bluuebunny/crossref_metadata_2025 huggingface dataset:
Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors
Authors: Li Hu , Zhang Xiao , Xu Zhenyi , Li Lingrui , Liu Wenchao , Dai Zhenyu , Zhao Zhongrun , Xiao Lili , Li Hongfeng , Hu Chaohong
Published: August 2021

Background

ERBB2 is a proto-oncogene of multiple cancers including breast and gastric cancers with HER2 protein overexpression or gene amplification and has been proven clinically as a valid target for these cancers. HER2-targeting agents such as Herceptin®, Kadcyla® and ENHERTU® have been approved by the FDA for the treatment of breast cancer, but these drugs still face the challenge of acquired resistance and/or severe adverse reactions in clinical use. Therefore, there is significant unmet medical need for developing new agents that are more effective and safer for patients with advanced HER2-positive solid tumors including breast and gastric cancers.

Methods

We report here the making of MRG002, a novel HER2-targeted antibody drug conjugate (ADC), and preclinical characterization including pharmacology, pharmacodynamics and toxicology and discuss its potential as a novel agent for treating patients with HER2-positive solid tumors.

Results

MRG002 exhibited similar antigen binding affinity but much reduced antibody-dependent cellular cytotoxicity (ADCC) activity compared to trastuzumab. In addition to potent in vitro cytotoxicity, MRG002 showed tumor regression in both high- and medium-to-low HER2 expressing in vivo xenograft models. Furthermore, MRG002 showed enhanced antitumor activity when used in combination with an anti-PD-1 antibody. Main findings from toxicology studies are related to the payload and are consistent with literature report of other ADCs with monomethyl auristatinE.

Conclusion

MRG002 has demonstrated a favorable toxicity profile and potent antitumor activities in the breast and gastric PDX models with varying levels of HER2 expression, and/or resistance to trastuzumab or T-DM1. A phase I clinical study of MRG002 in patients with HER2-positive solid tumors is ongoing (CTR20181778).
Disrupting porcine glutaminase does not block preimplantation development and elongation nor decrease mTORC1 activation in conceptuses
Authors: Chen Paula R , Lucas Caroline G , Cecil Raissa F , Pfeiffer Caroline A , Fudge Melissa A , Samuel Melissa S , Zigo Michal , Seo Heewon , Spate Lee D , Whitworth Kristin M , Sutovsky Peter , Johnson Gregory A , Wells Kevin D , Geisert Rodney D , Prather Randall S
Published: August 2021

Elongation of pig conceptuses is a dynamic process, requiring adequate nutrient provisions. Glutamine is used as an energy substrate and is involved in the activation of mechanistic target of rapamycin complex 1 (mTORC1) during porcine preimplantation development. However, the roles of glutamine have not been extensively studied past the blastocyst stage. Therefore, the objective of the current study was to determine if glutaminase (GLS), which is the rate-limiting enzyme in glutamine metabolism, was necessary for conceptus elongation to proceed and was involved in mTORC1 activation. The CRISPR/Cas9 system was used to induce loss-of-function mutations in the GLS gene of porcine fetal fibroblasts. Wild type (GLS+/+) and knockout (GLS−/−) fibroblasts were used as donor cells for somatic cell nuclear transfer, and GLS+/+ and GLS−/− blastocyst-stage embryos were transferred into surrogates. On day 14 of gestation, GLS+/+ conceptuses primarily demonstrated filamentous morphologies, and GLS−/− conceptuses exhibited spherical, ovoid, tubular, and filamentous morphologies. Thus, GLS−/− embryos were able to elongate despite the absence of GLS protein and minimal enzyme activity. Furthermore, spherical GLS−/− conceptuses had increased abundance of transcripts related to glutamine and glutamate metabolism and transport compared to filamentous conceptuses of either genotype. Differences in phosphorylation of mTORC1 components and targets were not detected regarding conceptus genotype or morphology, but abundance of two transcriptional targets of mTORC1, cyclin D1, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha was increased in spherical conceptuses. Therefore, porcine GLS is not essential for conceptus elongation and is not required for mTORC1 activation at this developmental timepoint.
Dissociable effects of age and Parkinson’s disease on instruction-based learning
Authors: Parkin Beth L , Daws Richard E , Das-Neves Ines , Violante Ines R , Soreq Eyal , Faisal A Aldo , Sandrone Stefano , Lao-Kaim Nicholas P , Martin-Bastida Antonio , Roussakis Andreas-Antonios , Piccini Paola , Hampshire Adam
Published: August 2021

