bluuebunny/crossref_metadata_2025 huggingface dataset:
Prison officers’ experiences of aggression: implications for sleep and recovery
Authors: Kinman G , Clements A J
Published: November 2022

Background

Prison officers are at high risk of assault that can impair their mental as well as physical health. Such experiences can also disrupt sleep, with negative implications for well-being and job performance. To manage this risk, insight is needed into the mechanisms by which experiencing aggression from prisoners can affect officers’ sleep quality. By impairing recovery processes, work-related hypervigilance and rumination might be key factors in this association.

Aims

To examine prison officers’ personal experiences of aggression and associations with sleep quality. Also, to consider whether work-related hypervigilance and rumination mediate the relationship between exposure to aggression and sleep.

Methods

We assessed prison officers’ experiences of aggression and violence, work-related hypervigilance and rumination via an online survey. The PROMIS was used to measure the quality of sleep.

Results

The study sample comprised 1,806 prison officers (86.8% male). A significant relationship was found between the frequency of experiences of aggression at work and the quality of sleep. Work-related hypervigilance and rumination were significantly associated with sleep quality and mediated the relationship between workplace aggression and sleep quality.

Conclusions

Our findings suggest that enhancing the safety climate in prisons might improve officers’ quality of sleep that, in turn, could benefit their wellbeing and performance. Implementing individual-level strategies to help prison officers manage hypervigilance and rumination, and therefore facilitate recovery, should also be effective in improving their sleep.
Prevalence of Polypharmacy in Patients With Vestibular and Balance Complaints
Authors: Jeong Seth S. , Chen Tiffany , Timor Tatianna A. , Busch Adrienne L. , Meyer Ted A. , Nguyen Shaun A. , Rizk Habib G.
Published: November 2022

Objectives:

To determine the prevalence of polypharmacy in patients presenting with dizziness to a tertiary neurotology clinic and analyze the association between polypharmacy and clinical characteristics.

Design:

Retrospective, cross-sectional review. Demographics, symptoms, diagnoses, medications, audiometry, dizziness handicap index (DHI) scores, and cognitive failure questionnaire (CFQ) scores were extracted from charts of patients seen as new patients from September 1, 2019, to March 31, 2020, with a primary complaint of dizziness.

Results:

A total of 382 patients were included. More than two-thirds of the patients (n = 265, 69.4%) met criteria for polypharmacy (≥5 medications), of which most (n = 249, 94.0%) were prescribed a potentially ototoxic drug. Approximately 10% of patients were taking five or more ototoxic medications (oto-polypharmacy). Polypharmacy was correlated to age and was more common for patients with diabetes, hypertension, other cardiovascular comorbidities, and depression (odds ratio [OR], 3.73–6.67; p < 0.05). Polypharmacy was twice as likely in patients with mild to moderate hearing loss (OR 2.02 [1.24–3.29] and OR 2.13 [1.06–4.27], respectively; p < 0.05) and ~1.5× more likely in patients who had moderate to severe DHI scores (OR 1.65 [1.05–2.59] and OR 1.63 [1.00–2.65], respectively; p < 0.05). Patients with polypharmacy also had higher CFQ scores compared to those without polypharmacy (CFQ 32.5 [19.0–48.0] versus CFQ 25.0 [13.0–40.0]; p = 0.002. Oto-polypharmacy was more common for patients with lightheadedness as a dizziness descriptor (OR 3.16 [1.56–6.41]; p < 0.01). However, oto-polypharmacy was only more common for patients with mild to moderate hearing loss (OR 2.69 [1.33–5.45] and OR 2.86 [1.31–6.20], respectively; p < 0.01) and severe DHI scores (2.31 [1.12–4.77], p = 0.02).

Conclusions:

The prevalence of polypharmacy in patients with vestibular disorders is high. Some of the medications that patients are on are also potentially ototoxic at variable degrees. Polypharmacy is more common when lightheadedness is one of the dizziness descriptors and seems to be associated with worse scores on patient-reported outcome measures (DHI, CFQ). Medication reconciliation and multidisciplinary involvement could help to better address polypharmacy in this patient population. However, further investigation is needed to elucidate polypharmacy’s role in symptom presentation, vestibular testing results, and therapeutic strategies.
Association between thyroid hormone levels and frailty in the community-dwelling oldest-old: a cross-sectional study
Authors: Guan Bo , Luo Jiakun , Huang Xin , Tian Fan , Sun Shasha , Ma Yufei , Yu Yan , Liu Ruihan , Cao Jian , Fan Li
Published: November 2022

Background:

Changes in thyroid hormone levels are commonly recognized characters among the elderly, which were reported to potentially influence incident frailty. Therefore, we examined the cross-sectional associations of thyroid hormones (THs) with frailty as well as the five components characterizing frailty (fatigue, resistance, ambulation, number of illnesses, and loss of weight) among the oldest-old.

Methods:

Four hundred and eighty-seven community-dwelling oldest-old from a local community in Haidian District, Beijing, participated in our recruitment campaign between April 2019 and May 2020. The primary outcomes were a definitive diagnosis of frailty according to the FRAIL scale (Fatigue, Resistance, Ambulation, Illnesses, Loss of weight) and a positive score for each frailty subdomain. Demographic information (age, sex, marital status, and educational status), comorbidities, and details on the participants’ lifestyles were recorded. Serum THs including free triiodothyronin (fT3), triiodothyronine (T3), free thyroxine (fT4), and thyroxine (T4) and thyroid stimulating hormone (TSH) levels were also measured at the beginning of our study. Logistic regressions were conducted to screen for potential risk factors for frailty and its subdomains.

