged 18 to 59 years, 50.3% were women. In current obese marijuana consumers, mean FINS in those with less than four uses per month was 52% (95% confidence interval [CI] 19%‐71%) lower than in never users. In former obese consumers with eight or more uses per month and who stopped marijuana use <12 months ago, mean FINS was 47% (95% CI 18%‐66%) lower than in never users. Mean FINS in those who quit marijuana 12 to 119 and 120 months and more prior the survey was 36% (95% CI 7%‐57%) and 36% (95% CI 10%‐54%) lower, respectively.

Conclusions

Marijuana use is associated with lower FINS and HOMA‐IR in obese but not non‐obese adults, even at low frequency of less than four uses per month. Former marijuana consumers with high lifetime use had significantly lower FINS levels that persisted, independent of the duration of time since last use.
What We Share Is Who We Are and What We Do: How Emotional Intimacy Shapes Organizational Identification and Collaborative Behaviors
Authors: Sguera Francesco , Bagozzi Richard P. , Huy Quy N. , Boss R. Wayne , Boss David S.
Published: June 2019

We focus on the concept of emotional intimacy among organizational members and investigate its influence on both their (a) perceptions and (b) behaviors. With regard to employees’ perceptions, we test whether it is organizational identification (operationalized as cognitive and affective identification with the organization) that influences emotional intimacy or the reverse. At the behavioral level, we investigate the interplay between employee emotional intimacy and organizational identification and their effects on employee interpersonal helping (OCB‐Is; interpersonal organizational citizenship behaviors) and interpersonal conflict (CWB‐Is; interpersonal counterproductive workplace behaviors). Based on a three‐wave panel study among nurses working in a public hospital, our findings show that emotional intimacy influences organizational identification, and it represents a unique antecedent of OCB‐Is and CWB‐Is.
Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy
Authors: Hatakeyama Keiichi , Nagashima Takeshi , Ohshima Keiichi , Ohnami Sumiko , Ohnami Shumpei , Shimoda Yuji , Serizawa Masakuni , Maruyama Koji , Naruoka Akane , Akiyama Yasuto , Urakami Kenichi , Kusuhara Masatoshi , Mochizuki Tohru , Yamaguchi Ken
Published: June 2019

Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole‐exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures—microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double‐strand break repair, and Signature 16—were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune‐related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation‐driven tumorigenesis.
Jarid1b promotes epidermal differentiation by mediating the repression of Ship1 and activation of the AKT/Ovol1 pathway
Authors: Sun Xuewei , Li Zhiyuan , Niu Yanfang , Zhao Lijuan , Huang Yichuan , Li Qiang , Zhang Shengnan , Chen Ting , Fu Tao , Yang Tao , An Xiaofei , Jiang Yan , Zhang Jisheng
Published: June 2019

Objectives

Terminally differentiated stratified squamous epithelial cells play an important role in barrier protection of the skin. The integrity of epidermal cells is maintained by tight regulation of proliferation and differentiation. The aim of this study was to investigate the role of epigenetic regulator H3K4me3 and its demethylase Jarid1b in the control of epithelial cell differentiation.

Materials and methods

RT‐qPCR, Western blotting and IHC were used to detect mRNA and protein levels. We analysed cell proliferation by CCK8 assay and cell migration by wound healing assay. ChIP was used to measure H3K4me3 enrichment. A chamber graft model was established for epidermal development.

Results

Our studies showed that H3K4me3 was decreased during epidermal differentiation. The H3K4me3 demethylase Jarid1b positively controlled epidermal cell differentiation in vitro and in vivo. Mechanistically, we found that Jarid1b substantially increased the expression of mesenchymal‐epithelial transition (MET)‐related genes, among which Ovol1 positively regulated differentiation gene expression. In addition, Ovol1 expression was repressed by PI3K‐AKT pathway inhibitors and overexpression (O/E) of the PI3K‐AKT pathway suppressor Ship1. Knockdown (KD) of Ship1 activated downstream PI3K‐AKT pathway and enhanced Ovol1 expression in HaCaT. Importantly, we found that Jarid1b negatively regulated Ship1 expression, but not that of Pten, by directly binding to its promoter to modulate H3K4me3 enrichment.

