bluuebunny/crossref_metadata_2025 huggingface dataset:
Suppression of neuropathic pain in the circadian clock–deficient Per2m/m mice involves up-regulation of endocannabinoid system
Authors: Yamakawa Wakaba , Yasukochi Sai , Tsurudome Yuya , Kusunose Naoki , Yamaguchi Yuta , Tsuruta Akito , Matsunaga Naoya , Ushijima Kentaro , Koyanagi Satoru , Ohdo Shigehiro
Published: January 2024

Neuropathic pain often results from injuries and diseases that affect the somatosensory system. Disruption of the circadian clock has been implicated in the exacerbation of the neuropathic pain state. However, in this study, we report that mice deficient in a core clock component Period2 (Per2m/m mice) fail to develop tactile pain hypersensitivity even following peripheral nerve injury. Similar to male wild-type mice, partial sciatic nerve ligation (PSL)-Per2m/m male mice showed activation of glial cells in the dorsal horn of the spinal cord and increased expression of pain-related genes. Interestingly, α1D-adrenergic receptor (α1D-AR) expression was up-regulated in the spinal cord of Per2m/m mice, leading to increased production of 2-arachidonoylglycerol (2-AG), an endocannabinoid receptor ligand. This increase in 2-AG suppressed the PSL-induced tactile pain hypersensitivity. Furthermore, intraspinal dorsal horn injection of adeno-associated viral vectors expressing α1D-AR also attenuated pain hypersensitivity in PSL-wild-type male mice by increasing 2-AG production. Our findings reveal an uncovered role of the circadian clock in neuropathic pain disorders and suggest a link between α1D-AR signaling and the endocannabinoid system.
Exactness of the First Born Approximation in Electromagnetic Scattering
Authors: Loran Farhang , Mostafazadeh Ali
Published: January 2024

For the scattering of plane electromagnetic waves by a general possibly anisotropic stationary linear medium in three dimensions, we give a condition on the permittivity and permeability tensors of the medium under which the first Born approximation yields the exact expression for the scattered wave whenever the incident wavenumber k does not exceed a preassigned value α. We also show that under this condition the medium is omnidirectionally invisible for k ≤ α/2, i.e. it displays broadband invisibility regardless of the polarization of the incident wave.
Granular Search, Market Structure, and Wages
Authors: Jarosch Gregor , Nimczik Jan Sebastian , Sorkin Isaac
Published: January 2024

We develop a model of size-based market power in a frictional labour market. In the canonical search environment, competition for workers is encoded in outside options. In our granular setting, large employers remove their own job postings from their workers’ outside option. Thus, size gives market power and a more concentrated market structure depresses wages because it reduces competition for workers. We calibrate the model to Austrian data and find that such size-based market power depresses wages by about 2.6% or 1,500 euros annually per worker.
The Benefits of Cochlear Implantation for Adults: A Systematic Umbrella Review
Authors: Tang Diana , Tran Yvonne , Lo Charles , Lee Jien Nien , Turner Jessica , McAlpine David , McMahon Catherine , Gopinath Bamini
Published: January 2024

Objectives:

The uptake of cochlear implants among adults who could benefit (based on pure-tone audiometry) in developed countries is estimated to be less than 10%. Concerns about potential surgical complications, fear of losing residual hearing, and limited awareness about the benefits of this intervention contribute to the low adoption rate. To enhance quality of life and improve the uptake of cochlear implants, it is essential to have a clear understanding of their benefits.

Design:

This umbrella review aims to summarize the major benefits of cochlear implant usage in adults, by synthesizing findings from published review articles. A comprehensive search of databases including MEDLINE, EMBASE, PsycINFO, and Google Scholar, was conducted. The search was limited to English-language review articles published between 1990 and 2022, focusing on cochlear implant outcomes in at least 5 adults (aged ≥18 years). Two independent reviewers screened titles, abstracts, and full-text articles, and conducted a quality assessment using the Joanna Briggs Checklist for Systematic Reviews and Research Syntheses.

Results:

Forty-two articles were included in this review. There were 15 systematic reviews with meta-analysis, 25 systematic reviews without meta-analysis, and 2 systematic scoping reviews. All 42 articles underwent quality assessment using the Joanna Briggs Institute Checklist for Systematic Reviews and Research Syntheses, of which 40% (n = 17) satisfied 9 out of 11 quality criteria. This umbrella review shows that cochlear implants are associated with improvements in speech perception and recognition as well as improved quality of life and cognition. These benefits are observed in a significant proportion of adults undergoing the procedure, highlighting its effectiveness as a viable intervention for individuals with severe to profound hearing loss.

Conclusions:

The potential benefits of cochlear implantation appear to outweigh the risks and complications associated with the procedure. It is recommended that adults with severe to profound hearing loss in particular, engage in informed discussions with healthcare professionals to consider cochlear implantation as a viable treatment option.
In-Hospital Violence and Its Impact on Critical Care Practitioners
Authors: Bass Gary A. , Chang Cherylee W.J. , Winkle Julie M. , Cecconi Maurizio , Kudchadkar Sapna R. , Akuamoah-Boateng Kwame , Einav Sharon , Duffy Caoimhe C. , Hidalgo Jorge , Rodriquez-Vega Gloria M. , Gandra-d’Almeida Antonio J. , Barletta Jeffrey F. , Kaplan Lewis J.
Published: January 2024

OBJECTIVES:

To provide a narrative review of hospital violence (HV) and its impact on critical care clinicians.