Results:

Among the total 487 subjects at enrollment, 60 (12.23%) of them were diagnosed with subclinical hypothyroidism and 110 (22.59%) of the total population scored positive for frailty. Logistic regression analyses adjusted for all potential confounders, showed that frailty was significantly associated with the serum TSH concentration (odds ratio [OR]: 1.06), fT3 concentration (OR: 0.54), and subclinical hypothyroidism score (OR: 2.18). The association between fT4 and frailty was absent in our observational study. The fT3/fT4 ratio characterizing peripheral hormone conversion was also tested to be correlated with frailty.

Conclusion:

Subclinical hypothyroidism, higher TSH level, lower fT3 level, and decreased fT3/fT4 ratio were all associated with frailty assessed by the FRAIL scale among the community-dwelling oldest-old, suggesting a relevant role of thyroid function in aging. Future longitudinal studies are warranted to determine the casual relationship between thyroid dysfunction and frailty in the oldest-old.
Efficacy and Safety of Obinutuzumab-chemotherapy Combinations in Front-line Treatment of Follicular Non-Hodgkin Lymphoma During the COVID-19 Pandemic: A Study of KROHEM, the Croatian Cooperative Group for Hematologic Diseases
Authors: Galusic Davor , Basic-Kinda Sandra , Pijuk Andela , Milunovic Vibor , Dreta Barbara , Franjic Neven , Coha Bozena , Sincic-Petricevic Jasminka , Gacina Petar , Pejsa Vlatko , Lucijanic Marko , Aurer Igor
Published: November 2022

Obinutuzumab (G) has become part of front-line treatment of follicular lymphoma (FL) based on results of a large randomized study. Data on patients treated outside of clinical trials are lacking. We have retrospectively investigated efficacy and safety of G-based immunochemotherapy regimens in 114 patients treated in a real-life setting during a period of 2 years, largely coinciding with the COVID-19 pandemic. The response rate was 93.8%; 18-months overall (OS) and progression-free survival (PFS) were 88% and 84%, respectively. Patients treated with G-cyclophosphamide, vincristine and glucocorticoid + doxorubicine (CHOP) had statistically significantly superior OS and PFS compared to patients treated with G-bendamustine (G-B) (P = 0.002 and P = 0.006, respectively) due to an increase in lethal infections, most notably COVID-19, in the latter group. A total of 12 patients died during follow-up; 9 of 61 treated with G-B, 1 of 49 treated with G-CHOP and 2 of 4 treated with G-cyclophosphamide, vincristine and glucocorticoid (CVP). SARS-CoV-2 infection was diagnosed in 20 (17.5%) patients. All of the 7 treated with G-CHOP recovered, while 4 of 12 treated with G-B died. Immunoglobulin levels and severity of neutropenia were similar between the groups. In multivariate analysis, G-B in comparison to G-CHOP was an independent prognostic factor (P = 0.044, hazard ratio = 9.81) after adjustment for age, sex and Follicular Lymphoma International Prognostic Index (FLIPI). Based on our experience G has excellent antilymphoma activity in patients receiving front-line treatment for FL in real-life setting, but during the COVID-19 pandemic, it should be preferentially combined with CHOP, at least in patients younger than 65.
Resident involvement in cataract surgery at the Veterans Health Administration: complications, case complexity, and the role of experience
Authors: Aggarwal Sahil , Wisely C. Ellis , Pepin Marc J. , Bryan William , Raghunathan Karthik , Challa Pratap
Published: November 2022

Purpose:

To characterize intraoperative complications, case complexity, and changes in complication rates with surgical experience for cataract surgeries involving residents at the Veterans Health Administration (VHA).

Setting:

All VHA facilities where cataract surgery was performed.

Design:

Multicenter, retrospective cohort study.

Methods:

A retrospective review of all cataract surgeries within the VHA between July 2010 and June 2021 was conducted. Several parameters, including resident involvement, intraoperative complications, and case complexity as determined by Current Procedural Terminology codes, and use of pupil expansion or capsular support devices, were collected. Complication rates were compared between residents and attendings.

Results:

Of 392 428 cataract surgeries completed across 108 VHA facilities, 90 504 were performed by attendings alone, while 301 924 involved a resident. Of these, 10 244 (11.3%) of attending cases were complex compared with 32 446 (10.7%) of resident cases. Pupil expansion devices were required in 8191 of attending cases (9.05%) and 31 659 (10.5%) of cases involving residents (P < .001). Similarly, cases involving residents were more likely than attending-only cases to require a capsular support device (0.835% vs 0.586%, P < .001). Cases involving residents were more likely to have posterior capsular rupture (4.75% vs 2.58%, P < .001) and dropped nucleus (0.338% vs 0.198%, P < .001). Higher resident case volumes were associated with significantly lower complication rates for posterior capsular rupture, dropped nucleus, zonular loss, and suprachoroidal hemorrhage.

