Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/y male mice on the inbred genetic background in this different animal facility.

Evaluating possible maternal effect lethality and genetic background effects in Naa10 knockout mice.

Amino-terminal (Nt-) acetylation (NTA) is a common protein modification, affecting approximately 80% of all human proteins. The human essential X-linked gene, NAA10, encodes for the enzyme NAA10, which is the catalytic subunit in the N-terminal acetyltransferase A (NatA) complex. There is extensive genetic variation in humans with missense, splice-site, and C-terminal frameshift variants in NAA10. In mice, Naa10 is not an essential gene, as there exists a paralogous gene, Naa12, that substantially rescues Naa10 knockout mice from embryonic lethality, whereas double knockouts (Naa10-/Y Naa12-/-) are embryonic lethal. However, the phenotypic variability in the mice is nonetheless quite extensive, including piebaldism, skeletal defects, small size, hydrocephaly, hydronephrosis, and neonatal lethality. Here we replicate these phenotypes with new genetic alleles in mice, but we demonstrate their modulation by genetic background and environmental effects. We cannot replicate a prior report of "maternal effect lethality" for heterozygous Naa10-/X female mice, but we do observe a small amount of embryonic lethality in the Naa10-/Y male mice on the inbred genetic background in this different animal facility.

Assessment of treatment-specific tethering survival bias for the juvenile blue crab Callinectes sapidus in a simulated salt marsh.

The blue crab (Callinectes sapidus) is ecologically and economically important in Chesapeake Bay. Nursery habitats, such as seagrass beds, disproportionately contribute individuals to the adult segment of populations. Salt marshes dominated by smooth cordgrass Spartina alterniflora are intertidal nursery habitats which may serve as a refuge from predation for juvenile blue crabs. However, the effects of various characteristics of salt marshes on nursery metrics, such as survival, have not been quantified. Comparisons of juvenile survival between salt marshes and other habitats often employ tethering to assess survival. Although experimental bias when tethering juvenile prey is well recognized, the potential for habitat-specific bias in salt marshes has not been experimentally tested. Using short-term mesocosm predation experiments, we tested if tethering in simulated salt marsh habitats produces a habitat-specific bias. Juvenile crabs were tethered or un-tethered and randomly allocated to mesocosms at varying simulated shoot densities and unstructured sand. Tethering reduced survival, and its effect was not habitat specific, irrespective of shoot density, as evidenced by a non-significant interaction effect between tethering treatment and habitat. Thus, tethering juvenile blue crabs in salt marsh habitat did not produce treatment-specific bias relative to unvegetated habitat across a range of shoot densities; survival of tethered and un-tethered crabs was positively related to shoot density. These findings indicate that tethering is a useful method for assessing survival in salt marshes, as with other nursery habitats including seagrass beds, algae and unstructured sand.

Mechanistic Study of Coffee Effects on Gut Microbiota and Motility in Rats.

Consumption of coffee has benefits in postoperative ileus. We tested the hypothesis that the benefits may be related to the effects of coffee on gut microbiota and motility and studied the mechanisms of action in rats. The in vitro and in vivo effects of regular and decaffeinated (decaf) coffee on gut microbiota of the ileum and colon were determined by bacterial culture and quantitative RT-PCR. Ileal and colonic smooth muscle contractility was determined in a muscle bath. In the in vivo studies, coffee solution (1 g/kg) was administered by oral gavage daily for 3 days. Compared to regular LB agar, the growth of microbiota in the colon and ileal contents was significantly suppressed in LB agar containing coffee or decaf (1.5% or 3%). Treatment with coffee or decaf in vivo for 3 days suppressed gut microbiota but did not significantly affect gut motility or smooth muscle contractility. However, coffee or decaf dose-dependently caused ileal and colonic muscle contractions in vitro. A mechanistic study found that compound(s) other than caffeine contracted gut smooth muscle in a muscarinic receptor-dependent manner. In conclusion, coffee stimulates gut smooth muscle contractions via a muscarinic receptor-dependent mechanism and inhibits microbiota in a caffeine-independent manner.

A longitudinal study of topic classification on Twitter.