The cognitive deficits associated with Parkinson’s disease vary across individuals and change across time, with implications for prognosis and treatment. Key outstanding challenges are to define the distinct behavioural characteristics of this disorder and develop diagnostic paradigms that can assess these sensitively in individuals. In a previous study, we measured different aspects of attentional control in Parkinson’s disease using an established fMRI switching paradigm. We observed no deficits for the aspects of attention the task was designed to examine; instead those with Parkinson’s disease learnt the operational requirements of the task more slowly. We hypothesized that a subset of people with early-to-mid stage Parkinson’s might be impaired when encoding rules for performing new tasks. Here, we directly test this hypothesis and investigate whether deficits in instruction-based learning represent a characteristic of Parkinson’s Disease. Seventeen participants with Parkinson’s disease (8 male; mean age: 61.2 years), 18 older adults (8 male; mean age: 61.3 years) and 20 younger adults (10 males; mean age: 26.7 years) undertook a simple instruction-based learning paradigm in the MRI scanner. They sorted sequences of coloured shapes according to binary discrimination rules that were updated at two-minute intervals. Unlike common reinforcement learning tasks, the rules were unambiguous, being explicitly presented; consequently, there was no requirement to monitor feedback or estimate contingencies. Despite its simplicity, a third of the Parkinson’s group, but only one older adult, showed marked increases in errors, 4 SD greater than the worst performing young adult. The pattern of errors was consistent, reflecting a tendency to misbind discrimination rules. The misbinding behaviour was coupled with reduced frontal, parietal and anterior caudate activity when rules were being encoded, but not when attention was initially oriented to the instruction slides or when discrimination trials were performed. Concomitantly, Magnetic Resonance Spectroscopy showed reduced gamma-Aminobutyric acid levels within the mid-dorsolateral prefrontal cortices of individuals who made misbinding errors. These results demonstrate, for the first time, that a subset of early-to-mid stage people with Parkinson’s show substantial deficits when binding new task rules in working memory. Given the ubiquity of instruction-based learning, these deficits are likely to impede daily living. They will also confound clinical assessment of other cognitive processes. Future work should determine the value of instruction-based learning as a sensitive early marker of cognitive decline and as a measure of responsiveness to therapy in Parkinson's disease.
[18F]-AV-1451 binding in the substantia nigra as a marker of neuromelanin in Lewy body diseases
Authors: Mak Elijah , Kouli Antonina , Holland Negin , Nicastro Nicolas , Savulich George , Surendranathan Ajenthan , Malpetti Maura , Manavaki Roido , Hong Young T , Fryer Tim D , Aigbirhio Franklin , Rowe James B , O’Brien John T , Williams-Gray Caroline H
Published: August 2021

While [18F]-AV-1451 was developed as a PET radiotracer with high affinity for hyperphosphorylated tau, it has been proposed that loss of ‘off-target’ [18F]-AV-1451 binding to neuromelanin in the substantia nigra could be a surrogate marker of Lewy body diseases. [18F]-AV-1451 binding was measured in the substantia nigra of patients with Parkinson’s disease (n = 35), dementia with Lewy bodies (n = 10) and separate control groups (n = 37; n = 14). Associations with motor symptoms, cognition and disease duration were evaluated using linear regression models. The dementia with Lewy bodies group had significantly reduced substantia nigra [18F]-AV-1451 binding compared to controls after adjusting for age (P < 0.05). However, there were no significant differences in substantia nigra [18F]-AV-1451 binding between Parkinson’s disease and controls. Substantia nigra [18F]-AV-1451 binding was not associated with age, disease duration, Movement Disorders Society—Unified Parkinson’s Disease Rating Scale and cognitive scores in dementia with Lewy bodies and Parkinson’s disease groups. Despite the reduction of substantia nigra [18F]-AV-1451 binding in dementia with Lewy bodies, these findings suggest that substantia nigra [18F]-AV-1451 binding has no value as a diagnostic marker in early Parkinson’s disease. Further investigations in longitudinal cohorts are warranted.
Estimating the Latent Period of Coronavirus Disease 2019 (COVID-19)
Authors: Xin Hualei , Li Yu , Wu Peng , Li Zhili , Lau Eric H Y , Qin Ying , Wang Liping , Cowling Benjamin J , Tsang Tim K , Li Zhongjie
Published: August 2021

Using detailed exposure information on COVID-19 cases, we estimated the mean latent period to be 5.5 (95% CI: 5.1–5.9) days, shorter than the mean incubation period (6.9 days). Laboratory testing may allow shorter quarantines since 95% of COVID-19 cases shed virus within 10.6 (95% CI: 9.6–11.6) days of infection.
Novel Vector of Scrub Typhus in Sub-Antarctic Chile: Evidence From Human Exposure
Authors: Weitzel Thomas , Silva-de la Fuente María Carolina , Martínez-Valdebenito Constanza , Stekolnikov Alexandr A , Pérez Caricia , Pérez Ruth , Vial Cecilia , Abarca Katia , Acosta-Jamett Gerardo
Published: August 2021

The exposure of a research team to chigger mites in southern Chile allowed the first identification of a trombiculid species as vector and reservoir of scrub typhus outside the tsutsugamushi triangle, providing unique insights into the ecology and transmission of this recently discovered rickettsial infection in South America.
Adult-onset nephrotic syndrome following coronavirus disease vaccination
Authors: Biradar Vivek , Konnur Abhijit , Gang Sishir , Hegde Umapati , Rajapurkar Mohan , Patel Hardik , Pandey Sachida Nand , Soni Shailesh
Published: August 2021

A 22-year-old healthy man was admitted for oedema 15 days after the first injection of the COVISHIELD coronavirus disease 2019 (COVID-19) vaccine (Oxford AstraZeneca) vaccine. Nephrotic syndrome was diagnosed and a kidney biopsy showed minimal change disease. Oral prednisolone was started at 1 mg/kg/day resulting in complete remission within 1 week.
Bioproducts generation from carboxylate platforms by the non-conventional yeast Yarrowia lipolytica
Authors: Park Young-Kyoung , González-Fernández Cristina , Robles-Iglesias Raúl , Vidal Lea , Fontanille Pierre , Kennes Christian , Tomás Pejó Elia , Nicaud Jean-Marc , Fickers Patrick
Published: August 2021

