bluuebunny/crossref_metadata_2025 huggingface dataset:
Isochronous singing in 3 crested gibbon species (Nomascus spp.)
Authors: De Gregorio Chiara , Raimondi Teresa , Bevilacqua Valeria , Pertosa Chiara , Valente Daria , Carugati Filippo , Bandoli Francesca , Favaro Livio , Lefaux Brice , Ravignani Andrea , Gamba Marco
Published: June 2023

The search for common characteristics between the musical abilities of humans and other animal species is still taking its first steps. One of the most promising aspects from a comparative point of view is the analysis of rhythmic components, which are crucial features of human communicative performance but also well-identifiable patterns in the vocal displays of other species. Therefore, the study of rhythm is becoming essential to understand the mechanisms of singing behavior and the evolution of human communication. Recent findings provided evidence that particular rhythmic structures occur in human music and some singing animal species, such as birds and rock hyraxes, but only 2 species of nonhuman primates have been investigated so far (Indri indri and Hylobates lar). Therefore, our study aims to consistently broaden the list of species studied regarding the presence of rhythmic categories. We investigated the temporal organization in the singing of 3 species of crested gibbons (Nomascus gabriellae, Nomascus leucogenys, and Nomascus siki) and found that the most prominent rhythmic category was isochrony. Moreover, we found slight variation in songs’ tempo among species, with N. gabriellae and N. siki singing with a temporal pattern involving a gradually increasing tempo (a musical accelerando), and N. leucogenys with a more regular pattern. Here, we show how the prominence of a peak at the isochrony establishes itself as a shared characteristic in the small apes considered so far.
PETCH-DB: a Portal for Exploring Tissue-specific and Complex disease-associated 5-Hydroxymethylcytosines
Authors: Cai Qinyun , Zhang Zhou , Cui Xiaolong , Zeng Chang , Cai Jiabin , Cai Jiajun , Wu Kai , Zhang Xu , Shi Yixiang , Arvanitakis Zoe , Bissonnette Marc A , Chiu Brian C -H , Cheng Shi-Yuan , He Chuan , Zhang Wei
Published: June 2023

Epigenetic modifications play critical roles in gene regulation and disease pathobiology. Highly sensitive enabling technologies, including microarray- and sequencing-based approaches have allowed genome-wide profiling of cytosine modifications in DNAs in clinical samples to facilitate discovery of epigenetic biomarkers for disease diagnosis and prognosis. Historically, many previous studies, however, did not distinguish the most investigated 5-methylcytosines (5mC) from other modified cytosines, especially the biochemically stable 5-hydroxymethylcytosines (5hmC), which have been shown to have a distinct genomic distribution and regulatory role from 5mC. Notably, during the past several years, the 5hmC-Seal, a highly sensitive chemical labeling technique, has been demonstrated to be a powerful tool for genome-wide profiling of 5hmC in clinically feasible biospecimens (e.g. a few milliliter of plasma or serum). The 5hmC-Seal technique has been utilized by our team in biomarker discovery for human cancers and other complex diseases using circulating cell-free DNA (cfDNA), as well as the characterization of the first 5hmC Human Tissue Map. Convenient access to the accumulating 5hmC-Seal data will allow the research community to validate and re-use these results, potentially providing novel insights into epigenetic contribution to a range of human diseases. Here we introduce the PETCH-DB, an integrated database that was implemented to provide 5hmC-related results generated using the 5hmC-Seal technique. We aim the PETCH-DB to be a central portal, which will be available to the scientific community with regularly updated 5hmC data in clinical samples to reflect current advances in this field.

Database URL http://petch-db.org/
Unloading, ablation, bridging and transplant: different indications and treatments using the Impella 5.5 as longer-term circulatory support in one patient—an interdisciplinary case report
Authors: Volgmann Constanze , Barten Markus J , Al Assar Yousuf , Grahn Hanno , Metzner Andreas , Söffker Gerold , Schulte-Uentrop Leonie , Magnussen Christina , Kirchhof Paulus , Kluge Stefan , Doll Susanne , Doll Nicolas , Reichenspurner Hermann , Bernhardt Alexander M
Published: June 2023

Background

In patients with cardiogenic shock the clinical treatment often involves temporary mechanical circulatory support for initial haemodynamic stabilization to enable further assessment of therapeutic strategies. The surgically implanted Impella 5.5 can be used for several indications like ventricular unloading, haemodynamic support during high-risk interventions, and as a bridge-to-transplant strategy.

We present an interdisciplinary managed case of using Impella 5.5 for multiple indications and treatment strategies in one patient.

Case summary

A 66-year-old patient with known dilated cardiomyopathy was admitted with non-ST-elevation myocardial infarction and underwent urgent coronary bypass grafting. His native heart function did not recover and he experienced recurrent episodes of sustained ventricular tachycardia (VT) and electrical storm. He was evaluated for heart transplantation (OHT) and received a VT-ablation. However, he suffered an in-hospital cardiac arrest (IHCA) with subsequent implantation of an extracorporeal life support system (ECLS). After surgical placement of an Impella 5.5 due to left ventricular distension and pulmonary congestion, the ECLS was successfully weaned. He showed good neurological outcomes and underwent another high-risk VT-ablation. The patient was further stabilized under Impella 5.5 support in a bridge-to-transplant strategy. After 34 days he underwent a successful OHT.