Conclusions:

Although residents had higher intraoperative complication rates than attendings, these rates were reduced with surgical experience. Residents were involved in a similar number of complex surgical cases as attendings.
The contribution of endocytosis to sensitization of nociceptors and synaptic transmission in nociceptive circuits
Authors: Tonello Raquel , Anderson Wayne B. , Davidson Steve , Escriou Virginie , Yang Lei , Schmidt Brian L. , Imlach Wendy L. , Bunnett Nigel W.
Published: November 2022

Chronic pain involves sensitization of nociceptors and synaptic transmission of painful signals in nociceptive circuits in the dorsal horn of the spinal cord. We investigated the contribution of clathrin-dependent endocytosis to sensitization of nociceptors by G protein–coupled receptors (GPCRs) and to synaptic transmission in spinal nociceptive circuits. We determined whether therapeutic targeting of endocytosis could ameliorate pain. mRNA encoding dynamin (Dnm) 1 to 3 and adaptor-associated protein kinase 1 (AAK1), which mediate clathrin-dependent endocytosis, were localized to primary sensory neurons of dorsal root ganglia of mouse and human and to spinal neurons in the dorsal horn of the mouse spinal cord by RNAScope. When injected intrathecally to mice, Dnm and AAK1 siRNA or shRNA knocked down Dnm and AAK1 mRNA in dorsal root ganglia neurons, reversed mechanical and thermal allodynia and hyperalgesia, and normalized nonevoked behavior in preclinical models of inflammatory and neuropathic pain. Intrathecally administered inhibitors of clathrin, Dnm, and AAK1 also reversed allodynia and hyperalgesia. Disruption of clathrin, Dnm, and AAK1 did not affect normal motor functions of behaviors. Patch clamp recordings of dorsal horn neurons revealed that Dnm1 and AAK1 disruption inhibited synaptic transmission between primary sensory neurons and neurons in lamina I/II of the spinal cord dorsal horn by suppressing release of synaptic vesicles from presynaptic primary afferent neurons. Patch clamp recordings from dorsal root ganglion nociceptors indicated that Dnm siRNA prevented sustained GPCR-mediated sensitization of nociceptors. By disrupting synaptic transmission in the spinal cord and blunting sensitization of nociceptors, endocytosis inhibitors offer a therapeutic approach for pain treatment.
Antibody Drug Conjugates in Lung Cancer
Authors: Merle Geoffrey , Friedlaender Alex , Desai Aakash , Addeo Alfredo
Published: November 2022

An antibody-drug conjugate (ADC) comprises a monoclonal antibody that is specific to a tumor cell protein, bound to a cytotoxic agent, known as the payload. The use of ADCs is already common practice in several cancers, thanks to their efficacy and potentially more manageable toxicity profile, resulting from the release of the cytostatic payload directly in the tumors. Currently, early-phase trials of ADCs in non–small cell lung cancer are rapidly gaining ground, with promising results targeting HER2 (human epidermal growth factor 2), HER3, TROP2 (trophoblast cell surface antigen 2), MET, CEACAM5 (carcinoembryonic antigen–related cell adhesion molecule 5), and PTK7 (tyrosine protein kinase–like 7). Unfortunately, in small cell lung cancer, trials targeting the ubiquitous DLL3 (delta-like ligand 3) protein have failed to show clinically relevant results, despite significant toxicity.
TRAUMA INDUCES INTRAVASCULAR HEMOLYSIS, EXACERBATED BY RED BLOOD CELL TRANSFUSION AND ASSOCIATED WITH DISRUPTED ARGININE–NITRIC OXIDE METABOLISM
Authors: Schaid Terry R. , Cohen Mitchell J. , D’Alessandro Angelo , Silliman Christopher C. , Moore Ernest E. , Sauaia Angela , Dzieciatkowska Monika , Hallas William , Thielen Otto , DeBot Margot , Cralley Alexis , LaCroix Ian , Erickson Christopher , Mitra Sanchayita , Banerjee Anirban , Jones Kenneth , Hansen Kirk C.
Published: November 2022

Background: Severe injury can provoke systemic processes that lead to organ dysfunction, and hemolysis of both native and transfused red blood cells (RBCs) may contribute. Hemolysis can release erythrocyte proteins, such as hemoglobin and arginase-1, the latter with the potential to disrupt arginine metabolism and limit physiologic NO production. We aimed to quantify hemolysis and arginine metabolism in trauma patients and measure association with injury severity, transfusions, and outcomes. Methods: Blood was collected from injured patients at a level I trauma center enrolled in the COMBAT (Control of Major Bleeding After Trauma) trial. Proteomics and metabolomics were performed on plasma fractions through liquid chromatography coupled with mass spectrometry. Abundances of erythrocyte proteins comprising a hemolytic profile as well as haptoglobin, l-arginine, ornithine, and l-citrulline (NO surrogate marker) were analyzed at different timepoints and correlated with transfusions and adverse outcomes. Results: More critically injured patients, nonsurvivors, and those with longer ventilator requirement had higher levels of hemolysis markers with reduced l-arginine and l-citrulline. In logistic regression, elevated hemolysis markers, reduced l-arginine, and reduced l-citrulline were significantly associated with these adverse outcomes. An increased number of blood transfusions were significantly associated with elevated hemolysis markers and reduced l-arginine and l-citrulline independently of New Injury Severity Score and arterial base excess. Conclusions: Severe injury induces intravascular hemolysis, which may mediate postinjury organ dysfunction. In addition to native RBCs, transfused RBCs can lyse and may exacerbate trauma-induced hemolysis. Arginase-1 released from RBCs may contribute to the depletion of l-arginine and the subsequent reduction in the NO necessary to maintain organ perfusion.
Customized genomes for human and mouse ribosomal DNA mapping
Authors: George Subin S. , Pimkin Maxim , Paralkar Vikram R.
Published: November 2022

