bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of COVID-19 on Healthcare Resource Utilisation Among Patients with Inflammatory Bowel Disease in the USA
Authors: Ungaro Ryan C , Chou Bonnie , Mo Jason , Ursos Lyann , Twardowski Rachel , Candela Ninfa , Colombel Jean-Frederic
Published: April 2022

Background and Aims

The impact of the COVID-19 pandemic on patients with inflammatory bowel disease [IBD] is largely unknown. We characterised the impact of COVID-19 on IBD care by conducting an analysis of US health care claims data.

Methods

We obtained de-identified, open-source, health insurance claims data, from January 2019 to December 2020, from the Symphony Health Integrated Dataverse for US adults with IBD, and measured the rates per 1000 patients of five outcomes: colonoscopies; new biologic or small molecule treatment initiations or treatment switches; new biologic or small molecule treatment initiations or treatment switches in patients who had a colonoscopy within the previous 60 days; IBD-related surgeries; and telehealth consultations.

Results

For 2019 and 2020, 1.32 million and 1.29 million patients with IBD, respectively, were included in the analysis. In March–April 2020, the rates of colonoscopies [17.39 vs 34.44], new biologic or small molecule treatment initiations or switches in patients who had a colonoscopy within the previous 60 days [0.76 vs 1.18], and IBD-related surgeries [2.33 vs 2.99] per 1000 patients were significantly decreased versus January–February 2020; significant year on year decreases versus 2019 were also observed. Telehealth utilisation increased in March 2020 and remained higher than in 2019 up to December 2020.

Conclusions

Reduction in colonoscopies and subsequent initiation/switching of treatments during the COVID-19 pandemic suggest lost opportunities for therapy optimisation which may have an impact on longer-term patient outcomes. Increased utilisation of telehealth services may have helped address gaps in routine clinical care.
Primary cardiac diffuse large B-cell lymphoma presenting with cardiac tamponade: a case report
Authors: Berton Laurens , Van Ballaer Valerie , Ghekiere Olivier , De Caluwé Eva
Published: April 2022

Background

Primary cardiac tumours are extremely rare with an autopsy incidence of 0.05%. They can present with a variety of symptoms, including life-threatening arrhythmia and cardiac tamponade. In this case report, we focus on the diagnostic process and management of a primary cardiac lymphoma (PCL) presenting with cardiac tamponade.

Case summary

We report on a 71-year-old male presenting with a large pericardial effusion, tamponade, and a mass in the right atrioventricular groove. Multimodality imaging was performed, including transthoracic echocardiography, computed tomography, magnetic resonance imaging, positron emission tomography, and computed tomography-guided transthoracic biopsy. The final diagnosis of a double-hit diffuse large-cell B-cell lymphoma was made, for which treatment consisting of a combination of chemotherapy and immunotherapy was initiated. Low-dose colchicine was also added to the treatment.

Discussion

Primary cardiac lymphoma remains a very rare diagnosis and this case highlights the need for multimodality imaging and imaging-guided biopsy to differentiate cardiac masses. First-line treatment for PCL remains a combination of chemotherapy with immunotherapy, with the addition of low-dose colchicine to prevent recurrence of malignant pericardial effusion.
May-Thurner syndrome in patients with postural orthostatic tachycardia syndrome and Ehlers-Danlos syndrome: a case series
Authors: Ormiston Cameron K. , Padilla Erika , Van David T. , Boone Christine , You Sophie , Roberts Anne C. , Hsiao Albert , Taub Pam R.
Published: April 2022

Background

Postural orthostatic tachycardia syndrome (POTS), Ehlers-Danlos syndrome (EDS), and May-Thurner syndrome (MTS) are three syndromes that are often misdiagnosed or underdiagnosed. The true prevalence of these syndromes may be higher than currently reported. The following case series is the first to report a three-way association between POTS, EDS, and MTS.

Case summary

We describe three patients with concomitant POTS, EDS, and MTS. Although abdominopelvic vasculature evaluation can be difficult via conventional imaging techniques, we present the use of novel dynamic contrast-enhanced magnetic resonance angiography with Differential Subsampling with Cartesian Ordering (DISCO) and four-dimensional flow magnetic resonance imaging to aid vasculature evaluation and the diagnosis of MTS. Two patients underwent left common iliac vein stenting to treat MTS, experiencing significant improvement in their POTS symptoms and quality of life.

Discussion

Ehlers-Danlos syndrome, POTS, and MTS may interact synergistically to exacerbate symptoms. Patients with EDS should be evaluated for possible POTS and pelvic venous complications. Left common iliac vein stenting for MTS can mitigate POTS symptoms by decreasing lower extremity venous pooling and should be considered in this patient population. Further research is needed to understand the exact mechanism and intricacies of this syndrome triad.
Dysregulation of ACE-1 in Normal Aging and the Early Stages of Alzheimer’s Disease
Authors: MacLachlan Robert , Kehoe Patrick Gavin , Miners J Scott
Published: April 2022

