bluuebunny/crossref_metadata_2025 huggingface dataset:
Predictions for anisotropic X-ray signatures in the circumgalactic medium: imprints of supermassive black hole driven outflows
Authors: Truong Nhut , Pillepich Annalisa , Nelson Dylan , Werner Norbert , Hernquist Lars
Published: September 2021

The circumgalactic medium (CGM) encodes signatures of the galaxy-formation process, including the interaction of galactic outflows driven by stellar and supermassive black hole (SMBH) feedback with the gaseous halo. Moving beyond spherically symmetric radial profiles, we study the angular dependence of CGM properties around z = 0 massive galaxies in the IllustrisTNG simulations. We characterize the angular signal of density, temperature, and metallicity of the CGM as a function of galaxy stellar mass, halo mass, distance, and SMBH mass, via stacking. TNG predicts that the CGM is anisotropic in its thermodynamical properties and chemical content over a large mass range, $M_*\sim 10^{10-11.5}\, \mathrm{M}_\odot$. Along the minor axis directions, gas density is diluted, whereas temperature and metallicity are enhanced. These feedback-induced anisotropies in the CGM have a magnitude of 0.1−0.3 dex, extend out to the halo virial radius, and peak at Milky Way-like masses, $M_*\sim 10^{10.8}\, \mathrm{M}_\odot$. In TNG, this mass scale corresponds to the onset of efficient SMBH feedback and the production of strong outflows. By comparing the anisotropic signals predicted by TNG versus other simulations – Illustris and EAGLE – we find that each simulation produces distinct signatures and mass dependencies, implying that this phenomenon is sensitive to the underlying physical models. Finally, we explore X-ray emission as an observable of this CGM anisotropy, finding that future X-ray observations, including the eROSITA all-sky survey, will be able to detect and characterize this signal, particularly in terms of an angular modulation of the X-ray hardness.
Anti-Ku antibody-positive myositis presenting as a wide range of axial myopathies and myocarditis: A case report and review of the literature
Authors: Kono Masanori , Komai Toshihiko , Yuki Hayato , Hanata Norio , Kakumoto Toshiyuki , Kubota Akatsuki , Hashimoto Maeda Meiko , Toda Tatsushi , Shoda Hirofumi , Fujio Keishi
Published: September 2021

Idiopathic inflammatory myopathies (IIMs) are autoimmune diseases predominantly affecting proximal muscles; paraspinal muscle involvement is relatively rare. Because paraspinal myopathies do not always cause clinically evident symptoms, the diagnosis of IIMs with axial myopathies can be challenging. Anti-Ku autoantibodies, initially reported in polymyositis/systemic sclerosis overlap syndrome, are myositis-associated antibodies observed in patients with a wide variety of connective tissue diseases. Few reports have been published demonstrating predominant axial myopathy in IIM patients with anti-Ku antibodies. Herein, we investigated a previously healthy Japanese woman in her early 70s who presented with Raynaud’s phenomenon, back pain, and exertional dyspnoea. The creatine kinase was elevated and antinuclear antibody staining was positive, but myositis-specific antibodies were negative. Magnetic resonance imaging revealed myocarditis and a wide range of axial muscle inflammation, including bilateral thoracolumbar paraspinal, infraspinatus, and trapezius muscles. The muscle biopsy was consistent with IIM. In addition, anti-Ku antibody was positive. The administration of prednisolone and tacrolimus quickly alleviated the symptoms, and the creatine kinase level returned to normal. The diagnosis of IIM was arduous in this case because she did not present with camptocormia, muscle weakness involving the proximal limbs was not apparent, and myositis-specific antibodies were negative. Whether axial myopathy and myocarditis are more prevalent in IIM patients with than without anti-Ku antibodies is uncertain. Clinicians should suspect axial myopathy and myositis-associated antibodies, such as anti-Ku antibodies, especially in patients in whom muscle weakness of the proximal limbs is not noticeable.
CPLM 4.0: an updated database with rich annotations for protein lysine modifications
Authors: Zhang Weizhi , Tan Xiaodan , Lin Shaofeng , Gou Yujie , Han Cheng , Zhang Chi , Ning Wanshan , Wang Chenwei , Xue Yu
Published: September 2021

Here, we reported the compendium of protein lysine modifications (CPLM 4.0, http://cplm.biocuckoo.cn/), a data resource for various post-translational modifications (PTMs) specifically occurred at the side-chain amino group of lysine residues in proteins. From the literature and public databases, we collected 450 378 protein lysine modification (PLM) events, and combined them with the existing data of our previously developed protein lysine modification database (PLMD 3.0). In total, CPLM 4.0 contained 592 606 experimentally identified modification events on 463 156 unique lysine residues of 105 673 proteins for up to 29 types of PLMs across 219 species. Furthermore, we carefully annotated the data using the knowledge from 102 additional resources that covered 13 aspects, including variation and mutation, disease-associated information, protein-protein interaction, protein functional annotation, DNA & RNA element, protein structure, chemical-target relation, mRNA expression, protein expression/proteomics, subcellular localization, biological pathway annotation, functional domain annotation, and physicochemical property. Compared to PLMD 3.0 and other existing resources, CPLM 4.0 achieved a >2-fold increase in collection of PLM events, with a data volume of ∼45GB. We anticipate that CPLM 4.0 can serve as a more useful database for further study of PLMs.
Hepatoid adenocarcinoma of the stomach with PIK3Ca mutation during pregnancy: A case report with molecular profile
Authors: Ranceva Anastasija , Stulpinas Rokas , Norvilas Rimvydas , Mickys Ugnius
Published: September 2021