Discussion

In this interdisciplinary case report the surgically implanted Impella 5.5 as temporary mechanical circulatory support was used for multiple different indications and treatment strategies like ventricular unloading, haemodynamic support during high-risk interventions, and as bridge-to-transplant strategy in one patient.
Joint association of loneliness and traditional risk factor control and incident cardiovascular disease in diabetes patients
Authors: Wang Xuan , Ma Hao , Li Xiang , Heianza Yoriko , Fonseca Vivian , Qi Lu
Published: June 2023

Aims

To investigate the prospective associations of the loneliness and social isolation scales with cardiovascular disease (CVD) risk in diabetes patients and compare the relative importance of loneliness and social isolation with traditional risk factors. Also, the interactions of loneliness or isolation with the degree of risk factor control in relation to CVD risk were evaluated.

Methods and results

A total of 18 509 participants diagnosed with diabetes from the UK Biobank were included. A two-item scale and a three-item scale were used to assess loneliness and isolation levels, respectively. The degree of risk factor control was defined as numbers of glycated hemoglobin (HbA1c), blood pressure (BP), low-density lipoprotein cholesterol (LDL-C), smoking, and kidney condition controlled within the target range. During a mean follow-up of 10.7 years, 3247 total CVD incidents were documented, including 2771 coronary heart disease and 701 strokes. In the fully adjusted model, compared with participants with the lowest loneliness score (zero), hazard ratios (95% confidence interval) for CVD were 1.11 (1.02 and 1.20) and 1.26 (1.11 and 1.42) for participants with a loneliness scale of 1 and 2, respectively (P-trend < 0.001). No significant associations were observed for social isolation. Loneliness ranked higher in relative strength for predicting CVD than the lifestyle risk factors in diabetes patients. A significant additive interaction between loneliness and the degree of risk factor control on the risk of CVD was observed (P for additive interaction = 0.005).

Conclusion

Among diabetes patients, loneliness, but not social isolation scale, is associated with a higher risk of CVD and shows an additive interaction with the degree of risk factor control.
Age-stratified comparison of prognosis in cardiac resynchronization therapy with or without prophylactic defibrillator for nonischemic cardiomyopathy—a nationwide cohort study
Authors: Farouq Maiwand , Rorsman Cecilia , Marinko Sofia , Mörtsell David , Chaudhry Uzma , Wang Lingwei , Platonov Pyotr G , Borgquist Rasmus
Published: June 2023

Aims

Prior studies have suggested that the benefit from primary preventive defibrillator treatment for patients with nonischemic cardiomyopathyy, treated with cardiac resynchronization therapy, may be age-dependent. We aimed to compare age-stratified mortality rates and mode of death in patients with nonischemic cardiomyopathy who are treated with either primary preventive cardiac resynchronization therapy with defibrillator (CRT-D) or CRT with pacemaker (CRT-P).

Methods and results

All patients with nonischemic cardiomyopathy and CRT-P or primary preventive CRT-D who were implanted in Sweden during the period 2005–2020 were included. Propensity scoring was used to create a matched cohort. Primary outcome was all-cause mortality within 5 years. In all, 4027 patients were included: 2334 with CRT-P and 1693 with CRT-D. Crude 5-year mortality was 635 (27%) vs. 246 (15%), P < 0.001. In Cox regression analysis, adjusted for clinically relevant covariables, CRT-D was independently associated with higher 5-year survival [0.72 (0.61–0.85), P < 0.001]. Cardiovascular mortality was similar between groups (62 vs. 64%, P = 0.64), but death from heart failure was more common in the CRT-D group (46 vs. 36%, P = 0.007). In the matched cohort (n = 2414), 5-year mortality was 21% (24 vs. 16%, P < 0.001). In age-stratified analyses, CRT-P was associated with higher mortality in age groups <60 years and 70–79 years, but there was no difference in age groups 60–69 years or 80–89 years.

Conclusion

In this nationwide registry-based study, patients with CRT-D had better 5-year survival compared to patients with CRT-P. The interaction between age and mortality reduction was not consistent, but patients with CRT-D aged <60 years had the largest absolute mortality reduction.
Delineation of conduction gaps of linear lesions during atrial fibrillation ablation using ultra-high-density mapping
Authors: Hashimoto Kenji , Kimura Takehiro , Seki Yuta , Ibe Susumu , Yamashita Terumasa , Miyama Hiroshi , Fujisawa Taishi , Katsumata Yoshinori , Fukuda Keiichi , Takatsuki Seiji
Published: June 2023

Aims

Linear lesions are routinely created by radiofrequency catheter ablation. Unwanted electrical conduction gaps can be produced and are often difficult to ablate. This study aimed to clarify the characteristics of conduction gaps during atrial fibrillation ablation by analysing bidirectional activation maps using a high-density mapping system (RHYTHMIA).

Methods and results

This retrospective study included 31 patients who had conduction gaps along pulmonary vein (PV) isolation or box ablation lesions. Activation maps were sequentially created during pacing from the coronary sinus and PV to reveal the earliest activation site, defined by the entrance and exit. The locations, length between the entrance and exit (gap length), and direction were analysed. Thirty-four bidirectional activation maps were drawn: 21 were box isolation lesions (box group), and 13 were PV isolation lesions (PVI group). Among the box group, nine conduction gaps were present in the roof region and 12 in the bottom region, while nine in right PV and four in left PV among the PVI group. Gap lengths in the roof region were longer than those in the bottom region (26.8 ± 11.8 vs. 14.5 ± 9.8 mm; P = 0.022), while those in right PV tended to longer than those in left PV (28.0 ± 15.3 vs. 16.8 ± 8.0 mm, P = 0.201).