Conclusion

Our results identify an essential role of Jarid1b in the regulation of the Ship1/AKT/Ovol1 pathway to promote epithelial cell differentiation.
The plus‐tip tracking and microtubule stabilizing activities of Javelin‐like regulate microtubule organization and cell polarity
Authors: Baskar Raju , Bahkrat Anna , Otani Tetsuhisa , Wada Housei , Davidov Geula , Pandey Himanshu , Gheber Larisa , Zarivach Raz , Hayashi Shigeo , Abdu Uri
Published: June 2019

Cell polarity is essential for building cell asymmetry in all eukaryotic cells. Drosophila oocyte and bristle development require the newly characterized Spn‐F protein complex, which includes Spn‐F, IKKε, and Javelin‐like (Jvl), to establish polarity. Jvl is a novel microtubule (MT)‐associated protein; however, the mechanism by which it regulates MT organization is still unknown. We found that overexpression of Jvl stabilizes MTs and that jvl is needed for stable MT arrangement at the bristle tip and organization of the dynamic MT throughout the bristle shaft. At low levels of expression in cultured cells, Jvl behaved as a microtubule plus‐end tracking protein. We demonstrated that Jvl physically interacts with the highly conserved MT end‐binding protein 1 (EB1) using yeast two‐hybrid and GST pull‐down assays. This interaction is, however, dispensable for Jvl function in oocyte and bristle development. In addition, using a MT‐binding assay, we saw that Jvl‐C terminus directly binds to MTs. We also revealed that oocyte developmental arrest caused by Jvl overexpression in the germline can be rescued by mutations in its partners, spn‐F and ikkε, suggesting that complex formation with Spn‐F and IKKε is required for Jvl function in vivo. In summary, our results show that the microtubule plus‐end tracking and stabilizing activities of Jvl are central for controlling cell polarity of oocytes and bristles.
Cross‐country spillovers of fiscal consolidations in the euro area
Authors: Poghosyan Tigran
Published: June 2019

This paper revisits the issue of cross‐country spillovers from fiscal consolidations using an innovative empirical methodology. We find evidence in support of fiscal spillovers in ten euro area countries. Fiscal consolidation in one country not only reduces domestic output (direct effect) but also reduces the output of other member countries (indirect/spillover effect). Fiscal spillovers are larger for (a) more closely located and economically integrated countries, and (b) fiscal shocks originating from relatively larger countries. On average, 1% of gross domestic product fiscal consolidation in ten euro area countries reduces the combined output by 0.6% on impact, out of which half is driven by indirect effects from fiscal spillovers. The impact peters out and becomes insignificant over the medium term. It is largely driven by tax measures, which have a relatively stronger effect on output compared to expenditure measures. The results are robust to alternative measures of bilateral links across countries.
End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum
Authors: Le Stephanie T. , Wang Jenny Z. , Alexanian Claire C. , Johng Stephanie Y. , Patel Forum B. , Wang Elizabeth A. , Ma Chelsea , Wilken Reason , Cheng Michelle Y. , Maverakis Emanual
Published: June 2019

Scurvy is a clinical syndrome, resulting from ascorbic acid deficiency. Prevalence of the condition is now extremely low in the Western population and its diagnosis can be challenging without a high index of suspicion. When cases do present, they are often misdiagnosed initially. Therefore, a thorough history, physical exam, and laboratory evaluation are key to showing this now rare but extremely well‐known disease. We report a case of scurvy manifesting as persistent non‐healing lower‐extremity ulcerations, initially mistaken for pyoderma gangrenosum. The patient responded to appropriate replacement therapy, but ulcers were slow to heal. As was the case in our patient, symptom reversal may require additional nutritional replacement. We encourage physicians to consider nutritional deficiencies in their differential diagnoses and highlight the incidence of malnutrition in the proper clinical setting to avoid diagnostic delay.
Association between periodontitis and cognitive impairment: Analysis of national health and nutrition examination survey (NHANES) III
Authors: Sung Cheng‐En , Huang Ren‐Yeong , Cheng Wan‐Chien , Kao Tung‐Wei , Chen Wei‐Liang
Published: June 2019

Objectives

Periodontitis has been hypothesized as being one of the most common potential risk factors for the development of dementia and cognitive impairment. In order to investigate the relationship between periodontitis and cognition impairment, the National Health and Nutrition Examination Survey (NHANES) database was analysed after adjusting for potential confounding factors, including age and other systemic co‐morbidities.

