bluuebunny/crossref_metadata_2025 huggingface dataset:
Intercellular extrachromosomal DNA copy number heterogeneity drives cancer cell state diversity
Authors: Stöber Maja C , González Rocío Chamorro , Brückner Lotte , Conrad Thomas , Wittstruck Nadine , Szymansky Annabell , Eggert Angelika , Schulte Johannes H , Koche Richard P , Henssen Anton G , Schwarz Roland F , Haase Kerstin
Published: January 2023

Neuroblastoma is characterised by extensive inter- and intra-tumour genetic heterogeneity and varying clinical outcomes. One possible driver for this heterogeneity are extrachromosomal DNAs (ecDNA), which segregate independently to the daughter cells during cell division and can lead to rapid amplification of oncogenes. While ecDNA-mediated oncogene amplification has been shown to be associated with poor prognosis in many cancer entities, the effects of ecDNA copy number heterogeneity on intermediate phenotypes are still poorly understood.

Here, we leverage DNA and RNA sequencing data from the same single cells in cell lines and neuroblastoma patients to investigate these effects. We utilise ecDNA amplicon structures to determine precise ecDNA copy numbers and reveal extensive intercellular ecDNA copy number heterogeneity. We further provide direct evidence for the effects of this heterogeneity on gene expression of cargo genes, includingMYCNand its downstream targets, and the overall transcriptional state of neuroblastoma cells.

These results highlight the potential for rapid adaptability of cellular states within a tumour cell population mediated by ecDNA copy number, emphasising the need for ecDNA-specific treatment strategies to tackle tumour formation and adaptation.
Adult-specific Reelin expression alters striatal neuronal organization. Implications for neuropsychiatric disorders
Authors: Pardo Mònica , Gregorio Sara , Montalban Enrica , Pujadas Lluís , Elias-Tersa Alba , Masachs Núria , Vílchez-Acosta Alba , Parent Annabelle , Auladell Carme , Girault Jean-Antoine , Vila Miquel , Nairn Angus C , Manso Yasmina , Soriano Eduardo
Published: January 2023

In addition to neuronal migration, brain development and adult plasticity, the extracellular matrix protein Reelin has been extensively implicated in human psychiatric disorders such as schizophrenia, bipolar disorder and autistic spectrum disorder. Moreover, heterozygousreelermice exhibit features reminiscent of these disorders, while overexpression of Reelin protects against its manifestation. However, how Reelin influences the structure and circuits of the striatal complex, a key region for the above-mentioned disorders, is far from being understood, especially when altered Reelin expression levels are found at adult stages. In the present study, we took advantage of complementary conditional gain- and loss-of-function mouse models to investigate how Reelin levels may modify adult brain’s striatal structure and neuronal composition. Using immunohistochemical techniques, we determined that Reelin does not seem to influence the striatal patch and matrix organization (studied by μ-opioid receptor immunohistochemistry) nor the density of medium spiny neurons (MSNs, studied with DARPP-32). We show that overexpression of Reelin leads to increased numbers of striatal Parvalbumin- and Cholinergic-interneurons, and to a slight increase in the tyrosine hydroxylase-positive projections. We conclude that increased Reelin levels might modulate the numbers of striatal interneurons and the density of the nigrostriatal dopaminergic projections, suggesting that these changes may be involved in the protection of Reelin against neuropsychiatric disorders.
Biochemical Properties of Naturally Occurring Human Bloom Helicase Variants
Authors: Cueny Rachel R. , Varma Sameer , Schmidt Kristina H. , Keck James L.
Published: January 2023

Bloom syndrome helicase (BLM) is a RecQ-family helicase implicated in a variety of cellular processes, including DNA replication, DNA repair, and telomere maintenance. Mutations in humanBLMcause Bloom syndrome (BS), an autosomal recessive disorder that leads to myriad negative health impacts including a predisposition to cancer. BS-causing mutations inBLMoften negatively impact BLM ATPase and helicase activity. WhileBLMmutations that cause BS have been well characterized bothin vitroandin vivo, there are other less studiedBLMmutations that exist in the human population that do not lead to BS. Two of these non-BS mutations, encoding BLM P868L and BLM G1120R, when homozygous, increase sister chromatid exchanges in human cells. To characterize these naturally occurring BLM mutant proteinsin vitro, we purified the BLM catalytic core (BLMcore, residues 636-1298) with either the P868L or G1120R substitution. We also purified a BLMcoreK869A K870A mutant protein, which alters a lysine-rich loop proximal to the P868 residue. We found that BLMcoreP868L and G1120R proteins were both able to hydrolyze ATP, bind diverse DNA substrates, and unwind G-quadruplex and duplex DNA structures. Molecular dynamics simulations suggest that the P868L substitution weakens the DNA interaction with the winged-helix domain of BLM and alters the orientation of one lobe of the ATPase domain. Because BLMcoreP868L and G1120R retain helicase functionin vitro, it is likely that the increased genome instability is caused by specific impacts of the mutant proteinsin vivo. Interestingly, we found that BLMcoreK869A K870A has diminished ATPase activity, weakened binding to duplex DNA structures, and less robust helicase activity compared to wild-type BLMcore. Thus, the lysine-rich loop may have an important role in ATPase activity and specific binding and DNA unwinding functions in BLM.
Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity
Authors: Yun Sanghee , Soler Ivan , Tran Fionya , Haas Harley A. , Shi Raymon , Bancroft Grace L. , Suarez Maiko , de Santis Chris R. , Reynolds Ryan P. , Eisch Amelia J.
Published: January 2023