Conclusion

The entrances and exits of electrical conduction gaps were separated, especially in the roof region, indicating that epicardial conduction might contribute to gap formation. Identifying the bidirectional conduction gap might indicate the location and direction of epicardial conduction.
Differences in the risk of premature cancer mortality between natives and immigrants in Spain
Authors: Grande Rafael , García-González Juan Manuel , Stanek Mikolaj
Published: June 2023

Background

The healthy immigrant paradox has found wide support in the literature. To evaluate this hypothesis that immigrants have better health outcomes than the native population, this study aimed to compare the premature cancer mortality between the native and immigrant populations in Spain.

Methods

We obtained the 2012–15 cause-specific mortality estimates from administrative records and participant characteristics data from the 2011 Spanish census. Using Cox proportional hazards regression models, we calculated the risks of mortality of the native and immigrant populations, and the latter populations’ risk based on their regions of origin, and determined the effects of covariates of interest on the calculated risk.

Results

Our results show that the risk of premature cancer mortality is lower among immigrants than among natives, and this gap is higher among men than among women. There is a lower mortality rate among Latin American immigrants (Latino men are 81% less likely to die prematurely from cancer than native-born men, and Latino women are 54% less). Moreover, despite social class disparities, immigrants’ advantage in cancer mortality remained constant and decreased with increasing length of residence in the host country.

Conclusions

This study provided novel evidence on the ‘healthy immigrant paradox’, associated with the fact that migrants are favorably selected at origin, cultural patterns of the societies of origin and, in the case of men, there is some convergence or an ‘unhealthy’ integration that explains the fact that this advantage over natives is lost with more years of residence in Spain.
Genome assemblies of the simultaneously hermaphroditic flatworms Macrostomum cliftonense and Macrostomum hystrix
Authors: Wiberg R Axel W , Brand Jeremias N , Viktorin Gudrun , Mitchell Jack O , Beisel Christian , Schärer Lukas
Published: June 2023

The free-living, simultaneously hermaphroditic flatworms of the genus Macrostomum are increasingly used as model systems in various contexts. In particular, Macrostomum lignano, the only species of this group with a published genome assembly, has emerged as a model for the study of regeneration, reproduction, and stem-cell function. However, challenges have emerged due to M. lignano being a hidden polyploid, having recently undergone whole-genome duplication and chromosome fusion events. This complex genome architecture presents a significant roadblock to the application of many modern genetic tools. Hence, additional genomic resources for this genus are needed. Here, we present such resources for Macrostomum cliftonense and Macrostomum hystrix, which represent the contrasting mating behaviors of reciprocal copulation and hypodermic insemination found in the genus. We use a combination of PacBio long-read sequencing and Illumina shot-gun sequencing, along with several RNA-Seq data sets, to assemble and annotate highly contiguous genomes for both species. The assemblies span ∼227 and ∼220 Mb and are represented by 399 and 42 contigs for M. cliftonense and M. hystrix, respectively. Furthermore, high BUSCO completeness (∼84–85%), low BUSCO duplication rates (8.3–6.2%), and low k-mer multiplicity indicate that these assemblies do not suffer from the same assembly ambiguities of the M. lignano genome assembly, which can be attributed to the complex karyology of this species. We also show that these resources, in combination with the prior resources from M. lignano, offer an excellent foundation for comparative genomic research in this group of organisms.
Preliminary surgical outcomes of laparoscopic right hemicolectomy with transrectal specimen extraction: a propensity score matching study of 120 cases (with video)
Authors: Zhang Mingguang , Liu Zheng , Sun Peng , Hu Xiyue , Zhou Haitao , Jiang Zheng , Tang Jianqiang , Liu Qian , Wang Xishan
Published: June 2023

Background

Compared with conventional laparoscopic surgery, natural orifice specimen extraction surgery (NOSES) has many advantages. Laparoscopic right colectomy with transvaginal specimen extraction has been reported, but the safety and feasibility of transrectal specimen extraction in male patients with ascending colon cancer remain to be verified. This study aimed to preliminarily evaluate the feasibility and safety of laparoscopic right hemicolectomy with transrectal specimen extraction.

Methods

The study was conducted at a single tertiary medical center in China. A total of 494 consecutive patients who underwent laparoscopic right colectomy between September 2018 and September 2020 were included. Transrectal specimen extraction was performed in 40 male patients (the NOSES group). Patients in the NOSES group were matched to the conventional laparoscopic group using propensity score matching at a 1:2 ratio. Short-term and long-term outcomes between the two groups were compared and evaluated.

Results

Forty patients in the NOSES group and 80 patients in the conventional laparoscopic group were matched for analysis. Baseline characteristics were balanced after propensity matching. The operative features, including operating time, intraoperative bleeding, and the number of harvested lymph nodes, were statistically comparable in both groups. In terms of post-operative recovery, patients in the NOSES group showed preferable outcomes, as evidenced by less post-operative pain and faster return to flatus, defecation, and discharge. The post-operative complications rate, according to the Clavien–Dindo classification system, was similar in both groups. No differences in overall survival or disease-free survival were observed between the two groups.

