bluuebunny/crossref_metadata_2025_split huggingface dataset:
Patients Follow Different Financial Hardship Trajectories in the Year after Injury
Authors: Nishtala Madhuri V. , Robbins Sarah E. , Savage Stephanie , Timsina Lava R. , Murphy Patrick B. , Marka Nicholas A. , Venkatesh Manasa , Zarzaur Ben L. 
Published: March 2022

Objective:
To determine if distinct financial trajectories exist and if they are associated with quality-of-life outcomes.

Summary of Background Data:
Financial hardship after injury measurably impacts Health-Related Quality of Life outcomes. Financial hardship, encompassing material losses, financial worry, and poor coping mechanisms, is associated with lower quality of life and increased psychological distress. However, recovery is dynamic and financial hardship may change over time.

Methods:
This is a secondary analysis of a cohort of 500 moderate-to-severe nonneurologic injured patients in which financial hardship and Health-related Quality of Life outcomes were measured at 1, 2, 4, and 12 months after injury using survey instruments (Short Form-36). Enrollment occurred at an urban, academic, Level 1 trauma center in Memphis, Tennessee during January 2009 to December 2011 and follow-up completed by December 2012.

Results:
Four hundred seventy-four patients had sufficient data for Group- Based Trajectory Analysis. Four distinct financial hardship trajectories were identified: Financially Secure patients (8.6%) had consistently low hardship over time; Financially Devastated patients had a high degree of hardship immediately after injury and never recovered (51.6%); Financially Frail patients had increasing hardship over time (33.6%); and Financially Resilient patients started with a high degree of hardship but recovered by year end (6.2%). At 12-months, all trajectories had poor Short Form-36 physical component scores and the Financial Frail and Financially Devastated trajectories had poor mental health scores compared to US population norms.

Conclusions and Relevance:
The Financially Resilient trajectory demonstrates financial hardship after injury can be overcome. Further research into understanding why and how this occurs is needed.
Virtual Assessment of Patients with Dry Eye Disease During the COVID-19 Pandemic: One clinician’s experience
Authors: Ibrahim Pierre , McKenna Caroline G. , Mather Rookaya 
Published: March 2022

ABSTRACTObjectivesTo report on 1) the impact of DED on social, mental, and financial well-being, and 2) the use of virtual consultations to assess DED during the COVID-19 pandemic.Design & MethodsAn exploratory retrospective review of 35 charts. Telephone consultations for patients with DED conducted during the first lock-down period in Ontario in 2020 were reviewed.ResultsThe most commonly reported DED symptoms were ocular dryness, visual disturbances, and burning sensation. The most common dry eye management practices were artificial tears, warm compresses, and omega-3 supplements. 20.0% of charts documented worsening of DED symptoms since the onset of the pandemic and 17.1% reported the lockdown had negatively affected their ability to perform DED management practices. 42.8% of patients reported an inability to enjoy their daily activities due to DED symptoms. 52.0% reported feeling either depressed, anxious, or both with 26.9% of patients accepting a referral to a social worker for counselling support. More than a quarter of the charts recorded financial challenges associated with the cost of therapy, and more than a fifth of patients reported that financial challenges were a direct barrier to accessing therapy.ConclusionsPatients living with DED reported that their symptoms negatively affected their daily activities including mental health and financial challenges, that in turn impacted treatment practices. These challenges may have been exacerbated during the COVID-19 pandemic. Telephone consultations may be an effective modality to assess DED symptom severity, the impact of symptoms on daily functioning, and the need for counselling and support.AUTHOR SUMMARYDry Eye Disease occurs when your tears do not provide enough lubrication for your eyes, which can be caused by either decreased tear production, or by poor quality tears. This study reviewed 35 patient charts to examine 1) the impact of Dry Eye Disease on patients’ well-being, and 2) the use of telephone appointments to assess Dry Eye Disease during the COVID-19 pandemic. Patients reported an inability to enjoy their daily activities due to symptoms of dry eye including burning sensation and blurred vision. Over half of patients reported mental health challenges. Over a quarter of patients reported that financial challenges prevented them from treating their Dry Eye Disease, such as affording eye drops, dietary supplements, and appointments to see their optometrist. These findings highlight that healthcare providers should considering quality of life, mental health, and financial challenges when treating patients with Dry Eye Disease. Through the experience of an ophthalmologist who specializes in Dry Eye Disease, telephone appointments may be an effective way to assess Dry Eye Disease symptoms, the impact of symptoms on daily functioning, and the need for counselling and support.
Mimicking tumor cell heterogeneity of colorectal cancer in a patient-derived organoid-fibroblast model
Authors: Atanasova Velina S , de Jesus Cardona Crhistian , Hejret Vaclav , Tiefenbacher Andreas , Tran Loan , Binder Carina , Mair Theresia , Kabiljo Julijan , Clement Janik , Woeran Katharina , Neudert Barbara , Hengstschläger Markus , Mitterhauser Markus , Müllauer Leonhard , Tichy Boris , Bergmann Michael , Schweikert Gabriele , Hartl Markus , Dolznig Helmut , Egger Gerda 
Published: March 2022