In recent years, there has been a growing interest in the use of renewable sources for bio-based production aiming at developing sustainable and feasible approaches towards a circular economy. Among these renewable sources, organic wastes (OWs) can be anaerobically digested to generate carboxylates like volatile fatty acids (VFAs), lactic acid, and longer-chain fatty acids that are regarded as novel building blocks for the synthesis of value-added compounds by yeasts. This review discusses on the processes that can be used to create valuable molecules from OW-derived VFAs; the pathways employed by the oleaginous yeast Yarrowia lipolytica to directly metabolize such molecules; and the relationship between OW composition, anaerobic digestion, and VFA profiles. The review also summarizes the current knowledge about VFA toxicity, the pathways by which VFAs are metabolized and the metabolic engineering strategies that can be employed in Y. lipolytica to produce value-added biobased compounds from VFAs.
Internal gravity waves in a stratified layer atop a convecting liquid core in a non-rotating spherical shell
Authors: Bouffard M , Favier B , Lecoanet D , Le Bars M
Published: August 2021

Seismic and magnetic observations have suggested the presence of a stably stratified layer atop Earth’s core. Such a layer could affect the morphology of the geomagnetic field and the evolution of the core, but the precise impact of this layer depends largely on its internal dynamics. Among other physical phenomena, stratified layers host internal gravity waves (IGW), which can be excited by adjacent convective motions. Internal waves are known to play an important role on the large-scale dynamics of the Earth’s climate and on the long-term evolution of stars. Yet, they have received relatively little attention in the Earth’s outer core so far and deserve detailed investigations in this context. Here, we make a first step in that direction by running numerical simulations of IGW in a non-rotating spherical shell in which a stratified layer lies on top of a convective region. We use a nonlinear equation of state to produce self-consistently such a two-layer system. Both propagating waves and global modes coexist in the stratified layer. We characterize the spectral properties of these waves and find that energy is distributed across a wide range of frequencies and length scales, that depends on the Prandtl number. For the control parameters considered and in the absence of rotational and magnetic effects, the mean kinetic energy in the layer is about 0.1 per cent that of the convective region. IGW produce perturbations in the gravity field that may fall within the sensitivity limit of present-day instruments and could potentially be detected in available data. We finally provide a road map for future, more geophysically realistic, studies towards a more thorough understanding of the dynamics and impact of internal waves in a stratified layer atop Earth’s core.
P-wave picking for earthquake early warning: refinement of aTpdmethod
Authors: Yamada Masumi , Mori Jim
Published: August 2021

Detecting P-wave onsets for online processing is an important component for real-time seismology. As earthquake early warning systems around the world come into operation, the importance of reliable P-wave detection has increased, since the accuracy of the earthquake information depends primarily on the quality of the detection. In addition to the accuracy of arrival time determination, the robustness in the presence of noise and the speed of detection are important factors in the methods used for the earthquake early warning. In this paper, we tried to improve the P-wave detection method designed for real-time processing of continuous waveforms. We used the new Tpd method, and proposed a refinement algorithm to determine the P-wave arrival time. Applying the refinement process substantially decreases the errors of the P-wave arrival time. Using 606 strong motion records of the 2011 Tohoku earthquake sequence to test the refinement methods, the median of the error was decreased from 0.15 to 0.04 s. Only three P-wave arrivals were missed by the best threshold. Our results show that the Tpd method provides better accuracy for estimating the P-wave arrival time compared to the STA/LTA method. The Tpd method also shows better performance in detecting the P-wave arrivals of the target earthquakes in the presence of noise and coda of previous earthquakes. The Tpd method can be computed quickly, so it would be suitable for the implementation in earthquake early warning systems.
Seismic velocity structure along the North Anatolian Fault beneath the Central Marmara Sea and its implication for seismogenesis
Authors: Yamamoto Yojiro , Kalafat Dogan , Pinar Ali , Takahashi Narumi , Polat Remzi , Kaneda Yoshiyuki , Ozener Haluk
Published: August 2021

The offshore part of the North Anatolian Fault (NAF) beneath the Marmara Sea is a well-known seismic gap for future M > 7 earthquakes in the sense that more than 250 yr have passed since the last major earthquake in the Central Marmara region. Although many studies discussed the seismic potential for the future large earthquake in this region on the basis of historical record, geodetic and geological observations, it is difficult to evaluate the actual situation on the seismic activity and structure along the NAF beneath the Marmara Sea due to the lack of ocean bottom seismic observations. Using ocean bottom seismometer observations, an assessment of the location of possible asperities that could host an expected large earthquake is undertaken based on heterogeneities in the microseismicity distribution and seismic velocity structure. Specifically, seismic tomography and precise hypocentre estimations are conducted using offshore seismic data whose recording period is 11 months. About five times more microearthquakes are detected with respect to events recorded in a land-based catalogue. A comparison with previously published results from offshore observation data suggests that the seismicity pattern had not changed from 2014 September to 2017 May. The location accuracy of microearthquakes is greatly improved from only the land-based earthquake catalogue, particularly for depth direction. There are several aseismic and inactive zones of microearthquake, and the largest one is detected using land-based seismic observation, whereas other zones are newly detected via offshore observations. The obtained velocity model shows a strong lateral contrast, with two changing points. The western changing point corresponds to a segmentation boundary, where the dip angle of the NAF segments changed. High-velocity zones from tomographic images are characterized by low seismicity eastward of the segment boundary. To the east of 28.50°E, the high-velocity zone becomes thicker in the depth direction and is characterized by low seismicity. Although the low seismic activity alone could be interpreted as both strong coupling and fully creeping, the high-velocity features at the same can be concluded that these zones are consist of brittle material and strong coupling. From comparison with other geodetic and seismic studies, we interpret these zones as locked zones that had been ruptured by the past large earthquakes and could be ruptured by future ones. These zones might accumulate strain since the main shock rupture associated with the 1766 May Ms 7.3 earthquake, the latest major earthquake in this region.
An economic evaluation of implementing a decentralized dengue screening intervention under the National Vector Borne Disease Control Programme in Tamil Nadu, South India
Authors: Muniyandi Malaisamy , Karikalan Nagarajan , Ravi Karunya , Sengodan Senthilkumar , Krishnan Rajendran , Tyagi Kirti , Rajsekar Kavitha , Raju Sivadhas , Selvavinayagam T S
Published: August 2021

