bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of FDA’s IQOS marketing authorisation and its policy impacts
Authors: Lempert Lauren Kass , Glantz Stanton 
Published: June 2020

BackgroundPhilip Morris Products SA (PMPSA) submitted a premarket tobacco application (PMTA) to US Food and Drug Administration (FDA) seeking an order permitting it to market IQOS in the USA. US law requires FDA to deny marketing authorisation if applicants fail to demonstrate that their product is ‘appropriate for the protection of the public health’. FDA issued a marketing order for IQOS in April 2019, which Philip Morris is using to promote IQOS outside the USA.MethodsWe analysed FDA’s Technical Project Lead Review and marketing order for IQOS, relevant law and guidance on PMTAs and independent research on the health impacts of IQOS.ResultsFDA found that the evidence PMPSA submitted did not demonstrate reduction in long-term disease risks and that IQOS aerosol emits toxins with carcinogenic and genotoxic potential, some at higher levels than conventional cigarettes. PMPSA did not appropriately consider the health impacts of dual use, the product’s attractiveness to youth or data showing that consumers do not accurately perceive the addiction risks of IQOS. Despite FDA’s own scientists’ recommendations and independent research showing that IQOS presents serious risks to users including cytotoxic, genotoxic, hepatotoxic, cardiovascular and pulmonary risks, FDA concluded that IQOS is ‘appropriate for the protection of the public health’.ConclusionFDA’s decision allowing IQOS to be marketed in the USA disregarded valid scientific evidence and misapplied the public health standard mandated by law. This decision may have important health impacts, influence marketing IQOS outside the USA and erode public confidence in FDA’s future PMTA decisions.
Using ratios in cave guano to assess past environmental changes
Authors: Cleary Daniel M. , Onac Bogdan P. 
Published: June 2020

Abstract

Stable isotope ratios of cave bat guano reflect environmental influences at the soil and plant level within the foraging range of the bats. Carbon, nitrogen and hydrogen isotopes have utility in reconstructing precipitation and temperature as well as in tracing the influence of large-scale atmospheric circulation and climate variability. Guano-derived stable isotope time series have been demonstrated to effectively provide high-resolution records of palaeoenvironmental variation from the late Pleistocene to present. Owing to their influence on these isotopes, factors such as bat ecology, species foraging range and site location must be considered when interpreting such records. Research analysing the isotopic composition of guano has provided a highly resolved history of vegetation and climate dynamics previously less understood. In this chapter we discuss the factors influencing the
δ
13
C,
δ
15
N and
δ
2
H values in guano and provide an up-to-date review of cave guano as palaeo-climate archive.
HDAC6 Plays a Noncanonical Role in the Regulation of Antitumor Immune Responses, Dissemination, and Invasiveness of Breast Cancer
Authors: Banik Debarati , Noonepalle Satish , Hadley Melissa , Palmer Erica , Gracia-Hernandez Maria , Zevallos-Delgado Christian , Manhas Namratta , Simonyan Hayk , Young Colin N. , Popratiloff Anastas , Chiappinelli Katherine B. , Fernandes Rohan , Sotomayor Eduardo M. , Villagra Alejandro 
Published: June 2020

AbstractDespite the outstanding clinical results of immune checkpoint blockade (ICB) in melanoma and other cancers, clinical trials in breast cancer have reported low responses to these therapies. Current efforts are now focused on improving the treatment efficacy of ICB in breast cancer using new combination designs such as molecularly targeted agents, including histone deacetylase inhibitors (HDACi). These epigenetic drugs have been widely described as potent cytotoxic agents for cancer cells. In this work, we report new noncanonical regulatory properties of ultra-selective HDAC6i over the expression and function of epithelial–mesenchymal transition pathways and the invasiveness potential of breast cancer. These unexplored roles position HDAC6i as attractive options to potentiate ongoing immunotherapeutic approaches. These new functional activities of HDAC6i involved regulation of the E-cadherin/STAT3 axis. Pretreatment of tumors with HDAC6i induced critical changes in the tumor microenvironment, resulting in improved effectiveness of ICB and preventing dissemination of cancer cells to secondary niches. Our results demonstrate for the first time that HDAC6i can both improve ICB antitumor immune responses and diminish the invasiveness of breast cancer with minimal cytotoxic effects, thus departing from the cytotoxicity-centric paradigm previously assigned to HDACi.Significance:Ultraselective HDAC6 inhibitors can reduce tumor growth and invasiveness of breast cancer by noncanonical mechanisms unrelated to the previously cytotoxic properties attributed to HDAC inhibitors.
Obesity/Type 2 Diabetes-Associated Liver Tumors Are Sensitive to Cyclin D1 Deficiency
Authors: Luo Chi , Liang Jiaxin , Sharabi Kfir , Hatting Maximilian , Perry Elizabeth A. , Tavares Clint D.J. , Goyal Lipika , Srivastava Amitabh , Bilodeau Marc , Zhu Andrew X. , Sicinski Piotr , Puigserver Pere 
Published: June 2020

