bluuebunny/crossref_metadata_2025 huggingface dataset:
Olig2-Induced Semaphorin Expression Drives Corticospinal Axon Retraction After Spinal Cord Injury
Authors: Ueno Masaki , Nakamura Yuka , Nakagawa Hiroshi , Niehaus Jesse K , Maezawa Mari , Gu Zirong , Kumanogoh Atsushi , Takebayashi Hirohide , Lu Qing Richard , Takada Masahiko , Yoshida Yutaka
Published: May 2020

Axon regeneration is limited in the central nervous system, which hinders the reconstruction of functional circuits following spinal cord injury (SCI). Although various extrinsic molecules to repel axons following SCI have been identified, the role of semaphorins, a major class of axon guidance molecules, has not been thoroughly explored. Here we show that expression of semaphorins, including Sema5a and Sema6d, is elevated after SCI, and genetic deletion of either molecule or their receptors (neuropilin1 and plexinA1, respectively) suppresses axon retraction or dieback in injured corticospinal neurons. We further show that Olig2+ cells are essential for SCI-induced semaphorin expression, and that Olig2 binds to putative enhancer regions of the semaphorin genes. Finally, conditional deletion of Olig2 in the spinal cord reduces the expression of semaphorins, alleviating the axon retraction. These results demonstrate that semaphorins function as axon repellents following SCI, and reveal a novel transcriptional mechanism for controlling semaphorin levels around injured neurons to create zones hostile to axon regrowth.
Signet ring gastric and esophageal adenocarcinomas: characteristics and prognostic implications
Authors: Khan Niall , Donohoe Claire L , Phillips Alexander W , Griffin S Michael , Reynolds John V
Published: May 2020

Controversy exists as to the relevance of the signet ring carcinoma (SRC) histological subtype of esophagogastric adenocarcinoma to long-term prognosis, with some studies reporting a worsened oncological outcome and others no clinically relevant impact. A retrospective analysis of outcomes of patients who underwent surgery with curative intent in two high-volume centers (2000–2015) was undertaken. Tumors were analyzed according to location (esophageal, junctional or gastric). Propensity score matching (PSM) analysis was used to match patients with signet ring histology to those without (195 SRC vs. 573 non-SRC), based on age, tumor location, use of neoadjuvant and adjuvant chemotherapy and pathological stage. A total of 2,500 patients with esophagogastric adenocarcinomas were treated, of whom 198 (7.9%) had signet ring histology. Signet ring tumors were more likely to have positive lymph nodes at pathological analysis (59% vs. 50%, P = 0.009). The 5-year survival rate for patients with early signet ring tumors (Stage 0/I/IIa) was 65% versus 85% for other early cancers (P < 0.003). Patients with esophageal signet ring tumors had a particularly poor prognosis with 23% 2-year survival and none alive at 5 years. With PSM, overall survival (OS) was significantly poorer in the signet ring group (44.3 ± 8.6 vs. 59.8 ± 8.5 months, 5-year OS 41% vs. 50%, P = 0.027). Signet ring cells within esophagogastric adenocarcinoma are associated with a poorer prognosis. Genomic studies to identify the composition of such tumors as well as identify strategies to improve treatment for this subtype are warranted.
Practice patterns and adherence to clinical guidelines for diagnosis and management of eosinophilic esophagitis among gastroenterologists
Authors: Eluri Swathi , Iglesia Edward G A , Massaro Michael , Peery Anne F , Shaheen Nicholas J , Dellon Evan S
Published: May 2020

Real-world practice patterns of eosinophilic esophagitis (EoE) among gastroenterologists are not well-described. The aim is to describe practice patterns of EoE diagnosis and management and assess concordance with consensus guidelines. We conducted a cross-sectional online survey of gastroenterologists in the USA using Qualtrics, which was dispersed through the North Carolina Society of Gastroenterology (NCSG) and the American College of Gastroenterology member listservs. A similar survey was sent to NCSG members in 2010 and responses were compared in a subanalysis. Of 240 respondents, 37% (n = 80) worked in an academic setting versus 63% (n = 138) community practice setting. Providers saw a median of 18 (interquartile range 2–100) EoE patients annually and 24% (n = 52) were ‘very familiar’ with EoE guidelines. A proton-pump inhibitor (PPI) trial was required by 37% of providers prior to EoE diagnosis. In total, 60% used a ≥15 eosinophils per high-power field cut point for diagnosis and 62% biopsied from the proximal and distal esophagus on initial exam. Only 12% (n = 28) followed EoE diagnosis guidelines. For first-line treatment, 7% used dietary therapy, 32% topical steroids, and 61% used PPIs; 67% used fluticasone as first-line steroid; 41% used maintenance steroid treatment in responders. In the NCSG cohort, a higher proportion in 2017 followed guideline diagnosis recommendations compared with 2010 (14% vs. 3%; P = 0.03) and a higher proportion used dietary therapy as first-line treatment (13% vs. 3%; P = 0.046). There is variability in EoE practice patterns for EoE management, with management differing markedly from consensus guidelines. Further education and guideline dissemination are needed to standardize practice.
The carbon sequestration potential of ‘analog’ forestry in Ecuador: an alternative strategy for reforestation of degraded pastures
Authors: Veintimilla Raúl Armando Ramos , MacFarlane David , Cooper Lauren
Published: May 2020