Behavioral pattern separation and cognitive flexibility are essential cognitive abilities which are disrupted in many brain disorders. Better understanding of the neural circuitry involved in these abilities will open paths to treatment. In humans and mice, discrimination and adaptation rely on integrity of the hippocampal dentate gyrus (DG) which both receive glutamatergic input from the entorhinal cortex (EC), including the lateral EC (LEC). Inducible increase of EC-DG circuit activity improves simple hippocampal-dependent associative learning and increases DG neurogenesis. Here we asked if the activity of LEC fan cells that directly project to the DG (LEC➔DG neurons) regulates behavioral pattern separation or cognitive flexibility. C57BL6/J male mice received bilateral LEC infusions of a virus expressing shRNA TRIP8b, an auxiliary protein of an HCN channel or a control virus (SCR shRNA); this approach increases the activity of LEC➔DG neurons. Four weeks later, mice underwent testing for behavioral pattern separation and reversal learning (touchscreen-based Location Discrimination Reversal [LDR] task) and innate fear of open spaces (elevated plus maze [EPM]) followed by counting of new DG neurons (doublecortin-immunoreactive cells [DCX+] cells). TRIP8b and SCR shRNA mice performed similarly in general touchscreen training and LDR training. However, in late LDR testing, TRIP8b shRNA mice reached the first reversal more quickly and had more accurate discrimination vs. SCR shRNA mice, specifically when pattern separation was challenging (lit squares close together or “small separation”). Also, TRIP8b shRNA mice achieved more reversals in late LDR testing vs. SCR shRNA mice. Supporting a specific influence on cognitive behavior, SCR shRNA and TRIP8b shRNA mice did not differ in total distance traveled or in time spent in the closed arms of the EPM. Supporting an inducible increase in LEC-DG activity, DG neurogenesis was increased. These data indicate TRIP8b shRNA mice had better pattern separation and reversal learning and more neurogenesis vs. SCR shRNA mice. This work advances fundamental and translational neuroscience knowledge relevant to two cognitive functions critical for adaptation and survival — behavioral pattern separation and cognitive flexibility — and suggests the activity of LEC➔DG neurons merits exploration as a therapeutic target to normalize dysfunctional DG behavioral output.
The Omicron variant BQ.1* with mutations at positions 28,311 and 28,312 in the SARS-CoV-2 N gene have minimal impact on CDC N1 target detection
Authors: Ren Guoping , Langhorst Bradley W. , Patton Gregory C.
Published: January 2023

Ensuring COVID-19 testing remains accurate and reliable is of critical importance as the SARS-CoV-2 virus continues to evolve. Currently, a number of Omicron variants are dominating infection across the globe in including BQ.1 and XBB. Both variants and their sublineages (BQ.1* and XBB*) contain a 28,311 C/U mutation inherited from the original Omicron variant (BA.1). This mutation overlaps with a commonly used fluorescent probe for N gene detection in many Emergency Use Authorization (EUA) assays, as this target was originally established by the U.S. Centers for Disease Control and Prevention (CDC) in their EUA test for COVID-19 (2019-nCoV_N1). This C to U mutation was previously shown to have no impact on CDC N1 target detection. The rise of Omicron sublineages has increased the likelihood of additional point mutations occurring within the same assay target. A subpopulation of BQ.1* has an additional 28,312 C/U mutation within the CDC 2019_nCoV_N1 fluorescent probe in addition to the 28,311 C/U mutation. The double mutation could adversely affect the ability of diagnostic assays to detect the virus in patient samples and therefore it is important to verify the impacts of this additional mutation. Using in vitro transcribed (IVT) N gene RNA representing the wildtype (GenBank/GISAID IDMN908947.3) and Omicron BQ.1.1 variant (BQ.1, GISAID ID EPI_ISL_ 15155651), we evaluated the performance of two different amplification protocols, both of which include the CDC 2019-nCoV_N1 primer-probe set. Both assays successfully detected the mutant N gene sequence efficiently even at 10 copies of input, although the double mutation caused a 0.5∼1 Cqdelay on average when compared to the wild-type sequence. These data suggest that circulating BQ.1* lineage viruses with this double mutation likely have minimal impact on diagnostic assays that use the 2019-nCoV-N1 primer-probe.
A Performative Theory of Judicial Dissent
Authors: Mistry Hemi
Published: January 2023

This article introduces a ritual theory of judicial dissent. Conventional accounts of the functions of judicial dissent, whether in the context of domestic or international judicial systems, can be grouped into three thematic categories: ‘dissent as transparency’, ‘dissent as opposition’ and ‘dissent as conscience’. Leaving aside the disagreement over whether judicial dissent should be institutionalised at all, these accounts of the institutional functions of dissent are generally accepted with little dispute. Yet, while these conventional accounts may be normatively unproblematic, they fail to fully or coherently capture the mechanics by which judicial dissent operates upon institutional authority in practice. Irrespective of judicial dissent's capacity to function, or be seen to function, in the ways envisaged by doctrine, this article considers how a ritual theory analysis of dissent – with its focus on form – may supplement conventional accounts of judicial dissent.
Statins in pre‐eclampsia or fetal growth restriction: A systematic review and meta‐analysis on maternal blood pressure and fetal growth across species
Authors: Meijerink Lotte , Wever Kim E. , Terstappen Fieke , Ganzevoort Wessel , Lely A. Titia , Depmann Martine
Published: January 2023

Background

Several human randomised controlled trials (RCTs) are investigating the effects of statins on pre‐eclampsia (PE) and fetal growth restriction (FGR). This cross‐species meta‐analysis summarises the preclinical evidence of statin use for PE and FGR.

