bluuebunny/crossref_metadata_2025 huggingface dataset:
615. TREATMENT PATTERN AND OUTCOMES OF ANASTOMOTIC LEAKAGE AFTER ESOPHAGECTOMY
Authors: Jeon Yeong Jeong , Jung Younggi , Kim Hong Kwan , Shim Young Mog
Published: September 2022

Anastomotic leak (AL) is one of the most common complications after esophagectomy and is frequently associated with repeated interventions; nothing by mouth (NPO), endoscopic vacuum therapy (EVT), or surgery. This study aimed to evaluate treatment pattern and its outcomes for patients with AL after esophagectomy.

We retrospectively reviewed patients who underwent esophagectomy at a single center from 2003 to 2020. A total of 3096 patients were reviewed and 181 (5.8%) patients with AL, excluding graft necrosis, were included in this study. We classified patients with AL according to the site of the anastomosis; 114 (63%) patients with cervical anastomosis (CA) and 67 (37%) patients with intrathoracic anastomosis (TA).

The incidence of AL was 11.9% and 3.2% in patients with CA and TA, respectively (p < 0.001). For patients with CA, 87 (76.3%), 15 (13.2%) and 12 (10.5%) patients were treated with NPO, EVT and surgery, respectively. Consequently, more than 90% of CA patients achieved oral diet at discharge regardless of management. For patients with TA, 36 patients underwent NPO (53.7%), of which 34 achieved oral diet. In addition, 25 patients were treated with EVT (37.3%), and 19 achieved oral diet. However, only 2 out of 6 patients treated with surgery achieved oral intake and 2 required subsequent EVT.

In patients with CA, the incidence rate of AL was higher, nevertheless, success rate of oral diet was higher than in patients with TA regardless of management. For AL in patients with TA, EVT applied more frequent than in patient with CA, and seems to be effective therapy.
617. OESOPHAGO-GASTRIC JUNCTION-PLASTY: PARAESOPHAGEAL HERNIA REPAIR + ANTI REFLUX SURGERY REVISITED
Authors: Di Maggio Francesco , