bluuebunny/crossref_metadata_2025 huggingface dataset:
The Subjective Component of the Dutch Objective Burden Inventory
Authors: Grant Joan S. , Graven Lucinda J. , Wang Danny , Luttik Marie Louise , Azuero Andres
Published: March 2022

Background

The reliability and validity of the subjective component of the Dutch Objective Burden Inventory (DOBI) are unknown.

Objective

The validity and reliability of the subjective component of the DOBI were examined in caregivers of individuals with heart failure, using the original 38- and a 24-item version.

Methods

In an online cross-sectional investigation, confirmatory factor analysis was used to examine factorial validity. In examining convergent validity, corrected item-dimension correlations assessed item performance and associations between subjective subscale scores and the Bakas Caregiving Outcomes Scale. Cronbach's α examined internal consistency.

Results

The original 4-factor solution was retained and both the original and shorter versions of the subjective component of the DOBI supported adequate construct validity and internal consistency.

Conclusions

Both the 38- and 24-item forms of the subjective DOBI supported construct validity and reliability. Further studies examining the usefulness of both versions are needed in carers of individuals with more severe HF.
How technology can save lives in cardiac arrest
Authors: Scquizzato Tommaso , Gamberini Lorenzo , Semeraro Federico
Published: March 2022

Purpose of review

Technology is being increasingly implemented in the fields of cardiac arrest and cardiopulmonary resuscitation. In this review, we describe how recent technological advances have been implemented in the chain of survival and their impact on outcomes after cardiac arrest. Breakthrough technologies that are likely to make an impact in the future are also presented.

Recent findings

Technology is present in every link of the chain of survival, from prediction, prevention, and rapid recognition of cardiac arrest to early cardiopulmonary resuscitation and defibrillation. Mobile phone systems to notify citizen first responders of nearby out-of-hospital cardiac arrest have been implemented in numerous countries with improvement in bystanders’ interventions and outcomes. Drones delivering automated external defibrillators and artificial intelligence to support the dispatcher in recognising cardiac arrest are already being used in real-life out-of-hospital cardiac arrest. Wearables, smart speakers, surveillance cameras, and artificial intelligence technologies are being developed and studied to prevent and recognize out-of-hospital and in-hospital cardiac arrest.

This review highlights the importance of technology applied to every single step of the chain of survival to improve outcomes in cardiac arrest. Further research is needed to understand the best role of different technologies in the chain of survival and how these may ultimately improve outcomes.
Prospective collagen IVα345 therapies for Alport syndrome
Authors: Boudko Sergei P. , Pokidysheva Elena , Hudson Billy G.
Published: March 2022

Purpose of review

In Alport syndrome, over 1,700 genetic variants in the COL4A3, COL4A4, and COL4A5 genes cause the absence or malfunctioning of the collagen IVα345 scaffold – an essential component of the glomerular basement membrane (GBM). Therapies are limited to treatment with Angiotensin-Converting enzyme (ACE) inhibitors to slow progression of the disease. Here, we review recent progress in therapy development to replace the scaffold or restore its function.

Recent findings

Multiple approaches emerged recently for development of therapies that target different stages of production and assembly of the collagen IVα345 scaffold in the GBM. These approaches are based on (1) recent advances in technologies allowing to decipher pathogenic mechanisms that underlie scaffold assembly and dysfunction, (2) development of DNA editing tools for gene therapy, (3) RNA splicing interference, and (4) control of mRNA translation.

There is a growing confidence that these approaches will ultimately provide cure for Alport patients. The development of therapy will be accelerated by studies that provide a deeper understanding of mechanisms that underlie folding, assembly, and function of the collagen IVα345 scaffold.
Coronavirus disease 2019 and the liver
Authors: Esteban James Philip , Sobotka Lindsay , Rockey Don C.
Published: March 2022

Purpose of review

The objective of this review is to examine the epidemiology and pathogenesis of liver injury in coronavirus disease 2019 (COVID-19) and the impact of COVID-19 on patients with chronic liver disease (CLD) and liver transplant recipients.