‘Analog’ forestry is a novel silvicultural approach for reforestation of degraded land that seeks to establish trees that are analogous in structure and ecological function to the original climax or subclimax vegetation of the region where they are planted. Analog forestry aims to strengthen rural communities, both socially and economically, with tree plantings of high biodiversity, which provide commercial products and resiliency, while avoiding agrochemicals and fossil fuels. The latter links this strategy to climate change mitigation and adaptation strategies, but there has been little analysis comparing the potential for above- and below-ground carbon storage in analog forests, as compared with more typical reforestation efforts via single-species plantations. We present the results of a study to estimate carbon sequestration levels, above- and below-ground, from an experimental analog forest system and a teak (Tectona grandis L.f.) plantation system, in comparison with a degraded pasture system. The study found that the analog and teak plantation forest systems stored higher quantities of total carbon (178 and 141 t C ha−1, respectively), when compared with a degraded pasture system (124 t C ha−1). However, the teak plantation had decreased soil carbon stocks, relative to the degraded pasture. The analog forest had the best balance of both above- and below-ground carbon stored over the 17-year study period and provided a more diverse array of timber and non-timber forest products when compared with the teak plantation. This suggests that analog forestry could be a viable social–ecological approach to carbon storage and reforestation in the study region and other places with large areas of degraded pasture and a good understanding of the structure and function of the original vegetation.
Childhood Friendship Experiences and Cognitive Functioning in Later Life: The Mediating Roles of Adult Social Disconnectedness and Adult Loneliness
Authors: Burr Jeffrey A , Han Sae Hwang , Peng Changmin
Published: May 2020

Background and Objectives

This study investigated the relationship between childhood friendships and cognitive functioning, as assessed with cognitive status and decline among adults aged 45 and older in China. We also examined the mediating effect of adult social disconnectedness and adult loneliness for this relationship.

Research Design and Methods

This study was based on 3 waves of data from the China Health and Retirement Longitudinal Study (CHARLS; 2011, 2013, 2015; N = 13,959). Cognitive functioning was assessed with episodic memory. Childhood friendship measures were taken from the 2014 life history module of the CHARLS. Two dimensions of adult social isolation, loneliness and social disconnectedness, were included as mediators. Latent growth curve modeling was utilized to test the associations between childhood friendships, adult social isolation, and cognitive functioning.

Results

Adverse childhood friendship experiences were found to be significantly associated with both lower initial cognitive status and the rate of decline in cognitive functioning. Our findings indicated that adult loneliness and social disconnectedness partly mediated the link between childhood friendship experiences and the initial level of cognitive functioning, but not cognitive decline later in life.

Discussion and Implications

The findings emphasized the enduring importance of childhood friendships for cognitive functioning later in life. Interventions that focus on improving social participation through fostering friendships in childhood may have long-term benefits for cognition later in life.
Reconciling elasticity tensor constraints from mineral physics and seismological observations: applications to the Earth’s inner core
Authors: Delbridge Brent G , Ishii Miaki
Published: May 2020

This study establishes the proper framework in which to compare seismic observations with mineral physics constraints for studies of the inner core by determining how the elements of the elasticity tensor are sampled by the normal modes of the Earth. The obtained mapping between the elements of the elasticity tensor and the seismic wave speeds shows that the choice of averaging scheme used to calculate isotropic properties is crucial to understand the composition of the inner core, especially for comparison with the shear wave speed such as that provided in PREM. For example, the appropriate shear wave speed calculated for an Fe-Ni-Si hcp alloy at inner-core conditions differs from the shear wave speed obtained by taking a Reuss average by as much as $27\, {\rm per\, cent}$. It is also shown for the first time that by combining the isotropic observations based upon normal-mode characteristic frequencies and anisotropic parameters from their splitting, the five independent elastic parameters (A, C, F, L and N) that fully describe a transversely isotropic inner core can be uniquely constrained. The elastic values based upon a variety of mode-splitting studies are reported, and the differences between models from various research groups are shown to be relatively small ($\lt 10\, {\rm per\, cent}$). Additionally, an analogous body-wave methodology is developed to approximately estimate the five independent elastic constants from observations of compressional wave traveltime anomalies. The body-wave observations are utilized to consider the depth dependence of inner-core anisotropy, in particular, the structure of the innermost inner core. Finally, we demonstrate that substantial errors may result when attempting to relate seismically observed P and S wave speeds from Debye velocities obtained through nuclear resonant inelastic X-ray scattering. The results of these experiments should be compared directly with the Debye velocity calculated from seismically constrained elastic constants. This manuscript provides a new set of formulae and values of seismic observations of the inner core that can be easily compared against mineral physics constraints for better understanding of the inner-core composition.
How images frame China's role in African development
Authors: Karavas George
Published: May 2020