Objectives

Evaluate the effects of statins on maternal blood pressure (MBP) and birthweight (BW) in pregnancies complicated by PE or FGR.

Search Strategy

PubMed and Embase.com were searched on 10 May 2022 using ‘statins’ and ‘pregnancy’.

Selection Criteria

We included RCTs and cohorts with matched control groups as well as animal studies.

Data Collection and Analysis

The main outcomes were MBP in mmHg and BW in grams. The standardised mean difference (SMD) with a 95% confidence interval (CI) was calculated. Subgroup analyses on species, statin, dose, timing and route of administration were performed if subgroups included at least three studies.

Main Results

Our data included one human and 12 animal studies. Prenatal administration of statins significantly reduced MBP during pregnancy (SMD  −2.49 mmHg [95% CI −4.26 to −0.71], p = 0.01). There was no significant effect of statins on BW (SMD 0.69 [95% CI −0.65 to 2.03], p = 0.28). Our subgroup analyses showed no effect on MBP of different doses, species or route of administration.

Conclusions

Our cross‐species meta‐analyses demonstrate that statins only reduce maternal blood pressure in rodent pregnancies complicated by pre‐eclampsia or fetal growth restriction and have no effect on birthweight across species. The broad confidence intervals, inconsistent direction of the observed effects across the studies and large risk of bias lead us to conclude that a solid base for further human RCTs is lacking.
Production of selenium nanoparticles occurs through an interconnected pathway of sulphur metabolism and oxidative stress response in Pseudomonas putida KT2440
Authors: Avendaño Roberto , Muñoz‐Montero Said , Rojas‐Gätjens Diego , Fuentes‐Schweizer Paola , Vieto Sofía , Montenegro Rafael , Salvador Manuel , Frew Rufus , Kim Juhyun , Chavarría Max , Jiménez Jose I.
Published: January 2023

The soil bacterium Pseudomonas putida KT2440 has been shown to produce selenium nanoparticles aerobically from selenite; however, the molecular actors involved in this process are unknown. Here, through a combination of genetic and analytical techniques, we report the first insights into selenite metabolism in this bacterium. Our results suggest that the reduction of selenite occurs through an interconnected metabolic network involving central metabolic reactions, sulphur metabolism, and the response to oxidative stress. Genes such as sucA, D2HGDH and PP_3148 revealed that the 2‐ketoglutarate and glutamate metabolism is important to convert selenite into selenium. On the other hand, mutations affecting the activity of the sulphite reductase decreased the bacteria's ability to transform selenite. Other genes related to sulphur metabolism (ssuEF, sfnCE, sqrR, sqr and pdo2) and stress response (gqr, lsfA, ahpCF and sadI) were also identified as involved in selenite transformation. Interestingly, suppression of genes sqrR, sqr and pdo2 resulted in the production of selenium nanoparticles at a higher rate than the wild‐type strain, which is of biotechnological interest. The data provided in this study brings us closer to understanding the metabolism of selenium in bacteria and offers new targets for the development of biotechnological tools for the production of selenium nanoparticles.
Chytridiomycosis and climate change: exposure to Batrachochytrium dendrobatidis and mild winter conditions do not increase mortality in juvenile agile frogs during hibernation
Authors: Kásler A. , Holly D. , Herczeg D. , Ujszegi J. , Hettyey A.
Published: January 2023

Hibernation is often associated with high mortality, especially during early life stages, and losses can be exacerbated by unusual winter conditions or if animals enter hibernation carrying a disease. Here, we examined how overwintering amphibians may be affected by the combined effects of mild winters, which are projected to increase in frequency due to climate change, and of chytridiomycosis, a disease that has contributed to the decline of hundreds of species worldwide. We exposed juvenile agile frogs Rana dalmatina to Batrachochytrium dendrobatidis (Bd), the causative agent of chytridiomycosis, and subsequently subjected them to either a long, cold winter (1.5°C for 91 days) or a short, mild winter (4.5°C for 61 days) under laboratory conditions. Agile frogs proved to be highly resistant to Bd as only 37% of Bd‐exposed individuals became infected as determined before hibernation, and prevalence further decreased to 8% by the end of hibernation, with individuals showing very low infection intensity values. We observed lack of mortality in control and Bd‐exposed groups also, in both types of winter. The two types of winter we simulated did not result in differing body mass loss either alone or in combination with experimental infection. In the Bd‐exposed group, the two types of winter also did not cause differences in prevalence and infection intensity. However, among Bd‐exposed frogs, individuals that were Bd negative when entering hibernation lost more body mass than their conspecifics that carried the fungus at the onset of overwintering. Based on our results, warming winter climate conditions, with or without Bd infection, do not decrease body mass and survival rate of hibernating agile frogs, and do not increase susceptibility of individuals to chytridiomycosis. It remains to be seen to what extent the relatively weak effects of milder winters can be generalized to other amphibians of the temperate climate zone.
Comparative performance of a multi‐locus barcoding approach to enhance taxonomic resolution of New Zealand mosquitoes (Diptera: Culicidae)
Authors: Wu Jieyun , Li Dongmei , Boyd Ben , Balan Rebijith K. , George Sherly , Peacock Lora , Pal Chandan
Published: January 2023