An imbalance in the renin–angiotensin system (RAS) is associated with cognitive decline and disease pathology in Alzheimer’s disease (AD). In this study, we have investigated changes in the brain angiotensin-converting enzyme-1 (ACE-1) and angiotensin-II (Ang-II), and the counter-regulatory angiotensin-converting enzyme-2 (ACE-2), in the frontal and temporal cortex during normal aging and in the early stages of AD. We studied a cohort of normal aging (n = 121; 19–95 years age-at-death) from the Sudden Death Brain Bank, University of Edinburgh, United Kingdom, and AD and age-matched controls (n = 60) from the South West Dementia Brain Bank, University of Bristol, United Kingdom, stratified according to Braak tangle stage (BS): 0–II, III–IV (intermediate disease), and V–VI (end-stage disease). ACE-1 and ACE-2 enzyme activity were measured using fluorogenic peptide activity assays. ACE-1, ACE-2, and Ang-II protein level were measured by enzyme-linked immunosorbent assay (ELISA). In both regions, ACE-1 protein and Ang-II levels correlated positively with age whereas ACE-1 enzyme activity was inversely related to age. ACE-1 protein correlated positively with Ang-II, whilst ACE-1 activity correlated inversely with Ang-II in normal aging. ACE-1 enzyme activity was elevated at an early/intermediate stage, BS III–IV compared to BS 0–II in the temporal cortex in AD. ACE-2 protein and enzyme activity were unchanged with aging and in AD. In conclusion, ACE-1 activity is induced in the early stages of AD independently from normal physiological age-related changes in ACE-1 protein.
Ownership Change and Care Quality: Lessons From Minnesota’s Experience With Value-Based Purchasing
Authors: Hass Zachary , Abrahamson Kathleen , Arling Greg
Published: April 2022

Background and Objectives

Minnesota’s implementation of a new nursing home value-based reimbursement (VBR) system in 2016 presented an opportunity to compare the response of nursing homes (NHs) to financial incentives to improve their quality and efficiency. The state substantially increased reimbursement for care-related costs and tied this rate increase to a composite quality score. Coinciding with rate increases of the new VBR system was an increase in ownership changes, with new owners being primarily for-profit entities from outside of Minnesota, including several private equity firms. Our objective was to examine NHs that underwent a change in ownership to determine their cost and quality response to the change.

Research Design and Methods

Our sample consists of 342 Minnesota NHs that submitted Medicaid cost reports each year from 2013 to 2019. A time differential two-way fixed-effects difference-in-difference model is used to assess changes in quality metrics by comparing measures in years prior to and years following the sale for NHs that changed ownership versus NHs with consistent ownership. Nursing home characteristics, revenue, and spending patterns are examined to understand differences in performance.

Results

Those NHs with ownership change experienced a decline in quality scores with notable changes to expenditure patterns. They performed worse on Minnesota Department of Health inspection scores and had nonsignificant declines in measures of quality of life and clinical care. They had declining staff dental and medical benefits and occupancy rates, greater revenue growth from Medicare Part B, and larger increases in administrative management fees.

Discussion and Implications

Minnesota like many other states has given wide latitude for nursing home ownership changes, without specific oversight for the quality of care and expenditure patterns of new owners. Recommendations include strict guidelines for the transparency of ownership structures, quality performance targets, rigorous financial auditing, and enhanced regulatory oversight.
Histologic Activity and Steroid Use History Are Risk Factors of Clinical Relapse in Ulcerative Colitis With Mayo Endoscopic Subscore of 0 or 1
Authors: Seong Gyeol , Song Joo Hye , Kim Ji Eun , Kim Tae Jun , Kim Eun Ran , Hong Sung Noh , Chang Dong Kyung , Kim Seok-Hyung , Ha Sang Yun , Kim Young-Ho
Published: April 2022

Background

The treatment goal of ulcerative colitis (UC) has changed from the control of symptoms to mucosal healing, previously evaluated mainly by endoscopy. Recently, the importance of histologic activity has emerged. Therefore, this study aimed to investigate the risk of clinical relapse according to histologic activity in UC with a Mayo endoscopic subsccore (MES) of 0 or 1.

Methods

In a retrospective cohort after our center’s biopsy guideline for UC was instituted, 492 UC patients with an MES of 0 or 1 were enrolled and analyzed. The primary outcome was the development of a clinical relapse including changes in medication, hospitalization, colectomy, and the development of colorectal cancer during the follow-up period.

Results

During the median 549 days of follow-up, 92 (18.7%) patients had a clinical relapse. All the patients changed their medication, including 4 hospitalized patients. Histologic activity defined by a Geboes score of ≧3.1 (hazard ratio [HR], 1.732; P = .035) and steroid use history (HR, 1.762; P = .008) were independent factors associated with clinical relapse. When stratified, the 1- and 2-year incidence rates of clinical relapse were 4.1% and 10.6%, respectively, for patients with histologic improvement and no steroid use history, whereas the rates were 23.9% and 39.4% for patients with histologic activity and steroid use history.

Conclusions

In UC with an MES of 0 or 1, histologic activity and steroid use history can be used to stratify the risk of clinical relapse.
Prevalence of SARS-COV-2 Vaccination and Factors Impacting Likelihood of Vaccination in a Nationwide Veterans Affairs Cohort of IBD Patients
Authors: Mahmud Nadim , Shah Yash , Khan Nabeel
Published: April 2022

Lay Summary

Despite all efforts, about one-third of IBD patients are still not vaccinated. Although there is an emphasis on the booster dose, there is still a large population that has received no vaccination. Younger, healthy smokers with CD and on anti-TNF agents residing in the South and Midwest are less likely to get vaccinated. Targeted efforts should be made at this subset of IBD patients to increase vaccination rates.
Assessing socioeconomic bias in machine learning algorithms in health care: a case study of the HOUSES index
Authors: Juhn Young J , Ryu Euijung , Wi Chung-Il , King Katherine S , Malik Momin , Romero-Brufau Santiago , Weng Chunhua , Sohn Sunghwan , Sharp Richard R , Halamka John D
Published: April 2022

Objective

Artificial intelligence (AI) models may propagate harmful biases in performance and hence negatively affect the underserved. We aimed to assess the degree to which data quality of electronic health records (EHRs) affected by inequities related to low socioeconomic status (SES), results in differential performance of AI models across SES.

