bluuebunny/crossref_metadata_2025_split huggingface dataset:
RBFOX2 deregulation promotes pancreatic cancer progression and metastasis through alternative splicing
Authors: Maurin Michelle , Ranjouri Mohammadreza , Martin Katelyn , Miner Robert , Newberg Justin Y. , Du Dongliang , Centeno Barbara , Fleming Jason B. , Yu Xiaoqing , Guccione Ernesto , Black Michael A. , Mann Karen M. 
Published: June 2022

ABSTRACTRNA splicing is an important biological process associated with cancer initiation and progression, yet in pancreatic cancer the role and regulation of splicing is not well understood. From a forward genetic screen in a mouse model of pancreatic cancer, we identified an enrichment of RNA binding proteins (RBPs) associated with the spliceosome. Here, we link deregulation of RBFOX2, an RBP of the FOX family, to pancreatic cancer progression and liver metastasis. We show that RBFOX2 regulation in pancreatic cancer occurs at both the RNA and protein level, and that nuclear localization of RBFOX2 is significantly reduced in poorly differentiated PDAC. Deregulation of RBFOX2 in PDAC is associated with an enrichment of exon exclusion events in transcripts encoding proteins involved in cytoskeletal remodeling and invadopodia programs that potentiate metastatic potential in vivo. Using splice-switching antisense oligonucleotides (AONs) and inducible cDNA isoforms, we demonstrate that RBFOX2 mediated exon exclusion in ABI1 controls the abundance and localization of ABI1 protein isoforms in pancreatic cancer cells, and that ABI1 splice-switching enhances cellular phenotypes associated with cancer cell stemness. Together, our data identify a novel role for RBFOX2 deregulation in promoting PDAC progression through alternative splicing regulation.
Independently ambulatory children with spina bifida experience near-typical joint moments and forces during walking
Authors: Lee Marissa R. , Hicks Jennifer L. , Wren Tishya A. L. , Delp Scott L. 
Published: June 2022

AbstractBackgroundSpina bifida, a neurological defect, can result in lower-limb muscle weakness. Altered ambulation and reduced musculoskeletal loading can yield decreased bone strength in individuals with spina bifida, yet individuals who remain ambulatory can exhibit normal bone outcomes.Research questionDuring walking, how do lower-limb joint kinematics, moments, and forces in independently ambulatory children with spina bifida differ from those of children with typical development?MethodsWe retrospectively analyzed data from 16 independently ambulatory children with spina bifida and 16 children with typical development and confirmed that bone strength was similar between the two groups. Plantar flexor muscle strength was measured by manual muscle testing, and 14 of the children with spina bifida wore activity monitors for one week. We estimated joint forces using motion capture data and musculoskeletal simulations. We used Statistical Parametric Mappingt-tests to compare lower-limb joint kinematic and kinetic waveforms between the groups with spina bifida and typical development. Within the group with spina bifida, we examined relationships between plantar flexor muscle strength and peak tibial forces by calculating Spearman correlations.ResultsActivity monitors from the children with spina bifida reported typical daily steps (9656 [SD 3095]). Despite slower walking speeds (p=0.004) and altered lower-body kinematics (p<0.0001), children with spina bifida had joint moments and forces similar to those of children with typical development, with no detectable differences during stance. Plantar flexor muscle weakness was associated with increased compressive knee force (p=0.001) and shear ankle force (p=0.006).SignificanceHigh-functioning, independently ambulatory children with spina bifida exhibited near-typical bone strength and near-typical step counts and load magnitudes. Our results suggest that maintaining ambulation and muscle strength can promote bone health in this population.HighlightsGait analysis was performed in high-functioning children with spina bifidaOn average, these children had typical knee & ankle moments & forces during walkingWeak plantar flexor muscles were associated with increased tibial forces
Dismantling cognitive-behavioral therapy for chronic insomnia: a protocol for a systematic review and component network meta-analysis
Authors: Furukawa Yuki , Sakata Masatsugu , Funada Satoshi , Kikuchi Shino , Furukawa Toshi A. , Ostinelli Edoardo G. , Efthimiou Orestis , Perlis Michael 
Published: June 2022