Materials and Methods

In total, 4,663 participants aged 20–59 years who had received full‐mouth periodontal examination and undergone the cognitive functional test were enrolled. The grade of periodontal disease was categorized into severe, moderate, and mild. Cognitive function examinations, including the simple reaction time test (SRTT), symbol digit substitution test (SDST), and serial digit learning test (SDLT), were adopted for the evaluation of cognitive impairment.

Results

The subjects with mild and moderate to severe periodontitis had higher SDLT and SDST scores, which indicated decreased cognitive function, compared with the healthy group. After adjusting for demographic factors, education, smoking, cardiovascular diseases, and laboratory data, periodontitis was significantly correlated with elevated SDST and SDLT scores (p values for trend = 0.014 and 0.038, respectively) by generalized linear regression models.

Conclusion

Our study highlighted that periodontal status was associated with cognitive impairment in a nationally representative sample of US adults.
Comparison of periodontitis patients’ classification in the 2018 versus 1999 classification
Authors: Graetz Christian , Mann Lucas , Krois Joachim , Sälzer Sonja , Kahl Maren , Springer Claudia , Schwendicke Falk
Published: June 2019

Objectives

We aimed to assess how the 2018 and 1999 classifications of periodontal diseases reflect (a) patients’ characteristics, (b) disease severity/extent/progression and (c) tooth loss (TL) during observation period.

Methods

A total of 251 patients were followed over 21.8 ± 6.2 years. For the 1999 classification, using clinical attachment level (CAL), patients were classified as localized/generalized, mild/moderate/severe and aggressive/chronic periodontitis. For the 2018 classification, patients were staged according to their CAL or bone loss (BL) and the number of lost teeth (stages I–IV). Further factors like probing pocket depths (PPD) or furcation involvement modified the stage. The extent was sub‐classified as generalized/localized. Patients were graded according to the BL/age index, smoking and/or diabetes.

Results

According to the 1999 classification, most patients suffered from generalized severe chronic periodontitis (203/251) or generalized aggressive periodontitis (45/251). Patients with aggressive periodontitis were younger and less often female or smokers. They showed similar TL (0.25 ± 0.22 teeth/patient*year) as generalized severe chronic periodontitis patients (0.23 ± 0.25 teeth/patient*year). According to the 2018 classification, most patients were classified as generalized III‐C (140/251), III‐B (31/251) or IV‐C (64/251). Patients’ age, smoking status, CAL, PPD and BL were well reflected. TL differed between IV‐C (0.36 ± 0.47), generalized III‐C (0.21 ± 0.24) and localized forms (0.10–0.15).

Conclusions

Patients’ characteristics, disease severity/extent/progression and TL were well reflected by the 2018 classification.
Relationship between social cognition and fatigue, depressive symptoms, and anxiety in multiple sclerosis
Authors: Genova Helen M. , Lancaster Katie , Lengenfelder Jean , Bober Christopher P. , DeLuca John , Chiaravalloti Nancy D.
Published: June 2019

Emerging research indicates that in addition to physical and cognitive deficits, individuals with multiple sclerosis (MS) may also have impairments in social cognition, such as facial affect recognition and Theory of Mind (ToM). However, there is little research into how social cognition impairments relate to other domains in MS, such as mood and fatigue levels. The current study investigated whether social cognitive ability is associated with fatigue, depressive symptoms and anxiety in MS. Twenty‐eight individuals with MS completed questionnaires assessing fatigue (Modified Fatigue Impact Scale), depression (Beck Depression Inventory) and anxiety (State‐Trait Anxiety Inventory), as well as tasks of facial affect recognition and ToM (Reading the Mind in the Eyes; Strange Stories). Bivariate correlations were run to examine relationships between variables; partial correlations were subsequently used to ascertain whether these relationships persisted after controlling for cognitive ability (measured with the Symbol Digit Modalities Test). The results indicated that worse performance in both facial affect recognition and ToM were associated with higher rates of psychosocial fatigue, depressive symptoms, and anxiety levels; furthermore, these relationships were not explained by participants’ cognitive ability. These preliminary results help us better understand the association between social cognitive abilities and other symptoms in MS, including depressive symptomatology, anxiety and fatigue.
Interest Group Activists and the Polarization of State Legislatures
Authors: Grumbach Jacob M.
Published: June 2019