DATA SOURCES:

Detailed search strategy using PubMed and OVID Medline for English language articles describing HV, risk factors, precipitating events, consequences, and mitigation strategies.

STUDY SELECTION:

Studies that specifically addressed HV involving critical care medicine clinicians or their practice settings were selected. The time frame was limited to the last 15 years to enhance relevance to current practice.

DATA EXTRACTION:

Relevant descriptions or studies were reviewed, and abstracted data were parsed by setting, clinician type, location, social media events, impact, outcomes, and responses (agency, facility, health system, individual).

DATA SYNTHESIS:

HV is globally prevalent, especially in complex care environments, and correlates with a variety of factors including ICU stay duration, conflict, and has recently expanded to out-of-hospital occurrences; online violence as well as stalking is increasingly prevalent. An overlap with violent extremism and terrorism that impacts healthcare facilities and clinicians is similarly relevant. A number of approaches can reduce HV occurrence including, most notably, conflict management training, communication initiatives, and visitor flow and access management practices. Rescue training for HV occurrences seems prudent.

CONCLUSIONS:

HV is a global problem that impacts clinicians and imperils patient care. Specific initiatives to reduce HV drivers include individual training and system-wide adaptations. Future methods to identify potential perpetrators may leverage machine learning/augmented intelligence approaches.
25-gauge versus 27-gauge Vitrectomy for Management of Vitreoretinal Diseases: A Large Prospective Randomized Trial.
Authors: Benzerroug Mounir , Marchand Maude , Coisy Solène , Briend Bénédicte , Boussion Bertrand , Mazit Chérif
Published: January 2024

Purpose:

To compare the safety and performance clinical outcomes of the 27-gauge (G) two-dimensional cutting vitrectomy probe versus a standard 25-G probe for retinal procedures.

Methods:

In this large randomized prospective study, all candidates for epiretinal membrane or macular hole surgery were randomized to the 27-G group or 25-G group. Outcome measures included surgery time, changes in best-corrected distance visual acuity (BCDVA), intraocular pressure (IOP), central macular thickness (CMT) between baseline and 1- and 3-months follow-up timepoints. Moreover, intraoperative and postoperative complications were evaluated as well as the rate of sutureless vitrectomy.

Results:

A total of 463 patients were included in this study, 227 patients in the 27-G group and 236 patients in the 25-G group. A similar total surgery time was found between both groups (p=0.0911). Similar BCDVA and CMT changes were observed between baseline and the 1- and 3-mont follow-up visits. No significant differences were reported in terms of intraoperative and postoperative complications rates. The rate of sutureless vitrectomy was 96.5% for 27-G group and 91.1% for 25-G group (p=0.0170).

Conclusion:

These results suggest that 27-G vitrectomy probe is similar to 25-G probe in terms of surgery time and complications, while decreasing the need for vitrectomy sutures.
SF6 compared to C2F6 for inferior rhegmatogenous retinal detachment repair; The Manchester Pseudophakic Retinal Detachment Study
Authors: Moussa George , Jalil Assad , Lippera Myrta , Cristescu Irina-Elena , Ferrara Mariantonia , Ally Naseer , Ziaei Hadi , El-Faouri Muhannd , Patton Niall , Jasani Kirti M , Dhawahir-Scala Felipe , Ivanova Tsveta
Published: January 2024

Purpose-

To compare SF6 relative to C2F6 in the anatomical and functional outcomes following pars plana vitrectomy (PPV) for uncomplicated primary pseudophakic rhegmatogenous retinal detachment (PRD) with inferior causative breaks.

Methods-

This is a retrospective, comparative study on eyes with PRD with inferior causative breaks that had small-gauge PPV repair using SF6 and C2F6 tamponade between 2011-2020 at a tertiary centre in the UK. Primary outcome was single surgery anatomical success (SSAS) and the secondary outcomes, best-corrected visual acuity (BCVA). Propensity score matching (PSM), using preoperative findings as covariates to account for relevant confounders, was performed.

Results-

From 162 PRD eyes with inferior causative breaks, the median (interquartile range) follow-up was 82 (52-182) days. The SSAS was 156 (96.3%) overall; 47/47 (100.0%) and 109/115 (94.8%) in the SF6 and C2F6 groups, respectively (p=0.182). Relative to the SF6 group, the C2F6 group had a higher mean number of tears (SF6:3.1[2.0], C2F6:4.5[2.7], p=0.002) and greater RD extent (SF6:5.3[2.9], C2F6:6.2[2.6] clock hours, p=0.025). Following PSM analysis, 80 eyes were matched with 40 in each group to homogenise preoperative factors. No significant difference was found in SSAS and BCVA between groups following PSM.

Conclusions-

Primary PPV with gas tamponade leads to a high SSAS rate in uncomplicated PRD with inferior causative breaks with no additional benefit associated with long-acting tamponade when comparing C2F6 with SF6.
Ocular Surface Squamous Neoplasia: Changes in the Standard of Care 2003 to 2022
Authors: Greenfield Jason A. , Cohen Adam K. , Galor Anat , Chodosh James , Stone Donald , Karp Carol L.
Published: January 2024

Purpose:

The aim of this review was to elucidate treatment preferences for ocular surface squamous neoplasia and to examine the changes in treatment modalities over the past 2 decades.

Methods:

An electronic survey was distributed to members of The Cornea Society, Ocular Microbiology and Immunology Group, and 4 international corneal specialist listservs. Questions examined medical and surgical treatment preferences, and results were compared with surveys administered in 2003 and 2012.