AbstractPatient-derived organoid (PDO) cancer models are generated from epithelial tumor cells. Although they reflect the molecular tumor characteristics, they lack the complexity of the tumor microenvironment, which is a key driver of tumorigenesis and therapy response. Here, we present a colorectal cancer (CRC) organoid model that incorporates epithelial cells and stromal fibroblasts from the same patient. Molecular characterization of primary cancer associated fibroblasts (CAFs) and matched normal fibroblasts (NF) revealed proteomic, secretome and gene expression differences in pathways associated with tumor related fibroblast function. Further, CAFs retained higher motility compared to NFsin vitro. Importantly, both CAFs and NFs supported cancer cell proliferation in 3D co-cultures, without the addition of classical niche factors. PDOs grown together with fibroblasts displayed a larger cellular heterogeneity of tumor cells compared to mono-cultures, and closely resembled thein vivotumor morphology. This was also confirmed by the calculation of cellular proportions of epithelial cell subtypes in organoid mono-versus co-cultures, which were inferred through bioinformatics deconvolution of bulk RNA sequencing data using published single cell RNA sequencing datasets from CRC tissues. Additionally, we observed a mutual crosstalk between tumor cells and fibroblasts in the co-cultures. This was manifested by majorly deregulated pathways such as cell-cell communication and extracellular matrix remodeling in the organoids. For the fibroblasts, we observed enhanced expression of tumor induced marker genes and cytokines characteristic for myo- and immunogenic fibroblasts. This model will be vital as a physiological personalized tumor model to study disease mechanisms and therapy response in CRC.One Sentence SummaryPatient matched fibroblasts support tumor organoid growth in 3D co-culture and maintain intratumoral cellular heterogeneity and histo-morphology.
Identification of genes required for swarming motility in Bacillus subtilis using transposon mutagenesis and high-throughput sequencing (TnSeq)
Authors: Sanchez Sandra , Snider Elizabeth V. , Wang Xindan , Kearns Daniel B. 
Published: March 2022

ABSTRACTBacillus subtilis exhibits swarming motility, a flagellar-mediated form of surface motility. Here we use high-throughput transposon mutagenesis and sequencing (TnSeq) to identify candidate genes required for swarming. The TnSeq approach identified all of the known genes required for flagellar biosynthesis as well as nearly all of the previously reported regulators that promote swarming. Moreover, we identified an additional 36 genes that improve swarming and validated them individually. Among these, two mutants with severe defects were recovered including fliT, required for flagellar biosynthesis, and a gene of unknown function yolB, whose defect could not be attributed to a lack of flagella. Our work indicates that TnSeq is a powerful approach for the identification of genes required for motility that drives outward expansion of a colony on plates.IMPORTANCEIn TnSeq, transposons are randomly inserted throughout the chromosome at a population level, but insertions that disrupt genes of essential function cause strains that carry them to fall out of the population and appear under-represented at the sequence level. Here we apply TnSeq to the non-essential phenotype of motility in B. subtilis and spatially select for cells proficient in swarming. We find that insertions in nearly all genes previously identified as required for swarming are under-represented in TnSeq analysis, and we identify 36 additional genes that enhance swarming. We suggest that TnSeq is a powerful tool for the genetic analysis of motility and likely other non-lethal screens for which enrichment is strong.
Multi-steroid profiling by uPLC-MS/MS with post-column infusion of ammonium fluoride
Authors: Schiffer Lina , Shaheen Fozia , Gilligan Lorna C. , Storbeck Karl-Heinz , Hawley James , Keevil Brian G. , Arlt Wiebke , Taylor Angela E. 
Published: March 2022