Political leaders, policy-makers and academics routinely refer to development as an objective process of social change through the use of technical, value-free terms. Images of poverty and inequality are regularly presented as evidence of a world that exists ‘out there’ where development unfolds. This way of seeing reflects the value of scientific forms of knowledge but also sits in tension with the normative foundations of development that take European modernization and industrialization as the benchmark for comparison. The role images play in this process is often overlooked. This article argues that a dominant mode of visuality based on a Cartesian separation between subject and object, underpinning the ascendance of European hegemony and colonialism, aligns with the core premises of orthodox development discourse. An example of how visual representations of development matter is presented through images of Africa–China relations in western media sources. Using widely circulated images depicting China's impact on African development in western news media sources as an example of why visual politics matters for policy-making, the article examines how images play a role in legitimizing development planning by rendering associated forms of epistemological and structural violence ‘invisible to the viewer’.
Politics, policy-making and the presence of images of suffering children
Authors: Berents Helen
Published: May 2020

In 2017 Trump expressed pity for the ‘beautiful babies’ killed in a gas attack on Khan Shaykhun in Syria before launching airstrikes against President Assad's regime. Images of suffering children in world politics are often used as a synecdoche for a broader conflict or disaster. Injured, suffering, or dead; the ways in which images of children circulate in global public discourse must be critically examined to uncover the assumptions that operate in these environments. This article explores reactions to images of children by representatives and leaders of states to trace the interconnected affective and political dimensions of these images. In contrast to attending to the expected empathetic responses prompted by images of children, this article particularly focuses on when such images prompt bellicose foreign policy decision-making. In doing this, the article forwards a way of thinking about images as contentious affective objects in international relations. The ways in which images of children's bodies and suffering are strategically deployed by politicians deserves closer scrutiny to uncover the visual politics of childhood inherent in these moments of international politics and policy-making.
Misconceptions about Conception and Other Fallacies: Historical Bias in Reproductive Biology
Authors: Hayssen Virginia
Published: May 2020

Natural selection (differential reproduction) is a major tenet of evolutionary theory. In mammals the success of reproduction is primarily controlled by females who provide the majority of offspring care via gestation and lactation. In some species, maternal care also extends post-weaning. This primacy of female reproduction in evolution has not quite crept into our understanding of organismal adaptations in anatomy, physiology, and behavior. This cultural legacy has left its mark and led to misconceptions in our understanding of reproductive biology that are especially prominent in the understanding of reproduction in the general public. Here, I give examples of such misconceptions. I focus on aspects of physiology (the “sperm race,” the “estrous cycle,” the “28-day” menstrual cycle, “sex” hormones, and meiosis) as well as aspects of terminology in morphology and behavior. The issues I raise are not new, but all remain embedded in the teaching of reproductive biology especially at the introductory level. For each issue, I examine the historical bias, the consequences of that bias, and, more importantly, ways to ameliorate that bias going forward.
Comparative Reactogenicity of Enhanced Influenza Vaccines in Older Adults
Authors: Cowling Benjamin J , Thompson Mark G , Ng Tiffany W Y , Fang Vicky J , Perera Ranawaka A P M , Leung Nancy H L , Chen Yuyun , So Hau Chi , Ip Dennis K M , Iuliano A Danielle
Published: May 2020

Background

We analyzed data from a randomized controlled trial on the reactogenicity of 3 enhanced influenza vaccines compared with standard-dose (SD) inactivated influenza vaccine.

Methods

We enrolled community-dwelling older adults in Hong Kong, and we randomly allocated them to receive 2017–2018 northern hemisphere formulations of SD vaccine (FluQuadri; Sanofi Pasteur), MF59-adjuvanted vaccine (FLUAD; Seqirus), high-dose (HD) vaccine (Fluzone High-Dose; Sanofi Pasteur), or recombinant hemagglutinin vaccine (Flublok; Sanofi Pasteur). Local and systemic reactions were evaluated at days 1, 3, 7, and 14 after vaccination.

Results

Reported reactions were generally mild and short-lived. Systemic reactions occurred in similar proportions of participants by vaccine. Some local reactions were slightly more frequently reported among recipients of the MF59-adjuvanted and HD vaccines than among SD vaccine recipients. Participants reporting feverishness 1 day after vaccination had mean fold rises in postvaccination hemagglutination inhibition titers that were 1.85-fold higher (95% confidence interval, 1.01–3.38) for A(H1N1) than in those who did not report feverishness.

Conclusions

Some acute local reactions were more frequent after vaccination with MF59-adjuvanted and HD influenza vaccines, compared with SD inactivated influenza vaccine, whereas systemic symptoms occurred at similar frequencies in all groups. The association between feverishness and immunogenicity should be further investigated in a larger population.

Clinical Trials Registration

NCT03330132.
High Risk of Clinical Relapse in Patients With Chronic Hepatitis B Virus Infection After Cessation of Prophylactic Antiviral Therapy for Rituximab-Containing Chemotherapy
Authors: Chang Wei-Yuan , Chiu Yen-Cheng , Chiu Fang-Wei , Hsu Yao-Chun , Tseng Tai-Chung , Cheng Pin-Nan , Yang Sheng-Shun , Liu Chun-Jen , Su Tung-Hung , Yang Hung-Chih , Liu Chen-Hua , Chen Pei-Jer , Chen Ding-Shinn , Kao Jia-Horng
Published: May 2020

Background

Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)–positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA.

Methods

We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored.