Conclusions

Laparoscopic right colectomy with transrectal specimen extraction is oncologically safe. Compared with conventional laparoscopic right colectomy, it can reduce post-operative pain, accelerate post-operative recovery, shorten the hospital stay, and achieve better cosmetic effect.
The largest induced earthquakes during the GEOVEN deep geothermal project, Strasbourg, 2018–2022: from source parameters to intensity maps
Authors: Lengliné O , Schmittbuhl J , Drif K , Lambotte S , Grunberg M , Kinscher J , Sira C , Schlupp A , Schaming M , Jund H , Masson F
Published: June 2023

Between 2019 November and 2021 July, four induced earthquakes of local magnitude equal to or greater than than three were felt by the population of Strasbourg, France. These events were related to activity at the deep geothermal site GEOVEN located in Vendenheim in the northern suburb area of the city of Strasbourg. The first earthquake, with a local magnitude (Mlv) of 3.0, occurred on 2019 November 12, at the same depth as the bottom of the wells (approximately 4 km) but 5 km to the south. The second (Mlv 3.6) occurred a year later, on 2020 December 4, below the wells, and led to the termination of the project by the authorities. The third (Mlv 3.3) was initiated three weeks after shut-in on 2021 January 22, while the largest earthquake to date (Mlv 3.9) occurred on 2021 June 26, more than 6 months after shut-in. We constrained these four events’ absolute locations using a 3-D velocity model of the area and here present regional intensity maps. We estimated moment magnitude and focal mechanism trough waveform inversion and inferred the fault plane activated during the largest event from an analysis of rupture directivity effects in the recorded waveforms. Our analysis highlights the existence of a critically stressed fault that hosted three of these widely felt events. We show how the derived source properties of these four earthquakes are directly linked to ground shaking observations at the surface. Notably, we demonstrate how earthquake moment, location, direction of rupture and stress drop impact the regional intensity distribution. Our results suggest that the traffic light system could benefit from including ground shaking scenarios based on realistic subsurface properties and potential earthquake source models.
Blockade of innate inflammatory cytokines TNFα, IL-1β, or IL-6 overcomes virotherapy-induced cancer equilibrium to promote tumor regression
Authors: Walsh Michael J , Ali Lestat R , Lenehan Patrick , Kureshi Courtney T , Kureshi Rakeeb , Dougan Michael , Knipe David M , Dougan Stephanie K
Published: June 2023

Cancer therapeutics can lead to immune equilibrium in which the immune response controls tumor cell expansion without fully eliminating the cancer. The factors involved in this equilibrium remain incompletely understood, especially those that would antagonize the anti-tumor immune response and lead to tumor outgrowth. We previously demonstrated that continuous treatment with a non-replicating herpes simplex virus 1 expressing interleukin (IL)-12 induces a state of cancer immune equilibrium highly dependent on interferon-γ. We profiled the IL-12 virotherapy-induced immune equilibrium in murine melanoma, identifying blockade of innate inflammatory cytokines, tumor necrosis factor alpha (TNFα), IL-1β, or IL-6 as possible synergistic interventions. Antibody depletions of each of these cytokines enhanced survival in mice treated with IL-12 virotherapy and helped to overcome equilibrium in some tumors. Single-cell RNA-sequencing demonstrated that blockade of inflammatory cytokines resulted in downregulation of overlapping inflammatory pathways in macrophages, shifting immune equilibrium towards tumor clearance, and raising the possibility that TNFα blockade could synergize with existing cancer immunotherapies.
Yeast culture supplementation of sow diets regulates the immune performance of their weaned piglets under lipopolysaccharide stress
Authors: Liu Yalei , Jia Xinlin , Chang Junlei , Pan Xunjing , Jiang Xuemei , Che Lianqiang , Lin Yan , Zhuo Yong , Feng Bin , Fang Zhengfeng , Li Jian , Hua Lun , Wang Jianping , Sun Mengmeng , Wu De , Xu Shengyu
Published: June 2023

The aim of this study was to investigate the effect of dietary supplementation of sows with yeast cultures (XPC) during late gestation and lactation on the immune performance of their weaned offspring under lipopolysaccharide (LPS) stress. A total of 40 Landrace × Yorkshire sows (parity 3 to 7) with similar backfat thickness were selected and randomly divided into two treatment groups: a control group (basal diet) and a yeast culture group (basal diet + 2.0 g/kg XPC). The trial was conducted from day 90 of gestation to day 21 of lactation. At the end of the experiment, 12 piglets with similar weights were selected from each group and slaughtered 4 h after intraperitoneal injection with either saline or LPS. The results showed that the concentrations of interleukin-6 (IL-6) in the thymus and tumor necrosis factor-α in the liver increased significantly (P < 0.05) in weaned piglets after LPS injection. Maternal dietary supplementation with XPC significantly reduced the concentration of inflammatory factors in the plasma and thymus of weaned piglets (P < 0.05). LPS injection significantly upregulated the expression of some tissue inflammation-related genes, significantly downregulated the expression of intestinal tight junction-related genes, and significantly elevated the protein expression of liver phospho-nuclear factor kappa B (p-NF-κB), the phospho-inhibitory subunit of NF-κB (p-IκBα), phospho-c-Jun N-terminal kinase (p-JNK), Nuclear factor kappa-B (NF-κB), and the inhibitory subunit of NF-κB (IκBα) in weaned piglets (P < 0.05). Maternal dietary supplementation with XPC significantly downregulated the gene expression of IL-6 and interleukin-10 (IL-10) in the thymus and decreased the protein expression of c-Jun N-terminal kinase (JNK) in the liver of weaned piglets (P < 0.05). In summary, injection of LPS induced an inflammatory response in weaned piglets and destroyed the intestinal barrier. Maternal dietary supplementation of XPC improved the immune performance of weaned piglets by inhibiting inflammatory responses.
A C3 continuous double circumscribed corner rounding method for five-axis linear tool path with improved kinematics performance
Authors: Yan Guangwen , Zhang Desheng , Xu Jinting , Sun Yuwen
Published: June 2023