Materials and Methods

This study utilized existing machine learning models for predicting asthma exacerbation in children with asthma. We compared balanced error rate (BER) against different SES levels measured by HOUsing-based SocioEconomic Status measure (HOUSES) index. As a possible mechanism for differential performance, we also compared incompleteness of EHR information relevant to asthma care by SES.

Results

Asthmatic children with lower SES had larger BER than those with higher SES (eg, ratio = 1.35 for HOUSES Q1 vs Q2–Q4) and had a higher proportion of missing information relevant to asthma care (eg, 41% vs 24% for missing asthma severity and 12% vs 9.8% for undiagnosed asthma despite meeting asthma criteria).

Discussion

Our study suggests that lower SES is associated with worse predictive model performance. It also highlights the potential role of incomplete EHR data in this differential performance and suggests a way to mitigate this bias.

Conclusion

The HOUSES index allows AI researchers to assess bias in predictive model performance by SES. Although our case study was based on a small sample size and a single-site study, the study results highlight a potential strategy for identifying bias by using an innovative SES measure.
Comparing the Efficiency of Tumescent Infiltration Techniques in Burn Surgery
Authors: Fouché Tom W , Bond Stephanie M , Vrouwe Sebastian Q
Published: April 2022

Tangential excision and grafting of burn wounds result in significant intraoperative blood loss, and infiltration of a dilute epinephrine solution (tumescence) is routinely performed to reduce such bleeding. Tumescent infiltration has been described using both a manual technique (syringe) and a pump device. The purpose of this study is to compare the efficiency of these two methods in terms of time and economy of motion. Consecutive adult burn patients at a single center requiring excision and grafting were enrolled in the study and randomized into either the manual or pump technique. Excisions involving less than 2% TBSA were excluded, along with specific anatomic regions (eg, head and neck). Infiltration with epinephrine solution (1:500,000) was performed to the endpoint of tumescence by a single surgeon and filmed/coded for duration, number of maneuvers, and volume of tumescence injected. Fourteen patients were enrolled, and 16 cases were randomized to either manual (N = 8) or pump infiltration (N = 8). The pump method required less time (2.0 vs 1.1 cm2/s, P < .001) and fewer maneuvers (37.8 vs 1.1 cm2/move, P < .001) to reach the desired endpoint of tumescence. Use of the infiltration pump also resulted in a reduced volume of tumescent fluid required to reach this point of tumescence (1.7 vs 2.4 mL/cm2, P = .01). Compared to the manual technique, an infiltration pump was significantly more efficient in terms of both time and economy of motion. These reductions are potentially useful for improving operating room efficiency as well as minimizing operator fatigue.
Is there a persistent capital femoral epiphysis growth after screw fixation for slipped capital femoral epiphysis?
Authors: Sleth Camille , Bauzou François , De Cristo Claudia , Alkar Fanny , Joly-Monrigal Pauline , Jeandel Clément , Cottalorda Jérôme , Louahem M’Sabah Djamel , Delpont Marion
Published: April 2022

Femoral neck screwing during child development is controversial. The objective of this study was to evaluate the residual growth of the capital femoral physis after screw fixation. This retrospective study included children aged younger than 12 years treated for slipped capital femoral epiphysis (SCFE) with a single percutaneous partially threaded cannulated screw. The children were followed up for at least 1 year. Some patients also underwent prophylactic contralateral screwing. Preoperative, immediate postoperative and final follow-up X-rays were evaluated to determine the degree of slippage, pin–joint ratio (PJR), neck–pin ratio (NPR), number of threads crossing the physis, neck–shaft angle (NSA), screw–physis angle and screw position in the physis. We included 17 patients (29 hips: 18 SCFE and 11 prophylactic) with a mean age of 10.1 years (range: 7.1–11.9 years) at the time of surgery. Significant evolution of radiological growth parameters of the proximal femoral physis was noted during a mean follow-up of 2.4 years (range: 1–4.3 years). The mean PJR significantly decreased from 7.3 to 6.0, the mean NPR significantly decreased from 106 to 96 and the mean number of threads beyond the physis decreased from 3.3 to 1.8. The mean NSA decreased by 6.5°, from 139° to 132.5°. Persistent capital femoral epiphysis growth occurs after screw fixation. The NSA significantly decreases over time but remains within the physiological limits.

Level of evidence: IV (case series)
Universal rule and regional variation of vegetation height assembly of typical grasslands in China
Authors: Hou Jihua , Li Qiuyue , Yan Pu , Xu Li , Li Mingxu , He Nianpeng
Published: April 2022

Measuring plant heights one by one is an important way to explore the height structure of grassland plant communities, and can be used to analyze the universal rules and regional variations of vegetation growth under environmental change. We chose grasslands in three plateaus, namely Tibetan Plateau (TP), Mongolian Plateau (MP) and Loess Plateau (LP), and set up three grassland transects along the precipitation gradients from meadow, steppe to desert. The mean height of grassland vegetation was 30.38 ± 22.44 cm, and the mean height from TP, MP to LP increased significantly. The aggregation of grassland vegetation exhibited a positive skew distribution (0.91, 3.60), and the community aggregation from TP, MP to LP tended to a normal distribution (0, 3). However, for TP, there was an exponential distribution in community aggregation of meadows, and a uniform distribution in that of desert. The explanatory effect of climate and soil nutrients on the variation of mean height in each region was more than 70%, while the explanatory effect on the community aggregation was the highest at TP, only 29%. From TP, MP to LP, response intensity of mean height to environmental changes increased significantly, and the influence of temperature and precipitation gradually increased, the influence of radiation, wind speed, and nutrients gradually weakened, and the synergy among environmental factors strengthened. Our study shows that normal distribution is a universal rule of grassland height construction, and that the synergy of environmental factors varies from region to region.
Queering Ethnic Rites of Passage: Transparent and One Day at a Time
Authors: Pridgeon Stephanie
Published: April 2022