Results

Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs <2000 IU/mL) was associated with increased risks of clinical relapse (hazard ratio, 3.47; 95% confidence interval, 1.56–7.73) and hepatic decompensation (9.91; 2.14–45.92). Of 51 patients with pretreatment viral load <2000 IU/mL, clinical relapse occurred in 10 (19.6 %) and hepatic decompensation in 2 (3.9%).

Conclusions

Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy.
Mating Disruption of Chilo suppressalis From Sex Pheromone of Another Pyralid Rice Pest Cnaphalocrocis medinalis (Lepidoptera: Pyralidae)
Authors: Liang Yu-yong , Luo Mei , Fu Xiao-gang , Zheng Li-xia , Wei Hong-yi
Published: May 2020

The rice stem borer, Chilo suppressalis (Walker), and the rice leaf folder, Cnaphalocrocis medinalis Guenée, are two of the most destructive lepidopteran pests in rice. Since these two pyralid insects overlap in their occurrence in rice paddy fields, farmers prefer to set their pheromone-baited traps together in the rice fields for their monitoring. However, our field observation demonstrated that no male adult of C. suppressalis was captured in traps baited with commercial sex pheromone of C. suppressalis (CCS) combined with commercial sex pheromone of C. medinalis (CCM). To confirm that the C. medinalis sex pheromone component(s) interfere with the attraction of males of the rice stem borers to their conspecific females, single components of C. medinalis sex pheromone combined with CCS in traps were tested in the laboratory and rice paddy field. The results revealed that the two alcohol components in CCM, i.e., (Z)-11-octadecen-1-ol (Z11-18: OH) and (Z)-13-octadecen-1-ol (Z13-18: OH) may cause a significant reduction in capturing C. suppressalis males caused by CCS. We recommend against using these sex pheromones together in the field and suggest that Z11-18: OH and Z13-18: OH could be potential inhibitors or antagonists of C. suppressalis sex pheromone to control the rice stem borer.
Accelerated partial breast irradiation by brachytherapy: present evidence and future developments
Authors: Galalae Razvan , Hannoun-Lévi Jean-Michel
Published: May 2020

Accelerated partial breast irradiation (APBI) delivers a short course of adjuvant RT after breast conserving surgery to only a limited part of the breast where the tumor was located. This procedure requires expertise, good communication, and close collaboration between specialized surgeons and attending radiation oncologists with adequate intraoperative tumor bed clip marking. However, APBI offers several intrinsic benefits when compared with whole breast irradiation (WBIR) including reduced treatment time (1 versus 4–6 weeks) and better sparing of surrounding healthy tissues. The present publication reviews the APBI level 1-evidence provided with various radiation techniques supplemented by long-term experience obtained from large multi-institutional phase II studies. Additionally, it offers an outlook on recent research with ultra-short or single-fraction APBI courses and new brachytherapy sources. Mature data from three randomized controlled trials (RCTs) clearly prove the noninferiority of APBI with ‘only two techniques—1/MIBT (multicatheter interstitial brachytherapy) (two trials) and 2/intensity modulated radiotherapy (one trial)’—in terms of equivalent local control/overall survival to the previous standard ‘conventionally fractionated WBIR’. However, MIBT-APBI techniques were superior in both toxicity and patient-reported outcomes (PROs) versus WBIR at long-term follow-up. Currently, in RCT-setting, alternative APBI techniques such as intraoperative electrons, 50-kV x-rays and three-dimensional conformal external beam radiotherapy (3D-CRT) failed to demonstrate noninferiority to conventionally fractionated WBIR. However, 3D-CRT-APBI compared noninferior to hypo-fractionated WBIR in preventing ipsilateral breast tumor recurrence (randomized RAPID-trial) but was associated with a higher rate of late radiation toxicity. Ultimately, MIBT remains the only APBI modality with noninferior survival/superior toxicity/PROs at 10-years and therefore should be prioritized over alternative methods in patients with breast cancer considered at low-risk for local recurrence according to recent international guidelines.
Clinical significance of tumour mutation burden in immunotherapy across multiple cancer types: an individual meta-analysis
Authors: Yang Zhenyu , Wei Shiyou , Deng Yulan , Wang Zihuai , Liu Lunxu
Published: May 2020

Background

Biomarkers for stratifying patients that could benefit from immune checkpoint inhibitors are necessary. Tumour mutation burden has recently become a promising biomarker in cancer, but the associations between tumour mutation burden and outcomes of immune checkpoint inhibitors treatment were not well-documented in present studies.

Methods

We searched PubMed, Web of Science and EMBASE databases up to 1 October 2019. Studies evaluated the association between tumour mutation burden and clinical outcomes were included. Hazard ratios and odds ratios were applied to estimate the association of tumour mutation burden score with overall survival, progression-free survival and response rate, respectively. The best cut-off value was chosen by best discriminated overall survival using Contal and O’Quigley method.

Results

Twenty-two studies involving 6171 patients in diverse cancers were included. The individual participant data meta-analysis demonstrated that high tumour mutation burden was associated with better overall survival (HR = 0.57, 95% CI = 0.50–0.64) and progression-free survival (HR = 0.50, 95% CI = 0.40–0.63) and higher response rate. The best cut-off values in each cancer type were 17.7/MB in non-small cell lung cancer, 7.9/MB in bladder cancer, 6.1/MB in melanoma, 12.3/MB in colorectal cancer, 6.9/MB in esophagogastric cancer, 10.5/MB in head and neck cancer. The pooled meta-analysis showed the prognosis value was robust and the sensitivity, specificity and area under the receiver operating characteristic curves in predicting response rates were 0.63, 0.71 and 0.73, respectively.