Results:

A total of 285 individuals responded to the survey; 90% of respondents were self-classified as corneal specialists. Seventy-three percent reported using primary topical monotherapy to treat ocular surface squamous neoplasia as compared with 58% in 2012 (P = 0.008). Compared with 2003, the percentage use of topical interferon significantly increased (P < 0.0001) from 14% to 55%, 5-fluorouracil increased (P < 0.0001) from 5% to 23%, and mitomycin C decreased (P < 0.0001) from 76% to 19% as a primary monotherapy. The frequency of performing excision without the use of postoperative adjunctive medical therapy decreased significantly (P < 0.0001), from 66% to 26% for lesions <2 mm, 64% to 12% for lesions between 2 and 8 mm, and 47% to 5% for lesions >8 mm from 2003 to 2022. More clinicians initiated topical immuno/chemotherapy without performing a biopsy as compared to 2003 (31% vs. 11%, P < 0.0001).

Conclusions:

These results demonstrate a paradigm shift in the management of ocular surface squamous neoplasia. The use of primary medical therapy as a first approach has significantly increased, with a reduction in the frequency of performing surgical excision alone.
Artificial Endothelial Layer Implantation After Multiple Failed Keratoplasties
Authors: Rens Jasmien , Krolo Iva , Koppen Carina , Ni Dhubhghaill Sorcha
Published: January 2024

Purpose:

Presenting the first case of noncellular corneal endothelial substitute after multiple failed penetrating keratoplasty (PK) and lamellar endothelial keratoplasty.

Methods:

Our case presented with pseudophakic bullous keratopathy after a history of 2 rejected PKs and 1 rejected Descemet stripping automated endothelial keratoplasty. We implanted an artificial endothelial layer.

Results:

The implant remained fully attached for a follow-up period of 12 months, and central corneal thickness decreased significantly. The patient reported improvement in her subjective vision, although ocular comorbidities limited the visual potential.

Conclusions:

This new device could serve as an alternative to lamellar endothelial corneal transplantation in cases where tissue rejection has occurred and is highly likely to recur. The technique is simple, and the deswelling effect on the cornea persisted, although the visual results require further validation in patients with a higher visual potential.
Characterizing glare effects associated with diffractive optics in presbyopia-correcting intraocular lenses
Authors: Łabuz Grzegorz , Khoramnia Ramin , Yan Weijia , van den Berg Thomas J.T.P. , Auffarth Gerd U. , Naujokaitis Tadas , Tandogan Tamer
Published: January 2024

Purpose:

To objectively quantify glare of intraocular lenses (IOLs) using a diffractive principle to extend the visual range and to identify models with increased susceptibility to inducing glare.

Setting:

David J Apple Laboratory, Heidelberg, Germany.

Design:

Laboratory investigation.

Methods:

Glare was assessed by means of a straylight parameter with a standard C-Quant intended for 7 degrees. In addition, 2 C-Quant modifications were used to test lower angles (ie, 2.5 degrees and 3.5 degrees). The following IOL models were assessed: PanOptix, AT Lisa Tri, Synergy, and Triumf, the latter 2 with chromatic aberration correction at distance. Straylight from trifocal IOLs was compared against a monofocal W-60R lens. The C-Quant test was performed through the studied IOLs by using additional optical components attached to their ocular.

Results:

Straylight (deg2sr−1) of the control was <1 at all tested angles, with the trifocal models showing comparable straylight at 7 degrees. At 3.5 degrees, Triumf's straylight increased to 15.5 ± 0.6, followed by Synergy (6.2 ± 1.1), PanOptix (4.1 ± 0.3), and AT Lisa Tri (2.0 ± 0.8). The chromatic aberration–correcting models demonstrated correspondingly higher straylight (Synergy: 18.8 ± 1.3; Triumf: 17.3 ± 0.5) at 2.5 degrees compared with PanOptix (4.3 ± 0.4), AT Lisa Tri (2.1 ± 0.1), and monofocal IOLs yielding minimal or no increase.

Conclusions:

Trifocal IOLs induced increased straylight, but it was limited to lower angles, which may cause difficulties detecting these effects using a standard clinical approach. The latest IOL designs featuring chromatic aberration correction at far focus seem more susceptible than the established trifocal IOLs to inducing a glare phenomenon.
Subclinical Measures of Cardiovascular Health Among Wildland Firefighters
Authors: Hasan Md Zahid , Semmens Erin O. , Navarro DuBose Kathleen , McCray L. Kaili , Noonan Curtis W.
Published: January 2024

Objective

The aim of the study is to compare subclinical measures of cardiovascular health among wildland firefighters (WFFs) to the US general population.

Methods

Our cross-sectional study compared body mass index, total cholesterol, and blood pressure in 11,051 WFFs aged 17 to 64 years using Department of the Interior Medical Screening Program clinical screening examinations between 2014–2018 to National Health and Nutrition Examination Survey of 2015–2016 cycle using adjusted logistic regression analyses.

Results

The logistic regression model shows significantly higher odds of hypertension and prehypertension in WFFs (2.84 times more with 95% CI: 2.28–3.53) than US general population. There were no consistent differences in body mass index or total cholesterol between the two population.