Background

Lack of effective early screening is a major obstacle for reducing the fatality rate and disease burden of dengue. In light of this, the government of Tamil Nadu has adopted a decentralized dengue screening strategy at the primary healthcare (PHC) facilities using blood platelet count. Our objective was to determine the cost-effectiveness of a decentralized screening strategy for dengue at PHC facilities compared with the current strategy at the tertiary health facility (THC) level.

Methods

Decision tree analysis followed a hypothetical cohort of 1000 suspected dengue cases entering the model. The cost-effectiveness analysis was performed at a 3% discount rate for the proposed and current strategy. The outcomes are expressed in incremental cost-effectiveness ratios (ICERs) per quality-adjusted life years gained. One-way sensitivity analysis and probabilistic sensitivity analysis were done to check the uncertainty in the outcome.

Results

The proposed strategy was found to be cost-saving and ICER was estimated to be −41 197. PSA showed that the proposed strategy had a 0.84 probability of being an economically dominant strategy.

Conclusions

The proposed strategy is cost-saving, however, it is recommended to consider optimal population coverage, costs to economic human resources and collateral benefits of equipment.
Rebel Primary Commodity Markets, Price Shocks, and Supplier Victimization
Authors: Estancona Chelsea L
Published: August 2021

Rebel organizations often benefit from the sale of primary commodities. However, producing these commodities may require labor from noncombatants. Rebels provide security and payment to civilian suppliers, but their ability to do so depends on consistent profits. How, then, do price shocks to labor-intensive primary commodities undermine rebel–supplier relationships? I hypothesize that negative commodity price shocks lead cash-strapped rebels to ensure suppliers’ loyalty by substituting coercion for positive incentives. Conversely, states seek to limit rapid increases in rebels’ profit while avoiding the reputational costs of civilian victimization. Thus, victimization of rebel suppliers from groups such as pro-government paramilitaries is hypothesized to increase after positive commodity price shocks. I test these hypotheses with a new dataset covering 1999–2007 that combines monthly US STRIDE (System to Retrieve Information from Drug Evidence) data on cocaine price with municipal-level data from the Colombian Centro Nacional de Memoria Histórica about the FARC (Fuerzas Armadas Revolucionarias de Colombia) and paramilitary groups’ use of civilian victimization.
High-level resistance to bictegravir and cabotegravir in subtype A- and D-infected HIV-1 patients failing raltegravir with multiple resistance mutations
Authors: Ndashimye Emmanuel , Li Yue , Reyes Paul S , Avino Mariano , Olabode Abayomi S , Kityo Cissy M , Kyeyune Fred , Nankya Immaculate , Quiñones-Mateu Miguel E , Barr Stephen D , Arts Eric J
Published: August 2021

Objectives

The second-generation integrase strand transfer inhibitor (INSTI) bictegravir is becoming accessible in low- and middle-income countries (LMICs), and another INSTI, cabotegravir, has recently been approved as a long-acting injectable. Data on bictegravir and cabotegravir susceptibility in raltegravir-experienced HIV-1 subtype A- and D-infected patients carrying drug resistance mutations (DRMs) remain very scarce in LMICs.

Patients and methods

HIV-1 integrase (IN)-recombinant viruses from eight patients failing raltegravir-based third-line therapy in Uganda were genotypically and phenotypically tested for susceptibility to bictegravir and cabotegravir. Ability of these viruses to integrate into human genomes was assessed in MT-4 cells.

Results

HIV-1 IN-recombinant viruses harbouring single primary mutations (N155H or Y143R/S) or in combination with secondary INSTI mutations (T97A, M50I, L74IM, E157Q, G163R or V151I) were susceptible to both bictegravir and cabotegravir. However, combinations of primary INSTI-resistance mutations such as E138A/G140A/G163R/Q148R or E138K/G140A/S147G/Q148K led to decreased susceptibility to both cabotegravir (fold change in EC50 values from 429 to 1000×) and bictegravir (60 to 100×), exhibiting a high degree of cross-resistance. However, these same IN-recombinant viruses showed impaired integration capacity (14% to 48%) relative to the WT HIV-1 NL4-3 strain in the absence of drug.