Ribosomal RNAs (rRNAs) are transcribed from rDNA repeats, the most intensively transcribed loci in the genome. Due to their repetitive nature, there is a lack of genome assemblies suitable for rDNA mapping, creating a vacuum in our understanding of how the most abundant RNA in the cell is regulated. Our recent work1revealed binding of numerous mammalian transcription and chromatin factors to rDNA. Several of these factors were known to play critical roles in development, tissue function, and malignancy, but their potential rDNA roles had remained unexplored. Our work demonstrated the blind spot into which rDNA has fallen in genetic and epigenetic studies, and highlighted an unmet need for public rDNA-optimized genome assemblies.

We customized five commonly used human and mouse assemblies - hg19 (GRCh37), hg38 (GRCh38), hs1 (T2T-CHM13), mm10 (GRCm38), mm39 (GRCm39) - to render them suitable for rDNA mapping. The standard builds of these genomes contain numerous fragmented or repetitive rDNA loci. We identified and masked all rDNA-like regions, added a single rDNA reference sequence of the appropriate species as a ∼45kb chromosome R, and created annotation files to aid visualization of rDNA features in browser tracks. We validated these customized genomes for mapping of known rDNA binding proteins, and present in this paper a simple workflow for mapping ChIP-seq datasets. These resources make rDNA mapping and visualization readily accessible to a broad audience.

Customized genome assemblies, annotation files, positive and negative control tracks, and Snapgene files of standard rDNA reference sequence are deposited to GitHub.
Comparison of machine learning to deep learning for automated annotation of Gleason patterns in whole mount prostate cancer histology
Authors: Duenweg Savannah R. , Brehler Michael , Bobholz Samuel A. , Lowman Allison K. , Winiarz Aleksandra , Kyereme Fitzgerald , Nencka Andrew , Iczkowski Kenneth A. , LaViolette Peter S.
Published: November 2022

Background

One in eight men will be affected by prostate cancer (PCa) in their lives. While the current clinical standard prognostic marker for PCa is the Gleason score, it is subject to interreviewer variability. This study compares two machine learning methods for discriminating between high- and low-grade PCa on histology from 47 PCa patients.

Methods

Digitized slides were annotated by a GU fellowship-trained pathologist. High-resolution tiles were extracted from annotated and unlabeled tissue. Glands were segmented and pathomic features were calculated and averaged across each patient. Patients were separated into a training set of 31 patients (Cohort A, n=9345 tiles) and a testing cohort of 16 patients (Cohort B, n=4375 tiles). Tiles from Cohort A were used to train a compact classification ensemble model and a ResNet model to discriminate tumor and were compared to pathologist annotations.

Results

The ensemble and ResNet models had overall accuracies of 89% and 88%, respectively. The ResNet model was additionally able to differentiate Gleason patterns on data from Cohort B while the ensemble model was not.

Conclusions

Our results suggest that quantitative pathomic features calculated from PCa histology can distinguish regions of cancer; how-ever, texture features captured by deep learning frameworks better differentiate unique Gleason patterns.
Turnover number predictions for kinetically uncharacterized enzymes using machine and deep learning
Authors: Kroll Alexander , Hu Xiao-Pan , Liebrand Nina A. , Lercher Martin J.
Published: November 2022

The turnover numberkcat, a measure of enzyme efficiency, is central to understanding cellular physiology and resource allocation. As experimentalkcatestimates are unavailable for the vast majority of enzymatic reactions, the development of accurate computational prediction methods is highly desirable. However, existing machine learning models are limited to a single, well-studied organism, or they provide inaccurate predictions except for enzymes that are highly similar to proteins in the training set. Here, we present TurNuP, a general and organism-independent model that successfully predicts turnover numbers for natural reactions of wild-type enzymes. We constructed model inputs by representing complete chemical reactions through difference fingerprints and by representing enzymes through a modified and re-trained Transformer Network model for protein sequences. TurNuP outperforms previous models and generalizes well even to enzymes that are not similar to proteins in the training set. Parameterizing metabolic models with TurNuP-predictedkcat values leads to improved proteome allocation predictions. To provide a powerful and convenient tool for the study of molecular biochemistry and physiology, we implemented a TurNuP web server athttps://turnup.cs.hhu.de.
Interpreting phytoliths assemblages at chimpanzee (Pan troglodytes verus) nut-cracking sites in Bossou Forest, Guinea
Authors: Phillips C , Almeida-Warren K , Bamford MK
Published: November 2022