I take account of queered ethnic rites of passage in the popular television series Transparent (2014-19) and One Day at a Time (2017-20), shows through which directors Joey Soloway and Gloria Calderón Kellett explore the intersections between queer youth and Jewish and Latinx identities, respectively. Transparent uses flashbacks to character Ari’s decision to forego their bat mitzvah in such a way that is inexorable from both their vexed relationship to their family’s immigrant history and their burgeoning queer (and later nonbinary) identification as a twenty-something in the series’ present. Likewise, One Day at a Time presents character Elena’s process of coming to terms with whether or not to celebrate her quinceañera, which she perceives as a misogynist, patriarchal tradition, as she duly grapples with coming out. Both series include gendered rites of passages, the Latinx quinceañera and the Jewish bat mitzvah, in a way that shows sexuality and ethnicity to sit uncomfortably with one another for queer adolescents whose grandparents immigrated to the United States. The two storylines share a family as a site of compulsory heterosexuality, adolescent characters who negotiate their sexual identities as they grapple with a rite of passage, and the use of humor as a tactic to question, resist, and at times reify patriarchal norms.
Impact of extreme spins and mass ratios on the post-merger observables of high-mass binary neutron stars
Authors: Papenfort L Jens , Most Elias R , Tootle Samuel , Rezzolla Luciano
Published: April 2022

The gravitational-wave events GW170817 and GW190425 have led to a number of important insights on the equation of state of dense matter and the properties of neutron stars, such as their radii and the maximum mass. Some of these conclusions have been drawn on the basis of numerical-relativity simulations of binary neutron-star mergers with vanishing initial spins. While this may be a reasonable assumption in equal-mass systems, it may be violated in the presence of large mass asymmetries accompanied by the presence of high spins. To quantify the impact of high spins on multimessenger gravitational-wave events, we have carried out a series of high-mass binary neutron-star mergers with a highly spinning primary star and large mass asymmetries that have been modelled self-consistently using two temperature-dependent equations of state. We show that, when compared with equal-mass, irrotational binaries, these systems can lead to significant differences in the remnant lifetime, in the dynamical ejecta, in the remnant disc masses, in the secular ejecta, and on the bulk kilonova properties. These differences could be exploited to remove the degeneracy between low- and high-spin priors in the detection of gravitational waves from binary neutron-star mergers.
Magneto-thermal instability in galaxy clusters – I. Theory and two-dimensional simulations
Authors: Perrone Lorenzo M , Latter Henrik
Published: April 2022

Determining the origin of turbulence in galaxy clusters, and quantifying its transport of heat, is an outstanding problem, with implications for our understanding of their thermodynamic history and structure. As the dilute plasma of the intracluster medium (ICM) is magnetized, heat and momentum travel preferentially along magnetic field lines. This anisotropy triggers a class of buoyancy instabilities that destabilize the ICM, and whose turbulent motions can augment or impede heat transport. We focus on the magneto-thermal instability (MTI), which may be active in the periphery of galaxy clusters. We aim to take a fresh look at the problem and construct a general theory that explains the MTI saturation mechanism and provides scalings and estimates for the turbulent kinetic energy, magnetic energy, and heat flux. We simulate MTI turbulence with a Boussinesq code, snoopy, which, in contrast to previous work, allows us to perform an extensive sampling of the parameter space. In two dimensions the saturation mechanism involves an inverse cascade that carries kinetic energy from the short MTI injection scales to larger scales, where it is arrested by the stable entropy stratification; at a characteristic ‘buoyancy scale’, the energy is dumped into large-scale g-modes, which subsequently dissipate. Consequently, the entropy stratification sets an upper limit on the size and strength of turbulent eddies. Meanwhile, the MTI conveys a substantial fraction of heat, despite the tangled geometry of the magnetic field. In a companion paper, these results are extended to three-dimensional flows, and compared to observations of real clusters.
Stochastic gravitational-wave background searches and constraints on neutron-star ellipticity
Authors: De Lillo Federico , Suresh Jishnu , Miller Andrew L
Published: April 2022