Abstract

Type 2 diabetes, which is mainly linked to obesity, is associated with increased incidence of liver cancer. We have previously found that in various models of obesity/diabetes, hyperinsulinemia maintains heightened hepatic expression of cyclin D1, suggesting a plausible mechanism linking diabetes and liver cancer progression. Here we show that cyclin D1 is greatly elevated in human livers with diabetes and is among the most significantly upregulated genes in obese/diabetic liver tumors. Liver-specific cyclin D1 deficiency protected obese/diabetic mice against hepatic tumorigenesis, whereas lean/nondiabetic mice developed tumors irrespective of cyclin D1 status. Cyclin D1 dependency positively correlated with liver cancer sensitivity to palbociclib, an FDA-approved CDK4 inhibitor, which was effective in treating orthotopic liver tumors under obese/diabetic conditions. The antidiabetic drug metformin suppressed insulin-induced hepatic cyclin D1 expression and protected against obese/diabetic hepatocarcinogenesis. These results indicate that the cyclin D1–CDK4 complex represents a potential selective therapeutic vulnerability for liver tumors in obese/diabetic patients.

Significance:
Obesity/diabetes-associated liver tumors are specifically vulnerable to cyclin D1 deficiency and CDK4 inhibition, suggesting that the obese/diabetic environment confers cancer-selective dependencies that can be therapeutically exploited.
Long-term Follow-up of Standard-Dose Pembrolizumab Plus Reduced-Dose Ipilimumab in Patients with Advanced Melanoma: KEYNOTE-029 Part 1B
Authors: Carlino Matteo S. , Menzies Alexander M. , Atkinson Victoria , Cebon Jonathan S. , Jameson Michael B. , Fitzharris Bernard M. , McNeil Catriona M. , Hill Andrew G. , Ribas Antoni , Atkins Michael B. , Thompson John A. , Hwu Wen-Jen , Hodi F. Stephen , Guminski Alexander D. , Kefford Richard , Wu Haiyan , Ibrahim Nageatte , Homet Moreno Blanca , Long Georgina V. 
Published: June 2020

Abstract

Purpose:
Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte–associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma.

Patients and Methods:
Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS).

Results:
A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively.

Conclusions:
Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
Genome-Wide Association of Kidney Traits in Hispanics/Latinos Using Dense Imputed Whole-Genome Sequencing Data
Authors: Qian Huijun , Kowalski Madeline H. , Kramer Holly J. , Tao Ran , Lash James P. , Stilp Adrienne M. , Cai Jianwen , Li Yun , Franceschini Nora 
Published: June 2020

Background:
Genetic factors that influence kidney traits have been understudied for low-frequency and ancestry-specific variants.

Methods:
This study used imputed whole-genome sequencing from the Trans-Omics for Precision Medicine project to identify novel loci for estimated glomerular filtration rate and urine albumin-to-creatinine ratio in up to 12 207 Hispanics/Latinos. Replication was performed in the Women’s Health Initiative and the UK Biobank when variants were available.