AbstractBackgroundMulti-steroid profiling is a powerful analytical tool that simultaneously quantifies steroids from different biosynthetic pathways. Here we present an ultra-high performance liquid chromatography-tandem mass spectrometry (uPLC-MS/MS) assay for the profiling of 25 steroids using post-column infusion of ammonium fluoride.MethodsFollowing liquid-liquid extraction, steroids were chromatographically separated over 5 minutes using a Phenomenex Luna Omega C18 column and a water (0.1 % formic acid) methanol gradient. Quantification was performed on a Waters Acquity uPLC and Xevo® TQ-XS mass spectrometer. Ammonium fluoride (6 mmol/L, post-column infusion) and formic acid (0.1 % (vol/vol), mobile phase additive) were compared as additives to aid ionisation.ResultsPost-column infusion (PCI) of ammonium fluoride (NH4F) enhanced ionisation in a steroid structure-dependent fashion compared to formic acid (122-140% for 3βOH-Δ5 steroids and 477-1274% for 3-keto-Δ4 steroids). Therefore, we fully analytically validated PCI with NH4F. Lower limits of quantification ranged from 0.28 to 3.42 nmol/L; 23 of 25 analytes were quantifiable with acceptable accuracy (bias range −14% to 11.9%). Average recovery ranged from 91.6% to 113.6% and average matrix effects from −29.9% to 19.9%. Imprecision ranged from 2.3% to 23.9% for all analytes and was <15% for 18/25 analytes. The serum multi-steroid profile of 10 healthy men and 10 healthy women was measured.ConclusionsuPLC-MS/MS with post-column infusion of ammonium fluoride enables comprehensive multi-steroid profiling through enhanced ionisation particularly benefiting the detection of 3-keto-Δ4 steroids.HighlightsThis multi-steroid profiling assay quantifies 25 steroids in 5.5 minutesPost-column infusion of NH4F enhances the ionisation of 3-keto-Δ4 steroidsThe assay simultaneously quantifies steroids from several biosynthetic pathwaysWe present analytical data validated for serum steroid profiling
Impacts of COVID-19 on glycemia and risk of diabetic ketoacidosis
Authors: Sharma Anukriti , Misra-Hebert Anita D. , Mariam Arshiya , Milinovich Alex , Kattan Michael W. , Pantalone Kevin M. , Rotroff Daniel M. 
Published: March 2022

AbstractBackgroundReports indicate that COVID-19 may impact pancreatic function and increase type 2 diabetes (T2D) risk, although real-world COVID-19 impacts on HbA1c and T2D are unknown. We tested whether COVID-19 increased HbA1c, risk of T2D, or diabetic ketoacidosis (DKA).MethodsWe compared pre- and post-COVID-19 HbA1c, and risk of developing T2D in a large real-world clinical cohort of 8,755 COVID-19(+) patients and a matched control cohort of 11,998 COVID-19(-) patients. We investigated if DKA risk was modified in COVID-19(+) patients with type 1 diabetes (T1D) (N=704) or T2D (N=22,904), or by race and sex.FindingsWe observed a statistically significant, albeit clinically insignificant, HbA1c increase post-COVID-19 (all patients ΔHbA1c=0.06%,P<.001; with T2D ΔHbA1c=0.1%;P<.001), and no increase among COVID-19(-) patients (P>.05). COVID-19(+) patients were 40% more likely to be diagnosed with T2D compared to COVID-19(-) patients (P<.001) and 28% more likely to be diagnosed with T2D for the same HbA1c change as COVID-19(-) patients (P<.001). COVID-19(+) patients with T2D on insulin were 34% more likely to develop DKA compared to COVID-19(-) patients on insulin (P<.05), and COVID-19(+) Black patients with T2D displayed disproportionately increased DKA risk (HR:1.63,P=.007). There was no significant difference in DKA risk between COVID-19(+) and COVID-19(-) patients with T1D.InterpretationDKA risk is increased in T2D patients on insulin and in Black patients with T2D after COVID-19 infection.T2D risk is greater in COVID-19(+) patients for the same HbA1c increase in COVID-19(-) patients, indicating that T2D risk attributed to COVID-19 may be due to increased recognition during COVID-19 management.FundingNo funding to report.
Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank
Authors: Pilling Luke C. , Atkins Janice L. , Melzer David 
Published: March 2022