Conclusions

Hypertension and prehypertension were more prevalent in WFFs compared with the US general population, which suggests the need for actions for protecting against cardiovascular disease among WFFs.
Reconceptualizing sensitization in pain: back to basics
Authors: van den Broeke Emanuel N. , Crombez Geert , Vlaeyen Johan W.S.
Published: January 2024

Associated commentary:

Fillingim RB. Redefining sensitization could be a sensitive issue. PAIN Rep 2024;9:e1126.
Somatic mosaicism in focal epilepsies
Authors: Gooley Samuel , Perucca Piero , Tubb Caitlin , Hildebrand Michael S. , Berkovic Samuel F.
Published: January 2024

Purpose of review

Over the past decade, it has become clear that brain somatic mosaicism is an important contributor to many focal epilepsies. The number of cases and the range of underlying pathologies with somatic mosaicism are rapidly increasing. This growth in somatic variant discovery is revealing dysfunction in distinct molecular pathways in different focal epilepsies.

Recent findings

We briefly summarize the current diagnostic yield of pathogenic somatic variants across all types of focal epilepsy where somatic mosaicism has been implicated and outline the specific molecular pathways affected by these variants. We will highlight the recent findings that have increased diagnostic yields such as the discovery of pathogenic somatic variants in novel genes, and new techniques that allow the discovery of somatic variants at much lower variant allele fractions.

A major focus will be on the emerging evidence that somatic mosaicism may contribute to some of the more common focal epilepsies such as temporal lobe epilepsy with hippocampal sclerosis, which could lead to it being re-conceptualized as a genetic disorder.
Hidden stories of caregivers with children living with sickle cell disease in Uganda: experiences, coping strategies and outcomes
Authors: Alinda Isaac , Kabiri Lydia
Published: January 2024

Background

Sickle Cell Disease (SCD) poses a substantial public health challenge in Uganda, exhibiting distinct regional variations in prevalence. The Uganda Sickle Cell Surveillance Study has estimated an overall SCD prevalence of 13.3%. Notably, this prevalence diverges significantly across the country’s regions, reaching its highest in the northern region at 22.2% and it’s lowest in the central region at 5.3%. This variation reflects the diverse impact of SCD and underscores the need for a comprehensive understanding of its regional implications.

SCD places substantial physical, social, and psychological burdens on caregivers, potentially leading to heightened parental stress. However, limited research has focused on the daily challenges and experiences of SCD caregivers, despite evidence showing the detrimental impact on their emotional well-being, personal lives, employability, and socioeconomic status. This study explored the undisclosed struggles of Ugandan caregivers tending to children with SCD, uncovering their coping strategies and subsequent outcomes.

Methods

From June 23rd to July 30th, 2023, we engaged in the recruitment of participants for our study, we conducted in-depth interviews with caregivers at Mulago sickle cell clinic after obtaining their informed consent. An interview guide was used as the primary data collection tool, with interviews lasting 30-45 minutes. Twelve participants were recruited, ensuring comprehensive data collection by following the data saturation principle. We analyzed the collected data using open coding.

Results

Three key themes emerged: caregiver experiences, coping strategies, and outcomes. Initially, caregivers grappled with confusion and uncertainty before a formal diagnosis. Financial strain and inadequate support posed persistent challenges, affecting their emotional well-being. Coping strategies varied, encompassing traditional remedies and modern medical treatments for symptom relief. Coping outcomes were complex, reflecting caregivers’ resilience alongside substantial emotional distress and sleep disturbances. The substantial financial burden further exacerbated their overall well-being.

Conclusion

Elevating awareness and knowledge about sickle cell disease within communities is essential. Such awareness can empower caregivers of children living with sickle cell disease, promoting emotional resilience and mitigating family disruptions.
Exposure to angiotensin-converting enzyme inhibitors that cross the blood-brain barrier and the risk of dementia among patients with human immunodeficiency virus
Authors: Cummings Tammy H. , Magagnoli Joseph , Sikirzhytskaya Aliaksandra , Tyagin Ilya , Safro Ilya , Wyatt Michael D. , Shtutman Michael , Sutton S. Scott
Published: January 2024

More than one million people in the United States and over 38 million people worldwide are living with human immunodeficiency virus (HIV) infection. Antiretroviral therapy (ART) greatly improves the health of people living with HIV (PLWH); however, the increased life longevity of PLWH has revealed consequences of HIV-associated comorbidities. HIV can enter the brain and cause inflammation even in individuals with well-controlled HIV infection. The quality of life for PLWH can be compromised by cognitive deficits and memory loss, termed HIV-associated neurological disorders (HAND). HIV-associated dementia is a related but distinct diagnosis. Common causes of dementia in PLWH are similar to the general population and can affect cognition. There is an urgent need to identify treatments for the aging PWLH population. We previously developed AI-based biomedical literature mining systems to uncover a potential novel connection between HAND the renin-angiotensin system (RAAS), which is a pharmacological target for hypertension. RAAS-targeting anti-hypertensives are gaining attention for their protective benefits in several neurocognitive disorders. To our knowledge, the effect of RAAS-targeting drugs on the cognition of PLWH development of dementia has not previously been analyzed. We hypothesized that exposure to angiotensin-converting enzyme inhibitors (ACEi) that cross the blood brain barrier (BBB) reduces the risk/occurrence of dementia in PLWH. We report a retrospective cohort study of electronic health records (EHRs) to examine the proposed hypothesis using data from the United States Department of Veterans Affairs, in which a primary outcome of dementia was measured in controlled cohorts of patients exposed to BBB-penetrant ACEi versus those unexposed to BBB-penetrant ACEi. The results reveal a statistically significant reduction in dementia diagnosis for PLWH exposed to BBB-penetrant ACEi. These results suggest there is a potential protective effect of BBB ACE inhibitor exposure against dementia in PLWH that warrants further investigation.
Conventional electrode catheter placement can miss crucial atypical atrioventricular nodal reentrant tachycardia circuit details. -New insights into the retrograde slow pathways-
Authors: Kawabata Mihoko , Maeda Shingo , Okishige Kaoru , Shirai Yasuhiro , Kamata Tatsuaki , Kawashima Tomoyuki , Yonai Ryo , Atarashi Hirotsugu , Hirao Kenzo
Published: January 2024