Recent findings

Abnormal liver chemistries occur in up to 60% of COVID-19 patients and are typically mild. COVID-19- associated liver injury may be because of direct viral cytopathic effect, immune-mediated damage, hypoxia, drug-induced liver injury (DILI), or exacerbation of CLD. COVID-19 patients with CLD and who are liver transplant recipients are at risk for severe disease and mortality. COVID-19 precipitated hepatic decompensation in 20–46% of cirrhotic patients. Alcohol consumption and cases of acute alcohol- associated hepatitis increased during the COVID-19 pandemic. Corticosteroids and calcineurin inhibitors are well tolerated to use during COVID-19 but immunomodulators have been associated with mortality. Less than 50% of transplant recipients produce adequate antibody titers after COVID-19 vaccination.

COVID-19 patients with CLD should be monitored for liver injury and hepatic decompensation. Patients with CLD and liver transplant recipients should be considered for targeted COVID-19 pharmacotherapeutics and advised vaccination against COVID-19, including a third booster dose. CLD treatments and immunosuppression in liver transplant recipients could generally continue without interruption during COVID-19 infection, with the possible exception of immunomodulators.
Cryptogenic multifocal ulcerating stenosing enteritis and other under-recognised small bowel inflammatory enteropathies
Authors: McAlindon Mark E.
Published: March 2022

Purpose of review

Capsule endoscopy and more sensitive radiological techniques have resulted in more enteropathies being detected. A rare disease of unknown aetiology, ‘cryptogenic multifocal ulcerating stenosing enteritis’ or ‘chronic nonspecific multiple ulcers of the small intestine’ (CNSU), has long been recognised. This review aims to describe how disease can be better diagnosed and differentiated from other small bowel inflammatory disorders.

Recent findings

Genetic studies have shown that some patients with CNSU (the term used in Japanese studies) express SLCO2A1 gene mutations, a gene which encodes a prostaglandin transporter expressed on vascular endothelium, allowing a more specific diagnosis of ‘chronic enteropathy associated with SLCO2A1’. Mutations in the PLA2G4A gene result in cytosolic phospholipase A2α deficiency and reduced arachidonic acid for prostaglandin synthesis leading to a severe ulcerating, stenosing and fistulating small bowel disease.

A ‘prostaglandin-related enteropathy’ should be considered in patients with atypical small bowel ulceration and stenosis. Genetic analysis will allow the detection of SLCO2A1 and PLA2G4A gene mutations. However, a careful history of medication use and a urinary metabolite screen may reveal the use of nonsteroidal anti-inflammatory drugs, a common cause of small bowel injury which is well recognised as being mediated by prostaglandin inhibition.
Role of albumin in the treatment of decompensated liver cirrhosis
Authors: Trebicka Jonel
Published: March 2022

Purpose of review

Albumin has been used primarily as a plasma expander, since it leads to an increase in the circulating blood volume. Current generally recommended indications for albumin therapy in cirrhotic patients are the prevention of circulatory dysfunction after large-volume paracentesis, the prevention of hepatorenal syndrome (HRS) in patients with spontaneous bacterial peritonitis (SBP), and the management of HRS in combination with vasoconstrictors. Yet, new indications for albumin have been tested in the recent years and are outlined in this short review.

Recent findings

New data show that albumin both supports the circulation and reduces systemic inflammation. In addition, to its oncotic function, it acts as an antioxidant, radical scavenger, and immune modulator. These nononcotic properties explain why long-term albumin administration in patients with decompensated cirrhosis may be useful in the prevention of associated complications (acute-on-chronic liver failure, infections). New data show that long-term albumin therapy in patients with cirrhosis and ascites improves survival, prevents complications, simplifies ascites management, and lowers hospitalization rates. The so-called disease-modifying effects of long-term albumin therapy may have a favorable effect on the course of the disease. Nevertheless, the optimal dosage and administration intervals have not yet been finally defined.

Albumin therapy is effective in the indications already recommended by the guidelines. A possible extension of the indication for albumin administration in non-SBP infections and as long-term therapy is promising, but should be confirmed by further studies.
Assessment after focal therapy: what is the latest?
Authors: Kotamarti Srinath , Séguier Denis , Arcot Rohith , Polascik Thomas J.
Published: March 2022

Purpose of review

To review assessment after focal therapy (FT) in the context of developments from the past two years.