Theories in campaign finance research suggest that interest group contributions moderate, and individual contributions polarize, state legislators. However, interest groups are comprised of individuals, and public opinion data suggest that group‐affiliated individual donors are more politically active and have especially extreme attitudes. This article investigates the relationship between group‐affiliated donors and legislative polarization in the U.S. states. In recent elections, individual contributors have grown more closely affiliated with activist organizations, such as environmental and anti‐abortion groups. Contributions from these group‐affiliated contributors predict legislative extremism at least as well as overall contributions from interest groups, individual donors, party committees, and party‐affiliated individuals. Using a novel data set of state legislative primary dates, results suggest that this relationship may be concentrated in the nomination process. Although the potential for endogeneity merits caution, the findings complicate theoretical firewalls between organizations and individuals in research on parties, interest groups, and campaign finance.
Cassava brown streak virus Ham1 protein hydrolyses mutagenic nucleotides and is a necrosis determinant
Authors: Tomlinson Katie R. , Pablo‐Rodriguez José Luis , Bunawan Hamidun , Nanyiti Sarah , Green Patrick , Miller Josie , Alicai Titus , Seal Susan E. , Bailey Andy M. , Foster Gary D.
Published: June 2019

Cassava brown streak disease (CBSD) is a leading cause of cassava losses in East and Central Africa, and is currently having a severe impact on food security. The disease is caused by two viruses within the Potyviridae family: Cassava brown streak virus (CBSV) and Ugandan cassava brown streak virus (UCBSV), which both encode atypical Ham1 proteins with highly conserved inosine triphosphate (ITP) pyrophosphohydrolase (ITPase) domains. ITPase proteins are widely encoded by plant, animal, and archaea. They selectively hydrolyse mutagenic nucleotide triphosphates to prevent their incorporation into nucleic acid and thereby function to reduce mutation rates. It has previously been hypothesized that U/CBSVs encode Ham1 proteins with ITPase activity to reduce viral mutation rates during infection. In this study, we investigate the potential roles of U/CBSV Ham1 proteins. We show that both CBSV and UCBSV Ham1 proteins have ITPase activities through in vitro enzyme assays. Deep‐sequencing experiments found no evidence of the U/CBSV Ham1 proteins providing mutagenic protection during infections of Nicotiana hosts. Manipulations of the CBSV_Tanza infectious clone were performed, including a Ham1 deletion, ITPase point mutations, and UCBSV Ham1 chimera. Unlike severely necrotic wild‐type CBSV_Tanza infections, infections of Nicotiana benthamiana with the manipulated CBSV infectious clones do not develop necrosis, indicating that that the CBSV Ham1 is a necrosis determinant. We propose that the presence of U/CBSV Ham1 proteins with highly conserved ITPase motifs indicates that they serve highly selectable functions during infections of cassava and may represent a euphorbia host adaptation that could be targeted in antiviral strategies.
Spectral characteristics of visible light‐induced pigmentation and visible light protection factor
Authors: Kohli Indermeet , Nahhas Amanda F. , Braunberger Taylor L. , Chaowattanapanit Suteeraporn , Mohammad Tasneem F. , Nicholson Cynthia L. , Kollias Nikiforos , Lim Henry W. , Hamzavi Iltefat H.
Published: June 2019

Solar radiation is a major contributor to the development of skin cancer. Recent studies have shown that visible light (VL), a major portion of solar spectrum, induces biologic effects on the skin. Ultraviolet filters in currently available broad‐spectrum sunscreens do not offer protection against VL. This study was designed to identify the spectral characteristics of the skin responses induced by VL, which can be utilized for time efficient in vivo VL testing. Thirty‐one subjects were irradiated with a light source emitting visible light with less than 0.5% long wavelength UVA1 (VL + UVA1, 370‐700 nm), and 41 subjects were irradiated with pure visible light (pure VL, 400‐700 nm). Assessments including clinical photography, investigator's global assessment of pigmentation and erythema, and diffuse reflectance spectroscopy (DRS) performed immediately and seven days after irradiation. Clinical and spectroscopic data showed that VL + UVA1 spectral output induced significantly darker and persistent skin responses as compared to those induced by pure VL. Spectroscopic signatures of skin responses induced by both radiation sources were identified. The signatures were found to be specific to the radiation source and time of collection. A method to evaluate VL protection factor, using quantitative information from the spectral signatures obtained, was proposed.
Generalization of appetitive conditioned responses
Authors: Andreatta Marta , Pauli Paul
Published: June 2019