Background

During atypical atrioventricular nodal reentrant tachycardia (AVNRT), the earliest atrial activation site following retrograde slow pathway (SP) conduction is at the atrial exit of the left inferior extension of the compact node (LIE) in the coronary sinus (CS) or the right inferior extension (RIE) on the tricuspid annulus (TA). We tested the validity of conventional electrode placement-based mapping of the atrial ends of these extensions.

Methods

We retrospectively evaluated the efficiency of the two catheter (His bundle and CS) mapping method for localization of LIE and RIE in atypical AVNRT patient using electroanatomical 3D mapping validation.

Results

Among 19 atypical AVNRTs (15 fast/slow and 4 slow/slow) in 14 patients (9 females, age 59±17), 8 AVNRTs had LIE involvement and 11 had RIE. The 8 LIE exits were inside the CS, and localization by 3D mapping and CS electrode catheter matched in all. In contrast, RIE exits were on the posterior TA where electrode catheters are conventionally not placed. All RIE exits required 3D mapping for accurate localization. During retrograde RIE conduction, comparison of the activation time of the CS ostium and HBE showed that the CS ostium was earlier in 7 RIEs, HBE was earlier in 1, and they were simultaneous in 3, resulting in the presence of RIE being missed in 4/11 (36%) AVNRTs using current diagnostic criteria. Activation time of the CS ostium and His bundle were determined by their relative closeness to the RIE exit.

Conclusions

Conventionally placed electrode catheter mapping in atypical AVNRT was able to identify 100% of LIE, but only 64% of RIE. It is critical to place a catheter on or use a 3D mapping system for the posterior TA in cases of suspected atypical AVNRT, so that all inferior extensions of the AV node can be identified and targeted for treatment.
DNA damage-induced PARP/ALC1 activation leads to Epithelial-to-Mesenchymal transition stimulating homologous recombination
Authors: Rajabi Fatemeh , Smith Rebecca , Liu-Bordes Win-Yan , Schertzer Michael , Huet Sebastien , Londoño-Vallejo Arturo
Published: January 2024

Epithelial-to-mesenchymal transition (EMT) allows cancer cells to metastasize while acquiring resistance to apoptosis and to chemotherapeutic agents with significant implications in patients’ prognosis and survival. Despite its clinical relevance, the mechanisms initiating EMT during cancer progression remain poorly understood. We demonstrate that DNA damage triggers EMT by activating PARP and the PARP-dependent chromatin remodeler ALC1 (CHD1L). We show that this activation directly facilitates the access to chromatin of EMT transcriptional factors (TFs) which then initiate cell reprogramming. We also show that EMT-TFs bind to the RAD51 promoter to stimulate its expression and to promote DNA repair by recombination. Importantly, a clinically relevant PARP inhibitor totally reversed or prevented EMT in response to DNA damage while resensitizing tumor cells to other genotoxic agents. Overall, our observations shed light on the intricate relationship between EMT, DNA damage response and PARP inhibitors, providing valuable insights for future therapeutic strategies in cancer treatment.
Root-specific secondary metabolism at the single-cell level: a case study of theanine metabolism and regulation in the roots of tea plants (Camellia sinensis)
Authors: Lin Shijia , Zhang Yiwen , Zhang Shupei , Wei Yijie , Han Mengxue , Deng Yamei , Guo Jiayi , Zhu Biying , Yang Tianyuan , Xia Enhua , Wan Xiaochun , Lucas William J. , Zhang Zhaoliang
Published: January 2024

Root-synthesized secondary metabolites are critical quality-conferring compounds of foods, plant-derived medicines, and beverages. However, information at a single-cell level on root-specific secondary metabolism remains largely unexplored. L-theanine, an important quality component of tea, is primarily synthesized in roots, from which it is then transported to new shoots of tea plant. In this study, we present a single-cell RNA sequencing (scRNA-seq)-derived map for the tea plant root, which enabled cell-type-specific analysis of glutamate and ethylamine (two precursors of theanine biosynthesis) metabolism, and theanine biosynthesis, storage, and transport. Our findings support a model in which the theanine biosynthesis pathway occurs via multicellular compartmentation and does not require high co-expression levels of transcription factors and their target genes within the same cell cluster. This study provides novel insights into theanine metabolism and regulation, at the single-cell level, and offers an example for studying root-specific secondary metabolism in other plant systems.
Chromosome-scale genome assembly of bread wheat’s wild relativeTriticum timopheevii
Authors: Grewal Surbhi , Yang Cai-yun , Scholefield Duncan , Ashling Stephen , Ghosh Sreya , Swarbreck David , Collins Joanna , Yao Eric , Sen Taner Z. , Wilson Michael , Yant Levi , King Ian P. , King Julie
Published: January 2024

Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world.Triticum timopheevii(2n = 4x = 28) is an allotetraploid wheat wild relative species containing the Atand G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly ofT. timopheeviiaccession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb, and 166,325 predicted gene models. DNA methylation analysis showed that the G genome had on average more methylated bases than the Atgenome. The G genome was also more closely related to the S genome ofAegilops speltoidesthan to the B genome of hexaploid or tetraploid wheat. In summary, theT. timopheeviigenome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.
The general transcription factor TFIIB is a target for transcriptome control during cellular stress and viral infection
Authors: Gulyas Leah , Glaunsinger Britt A.
Published: January 2024