Results:

Two low-frequency intronic variants were associated with estimated glomerular filtration rate (rs58720902 at
AQR
, minor allele frequency=0.01,
P
=1.6×10
−8
) or urine albumin-to-creatinine ratio (rs527493184 at
ZBTB16
, minor allele frequency=0.002,
P
=1.1×10
−8
). An additional variant at
PRNT
(rs2422935, minor allele frequency=0.54,
P
=2.89×10
−8
) was significantly associated with estimated glomerular filtration rate in meta-analysis with replication samples. We also identified 2 known loci for urine albumin-to-creatinine ratio (
BCL2L11
rs116907128,
P
=5.6×10
−8
and
HBB
rs344,
P
=9.3×10
−11
) and validated 8 loci for urine albumin-to-creatinine ratio previously identified in the UK Biobank.

Conclusions:
Our study shows gains in gene discovery when using dense imputation from multi-ethnic whole-genome sequencing data in admixed Hispanics/Latinos. It also highlights limitations in genetic research of kidney traits, including the lack of suitable replication samples for variants that are more common in non-European ancestry and those at low frequency in populations.
Cladistic analysis of Spartocerini Amyot & Serville 1843 (Hemiptera, Coreidae, Coreinae)
Authors: da Silva Costa Wanessa , Barcellos Aline , Brailovsky Harry 
Published: June 2020

Abstract
Among the 32 tribes of Coreinae currently recognized, Spartocerini comprises 66 extant species distributed in six genera: Euagona Dallas, Eubule Stål, Menenotus Laporte, Molchina Amyot & Serville, Sephina Amyot & Serville and Spartocera Laporte, distributed exclusively in the Western Hemisphere. We performed cladistic analyses using equal (EW) and also implied weighting (IW) based on 56 terminals (23 belonging to the ingroup) and 115 morphological characters, including male and female genitalia. Spartocerini was polyphyletic both under EW and IW because Molchina was nested in Mictini. We remove Molchina from Spartocerini and consider the genus as incertae sedis. Spartocera, Eubule, and Sephina were not recovered as monophyletic. Sephina pubera (Erichson) is considered as incertae sedis within Spartocerini, Eubule ampliata (Valdés) is transferred to Spartocera as a new combination, and Mamurius is included in Anisoscelini.
African Basin Management Organizations
Authors: Sangbana Komlan 
Published: June 2020

Abstract
In Africa, basin organizations are almost indispensable mechanisms for any attempt to achieve the sustainable protection of transboundary water resources. Indeed, transboundary freshwater pollution is a growing concern at the African transboundary basin level. In this context, African basin organizations play a central role in the protection of transboundary water resources and their ecosystems. In order to prevent pollution damage and protect water resources, basin institutions have been entrusted with a variety of functions and tasks in the formation and implementation of pollution control standards. This monograph explores and highlights the increasingly important role of basin organizations in this area and provides some avenues for strengthening the work they perform to protect river systems.
Managing for a Changing Climate: A Blended Interdisciplinary Climate Course
Authors: Martin Elinor , McPherson Renee , Kuster Emma , Bamzai-Dodson Aparna 
Published: June 2020

AbstractWe developed a blended (or hybrid) interactive course—Managing for a Changing Climate—that provides a holistic view of climate change. The course results from communication with university students and natural and cultural resource managers as well as the need for educational efforts aimed at the public, legislators, and decision-makers. Content includes the components of the physical climate system, natural climate variability, anthropogenic drivers of climate change, climate models and projections, climate assessments, energy economics, environmental policy, vulnerabilities to climate hazards, impacts of climate change, and decision-making related to climate adaptation and mitigation efforts. To convey most of the content, the course-development team created over 50 short videos (3–10 min each) in partnership with experts from a variety of academic, government, and industry institutions. The blended course has been offered as an upper-division, undergraduate course in the Department of Geography and Environmental Sustainability and School of Meteorology (four times) and College of International Studies (in Italy, once) at the University of Oklahoma with over 100 total students. The course has also been presented online-only at no cost to the participants in four fall semesters with over 1,000 total registrations. Videos created for this course are freely available on the YouTube page of the South Central Climate Adaptation Science Center. This course and its associated materials comprise high-quality, formal climate training and education that can be adapted to other formal and informal education settings beyond the walls of the university.
Systematic Review of Outcomes After Cochlear Implantation in Children With X‐Linked Deafness‐2
Authors: Smith Joshua D. , El‐Kashlan Nour , Darr Owen A. F. , Thorne Marc C. 
Published: June 2020