Rotating neutron stars (NSs) are promising sources of gravitational waves (GWs) in the frequency band of ground-based detectors. They are expected to emit quasi-monochromatic, long-duration GW signals, called continuous waves (CWs), due to their deviations from spherical symmetry. The degree of such deformations, and hence the information about the internal structure of an NS, is encoded in a dimension-less parameter ε called ellipticity. Searches for CW signals from isolated Galactic NSs have shown to be sensitive to ellipticities as low as $\varepsilon \sim \mathcal {O}(10^{-9})$. These searches are optimal for detecting and characterizing GWs from individual NSs, but they are not designed to measure the properties of NSs as population, such as the average ellipticity εav. These ensemble properties can be determined by the measurement of the stochastic gravitational-wave background (SGWB) arising from the superposition of GW signals from individually undetectable NSs. In this work, we perform a cross-correlation search for such a SGWB using the data from the first three observation runs of Advanced LIGO and Virgo. Finding no evidence for an SGWB signal, we set upper limits on the dimension-less energy density parameter Ωgw(f). Using these results, we also constrain the average ellipticity of Galactic NSs and five NS ‘hotspots’, as a function of the number of NSs emitting GWs within the frequency band of the search Nband. We find $\varepsilon _{\mathrm{av}} \lesssim 1.8 \times 10^{-8}$, with Nband = 1.6 × 107, for Galactic NSs, and $\varepsilon _{\mathrm{av}} \lesssim [3.5-11.8]\times 10^{-7}$, with Nband = 1.6 × 1010, for NS hotspots.
Intermediate- and high-velocity clouds in the Milky Way – I. Covering factors and vertical heights
Authors: Lehner Nicolas , Howk J Christopher , Marasco Antonino , Fraternali Filippo
Published: April 2022

Intermediate- and high-velocity clouds (IVCs, HVCs) are a potential source of fuel for star formation in the Milky Way (MW), but their origins and fates depend sensitively on their distances. We search for IVCs and HVCs in HST high-resolution ultraviolet spectra of 55 halo stars at vertical heights $|z|\gtrsim \,1$ kpc. We show that IVCs (40 ≤ |$v$LSR| < 90 ${\rm km\, s}^{-1}$) have a high detection rate – the covering factor, fc – that is about constant (fc = 0.90 ± 0.04) from $z$ = 1.5 to 14 kpc, implying IVCs are essentially confined to |$z$| ≲ 1.5 kpc. For the HVCs (90 ≤ |$v$LSR| ≲ 170 ${\rm km\, s}^{-1}$), we find fc increases from fc ≃ 0.14 ± 0.10 at |$z$| ≲ 2–3 kpc to fc = 0.60 ± 0.15 at 6 ≲ |$z$| ≲ 14 kpc, the latter being similar to that found towards QSOs. In contrast, the covering factor of very high-velocity clouds (VHVCs; |$v$LSR| ≳ 170 ${\rm km\, s}^{-1}$) is $f_c \lt 0.04$ in the stellar sample compared to 20 per cent towards QSOs, implying these clouds must be at d ≳ 10–15 kpc (|$z$| ≳ 10 kpc). Gas clouds with |$v$LSR| > 40 ${\rm km\, s}^{-1}$ at |b| ≳ 15° have therefore |$v$LSR| decreasing with decreasing |$z$|. Our findings are consistent with a Galactic rain and/or fountain origin for these clouds. In the latter scenario, VHVCs may mostly serve as fuel for the MW halo. In view of their high covering factors and since all the IVCs and some HVCs are found in the thick disc, they appear good candidates as gas reservoirs to help sustain star formation in the MW.
Sakurai’s Object revisited: new laboratory data for carbonates and melilites suggest the carrier of 6.9-μm excess absorption is a carbonate
Authors: Bowey J E , Hofmeister A M
Published: April 2022

We present new room-temperature 1100–1800-cm−1 spectra of melilite silicates and 600–2000-cm−1 spectra of three randomly orientated fine-grained carbonates to determine the possible carrier(s) of a 6.9-μm absorption feature observed in a variety of dense astronomical environments, including young stellar objects and molecular clouds. We focus on the low-mass post-asymptotic giant branch star Sakurai’s Object, which has been forming substantial quantities of carbonaceous dust since an eruptive event in the 1990s. Large melilite grains cannot be responsible for the 6.9-μm absorption feature because the similarly shaped feature in the laboratory spectrum was produced by very low (0.1 per cent by mass) carbonate contamination, which was not detected at other wavelengths. Due to the high band strength of the 6.9-μm feature in carbonates, we conclude that carbonates carry the astronomical 6.9-μm feature. Replacement of melilite with carbonates in models of Sakurai’s Object improves fits to the 6–7-μm Spitzer spectra without significantly altering other conclusions of Bowey’s previous models except that there is no link between the feature and the abundance of melilite in meteorites. With magnesite (MgCO3), the abundance of 25-μm-sized SiC grains is increased by 10–50 per cent and better constrained. The mass of carbonate dust is similar to the mass of polycyclic aromatic hydrocarbon dust. Existing experiments suggest that carbonates are stable below 700 K; however, it is difficult to ascertain the applicability of these experiments to astronomical environments, and more studies are required.
Oncogenic RABL6A promotes NF1-associated MPNST progression in vivo
Authors: Kohlmeyer Jordan L , Kaemmer Courtney A , Lingo Joshua J , Voigt Ellen , Leidinger Mariah R , McGivney Gavin R , Scherer Amanda , Koppenhafer Stacia L , Gordon David J , Breheny Patrick , Meyerholz David K , Tanas Munir R , Dodd Rebecca D , Quelle Dawn E
Published: April 2022

Background

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas with complex molecular and genetic alterations. Powerful tumor suppressors CDKN2A and TP53 are commonly disrupted along with NF1, a gene that encodes a negative regulator of Ras. Many additional factors have been implicated in MPNST pathogenesis. A greater understanding of critical drivers of MPNSTs is needed to guide more informed targeted therapies for patients. RABL6A is a newly identified driver of MPNST cell survival and proliferation whose in vivo role in the disease is unknown.

Methods

Using CRISPR-Cas9 targeting of Nf1 + Cdkn2a or Nf1 + Tp53 in the mouse sciatic nerve to form de novo MPNSTs, we investigated the biological significance of RABL6A in MPNST development. Terminal tumors were evaluated by western blot, qRT-PCR, and immunohistochemistry.