Many stressors, including viral infection, induce a widespread suppression of cellular RNA polymerase II (RNAPII) transcription, yet the mechanisms underlying transcriptional repression are not well understood. Here we find that a crucial component of the RNA polymerase II holoenzyme, general transcription factor IIB (TFIIB), is targeted for post-translational turnover by two pathways, each of which contribute to its depletion during stress. Upon DNA damage, translational stress, apoptosis, or replication of the oncogenic Kaposi’s sarcoma-associated herpesvirus (KSHV), TFIIB is cleaved by activated caspase-3, leading to preferential downregulation of pro-survival genes. TFIIB is further targeted for rapid proteasome-mediated turnover by the E3 ubiquitin ligase TRIM28. KSHV counteracts proteasome-mediated turnover of TFIIB, thereby preserving a sufficient pool of TFIIB for transcription of viral genes. Thus, TFIIB may be a lynchpin for transcriptional outcomes during stress and a key target for nuclear replicating DNA viruses that rely on host transcriptional machinery.

Graphical Abstract

Significance Statement

Transcription by RNA polymerase II (RNAPII) synthesizes all cellular protein-coding mRNA. Many cellular stressors and viral infections dampen RNAPII activity, though the processes underlying this are not fully understood. Here we describe a two-pronged degradation strategy by which cells respond to stress by depleting the abundance of the key RNAPII general transcription factor, TFIIB. We further demonstrate that an oncogenic human gammaherpesvirus antagonizes this process, retaining enough TFIIB to support its own robust viral transcription. Thus, modulation of RNAPII machinery plays a crucial role in dictating the outcome of cellular perturbation.
Alcohol Use Disorder-Associated DNA Methylation in the Nucleus Accumbens and Dorsolateral Prefrontal Cortex
Authors: White Julie D. , Minto Melyssa S. , Willis Caryn , Quach Bryan C. , Han Shizhong , Tao Ran , Deep-Soboslay Amy , Zillich Lea , Clark Shaunna L. , van den Oord Edwin J. C. G. , Hyde Thomas M. , Mayfield R. Dayne , Webb Bradley T. , Johnson Eric O. , Kleinman Joel E. , Bierut Laura J. , Hancock Dana B.
Published: January 2024

Background

Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Here, we interrogate AUD-associated DNA methylation (DNAm) changes within and across addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC).

Methods

Illumina HumanMethylation EPIC array data from 119 decedents of European ancestry (61 cases, 58 controls) were analyzed using robust linear regression, with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public gene regulatory data and published genetic and epigenetic studies. We additionally tested for brain region-shared and -specific associations using mixed effects modeling and assessed implications of these results using public gene expression data.

Results

At a false discovery rate ≤ 0.05, we identified 53 CpGs significantly associated with AUD status for NAc and 31 CpGs for DLPFC. In a meta-analysis across the regions, we identified an additional 21 CpGs associated with AUD, for a total of 105 unique AUD-associated CpGs (120 genes). AUD-associated CpGs were enriched in histone marks that tag active promoters and our strongest signals were specific to a single brain region. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors; all others represent novel associations.

Conclusions

Our findings identify AUD-associated methylation signals, the majority of which are specific within NAc or DLPFC. Some signals may constitute predisposing genetic and epigenetic variation, though more work is needed to further disentangle the neurobiological gene regulatory differences associated with AUD.
Overweight followed by obesity have the lowest mortality among patients with systolic or diastolic heart failure independent of comorbidities whereas cachexia has the highest mortality
Authors: Movahed Mohammad Reza , Mineer Austin , Hashemzadeh Mehrtash
Published: January 2024

Introduction

A phenomenon known as the obesity paradox has been reported in patients with heart failure (HF) suggesting lower mortality with increasing weight. The goal of this study is to characterize this observation in HF using the largest available inpatient database of adult patients.

Method

We searched the National Inpatient Sample (NIS) database for patients for the years 2016-2020 with a diagnosis of systolic (SHF) or diastolic heart failure (DHF) using International Classification of Diseases, Tenth Revision (ICD-10) diagnosis codes. We evaluated mortality association based on body weight. Multivariate statistical analysis was performed to adjust all-cause inpatient mortality for comorbidities.

Results

There was a total of 7,364,023 patients with a diagnosis of SHF and 10,064,223 patients with a diagnosis of DHF. All-cause inpatient mortality was lowest in overweight patients followed by those with obesity and morbid obesity, whereas mortality was highest in cachexia compared to normal weight for SHF and DHF patients (mortality: overweight 2.56%, obese 3.12%, morbidly obese 3.70%, normal weight 5.60%, and cachexia 15.22%; p<0.001) and DHF patients (mortality: overweight 2.08%, obese 2.43%, morbidly obese 2.93%, normal weight 4.58%, and cachexia 14.25%; p<0.001). This relationship remains similar after multivariate analysis. (SHF patients: overweight OR: 0.49 (0.41-0.58), obesity OR: 0.64 (0.62-0.66), morbid obesity OR: 0.85 (0.83-0.88), and cachexia OR: 2.78 (2.67-2.90); p<0.001; DHF patients: overweight OR: 0.47 (0.40-0.56), obesity OR: 0.61 (0.59-0.63), morbid obesity OR: 0.83 (0.81-0.85), and cachexia OR: 3.09 (2.96-3.23); p<0.001).