AbstractBackgroundThe iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. In Europeans, most HH disease occurs in male HFE p.C282Y homozygotes, yet only a minority of homozygotes in the general population develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or risks for liver, diabetes or arthritis diagnoses in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers.Methods1,294 male and 1,596 female UK Biobank European-ancestry HFE p.C282Y homozygous participants with electronic medical records up to 14 years after baseline assessment were studied. Polygenic risk scores (PRS) quantified genetic effects on blood iron biomarkers and relevant diseases (identified in the general population). Analyses were repeated in 10,699 p.C282Y/p.H63D compound heterozygotes.ResultsIn male p.C282Y homozygotes, higher iron PRS increased risk of liver fibrosis or cirrhosis diagnoses (top 20% of iron PRS had Odds Ratio 4.90: 95% Confidence Intervals 1.63 to 14.73, p=0.005 versus bottom 20%), liver cancer, and osteoarthritis, but not diabetes. The liver cirrhosis PRS also associated with increased liver cancer diagnoses, and greater type-2 diabetes PRS increased risk of type-2 diabetes. In female p.C282Y homozygotes, osteoarthritis PRS was associated with increased osteoarthritis diagnoses, and type-2 diabetes PRS with type-2 diabetes. However, the iron PRS was not robustly associated with diagnoses in p.C282Y homozygote females, or in other p.C282Y/p.H63D genotypes.ConclusionsHFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population. Including PRS in HH screening and diagnosis may help in estimating prognosis and treatment planning.Lay SummaryTwo or three sentences summarizing the main message of the article expressed in plain English to describe your findings to a non-medical audience.Hereditary Haemochromatosis, an iron overload condition, is the most common genetic disease in Northern Europeans; 1 in 150 people carry two copies of the highest risk mutation (called HFE p.C282Y).Only a minority of those with high risk HH variants actually develop iron overload diseases, such as liver cancer, cirrhosis, diabetes and arthritis. We tested whether known genetic variants with smaller effects on iron levels in the whole population modify risk of iron overload related disease in those with the HH high risk variants. We did similar tests for variants linked to each of the diseases caused by iron overload.Increased genetic risk for higher iron significantly raised the likelihood of liver fibrosis, cirrhosis and cancer in mutation carriers. In the future this information could help identify at-risk haemochromatosis patients early.
The Construction of Multi-ethnic Polygenic Risk Score using Transfer Learning
Authors: Zhao Zhangchen , Fritsche Lars G. , Smith Jennifer A. , Mukherjee Bhramar , Lee Seunggeun 
Published: March 2022

AbstractAs most existing genome-wide association studies (GWAS) were conducted in European ancestry cohorts and as the existing PRS models have limited transferability across ancestry groups, PRS research on non-European ancestry groups is negatively impacted. Here we propose a novel PRS method using transfer learning techniques. Our approach, TL-PRS, uses gradient descent to fine-tune the baseline PRS model from an ancestry group with large sample GWAS to the dataset of target ancestry. In our application of constructing PRS for the six quantitative and two dichotomous traits for 10,285 South Asian and 8,168 African ancestry individuals in UK Biobank, TL-PRS achieved up to 42% average relative improvement compared to the existing methods. Our approach increases the transferability of PRSs across ancestries and thereby helps reduce existing inequities in genetics research.
Alcohol-sourced acetate impairs T cell function by promoting cortactin acetylation
Authors: Azizov Vugar , Frech Michael , Hübner Michel , Hofmann Jörg , Kubankova Marketa , Lapuente Dennis , Tenbusch Matthias , Guck Jochen , Schett Georg , Zaiss Mario M. 
Published: March 2022

SummaryAlcohol is among the most widely consumed dietary substances. Excessive alcohol consumption damages the liver, heart and brain. Alcohol also has strong immunoregulatory properties. Here we report how alcohol impairs T cell function via acetylation of cortactin, a protein that binds filamentous actin and facilitates branching. Upon alcohol consumption, acetate, the metabolite of alcohol, accumulates in lymphoid organs. T cells exposed to acetate, exhibit increased acetylation of cortactin. Acetylation of cortactin inhibits filamentous actin binding and hence reduces T cell migration, immune synapse formation and activation. While mutated, acetylation-resistant cortactin rescued the acetate-induced inhibition of T cell migration, primary mouse cortactin knock-out T cells exhibited impaired migration. Furthermore, acetate-induced cytoskeletal changes effectively inhibited activation, proliferation, and immune synapse formation in T cells in vitro and in vivo in an influenza infection model in mice. Together these findings reveal cortactin as a possible target for mitigation of T cell driven autoimmune diseases.
Neonatal exposures to sevoflurane in rhesus monkeys alter synaptic ultrastructure in later life
Authors: Fehr Tristan , Janssen William G.M. , Park Janis , Baxter Mark G. 
Published: March 2022