The nut-cracking behaviour of the chimpanzees of Bossou Forest has been long documented and studied in order to understand ultimate drivers for this form of durophagy by these apes. At sites in which they break open the nuts of the oil palm (Elaeis guineaeensis) on stone anvils with stone hammers, fragments of the tools as well as remnants of the nuts may be deposited into local sediments; however, they may become less visible at the macroscopic level as these sites are no longer used (become dormant). We build upon work that has been done to document this unique cultural heritage in West African chimpanzees by interpreting phytolith assemblages in sediments at active nut-cracking sites (used within the last two months). We compare these assemblages with those found in sediments of sites that have been dormant for ~10 years and sites where chimpanzees have not been observed to access and crack open oil palm nuts with stone tools. We predicted that larger assemblages of spheroid echinates, a phytolith associated with palms, would be found at active nut-cracking sites, however we found no statistical difference between total spheroid echinates (measured as total number found per gram of dry sediment) assemblages produced across active nut-cracking, dormant, or non-nut-cracking sites. This may have been due to small sample size (N≤6 sediment samples for each of the three sites) and so further sample collection and analyses are needed for inter-site comparisons. We also measured 2D area (μm2), perimeter and maximum diameter of spheroid echinates found in nut endocarps (shells) and leaflets from an oil palm frond. Intra-specific differences from all three measurements were found with these phytoliths being larger in the nut endocarp than the leaflet. This has implications for (re)interpreting the assemblages of spheroid echinate phytoliths at the three sites to determine if there is a greater productivity larger-sized spheroid echinates that fall within the size range of those measured for the nut endocarp (mean maximum diameter of 14.9 μmversus7.8 μm for those found in oil palm leaflet). Finally, we argue for the importance of initialising and continuing the interpretation of phytolith assemblages in local sediments that are located near sites where directed plant input by non-human taxa has occurred, in this case, chimpanzees cracking open oil palm nuts using stone tools. This is important to refine our interpretation of phytolith assemblages where human and non-human taxa who use complex foraging strategies share ecological spaces.
FINDEL: A Deep Learning Approach to Efficient Artifact Removal From Cancer Genomes
Authors: Tan Denis , Zhou Pengfei , Zhang Shaoting , Wong VicPearly , Zhang Jie , Long Edwin
Published: November 2022

Next-generation sequencing technologies have increased sequencing throughput by 100-1000 folds and subsequently reduced the cost of sequencing a human genome to approximately US$1,000. However, the existence of sequencing artifacts can cause erroneous identification of variants and adversely impact the downstream analyses. Currently, the manual inspection of variants for additional refinement is still necessary for high-quality variant calls. The inspection is usually done on large binary alignment map (BAM) files which consume a huge amount of labor and time. It also suffers from a lack of standardization and reproducibility. Here we show that the use of mutational signatures coupled with deep learning can replace the current standards in the bioinformatics workflow. This software, called FINDEL, can efficiently remove sequencing artifacts from cancer samples. It queries the variant call format file which is much more compact than BAM files. The software automates the variant refinement process and produces high-quality variant calls.
3D Bioprinting of Stem Cell-Derived Central Nervous System Cells Enables Astrocyte Growth, Vasculogenesis and Enhances Neural Differentiation/Function
Authors: Sullivan Michael A. , Lane Samuel D. , Volkerling Alexander , Engel Martin , Werry Eryn L. , Kassiou Michael
Published: November 2022

Current research tools for pre-clinical drug development such as rodent models and 2D immortalised monocultures have failed to serve as effective translational models for human CNS disorders. Recent advancements in the development of iPSCs and 3D culturing can improve thein vivo-relevanceof pre-clinical models, while generating 3D cultures though novel bioprinting technologies can offer increased scalability and replicability. As such, there is a need to develop platforms that combine iPSC-derived cells with 3D bioprinting to produce scalable, tunable and biomimetic cultures for preclinical drug discovery applications. We report a biocompatible PEG-based matrix which incorporates RGD and YIGSR peptide motifs and full length collagen IV at a stiffness similar to the human brain (1.5 kPa). Using a high-throughput commercial bioprinter we report the viable culture and morphological development of iPSC-derived astrocytes, brain microvascular endothelial cells, neural progenitors and neurons in our novel matrix. We also show that this system supports endothelial vasculogenesis and enhances neural differentiation and spontaneous activity. This platform forms a foundation for more complex, multicellular models to facilitate high-throughput translational drug discovery for CNS disorders.
Vitamin D and changes in cognitive performance in mid and later life: findings from the English Longitudinal Study of Ageing (ELSA)
Authors: Grajdean Sergiu , de Oliveira Cesar , Cadar Dorina
Published: November 2022

Background

Vitamin D has been found to be protective against biological processes associated with Alzheimer’s disease and cognition, including amyloid-β deposition, but the evidence in relation to cognitive decline is scarce.

Objective

This study aims to investigate the relationship between 25(OH)D serum levels and changes in cognitive performance over time in middle-aged and older English adults.

Research Design and Methods

An observational study design. We analyzed data collected biannually over a 6-year follow-up from a prospective cohort, the English Longitudinal Study of Ageing (ELSA). Mixed Linear Models analyses were conducted. The analytical sample consisted of 5,365 participants aged 50 and older without a diagnosis of dementia at baseline. Cognitive performance was ascertained with memory and orientation. Both tests were administered at every ELSA wave from Wave 6 (2012-2013) to Wave 9 (2018-2019). The values of blood levels of 25(OH)D and all covariates were considered at Wave 6 since this was the first time 25(OH)D was assessed. Blood levels of 25(OH)D were dichotomized in high versus low using the common threshold of 31nmol/l.

Results

A significant positive association was found between low serum levels of 25(OH)D and baseline memory scores (β= -0.28, SE=0.05, p≤0.001), but not with changes in memory over time. Furthermore, baseline blood levels of 25(OH)D were not associated with baseline orientation or changes in orientation over time.

Discussion

In this representative sample of the English population, we found that lower 25(OH)D serum levels were associated with a lower baseline memory but did not influence the change in cognitive functioning over time.