A stimulus (conditioned stimulus, CS) associated with an appetitive unconditioned stimulus (US) acquires positive properties and elicits appetitive conditioned responses (CR). Such associative learning has been examined extensively in animals with food as the US, and results are used to explain psychopathologies (e.g., substance‐related disorders or obesity). Human studies on appetitive conditioning exist, too, but we still know little about generalization processes. Understanding these processes may explain why stimuli not associated with a drug, for instance, can elicit craving. Forty‐seven hungry participants underwent an appetitive conditioning protocol during which one of two circles with different diameters (CS+) became associated with an appetitive US (chocolate or salty pretzel, according to participants’ preference) but never the other circle (CS−). During generalization, US were delivered twice and the two CS were presented again plus four circles (generalization stimuli, GS) with gradually increasing diameters from CS− to CS+. We found successful appetitive conditioning as reflected in appetitive subjective ratings (positive valence, higher contingency) and physiological responses (startle attenuation and larger skin conductance responses) to CS+ versus CS−, and, importantly, both measures confirmed generalization as indicated by generalization gradients. Small changes in CS‐US contingency during generalization may have weakened generalization processes on the physiological level. Considering that appetitive conditioned responses can be generalized to non‐US‐associated stimuli, a next important step would be to investigate risk factors that mediate overgeneralization.
A Latent Class Growth Model for Migrants’ Remittances: An Application to the German Socio-Economic Panel
Authors: Bacci Silvia , Bartolucci Francesco , Bettin Giulia , Pigini Claudia
Published: June 2019

We propose a latent class mixture growth model with concomitant variables to study the time profiles of international remittances sent by first-generation migrants in Germany from 1996 to 2012. The latent class approach enables us to identify homogeneous subgroups of migrants associated with different trajectories for their remitting behaviour, which can be interpreted in the light of the theoretical economic background. In addition, the inclusion of concomitant covariates allows us to uncover whether the assignment of migrants to a specific subgroup can be ascribed to their observable characteristics (e.g. their intention to return home), as conjectured by the theoretical models. The model proposed is easily estimated through an expectation–maximization algorithm. Results show that migrants can be clustered in three groups, two of which reflect the evolution of remittances predicted by economic theory.
MALMEM: Model Averaging in Linear Measurement Error Models
Authors: Zhang Xinyu , Ma Yanyuan , Carroll Raymond J.
Published: June 2019

We develop model averaging estimation in the linear regression model where some covariates are subject to measurement error. The absence of the true covariates in this framework makes the calculation of the standard residual-based loss function impossible. We take advantage of the explicit form of the parameter estimators and construct a weight choice criterion. It is asymptotically equivalent to the unknown model average estimator minimizing the loss function. When the true model is not included in the set of candidate models, the method achieves optimality in terms of minimizing the relative loss, whereas, when the true model is included, the method estimates the model parameter with root n rate. Simulation results in comparison with existing Bayesian information criterion and Akaike information criterion model selection and model averaging methods strongly favour our model averaging method. The method is applied to a study on health.
One-year outcomes of infants born with congenital diaphragmatic hernia: a national population cohort study
Authors: Long Anna-May , Bunch Kathryn J , Knight Marian , Kurinczuk Jennifer J , Losty Paul Damian
Published: June 2019

Objective

To report outcomes to 1 year, in infants born with congenital diaphragmatic hernia (CDH), explore factors associated with infant mortality and examine the relationship between surgical techniques and postoperative morbidity.

Design

Prospective national population cohort study.

Setting

Paediatric surgical centres in the UK and Ireland.

Method

Data were collected to 1 year for infants with CDH live-born between 1 April 2009 to 30 September 2010. Factors associated with infant mortality are explored using logistic regression. Postoperative morbidity following patch versus primary closure, minimally invasive versus open surgery and biological versus synthetic patch material is described. Data are presented as n (%) and median (IQR).

Results

Overall known survival to 1 year was 75%, 95% CI 68% to 81% (138/184) and postoperative survival 93%, 95% CI 88% to 97% (138/148). Female sex, antenatal diagnosis, use of vasodilators or inotropes, being small for gestational age, patch repair and use of surfactant were all associated with infant death. Infants undergoing patch repair had a high incidence of postoperative chylothorax (11/54 vs 2/96 in infants undergoing primary closure) and a long length of hospital stay (41 days, IQR 24–68 vs 16 days, IQR 10–25 in primary closure group). Infants managed with synthetic patch material had a high incidence of chylothorax (11/34 vs 0/19 with biological patch).