ABSTRACTIntroductionInsomnia is highly prevalent and disabling. Clinical practice guidelines recommend cognitive-behavioral therapy for insomnia (CBTI) as the first-line treatment. However, CBTI includes various combinations of many different components and its clinical benefits have been shown as a package, whereas the effect of each component remains unclear. In this study, we will explore the effect of each component of CBTI with the use of component network meta-analysis.Methods and analysisWe will include all randomized controlled trials that compared any form of CBTI against another form of CBTI or a control condition in the treatment of adults with chronic insomnia. Concomitant treatments will be allowed as long as they are equally distributed among the arms. We will include both primary and secondary insomnia. The primary outcome of interest in this study is (1) treatment efficacy (remission defined as reaching a satisfactory state at endpoint measured by any validated self-reported scale) at four weeks post-treatment or at its closest time point. Secondary outcomes are (2) acceptability, (3) sleep diary measures and (4) efficacy at long-term follow-up. We will systematically search in PubMed, CENTRAL, PsycINFO and WHO International Clinical Trials Registry Platform. We will assess risk of bias using Cochrane Risk of Bias 2.0 tool. We will conduct component network meta-analysis with the netmeta package in R.Ethics and disseminationThis study will use published data and does not require ethical approval. Findings will be disseminated in a peer-reviewed journal.PROSPEROCRD42022324233.
Comparative analysis of capture methods for genomic profiling of circulating tumor cells in colorectal cancer
Authors: Alves Joao M. , Estévez-Gómez Nuria , Valecha Monica , Prado-López Sonia , Tomás Laura , Alvariño Pilar , Piñeiro Roberto , Muinelo-Romay Laura , Mondelo-Macía Patricia , Salgado Mercedes , Iglesias-Gómez Agueda , Codesido-Prada Laura , Cubiella Joaquin , Posada David 
Published: June 2022

AbstractThe genomic profiling of circulating tumor cells (CTCs) in the bloodstream should provide clinically relevant information on therapeutic efficacy and help predict cancer survival. However, the molecular characterization of CTCs has so far proven extremely difficult. A variety of technologies have been developed for CTC isolation, but so far the impact on the genomic assessment of CTCs has not been fully evaluated. To fill this gap, here we contrasted the genomic profiles of CTC pools recovered from blood samples obtained from four metastatic colorectal cancer (mCRC) patients using three different enrichment strategies (CellSearch, Parsortix, and FACS). Our results suggest clear differences in the mutational burden of CTC pools depending on the enrichment method used, with all evaluated methods returning a somewhat limited representation of the mutational spectrum of individual tumors, potentially due to allelic dropout during whole-genome amplification. Nevertheless, the CTC pools from Parsortix, and in part, CellSearch, showed diversity estimates, mutational signatures and drug-suitability scores remarkably close to the ones found in matching primary tumor samples. In contrast, FACS CTC pools were substantially enriched in apparent sequencing artifacts, which led to much higher estimates of genomic diversity. Although CTC genomics still faces technical challenges, our results suggest that CTC-derived metrics can reflect the diversity scores seen in primary tumor lesions thus highlighting the utility of CTCs to assess the heterogeneity status of individual tumors, and to help clinicians prioritize drugs in mCRC.
Delays in COVID-19 Diagnosis and Hospitalization and Outcomes — New York City, New York, USA, October 2020–November 2021
Authors: Graf Laura E. , Peterson Eric R. , Baumgartner Jennifer , Fine Anne , Thompson Corinne N. , Blaney Kathleen , Greene Sharon K. 
Published: June 2022

AbstractCOVID-19 patients diagnosed ≥3 days after symptom onset had increased odds of hospitalization. The 75th percentile for diagnosis delay was 5 days for residents of low-privilege areas and Black and Hispanic people diagnosed before SARS-CoV-2 Delta predominance, compared with 4 days for other patients, indicating inequities in prompt diagnosis.
Glucagon/GLP-1 receptor co-agonist NNC9204-1177 reduced body weight in adults with overweight or obesity but was associated with safety issues
Authors: Friedrichsen Martin , Endahl Lars , Kreiner Frederik Flindt , Goldwater Ronald , Kankam Martin , Toubro Søren , Nygård Sune Boris 
Published: June 2022