Recent findings

With a paucity of high-quality studies, recent findings are primarily reliant on results from institutional-based cohorts and reports of expert consensus. Notably, oncologic treatment failure should be further stratified into recurrence in the in-field or out-of-field ablation zone, and both regions should be surveilled postoperatively. Monitoring primarily consists of periodic evaluations of prostate-specific antigen (PSA) testing and magnetic resonance imaging, with histologic sampling needed to confirm suspicion of recurrence. Recent investigations into PSA derivatives, contrast-enhanced ultrasound, and prostate-specific membrane antigen imaging have shown preliminary promise. Although postablation functional outcomes are generally accepted to be excellent, they are limited by the wide range of patient-reported measures, variability in individual practice, and low questionnaire completion rates.

There is still a need for high-level, long-term data to inform exact standardized protocols to manage patients after FT. A multifaceted approach is required to surveil patients and identify those at risk of recurrence. Embracing shared responsibility between the patient and clinician to fastidiously monitor the infield and out-of-field ablation zones postoperatively is critical to maximize oncologic outcomes.
Benefits and Risks of Bilateral Salpingectomy Compared With Standard Tubal Ligation During Cesarean Delivery for Permanent Postpartum Contraception
Authors: Luke Shauntell , Addae-Konadu Kateena , Davidson Brittany , Kuller Jeffrey , Dotters-Katz Sarah
Published: March 2022

Importance

Ovarian cancer is the second most common gynecologic malignancy, but the most deadly female reproductive cancer in the United States. Epithelial ovarian cancer makes up approximately 90% of all cases and is responsible for more than 90% of ovarian cancer deaths. Elective salpingectomy has been shown to reduce ovarian cancer risk when performed at the time of a benign hysterectomy. Data regarding the risks and benefits of opportunistic bilateral salpingectomy performed at the time of cesarean delivery are limited.

Objective

We aim to review the current evidence regarding safety and benefits of opportunistic bilateral salpingectomy at the time of cesarean delivery compared with bilateral tubal ligation.

Evidence Acquisition

Original research articles, review articles, and guidelines on contraception were reviewed.

Conclusions and Relevance

Opportunistic bilateral salpingectomy at the time of cesarean delivery is feasible and safe. Operative time may be increased up to 15 minutes for salpingectomy performed by suture ligation compared with standard tubal ligation. Women with a history of 3 or more cesarean deliveries are more likely to require an alternative procedure. It is important to counsel women that although opportunistic bilateral salpingectomy may significantly decrease the risk of ovarian cancer, it does not eliminate the risk entirely.

Target Audience

Obstetricians and gynecologists, family physicians

Learning Objectives

After participating in this activity, the provider should be better able to: describe the benefits to opportunistic bilateral salpingectomy at the time of cesarean delivery; outline the risks associated with opportunistic bilateral salpingectomy as a means of postpartum contraception; and identify what populations would benefit from opportunistic bilateral salpingectomy at the time of cesarean delivery.
Animal models in compartment syndrome: a review of existing literature
Authors: O’Neill Dillon C. , Boes Emily A. , McCutcheon Chance , Haller Justin M.
Published: March 2022

Objective:

Extremity compartment syndrome (ECS) is a morbid condition resulting in permanent myoneural damage. Currently, the diagnosis of compartment syndrome relies on clinical symptoms and/or intracompartment pressure measurements, both of which are poor predictors of ECS. Animal models have been used to better define cellular mechanisms, diagnosis, and treatment of ECS. However, no standardized model exists. The purpose of this study was to identify existing animal research on extremity compartment syndrome to summarize the current state of the literature and to identify weaknesses that could be improved with additional research.

Methods:

A MEDLINE database search and reverse inclusion protocol were utilized. We included all animal models of ECS.

Results:

Forty-one studies were included. Dogs were the most commonly used model species, followed by pigs and rats. Most studies sought to better define the pathophysiology of compartment syndrome. Other studies evaluated experimental diagnostic modalities or potential treatments. The most common compartment syndrome model was intracompartment infusion, followed by tourniquet and intracompartment balloon models. Few models incorporated additional soft tissue or osseous injury. Only 65.9% of the reviewed studies confirmed that their model created myoneural injury similar to extremity compartment syndrome.

Conclusions:

Study purpose, methodology, and outcome measures varied widely across included studies. A standardized definition for animal compartment syndrome would direct more consistent research in this field. Few animal models have investigated the pathophysiologic relationship between traumatic injury and the development of compartment syndrome. A validated, clinically relevant animal model of extremity compartment syndrome would spur improvement in diagnosis and therapeutic interventions.
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.
Invasion and diversity in Pseudomonas aeruginosa urinary tract infections
Authors: Newman JN , Floyd RV , Fothergill JL
Published: March 2022

Introduction.