Conclusion

The majority of infant deaths in babies born with CDH occur before surgical correction. Female sex, being born small for gestational age, surfactant use, patch repair and receipt of cardiovascular support were associated with a higher risk of death. The optimum surgical approach, timing of operation and choice of patch material to achieve lowest morbidity warrants further evaluation.
Measurement of gut oxygenation in the neonatal population using near-infrared spectroscopy: a clinical tool?
Authors: Seager Emilie , Longley Catherine , Aladangady Narendra , Banerjee Jayanta
Published: June 2019

Context

Near-infrared spectroscopy (NIRS) is a non-invasive bedside monitor of tissue oxygenation that may be a useful clinical tool in monitoring of gut oxygenation in newborn infants.

Objective

To systematically review literature to determine whether NIRS is a reliable tool to monitor gut oxygenation on neonatal units.

Data sources

PubMed and Embase databases were searched using the terms ‘neonate’, ‘preterm infants’, ‘NIRS’ and ‘gut oxygenation’ (2001–2018).

Study selection

Studies were included if they met inclusion criteria (clinical trial, observational studies, neonatal population, articles in English and reviewing regional gut oxygen saturations) and exclusion criteria (not evaluating abdominal NIRS or regional oxygen saturations).

Data extraction

Two authors independently searched PubMed and Embase using the predefined terms, appraised study quality and extracted from 30 studies the study design and outcome data.

Limitations

Potential for publication bias, majority of studies were prospective cohort studies and small sample sizes.

Results

Thirty studies were reviewed assessing the validity of abdominal NIRS and potential application in neonates. Studies reviewed assessed abdominal NIRS in different settings including normal neonates, bolus and continuous feeding, during feed intolerance, necrotising enterocolitis and transfusion with packed red cells. Several observational studies demonstrated how NIRS could be used in clinical practice.

Conclusions

NIRS may prove to be a useful bedside tool on the neonatal unit, working alongside current clinical tools in the monitoring of newborn infants (preterm and term) and inform clinical management. We recommend further studies including randomised controlled trials looking at specific measurements and cut-offs for abdominal NIRS for use in further clinical practice.
Sequential co-enrolment in randomised trials in neonatal intensive care medicine
Authors: Yoder Whitney , Groenendaal Floris , Onland Wes , van Oploo Anna , Rietbergen Charlotte , Groenwold Rolf
Published: June 2019

In many medical research settings, such as the neonatal intensive care unit, the number of patients who are eligible for a randomised clinical trial is relatively small and recruiting a sufficient number of patients into trials is often difficult. Furthermore, some infants may have already been enrolled into a trial as a fetus. Sequential co-enrolment of patients into more than one trial may offer a solution, yet runs the risk of contaminated results. We consider the situation of two sequential trials and describe requirements for different possible treatments effects (‘estimands’) to be estimated in such situations. These estimands differ regarding the extent to which participation status and treatment status in the previous trial is accounted for. Because of differences in available information about previous trials, analyses may result in estimated effects which differ in terms of interpretation and generalisability, except when in the absence of an interaction between the studied treatments. If co-enrolment cannot be ruled out, researchers should collect information about co-enrolment and treatment status in a previous or concurrent trial and mitigate the trial analysis plan in order to estimate meaningful effects.
Methotrexate and doxycycline interaction: a rare cause of pancytopenia
Authors: Arslan Ahmad , Zain Muhammad Abdullah , Mukhtar Maryam , Ullah Waqas , Roomi Sohaib
Published: June 2019

Methotrexate (MTX) was originally formulated as one of the first antitumour drugs due to its ability to alter folate metabolism, which renders it to be an antiproliferative agent. Classically, the higher dosage is administered via parenteral route, in a cyclical fashion, to achieve antitumour effects. Patients on high doses of MTX are prone to develop rare complications of myelosuppression and pancytopenia, in a dose-dependent fashion, secondary to altered folate metabolism.1Herein, we present a unique case of rheumatoid arthritis presented with pancytopenia due to low-dose MTX and doxycycline drug interaction. We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.
Does the ethnic density effect extend to obesity? A cross-sectional study of 415 166 adults in east London
Authors: Sutaria Shailen , Mathur Rohini , Hull Sally A
Published: June 2019

Objectives

To examine the prevalence of obesity by ethnic group and to examine the association between ethnic density and obesity prevalence.

Design and setting

Cross-sectional study utilising electronic primary care records of 128 practices in a multiethnic population of east London.

Participants

Electronic primary care records of 415 166 adults with a body mass index recorded in the previous 3 years.