Hepatoid adenocarcinoma is an extremely aggressive special subtype of gastric tumors. It can be lethal as no standard treatment options for this type of gastric cancer exist. Here, we describe a very rare case of a young female on her 21st week of pregnancy who was diagnosed with stage IV hepatoid adenocarcinoma of the stomach with elevated α fetoprotein (AFP) level. Gene mutation analysis performed by next-generation sequencing identified somatic mutations in the PIK3CA gene. Despite the treatment, patient died 2 months after the initial disease presentation. To our best knowledge, this case represents the first report of pregnancy-associated hepatoid gastric adenocarcinoma with the PIK3CA gene mutations, which can provide further clues for the understanding of molecular features of this type of tumor that can reflect biological behavior and may lead to further effective treatment options.
‘Unique does not mean impossible: infant presenting with complicated course of ulceroglandular tularemia.’
Authors: Miącz Karolina , Śledź Jakub , Karwacki Marek W
Published: September 2021

Tularemia is a disease caused by Francisella tularensis—gram-negative coccobacillus. The ulceroglandular type characterized by skin ulcers and painful regional adenopathy is recognized as the most common.

A 1-year-old patient was admitted with severe normocytic anemia, high fever and hepatosplenomegaly. A nonspecific lesion in the axillary region with a homogenous nodal reaction was found, combined with a history of a tick-bite in the pectoral muscle. Primary differentiation included leukemia, lymphoma, mononucleosis, borrelial lymphoma and simple abscess. All of the above were excluded. A further search for diagnosis focused on tick-borne diseases: TIBOLa or anaplasmosis. The ulceroglandular tularemia was eventually confirmed serologically.

Besides the fact that tularemia is a rare diagnosis nowadays, it is still necessary to include this disease in the differentiation of a nonresolving tick-bite abscess with lymphadenopathy. Diagnostic vigilance is the key to effective treatment because other obvious symptoms such as severe anemia might delay the diagnosis.
$SU(5)_{L} \times U(1)_{Y}$
electroweak unification
Authors: Palcu Adrian
Published: September 2021

We propose here—for the first time in the literature, to our best knowledge—an electroweak unification based on the $SU(5)_{L}\times U(1)_{Y}$ gauge group. The spontaneous symmetry breaking takes place in the manner $SU(5)_{L}\times U(1)_{Y} \rightarrow U(1)_{em}$, due to a particular Higgs sector consisting of five scalar quintuplets. Each scalar quintuplet acquires its own vacuum expectation value, by means of a proper parametrization which is worked out once an overall vacuum expectation value in the model is established. The decoupling of the low-energy regime (corresponding to the Standard Model) from the high scale (required by our model here) is straightforwardly achieved in order to preserve the consistency with the present experimental data. Finally, a promising phenomenological outcome is derived by simply tuning a single free parameter. Our results also include, besides a viable one-parameter mass spectrum, the prediction of precisely three generations in the fermion sector and the electric charge quantization.
Heterogenous electrophysiological responses of functionally distinct striatal subregions to circadian and sleep-related homeostatic processes
Authors: Fifel Karim , Deboer Tom
Published: September 2021

Basal ganglia (BG) are a set of subcortical nuclei that are involved in the control of a wide variety of motor, cognitive, and affective behaviors. Although many behavioral abnormalities associated with BG dysfunction overlap with the clinical picture precipitated by the lack of sleep, the impact of sleep alterations on neuronal activity in BG is unknown. Using wild-type C57BI mice, we investigated the circadian and sleep-related homeostatic modulation of neuronal activity in the three functional subdivisions of the striatum (i.e. sensorimotor, associative, and limbic striatum). We found no circadian modulation of activity in both ventral and dorsomedial striatum while the dorsolateral striatum displayed a significant circadian rhythm with increased firing rates during the subjective dark, active phase. By combining neuronal activity recordings with electroencephalogram (EEG) recordings, we found a strong modulation of neuronal activity by the nature of vigilance states with increased activity during wakefulness and rapid eye movement sleep relative to nonrapid eye movement sleep in all striatal subregions. Depriving animals of sleep for 6 h induced significant, but heterogenous alterations in the neuronal activity across striatal subregions. Notably, these alterations lasted for up to 48 h in the sensorimotor striatum and persisted even after the normalization of cortical EEG power densities. Our results show that vigilance and sleep states as well as their disturbances significantly affect neuronal activity within the striatum. We propose that these changes in neuronal activity underlie both the well-established links between sleep alterations and several disorders involving BG dysfunction as well as the maladaptive changes in behavior induced in healthy participants following sleep loss.
Physiological responses of Douglas-fir to climate and forest disturbances as detected by cellulosic carbon and oxygen isotope ratios
Authors: Lee Edward Henry , Beedlow Peter A , Brooks J Renée , Tingey David T , Wickham Charlotte , Rugh William
Published: September 2021