ObjectiveOutcomes following cochlear implantation in children with X‐linked deafness‐2 are variable, resulting in challenges in appropriate preoperative counseling. To address this uncertainty, we performed a systematic review and synthesis of the literature on audiologic and speech outcomes after cochlear implantation in these patients to inform prognostic counseling.Data SourcesPubMed, Embase, and Cochrane Library were queried for articles published between January 2000 and July 2019.Review MethodsWe performed a systematic review of all studies published between 2000 and 2019 that reported on (1) children with confirmed X‐linked deafness‐2 undergoing cochlear implantation and (2) formal assessment of hearing and/or speech capabilities postimplantation.ResultsOur initial database search yielded 313 articles. Fourteen articles met inclusion criteria. These studies reported on 61 children with X‐linked deafness‐2 who underwent implantation at a wide age range (1‐29 years) for severe‐profound sensorineural hearing loss of prelingual onset. The mean follow‐up duration after implant activation was 32 months (range, 12‐61). Outcome domains assessed at follow‐up were heterogeneous, though each study employed at least 1 assessment of hearing (eg, pure tone audiometry), speech perception (eg, Early Speech Perception Test), or auditory perception (eg, Categories of Auditory Perception scores). In 10 of 14 studies, cochlear implantation afforded significant improvement in hearing and speech capabilities relative to preoperative performance or as compared with age‐matched, normal‐hearing controls.ConclusionThe majority of studies demonstrate that cochlear implantation provides improvements in hearing and speech performance in patients with X‐linked deafness‐2. This information is valuable for decision making regarding cochlear implantation in these patients.
Otopathologic Analysis of Patterns of Postmeningitis Labyrinthitis Ossificans
Authors: Trakimas Danielle R. , Knoll Renata M. , Castillo‐Bustamante Melissa , Kozin Elliott D. , Remenschneider Aaron K. 
Published: June 2020

ObjectiveLabyrinthitis ossificans (LO) may occur following meningitis and, in cases where cochlear implantation is indicated, complicate electrode insertion. LO is critical to identify for successful cochlear implantation, and histopathology is more sensitive than imaging for identification of LO. Herein we utilize otopathologic techniques to study the timing and location of intracochlear tissue formation following meningitic labyrinthitis (ML).Study DesignRetrospective review.SettingAcademic institution.MethodsTemporal bone specimens with a history of bacterial ML were histologically evaluated. The location and extent of intracochlear tissue formation within the scala tympani (ST) and scala vestibuli (SV) were graded, and spiral ganglion neurons were counted.ResultsFifty‐one temporal bones were identified: 32 with no intracochlear tissue formation, 9 with fibrosis alone, and 10 with LO. Fibrosis was identified as early as 1.5 weeks after ML, while ossification was found only in specimens that survived multiple years after ML. All LO cases showed ossification of the ST at the round window membrane (RWM) with continuous extension throughout the basal turn. Extent of SV ossification correlated with that in the ST but showed frequent isolated distal involvement of the cochlea. Spiral ganglion neuron counts were lower than those in age‐matched controls.ConclusionIn this human temporal bone study, we found that postmeningitic LO results in ossification at the RWM with continuous extension into the ST of the basal turn and variable involvement of the SV. Identification of a patent basal turn beyond RWM ossification of the ST should permit full electrode insertion.Level of EvidenceRetrospective review.
A Sustainable and Scalable Multidisciplinary Airway Teaching Mission: The Operation Airway 10‐Year Experience
Authors: Jayawardena Asitha D. L. , Ghersin Zelda J. , Mirambeaux Marcos , Bonilla Jose A. , Quiñones Ernesto , Zablah Evelyn , Callans Kevin , Hartnick Marina , Sahani Nita , Cayer Makara , Hersh Cheryl , Gallagher Thomas Q. , Yager Phoebe H. , Hartnick Christopher J. 
Published: June 2020