Conclusions

Though not currently widely accessible in most LMICs, bictegravir and cabotegravir offer a valid alternative to HIV-infected individuals harbouring subtype A and D HIV-1 variants with reduced susceptibility to first-generation INSTIs but previous exposure to raltegravir may reduce efficacy, more so with cabotegravir.
Efficacy of dihydroartemisinin/piperaquine in patients with non-complicated Plasmodium falciparum malaria in Yaoundé, Cameroon
Authors: Mairet-Khedim Mélissa , Nsango Sandrine , Ngou Christelle , Menard Sandie , Roesch Camille , Khim Nimol , Srun Sreynet , Iriart Xavier , Lanot Thomas , Otam Laure , Abega Francis , Ayong Lawrence , Morlais Isabelle , Gandia Peggy , Witkowski Benoit , Berry Antoine
Published: August 2021

Background

Dihydroartemisinin/piperaquine is increasingly used for the treatment of uncomplicated Plasmodium falciparum malaria in Africa. The efficacy of this combination in Cameroon is poorly documented, while resistance to dihydroartemisinin/piperaquine readily spreads in Southeast Asia.

Objectives

This study evaluated the clinical efficacy of dihydroartemisinin/piperaquine in Cameroon, as well as the molecular profile and phenotypic susceptibility of collected isolates to dihydroartemisinin and piperaquine.

Patients and methods

Dihydroartemisinin/piperaquine efficacy in 42 days was followed-up for 138 patients presenting non-complicated falciparum malaria. Piperaquine concentration was determined at day 7 for 124 patients. kelch13 gene polymorphisms (n = 150) and plasmepsin2 gene amplification (n = 148) were determined as molecular markers of resistance to dihydroartemisinin and piperaquine, respectively. Parasite susceptibility to dihydroartemisinin and piperaquine was determined using validated in vitro survival assays.

Results

The efficacy of dihydroartemisinin/piperaquine treatment was 100% after PCR correction. The reinfections were not associated with a variation of piperaquine concentration at day 7. Ninety-six percent (144/150) of the samples presented a WT allele of the kelch13 gene. Two percent (3/150) presented the non-synonymous mutation A578S, which is not associated with resistance to dihydroartemisinin. No duplication of the plasmepsin2 gene was observed (0/148). All the samples tested in vitro by survival assays (n = 87) were susceptible to dihydroartemisinin and piperaquine.

Conclusions

Dihydroartemisinin/piperaquine has demonstrated excellent therapeutic efficacy with no evidence of emerging artemisinin or piperaquine resistance in Yaoundé, Cameroon. This observation suggests that dihydroartemisinin/piperaquine could be a sustainable therapeutic solution for P. falciparum malaria if implemented in areas previously free of artemisinin- and piperaquine-resistant parasites, unlike Southeast Asia.
Reasons for Listening to Music Vary by Listeners’ Anxiety Sensitivity Levels
Authors: Pridy Colin B , Watt Margo C , Romero-Sanchiz Pablo , Lively Christopher J , Stewart Sherry H
Published: August 2021

Listening to music aids regulation of emotional arousal and valence (positive vs. negative). Anxiety sensitivity (AS; fear of arousal-related sensations) increases the risk for emotion dysregulation and associated coping behaviors such as substance use and exercise avoidance. The relationship between AS and music listening, however, has received very little attention. This study (1) used exploratory factor analysis of 53 items drawn from three previously validated measures of reasons for music listening to identify the core reasons for listening to music among university students and (2) explored associations between AS and reasons for music listening. Undergraduates (N = 788; 77.7% women; Mage = 19.20, SDage = 2.46) completed the Anxiety Sensitivity Index-3, Motives for Listening to Music Questionnaire, Barcelona Musical Reward Questionnaire, and Brief Music in Mood Regulation Scale. Six core reasons for music listening were identified: Coping, Conformity, Revitalization, Social Enhancement, Connection, and Sensory-Motor. Over and above age and gender, AS was associated with Coping and Conformity—reasons that involve relief from aversive emotions. AS also was associated with listening for Connection reasons. AS was not associated with Revitalization, Social Enhancement, or Sensory-Motor—reasons that involve rewards such as heightened positive emotions. Results suggest that individual differences may influence why people incorporate music listening into their day-to-day lives. Further longitudinal and experimental research is needed to establish directionality and causality in the observed relationship of AS to relief-oriented reasons for music listening. Findings may guide music therapists’ efforts to tailor treatment for individuals at risk for anxiety and related mental health problems.
Immunogenicity and Safety of the BNT162b2 mRNA COVID-19 Vaccine Among Actively Treated Cancer Patients
Authors: Ligumsky Hagai , Safadi Esraa , Etan Tal , Vaknin Noam , Waller Manuel , Croll Assaf , Nikolaevski-Berlin Alla , Greenberg Inbal , Halperin Tami , Wasserman Asaf , Galazan Lior , Arber Nadir , Wolf Ido
Published: August 2021

Background

Activity and safety of the SARS-CoV-2 BNT162b2 vaccine in actively treated patients with solid tumors is currently unknown.

Methods

We conducted a retrospective study of 326 patients with solid tumors treated with anticancer medications to determine the proportion of cancer patients with immunogenicity against SARS-CoV-2 following 2 doses of the BNT162b2 vaccine. The control group comprised 164 vaccinated healthy adults. Anti-SARS-CoV-2 S immunoglobulin G antibodies were measured using a level greater than 50 AU/mL as a cutoff for seropositivity. Information on adverse effects was collected using a questionnaire. All statistical tests were 2-sided.