Conclusions

The present meta-analysis indicates tumour mutation burden is a promising predictor of immune checkpoint inhibitors therapy but the cut-off value differs in different cancers.
Quality of Life With Pembrolizumab for Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma: KEYNOTE-040
Authors: Harrington Kevin J , Soulières Denis , Le Tourneau Christophe , Dinis Jose , Licitra Lisa F , Ahn Myung-Ju , Soria Ainara , Machiels Jean-Pascal H , Mach Nicolas , Mehra Ranee , Burtness Barbara , Ellison Misoo C , Cheng Jonathan D , Chirovsky Diana Romana , Swaby Ramona F , Cohen Ezra E W
Published: May 2020

Background

Head and neck squamous cell carcinoma (HNSCC) affects health-related quality of life (HRQoL); few treatments have demonstrated clinically meaningful HRQoL benefit. KEYNOTE-040 evaluated pembrolizumab vs standard of care (SOC) in patients with recurrent and/or metastatic HNSCC whose disease recurred or progressed after platinum-containing regimen.

Methods

Patients received pembrolizumab 200 mg or SOC (methotrexate, docetaxel, or cetuximab). Exploratory HRQoL analyses used European Organisation for Research and Treatment of Cancer (EORTC) 30 quality-of-life, EORTC 35-question quality-of-life head and neck cancer-specific module, and EuroQoL 5-dimensions questionnaires.

Results

The HRQoL population comprised 469 patients (pembrolizumab = 241, SOC = 228). HRQoL compliance for patients in the study at week 15 was 75.3% (116 of 154) for pembrolizumab and 74.6% (85 of 114) for SOC. The median time to deterioration in global health status (GHS) and QoL scores were 4.8 months with pembrolizumab and 2.8 months with SOC (hazard ratio = 0.79, 95% confidence interval [CI] = 0.59 to 1.05). At week 15, GHS / QoL scores were stable for pembrolizumab (least squares mean [LSM] = 0.39, 95% CI = –3.00 to 3.78) but worsened for SOC (LSM = −5.86, 95% CI = −9.68 to −2.04); the LSM between-group difference was 6.25 points (95% CI = 1.32 to 11.18; nominal 2-sided P = .01). A greater difference in the LSM for GHS / QoL score occurred with pembrolizumab vs docetaxel (10.23, 95% CI = 3.15 to 17.30) compared with pembrolizumab vs methotrexate (6.21, 95% CI = −4.57 to 16.99) or pembrolizumab vs cetuximab (−1.44, 95% CI = −11.43 to 8.56). Pembrolizumab-treated patients had stable functioning and symptoms at week 15, with no notable differences from SOC.

Conclusions

GHS / QoL scores were stable with pembrolizumab but declined with SOC in patients at week 15, supporting the clinically meaningful benefit of pembrolizumab in recurrent and/or metastatic HNSCC.
Prostate Cancer Incidence 5 Years After US Preventive Services Task Force Recommendations Against Screening
Authors: Jemal Ahmedin , Culp MaryBeth B , Ma Jiemin , Islami Farhad , Fedewa Stacey A
Published: May 2020

Background

Previous studies reported that prostate cancer incidence rates in the United States declined for local-stage disease and increased for regional- and distant-stage disease following the US Preventive Services Task Force recommendations against prostate-specific antigen-based screening for men aged 75 years and older in 2008 and for all men in 2012. It is unknown, however, whether these patterns persisted through 2016.

Methods

Based on the US Cancer Statistics Public Use Research Database, we examined temporal trends in invasive prostate cancer incidence from 2005 to 2016 in men aged 50 years and older stratified by stage (local, regional, and distant), age group (50-74 years and 75 years and older), and race and ethnicity (all races and ethnicities, non-Hispanic Whites, and non-Hispanic Blacks) with joinpoint regression models to estimate annual percent changes. Tests of statistical significance are 2-sided (P < .05).

Results

For all races and ethnicities combined, incidence for local-stage disease declined beginning in 2007 in men aged 50-74 years and 75 years and older, although the decline stabilized during 2013-2016 in men aged 75 years and older. Incidence decreased by 6.4% (95% CI = 4.9%-9% to 7.9%) per year from 2007 to 2016 in men aged 50-74 years and by 10.7% (95% CI = 6.2% to 15.0%) per year from 2007 to 2013 in men aged 75 years and older. In contrast, incidence for regional- and distant-stage disease increased in both age groups during the study period. For example, distant-stage incidence in men aged 75 years and older increased by 5.2% (95% CI = 4.2% to 6.1%) per year from 2010 to 2016.