Swiss needle cast (SNC), caused by a fungal pathogen, Nothophaeocryptopus gaeumannii, is a major forest disease of Douglas-fir (Pseudotsuga menziesii) stands of the Pacific Northwest (PNW). There is mounting concern that the current SNC epidemic occurring in Oregon and Washington will continue to increase in severity, frequency and spatial extent with future warming. Nothophaeocryptopus gaeumannii occurs wherever its host is found, but very little is known about the history and spatial distribution of SNC and its effects on growth and physiological processes of mature and old-growth forests within the Douglas-fir region of the PNW. Our findings show that stem growth and physiological responses of infected Douglas-fir to climate and SNC were different between sites, growth periods and disease severity based on cellulosic stable carbon and oxygen isotope ratios and ring width data in tree rings. At a coastal Oregon site within the SNC impact zone, variations in stem growth and Δ13C were primarily influenced by disproportional reductions in stomatal conductance (gs) and assimilation (A) caused by a loss of functioning stomates through early needle abscission and stomatal occlusion by pseudothecia of N. gaeumannii. At the less severely infected inland sites on the west slopes of Oregon’s Cascade Range, stem growth correlated negatively with δ18O and positively with Δ13C, indicating that gs decreased in response to high evaporative demand with a concomitant reduction in A. Current- and previous-years summer vapor pressure deficit was the principal seasonal climatic variable affecting radial stem growth and the dual stable isotope ratios at all sites. Our results indicate that rising temperatures since the mid-1970s has strongly affected Douglas-fir growth in the PNW directly by a physiological response to higher evaporative demand during the annual summer drought and indirectly by a major SNC epidemic that is expanding regionally to higher latitudes and higher elevations.
Genomic analysis of human noroviruses using combined Illumina–Nanopore data
Authors: Flint Annika , Reaume Spencer , Harlow Jennifer , Hoover Emily , Weedmark Kelly , Nasheri Neda
Published: September 2021

Whole-genome sequence analysis of noroviruses is routinely performed by employing a metagenomic approach. While this methodology has several advantages, such as allowing for the examination of co-infection, it has some limitations, such as the requirement of high viral load to achieve full-length or near full-length genomic sequences. In this study, we used a pre-amplification step to obtain full-length genomic amplicons from 39 Canadian GII isolates, followed by deep sequencing on Illumina and Oxford Nanopore platforms. This approach significantly reduced the required viral titre to obtain full-genome coverage. Herein, we compared the coverage and sequences obtained by both platforms and provided an in-depth genomic analysis of the obtained sequences, including the presence of single-nucleotide variants and recombination events.
Leveraging Telemedicine for Quality Improvement Video Review of Critical ICU Events: A Novel Multidisciplinary Form of Education
Authors: Gold Andrew K. , Huffenberger Ann , Lane-Fall Meghan , Pascual Lopez Jose L. , Rock Kristen C.
Published: September 2021

Objectives:

The objectives of this study were to codify the events triggering bedside recording and to report the types of performance issues identified that were then used to inform dedicated ICU quality improvement efforts.

Design:

This is a retrospective descriptive analysis of a video review program conducted at a single institution from July 2016 to November 2019.

Setting:

Surgical and Trauma ICU at a single urban academic quaternary care center.

Patients:

All patients admitted to the surgical and trauma ICU between July 2016 and November 2019 were eligible for the study as all ICU beds in our health system institutions are equipped with closed circuit video/audio monitoring. Through an institutional review board approved program, any event triggering the immediate bedside presence of a provider in the ICU is routinely recorded at the discretion of the care team or tele-intensivist.

Interventions:

A database of these events was created over a 3-year period, and cases were reviewed for content, quality improvement, and educational opportunities. Select recordings were analyzed and shared at multidisciplinary/multiprofessional video review sessions.

Measurements and Main Results:

There were 286 critical events video recorded and reviewed in the ICUs between July 2016 and November 2019. The most commonly recorded events included: cardiopulmonary arrests (n = 75), intubations (n = 71), and acute clinical decompensation triggered by nonreassuring vital signs (n = 57) or arrhythmias (n = 13). Of these recordings, 59 were shared at video review conferences, where quality of care was assessed and thematic opportunities for improvement were characterized. Recurrent quality improvement themes that were identified included adherence to protocols, the importance of teamwork and closed-loop communication, clearly designated team leadership, and the use of universal precautions.

Conclusions:

Video review in the ICU is feasible and presents valuable opportunities for quality improvement and educational discussions.
Facile preparation protocol of magnetic mesoporous carbon acid catalysts via soft-template self-assembly method and their applications in conversion of xylose into furfural
Authors: Toumsri P. , Auppahad W. , Saknaphawuth S. , Pongtawornsakun B. , Kaowphong S. , Dechtrirat D. , Panpranot J. , Chuenchom L.
Published: September 2021

Furfural is a valuable dehydration product of xylose. It has a broad spectrum of industrial applications. Various catalysts containing SO
3
H have been reported for the conversion of xylose into furfural. Nevertheless, the multi-step preparation is tedious, and the catalysts are usually fine powders that are difficult to separate from the suspension. Novel magnetic mesoporous carbonaceous materials (Fe/MC) were successfully prepared via facile self-assembly in a single step. A facile subsequent hydrothermal sulfonation of Fe/MC with concentrated H
2
SO
4
at 180°C gave mesoporous carbon bearing SO
3
H groups (SO
3
H@Fe/MC) without loss of the magnetic properties. Various techniques were employed to characterize the SO
3
H@Fe/MC as a candidate catalyst. It showed strong magnetism due to its Fe particles and possessed a 243 m
2
 g
−1
BET-specific surface area and a 90% mesopore volume. The sample contained 0.21 mmol g
−1
of SO
3
H and gave a high conversion and an acceptable furfural yield and selectivity (100%, 45% and 45%, respectively) when used at 170°C for 1 h with γ-valerolactone as solvent. The catalyst was easily separated after the catalytic tests by using a magnet, confirming sufficient magneticstability.