Mosquitoes (Diptera: Culicidae) pose a serious threat to human health globally and the accurate identification of mosquito species is fundamental to entomological diagnostics and surveillance implementing effective vector control and management. However, cryptic species complexes, incomplete or damaged specimens, and juvenile life stages complicates the task. Molecular characterisation has shown the potential to identify the mosquito species accurately and overcomes the difficulties that morphological diagnosis face. Here, we assessed the effectiveness of a multi‐locus barcoding approach using cytochrome c oxidase subunit I (COI), internal transcribed spacer 1 (ITS1) and internal transcribed spacer 2 (ITS2) regions to identify the New Zealand mosquito species (n = 16) at the highest taxonomic resolution, which can make diagnosis more accurate and efficient. Our results show that most of the New Zealand mosquito species could be distinctly separated from each other as well as from other exotic species using either of these barcoding regions (i.e., COI, ITS1 and ITS2). The assessment of taxonomic discriminatory power of COI, ITS1 and ITS2 barcodes suggests that ITS2 can better distinguish the New Zealand closely‐related species. Two closely‐related endemic species from the Culex pervigilans species complex (Cx. rotoruae and Cx. pervigilans) were difficult to distinguish using COI and ITS1 regions. However, the ITS2 barcode could detect a greater genetic variation among individuals of those two species and demonstrate the potential to resolve the relationships among them to provide better resolution as a complementary to COI. Overall, this study provides a reference DNA barcode database of COI and ITS2 for New Zealand mosquito species, which will aid in their accurate identification at a higher taxonomic resolution and corroborate the traditional morphological approaches to perform better species discrimination among closely‐related species complex. The study also assessed the preliminary genetic diversity of the mosquito species from different regions of New Zealand, which can be used as a baseline for uncovering the environmental and geographical effect on genomic variations among New Zealand mosquito populations in the future.
Non‐linear association between testosterone and LDL concentrations in men
Authors: Lee Jun Ho , Jung Hyuk‐Dal , Choi Jae Duck , Kang Jung Yoon , Yoo Tag Keun , Park Yeon Won
Published: January 2023

Background

Contradictory data have been reported about the association between testosterone levels and the levels of low‐density lipoprotein cholesterol (LDL).

Objectives

The aim of this study was to elucidate the association between testosterone and LDL levels.

Materials and methods

A cross‐sectional study was conducted that included 7268 men who had participated in a health examination. Men who took agents that influence serum lipid profiles within the previous 6 months were excluded. A full metabolic work‐up and serum testosterone level checks were performed. The main outcome measures included the testosterone level and testosterone <3.5 ng/ml prevalence of each decile of LDL and their polynomial trendlines and the odds ratio (OR) of testosterone <3.5 ng/ml according to the LDL level.

Results

The polynomial trendline suggests the inverse association of testosterone with the deciles of triglycerides, the positive association of testosterone with the deciles of high‐density lipoprotein cholesterol and the inverted U‐shaped association between testosterone and the deciles of LDL. The polynomial trendline suggests a U‐shaped curvilinear relationship between the deciles of LDL and the prevalence of testosterone <3.5 ng/ml. The adjusted ORs of testosterone <3.5 ng/ml in men in the lowest and highest deciles were significantly higher than those of men in the 10th–90th deciles of LDL (OR [95% CI], < 10th LDL: 1.4[1.2–1.8]; 10th – 90th LDL: 1.0 [reference]; >90th LDL: 1.3[1.0–1.6]), which reinforces the U‐shaped curvilinear relationship between LDL levels and the prevalence of testosterone <3.5 ng/ml.

Discussion and conclusion

Further research is needed to elucidate the association of very low or very high LDL concentrations with circulating testosterone in men.
How we approach the perioperative management of patients with chronic lymphocytic leukaemia receiving continuous cancer‐directed therapies
Authors: Ma Helen , Wang Stephani , O'Brien Susan , Kern Morton , Gupta Pankaj
Published: January 2023

Historically, invasive procedures and surgeries were deferred in patients with haematological malignancies including advanced stage chronic lymphocytic leukaemia (CLL) because of limited life expectancy. However, novel, and often continuous, treatments have markedly improved outcomes in CLL. Some patients may expect years of treatment response and disease control, overcoming the short life expectancy that deters interventionalists. Such patients now often undergo various invasive procedures including major surgery. To inform peri‐operative management, we summarize the relevant side effects and drug interactions of continuous CLL therapies, highlight potential surgical risks, and provide recommendations on withholding specific CLL drugs around invasive procedures.
TNTversion 1.6, with a graphical interface forMacOSand Linux, including new routines in parallel
Authors: Goloboff Pablo A. , Morales Martín E.
Published: January 2023