Conclusions

Regional- and distant-stage prostate cancer incidence continue to increase in the United States in men aged 50 years and older, and future studies are needed to identify reasons for the rising trends.
Overall Survival of CDK4/6-Inhibitor–Based Treatments in Clinically Relevant Subgroups of Metastatic Breast Cancer: Systematic Review and Meta-Analysis
Authors: Schettini Francesco , Giudici Fabiola , Giuliano Mario , Cristofanilli Massimo , Arpino Grazia , Del Mastro Lucia , Puglisi Fabio , De Placido Sabino , Paris Ida , De Placido Pietro , Venturini Sergio , De Laurentis Michelino , Conte PierFranco , Juric Dejan , Llombart-Cussac Antonio , Pusztai Lajos , Prat Aleix , Jerusalem Guy , Di Leo Angelo , Generali Daniele
Published: May 2020

Background

Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors + endocrine therapy (ET) prolonged progression-free survival as first- or second-line therapy for hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer prognosis. Given the recent publication of overall survival (OS) data for the 3 CDK4/6-inhibitors, we performed a meta-analysis to identify a more precise and reliable benefit from such treatments in specific clinical subgroups.

Methods

We conducted a systematic literature search to select all available phase II or III randomized clinical trials of CDK4/6-inhibitors + ET reporting OS data in first- or second-line therapy of HR+/HER2-negative pre- or postmenopausal metastatic breast cancer. A random effect model was applied for the analyses. Heterogeneity was assessed with I2statistic. Subgroup analysis was performed to explore the effect of study-level factors. The project was registered in the Open Science Framework database (doi: 10.17605/OSF.IO/TNZQP).

Results

Six studies were included in our analyses (3421 patients). A clear OS benefit was observed in patients without (hazard ratio [HR] = 0.68, 95% confidence interval [CI] = 0.54 to 0.85, I2 = 0.0%) and with visceral involvement (HR = 0.76, 95% CI = 0.65 to 0.89, I2 = 0.0%), with at least 3 metastatic sites (HR = 0.75, 95% CI = 0.60 to 0.94, I2 = 11.6%), in an endocrine-resistant (HR = 0.79, 95% CI = 0.67 to 0.93, I2 = 0.0%) and sensitive subset (HR = 0.73, 95% CI = 0.61 to 0.88, I2 = 0.0%), for younger than 65 years (HR = 0.80, 95% CI = 0.67 to 0.95, I2 = 0.0%) and 65 years or older (HR = 0.71, 95% CI = 0.53 to 0.95, I2 = 44.4%), in postmenopausal (HR = 0.76, 95% CI = 0.67 to 0.86, I2 = 0.0%) and pre- or perimenopausal setting (HR = 0.76, 95% CI = 0.60 to 0.96, I2 = 0.0%) as well as in chemotherapy-naïve patients (HR = 0.72, 95% CI = 0.55 to 0.93, I2 = 0.0%).

Conclusions

CDK4/6-inhibitors + ET combinations compared with ET alone improve OS independent of age, menopausal status, endocrine sensitiveness, and visceral involvement and should be preferred as upfront therapy instead of endocrine monotherapy.
Excessive Weight Gain Associated With Dolutegravir Initiation in a 10-Year-Old Female With Perinatally Acquired Human Immunodeficiency Virus: A Case Report and Review of the Literature
Authors: Li J , Yusuf E H , Agwu A L
Published: May 2020

Children with perinatally acquired human immunodeficiency virus (PHIV) face a lifetime of combination antiretroviral treatment that often includes dolutegravir (DTG). DTG, an integrase strand inhibitor that has been linked to weight gain in adults, is increasingly being used in children. Understanding its potential short- and long-term sequelae in children is critically important. We report a case of excessive weight gain in a child with PHIV on DTG and provide a brief literature review.
An evolutionary view of melatonin synthesis and metabolism related to its biological functions in plants
Authors: Tan Dun-Xian , Reiter Russel J
Published: May 2020

Plant melatonin research is a rapidly developing field. A variety of isoforms of melatonin’s biosynthetic enzymes are present in different plants. Due to the different origins, they exhibit independent responses to the variable environmental stimuli. The locations for melatonin biosynthesis in plants are chloroplasts and mitochondria. These organelles have inherited their melatonin biosynthetic capacities from their bacterial ancestors. Under ideal conditions, chloroplasts are the main sites of melatonin biosynthesis. If the chloroplast pathway is blocked for any reason, the mitochondrial pathway will be activated for melatonin biosynthesis to maintain its production. Melatonin metabolism in plants is a less studied field; its metabolism is quite different from that of animals even though they share similar metabolites. Several new enzymes for melatonin metabolism in plants have been cloned and these enzymes are absent in animals. It seems that the 2-hydroxymelatonin is a major metabolite of melatonin in plants and its level is ~400-fold higher than that of melatonin. In the current article, from an evolutionary point of view, we update the information on plant melatonin biosynthesis and metabolism. This review will help the reader to understand the complexity of these processes and promote research enthusiasm in these fields.
Political Risk
Authors: Rubins Noah D , Papanastasiou Thomas-Nektarios , Kinsella N Stephan
Published: May 2020

This chapter discusses the types of political risk that foreign investors are likely to encounter, the factors that contribute to political risk, and some practical steps that investors might take to measure political risks in a particular State before investing capital. For investors concerned with political risk, the primary distinction to be made is between detriment (loss) proximately caused by the host State or its agents, and that caused by the commercial realities of supply and demand, or by natural disasters. This line is far harder to draw in practice than in theory: the scenarios investors face in carrying out a long-term business project on foreign soil are complex and affected by a range of factors, both within and outside government control.
Courting Failure
Authors: Milanović Marko
Published: May 2020