AbstractGlucagon/glucagon-like peptide-1 (GLP-1) receptor co-agonists may provide greater weight loss than agonists targeting the GLP-1 receptor alone. We report results from three phase 1 trials investigating the glucagon/GLP-1 receptor co-agonist NNC9204-1177 (NN1177) for once-weekly subcutaneous use in adults with overweight or obesity.Our focus was a 12–week multiple ascending dose (MAD), placebo-controlled, double-blind trial in which adults (N=99) received NN1177 (dose-escalated to treatment doses of 200, 600, 1,300, 1,900, 2,800, 4,200, and 6,000 μg) or placebo. Two other trials also contribute to the findings in this report: a first human dose (FHD) / single ascending dose (SAD), placebo-controlled, double-blind trial in which adults (N=49) received NN1177 (treatment doses of 10, 40, 120, 350, 700 and 1,100 μg) or placebo, and a drug–drug interaction (DDI), open-label, single-sequence trial in which adults (N=45) received a 4,200 μg dose of NN1177. Pharmacokinetic, safety and tolerability, and pharmacodynamic endpoints were assessed.For the MAD and FHD/SAD trials, baseline characteristics were generally balanced across groups. The half-life of NN1177 was estimated at between 77.3 and 111 hours. NN1177 appeared tolerable across trials; however, a number of safety concerns were observed, including an increase in heart rate (range 5–22 beats per minute) and decrease in reticulocyte count, which were both dose dependent, and increased markers of inflammation (fibrinogen and C-reactive protein), hepatic disturbances (increased aspartate aminotransferase and alanine aminotransferase), impaired glucose tolerance (dose groups 2,800–6,000 ug) and reduced blood levels of some amino acids. Clinically relevant weight loss was achieved (up to 12.6% at week 12; 4,200 ug in the MAD trial), but this was not accompanied by cardiometabolic improvements.In conclusion, although treatment with NN1177 was associated with dose-dependent and clinically relevant weight loss, unacceptable safety concerns precluded further clinical development.
Outcomes Associated with Rural Emergency Department Provider-to-Provider Telehealth for Sepsis Care: A Multicenter Cohort Study
Authors: Mohr Nicholas M. , Okoro Uche , Harland Karisa K. , Fuller Brian M. , Campbell Kalyn , Swanson Morgan B. , Wymore Cole , Faine Brett , Zepeski Anne , Parker Edith A. , Mack Luke , Bell Amanda , DeJong Katie , Mueller Keith , Chrischilles Elizabeth , Carpenter Christopher R. , Wallace Kelli , Jones Michael P. , Ward Marcia M. 
Published: June 2022

ABSTRACTObjectiveTo test the hypothesis that provider-to-provider tele-emergency department (tele-ED) care is associated with more 28-day hospital-free days and improved Surviving Sepsis Campaign (SSC) guideline adherence in rural emergency departments (EDs).MethodsMulticenter (n=23), propensity-matched, cohort study using medical records of sepsis patients from rural hospitals in a well-established, on-demand, rural video tele-ED network in the upper Midwest between August 2016 and June 2019. The primary outcome was 28-day hospital-free days, with secondary outcomes of 28-day in-hospital mortality and SSC guideline adherence.ResultsA total of 1,191 patients were included in the analysis, with tele-ED used for 326 (27%). Tele-ED cases were more likely to be transferred to another hospital (88% vs. 8%, difference 79%, 95% CI 75–83%). After matching and regression adjustment, tele-ED cases did not have more 28-day hospital-free days (difference 0.80 days longer for non-tele-ED, 95% confidence interval [CI] [-0.87]–2.47) or 28-day in-hospital mortality (adjusted odds ratio [aOR] 1.61, 95% CI 0.74-3.57). Adherence with both the SSC 3-hour bundle (aOR 0.80, 95% CI 0.24– 2.70) and complete bundle (aOR 0.81, 95% CI 0.15–4.41) were similar. An a priori–defined subgroup analysis of patients treated by advanced practice providers suggested that the mortality was lower in the cohort with tele-ED use (aOR 0.19, 95% CI 0.04–0.90) despite no significant difference in complete SSC bundle adherence (aOR 2.48, 95% CI 0.45–13.76).ConclusionsRural ED patients treated with provider-to-provider tele-ED care in a mature network appear to have similar clinical outcomes to those treated without.
Data Source Concordance for Infectious Disease Epidemiology
Authors: Majumder Maimuna , Cusick Marika Mae , Rose Sherri 
Published: June 2022