This article is part of the theme issue ‘Bio-derived and bioinspired sustainable advanced materials for emerging technologies (part 2)’.
A standardized system and App for continuous patient symptom logging in gastroduodenal disorders: design, implementation, and validation
Authors: Sebaratnam G , Karulkar N , Calder S , Woodhead JST , Keane C , Carson D , Varghese C , Du P , Waite S , Tack J , Andrews CN , Broadbent E , Gharibans A , O’Grady G
Published: September 2021

Background

Functional gastroduodenal disorders include functional dyspepsia, chronic nausea and vomiting syndromes, and gastroparesis. These disorders are common, but their overlapping symptomatology poses challenges to diagnosis, research, and therapy. This study aimed to introduce and validate a standardized patient symptom-logging system and App to aid in the accurate reporting of gastroduodenal symptoms for clinical and research applications.

Methods

The system was implemented in an iOS App including pictographic symptom illustrations, and two validation studies were conducted. To assess convergent and concurrent validity, a diverse cohort with chronic gastroduodenal symptoms undertook App-based symptom logging for 4-hours after a test meal. Individual and total post-prandial symptom scores were averaged and correlated against two previously validated instruments: PAGI-SYM (for convergent validity) and PAGI-QOL (for concurrent validity). To assess face and content validity, semi-structured qualitative interviews were conducted with patients.

Key Results

App-based symptom reporting demonstrated robust convergent validity with PAGI-SYM measures of nausea (rS=0.68), early satiation (rS=0.55), bloating (rS=0.48), heartburn (rS=0.47), upper gut pain (rS=0.40) and excessive fullness (rS=0.40); allp<0.001(n=79). The total App-reported Gastric Symptom Burden Score correlated positively with PAGI-SYM (rS=0.56; convergent validity;p<0.001), and negatively with PAGI-QOL (rS=-0.34; concurrent validity;p=0.002). Interviews demonstrated that the pictograms had adequate face and content validity.

Conclusions and Inferences

The continuous patient symptom-logging App demonstrated robust convergent, concurrent, face, and content validity when used within a 4-hour post-prandial test protocol. The App will enable standardized symptom reporting and is anticipated to provide utility in both research and clinical practice.
Reduced magnitude and durability of humoral immune responses by COVID-19 mRNA vaccines among older adults
Authors: Brockman Mark A. , Mwimanzi Francis , Lapointe Hope R. , Sang Yurou , Agafitei Olga , Cheung Peter , Ennis Siobhan , Ng Kurtis , Basra Simran , Lim Li Yi , Yaseen Fatima , Young Landon , Umviligihozo Gisele , Omondi F. Harrison , Kalikawe Rebecca , Burns Laura , Brumme Chanson J. , Leung Victor , Montaner Julio S.G. , Holmes Daniel , DeMarco Mari , Simons Janet , Pantophlet Ralph , Niikura Masahiro , Romney Marc G. , Brumme Zabrina L.
Published: September 2021

Background

mRNA vaccines reduce COVID-19 incidence and severity, but the durability of vaccine-induced immune responses, particularly among the elderly, remains incompletely characterized.

Methods

Anti-spike RBD antibody titers, ACE2 competition and virus neutralizing activities were longitudinally assessed in 151 healthcare workers and older adults (overall aged 24-98 years) up to three months after vaccination.

Results

Older adults exhibited lower antibody responses after one and two vaccine doses for all measures. In multivariable analyses correcting for sociodemographic, chronic health and vaccine-related variables, age remained independently associated with all response outcomes. The number of chronic health conditions was additionally associated with lower binding antibody responses after two doses, and male sex with lower ACE2 competition activity after one dose. Responses waned universally at three months after the second dose, but binding antibodies, ACE2 competition and neutralizing activities remained significantly lower with age. Older adults also displayed reduced ability to block ACE2 binding by the Delta variant.

Conclusions

The humoral immune response to COVID-19 mRNA vaccines is significantly weaker with age, and universally wanes over time. This will likely reduce antibody-mediated protection against SARS-CoV-2 and the Delta variant as the pandemic progresses. Older adults may benefit from additional immunizations as a priority.
The Histological Diagnosis of Breast Cancer by Employing scale invariant ResNet 18 With Spatial Supervised Technique
Authors: Khalid Bukhari Syed Usama , Syed Asmara , Khalid Syed Safwan , Hussain Shah Syed Sajid
Published: September 2021

Background

Breast cancer is one of the most prevalent cause of morbidity and mortality in women all over the world. Histopathological diagnosis is a vital component in the management of breast cancer. The application of artificial intelligence is yielding promising results for the better patient care.