ABSTRACTEarly-life exposure to anesthesia in infant humans and monkeys increases the risk for cognitive and socioemotional impairments. However, the long-term effects of neonatal anesthesia on synaptic ultrastructure have not been thoroughly investigated in primates. We used electron microscopy with unbiased stereological sampling to assess synaptic ultrastructure in the CA1 of the hippocampus and the dorsolateral prefrontal cortex (dlPFC) of female and male rhesus macaques four years after three 4-hour exposures to sevoflurane during the first five postnatal weeks. We counted synapses and measured synapse areas for all synapses and those classified as perforated or nonperforated with spine or dendritic shaft targets. We measured numbers and shapes of mitochondria within presynaptic boutons and calculated vesicle docking rates. In monkeys exposed to anesthesia as infants, synapse areas were reduced in the largest 20% of synapses in CA1 and the largest 5% of synapses in dlPFC, with differential sex effects for the largest 10% of synapses in CA1. Synapse areas were reduced by 7.6% for perforated spinous synapses in CA1, and by 10.4% for nonperforated spinous synapses in dlPFC. Perforated and nonperforated dendritic synapse numbers in CA1 increased by 180% and 63% respectively. Curved mitochondria decreased 25% in CA1 after anesthesia exposure, and dlPFC boutons with 0 mitochondria showed an interaction of anesthesia and sex. These results demonstrate that exposure to anesthesia in infancy can cause long-term structural deficits in primates. These structural changes may be substrates for long-term alterations in the strength and efficiency of synaptic transmission in hippocampus and prefrontal cortex.Key pointsExposure to anesthesia in early life causes lasting cognitive and socioemotional impairments in human and nonhuman primates, but the extent to which early-life exposure to anesthesia alters synaptic ultrastructure in later life has not been known.Four years after rhesus monkeys were given multiple exposures to anesthesia in infancy, the area of spinous synapses was reduced in CA1 and dlPFC, dendritic synapse numbers were elevated in CA1, there were fewer curved presynaptic mitochondria in CA1, and numbers of presynaptic boutons without mitochondria were altered in dlPFC.The long-term ultrastructural changes to synapses and presynaptic mitochondria of rhesus monkeys that were exposed to anesthesia as infants could help explain their behavioral deficits later in life.
Reliable one-step assessment of IGHV mutational status and gene mutations in Chronic Lymphocytic Leukemia by capture-based high throughput sequencing
Authors: Bris Yannick Le , Thonier Florian , Menard Audrey , Theisen Olivier , Mahe Béatrice , Lok Anne , Bouzy Simon , Béné Marie C 
Published: March 2022

AbstractProper management of chronic lymphocytic leukemia (CLL) patients requiring therapy relies on two important prognostic and theranostic molecular features: respectively, the mutational status of tumoral cells immunoglobulin heavy chain variable domain (IGHV) and the characteristics of TP53. Both these (immuno)genetic analyses require multiple time-consuming amplification and sequencing techniques by Sanger or HTS. The capture-HTS technology, allowing to select regions of interest, represents an attractive alternative and has already been applied for the detection of clonality in lymphoproliferative disorders. Here, a single-step capture design was developed to concomitantly investigate for IGHV and TP53. This was applied to a training retrospective (n=14) and a validation prospective (n=91) cohorts of CLL patients. The training cohort demonstrated the robustness of the method by comparison with the classical Sanger sequencing technology (100% identical results) for the IGHV mutational status. This consistency was confirmed for the first 59 patients of the validation cohort. Overall, the IGHV status of whole population (n=103) was accurately identified. Simultaneously, deletion or mutations of TP53 were identified from the same capture-library and HTS-sequencing run for each patient. This novel approach provides, in a single assay, useful answers about the molecular landscape of CLL patients, allowing for a documented choice of therapy.Graphical abstract