A new graphical user interface (GUI) for the parsimony program TNT is presented that works under the Linux and Mac operating systems, as well as the Cygwin environment (which runs under Windows). The new interface is based on the GIMP Tool Kit, GTK (version 3). Formerly, only Windows versions of TNT had a GUI. The new interface improves upon the existing Windows GUI in several respects. These changes, together with several additions to the program since the publication of version 1.5, warrant a change in minor version, thus moving from version 1.5 to 1.6. Among the most notable improvements are the possibility to access graphical user dialogs by means of simple commands, to easily save trees in SVG format (“Scalable Vector Graphics”) directly from any tree‐diagram being displayed, and to manage analyses in parallel (using multiple processors, by means of the PVM system or “Parallel Virtual Machine”), as well as a generally more stable and consistent behaviour. As the binaries for the new version are compiled as native 64‐bit applications, this removes the limitations for accessing large amounts of memory in the previous GUI Windows interface (which is a 32‐bit application).
Impact and recovery of the COVID‐19 pandemic on weight status of children and adolescents
Authors: Bond Diana M. , Seimon Radhika , Schneuer Francisco J. , Baur Louise A. , Craig Maria , Alexander Shirley , Garnett Sarah P. , Henderson Joanne , Nassar Natasha
Published: January 2023

Recent evidence suggests the immediate effects of the COVID‐19 lockdowns and restrictions have resulted in increased weight in children and adolescents. However, the longer‐term effects have not been assessed. The aim of this study was to examine the impact and longer‐term effects of the COVID‐19 pandemic on BMI and weight status of children and adolescents. This study used routinely collected clinical data from the Sydney Children's Hospitals Network, comprising two socio‐demographically diverse children's hospitals in New South Wales, Australia from 2018 to 2021. Of 245 836 individuals ≤18‐years assessed, mean BMI percentile increased from 58.7 (SD 31.6) pre‐COVID‐19 to 59.8 (SD 31.7) (p < .05) post‐restrictions and overweight/obesity increased by 5.5% (obesity alone 6.3%), predominantly in children <12‐years and from lower socioeconomic backgrounds. The trend in BMI percentile was steady pre‐COVID‐19 (β = −0.03 [95% CI −0.07, 0.01]), peaked immediately following COVID‐19 restrictions (β = 1.28 [95% CI 0.24, 2.32]) and returned to pre‐pandemic levels over ensuing 21 months (β = −0.04 [95% CI –0.13, 0.04]). Routine anthropometric measurement facilitates ongoing monitoring and evaluation of the weight status of children and adolescents, helping to identify those at‐risk. Despite initial BMI and weight increases among children and adolescents, longer‐term follow‐up highlighted a return to pre‐pandemic rates, possibly attributed to state‐wide policies aimed at reducing childhood obesity.
Comprehensive analysis of pyroptosis‐related gene signatures for glioblastoma immune microenvironment and target therapy
Authors: Wang Zeyu , Dai Ziyu , Zhang Hao , Zhang Nan , Liang Xisong , Peng Luo , Zhang Jian , Liu Zaoqu , Peng Yun , Cheng Quan , Liu Zhixiong
Published: January 2023

Glioblastoma (GBM) is a malignant brain tumour, but its subtypes (mesenchymal, classical, and proneural) show different prognoses. Pyroptosis is a programmed cell death relating to tumour progression, but its association with GBM is poorly understood. In this work, we collected 73 GBM samples (the Xiangya GBM cohort) and reported that pyroptosis involves tumour‐microglia interaction and tumour response to interferon‐gamma. GBM samples were grouped into different subtypes, cluster 1 and cluster 2, based on pyroptosis‐related genes. Cluster 1 samples manifested a worse prognosis and had a more complicated immune landscape than cluster 2 samples. Single‐cell RNA‐seq data analysis supported that cluster 1 samples respond to interferon‐gamma more actively. Moreover, the machine learning algorithm screened several potential compounds, including nutlin‐3, for cluster 1 samples as a novel treatment. In vitro experiments supported that cluster 1 cell line, T98G, is more sensitive to nutlin‐3 than cluster 2 cell line, LN229. Nutlin‐3 can trigger oxidative stress by increasing DHCR24 expression. Moreover, pyroptosis‐resistant genes were upregulated in LN229, which may participate against nutlin‐3. Therefore, we hypothesis that GBM may be able to upregulate pyroptosis resistant related genes to against nutlin‐3‐triggered cell death. In summary, we conclude that pyroptosis highly associates with GBM progression, tumour immune landscape, and tumour response to nutlin‐3.
Patterns and outcomes of COVID‐19 donor utilization for heart transplant
Authors: Vaidya Gaurang Nandkishor , Anaya Paul , Ignaszewski Maya , Kolodziej Andrew , Malyala Rajasekhar , Sekela Michael , Birks Emma
Published: January 2023

Background

The outcomes following COVID‐19 positive donor (CPD) utilization for heart transplant are unknown.

Methods

UNOS database was analyzed for heart transplants performed from the declaration of COVID‐19 pandemic until September 30, 2022.