Aim

The main aim of the present research project is to explore the potential of spatial supervised technique to develop scale invariant system for the histological diagnosis of breast cancer.

Materials and Methods

The anonymized images of hematoxylin and eosin stained section of the dataset, which has been acquired from the website. The slides were taken at different zoom (magnification) levels. Spatial supervised learning has been employed to make a scale invariant system. We used 400x and 40x to generate the results. For the 400x, we trained our network on a dataset of 200x,100x, and 40x images. The datasets were split into training and validation sets. The training set contained 80% digital slides of the respected dataset, and the validation set contained 20% digital slides of the respected dataset. The final result was generated by splitting the dataset of 400x into the training and test dataset. The training set contained 50% digital slides, and the test set also contained 50% digital slides. This unusual split is done to show how good spatial supervised learning works. Similarly, for 40x, we trained our networks on a dataset of 400x,200x, and 100x. The same steps were followed to obtain the 40x results.

Results

The result analysis revealed that the ResNet 18 with spatial supervised learning on dataset of 40x yielded the F-1 score of 1.0, while ResNet 18 with supervised learning only, on dataset of 40x yielded F-1 score of 0.9823. ResNet 18 with spatial supervised learning on dataset of 400x revealed F-1 score of 0.9957, and ResNet 18 with supervised learning only, on dataset of 400x showed the F-1 score of 0.9591. For supervised learning dataset is spited into training (80%) and testing (20% of dataset).

Conclusion

The analysis of digitized pathology images with the application of convolutional neural network Resnet -18 architecture with spatial supervised learning revealed excellent results, which is demonstrated by a very high F-1 score of 1.0.

The development of scale invariant system with application of spatial supervised technique solved the problem of images with variable magnifications. The finding would further pave the pathway for application of deep learning for the histological diagnosis of pathological lesions.
Comprehensive Evaluation of COVID-19 Patient Short- and Long-term Outcomes: Disparities in Healthcare Utilization and Post-Hospitalization Outcomes
Authors: Salerno Stephen , Sun Yuming , Morris Emily , He Xinwei , Li Yajing , Pan Ziyang , Han Peisong , Kang Jian , Sjoding Michael W. , Li Yi
Published: September 2021

Background

Understanding risk factors for short- and long-term COVID-19 outcomes have implications for current guidelines and practice. We study whether early identified risk factors for COVID-19 persist one year later and through varying disease progression trajectories.

Methods

This was a retrospective study of 6,731 COVID-19 patients presenting to Michigan Medicine between March 10, 2020 and March 10, 2021. We describe disease progression trajectories from diagnosis to potential hospital admission, discharge, readmission, or death. Outcomes pertained to all patients: rate of medical encounters, hospitalization-free survival, and overall survival, and hospitalized patients: discharge versus in-hospital death and readmission. Risk factors included patient age, sex, race, body mass index, and 29 comorbidity conditions.

Results

Younger, non-Black patients utilized healthcare resources at higher rates, while older, male, and Black patients had higher rates of hospitalization and mortality. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss anemia were risk factors for these outcomes. Diabetes with complications, coagulopathy, fluid and electrolyte disorders, and blood loss were associated with lower discharge and higher inpatient mortality rates.

Conclusions

This study found differences in healthcare utilization and adverse COVID-19 outcomes, as well as differing risk factors for short- and long-term outcomes throughout disease progression. These findings may inform providers in emergency departments or critical care settings of treatment priorities, empower healthcare stakeholders with effective disease management strategies, and aid health policy makers in optimizing allocations of medical resources.
Elevated plasma levels of CXCL16 in severe COVID-19 patients
Authors: Smieszek Sandra P. , Polymeropoulos Vasilios M. , Polymeropoulos Christos M. , Przychodzen Bartlomiej P. , Birznieks Gunther , Polymeropoulos Mihael H.
Published: September 2021

Genome-wide association studies have recently identified 3p21.31, with lead variant pointing to the CXCR6 gene, as the strongest thus far reported susceptibility risk locus for severe manifestation of COVID-19. In order the determine its role, we measured plasma levels of Chemokine (C□X□C motif) ligand 16 (CXCL16) in the plasma of COVID-19 hospitalized patients. CXCL16 interacts with CXCR6 promoting chemotaxis or cell adhesion. The CXCR6/CXCL16 axis mediates homing of T cells to the lungs in disease and hyper-expression is associated with localised cellular injury. To characterize the CXCR6/CXCL16 axis in the pathogenesis of severe COVID-19, plasma concentrations of CXCL16 collected at baseline from 115 hospitalized COVID-19 patients participating in ODYSSEY COVID-19 clinical trial were assessed together with a set of controls. We report elevated levels of CXCL16 in a cohort of COVID-19 hospitalized patients. Specifically, we report significant elevation of CXCL16 plasma levels in association with severity of COVID-19 (as defined by WHO scale) (P-value<0.02). Our current study is the largest thus far study reporting CXCL16 levels in COVID-19 hospitalized patients (with whole-genome sequencing data available). The results further support the significant role of the CXCR6/CXCL16 axis in the immunopathogenesis of severe COVID-19 and warrants further studies to understand which patients would benefit most from targeted treatments.
“Association between COVID-19 vaccination, infection, and risk of Guillain-Barre syndrome, Bell’s palsy, encephalomyelitis and transverse myelitis: a population-based cohort and self-controlled case series analysis”
Authors: Li Xintong , Martinez-Hernandez Eugenia , Roel Herranz Elena , Delmestri Antonella , Duarte-Salles Talita , Strauss Victoria , Burn Edward , Prieto-Alhambra Daniel
Published: September 2021

OBJECTIVE

We aimed to study the association between COVID-19 vaccines, SARS-CoV-2 infection, and the risk of immune-mediated neurological events.