Corner rounding methods have been widely developed to pursue the smooth motions of machine tools. However, most corner rounding methods, which adopt the double inscribed transitions, still remain an inherent issue of retaining large curvatures of transition curves. Even for those double circumscribed transitions-based methods with relatively small curvatures, they also constrain excessively the transition lengths and are limited to a low-order continuity, deteriorating the feedrate and jerk of machine tools. For addressing these problems, a C3 continuous double circumscribed corner rounding (DCCR) method is proposed for five-axis linear tool path. In this method, the C3 continuous double circumscribed B-splines are specially designed to round the corners of tool position and tool orientation, whose transition lengths are analytically determined by jointly constraining the approximation errors, overlaps elimination, and parameter synchronization. Moreover, the excessive constrains of transition lengths imposed by traditional methods are alleviated by fully considering the effects of overlaps and parameter synchronization, and the jerk of rotary axes is also limited with a high-order continuity. Compared to the existing double inscribed corner rounding (DICR) and DCCR methods, experiment results demonstrate that our method can improve further the feedrate while limiting the jerk of machine tools.
Disagreement in Market Index Options
Authors: Salome Guilherme , Tauchen George , Li Jia
Published: June 2023

We generate new evidence on disagreement among traders in the S&P 500 options market from high-frequency intraday price and volume data. Inference on disagreement is based on a model where investors observe public information but agree to disagree on its interpretation; disagreement among investors is captured by the volume–volatility elasticity. For options, there are two natural variables related to disagreement: moneyness and tenor, which we relate to disagreement about the distribution of the market index at different quantiles and times. The estimated volume–volatility elasticity equals unity for options near the money and close to expiration, which is consistent with the case of no disagreement among investors. In contrast, the elasticity estimates decrease with increases in the absolute value of moneyness, indicating investors have a higher disagreement about rare events. Likewise, the elasticity decreases with increases in tenor, implying higher investors’ disagreement about more distant events.
Double-Blind, Placebo-Controlled Study of Bezlotoxumab in Children Receiving Antibacterial Treatment for Clostridioides difficile Infection (MODIFY III)
Authors: Sferra Thomas J , Merta Tomas , Neely Michael , Murta de Oliveira Claudia , Lassaletta Alvaro , Fortuny Guasch Claudia , Dorr Mary Beth , Winchell Gregory , Su Feng-Hsiu , Perko Sarah , Fernsler Doreen , Waskin Hetty , Holden Stephen R
Published: June 2023

Background

Therapies to prevent recurrence of Clostridioides difficile infection (CDI) in pediatric patients are needed. Bezlotoxumab is a fully human monoclonal antibody approved for prevention of recurrent CDI in adults. We assessed the pharmacokinetics, safety, tolerability, and efficacy of bezlotoxumab in pediatric patients.

Methods

MODIFY III was a multicenter, double-blind, placebo-controlled study of bezlotoxumab in children (1 to <18 years) receiving antibacterial treatment for CDI. Participants were randomized 3:1 to receive a single infusion of bezlotoxumab (10 mg/kg) or placebo and were stratified by age at randomization (cohort 1: 12 to <18 years, cohort 2: 1 to <12 years). The primary objective was to characterize bezlotoxumab pharmacokinetics to support dose selection for pediatric patients; the primary endpoint was the area under the bezlotoxumab serum concentration–time curve (AUC0-inf). Safety, tolerability, and efficacy were monitored for 12 weeks post-infusion.

Results

A total of 148 participants were randomized and 143 were treated: 107 with bezlotoxumab and 36 with placebo (cohort 1 n = 60, cohort 2 n = 83; median age 9.0 years); 52.4% of participants were male and 80.4% were white. Geometric mean ratios (90% CI) for bezlotoxumab AUC0-inf were 1.06 (0.95, 1.18) and 0.82 (0.75, 0.89) h * μg/mL for cohorts 1 and 2, respectively. Bezlotoxumab 10 mg/kg was generally well-tolerated with an adverse event profile similar to placebo, including no treatment discontinuations due to adverse events. CDI recurrence was low and comparable for bezlotoxumab (11.2%) and placebo (14.7%).

Conclusions

The results of this study support the bezlotoxumab dose of 10 mg/kg for pediatric patients.