ABSTRACTBackgroundAs highlighted by the COVID-19 pandemic, researchers are eager to make use of a wide variety of data sources, both government-sponsored and alternative, to characterize the epidemiology of infectious diseases. To date, few studies have investigated the strengths and limitations of sources currently being used for such research. These are critical for policy makers to understand when interpreting study findings.MethodsTo fill this gap in the literature, we compared infectious disease reporting for three diseases (measles, mumps, and varicella) across four different data sources: Optum (health insurance billing claims data), HealthMap (online news surveillance data), Morbidity and Mortality Weekly Reports (official government reports), and National Notifiable Disease Surveillance System (government case surveillance data). We reported the yearly number of national- and state-level disease-specific case counts and disease clusters according to each of our sources during a five-year study period (2013–2017).FindingsOur study demonstrated drastic differences in reported infectious disease incidence across data sources. When compared against the other three sources of interest, Optum data showed substantially higher, implausible standardized case counts for all three diseases. Although there was some concordance in identified state-level case counts and disease clusters, all four sources identified variations in state-level reporting.InterpretationResearchers should consider data source limitations when attempting to characterize the epidemiology of infectious diseases. Some data sources, such as billing claims data, may be unsuitable for epidemiological research within the infectious disease context.
Gendered time, financial & nutritional benefits from access to pay-as-you-go LPG for cooking in an informal settlement in Nairobi, Kenya
Authors: Shupler Matthew , Karl Jonathan , O’Keefe Mark , Osiolo Helen Hoka , Perros Tash , Simiyu Willah Nabukwangwa , Gohole Arthur , Lorenzetti Federico , Puzzolo Elisa , Mwitari James , Pope Daniel , Nix Emily 
Published: June 2022

ABSTRACTIntroductionFew studies have examined gendered benefits of transitioning from polluting cooking fuels (e.g. charcoal, kerosene) to cleaner fuels (e.g. liquefied petroleum gas (LPG)). This study investigates pathways between adoption of pay-as-you-go (PAYG) LPG and women’s empowerment in Nairobi, Kenya.MethodsFemale (N=304) and male (N=44) primary cooks in an informal settlement in Nairobi were surveyed from December 2021-January 2022. The majority (84%; N=293) were customers of PayGo Energy, a company offering PAYG LPG. Other individuals (16%; N=55) cooking with full cylinder LPG or polluting fuels were randomly sampled from the community. The 45-minute telephonic survey examined how access to PAYG LPG affected the livelihoods of PayGo Energy’s customers.ResultsPayGo Energy customers were 50% more likely to cook exclusively with LPG (60%) than those using full cylinder LPG (40%). Due to reduced cooking times (average reduction: 42 min/day among previous polluting fuel users) from the adoption of PAYG LPG, the majority (58%; N=70) of female household heads took on additional employment compared with 36% (N=55) of females living in male-headed households. A greater proportion of married female household heads used their monetary savings from cooking with PAYG LPG for investment (41%) or savings (35%), compared with married women that were not household heads (3% and 21%, respectively). Increased dietary diversity and consumption of protein-rich foods (legumes, meat, fish) from cooking with PAYG LPG was reported by 15% of female household heads.ConclusionFemale household heads were more likely than non-household heads to experience economic and nutritional gains when adopting PAYG LPG, illustrating how the agency of women influences their social co-benefits when undergoing clean energy transitions.
Less is more in language production: Shorter sentences contain more informative words
Authors: Rezaii Neguine , Ren Boyu , Quimby Megan , Hochberg Daisy , Dickerson Bradford 
Published: June 2022

AbstractAgrammatism is characterized by short sentences, the omission of function words, a higher ratio of heavy to light verbs, and a decreased use of verbs relative to nouns. Despite the observation of these phenomena more than two centuries ago, there has been no unifying theory to explain all features of agrammatism. Here, by first examining the language of patients with primary progressive aphasia, we show that the seemingly heterogeneous features of agrammatism can be explained by a process that selects lower frequency words over their higher frequency alternatives in the context of a limitation in sentence production, likely to increase the informational content of sentences. We further show that when healthy speakers are constrained to produce short sentences, features of agrammatism emerge in their language. Finally, we show that these findings instantiate a general property in healthy language production in which shorter sentences are constructed by selecting lower frequency words.
Association between mild traumatic brain injury, brain structure, and mental health outcomes in the Adolescent Brain Cognitive Development Study
Authors: Lopez Daniel A. , Christensen Zachary P. , Foxe John J. , Ziemer Laura R. , Nicklas Paige R. , Freedman Edward G. 
Published: June 2022