Twitter represents a massively distributed information source over topics ranging from social and political events to entertainment and sports news. While recent work has suggested this content can be narrowed down to the personalized interests of individual users by training topic filters using standard classifiers, there remain many open questions about the efficacy of such classification-based filtering approaches. For example, over a year or more after training, how well do such classifiers generalize to future novel topical content, and are such results stable across a range of topics? In addition, how robust is a topic classifier over the time horizon, e.g., can a model trained in 1 year be used for making predictions in the subsequent year? Furthermore, what features, feature classes, and feature attributes are most critical for long-term classifier performance? To answer these questions, we collected a corpus of over 800 million English Tweets via the Twitter streaming API during 2013 and 2014 and learned topic classifiers for 10 diverse themes ranging from social issues to celebrity deaths to the "Iran nuclear deal". The results of this long-term study of topic classifier performance provide a number of important insights, among them that: (i) such classifiers can indeed generalize to novel topical content with high precision over a year or more after training though performance degrades with time, (ii) the classes of hashtags and simple terms contain the most informative feature instances, (iii) removing tweets containing training hashtags from the validation set allows better generalization, and (iv) the simple volume of tweets by a user correlates more with their informativeness than their follower or friend count. In summary, this work provides a long-term study of topic classifiers on Twitter that further justifies classification-based topical filtering approaches while providing detailed insight into the feature properties most critical for topic classifier performance.

Higher Mortality in Women After Coronary Artery Bypass: Meta-analysis and Bias Analysis of Confounding.

BACKGROUND: Some studies suggest that the observed higher mortality in women compared with men after coronary artery bypass grafting (CABG) is due to confounding. Our meta-analysis aimed to (1) summarize the effect of sex on mortality after CABG and (2) identify whether unmeasured confounding likely explains the apparent higher mortality in women. METHODS: We searched MEDLINE, Embase, and CENTRAL databases for studies examining sex and 30-day mortality after CABG. We used random-effects meta-analysis to estimate the summary odds ratio (OR) of mortality in women versus men using (1) unadjusted study results and (2) adjusted study results. Available confounders data from included studies were identified. Using the OR of measured confounders and the risk of death to inform unmeasured confounding effects, we performed bias analysis simulation to correct potential unmeasured confounding in the summary OR. RESULTS: From 7,138 retrieved studies, 112 were included (N = 5,008,262 patients); 25 studies reported adjusted OR (N = 770,450 patients). Overall 30-day mortality was 4.9% in women versus 3.3% in men. The unadjusted summary OR (1.81; 95% confidence interval, 1.72-1.91) and adjusted summary OR (1.40, 95% confidence interval, 1.35-1.45) demonstrated women had an increased risk for 30-day mortality compared with men. Simulations correcting for unmeasured confounding mostly ranged from 1.05 to 1.80, which supports a higher risk for death in women after CABG. CONCLUSIONS: The findings of this review suggest that confounding is unlikely to account for the increased risk for mortality in women after CABG and that biological factors have a causal effect.

Neurological outcomes after traumatic cardiopulmonary arrest: a systematic review.

BACKGROUND: Despite appropriate care, most patients do not survive traumatic cardiac arrest, and many survivors suffer from permanent neurological disability. The prevalence of non-dismal neurological outcomes remains unclear. OBJECTIVES: The aim of the current review is to summarize and assess the quality of reporting of the neurological outcomes in traumatic cardiac arrest survivors. DATA SOURCES: A systematic review of Embase, Medline, PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), and ProQuest databases was performed from inception of the database to July 2020. STUDY ELIGIBILITY CRITERIA: Observational cohort studies that reported neurological outcomes of patients surviving traumatic cardiac arrest were included. PARTICIPANTS AND INTERVENTIONS: Patients who were resuscitated following traumatic cardiac arrest. STUDY APPRAISAL AND SYNTHESIS METHODS: The quality of the included studies was assessed using ROBINS-I (Risk of Bias in Non-Randomized Studies - of Interventions) for observational studies. RESULTS: From 4295 retrieved studies, 40 were included (n=23 644 patients). The survival rate was 9.2% (n=2168 patients). Neurological status was primarily assessed at discharge. Overall, 45.8% of the survivors had good or moderate neurological recovery, 29.0% had severe neurological disability or suffered a vegetative state, and 25.2% had missing neurological outcomes. Seventeen studies qualitatively described neurological outcomes based on patient disposition and 23 studies used standardized outcome scales. 28 studies had a serious risk of bias and 12 had moderate risk of bias. LIMITATIONS: The existing literature is characterized by inadequate outcome reporting and a high risk of bias, which limit our ability to prognosticate in this patient population. CONCLUSIONS OR IMPLICATIONS OF KEY FINDINGS: Good and moderate neurological recoveries are frequently reported in patients who survive traumatic cardiac arrest. Prospective studies focused on quality of survivorship in traumatic arrest are urgently needed. LEVEL OF EVIDENCE: Systematic review, level IV. PROSPERO REGISTRATION NUMBER: CRD42020198482.