Outcome measures

(1) Odds of obesity for different ethnic groups compared with white British. (2) Prevalence of obesity associated with each 10% increase in own-group ethnic density, by ethnic group.

Results

Using multilevel logistic regression models, we find that compared with white British/Irish males, the odds of obesity were significantly higher among black ethnic groups and significantly lower among Asian and white other groups. Among females, all ethnic groups except Chinese and white other were at increased odds of obesity compared with white British/Irish. There was no association between increasing ethnic density and obesity prevalence, except among black Africans and Indian females. A 10% increase in black ethnic density was associated with a 15% increase in odds of obesity among black African males (95% CI 1.07 to 1.24) and 18% among black African females (95% CI 1.08 to 1.30). Among Indian females, a 10% increase in Indian ethnic density was associated with a 7% decrease in odds of obesity (95% CI 0.88 to 0.99).

Conclusion

Wider environmental factors play a greater role in determining obesity than the ethnic composition of the area for most ethnic groups. Further research is needed to understand the mechanism through which increasing ethnic density is associated with increased odds of obesity among black Africans and decreased odds of obesity among Indian females.
Mixed methods study exploring parent engagement in child health research in British Columbia
Authors: Smith Jennifer , Pike Ian , Brussoni Mariana , Tucker Lori , Mâsse Louise , Mah Janet W T , Boudreau Ainsley , Mount Dawn , Bonaguro Russell , Glegg Stephanie , Amed S
Published: June 2019

Objectives

The objective of this study was to explore parent perspectives of and interest in an interactive knowledge translation platform called Child-Sized KT that proposes to catalyse the collaboration of patients, families, practitioners and researchers in patient-oriented research at British Columbia Children’s Hospital (BCCH).

Methods

An explanatory sequential mixed methods design was used over 1 year. Over 500 parents across BC completed an online survey, including a subsample of 102 parents who had accessed care at BCCH within the past 2 years. The survey explored parent perspectives about the value of their engagement at all stages of the research process and their interest in and concerns with using an online platform. Following the online survey, two focus groups were held with parents in the Vancouver area to explore themes emerging from the survey.

Results

Parents expressed keen interest in engaging in research at BCCH. Parents perceived benefit from their input at all stages of the research process; however, they were most interested in helping to identify the problem, develop the research question and share the results. Although parents preferred online participation, they had concerns about protecting the privacy of their child’s information.

Conclusions

Parents see value in their involvement in all stages of child health research at BCCH. Their input suggests that Child-Sized KT, a hypothetical online platform, would facilitate meaningful stakeholder engagement in child health research, but should offer a customised experience and ensure the highest standard of data privacy and protection.
Feasibility, acceptability and preliminary outcomes of a mindfulness-based relapse prevention program in a naturalistic setting among treatment-seeking patients with alcohol use disorder: a prospective observational study
Authors: von Hammerstein Cora , Khazaal Yasser , Dupuis Mathilde , Aubin Henri-Jean , Benyamina Amine , Luquiens Amandine , Romo Lucia
Published: June 2019

Objectives

Cultural differences between the USA and France led us to examine the feasibility, acceptability and preliminary efficacy data on craving, quality of life and psychological flexibility of the add-on Mindfulness-Based Relapse Prevention (MBRP) programme in alcohol use disorder (AUD) in France.

Design

We conducted a prospective observational study with a 6-month follow-up.

Setting

The study was performed in a naturalistic setting with adult outpatients from an addiction department.

Participants

We included all patients with a current AUD who participated in the MBRP programme (n=52). There was no non-inclusion criterion.

Interventions

The intervention was an 8-week MBRP programme, combining elements of traditional relapse prevention cognitive behavioural therapy and mindfulness meditation training. This was an eight-session closed-group programme.

Primary and secondary outcome measures

Primary outcomes were the number of attended treatment sessions, home practice frequency and dropout rate. Secondary outcomes were changes in craving, quality of life, psychological flexibility, drinking outcomes, depression, anxiety and mindfulness levels.

Results

The average number of completed sessions was 6.6 (SD: 1.9). Most participants introduced mindfulness meditation into their everyday lives: 69% and 49% of included patients maintained formal practice at 3 and 6 months, respectively, and 80% and 64% maintained informal practice at 3 and 6 months, respectively. Most participants used mindfulness techniques to face high-risk situations (56% at 6 months). Participants reported a significant reduction in craving, days of alcohol use, depression and anxiety and an increase in mindfulness and psychological flexibility at 6 months.