AbstractBackgroundChildren that experience a mild traumatic brain injury (mTBI) are at an increased risk of neural alterations that can deteriorate mental health. We test the hypothesis that mTBI is associated with behavioral and emotional problems and that structural brain metrics (e.g., volume, area) meaningfully mediate the relation in an adolescent population.MethodsWe analyzed behavioral and brain MRI data from 11,876 children who participated in the Adolescent Brain Cognitive Development (ABCD) Study. Mixed-effects models were used to examine the longitudinal association between mTBI and mental health outcomes. Bayesian methods were used to investigate brain regions that are intermediate between mTBI and symptoms of poor mental health.ResultsThere were 199 children with mTBI and 527 with possible mTBI across the three ABCD Study visits. There was a 7% (IRR = 1.07, 95% CI: 1.01, 1.13) and 15% (IRR = 1.16, 95% CI: 1.05, 1.26) increased risk of emotional or behavioral problems in children that experienced possible mTBI or mTBI, respectively. Possible mTBI was associated with a 17% (IRR: 1.17, 95% CI: 0.99, 1.40) increased risk of experiencing distress following a psychotic-like experience. We did not find any brain regions that meaningfully mediated the relationship between mTBI and mental health outcomes. Analysis of volumetric measures found that 3 to 5% of the total effect of mTBI on mental health outcomes operated through total cortical volume. Image intensity measure analyses determined that 2 to 5% of the total effect was mediated through the left-hemisphere of the dorsolateral prefrontal cortex.ConclusionResults indicate an increased risk of emotional and behavioral problems in children that experienced possible mTBI or mTBI. Mediation analyses did not elucidate the mechanisms underlying the association between mTBI and mental health outcomes.
A recurrent de novo splice site variant involving DNM1 exon 10a causes developmental and epileptic encephalopathy through a dominant-negative mechanism
Authors: Parthasarathy Shridhar , Ruggiero Sarah M , Gelot Antoinette , Soardi Fernanda C , Ribeiro Bethânia F R , Pires Douglas E V , Ascher David B , Schmitt Alain , Rambaud Caroline , Xie Hongbo M , Lusk Laina , Wilmarth Olivia , McDonnell Pamela Pojomovsky , Juarez Olivia A , Grace Alexandra N , Buratti Julien , Mignot Cyril , Gras Domitille , Nava Caroline , Pierce Samuel R , Keren Boris , Kennedy Benjamin C , Pena Sergio D J , Helbig Ingo , Cuddapah Vishnu Anand 
Published: June 2022

AbstractHeterozygous pathogenic variants in DNM1 cause developmental and epileptic encephalopathy (DEE) due to a dominant-negative mechanism impeding vesicular fission. Thus far, pathogenic variants in DNM1 have been studied using a canonical transcript that includes the alternatively spliced exon 10b. However, after performing RNA sequencing in thirty-nine pediatric brain samples, we find the primary transcript expressed in the brain includes the downstream exon 10a instead. Using this information, we evaluated genotype-phenotype correlations of variants affecting exon 10a and identified a cohort of eleven previously unreported individuals. Eight individuals harbor a recurrent de novo splice site variant, NG_029726.1(NM_001288739.1):c.1197-8G>A, which affects exon 10a and leads to DEE consistent with the classical DNM1 phenotype. We find this splice site variant leads to disease through an unexpected dominant-negative mechanism. Functional testing reveals an in-frame upstream splice acceptor causing insertion of two amino acids predicted to impair oligomerization-dependent activity. This is supported by neuropathological samples showing accumulation of synaptic vesicles adherent to the plasma membrane consistent with impaired vesicular fission. Two additional individuals with missense variants affecting exon 10a, p.(Arg399Trp) and p.(Gly401Asp), had a similar DEE phenotype. In contrast, a single individual with a missense variant affecting exon 10b, p.(Pro405Leu), which is less expressed in the brain, had a correspondingly less severe presentation. Thus, we implicate variants affecting exon 10a as causing the severe DEE typically associated with DNM1-related disorders. We highlight the importance of considering relevant isoforms for disease-causing variants, as well as the possibility of splice site variants acting through a dominant-negative mechanism.