Prognostic Factors for Venous Thromboembolism in Patients with Solid Tumours on Systemic Therapy: A Systematic Review.

Background Patients undergoing systemic cancer therapy are susceptible to developing venous thromboembolism (VTE). The most pertinent prognostic factors for VTE remain unclear. This systematic review aims to summarize prognostic factors associated with VTE in this population. Methods MEDLINE, Embase, and CENTRAL databases were searched for observational or randomized studies that used multivariable analysis adjusted for tumor type and/or metastatic disease to model the risk of VTE. Adjusted effect estimates for each prognostic factor were collected for all of the included studies. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Results From 5,988 search results, 15 eligible studies and 42 prognostic factors were identified. A total of 8,554 patients of whom 456 (5.33%) developed VTE were included. Fourteen studies had a high risk of bias and one study had a moderate risk. The most commonly reported prognostic factors include age, gender, tumor site, metastasis, performance status, and systemic therapy type. Poor performance status and the use of platinum-based chemotherapy compounds were associated with an increased risk of VTE across the majority of studies. The evidence to suggest that the other prognostic factors identified were associated with VTE development was inconclusive. Several individual studies identified novel biomarkers for VTE. Heterogeneity in statistical methods and prognostic factor definitions across studies precluded meta-analysis. Conclusion Overall, many prognostic factors were identified; however, the evidence for association with development of VTE for most of the factors is inconclusive. Findings were limited by high heterogeneity and risk of bias in the included studies.

Genetic syndromes with diabetes: A systematic review.

Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.

An opioid receptor-independent mechanism underlies motility dysfunction and visceral hyperalgesia in opioid-induced bowel dysfunction.

Constipation and abdominal pain are commonly encountered in opioid-induced bowel dysfunction (OBD). The underlying mechanisms are incompletely understood, and treatments are not satisfactory. As patients with OBD often have fecal retention, we aimed to determine whether fecal retention plays a pathogenic role in the development of constipation and abdominal pain in OBD, and if so to investigate the mechanisms. A rodent model of OBD was established by daily morphine treatment at 10 mg/kg for 7 days. Bowel movements, colonic muscle contractility, visceromotor response to colorectal distention, and cell excitability of colon-projecting dorsal root ganglion neurons were determined in rats fed with normal pellet food, or with clear liquid diet. Morphine treatment (Mor) reduced fecal outputs starting on day 1, and caused fecal retention afterward. Compared with controls, Mor rats demonstrated suppressed muscle contractility, increased neuronal excitability, and visceral hypersensitivity. Expression of cyclooxygenase-2 (COX-2) and nerve growth factor (NGF) was upregulated in the smooth muscle of the distended colon in Mor rats. However, prevention of fecal retention by feeding rats with clear liquid diet blocked upregulation of COX-2 and NGF, restored muscle contractility, and attenuated visceral hypersensitivity in Mor rats. Moreover, inhibition of COX-2 improved smooth muscle function and fecal outputs, whereas anti-NGF antibody administration attenuated visceral hypersensitivity in Mor rats. Morphine-induced fecal retention is an independent pathogenic factor for motility dysfunction and visceral hypersensitivity in rats with OBD. Liquid diet may have therapeutic potential for OBD by preventing fecal retention-induced mechanotranscription of COX-2 and NGF.NEW & NOTEWORTHY Our preclinical study shows that fecal retention is a pathogenic factor in opioid-induced bowel dysfunction, as prevention of fecal retention with liquid diet improved motility and attenuated visceral hyperalgesia in morphine-treated animals by blocking expression of cyclooxygenase-2 and nerve growth factor in the colon.