Trial registration

NCT03182907 at ClinicalTrials.gov
Understanding the politics of refugee law and policy making: Interdisciplinary and empirical approaches
Authors: Ghezelbash Daniel , Dorostkar Keyvan
Published: June 2023

In this article, we argue that building a stronger empirical understanding of the politics of domestic refugee law and policy making is essential for refugee law scholars to better advocate for protection-orientated reforms. While much of the legal scholarship is aimed at promoting policy change, the best way to achieve this goal has rarely been examined. We identify three key areas of interdisciplinary empirical research that can create a stronger evidence-base for improving domestic policy reform efforts. This includes understanding the institutions and actors involved in policy formulation, measuring the impact of refugee laws and policies in practice, and identifying how to influence public opinion and build support for progressive law and policy change. We showcase existing interdisciplinary research in each of these areas, and highlight topics ripe for further empirical inquiry.
A search for intercluster filaments with LOFAR and eROSITA
Authors: Hoang D N , Brüggen M , Zhang X , Bonafede A , Liu A , Liu T , Shimwell T W , Botteon A , Brunetti G , Bulbul E , Gennaro G Di , O’Sullivan S P , Pasini T , Röttgering H J A , Vernstrom T , van Weeren R J
Published: June 2023

Cosmological simulations predict the presence of warm hot thermal gas in the cosmic filaments that connect galaxy clusters. This gas is thought to constitute an important part of the missing baryons in the Universe. In addition to the thermal gas, cosmic filaments could contain a population of relativistic particles and magnetic fields. A detection of magnetic fields in filaments can constrain early magnetogenesis in the cosmos. So far, the resulting diffuse synchrotron emission has only been indirectly detected. We present our search for thermal and non-thermal diffuse emission from intercluster regions of 106 paired galaxy clusters by stacking the 0.6–2.3 keV X-ray and 144 MHz radio data obtained with the eROSITA telescope onboard the Spectrum-Roentgen-Gamma (SRG) observatory and LOw Frequency ARray (LOFAR), respectively. The stacked data do not show the presence of X-ray and radio diffuse emission in the intercluster regions. This could be due to the sensitivity of the data sets and/or the limited number of cluster pairs used in this study. Assuming a constant radio emissivity in the filaments, we find that the mean radio emissivity is not higher than $1.2\times 10^{-44}\, {\rm erg \, s^{-1} \, cm^{-3} \, Hz^{-1}}$. Under equipartition conditions, our upper limit on the mean emissivity translates to an upper limit of $\sim 75\, {\rm nG}$ for the mean magnetic field strength in the filaments, depending on the spectral index and the minimum energy cutoff. We discuss the constraint for the magnetic field strength in the context of the models for the formation of magnetic fields in cosmic filaments.
Evolution of the truncation radius in GX 339−4 from XMM–Newton spectral timing
Authors: O’Mathúna B , Young A J , Chainakun P , Webbe R
Published: June 2023

We investigate the changing geometry of the accretion disc in the X-ray binary GX 339−4 using a combination of spectral and timing models to fit six XMM–Newton observations taken during the end of the 2015 X-ray outburst. We use progressively more complex models of the X-ray reflection spectra, from simple disc lines to full relativistic reflection models. For the timing analysis, the Power Spectral Densities (PSDs) are generated from the light curves in the 0.3–0.7 and 0.7–1.5 keV energy bands. We fit PSD models that assume the standard accretion disc truncates at a specific radius, inside of which are two hot-flow zones, one spectrally soft and one spectrally hard, separated by a transition radius. Finally, we combine and jointly fit the full reflection spectral models and the truncated disc PSD models. Our final model is consistent with the spectroscopic and timing data. It suggests that the truncation radius of the disc increases towards the end of the outburst, which is self-consistent with the obtained reflection fraction that is smaller. During this, the source spectrum becomes harder and the soft excess becomes more prominent. The disc truncation radius that increases as the source flux decreases is intermediate between the results of previous studies. However, our analysis of the model performance leads us to believe that higher quality data and better models are required to fully understand the GX 339-4 system and reduce the effect of systematic uncertainties.
Tidal debris from Omega Centauri discovered with unsupervised machine learning
Authors: Youakim Kris , Lind Karin , Kushniruk Iryna
Published: June 2023

The gravitational interactions between the Milky Way and in-falling satellites offer a wealth of information about the formation and evolution of our Galaxy. In this paper, we explore the high-dimensionality of the GALAH DR3 plus Gaia eDR3 data set to identify new tidally stripped candidate stars of the nearby star cluster Omega Centauri ($\omega \, \mathrm{Cen}$). We investigate both the chemical and dynamical parameter space simultaneously, and identify cluster candidates that are spatially separated from the main cluster body, in regions where contamination by halo field stars is high. Most notably, we find candidates for $\omega \, \mathrm{Cen}$ scattered in the halo extending to more than 50° away from the main body of the cluster. Using a grid of simulated streams generated with $\omega \, \mathrm{Cen}$-like orbital properties, we then compare the on sky distribution of these candidates to the models. The results suggest that if $\omega \, \mathrm{Cen}$ had a similar initial mass as its present day mass, then we can place a lower limit on its time of accretion at tacc > 7 Gyr ago. Alternatively, if the initial stellar mass was significantly larger, as would be expected if $\omega \, \mathrm{Cen}$ is the remnant core of a dwarf Galaxy, then we can constrain the accretion time to tacc > 4 Gyr ago. Taken together, these results are consistent with the scenario that $\omega \, \mathrm{Cen}$ is the remnant core of a disrupted dwarf galaxy.
Futibatinib, an Irreversible FGFR1-4 Inhibitor for the Treatment ofFGFR-Aberrant Tumors
Authors: Javle Milind , King Gentry , Spencer Kristen , Borad Mitesh J
Published: June 2023