Results

Most patients (205, 62.9%) were treated with chemotherapy either alone or with additional therapy; 55 (16.9%) were treated with immune checkpoint inhibitors and 38 (11.7%) with targeted therapy alone; 28 (8.6%) received other combinations. The vaccine was well tolerated, and no severe side effects were reported. Among patients with cancer, 39 (11.9%) were seronegative compared with 5 (3.0%) of the control group (P = .001). Median immunoglobulin G titers were statistically significantly lower among patients with cancer compared with control (931 AU/mL vs 2817 AU/mL, P = .003). Seronegativity proportions were higher in the chemotherapy-treated group (n = 19; 18.8%) compared with the immune checkpoint inhibitor–treated patients (n = 5; 9.1%) and with those treated with targeted therapy (n = 1; 2.6%) (P = .02). Titers were also statistically significantly different among treatment types (P = .002).

Conclusions

The BNT162b2 vaccine is safe and effective in actively treated patients with cancer. The relatively lower antibody titers and lower proportion of seropositive patients, especially among chemotherapy-treated patients, call for continuing the use of personal protective measures in these patients, even following vaccination.
Obesity and Breast Cancer Risk in Men: A National Case-Control Study in England and Wales
Authors: Swerdlow Anthony J , Bruce Cydney , Cooke Rosie , Coulson Penny , Griffin James , Butlin Alison , Smith Beverley , Swerdlow M Jill , Jones Michael E
Published: August 2021

Background

Breast cancer is rare in men, and information on its causes is very limited from studies that have generally been small. Adult obesity has been shown as a risk factor, but more detailed anthropometric relations have not been investigated.

Methods

We conducted an interview population-based case-control study of breast cancer in men in England and Wales including 1998 cases incident during 2005-2017 at ages younger than 80 years and 1597 male controls, with questions asked about a range of anthropometric variables at several ages. All tests of statistical significance were 2-sided.

Results

Risk of breast cancer statistically significantly increased with increasing body mass index (BMI) at ages 20 (odds ratio [OR] = 1.07, 95% confidence interval [CI] = 1.02 to 1.12 per 2-unit change in BMI), 40 (OR = 1.11, 95% CI = 1.07 to 1.16), and 60 (OR = 1.14, 95% CI = 1.09 to 1.19) years, but there was also an indication of raised risk for the lowest BMIs. Large waist circumference 5 years before interview was more strongly associated than was BMI with risk, and each showed independent associations. Associations were similar for invasive and in situ tumors separately and stronger for HER2-positive than HER2-negative tumors. Of the tumors, 99% were estrogen receptor positive.

Conclusions

Obesity at all adult ages, particularly recent abdominal obesity, is associated with raised risk of breast cancer in men, probably because of the conversion of testosterone to estrogen by aromatase in adipose tissue. The association is particularly strong for HER2-expressing tumors.
Chrysanthemum embryo development is negatively affected by a novel ERF transcription factor, CmERF12
Authors: Xu Sujuan , Hou Huizhong , Wu Ze , Zhao Jingya , Zhang Fengjiao , Teng Renda , Chen Fadi , Teng Nianjun
Published: August 2021

Embryo abortion often occurs during distant hybridization events. Apetala 2/ethylene-responsive factor (AP2/ERF) proteins are key transcription factor (TF) regulators of plant development and stress resistance, but their roles in hybrid embryo development are poorly understood. In this study, we isolated a novel AP2/ERF TF, CmERF12, from chrysanthemum and show that it adversely affects embryo development during distant hybridization. Transcriptome and real-time quantitative PCR demonstrate that CmERF12 is expressed at significantly higher levels in aborted ovaries compared with normal ones. CmERF12 localizes to the cell nucleus and contains a conserved EAR motif that mediates its transcription repressor function in yeast and plant cells. We generated artificial microRNA (amiR) CmERF12 transgenic lines of Chrysanthemum morifolium var. ‘Yuhualuoying’ and conducted distant hybridization with the wild-type tetraploid, Chrysanthemum nankingense, and found that CmERF12-knock down significantly promoted embryo development and increased the seed-setting rates during hybridization. The expression of various genes related to embryo development was up-regulated in developing ovaries from the cross between female amiR-CmERF12 C. morifolium var. ‘Yuhualuoying’× male C. nankingense. Furthermore, CmERF12 directly interacted with CmSUF4, which is known to affect flower development and embryogenesis, and significantly reduced its ability to activate its target gene CmEC1 (EGG CELL1). Our study provides a novel method to overcome barriers to distant hybridization in plants and reveals the mechanism by which CmERF12 negatively affects chrysanthemum embryo development.
A gene regulatory network for tiller development mediated by Tin8 in maize
Authors: Lin Zhelong , Zhou Leina , Zhong Shuyang , Fang Xiaojian , Liu Hangqin , Li Yan , Zhu Can , Liu Jiacheng , Lin Zhongwei
Published: August 2021

The complex gene regulatory network underlying tiller development in maize remains largely unknown. Here we identified two major quantitative trait loci for tiller number, Tin8 on chromosome 8 and the previously known Tb1 on chromosome 1, in a population derived from a teosinte–maize cross. Map-based cloning and association mapping revealed that Tin8, corresponding to Zcn8 encoding a phosphatidylethanolamine-binding-related kinase, is down-regulated in transcription, which results in decreased tiller number. A strong interaction between Tin8 and the key gen Tb1 was detected for tiller number. Further RNA-seq analysis showed that the expression of 13 genes related to tiller development was controlled by Tin8. Our results support the existence of a complex gene regulatory network for the outgrowth of the tiller bud in maize, in which Zcn8 controls 13 tiller-related genes, including four genes for hormonal responses. In particular, Zcn8 represses Gt1, D14, and Tru1 through the interaction with Tb1.
Glymphatics: A Transformative Development in Medical Neuroscience Relevant to Injuries in Military Central Nervous System
Authors: Meyerhoff James , Chakraborty Nabarun , Hammamieh Rasha
Published: August 2021