The crossover design for studies of infertility employing in-vitro fertilization: A methodological survey.

BACKGROUND: Infertility has become increasingly common worldwide. There is a need for the infertility literature to evaluate new interventions with IVF. The crossover design presents many methodological advantages for IVF trials. In addition to providing a within-person comparison of outcomes, it offers participants the opportunity to potentially benefit from more than one available treatment. However, infertility studies present a unique challenge in terms of bias: successful participants do not cross over to the second treatment group. OBJECTIVES: The main objective of our study was to survey the methodological features of crossover trials for infertility with in-vitro fertilization (IVF) based interventions. A secondary focus was reporting key results. STUDY DESIGN & SETTING: We conducted a methodological survey by systematically searching Medline and Embase databases. The capture-recapture technique was used to estimate the number of relevant studies that were not retrieved by our search strategy. We employed the Cochrane risk of bias tool to assess methodological rigour. Crossover-specific methods features were summarized. Treatment effects for pregnancy outcomes across studies are also presented. RESULTS: 15 studies met inclusion criteria. Most studies were deemed to have high or unclear risks of bias, usually because of incomplete reporting of outcome data and assessment procedures. 13 studies did not employ crossover-specific methods to analyze outcome data by period, which may bias treatment effect estimates. Four studies reported pregnancy outcome data with sample sizes from both treatment periods. Of these four studies, three reported that the control intervention was favoured. CONCLUSIONS: The main limitation of our survey was the small sample size of studies. Future reviews should be larger and seek to encompass a broader range of the infertility literature. Despite the issues identified in the included trials, consideration should still be given to using the crossover design in future infertility research. Employing crossover-specific analysis methods, such as accounting for participant non-completion, along with strict adherence to CONSORT reporting guidelines, may significantly reduce the risk of bias in individual studies.

Catalytic Reduction of Hexavalent Chromium Using Iron/Palladium Bimetallic Nanoparticle-Assembled Filter Paper.

Iron/palladium bimetallic nanoparticles (Fe/Pd NPs) are important catalytic materials for the field of environmental remediation. In the present study, filter paper was employed as a substrate for the assembly of Fe/Pd NPs and further applied for the catalytic conversion of hexavalent chromium Cr(VI) toward trivalent Cr(III). First, a filter paper with negative charge was assembled with a layer of positively charged polyethylenimine (PEI) through electrostatic interaction; then, the abundant amine groups of PEI were used to complex Fe(III) ions, followed by reduction via sodium borohydride to produce an Fe NP-assembled filter paper. Thereafter, the Fe/Pd NPs were produced by the reduction of PdCl42- through Fe NPs. The prepared filter paper assembled with Fe/Pd NPs with a mean diameter of 10.1 nm was characterized by various techniques. The Fe/Pd NP-assembled filter paper possesses powerful catalytic activity and can be used to transform Cr(VI) to Cr(III). With its low cost, high sustainability, and convenient industrialization potential, the developed approach may be extended to produce other bimetallic NP-immobilized filter paper for different environmental remediation applications.

Reporting quality of pilot clinical trials in chronic kidney disease patients on hemodialysis: a methodological survey.

BACKGROUND: The conduct of high-quality pilot studies can help inform the success of larger clinical trials. Guidelines have been recently developed for the reporting of pilot trials. OBJECTIVE: This methodological survey evaluates the completeness of reporting in pilot randomized controlled trials in chronic kidney disease patients on hemodialysis (HD patients) and explores factors associated with better completion of reporting. METHODS: The authors searched Pubmed on July 1, 2018, for all pilot trials conducted in HD patients. Reporting quality was assessed against the 40-item Consolidated Standards of Reporting Trials (CONSORT) Extension for Pilot Trials. Study factors including year and country of publication, intervention, number of centers, type of funding, and journal endorsement of CONSORT were also examined. RESULTS: The mean number of items reported from the CONSORT extension for pilot trials across all included articles was 18.4 (standard deviation [SD] = 4.4). In the adjusted analysis, studies reported in later years (IRR = 1.026, 95% CI [1.018, 1.034], p < 0.001) and an increase of 20 persons in sample size (adjusted IRR = 1.021, 95% CI [1.010, 1.031], p < 0.001) were associated with a significantly higher number of CONSORT pilot items reported. CONCLUSIONS: Current reporting completeness of pilot trials in HD patients is suboptimal. Endorsing the CONSORT extension specific to pilot and feasibility studies and ensuring that pilot trials focus on the feasibility objectives may improve reporting completeness of these trials.