This chapter asks whether international tribunals are capable of healing a traumatized society. In that sense, it is not enough that a tribunal punish the guilty, it must also produce a social awakening concerning the community’s own culpability for the wrongdoing. Drawing on an empirical evaluation of the social response to the work of the International Criminal Tribunal for the former Yugoslavia (ICTY), the chapter questions whether this can occur. At least in the case of the ICTY—otherwise regarded as one of the most successful international tribunals—the work of the Tribunal has been shockingly ineffective because some sectors of the public simply refuse to accept the conclusions that the Tribunal has drawn. The chapter then broadens this conclusion into a general theory: that the work of a tribunal will be viewed positively by the local population unless the Tribunal is a threat to local elites who have the power to shape public opinion against the Tribunal.
The Two Cultures of International Criminal Law
Authors: d’Aspremont Jean
Published: May 2020

This chapter looks more globally at the methodologies used by international criminal justice, particularly its tendency towards expansionism: including more actors, more situations, and more offences under its umbrella. It does more than simply tell the story of this expansion; this chapter also systematizes it in an important way. The chapter argues that international criminal justice’s expansionism has taken two important forms. The first wave involved a sources-based expansionism, characterized by the field’s desire to expand its influence by increasing the number of legal sources—treaty, custom, general principles—that could be sources of international criminal law. But when that process was largely complete, the passage of the Rome Statute of the International Criminal Court heralded a new, hermeneutic form of expansionism—this one based on interpretation rather than on adding new sources of law. While the hermeneutic expansion is less overt and less recognized than the first wave, its consequences are still dramatic.
Historical Reasoning and Judicial Historiography in International Criminal Trials
Authors: Priemel Kim Christian
Published: May 2020

This chapter explores the overlaps and differences between historical reasoning and judicial historiography. It takes the reader from Nuremberg to the International Criminal Court to show that judicial proceedings have been a major site for the development of both micro- and macro-level histories, sometimes problematically so. The chapter addresses if, how, and to what extent macro-historical interpretations permeated the high-profile proceedings at Nuremberg and Tokyo and helps explain their dynamics and outcomes. This pattern was repeated in domestic trials of Nazi-era crimes throughout the post-war decades, yet largely overlooked in the creation and day-to-day operations of the ad hoc tribunals that sprang to life in the 1990s and early 2000s. To conclude, the chapter suggests that this unawareness may explain some of the Tribunals’ shortcomings and needs to be reflected by both lawyers and historians if the ICC is to avoid even more criticism than that levelled against it since its inception.
International Criminal Tribunal Backlash
Authors: Lovat Henry
Published: May 2020

This chapter explores the phenomenon of backlash against international criminal tribunals, defining backlash as ‘intense and sustained government disapproval of tribunal conduct, accompanied by aggressive steps to resist such conduct and to remove its legal force’. After promising beginnings, post-Cold War international criminal tribunals have increasingly faced strident criticism from important constituencies, including previously supportive governments. This has prompted concern about declining support for and ‘backlash’ against such tribunals, amidst broader debates about similar tendencies affecting international adjudication more generally. Drawing on International Relations theories, this chapter analyzes drivers and inhibitors to backlash against international criminal tribunals, specifically the International Criminal Court, the International Criminal Tribunal for the former Yugoslavia, and the Special Tribunal for Lebanon. It identifies several factors relevant for explaining tribunal backlash: domestic politics and the preferences and interests of powerful elites; external actors, particularly engaged regional and great powers; and transnational social pressure.
Inequality of Arms Reversed?
Authors: Glasius Marlies , Meijers Tim
Published: May 2020

This chapter discusses a communicative advantage for ‘defiant defendants’, otherwise known as the ‘inequality of arms reversed’. A common critique of international criminal justice is that international criminal trials, when faced with high-profile and charismatic defendants, are basically doomed: either they silence the defendant’s political rhetoric and become show trials, or they let the defendant speak of the bias and inconsistencies in their institutional set-up, thus equally imperilling their legitimacy. This chapter argues that international criminal courts are not doomed by the reverse inequality: the communicative outcomes of international criminal trials remain contingent. For instance, prosecutors can make arguments that are politically and culturally attuned to local audiences. Moreover, the procedure of the trial can influence the defendant’s attitude. This chapter contends that it is possible for prosecutors and judges to acknowledge the political dimension of international criminal processes without turning them into show trials. Indeed, it is desirable for judges and prosecutors to confront the politics of the defendant head on.
Invented Geographies: The Material and Immaterial Geopoetics of Sandra Cisneros’s “Pilón”
Authors: Hernández Teresa
Published: May 2020