Conclusion

Our data observed that all-cause inpatient mortality in SHF and DHF is lowest in overweight populations followed by obese and morbidly obese populations whereas cachexia has the highest mortality. However, increasing weight above the overweight reduces the obesity paradox benefit.
Cross-Center Validation of Deep Learning Model for Musculoskeletal Fracture Detection in Radiographic Imaging: A Feasibility Study
Authors: Hrubý Robert , Kvak Daniel , Dandár Jakub , Atakhanova Anora , Misař Matěj , Dufek Daniel
Published: January 2024

Fractures, often resulting from trauma, overuse, or osteoporosis, pose diagnostic challenges due to their variable clinical manifestations. To address this, we propose a deep learning-based decision support system to enhance the efficacy of fracture detection in radiographic imaging. For the purpose of our study, we utilized 720 annotated musculoskeletal (MSK) X-rays from the MURA dataset, augmented by bounding box-level annotation, for training the YOLO (You Only Look Once) model. The model’s performance was subsequently tested on two datasets, sampled FracAtlas dataset (Dataset 1, 840 images,nNORMAL= 696,nFRACTURE= 144) and own internal dataset (Dataset 2, 124 images,nNORMAL= 50,nFRACTURE= 74), encompassing a diverse range of MSK radiographs. The results showed a Sensitivity (Se) of 0.910 (95% CI: 0.852–0.946) and Specificity (Sp) of 0.557 (95% CI: 0.520–0.594) on the Dataset 1, and aSeof 0.622 (95% CI: 0.508–0.724) andSpof 0.740 (95% CI: 0.604–0.841) on the Dataset 2. This study underscores the promising role of AI in medical imaging, providing a solid foundation for future research and advancements in the field of radiographic diagnostics.
Unifying human infectious disease models and real-time awareness of population- and subpopulation-level intervention effectiveness
Authors: Seibel Rachel L. , Tildesley Michael J. , Hill Edward M.
Published: January 2024

During infectious disease outbreaks, humans often base their decision to adhere to an intervention strategy on individual choices and opinions. However, due to data limitations and inference challenges, infectious disease models usually omit these variables. We constructed a compartmental, deterministic Susceptible-Exposed-Infectious-Recovered (SEIR) disease model that includes a behavioural function with parameters influencing intervention uptake. The behavioural function accounted for an initial subpopulation opinion towards an intervention, their outbreak information awareness sensitivity and the extent they are swayed by the real-time intervention effectiveness information. Applying the model to vaccination uptake and three human pathogens - pandemic influenza, SARS-CoV-2 and Ebola virus - we explored through model simulation how these intervention adherence decision parameters and behavioural heterogeneity impacted epidemiological outcomes. From our model simulations we found that in some pathogen systems, different types of outbreak information awareness at different outbreak stages may be more informative to an information-sensitive population and lead to less severe epidemic outcomes. Incorporating behavioural functions that modify infection control intervention adherence into epidemiological models can aid our understanding of adherence dynamics during outbreaks. Ultimately, by parameterising models with what we know about human behaviour towards vaccination adherence, such models can help assist decision makers during outbreaks.
Contingency-based flexibility mechanisms through a reinforcement learning model in adults with Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder
Authors: Rodríguez-Herrera R. , León J.J. , Fernández-Martína P. , Sánchez Kuhn A. , Soto-Ontoso M. , Amaya-Pascasio L. , Martínez-Sánchez P. , Flores P.
Published: January 2024

Abtract

The probabilistic reversal learning paradigm is one of the most used to assess cognitive flexibility during a contingency-based learning process. Lack of cognitive flexibility is related to the symptomatology that characterizes disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD) and Obsessive-Compulsive Disorder (OCD). Resting-state functional connectivity (rsFC) could be a specific predictor of performance in contingency-based cognitive flexibility. However, the mechanisms underlying learning and flexibility in an environment of uncertainty with OCD or ADHD adults have not been widely explored. Computational modelling may be helpful to separate components of the behavioural processes and identify the source of the disorders. In the present study, we aimed to identify the mechanisms underlying contingency-based cognitive flexibility in a sample of the impulsive-compulsive spectrum and healthy controls, and explore the rsFC between the frontoparietal networks (FPN) regions as a possible neuromarker. 148 Spanish-speaking participants (43 patients with OCD, 53 with ADHD, and 52 healthy controls) completed a probabilistic reversal learning task (PRLT). Previously, we obtained a record of FNP rsFC using functional near-infrared spectroscopy (fNIRS). For this purpose, we applied the reinforcement learning model in combination with Bayesian GLM. We found that groups showed an optimal performance in the acquisition phase of the PRLT and higher performance of HC compared to the diagnostic groups in the reversal block, although performance is still optimal in all groups. Likewise, we found that the parameters studied (reinforcement learning rate, punishment learning rate and inverse temperature) predict task performance differently by phase and group. Regarding FNP rsFC, we found that rsFC between left posterior parietal cortex (lpPC) and right posterior parietal cortex (rpPC) seems to credibly predict performance in the acquisition block in the healthy controls. These findings suggest that reducing the uncertainty between action-outcome may help to improve the adaptation of ADHD and OCD patients to changing environments. Thus, understanding sensitivity to punishment or reinforcement and its influence on the decision-making may be important for designing case-specific interventions. According to our data, rsFC between lpPC and rpPC could be important for optimal learning of our task.
Altered IgG4 Antibody Response to Repeated mRNA versus Protein COVID Vaccines
Authors: Kalkeri Raj , Zhu Mingzhu , Cloney-Clark Shane , Plested Joyce S. , Parekh Anand , Gorinson Drew , Cai Rongman , Mahato Soham , Ramanathan Pradhipa , Aurelia L. Carissa , Selva Kevin John , Marchese Anthony M. , Fries Louis , Chung Amy W. , Dunkle Lisa M.
Published: January 2024