Result

Since the onset of pandemic, there were 9876 heart transplants reported. COVID‐19 antigen or NAT results were available in 7698 adult donors within 14 days of donation, of which 177 (2.3%) were positive. There was no difference in recipient demographics, including age (COVID positive donor vs. negative: 55 vs. 56 years, p = .2) and BMI. Listing status 1 and 2 were similar in both groups (7% vs. 10% and 48% vs. 49% respectively, p = .4). Durable and temporary mechanical support were similar in both groups pre‐transplant (both groups 33%, p = .9). There was no difference in days on the waitlist (median 31 days, p = .9). Simultaneous renal transplant rates were similar (11% vs. 10%, p = .9). CPD utilization has increased since the onset of the pandemic, and the adoption is present across most UNOS regions. Post‐transplant, there was no difference in length of stay (median 16 vs. 17 days, p = .9) and acute rejection episodes prior to discharge (3% vs. 8%, p = .1). In survival analysis of 90‐day follow up, number of deaths reported were comparable (5% in both groups, p = .9) Follow‐up LVEF was comparable (62% vs. 60%, p = .4).

Conclusion

Active COVID‐19 infection in donors did not affect survival or rejection rates in the short‐term post‐heart transplant.
Longitudinal and self‐attributed change in alcohol use among young adults during the COVID‐19 pandemic in Australia
Authors: Dolli Ishaan , Slade Tim , Teesson Maree , Chapman Cath
Published: January 2023

Introduction

The COVID‐19 pandemic introduced a unique concern regarding the potential for pandemic‐related increases in alcohol use. However, most studies which have measured pandemic‐related changes to date utilise self‐attribution measures of changes in alcohol use using cross‐sectional designs, which rely on accurate self‐attributions for validity. There has been minimal investigation of correspondence of self‐attributed and longitudinally measured changes in alcohol use during the pandemic. The current study seeks to examine this correspondence.

Methods

A total of 856 participants originally recruited from Australian secondary schools completed follow‐up surveys of an ongoing study at two timepoints (2018–2019, mean age 18.6 and 2020–2021, mean age 19.9; 65.3% female). Alcohol use was measured as any drinking (1+ drinks) and binge drinking (5+ drinks) frequency in the past 6 months. The correspondence and relationship between ‘longitudinal change’ measured from the first to the second timepoint and ‘self‐attributed change’ measured at the second timepoint were examined.

Results

For both any drinking and binge drinking frequency, moderate correspondence was observed between self‐attributed and longitudinal change in drinking (37.1% and 39.3%). Most participants with longitudinal increases in any drinking or binge drinking frequency failed to correctly self‐attribute this increase.

Discussion and Conclusions

The findings suggest that self‐attributed increases do not correspond well with longitudinally measured increases in pandemic‐related drinking and may underestimate increases measured longitudinally. Method of measurement needs to be taken into account if data are to be used to identify sub‐groups at risk of alcohol use increases and facilitate appropriate direction of public health efforts.
Future implications of telehealth for complex chronic disorders after COVID‐19
Authors: Banerjee Indrajit , Robinson Jared
Published: January 2023

This commentary is on the original article by Downs et al. on pages 489–497 of this issue.
Physician‐led medication reviews in polypharmacy patients treated with at least 12 medications in a type 2 diabetes outpatient clinic: A randomised trial
Authors: Johansson Karl Sebastian , Kornholt Jonatan , Bülow Cille , Petersen Tonny Studsgaard , Perrild Hans , Rungby Jørgen , Christensen Mikkel Bring
Published: January 2023

Aims

Medication reviews can be used to promote appropriate pharmacotherapy and negate the harmful consequences of polypharmacy. This study aimed to evaluate the effect of physician‐led medication reviews and increased cross‐sectoral communication as a supplement to standard care in a type 2 diabetes outpatient clinic.

Methods

This pragmatic randomised clinical trial enrolled patients with type 2 diabetes treated with at least 12 medications. The subjects were randomised to either standard care (standard care consultation at the outpatient clinic) or standard care plus a medication review consultation and increased cross‐sectoral communication. The primary outcome was the number of medications used after six months. Health‐related quality of life was quantified using the EuroQoL 5‐dimension 5‐level (EQ5D‐5 L) questionnaire.

Results

We recruited 50 participants with a median age of 72 (IQR 67–75) years. The mean number of medications per patient changed from 17.9 to 14.3 in the intervention group and 17.6 to 17.2 in the control group (rate ratio 0.81). The reasons for discontinuations were medication no longer indicated (60%), safety issues (20%), efficacy issues (15%) or patient preferences (5%). There was a significant difference in the change in health‐related quality of life (EQ5D‐5 L index score) in favour of the intervention (0.111, 95% CI 0.001 to 0.221).

Conclusions

Physician‐led medication reviews and increased cross‐sectoral communication in patients with type 2 diabetes treated with at least 12 medications reduced the number of medications used and improved health‐related quality of life. Implementing and further investigating similar interventions as standard care seems reasonable.
Medical and surgical treatment of epilepsy in older adults: A national survey
Authors: Husein Nafisa , Langlois‐Thérien Timothé , Rioux Bastien , Josephson Colin B. , Jetté Nathalie , Keezer Mark R.
Published: January 2023

Objective

There are no clinical guidelines dedicated to the treatment of epilepsy in older adults. We investigated physician opinion and practice regarding the treatment of people with epilepsy aged 65 years or older. We also sought to study how our opinion and practice varied between geriatricians, general neurologists, and epilepsy neurologists (i.e., epileptologists).