Results

Mice lacking Rabl6 displayed slower tumor progression and extended survival relative to wildtype animals in both genetic contexts. YAP oncogenic activity was selectively downregulated in Rabl6-null, Nf1 + Cdkn2a lesions whereas loss of RABL6A caused upregulation of the CDK inhibitor, p27, in all tumors. Paradoxically, both models displayed elevated Myc protein and Ki67 staining in terminal tumors lacking RABL6A. In Nf1 + p53 tumors, cellular atypia and polyploidy were evident and increased by RABL6A loss.

Conclusions

These findings demonstrate that RABL6A is required for optimal progression of NF1 mutant MPNSTs in vivo in both Cdkn2a and p53 inactivated settings. However, sustained RABL6A loss may provide selective pressure for unwanted alterations, including increased Myc, cellular atypia, and polyploidy, that ultimately promote a hyper-proliferative tumor phenotype akin to drug-resistant lesions.
Identifying Promising Themes for Adolescent Vaping Warnings: A National Experiment
Authors: Rohde Jacob A , Noar Seth M , Sheldon Jennifer Mendel , Hall Marissa G , Kieu Talia , Brewer Noel T
Published: April 2022

Introduction

Adolescent vaping remains a problem in the United States, yet little is known about what health warning themes most discourage vaping among adolescents. We sought to identify the most compelling themes for vaping warnings for US adolescents.

Methods

Participants were a national probability sample of 623 US adolescents aged 13–17 years, recruited in the summer of 2020. Adolescents were randomized to one of the five warning message themes about the potential health effects of vaping: 1. chemical harms, 2. lung harms, 3. Coronavirus Disease 2019 (COVID-19) harms, 4. nicotine addiction, or 5. control (messages about vape litter). The primary outcome was perceived message effectiveness (PME; 3-item scale). Secondary outcomes were negative affect (fear), attention, anticipated social interactions, and message novelty.

Results

Adolescents rated the chemical, lung, and COVID-19 harms warning messages higher on PME than nicotine addiction and control (all p < .05), while nicotine addiction was rated higher than control (p < .05). The chemical, lung, and COVID-19 harms warning themes also elicited greater negative affect than nicotine addiction and control (all p < .05). For all other secondary outcomes, the COVID-19 harms warning message theme was rated higher than nicotine addiction and control (all p < .05).

Conclusion

Adolescents perceived warning message themes about lung, chemical and COVID-19 health effects of vaping as more effective than nicotine addiction. To discourage vaping, the FDA and others should communicate to youth about the health effects of vaping beyond nicotine addiction.

Implications

Adolescents rated warning message themes about the lung, chemical, and COVID-19 health effects of vaping as more effective than nicotine addiction, while nicotine addiction was rated as more effective than control themes about vaping litter. To discourage vaping among adolescents, health messaging should expand message themes to communicate about a broader set of health effects of vaping beyond nicotine addiction.
Sleep irregularity and nonsuicidal self-injurious urges and behaviors
Authors: Burke Taylor A , Hamilton Jessica L , Seigel David , Kautz Marin , Liu Richard T , Alloy Lauren B , Barker David H
Published: April 2022

Study Objectives

The objectives of this study were to examine the relationships between sleep regularity and nonsuicidal self-injury (NSSI), including lifetime NSSI history and daily NSSI urges.

Methods

Undergraduate students (N = 119; 18–26 years), approximately half of whom endorsed a lifetime history of repetitive NSSI, completed a 10-day actigraphy and ecological momentary assessment (EMA) protocol. A Sleep Regularity Index was calculated for all participants using scored epoch by epoch data to capture rapid changes in sleep schedules. Participants responded to EMA prompts assessing NSSI urge severity and negative affect three times daily over the 10-day assessment period.

Results

Results indicate that individuals with a repetitive NSSI history were more likely to experience sleep irregularity than those without a history of NSSI. Findings also suggest that sleep irregularity was associated with more intense urges to engage in NSSI on a daily basis, even after accounting for average daily sleep duration, sleep timing, negative affect, and NSSI history. Neither sleep duration nor sleep timing was associated with NSSI history nor daily NSSI urge intensity.

Conclusions

Findings suggest that sleep irregularity is linked with NSSI, including NSSI history and intensity of urges to engage in NSSI. The present study not only supports the growing evidence linking sleep disturbance with the risk for self-injury but also demonstrates this relationship using actigraphy and real-time assessments of NSSI urge severity. Findings highlight the importance of delineating the nuances in sleep irregularity that are proximally associated with NSSI risk and identifying targets for intervention.
A formalism for sequential estimation of neural membrane time constant and input–output curve towards selective and closed-loop transcranial magnetic stimulation⋆
Authors: Alavi S.M.Mahdi , Vila-Rodriguez Fidel , Mahdi Adam , Goetz Stefan M.
Published: April 2022

Objective

To obtain a formalism for real-time concurrent sequential estimation of neural membrane time constant and input–output (IO) curve with transcranial magnetic stimulation (TMS).

Approach

First, the neural membrane response and depolarization factor, which leads to motor evoked potentials (MEPs) with TMS are analytically computed and discussed. Then, an integrated model is developed which combines the neural membrane time constant and input–output curve. Identifiability of the proposed integrated model is discussed. A condition is derived, which assures estimation of the proposed integrated model. Finally, sequential parameter estimation (SPE) of the neural membrane time constant and IO curve is described through closed-loop optimal sampling and open-loop uniform sampling TMS. Without loss of generality, this paper focuses on a specific case of commercialized TMS pulse shapes. The proposed formalism and SPE method are directly applicable to other pulse shapes.