Fibroblast growth factor receptors (FGFR) are emerging as an important therapeutic target for patients with advanced, refractory cancers. Most selective FGFR inhibitors under investigation show reversible binding, and their activity is limited by acquired drug resistance. This review summarizes the preclinical and clinical development of futibatinib, an irreversible FGFR1-4 inhibitor. Futibatinib stands out among FGFR inhibitors because of its covalent binding mechanism and low susceptibility to acquired resistance. Preclinical data indicated robust activity of futibatinib against acquired resistance mutations in the FGFR kinase domain. In early-phase studies, futibatinib showed activity in cholangiocarcinoma, and gastric, urothelial, breast, central nervous system, and head and neck cancers harboring various FGFR aberrations. Exploratory analyses indicated clinical benefit with futibatinib after prior FGFR inhibitor use. In a pivotal phase II trial, futibatinib demonstrated durable objective responses (42% objective response rate) and tolerability in previously treated patients with advanced intrahepatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements. A manageable safety profile was observed across studies, and patient quality of life was maintained with futibatinib treatment in patients with cholangiocarcinoma. Hyperphosphatemia, the most common adverse event with futibatinib, was well managed and did not lead to treatment discontinuation. These data show clinically meaningful benefit with futibatinib in FGFR2-rearrangement-positive cholangiocarcinoma and provide support for further investigation of futibatinib across other indications. Future directions for this agent include elucidating mechanisms of resistance and exploration of combination therapy approaches.
Association of FTH1-Expressing Circulating Tumor Cells With Efficacy of Neoadjuvant Chemotherapy for Patients With Breast Cancer: A Prospective Cohort Study
Authors: Jia Shijie , Yang Yaping , Zhu Yingying , Yang Wenqian , Ling Li , Wei Yanghui , Fang Xiaolin , Lin Qun , Hamaï Ahmed , Mehrpour Maryam , Gao Jingbo , Tan Weige , Xia Yuan , Chen Jiayi , Jiang Wenguo , Gong Chang
Published: June 2023

Background

The association between different phenotypes and genotypes of circulating tumor cells (CTCs) and efficacy of neoadjuvant chemotherapy (NAC) remains uncertain. This study was conducted to evaluate the relationship of FTH1 gene-associated CTCs (F-CTC) with/without epithelial-mesenchymal transition (EMT) markers, or their dynamic changes with the efficacy of NAC in patients with non-metastatic breast cancer.

Patients and Methods

This study enrolled 120 patients with non-metastatic breast cancer who planned to undergo NAC. The FTH1 gene and EMT markers in CTCs were detected before NAC (T0), after 2 cycles of chemotherapy (T1), and before surgery (T2). The associations of these different types of CTCs with rates of pathological complete response (pCR) and breast-conserving surgery (BCS) were evaluated using the binary logistic regression analysis.

Results

F-CTC in peripheral blood ≥1 at T0 was an independent factor for pCR rate in patients with HER2-positive (odds ratio [OR]=0.08, 95% confidence interval [CI], 0.01-0.98, P = .048). The reduction in the number of F-CTC at T2 was an independent factor for BCS rate (OR = 4.54, 95% CI, 1.14-18.08, P = .03).

Conclusions

The number of F-CTC prior to NAC was related to poor response to NAC. Monitoring of F-CTC may help clinicians formulate personalized NAC regimens and implement BCS for patients with non-metastatic breast cancer.
Leaf hydraulic maze: Abscisic acid effects on bundle sheath, palisade, and spongy mesophyll conductance
Authors: Yaaran Adi , Erez Eyal , Procko Carl , Moshelion Menachem
Published: June 2023

Leaf hydraulic conductance (Kleaf) facilitates the supply of water, enabling continual CO2 uptake while maintaining plant water status. We hypothesized that bundle sheath and mesophyll cells play key roles in regulating the radial flow of water out of the xylem by responding to abscisic acid (ABA). Thus, we generated transgenic Arabidopsis thaliana plants that are insensitive to ABA in their bundle sheath (BSabi) and mesophyll (MCabi) cells. We also introduced tissue-specific fluorescent markers to distinguish between cells of the palisade mesophyll, spongy mesophyll, and bundle sheath. Both BSabi and MCabi plants showed greater Kleaf and transpiration under optimal conditions. MCabi plants had larger stomatal apertures, higher stomatal index, and greater vascular diameter and biomass relative to the wild-type (WT) and BSabi plants. In response to xylem-fed ABA, both transgenic and WT plants reduced their Kleaf and transpiration. The membrane osmotic water permeability (Pf) of the WT's spongy mesophyll was higher than that of the WT's palisade mesophyll. While the palisade mesophyll maintained a low Pf in response to high ABA, the spongy mesophyll Pf was reduced. Compared to the WT, BSabi bundle sheath cells had a higher Pf, but MCabi spongy mesophyll had an unexpected lower Pf. These results suggest that tissue-specific regulation of Pf by ABA may be confounded by whole-leaf hydraulics and transpiration. ABA increased the symplastic permeability, but its contribution to Kleaf was negligible. We suggest that the bundle sheath spongy mesophyll pathway dynamically responds to the fluctuations in water availability, while the palisade mesophyll serves as a hydraulic buffer.
Development of a measure of dietary quality for the UK Biobank
Authors: Montague Chloe , D’Angelo Stefania , Harvey Nicholas , Vogel Christina , Baird Janis
Published: June 2023

Background

Previous studies of the UK Biobank have examined intake of single food items and their association with health outcomes. Our aim was to develop a dietary quality score and examine the relationship between this score and markers of cardiometabolic health.