METHODS

Design

Population-based historical rate comparison study and self-controlled case series (SCCS) analysis.

Setting

Primary care records from the United Kingdom.

Participants

Individuals who received the first dose of ChAdOx1 or BNT162b2 between 8 December 2020 and 6 March 2021. A cohort with a first positive RT-PCR test for SARS-CoV-2 between 1 September 2020 and 28 February 2021 was used for comparison.

Main outcome measures

Outcomes included Guillain-Barre syndrome (GBS), Bell’s palsy, encephalomyelitis, and transverse myelitis.

Incidence rates were estimated in the 28 days post first-dose vaccine, 90 days post-COVID-19, and between 2017 to 2019 for the general population cohort for background rates. Indirectly standardised incidence ratios (SIRs) were estimated. Adjusted incidence rate ratios (IRR) were estimated from the SCCS when sufficient statistical power was reached.

Results

We included 1,868,767 ChAdOx1 and 1,661,139 BNT162b2 vaccinees; 299,311 people infected with COVID-19; and 2,290,537 from the general population. SIRs for GBS were 1.91 [95% CI: 0.86 to 4.26] after ChAdOx1, 1.29 [0.49 to 3.45] after BNT162b2, and 5.20 [1.95 to 13.85] after COVID-19. In the same cohorts, SIRs for Bell’s palsy were 1.34 [1.05 to 1.72], 1.15 [0.88 to 1.50], and 1.23 [0.80 to 1.89], and for encephalomyelitis 1.62 [0.61 to 4.31], 0.86 [0.22 to 3.46], and 11.05 [5.27 to 23.17], respectively. Transverse myelitis was too rare to analyse (n<5 in all cohorts). SCCS analysis was only conducted for Bell’s palsy due to limited statistical power. We found no association between either vaccine and Bell’s palsy, with an IRR of 1.10 [0.81 to 1.46] and 1.15 [0.87 to 1.49] for BNT162b2 and ChAdOx1, respectively.

Conclusions

We found no consistent association between either vaccine and any of the studied neuroimmune adverse events studied. Conversely, we found a 5-fold increase in risk of GBS and an 11-fold of encephalomyelitis following COVID-19.
Intact corticostriatal and altered subcortical circuits in chronic pain
Authors: Park Su Hyoun , Baker Anne K. , Krishna Vinit , Martucci Katherine T.
Published: September 2021

Previous research has demonstrated the importance of the corticostriatal circuit in chronic pain. By focusing on nucleus accumbens (NAcc) circuits related to reward, we aimed to clarify how altered brain reward systems contribute to chronic pain. Using resting-state functional magnetic resonance imaging, we compared NAcc-medial prefrontal cortex (MPFC) functional connectivity in patients with fibromyalgia vs. healthy controls. Among patients, we analyzed the extent to which functional connectivity correlated with clinical measures. We also examined NAcc functional connectivity to subcortical regions. Lastly, we compared our results to a separate dataset of patients with chronic back pain. We identified robust NAcc-MPFC functional connectivity among patients with fibromyalgia and healthy controls, with no significant group differences. We found a positive correlational trend between NAcc-MPFC functional connectivity and total mood disturbance. Notably, patients with fibromyalgia showed significantly reduced functional connectivity of the right NAcc with mesolimbic circuit regions compared to controls. These results were largely similar to the results from the separate dataset. Our results provide novel evidence of intact corticostriatal but altered subcortical functional connectivity of the NAcc during resting-state in chronic pain and suggest that measured connectivity may relate to changes in mood and the level of cognitive demand during fMRI-based measurement.

Perspective

This article indicates complex brain valuation system alterations associated with chronic pain. Our findings expand our understanding of the valuation system and its relationship to clinical presentation in patients with fibromyalgia.
Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: shared and unique genetic architectures in a cross-ancestry sample
Authors: Kember Rachel L. , Vickers-Smith Rachel , Zhou Hang , Xu Heng , Dao Cecilia , Justice Amy C. , Gelernter Joel , Vujkovic Marijana , Kranzler Henry R.
Published: September 2021

Recent GWAS of alcohol-related traits have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications. We utilized longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption [measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)] and 2) genetic variants with direct effects on AUD not mediated through alcohol consumption. We identified 26 loci associated with AUD, including 5 ancestry-specific and 6 novel loci and 22 loci associated with AUDIT-C, including 3 ancestry-specific and 8 novel loci. In secondary GWAS that excluded individuals who report abstinence, we identify 7 additional loci for AUD and 8 additional loci for AUDIT-C. We demonstrate that, although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remains after the group is excluded. Finally, using mediation analysis, we identified a set of variants with effects on AUD that are not mediated through alcohol consumption. The distinct genetic architectures of alcohol consumption and AUD suggest different biological contributions to the traits. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and targets for translational prevention and treatment efforts.
Determinants of hospital outcomes for COVID-19 infections in a large Pennsylvania Health System
Authors: Shaw Pamela A. , Yang Jasper B. , Mowery Danielle L. , Schriver Emily R. , Mahoney Kevin B. , Bar Katharine J. , Ellenberg Susan S.
Published: September 2021

There is growing evidence that racial and ethnic minorities bear a disproportionate burden from COVID-19. Temporal changes in the pandemic epidemiology and diversity in the clinical course require careful study to identify determinants of poor outcomes.