Main results

The results confirm satisfactory estimation of the membrane time constant and IO curve parameters. By defining a stopping rule based on five times consecutive convergence of the estimation parameters with a tolerances of 0.01, the membrane time constant and IO curve parameters are estimated with 82 TMS pulses with absolute relative estimation errors (AREs) of less than 4% with the optimal sampling SPE method. At this point, the uniform sampling SPE method leads to AREs up to 16%. The uniform sampling method does not satisfy the stopping rule due to the large estimation variations.

Significance

This paper provides a tool for real-time closed-loop SPE of the neural time constant and IO curve, which can contribute novel insights in TMS studies. SPE of the membrane time constant enables selective stimulation, which can be used for advanced brain research, precision medicine and personalized medicine.
[18F]ROStrace detects oxidative stress in vivo and predicts progression of Alzheimer’s disease pathology in APP/PS1 mice
Authors: Hsieh Chia-Ju , Hou Catherine , Zhu Yi , Lee Ji Youn , Kohli Neha , Gallagher Evan , Xu Kuiying , Lee Hsiaoju , Li Shihong , McManus Meagan J. , Mach Robert H.
Published: April 2022

Purpose

Oxidative stress is implicated in the pathogenesis of the most common neurodegenerative diseases, such as Alzheimer’s disease (AD). However, tracking oxidative stress in the brain has proven difficult and impeded its use as a biomarker. Herein, we investigate the utility of a novel positron emission tomography (PET) tracer, [18F]ROStrace, as a biomarker of oxidative stress throughout the course of AD in the well-established APP/PS1 double mutant mouse model.

Methods

PET imaging studies were conducted in wild-type (WT) and APP/PS1 mice at 3 different time points, representing early (5 mo.), middle (10 mo.), and advanced (16 mo.) life (n = 6-12, per sex). Semi-quantitation SUVRs of the plateau phase (40-60min post-injection; SUVR40-60) of ten brain subregions were designated by the Mirrione atlas and analyzed by Pmod. Statistical parametric mapping (SPM) was used to distinguish brain regions with elevated ROS in APP/PS1 relative to WT in both sexes. The PET studies were validated by ex vivo autoradiography and immunofluorescence with the parent compound, dihydroethidium.

Results

[18F]ROStrace retention was increased in the APP/PS1 brain compared to age-matched controls by 10 mo. of age (p < 0.0001), and preceded the accumulation of oxidative damage in APP/PS1 neurons at 16mo. (p < 0.005). [18F]ROStrace retention and oxidative damages were higher and occurred earlier in female APP/PS1 mice as measured by PET (p < 0.001), autoradiography and immunohistochemistry (p < 0.05). [18F]ROStrace differences emerged mid-life, temporally and spatially correlating with increased Aβ burden (r2 = 0.36; p = 0.0003), which was also greatest in the female brain (p < 0.001).

Conclusions

[18F]ROStrace identifies increased oxidative stress and neuroinflammation in APP/PS1 female mice, concurrent with increased amyloid burden mid-life. Differences in oxidative stress during this crucial time may partially explain the sexual dimorphism in AD. [18F]ROStrace may provide a long-awaited tool to stratify at-risk patients who may benefit from antioxidant therapy prior to irreparable neurodegeneration.
Cochlear Neurotrophin-3 overexpression at mid-life prevents age-related cochlear synaptopathy and slows age-related hearing loss
Authors: Cassinotti Luis R. , Ji Lingchao , Borges Beatriz C. , Cass Nathan D. , Desai Aditi S. , Kohrman David C. , Liberman M. Charles , Corfas Gabriel
Published: April 2022

Age-related hearing loss (ARHL) is the most prevalent sensory deficit in the elderly. This progressive pathology often has psychological and medical comorbidities, including social isolation, depression, and cognitive decline. Despite ARHL’s enormous impact, no therapies to prevent or slow its progression exist. Loss of synapses between inner hair cells (IHCs) and spiral ganglion neurons (SGNs), a.k.a. cochlear synaptopathy, is an early event in ARHL, preceding neuronal and hair cell loss. To determine if age-related cochlear synaptopathy can be prevented, and if this impacts the time-course of ARHL, we tested the effects of cochlear overexpression of neurotrophin-3 (Ntf3) starting at middle-age. We chose Ntf3 because this neurotrophin regulates the formation of IHC-SGN synapses in the neonatal period. We now show that triggering Ntf3 overexpression by cochlear supporting cells starting in middle age rapidly increases the amplitude of sound-evoked neural potentials, indicating that Ntf3 improves cochlear function when pathology is minimal. Furthermore, near the end of their lifespan, Ntf3-overexpressing mice have milder ARHL, with enhanced cochlear neural function and reduced cochlear synaptopathy. Our results provide evidence that age-related decrease in cochlear Ntf3 expression contributes to ARHL. and Ntf3 supplementation could serve as a therapeutic for this prevalent disorder. Furthermore, these findings suggest that increased expression of factors that regulate synaptogenesis during development might prevent age-related synaptopathy, a process involved in several central nervous system degenerative disorders.
The natural diversity of the yeast proteome reveals chromosome-wide dosage compensation in aneuploids
Authors: Muenzner Julia , Trébulle Pauline , Agostini Federica , Messner Christoph B. , Steger Martin , Lehmann Andrea , Caudal Elodie , Egger Anna-Sophia , Amari Fatma , Barthel Natalie , De Chiara Matteo , Mülleder Michael , Demichev Vadim , Liti Gianni , Schacherer Joseph , Gossmann Toni , Berman Judith , Ralser Markus
Published: April 2022