Methods

We initially piloted our survey to measure test–retest reliability. Once finalized, we disseminated the survey via two rounds of facsimiles, and then conventional mail, to eligible individuals listed in a national directory of Canadian physicians. We used descriptive statistics such as stacked bar charts and tables to illustrate our findings.

Results

One hundred forty‐four physicians (104 general neurologists, 25 geriatricians, and 15 epileptologists) answered our survey in its entirety (overall response rate of 13.2%). Levetiracetam and lamotrigine were the preferred antiseizure medications (ASMs) to treat older adults with epilepsy. Two thirds of epileptologists and almost half of general neurologists would consider prescribing lacosamide in >50% of people aged >65 years; only one geriatrician was of the same opinion. More than 40% of general neurologists and geriatricians erroneously believed that none of the ASMs mentioned in our survey was previously studied in randomized controlled trials specific to the treatment of epilepsy in older adults. Epileptologists were more likely as compared to general neurologists and geriatricians to recommend epilepsy surgery (e.g., 66.6% vs. 22.9%–37.5% among older adults).

Significance

Therapeutic decisions for older adults with epilepsy are heterogeneous between physician groups and sometimes misalign with available clinical evidence. Our surveyed physicians differed in their approach to ASM choice as well as perception of surgery in older adults with epilepsy. These findings likely reflect the lack of clinical guidelines dedicated to this population and the deficient implementation of best practices.
In‐hospital and home‐based long‐term monitoring of focal epilepsy with a wearable electroencephalographic device: Diagnostic yield and user experience
Authors: Macea Jaiver , Bhagubai Miguel , Broux Victoria , De Vos Maarten , Van Paesschen Wim
Published: January 2023

Objective

The aim is to report the performance of an electroencephalogram (EEG) seizure‐detector algorithm on data obtained with a wearable device (WD) in patients with focal refractory epilepsy and their experience.

Methods

Patients used a WD, the Sensor Dot (SD), to measure two channels of EEG using dry electrode patches during presurgical evaluation and at home for up to 8 months. An automated seizure detection algorithm flagged EEG regions with possible seizures, which we reviewed to evaluate the algorithm's diagnostic yield. In addition, we collected data on usability, side effects, and patient satisfaction with an electronic seizure diary application (Helpilepsy).

Results

Sixteen inpatients used the SD for up to 5 days and had 21 seizures. Sixteen outpatients used the device for up to 8 months and reported 101 focal impaired awareness seizures during the periods selected for analysis. Focal seizure detection sensitivity based on behind‐the‐ear EEG was 52% in inpatients and 23% in outpatients. False detections/h, positive predictive value (PPV), and F1 scores were 7.13%, .11%, and .002% for inpatients and 7.77%, .04%, and .001% for outpatients. Artifacts and low signal quality contributed to poor performance metrics. The seizure detector identified 19 nonreported seizures during sleep, when the signal quality was better. Regarding patients' experience, the likelihood of using the device at 6 months was 62%, and side effects were the main reason for dropping out. Finally, daily and monthly questionnaire completion rates were 33% and 65%, respectively.

Significance

Focal seizure detection sensitivity based on behind‐the‐ear EEG was 52% in inpatients and 23% in outpatients, with high false alarm rates and low PPV and F1 scores. This unobtrusive wearable seizure detection device was well received but had side effects. The current workflow and low performance limit its implementation in clinical practice. We suggest different steps to improve these performance metrics and patient experience.
Depigmenting topical therapy based on a synergistic combination of compounds targeting the key pathways involved in melasma pathophysiology
Authors: Alfredo Martínez‐Gutiérrez , Maribel Pérez‐Martínez , Eloy Pena‐Rodríguez , Susana Gómez‐Escalante , Luis Luis G. S. , Carmen González Mari
Published: January 2023

Melasma has a complex pathophysiology with different cell types and signalling pathways involved. Paracrine factors secreted by keratinocytes, fibroblasts and endothelial cells act on melanocytes and stimulate melanogenesis. These paracrine factors are involved in the oxidative stress, inflammatory, vascular and hormonal pathways, among others. Damage of the dermoepidermal barrier also occurs and facilitates melanin deposition in the dermis, also known as dermal or mixed melasma. We used artificial intelligence tools to define the best combination of compounds for skin pigmentation inhibition. Mathematical models suggested the combination of retinol, diosmin and ferulic acid to be the most effective one. In vitro cellular tyrosinase activity assay proved that this combination had a synergistic depigmenting effect. Further assays proved that the combination could inhibit key pathways involved in melasma by downregulating ET‐1 and COX‐2 gene expression and IBMX‐induced dendricity in human melanocytes, and upregulated the gene expression of IL‐1b, TIMP3 and several endogenous antioxidant enzymes. The combination also reduced melanin levels in a phototype VI 3D epidermis model. These results indicate that the combination of retinol, diosmin and ferulic acid is an effective synergistic complex for the treatment of melasma by regulating the key molecular pathways involved in skin hyperpigmentation pathophysiology.
Urbanization and fragmentation have opposing effects on soil nitrogen availability in temperate forest ecosystems
Authors: Caron Stephen , Garvey Sarah M. , Gewirtzman Jonathan , Schultz Kyle , Bhatnagar Jennifer M. , Driscoll Charles , Hutyra Lucy R. , Templer Pamela H.
Published: January 2023