P. aeruginosa

is an opportunistic Gram-negative pathogen frequently isolated in urinary tract infections (UTI) affecting elderly and catheterized patients and associated with ineffective antibiotic treatment and poor clinical outcomes.

Gap statement. Invasion has been shown to play an important role in UTI caused by

E. coli

but has only recently been studied with

P. aeruginosa

. The ability of

P. aeruginosa

to adapt and evolve in chronic lung infections is associated with resistance to antibiotics but has rarely been studied in

P. aeruginosa

UTI populations.

Aim. We sought to determine whether phenotypic and genotypic heterogeneity exists in

P. aeruginosa

UTI isolates and whether, like urinary pathogenic

Escherichia coli

, these could invade human bladder epithelial cells – two factors that could complicate antibiotic treatment.

Methodology.

P. aeruginosa

UTI samples were obtained from five elderly patients at the Royal Liverpool University Hospital as part of routine diagnostics. Fourty isolates from each patient sample were screened for a range of phenotypes. The most phenotypically diverse isolates were genome sequenced. Gentamicin protection assays and confocal microscopy were used to determine capacity to invade bladder epithelial cells.

Results. Despite significant within-patient phenotypic differences, no UTI patient was colonized by distinct strains of

P. aeruginosa

. Limited genotypic differences were identified in the form of non-synonymous SNPs. Gentamicin protection assays and confocal microscopy provided evidence of

P. aeruginosa

’s ability to invade bladder epithelial cells.

Conclusions. Phenotypic variation and cell invasion could further complicate antibiotic treatment in some patients. More work is needed to better understand

P. aeruginosa

UTI pathogenesis and develop more effective treatment strategies.
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

Objectives

To 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 & Methods

An 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.

Results

The 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.

Conclusions

Patients 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 SUMMARY

Dry 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

Patient-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 Summary

Patient 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

Bacillus 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.

IMPORTANCE

In 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

Background

Multi-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.

Methods

Following 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.

Results

Post-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.

Conclusions

uPLC-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.

Highlights

This multi-steroid profiling assay quantifies 25 steroids in 5.5 minutes

Post-column infusion of NH4F enhances the ionisation of 3-keto-Δ4 steroids

The assay simultaneously quantifies steroids from several biosynthetic pathways

We 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

Background

Reports 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).

Methods

We 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.

Findings

We 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.

Interpretation

DKA 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.

Funding

No 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

Background

The 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.

Methods

1,294 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.

Results

In 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.

Conclusions

HFE 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 Summary

Two 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

As 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

Alcohol 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

Early-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 points

Exposure 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

Proper 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
The Fate of DIET Consortium exposed to continuous and intermittent electrochemical stimulation
Authors: Yee Mon Oo , Ottosen Lars D.M. , Rotaru Amelia-Elena
Published: March 2022

Electromethanogenesis is the electrochemical conversion of carbon dioxide (CO2) to methane (CH4) with microorganisms as catalysts, and it is a promising approach for biogas upgrading. Many studies have shown increased methane production by electrochemical stimulation, allegedly due to the enhancement of direct interspecies electron transfer (DIET) between electrogenic bacteria and methanogens. However, these studies were done with mixed cultures where the interspecies interactions were undefined, so the impact of an electrochemical stimulus on these interactions remains unresolved. Here we report that an electrochemical stimulus diminished the survival and activity of a defined DIET consortium. We investigated the impact of electrochemical stimulation on a co-culture of Geobacter metallireducens and Methanosarcina barkeri, where the two partners interact syntrophically via DIET. The electrochemical stimulus was a cathode poised at - 700 mV (versus the standard hydrogen electrode, SHE). Electrochemical stimulation was provided either continuously or intermittently, and so was the food substrate. Compared to the untreated DIET co-culture, all treatment strategies relying on cathodic current additions resulted in acetate accumulation, lower methane production and lower cell numbers for both partners, indicating a detrimental impact of electrochemical stimulation to a DIET consortium. These findings suggest that future bioelectrochemical technologies must guarantee the survival of the syntrophic partners during current additions.
Homophilic wiring principles underpin neuronal network topologyin vitro
Authors: Akarca Danyal , Dunn Alexander W. E. , Hornauer Philipp J. , Ronchi Silvia , Fiscella Michele , Wang Congwei , Terrigno Marco , Jagasia Ravi , Vértes Petra E. , Mierau Susanna B. , Paulsen Ole , Eglen Stephen J. , Hierlemann Andreas , Astle Duncan E. , Schröter Manuel
Published: March 2022