Aneuploidy, an imbalance in chromosome copy numbers, causes genetic disorders, and drives cancer progression, drug tolerance, and antimicrobial resistance. While aneuploidy can confer stress resistance, it is not well understood how cells overcome the fitness burden caused by aberrant chromosomal copy numbers. Studies using both systematically generated1–5and natural aneuploid yeasts6–8triggered an intense debate about the role of dosage compensation, concluding that aneuploidy is transmitted to the transcriptome and proteome without significant buffering at the chromosome-wide level, and is, at least in lab strains, associated with significant fitness costs. Conversely, systematic sequencing and phenotyping of large collections of natural isolates revealed that aneuploidy is frequent and has few – if any – fitness costs in nature9. To address these discrepant findings at the proteomic level, we developed a platform that yields highly precise proteomic measurements across large numbers of genetically diverse samples, and applied it to natural isolates collected as part of the 1011 genomes project9. For 613 of the isolates, we were able to match the proteomes to their corresponding transcriptomes and genomes, subsequently quantifying the effect of aneuploidy on gene expression by comparing 95 aneuploid with 518 euploid strains. We find, as in previous studies, that aneuploid gene dosage is not buffered chromosome-wide at the transcriptome level. Importantly, in the proteome, we detect an attenuation of aneuploidy by about 25% below the aneuploid gene dosage in natural yeast isolates. Furthermore, this chromosome-wide dosage compensation is associated with the ubiquitin-proteasome system (UPS), which is expressed at higher levels and has increased activity across natural aneuploid strains. Thus, through systematic exploration of the species-wide diversity of the yeast proteome, we shed light on a long-standing debate about the biology of aneuploids, revealing that aneuploidy tolerance is mediated through chromosome-wide dosage compensation at the proteome level.
Plant-produced RBD and cocktail-based vaccine candidates are highly effective against SARS-CoV-2, independently of its emerging variants
Authors: Mamedov Tarlan , Yuksel Damla , Gürbüzaslan Irem , Ilgın Merve , Gulec Burcu , Mammadova Gulshan , Ozdarendeli Aykut , Pavel Shaikh Terkis Islam , Yetiskin Hazel , Kaplan Busra , Uygut Muhammet Ali , Hasanova Gulnara
Published: April 2022

SARS-CoV-2 is a novel and highly pathogenic coronavirus, which has caused an outbreak in Wuhan City, China, in 2019 and then spread rapidly throughout the world. Although several COVID-19 vaccines are currently available for mass immunization, they are less effective against emerging SARS-CoV-2 variants, especially the Omicron (B.1.1.529). Recently, we successfully produced receptor-binding domain (RBD) variants of spike (S) protein of SARC-CoV-2 and an antigen cocktail in Nicotiana benthamiana, which are highly produced in plants and elicited high-titer antibodies with potent neutralizing activity against SARS-CoV-2. In this study, we demonstrate that these protein-based vaccine candidates are highly effective against Delta and Omicron variants. These data support that plant produced RBD and cocktail-based antigens are most promising vaccine candidates and may protect against Delta and Omicron-mediated COVID-19. Based on the neutralization ability, plant produced RBD and cocktail-based vaccine candidates are highly effective against SARS-CoV-2, independently of its emerging variants.
Hippo Signaling Pathway Activation during SARS-CoV-2 Infection Contributes to Host Antiviral Response
Authors: Garcia Gustavo , Wang Yijie , Irudayam Joseph Ignatius , Jeyachandran Arjit Vijey , Cario Sebastian Castillo , Sen Chandani , Li Shen , Li Yunfeng , Kumar Ashok , Nielsen-Saines Karin , French Samuel W. , Shah Priya S , Morizono Kouki , Gomperts Brigitte , Deb Arjun , Ramaiah Arunachalam , Arumugaswami Vaithilingaraja
Published: April 2022

SARS-CoV-2, responsible for the COVID-19 pandemic, causes respiratory failure and damage to multiple organ systems. The emergence of viral variants poses a risk of vaccine failures and prolongation of the pandemic. However, our understanding of the molecular basis of SARS-CoV-2 infection and subsequent COVID-19 pathophysiology is limited. In this study, we have uncovered a critical role for the evolutionarily conserved Hippo signaling pathway in COVID-19 pathogenesis. Given the complexity of COVID-19 associated cell injury and immunopathogenesis processes, we investigated Hippo pathway dynamics in SARS-CoV-2 infection by utilizing COVID-19 lung samples, and human cell models based on pluripotent stem cell-derived cardiomyocytes (PSC-CMs) and human primary lung air-liquid interface (ALI) cultures. SARS-CoV-2 infection caused activation of the Hippo signaling pathway in COVID-19 lung and in vitro cultures. Both parental and Delta variant of concern (VOC) strains induced Hippo pathway. The chemical inhibition and gene knockdown of upstream kinases MST1/2 and LATS1 resulted in significantly enhanced SARS-CoV-2 replication, indicating antiviral roles. Verteporfin a pharmacological inhibitor of the Hippo pathway downstream transactivator, YAP, significantly reduced virus replication. These results delineate a direct antiviral role for Hippo signaling in SARS-CoV-2 infection and the potential for this pathway to be pharmacologically targeted to treat COVID-19.