Implications

This study provides further clarification in understanding the deficient role of 25(OH)D on cognitive performance and the change in cognitive functioning over time.
Protection conferred by Delta and BA.1/BA.2 infection against BA.4/BA.5 infection and hospitalization: A Retrospective Cohort Study
Authors: Winchester Nicole E , Shrestha Nabin K. , Kim Priscilla , Tereshchenko Larisa G. , Rothberg Michael B
Published: November 2022

Background

SARS-CoV-2 immunity has declined with subsequent waves and accrual of viral mutations. In vitro studies raise concern for immune escape by BA.4/BA.5, and a study in Qatar showed moderate protection, but these findings have yet to be reproduced.

Methods

This retrospective cohort study included individuals tested for COVID-19 by PCR during Delta or BA.1/BA.2 and retested during BA.4/BA.5. The preventable fraction (PF) was calculated as ratio of the infection/hospitalization rate for initially positive patients divided by infection/hospitalization rate for initially negative patients, stratified by age, and adjusted for age, gender, comorbidities, and vaccination using logistic regression.

Results

20,987 patients met inclusion criteria. Prior Delta infection provided no protection against BA.4/BA.5 infection (Adjusted PF: 11.9% (95% confidence interval [CI], 0.8-21.8); p=0.036) and minimal protection against hospitalization (Adjusted PF: 10.7% (95%CI, 4.9-21.7); p=0.003). In adjusted models, prior BA.1/BA.2 infection provided 45.9% (95%CI, 36.2-54.1) (p <0.001) protection against BA.4/BA.5 reinfection and 18.8% (95% CI, 10.3-28.3) (p<0.0001) protection against hospitalization. Up-to-date vaccination provided modest protection against reinfection with BA.4/BA.5 and hospitalization.

Conclusions

Prior infection with BA.1/BA.2 and up-to-date vaccination provided modest protection against infection with BA.4/BA.5 and hospitalization, while prior Delta infection provided minimal protection against hospitalization, and no infection protection.
Volatile Organic Compounds for the Detection of Hepatocellular Carcinoma – a Systematic Review
Authors: Metwaly Sayed , Psica Alicja , Sogaolu Opeyemi , Ahmed Irfan , Mukhopadhya Ashis , Delibegović Mirela , Bekheit Mohamed
Published: November 2022

Background

Hepatocellular carcinoma (HCC) is an increasingly common and one of the leading causes of cancer mortality worldwide. Only a small percentage of HCC patients are eligible to curative treatment. There is a need for a point of care, early diagnostic or screening tool. It is not clear whether exhaled volatile organic compounds (VOCs) could fulfil those needs.

Hypothesis

We postulate that exhaled VOCs can identify potential biomarkers for non-invasive detection of HCC.

Aims

This systematic review aims to critically review the current knowledge regarding the exhaled VOCs linked to HCC detection.

Methods

A systematic electronic search was conducted. Search strategy included all studied published until the 24th of March 2021 using a combination of relevant keywords.

Results

The search yielded 6 publications using the PRISMA pathway. Two of the studies described in vitro experiments, and four clinical studies were conducted on small groups of patients. Overall, 42 headspace gases were analysed in the in vitro studies. Combined, the clinical studies included 164 HCC patients and 260 controls. The studies reported potential role for a combination of VOCs in the diagnosis of HCC. However, only limonene, acetaldehyde and ethanol could be traced back to their biological pathways using KEGG pathway enrichment analysis.

Conclusions

Although there appears to be promise in VOCs research associated with HCC, there is no single volatile biomarker in exhaled breath attributed to HCC and data from extracted studies indicates a lack of standardization. Large population studies are required to verify the existence of VOCs linked to HCC.
Costs and models used in the economic analysis of Total Knee Replacement (TKR): A Systematic Review
Authors: Gandhi Naline , Qadeer Amatullah Sana , Meher Ananda , Rachel Jennifer , Patra Abhilash , John Jebamalar , Anilkumar Aiswarya , Dutta Ambarish , Nanda Lipika , Rout Sarit Kumar
Published: November 2022

Objectives

The major objective of this review was to summarize the evidence on the core modelling specifications and procedures on the cost-effectiveness of TKR compared to non-surgical management. Another objective of this study was to synthesize evidence of TKR cost and compare it across countries using purchasing power parity (PPP).

Methodology

The electronic databases used were MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (CENTRAL), HTAIn repository and Cost effectiveness Analysis (CEA) registry. Consolidated Health Economic Evaluation Reporting Standards (CHEERS) was used to assess the validity of the methods and transparency in reporting the results of the included studies. The cost of TKR surgery from high income and low-or middle-income countries were extracted and converted to single USD ($) using purchasing power parities (PPP) method.

Result

29 studies were included in this review, out of which eight studies used Markov model, five studies used regression model, one study each reported Marginal structure model and discrete simulation model and decision tree analysis to assess cost-effectiveness of TKR. For PPP, 23 studies were included in the analysis of TKR cost. The average cost of TKR surgery was lowest in developing country like India ($3457) and highest in USA ($19,645).