Repeated mRNA SARS-CoV-2 vaccination has been associated with increases in the proportion of IgG4 in spike-specific antibody responses and concurrent reductions in Fcγ-mediated effector functions that may limit control of viral infection. Here, we assessed anti-Spike total IgG, IgG1, IgG2, IgG3 and IgG4, and surrogate markers for antibody-dependent cellular phagocytosis (ADCP, FcγRIIa binding), antibody-dependent cellular cytotoxicity (ADCC, FcγRIIIa binding), and antibody-dependent complement deposition (ADCD, C1q binding) associated with repeated SARS-CoV-2 vaccination with NVX-CoV2373 (Novavax Inc., Gaithersburg, MD). The NVX-CoV2373 protein vaccine did not induce notable increases in spike-specific IgG4 or negatively impact surrogates for Fcγ effector responses. Conversely, repeated NVX-CoV2373 vaccination uniquely enhanced IgG3 responses which are known to exhibit strong affinity for FcγRIIIa and have previously been linked to potent neutralization of SARS-CoV-2. Subsequent investigations will help to understand the immunological diversity generated by different SARS-CoV-2 vaccine types and have the potential to reshape public health strategies.
Genome-wide association studies reveal differences in genetic susceptibility between single events versus recurrent events of atrial fibrillation and myocardial infarction: the HUNT study
Authors: Hall Martina , Skogholt Anne Heidi , Surakka Ida , Dalen Haavard , Almaas Eivind
Published: January 2024

Genetic research into Atrial Fibrillation (AF) and Myocardial Infarction (MI) has predominantly concentrated on contrasting afflicted individuals with their healthy counterparts. However, this approach lacks granularity, overlooking the subtleties within patient populations. In this study, we explore the distinction between AF and MI patients experiencing only single events to those experiencing recurrent events. Integrating hospital records, questionnaire data, clinical measurements, and genetic data from more than 500, 000 HUNT and UKBB participants in our analysis, we compare the two groups for both clinical and genetic characteristics with GWAS meta-analyses, PheWAS-analyses, and gene co-expression networks. We find that the two groups of patients differs in both clinical characteristics and genetic risk. More specifically, recurrent AF patients are significantly younger with a better baseline health, in terms of lower cholesterol and blood pressure, than the single AF patients. The GWAS meta-analysis results indicate that recurrent AF patients seem to have a greater genetic risk of recurrent events and the PheWAS-analysis and gene co-expression network analyses highlight differences in the diseases and genetic functions associated to the set of SNPs and genes for to each group. In contrast, we find that for MI patients experiencing single events are significantly younger and have a better baseline health, yet they exhibit higher genetic risk. The GWAS meta-analysis identifies mostly genetic regions uniquely associated with single MI, and the PheWAS-analysis and gene co-expression networks support the genetic differences between these two groups.
Ratios Of Submitted Charge Amounts To Medicare Allowed Amounts Have Variably Worsened For Anesthesiologists And Certified Registered Nurse Anesthetists Serving Medicare Beneficiaries Across The United States During 2013-2021 Period
Authors: Gupta Deepak , Ismaeil Yara
Published: January 2024

Background

Interstate variations among anesthesia providers in terms of their submitted charge amounts with corresponding Medicare allowed amounts have not been recently explored.

Objective

To quantify interstate variations in submitted charge amounts in relation to corresponding Medicare allowed amounts for the services provided by anesthesia providers during 2013-2021 for Medicare beneficiaries in the United States (U.S.).

Materials and Methods

Public Use Files for 2013-2021 period from Centers for Medicare & Medicaid Services were accessed to generate cumulative excel sheets of de-identified anesthesia providers data according to anesthesia providers stated location in fifty U.S. states and the District of Columbia. Thereafter, total number of providers, total number of services, total submitted charge amounts and total Medicare allowed amounts were finally tabulated according to the year of billed anesthesia service as well as according to anesthesia providers state.

Results

The submitted charge amount to Medicare allowed amount ratios varied from 4-9 across the states in 2013 for anesthesiologists as well as certified registered nurse anesthetists (CRNAs). These ratios worsened to 5-13 across the states for anesthesiologists in 2021 while these ratios worsened to 5-12 across the states for CRNAs in 2021. The greatest number of anesthesiologists serving Medicare beneficiaries have been located in California across the years while the greatest number of CRNAs serving Medicare beneficiaries have been located in Florida across the years. Overall, some states have more anesthesiologists per 100,000 population serving Medicare beneficiaries with District of Columbia having the maximum (28 anesthesiologists per 100,000 population) while some states have more CRNAs per 100,000 population serving Medicare beneficiaries with North Dakota having the maximum (38 CRNAs per 100,000 population).

Conclusion

Over the years (2013-2021), ratios of submitted charge amounts to Medicare allowed amounts have variably worsened for anesthesiologists and CRNAs serving Medicare beneficiaries across U.S. irrespective of the state stated by anesthesiologists and CRNAs as their primary location per National Plan and Provider Enumeration System.