Economic efficiency has been a popular explanation for how networks self-organize within the developing nervous system. However, the precise nature of the economic negotiations governing this putative organizational principle remains unclear. Here, we address this question further by combining large-scale electrophysiological recordings, to characterize the functional connectivity of developing neuronal networksin vitro, with a generative modeling approach capable of simulating network formation. We find that the best fitting model uses a homophilic generative wiring principle in which neurons form connections to other neurons which are spatially proximal and have similar connectivity patterns to themselves. Homophilic generative models outperform more canonical models in which neurons wire depending upon their spatial proximity either alone or in combination with the extent of their local connectivity. This homophily-based mechanism for neuronal network emergence accounts for a wide range of observations that are described, but not sufficiently explained, by traditional analyses of network topology. Using rodent and human monolayer and organoid cultures, we show that homophilic generative mechanisms can accurately recapitulate the topology of emerging cellular functional connectivity, representing an important wiring principle and determining factor of neuronal network formationin vitro.
Genetic diversity and characterization of circular replication(Rep)-encoding single-stranded (CRESS) DNA viruses
Authors: Desingu Perumal Arumugam , Nagarajan K.
Published: March 2022

The CRESS-DNA viruses are the ubiquitous virus detected in almost all eukaryotic life trees and play an essential role in the maintaining ecosystem of the globe. Still, their genetic diversity is not fully understood. Here we bring to light the genetic diversity of Replication (Rep) and Capsid (Cap) proteins of CRESS-DNA viruses. We divided the Rep protein of the CRESS-DNA virus into ten clusters using CLANS and phylogenetic analyzes. Also, most of the Rep protein in Rep cluster 1 (R1) and R2 (Circoviridae, Smacoviridae, Nanoviridae, and CRESSV1-5) contain the Viral_Rep superfamily and P-loop_NTPase superfamily domains, while the Rep protein of viruses in other clusters has no such characterized functional domain. The Circoviridae, Nanoviridae, and CRESSV1-3 viruses contain two domains, such as Viral_Rep and P-loop_NTPase; the CRESSV4 and CRESSV5 viruses have only the Viral_Rep domain, and most of the sequences in the pCRESS-related group have only P-loop_NTPase, and Smacoviridae do not have these two domains. Further, we divided the Cap protein of the CRESS-DNA virus into 20 clusters using CLANS and phylogenetic analyzes. The Rep and Cap proteins of Circoviridae and Smacoviridae are grouped into a specific cluster. Cap protein of CRESS-DNA viruses grouped with one cluster and Rep protein with another cluster. Further, our study reveals that selection pressure plays a significant role in the evolution of CRESS-DNA viruses’ Rep and Cap genes rather than mutational pressure. We hope this study will help determine the genetic diversity of CRESS-DNA viruses as more sequences are discovered in the future.

Importance

The genetic diversity of CRESS-DNA viruses is not fully understood. CRESS-DNA viruses are classified as CRESSV1 to CRESSV6 using only Rep protein. This study revealed that the Rep protein of the CRESS-DNA viruses is classified as CRESSV1 to CRESSV6 groups and the new Smacoviridae-related, CRESSV2-related pCRESS-related, Circoviridae-related, and 1 to 4 outgroups, according to the Viral_Rep and P-loop_NTPase domain organization, CLANS, and phylogenetic analysis. Furthermore, for the first time in this study, the Cap protein of CRESS-DNA viruses was classified into 20 distinct clusters by CLANS and phylogenetic analysis. Through this classification, the genetic diversity of CRESS-DNA viruses clarifies the possibility of recombinations in Cap and Rep proteins. Finally, it has been shown that selection pressure plays a significant role in the evolution and genetic diversity of Cap and Rep proteins. This study explains the genetic diversity of CRESS-DNA viruses and hopes that it will help classify future detected viruses.