Conclusion

The findings of this review showed that the Markov model was most widely used in the analysis of the cost effectiveness of TKR. Our review also concluded that the cost of TKR was higher in developed countries as compared to developing countries.
Dysfunction of the Visual Sensory Thalamus in Developmental Dyslexia
Authors: Müller-Axt Christa , Kauffmann Louise , Eichner Cornelius , von Kriegstein Katharina
Published: November 2022

Developmental dyslexia (DD) is a reading disorder with a prevalence of 5-10%. Neuroscientific research has typically focused on explaining DD symptoms based on pathophysiological changes in the cerebral cortex. However, DD might also be associated with alterations in sensory thalami – central subcortical stations of sensory pathways. A post-mortem study on the visual sensory thalamus (lateral geniculate nucleus, LGN) showed histopathological changes in the magnocellular (M-LGN), but not in the parvocellular (P-LGN), subdivisions. M-LGN and P-LGN have different functional properties and belong to two different visual systems. Whether M-LGN alterations also exist in DDin-vivois unclear. Also, the potential relevance of M-LGN alterations to DD symptoms is unknown. This lack of knowledge is partly due to considerable technical challenges in investigating LGN subdivisions non-invasively in humans. Here, we employed recent advances in high-field 7 Tesla functional magnetic resonance imaging (fMRI) to map the M- and P-LGNin-vivoin DD adults (n=26) and matched controls (n=28). We show that (i) M-LGN responses differ between DD and control participants, (ii) these differences are more pronounced in male than in female DD participants, and (iii) M-LGN alterations predict a core symptom of DD in male DD participants only, i.e., rapid naming ability. Our results provide a first functional interpretation of M-LGN changes in DD and support DD theories that propose a direct relevance of sensory thalamus alterations for DD symptoms. In addition, the sex-specific behavioral relevance of M-LGN alterations within DD calls for taking sex differences into account when planning brain-based therapeutic interventions.

Significance Statement

Developmental dyslexia (DD) is one of the most common learning disorders affecting millions of children and adults world-wide. Several decades ago, pioneering research in five DD post-mortem brains suggested that DD is characterized not only by alterations of the cerebral cortex, but also by changes in a subsection of the visual sensory thalamus – the so-called M-LGN. The relevance of these findings for DD remained highly controversial. Using recent developments in high-resolution functional neuroimaging, we now discovered that M-LGN alterations are present also in DDin-vivoand predict a core symptom of DD in males. Our results provide a first functional interpretation of M-LGN alterations in DD and provide a basis for better understanding sex-specific differences in DD.
Chromatin states at homeoprotein loci distinguish axolotl limb segments prior to regeneration
Authors: Kawaguchi Akane , Wang Jingkui , Knapp Dunja , Murawala Prayag , Nowoshilow Sergej , Masselink Wouter , Taniguchi-Sugiura Yuka , Fei Jifeng , Tanaka Elly M.
Published: November 2022

The salamander limb regenerates only the missing portion. Each limb segment can only form segments equivalent to- or more distal to their own identity, relying on a property termed “positional information”. How positional information is encoded in limb cells has been unknown. By cell-type-specific chromatin profiling of upper arm, lower arm, and hand, we found segment-specific levels of histone H3K27me3 at limb homeoprotein gene loci but not their upstream regulators, constituting an intrinsic segment information code. During regeneration, regeneration-specific regulatory elements became active prior to the re-appearance of developmental regulatory elements. This means that, in the hand segment, the permissive chromatin state of the hand homeoprotein geneHoxA13engages with regeneration regulatory elements, bypassing the upper limb program.
Transcription regulates bleb formation and stability independent of nuclear rigidity
Authors: Berg Isabel K. , Currey Marilena L. , Gupta Sarthak , Berrada Yasmin , Viet Bao Nyugen , Pho Mai , Patteson Alison E. , Schwarz J. M. , Banigan Edward J. , Stephens Andrew D.
Published: November 2022

Chromatin is an essential component of nuclear mechanical response and shape that maintains nuclear compartmentalization and function. The biophysical properties of chromatin alter nuclear shape and stability, but little is known about whether or how major genomic functions can impact the integrity of the nucleus. We hypothesized that transcription might affect cell nuclear shape and rupture through its effects on chromatin structure and dynamics. To test this idea, we inhibited transcription with the RNA polymerase II inhibitor alpha-amanitin in wild type cells and perturbed cells that present increased nuclear blebbing. Transcription inhibition suppresses nuclear blebbing for several cell types, nuclear perturbations, and transcription inhibitors. Furthermore, transcription is necessary for robust nuclear bleb formation, bleb stabilization, and bleb-based nuclear ruptures. These morphological effects appear to occur through a novel biophysical pathway, since transcription does not alter either chromatin histone modification state or nuclear rigidity, which typically control nuclear blebbing. We find that active/phosphorylated RNA pol II Ser5, marking transcription initiation, is enriched in nuclear blebs relative to DNA. Thus, transcription initiation is a hallmark of nuclear blebs. Polymer simulations suggest that motor activity within chromatin, such as that of RNA pol II, can generate active forces that deform the nuclear periphery, and that nuclear deformations depend on motor dynamics. Our data provide evidence that the genomic function of transcription impacts nuclear shape stability, and suggests a novel mechanism, separate and distinct from chromatin rigidity, for regulating large-scale nuclear shape and function.
Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines TargetingMycobacterium tuberculosis
Authors: Berida Tomayo , McKee Samuel R. , Chatterjee Shamba , Li Wei , Pandey Pankaj , Tripathi Siddharth Kaushal , Doerksen Robert J. , Jackson Mary , Ducho Christian , Stallings Christina L. , Roy Sudeshna
Published: November 2022

Tuberculosis (TB) results in 1.5 million deaths every year. The rise in multi-drug resistant TB underscores the urgent need to develop new antibacterials, particularly those with new chemical entities and/or novel mechanisms of action that can be used in combination therapy with existing drugs to prevent the rapid emergence of resistance. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition ofMycobacterium tuberculosis(Mtb) growth and survival. Structure-activity relationship studies led us to identify potent analogs displaying nanomolar inhibitor activity, specifically againstMtb. These potent analogs exhibit a promising ADME/pharmacokinetic profile and no cytotoxicity in mammalian cells at over 100 times the effective dose inMtb. Our preliminary investigations into the mechanism of action suggest this series is not engaging promiscuous targets and, thereby, could be acting on a novel target.