Methods

Principal component analysis was performed on dietary data from UK Biobank participants. Linear regression was used to analyse the relationship between diet and cardiometabolic health.

Results

The first component explained 14% of the variation in the dietary data. It was characterised by high consumption of meat and low fibre carbohydrates, and a low intake of fruit and vegetables. A higher score, indicative of healthier diet, was associated with lower systolic and diastolic blood pressure (β −0.81, 95% CI −1.0, −0.62; β − .61, 95% CI −0.72, −0.5) and a healthier lipid profile (lower levels of cholesterol β −0.05, 95% CI −0.06, −0.04, triglycerides β −0.05, 95% CI −0.06, −0.03, and higher HDL cholesterol β 0.01, 95% CI 0, 0.01).

Conclusions

The dietary quality score was a good approximation of overall dietary quality. An unhealthy diet was associated with markers of poorer cardiometabolic health.
Long noncoding RNA AI662270 promotes kidney fibrosis through enhancing METTL3‐mediated m6A modification of CTGF mRNA
Authors: Sun Yanyan , Ge Jia , Shao Fang , Ren Zhengrong , Huang Zhen , Ding Zhi , Dong Lei , Chen Jiangning , Zhang Junfeng , Zang Yuhui
Published: June 2023

The sustained release of profibrotic cytokines, mainly transforming growth factor‐β (TGF‐β), leads to the occurrence of kidney fibrosis and chronic kidney disease (CKD). Connective tissue growth factor (CTGF) appears to be an alternative target to TGF‐β for antifibrotic therapy in CKD. In this study, we found that long noncoding RNA AI662270 was significantly increased in various renal fibrosis models. In vivo, ectopic expression of AI662270 alone was sufficient to activate interstitial fibroblasts and drive kidney fibrosis, whereas inhibition of AI662270 blocked the activation of interstitial fibroblasts and ameliorated kidney fibrosis in various murine models. Mechanistic studies revealed that overexpression of AI662270 significantly increased CTGF product, which was required for the role of AI662270 in driving kidney fibrosis. Furthermore, AI662270 binds to the CTGF promoter and directly interacts with METTL3, the methyltransferase of RNA N6‐methyladenosine (m6A) modification. Functionally, AI662270‐mediated recruitment of METTL3 increased the m6A methylation of CTGF mRNA and consequently enhanced CTGF mRNA stability. In conclusion, our results support that AI662270 promotes CTGF expression at the posttranscriptional stage by recruiting METTL3 to the CTGF promoter and depositing m6A modifications on the nascent mRNA, thereby, uncovering a novel regulatory mechanism of CTGF in the pathogenesis of kidney fibrosis.
Implications of MCU complex in metabolic diseases
Authors: Li Chen , Sun Jiyu , Zhang Xidan , Zhou Min , Gan Xueqi
Published: June 2023

Metabolic diseases are considered the primary culprit for physical and mental health of individuals. Although the diagnosis of these diseases is relatively easy, more effective and convenient potent drugs are still being explored. Ca2+ across the inner mitochondrial membrane is a vital intracellular messenger that regulates energy metabolism and cellular Ca2+ homeostasis and is involved in cell death. Mitochondria rely on a selective mitochondrial Ca2+ unidirectional transport complex (MCU complex) in their inner membrane for Ca2+ uptake. We found that the channel contains several subunits and undergoes dramatic transformations in various pathological processes, especially in metabolic diseases. In this way, we believe that the MCU complex becomes a target with significant potential for these diseases. However, there is no review linking the two factors, thus hindering the possibility of new drug production. Here, we highlight the connection between MCU complex‐related Ca2+ transport and the pathophysiology of metabolic diseases, adding understanding and insight at the molecular level to provide new insights for targeting MCU to reverse metabolism‐related diseases.
Gender Differences in Civil Commitment Hearing Experience for Persons Who Use Opioids
Authors: Hayaki Jumi , Cinq-Mars Haley , Christopher Paul P. , Anderson Bradley J. , Stewart Catherine , Stein Michael D.
Published: June 2023

Objectives

Civil commitment has increasingly served as a court-based legal intervention for severe opioid use, but little research has examined the civil commitment (CC) hearing process from the perspective of the person who is committed. Despite documented gender differences in opioid use and experiences within the legal system, past research has also not investigated gender differences in perceptions of the CC process for persons who use opioids.

Methods

Participants were 121 persons (43% female) with opioid use who were interviewed upon arrival at the CC facility about their experience of the CC hearing process in Massachusetts.

Results

Two thirds of participants were taken to the commitment hearing by police, and 59.5% shared a cell with others while waiting. Overall, the commitment intake process at the courthouse took over 5 hours. Participants spent, on average, less than 15 minutes with their lawyer before the hearing, and a majority of CC hearings lasted less than 15 minutes. Once transferred to a CC facility, opioid withdrawal management began within 4 hours. Compared with women, men reported longer wait times between the hearing and transfer, as well as longer wait times for withdrawal management at the facility (P < 0.05). Women perceived worse interactions with the judge and greater dissatisfaction with the commitment process compared with men (P < 0.05).

Conclusions

There were few gender differences in the experience of CC. However, overall, participants reported a lengthy court process and low levels of perceived procedural justice.