We analyzed 6255 individuals admitted with PCR-confirmed COVID-19 to one of 5 hospitals in the University of Pennsylvania Health System between March 2020 and March 2021, using electronic health records to assess risk factors and outcomes through 8 weeks post-admission. Discharge, readmission and mortality outcomes were analyzed in a multi-state model with multivariable Cox models for each transition.

Mortality varied markedly over time, with cumulative incidence (95% CI) 30 days post-admission of 19.1% (16.9, 21.3) in March-April 2020, 5.7% (4.2, 7.5) in July-October 2020 and 10.5% (9.1,12.0) in January-March 2021; 26% of deaths occurred after discharge. Average age (SD) at admission varied from 62.7 (17.6) to 54.8 (19.9) to 60.5 (18.1); mechanical ventilation use declined from 21.3% to 9-11%.

Compared to Caucasian, Black race was associated with more severe disease at admission, higher rates of co-morbidities and low-income resident zip code. Between-race risk differences in mortality risk diminished in multivariable models; while admitting hospital, increasing age, admission early in the pandemic, and severe disease and low blood pressure at admission were associated with increased mortality hazard. Hispanic ethnicity was associated with fewer baseline co-morbidities and lower mortality hazard (0.57, 95% CI: 0.37, .087).

Multi-state modeling allows for a unified framework to analyze multiple outcomes throughout the disease course. Morbidity and mortality for hospitalized COVID-19 patients varied over time but post-discharge mortality remained non-trivial. Black race was associated with more risk factors for morbidity and with treatment at hospitals with lower mortality. Multivariable models suggest there are not between-race differences in outcomes. Future work is needed to better understand the identified between-hospital differences in mortality.
Indirect effects of peaks in COVID admissions on access to surgery in the English NHS, differential effects by operation type, ethnicity and socio-economic status: a database study
Authors: Remsing Sandra C , Evison Felicity , Vohra Ravinder S , Morton Dion , Chilton Peter , Khunti Kamlesh , Lilford Richard J
Published: September 2021

Objectives

During the COVID pandemic the UK saw two peaks in the prevalence of hospital admissions resulting in disruption of routine hospital services in the English National Health Service. This study aimed to track the effect of these peaks on various types of surgery representing differences in urgency, importance, and complexity.

Design

Database study using the Hospital Episode Statistics database and surgical operations selected purposively, to represent different combinations of urgency, importance and complexity.

Setting

All hospitals within England that carried out procedures funded by the National Health Service.

Main Outcome Measures

Number of emergency routine surgeries; cancer-removal surgeries; transplant surgeries; renal transplants Deceased and living donors); and elective routine surgeries carried out prior to and during the COVID pandemic.

Results

While all surgeries declined, emergency or urgent operations held up better than elective cases. There was rapid rebound between peaks. Among emergency cases, coronary angioplasty for acute myocardial infarction held up well in contrast to appendectomy, where indications for surgery are more elastic. Among urgent cancer and transplant operations, those with the most complex pathways were the most severely affected. The pandemic affected socio-economic and ethnic groups similarly. Disruption during the second peak was slightly less than during the first peak despite even greater COVID admission rates.

Conclusion

The NHS titrated its response appropriately to the pandemic by prioritising emergency and urgent cases over elective cases. However, complex time critical conditions like organ transplants and certain cancers are also disrupted with implications for third peaks in hospital admissions that many countries are experiencing.
The Arabidopsis SAC9 Enzyme is enriched in a cortical population of early endosomes and restricts PI(4,5)P2 at the Plasma Membrane
Authors: Lebecq Alexis , Doumane Mehdi , Fangain Aurélie , Bayle Vincent , Leong Jia Xuan , Rozier Frédérique , Marquès-Bueno Maria del Mar , Armengot Laia , Boisseau Romain P. , Simon Mathilde Laetitia Audrey , Franz-Wachtel Mirita , Macek Boris , Üstün Suayb , Jaillais Yvon , Caillaud Marie-Cécile
Published: September 2021

Membrane lipids, and especially phosphoinositides, are differentially enriched within the eukaryotic endomembrane system. This generates a landmark code by modulating the properties of each membrane. Phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] specifically accumulates at the plasma membrane in yeast, animal and plant cells, where it regulates a wide range of cellular processes including endocytic trafficking. However, the functional consequences of mispatterning PI(4,5)P2 in plants are unknown. Here, we functionally characterized the putative phosphoinositide phosphatase SUPPRESSOR OF ACTIN9 (SAC9) in Arabidopsis thaliana (Arabidopsis). We found that SAC9 depletion led to the ectopic localization of PI(4,5)P2 on cortical intracellular compartments, which depends on PI4P and PI(4,5)P2 production at the plasma membrane. SAC9 localizes to a subpopulation of trans-Golgi Network/early endosomes that are enriched in a region close to the cell cortex and that are coated with clathrin. Furthermore, it interacts and colocalizes with Src Homology 3 Domain Protein 2 (SH3P2), a protein involved in endocytic trafficking. In the absence of SAC9, SH3P2 localization is altered and the clathrin-mediated endocytosis rate is reduced. Together, our results highlight the importance of restricting PI(4,5)P2 at the plasma membrane and illustrate that one of the consequence of PI(4,5)P2 misspatterning in plants is to impact the endocytic trafficking.