Conclusions

The MBRP programme showed good acceptability and feasibility. MBRP seemed to improve craving, mindfulness and psychological flexibility. Comparative studies are needed to evaluate the programme’s efficacy in AUD.

Trial registration number

2200863 v 0.
Impact of legal status change on undocumented migrants’ health and well-being (Parchemins): protocol of a 4-year, prospective, mixed-methods study
Authors: Jackson Yves , Courvoisier Delphine S , Duvoisin Aline , Ferro-Luzzi Giovanni , Bodenmann Patrick , Chauvin Pierre , Guessous Idris , Wolff Hans , Cullati Stéphane , Burton-Jeangros Claudine
Published: June 2019

Introduction

Migrants without residency permit, known as undocumented, tend to live in precarious conditions and be exposed to an accumulation of adverse determinants of health. Only scarce evidence exists on the social, economic and living conditions-related factors influencing their health status and well-being. No study has assessed the impact of legal status regularisation. The Parchemins study is the first prospective, mixed-methods study aiming at measuring the impact on health and well-being of a regularisation policy on undocumented migrants in Europe.

Methods and analysis

The Parchemins study will compare self-rated health and satisfaction with life in a group of adult undocumented migrants who qualify for applying for a residency permit (intervention group) with a group of undocumented migrants who lack one or more eligibility criteria for regularisation (control group) in Geneva Canton, Switzerland. Asylum seekers are not included in this study. The total sample will include 400 participants. Data collection will consist of standardised questionnaires complemented by semidirected interviews in a subsample (n=38) of migrants qualifying for regularisation. The baseline data will be collected just before or during the regularisation, and participants will subsequently be followed up yearly for 3 years. The quantitative part will explore variables about health (ie, health status, occupational health, health-seeking behaviours, access to care, healthcare utilisation), well-being (measured by satisfaction with different dimensions of life), living conditions (ie, employment, accommodation, social support) and economic situation (income, expenditures). Several confounders including sociodemographic characteristics and migration history will be collected. The qualitative part will explore longitudinally the experience of change in legal status at individual and family levels.

Ethics and dissemination

This study was approved by the Ethics Committee of Geneva, Switzerland. All participants provided informed consent. Results will be shared with undocumented migrants and disseminated in scientific journals and conferences. Fully anonymised data will be available to researchers.
Evaluating stress, satisfaction and the associated influencing factors of participants in cancer clinical trials: a cross-sectional study in China
Authors: Jiang Shiyu , Liu Peng , Yang Sheng , Yang Jianliang , Wu Dawei , Fang Hong , Qin Yan , Zhou Shengyu , Xu Jianping , Sun Yongkun , Mo Hongnan , Gui Lin , Xing Puyuan , Lan Bo , Zhang Bo , Tang Le , Sun Yan , Shi Yuankai
Published: June 2019

Objectives

Patients’ stress and satisfaction concerning cancer clinical trials (CCT) may affect study accrual and quality. Our study aimed to evaluate stress and satisfaction in CCT and the influencing factors.

Design

Cross-sectional analysis done by a questionnaire after informed consent.

Setting

Cancer Hospital, Chinese Academy of Medical Sciences.

Participants

199 CCT participants. Primary and secondary outcome measures self-assessed stress and satisfaction in CCT.

Results

Among 199 participants, 83.9% would join CCT again; 72.9% had enough time to decide on trial participation; 73.9% claimed complete awareness of CCT; 3.5% doubted CCT’s significance and scientific quality; 33.2% deemed CCT time-consuming; 73.9% scored satisfaction ≥9/10; and 25.6% claimed moderate to severe stress. Positive factors for satisfaction were enough decision time (OR=0.36, p=0.0003), better impressions of doctors (OR=0.41, p=0.047) and less time-consuming trials (OR=0.43, p<0.0001). Individuals with more prior uninsured medical expenses (OR=1.23, p=0.026), less time consumption (OR=2.35, p<0.0001) and more tests in CCT (OR=0.64, p=0.035) were less likely to experience stress. Phase III study participants bore less stress than phase II (OR=0.29, p=0.032) but more than phase I (OR=1.18, p=0.009).

Conclusions

Our study addressed factors influencing CCT participants’ stress and satisfaction. We suggested measures to improve patients’ experiences in CCT.

Trial registration number

NCT03412344; Pre-results.