Introduction

The glia-operated glymphatic system, analogous to but separate from the lymphatics in the periphery, is unique to brain and retina, where it is very closely aligned with the arteriolar system. This intimate relationship leads to a “blood vessel like” distribution pattern of glymphatic vessels in the brain. The spatial relationship of glymphatics, including their essential component aquaporin-4 with vascular pericytes of brain arterioles is critical to functionality and is termed “polarization”.

Materials and Methods

We review the available literature on the factors affecting the resting state of glymphatics under normal conditions, including the important role of sleep in supporting normal glymphatic function (including waste removal) as well as the critical role of “polarization” under normal conditions. We then examine the effects of traumatic brain injury (TBI) or seizures on the glymphatic system and its state of “polarization”.

Results

Injury, such as TBI, can disrupt polarization resulting in “depolarization” leading to brain edema.

Conclusion

Damage to the glymphatic system might explain the brain edema so often seen following TBI or other insult. Moreover, similar damage should be expected in response to seizures, which can often be associated with chemical exposures as well as with TBI. Military operations, whether night operations or continuous operations, quite often impose limitations on sleep. As glymphatic function is sleep-dependent, sleep deprivation alone could compromise glymphatic function, as well, and might in addition, explain some of the well-known performance deficits associated with sleep deprivation. Possible effects of submarine and diving operations, chemical agents (including seizures), as well as high altitude exposure and other threats should be considered. In addition to the brain, the retina is also served and protected by the glymphatic system. Accordingly, the effect of military-related risks (e.g., exposure to laser or other threats) to retinal glymphatic function should also be considered. An intact glymphatic system is absolutely essential to support normal central nervous system functionality, including cognition. This effects a broad range of military threats on brain and retinal glymphatics should be explored. Possible preventive and therapeutic measures should be proposed and evaluated, as well.
Carbapenem-Resistant Enterobacterales Infection After Massive Blast Injury: Use of Cefiderocol Based Combination Therapy
Authors: Carney B.W , Rizzo J A , Alderete J F , Cindass R , Markelz A E , Cancio L C
Published: August 2021

A military soldier sustained a blast injury in Afghanistan, resulting in amputations and hemipelvectomy. He developed New Delhi metallo-beta-lactamase-producing E. coli bacteremia, soft-tissue infection, and sacral osteomyelitis. These organisms are being increasingly discovered in different communities around the world. He was successfully treated with tigecycline and cefiderocol. Cefiderocol is a novel siderophore-based cephalosporine developed to treat serious infections, including those caused by carbapenem-resistant Enterobacterales.
Hallux Valgus Nonunion Correction in an Active Duty Military Member
Authors: Rezvani Aryan , Shazadeh Safavi Kiya , Fellars Todd A , Janney Cory F
Published: August 2021

Hallux valgus is one of the most common conditions treated by foot and ankle orthopedists; over 140 surgical procedures have been developed for management of the condition. A rare complication of hallux valgus repair is nonunion, and the literature regarding nonunion after hallux valgus repair is correspondingly sparse. We present a 39-year-old active duty male who underwent operative management after developing nonunion and transfer metatarsalgia following a proximal oblique metatarsal osteotomy. The patient underwent nonunion correction and metatarsal lengthening via bone allografting. No complications were observed during the intra- or perioperative periods. At 2.5-years postoperatively, the patient’s symptoms had largely resolved. He expressed high satisfaction with his outcome and was able to continue activity duty. Our findings indicate that nonunion repair can have excellent clinical outcomes with high patient satisfaction, even in an active military population.
A Case Report of Combat Blast Injury Requiring Combat Casualty Care, Far-Forward ECMO, Air Transport, and All Levels of Military Critical Care
Authors: Piper Lydia C , Nam Jason J , Kuckelman John P , Sams Valerie G , DellaVolpe Jeffry D , Biscotti Mauer , Negaard Kathryn A , Mason Phillip E , Gurney Jennifer M
Published: August 2021

We describe a 34-year-old soldier who sustained a blast injury in Syria resulting in tracheal 5 cm tracheal loss, cervical spine and cord injury with tetraplegia, multiple bilateral rib fractures, esophageal injury, traumatic brain injury, globe evisceration, and multiple extremity soft tissue and musculoskeletal injuries including a left tibia fracture with compartment syndrome. An emergent intubation of the transected trachea was performed in the field, and the patient was resuscitated with whole blood prehospital. During transport to the Role 2, the patient required cardiopulmonary resuscitation for cardiac arrest. On arrival, he underwent a resuscitative thoracotomy and received a massive transfusion exclusively with whole blood. A specialized critical care team transported the patient to the Role 3 hospital in Baghdad, and the DoD extracorporeal membrane oxygenation (ECMO) team was activated secondary to his unstable airway and severe hypoxia secondary to pulmonary blast injury. The casualty was cannulated in Baghdad approximately 40 hours after injury with bifemoral cannulae in a venovenous configuration. He was transported from Iraq to the U.S. Army Institute of Surgical Research Burn Center in San Antonio without issue. Extracorporeal membrane oxygenation support was successfully weaned, and he was decannulated on ECMO day 4. The early and en route use of venovenous ECMO allowed for maintenance of respiratory support during transport and bridge to operative management and demonstrates the feasibility of prolonged ECMO transport in critically ill combat casualties.
Clarification of Eosinophilic Esophagitis Treatment in the DoD Retention Standards
Authors: Gable Austin , Fiore Benjamin , Cheatham Joseph
Published: August 2021