Performing a catalysis reaction on filter paper: development of a metal palladium nanoparticle-based catalyst.

We report the polyethylenimine (PEI)-mediated immobilization of palladium nanoparticles (Pd NPs) onto filter paper for catalytic applications. In this work, filter paper was first assembled with PEI via electrostatic interaction, and the PEI-assembled filter paper was then complexed with PdCl4 2- ions, followed by sodium borohydride reduction to generate Pd NP-immobilized filter paper. Transmission electron microscopy reveals that Pd NPs have a diameter of 3 nm and are capable of being immobilized onto the filter paper. The Pd NP-immobilized filter paper exhibits remarkable catalytic activity and is reusable in the reductive transformation of Cr(vi) to Cr(iii) and 4-nitrophenol to 4-aminophenol. The strategy used to develop Pd NP-immobilized filter paper could be adopted to generate other metal NP-immobilized filter papers for other applications such as sensing materials, energy, environmental remediation, and biomedical sciences.

Agreement in reporting between trial publications and current clinical trial registry in high impact journals: A methodological review.

OBJECTIVES: The primary objective of this systematic survey was to examine the percentage of studies in which there was agreement in the reporting of the primary outcome between the currently updated version of the clinical trial registry and the published paper. We also investigated the factors associated with agreement in reporting of the primary outcome. METHODS: We searched PubMed for all randomized control trials (RCT)s published in 2012-2015 in the top five general medicine journals (based on the 2014 impact factor). Two hundred abstracts (50 from each year) were randomly selected for data extraction. Agreement in reporting of 11 key study conduct items (e.g., sample size) and study characteristics (e.g., funding, number of sites) were extracted by two independent reviewers. ANALYSIS: Descriptive analyses were conducted to determine the proportion of studies on which there was agreement in reporting of key study conduct items. Generalized estimating equations were used to explore factors associated with agreement in reporting of the primary outcome. RESULTS: Of the 200 included studies, 87% had agreement in reporting of the primary outcome. After adjusting for other covariates, having greater than 50 sites was associated with an increased likelihood of agreement in reporting of the primary outcome (odds ratio=7.1, 95% confidence interval=1.39, 36.27, p=0.018). CONCLUSIONS: We identified substantive disagreement in reporting between publications and current clinical trial registry, which were associated with several study characteristics. Further measures are needed to improve reporting given the potential threats to the quality and integrity of scientific research.

Bile acid flux through portal but not peripheral veins inhibits CYP7A1 expression without involvement of ileal FGF19 in rabbits.

It was proposed that CYP7A1 expression is suppressed through the gut-hepatic signaling pathway fibroblast growth factor (FGF) 15/19-fibroblast growth factor receptor 4, which is initiated by activation of farnesoid X receptor in the intestine rather than in the liver. The present study tested whether portal bile acid flux alone without ileal FGF19 could downregulate CYP7A1 expression in rabbits. A rabbit model was developed by infusing glycodeoxycholic acid (GDCA) through the splenic vein to bypass ileal FGF19. Study was conducted in four groups of rabbits: control; bile fistula + bovine serum albumin solution perfusion (BF); BF + GDCA (by portal perfusion); and BF + GDCA-f (by femoral perfusion). Compared with only BF, BF + GDCA (6 h portal perfusion) suppressed CYP7A1 mRNA, whereas BF + GDCA-f (via femoral vein) with the same perfusion rate of GDCA did not show inhibitory effects. Meanwhile, there was a decrease in ileal FGF19 expression and portal FGF19 protein levels, but an equivalent increase in biliary bile acid outputs in both GDCA perfusion groups. This study demonstrated that portal bile acid flux alone downregulated CYP7A1 expression with diminished FGF19 expression and protein levels, whereas the same bile acid flux reaching the liver through the hepatic artery via femoral vein had no inhibitory effect on CYP7A1. We propose that bile acid flux through the portal venous system may be a kind of "intestinal factor" that suppresses CYP7A1 expression.