Abstract Figure
Ketone ester-enriched diet ameliorates motor and dopamine release deficits in MitoPark mice
Authors: Mahajan Vikrant R. , Nadel Jacob A. , King M. Todd , Pawlosky Robert J. , Davis Margaret I. , Veech Richard L. , Lovinger David M. , Salinas Armando G.
Published: November 2022

Background

Parkinson’s disease is a progressive, neurodegenerative disease characterized by motor dysfunction and dopamine deficits. The MitoPark mouse recapitulates several facets of Parkinson’s disease, including gradual development of motor deficits, which enables the study of potential therapeutic interventions. One therapeutic strategy involves decreasing the mitochondrial metabolic load by inducing ketosis and providing an alternative energy source for neurons, leading to decreased neuronal oxidative stress.

Objective

We assessed whether administration of a ketone ester-enriched diet would improve motor and dopamine release deficits in MitoPark mice.

Methods

Motor function (rotarod and open field tests), dopamine release (fast-scan cyclic voltammetry), tissue dopamine levels (GC-MS), and dopamine neurons and axons (immunofluorescence) were assessed in MitoPark and control mice fed either the standard or ketone ester-enriched diets.

Results

When started on the ketone diet before motor dysfunction onset, MitoPark mice had preserved motor function relative to standard diet MitoPark mice. While the ketone ester enriched diet did not preserve dopamine neurons or striatal dopamine axons, dopamine release in ketone diet MitoPark mice was greater than standard diet MitoPark mice but less than control mice. In a follow up experiment, we began the ketone diet after motor dysfunction onset and observed a modest preservation of motor function in ketone diet MitoPark mice relative to standard diet MitoPark mice.

Conclusion

The improvement in motor dysfunction indicates that a ketone ester enriched diet or ketone supplement may represent a promising adjunct treatment for Parkinson’s disease.
Tracking lexical and semantic prediction error underlying the N400 using artificial neural network models of sentence processing
Authors: Lopopolo Alessandro , Rabovsky Milena
Published: November 2022

Recent research has shown that the internal dynamics of an artificial neural network model of sentence comprehension displayed a similar pattern to the amplitude of the N400 in several conditions known to modulate this event-related potential. These results led Rabovsky, Hansen, and McClelland (2018) to suggest that the N400 might reflect change in an implicit predictive representation of meaning corresponding to semantic prediction error. This explanation stands as an alternative to the hypothesis that the N400 reflects lexical prediction error as estimated by word surprisal (Frank, Otten, Galli, & Vigliocco, 2015). In the present study, we directly model the amplitude of the N400 elicited during naturalistic sentence processing by using as predictor the update of the distributed representation of sentence meaning generated by a Sentence Gestalt model (McClelland, St. John, & Taraban, 1989) trained on a large-scale text corpus. This enables a quantitative prediction of N400 amplitudes based on a cognitively motivated model, as well as quantitative comparison of this model to alternative models of the N400. Specifically, we compare the update measure from the SG model to surprisal estimated by a comparable language model trained on next word prediction. Our results suggest that both Sentence Gestalt update and surprisal predict aspects of N400 amplitudes. Thus, we argue that N400 amplitudes might reflect two distinct but probably closely related sub-processes that contribute to the processing of a sentence.
Cortical reactivations predict future sensory responses
Authors: Nguyen Nghia D. , Lutas Andrew , Fernando Jesseba , Vergara Josselyn , McMahon Justin , Dimidschstein Jordane , Andermann Mark L.
Published: November 2022

Prevailing theories of offline memory consolidation posit that the pattern of neurons activated during a salient sensory experience will be faithfully reactivated, thereby stabilizing the entire pattern1-3. However, sensory-evoked patterns are not stable, but instead drift across repeated experiences4-7. To investigate potential roles of reactivations in the stabilization and/or drift of sensory representations, we imaged calcium activity of thousands of excitatory neurons in mouse lateral visual cortex. Presentation of a stimulus resulted in transient, stimulus-specific reactivations during the following minute. These reactivations depended on local circuit activity, as they were abolished by local silencing during the preceding stimulus. Contrary to prevailing theories, reactivations systemically differed from previous patterns evoked by the stimulus. Instead, they were more similar to future patterns evoked by the stimulus, therebypredictingrepresentational drift. In particular, neurons that participated more or less in early reactivations than in stimulus response patterns subsequently increased or decreased their future stimulus responses, respectively. The rate and content of these reactivations was sufficient to accurately predict future changes in stimulus responses and, surprisingly, the decreasing similarity of responses to distinct stimuli. Thus, activity patterns during sensory cortical reactivations may guide the drift in sensory responses to improve sensory discrimination8.