ObjectiveTo address whether a multidisciplinary team of pediatric otolaryngologists, anesthesiologists, pediatric intensivists, speech‐language pathologists, and nurses can achieve safe and sustainable surgical outcomes in low‐resourced settings when conducting a pediatric airway surgical teaching mission that features a program of progressive autonomy.Study DesignConsecutive case series with chart review.SettingThis study reviews 14 consecutive missions from 2010 to 2019 in Ecuador, El Salvador, and the Dominican Republic.MethodsDemographic data, diagnostic and operative details, and operative outcomes were collected. A country’s program met graduation criteria if its multidisciplinary team developed the ability to autonomously manage the preoperative huddle, operating room discussion and setup, operative procedure, and postoperative multidisciplinary pediatric intensive care unit and floor care decision making. This was assessed by direct observation and assessment of surgical outcomes.ResultsA total of 135 procedures were performed on 90 patients in Ecuador (n = 24), the Dominican Republic (n = 51), and El Salvador (n = 39). Five patients required transport to the United States to receive quaternary‐level care. Thirty‐six laryngotracheal reconstructions were completed: 6 single‐stage, 12 one‐and‐a‐half‐stage, and 18 double‐stage cases. We achieved a decannulation rate of 82%. Two programs (Ecuador and the Dominican Republic) met graduation criteria and have become self‐sufficient. No mortalities were recorded.ConclusionThis is the largest longitudinal description of an airway reconstruction teaching mission in low‐ and middle‐income countries. Airway reconstruction can be safe and effective in low‐resourced settings with a thoughtful multidisciplinary team led by local champions.
Thyroplasty Type III to Lower the Vocal Pitch in Trans Men
Authors: Bultynck Charlotte , Cosyns Marjan , T’Sjoen Guy , Van Borsel John , Bonte Katrien 
Published: June 2020

About 20% of trans men do not achieve cisgender male frequencies (F0≤131 Hz) after gender‐affirming hormone treatment (GAHT) with testosterone. The surgical procedure Isshiki thyroplasty type III (TPIII) is described to lower F0, but data on this technique in trans men are lacking. In this study, 8 trans men, unsatisfied with their voice after a minimum of 12 months of GAHT, underwent TPIII to lower F0 at the Department of Head and Neck Surgery at Ghent University Hospital. TPIII was performed by 1 surgeon using the same method each time. Pre‐ and postoperatively, an acoustic evaluation of the voice took place. The F0 dropped significantly from the preoperative mean of (154.60 ± 12.29) Hz to the postoperative mean of (105.37 ± 10.52) Hz (t = 9.821, P <. 001). TPIII is an effective method for lowering the F0 in trans men who are not satisfied with their voice after long‐term GAHT.
Effect of Solanum macrocarpon Linn leaf aqueous extract on the brain of an alloxan-induced rat model of diabetes
Authors: Okesola Mary A. , Ajiboye Basiru O. , Oyinloye Babatunji E. , Osukoya Olukemi A. , Owero-ozeze Ofogho S. , I. Ekakitie Lisa , Kappo Abidemi P. 
Published: June 2020

Objective This study was designed to evaluate the protective effect of aqueous extract of Solanum macrocarpon Linn leaf in the brain of an alloxan-induced rat model of diabetes. Methods The experimental model of diabetes was induced by a single intraperitoneal injection of freshly prepared alloxan. Rats were then divided into six groups: normal control, diabetes control, diabetes group treated with metformin, and three diabetes groups treated with different concentrations of S. macrocarpon. Rats were sacrificed on day 14 of the experiment and different brain biochemical parameters were assessed and compared between groups. Results Administration of different doses of S. macrocarpon leaf aqueous extract was associated with significantly reduced levels of fasting blood glucose, lipid peroxidation, neurotransmitters, cholinesterases, cyclooxygenase-2 and nitric oxide compared with diabetes control rats. In addition, antioxidant enzyme activities were significantly increased in diabetes rats administered 12.45, 24.9 and 49.8 mg/kg body weight of S. macrocarpon versus diabetes control rats. Conclusion Aqueous extract of S. macrocarpon Linn leaf may be useful in the management of diabetic neuropathy.