One-sentence summary

SAC9 prevents the accumulation of PI(4,5)P2 in intracellular compartments, thereby contributing to clathrin-mediated endocytosis at the plasma membrane and regulating the cortical localization of its protein partner SH3P2.
A Drosophila Circuit for Habituation Override
Authors: Trisal Swati , Aranha Marcia , Chodankar Ankita , VijayRaghavan K. , Ramaswami Mani
Published: September 2021

Habituated animals retain a latent capacity for robust engagement with familiar stimuli. In most instances, the ability to override habituation is best explained by postulating that habituation arises from the potentiation of inhibitory inputs onto stimulus-encoding assemblies and that habituation override occurs through disinhibition. Previous work has shown that inhibitory plasticity contributes to specific forms of olfactory and gustatory habituation in Drosophila. Here we analyze how exposure to a novel stimulus causes override of gustatory (proboscis-extension reflex or “PER”) habituation. While brief sucrose contact with tarsal hairs causes naïve Drosophila to extend their proboscis, persistent exposure reduces PER to subsequent sucrose stimuli. We show that in so habituated animals, either brief exposure of the proboscis to yeast or direct thermogenetic activation of sensory neurons restores PER response to tarsal sucrose stimulation. Similar override of PER habituation can also be induced by brief thermogenetic activation of a population of TH (Tyrosine-Hydroxylase) positive neurons, a subset of which send projections to the subesophagial zone (SEZ). Significantly, sensory-neuron induced habituation override requires transmitter release from these TH-positive cells. Treatments that cause override specifically influence the habituated state, with no effect on the naïve sucrose response across a range of concentrations. Taken together with other findings, these observations in female flies are consistent with a model in which novel taste stimuli trigger activity in dopaminergic neurons which, directly or indirectly, inhibit GABAergic cells that drive PER habituation. The implications of these findings for general mechanisms of attentional and sensory override of habituation are discussed.
mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes
Authors: Leng Kun , Rooney Brendan , McCarthy Frank , Xia Wenlong , Rose Indigo V.L. , Bax Sophie , Chin Marcus , Fathi Saeed , Herrington Kari A. , Leonetti Manuel , Kao Aimee , Fancy Stephen P.J. , Elias Joshua E. , Kampmann Martin
Published: September 2021

Astrocytes respond and contribute to neuroinflammation by adopting inflammatory reactive states. Although recent efforts have characterized the gene expression signatures associated with these reactive states, the cell biology underlying inflammatory reactive astrocyte phenotypes remains under-explored. Here, we used CRISPR-based screening in human iPSC-derived astrocytes to identify mTOR activation a driver of cytokine-induced endolysosomal system remodeling, manifesting as alkalinization of endolysosomal compartments, decreased autophagic flux, and increased exocytosis of certain endolysosomal cargos. Through endolysosomal proteomics, we identified and focused on one such cargo – IL-32, a disease-associated pro-inflammatory cytokine not present in rodents, whose secretion mechanism is not well understood. We found that IL-32 was partially secreted in extracellular vesicles likely to be exosomes. Furthermore, we found that IL-32 was involved in the polarization of inflammatory reactive astrocyte states, was upregulated in astrocytes in multiple sclerosis lesions, and preferentially co-localized with astrocytes in hypoxic-ischemic encephalopathy. We believe that our results advance our understanding of cell biological pathways underlying inflammatory reactive astrocyte phenotypes and identify potential therapeutic targets.
Hedgehog signaling can enhance glycolytic ATP production in the Drosophila wing disc
Authors: Nellas Ioannis , Iyer K. Venkatesan , Iglesias-Artola Juan M. , Nadler André , Dye Natalie A. , Eaton Suzanne
Published: September 2021

Energy production and utilization is critically important for animal development and growth. How it is regulated in space and time during tissue growth remains largely unclear. Toward this end, we used a FRET-based adenosine triphosphate (ATP) sensor to dynamically monitor ATP levels across a growing tissue, using the Drosophila wing disc. We discovered that steady-state levels of ATP are spatially uniform across the wing pouch. Pharmacologically inhibiting oxidative phosphorylation, however, reveals spatial heterogeneities in metabolic behavior, whereby signaling centers at compartment boundaries produce more ATP from glycolysis than the rest of the tissue. Genetic perturbations indicate that the conserved Hedgehog (Hh) signaling pathway can enhance ATP production by glycolysis. Collectively, our work reveals a positive feedback loop between Hh signaling and energy metabolism, advancing our understanding of the connection between conserved developmental patterning genes and energy production during animal tissue development.