Current scholarship on Sandra Cisneros's novel Caramelo (2002) has focused on the Reyes family's transnational migrant narrative and their explicit traversing of the US-Mexico border. However, Cisneros's final offering at the close of the novel, “Pilón,” has been excluded from these significant discussions. My essay focuses primarily on this cuento and how it relates to Caramelo as an (im)material part of the novel. I propose that “Pilón” partakes in a dialogic relationship to the novel proper—existing inside and outside of Caramelo through its location after the “fin” of the novel but within the binding of the text. By assessing the material and immaterial borders presented—I particularly explore three fundamental borders in “Pilón” (textual, geopoetical, and corporal)—I claim that “Pilón” presents an urgency in redefining a transnational border experience. Ultimately, I explore the imagining of the US-Mexico (m)otherland within “Pilón,” the limits of this imagining, and the (im)possibility of its geography through the nostalgic and spiritual analytic of the ofrenda.
Runaway and walkaway stars from the ONC with Gaia DR2
Authors: Schoettler Christina , de Bruijne Jos , Vaher Eero , Parker Richard J
Published: May 2020

Theory predicts that we should find fast, ejected (runaway) stars of all masses around dense, young star-forming regions. N-body simulations show that the number and distribution of these ejected stars could be used to constrain the initial spatial and kinematic substructure of the regions. We search for runaway and slower walkaway stars within 100 pc of the Orion Nebula Cluster (ONC) using Gaia DR2 astrometry and photometry. We compare our findings to predictions for the number and velocity distributions of runaway stars from simulations that we run for 4 Myr with initial conditions tailored to the ONC. In Gaia DR2, we find 31 runaway and 54 walkaway candidates based on proper motion, but not all of these are viable candidates in three dimensions. About 40 per cent are missing radial velocities, but we can trace back nine 3D runaways and 24 3D walkaways to the ONC, all of which are low/intermediate mass (<8 M⊙). Our simulations show that the number of runaways within 100 pc decreases the older a region is (as they quickly travel beyond this boundary), whereas the number of walkaways increases up to 3 Myr. We find fewer walkaways in Gaia DR2 than the maximum suggested from our simulations, which may be due to observational incompleteness. However, the number of Gaia DR2 runaways agrees with the number from our simulations during an age of ∼1.3–2.4 Myr, allowing us to confirm existing age estimates for the ONC (and potentially other star-forming regions) using runaway stars.
Chemical modelling of dust–gas chemistry within AGB outflows – II. Effect of the dust-grain size distribution
Authors: Van de Sande M , Walsh C , Danilovich T
Published: May 2020

Asymptotic giant branch (AGB) stars are, together with supernovae, the main contributors of stellar dust to the interstellar medium (ISM). Dust grains formed by AGB stars are thought to be large. However, as dust nucleation and growth within their outflows are still not understood, the dust-grain size distribution (GSD) is unknown. This is an important uncertainty regarding our knowledge of the chemical and physical history of interstellar dust, as AGB dust forms ${\sim} 70{{\ \rm per\ cent}}$ of the starting point of its evolution. We expand on our chemical kinetics model, which uniquely includes a comprehensive dust–gas chemistry. The GSD is now allowed to deviate from the commonly assumed canonical Mathis, Rumpl & Nordsieck distribution. We find that the specific GSD can significantly influence the dust–gas chemistry within the outflow. Our results show that the level of depletion of gas-phase species depends on the average grain surface area of the GSD. Gas-phase abundance profiles and their possible depletions can be retrieved from observations of molecular emission lines when using a range of transitions. Because of degeneracies within the prescription of GSD, specific parameters cannot be retrieved, only (a lower limit to) the average grain surface area. None the less, this can discriminate between dust composed of predominantly large or small grains. We show that when combined with other observables such as the spectral energy distribution and polarized light, depletion levels from molecular gas-phase abundance profiles can constrain the elusive GSD of the dust delivered to the ISM by AGB outflows.
Familial primary ovarian insufficiency associated with an SYCE1 point mutation: defective meiosis elucidated in humanized mice
Authors: Hernández-López Diego , Geisinger Adriana , Trovero María Fernanda , Santiñaque Federico F , Brauer Mónica , Folle Gustavo A , Benavente Ricardo , Rodríguez-Casuriaga Rosana
Published: May 2020

More than 50% of cases of primary ovarian insufficiency (POI) and nonobstructive azoospermia in humans are classified as idiopathic infertility. Meiotic defects may relate to at least some of these cases. Mutations in genes coding for synaptonemal complex (SC) components have been identified in humans, and hypothesized to be causative for the observed infertile phenotype. Mutation SYCE1 c.721C>T (former c.613C>T)—a familial mutation reported in two sisters with primary amenorrhea—was the first such mutation found in an SC central element component-coding gene. Most fundamental mammalian oogenesis events occur during the embryonic phase, and eventual defects are identified many years later, thus leaving few possibilities to study the condition’s etiology and pathogenesis. Aiming to validate an approach to circumvent this difficulty, we have used the CRISPR/Cas9 technology to generate a mouse model with an SYCE1 c.721C>T equivalent genome alteration. We hereby present the characterization of the homozygous mutant mice phenotype, compared to their wild type and heterozygous littermates. Our results strongly support a causative role of this mutation for the POI phenotype in human patients, and the mechanisms involved would relate to defects in homologous chromosome synapsis. No SYCE1 protein was detected in homozygous mutants and Syce1 transcript level was highly diminished, suggesting transcript degradation as the basis of the infertility mechanism. This is the first report on the generation of a humanized mouse model line for the study of an infertility-related human mutation in an SC component-coding gene, thus representing a proof of principle.