Nitrogen (N) availability relative to plant demand has been declining in recent years in terrestrial ecosystems throughout the world, a phenomenon known as N oligotrophication. The temperate forests of the northeastern U.S. have experienced a particularly steep decline in bioavailable N, which is expected to be exacerbated by climate change. This region has also experienced rapid urban expansion in recent decades that leads to forest fragmentation, and it is unknown whether and how these changes affect N availability and uptake by forest trees. Many studies have examined the impact of either urbanization or forest fragmentation on nitrogen (N) cycling, but none to our knowledge have focused on the combined effects of these co‐occurring environmental changes. We examined the effects of urbanization and fragmentation on oak‐dominated (Quercus spp.) forests along an urban to rural gradient from Boston to central Massachusetts (MA). At eight study sites along the urbanization gradient, plant and soil measurements were made along a 90 m transect from a developed edge to an intact forest interior. Rates of net ammonification, net mineralization, and foliar N concentrations were significantly higher in urban than rural sites, while net nitrification and foliar C:N were not different between urban and rural forests. At urban sites, foliar N and net ammonification and mineralization were higher at forest interiors compared to edges, while net nitrification and foliar C:N were higher at rural forest edges than interiors. These results indicate that urban forests in the northeastern U.S. have greater soil N availability and N uptake by trees compared to rural forests, counteracting the trend for widespread N oligotrophication in temperate forests around the globe. Such increases in available N are diminished at forest edges, however, demonstrating that forest fragmentation has the opposite effect of urbanization on coupled N availability and demand by trees.
Determinants and consequences of auditor switching during fiscal year‐end audit fieldwork
Authors: Kim Bum‐Joon , Mande Vivek , Son Myungsoo
Published: January 2023

We compare a group of firms switching auditors while their annual audit is underway (LateSwitches) with two control groups: firms switching their auditors during the fourth quarter of the fiscal year and firms switching their auditors during the first three quarters. First, we find that LateSwitches tend to be riskier with regard to litigation risk, audit risk and business risk. Second, we find that LateSwitches have a higher chance of announcing restatements and receiving going concern opinions in the first year of audit with the successor auditor. Despite the higher risks, we fail to find that LateSwitches disclose more adverse events in Forms 8‐K than other groups. We also document that stock market returns following an auditor change are more negative for LateSwitches. These results indicate that LateSwitches stand to face significant negative consequences when the relationship with their auditor is terminated abruptly in the final phases of an audit.
Ataxin‐1 controls the expression of specific noncoding RNAs in B cells upon autoimmune demyelination
Authors: Ma Qin , Didonna Alessandro
Published: January 2023

B cells play a key mechanistic role in the pathogenesis of multiple sclerosis (MS), a chronic neurological disease of the central nervous system with an autoimmune etiology. B cells contribute to disease initiation and progression by acting as professional antigen‐presenting cells as well as via secreting autoantibodies and proinflammatory cytokines. We have recently shown that the polyglutamine protein ataxin‐1, which was first linked to the movement disorder spinocerebellar ataxia type 1, also acts as a master regulator of B‐cell functions in the context of central nervous system autoimmunity. In fact, ataxin‐1–deficient mice display an aggravated manifestation of the MS disease model experimental autoimmune encephalomyelitis along with aberrant B‐cell functions. Consistent with this scenario, transcriptomic analysis of Atxn1‐null B cells highlighted distinct genetic signatures involved in cell activation, proliferation and antigen presentation. To further characterize the role of ataxin‐1, we profiled the noncoding transcriptome controlled by ataxin‐1 in the B‐cell compartment upon an encephalitogenic challenge. We show that two specific classes of noncoding RNAs, namely, processed pseudogenes and intergenic long noncoding RNAs, are differentially regulated along disease. Furthermore, pathway and protein network analyses on their putative protein‐coding gene targets found a significant enrichment in ontologies related to cell mitosis, together with molecular processes relevant to MS such as chitin metabolism. Altogether, these findings shed light on the possible contribution of noncoding RNAs to B‐cell biology and MS pathogenesis, and further establish the immunomodulatory role of ataxin‐1 in autoimmune demyelination.
Trauma‐informed care in acute mental health units through the lifeworld of mental health nurses: A phenomenological study
Authors: Wilson Allyson , Hurley John , Hutchinson Marie , Lakeman Richard
Published: January 2023

Trauma‐informed care has gained increasing popularity in mental health services over the past two decades. Mental health nurses remain one of the largest occupations employed in acute mental health settings and arguably have a critical role in supporting trauma‐informed care in this environment. Despite this, there remains a limited understanding on how trauma‐informed care is applied to the context of mental health nursing in the hospital environment. The aim of this study was to explore what it means for mental health nurses to provide trauma‐informed care in the acute mental health setting. The study design was qualitative, using van Manen's (Researching lived experience: human science for an action sensitive pedagogy. State University of New York Press, 1990) approach to hermeneutic phenomenological inquiry. A total of 29 mental health nurses participated in this study. There were three overarching themes that emerged; these entail: embodied trauma‐informed milieu, trauma‐informed relationality and temporal dimensions of trauma‐informed mental health nursing. The study found that for mental health nurses, there are elements of trauma‐informed care that extend far beyond the routine application of the principles to nursing practice. For mental health nurses working in the acute setting, trauma‐informed care may offer a restorative function in practice back to the core tenants of therapeutic interpersonal dynamics it was once based upon.