The DoD Instruction 6130.03, Volume 2, outlines the retention standards for the U.S. Military, providing guidance on medical conditions and treatments that are disqualifying for all branches of the military. This document states that patients with conditions requiring immunomodulating or immunosuppressant medications do not meet retention standards. Eosinophilic esophagitis is a common, chronic inflammatory disease of the esophagus that typically presents with dysphagia. Although proton pump inhibitors are effective at treating this disease in some cases, swallowed topical steroids are the most frequently used therapy within the DoD. These medications act locally in the esophagus and do not cause systemic side effects typical of oral steroid therapy, including immunosuppression. They are effective at inducing and maintaining disease remission and are generally well tolerated, with minimal side effects. We propose a brief amendment to this document to clarify the language used and avoid inappropriate Medical Evaluation Board referrals.
X-ray spectra, light curves and SEDs of blazars frequently observed by Swift
Authors: Giommi Paolo , Perri M , Capalbi M , D’Elia V , Barres de Almeida U , Brandt C H , Pollock A M T , Arneodo F , Di Giovanni A , Chang Y L , Civitarese O , De Angelis M , Leto C , Verrecchia F , Ricard N , Di Pippo S , Middei R , Penacchioni A V , Ruffini R , Sahakyan N , Israyelyan D , Turriziani S
Published: August 2021

Blazars research is one of the hot topics of contemporary extragalactic astrophysics. That is because these sources are the most abundant type of extragalactic γ-ray sources and are suspected to play a central role in multimessenger astrophysics. We have used Swift$\_$xrtproc, a tool to carry out an accurate spectral and photometric analysis of the Swift-XRT data of all blazars observed by Swift at least 50 times between December 2004 and the end of 2020. We present a database of X-ray spectra, best-fit parameter values, count rates and flux estimations in several energy bands of over 31 000 X-ray observations and single snapshots of 65 blazars. The results of the X-ray analysis have been combined with other multifrequency archival data to assemble the broad-band Spectral Energy Distributions (SEDs) and the long-term light curves of all sources in the sample. Our study shows that large X-ray luminosity variability on different time-scales is present in all objects. Spectral changes are also frequently observed with a ‘harder-when-brighter’ or ‘softer-when-brighter’ behaviour depending on the SED type of the blazars. The peak energy of the synchrotron component (νpeak) in the SED of HBL blazars, estimated from the log-parabolic shape of their X-ray spectra, also exhibits very large changes in the same source, spanning a range of over two orders of magnitude in Mrk421 and Mrk501, the objects with the best data sets in our sample.
Primordial obliquities of brown dwarfs and super-Jupiters from fragmenting gravito-turbulent discs
Authors: Jennings R Michael , Chiang Eugene
Published: August 2021

Super-Jupiters, brown dwarfs, and stars can form from the collapse of self-gravitating discs. Such discs are turbulent, with flocculent spiral arms accelerating gas to transonic speeds horizontally and vertically. Objects that fragment from gravito-turbulent discs should spin with a wide range of directions, reflecting the random orientations of their parent eddies. We show by direct numerical simulation that obliquities of newly collapsed fragments can range up to 45○. Subsequent collisions between fragments can further alter the obliquity distribution, up to 90○ or down to near-zero. The large obliquities of newly discovered super-Jupiters on wide orbits around young stars may be gravito-turbulent in origin. Obliquely spinning fragments are born on orbits that may be inclined relative to their parent discs by up to 20○, and gravitationally stir leftover material to many times the pre-fragmentation disc thickness.
SDSS J154751.94+025550 with double-peaked broad H β but single-peaked broad H α: a candidate for central binary black hole system?
Authors: Zhang XueGuang
Published: August 2021

In this manuscript, an interesting blue active galactic nuclei (AGNs) SDSS J154751.94+025550 (=SDSS J1547) is reported with very different line profiles of broad Balmer emission lines: double-peaked broad H β but single-peaked broad H α. SDSS J1547 is the first AGN with detailed discussions on very different line profiles of the broad Balmer emission lines, besides the simply mentioned different broad lines in the candidate for a binary black hole (BBH) system in SDSS J0159+0105. The very different line profiles of the broad Balmer emission lines can be well explained by different physical conditions to two central BLRs in a central BBH system in SDSS J1547. Furthermore, the long-term light curve from CSS can be well described by a sinusoidal function with a periodicity about 2159 d, providing further evidence to support the expected central BBH system in SDSS J1547. Therefore, it is interesting to treat different line profiles of broad Balmer emission lines as intrinsic indicators of central BBH systems in broad line AGN. Under assumptions of BBH systems, 0.125 per cent of broad-line AGN can be expected to have very different line profiles of broad Balmer emission lines. Future study on more broad line AGN with very different line profiles of broad Balmer emission lines could provide further clues on the different line profiles of broad Balmer emission lines as indicator of BBH systems.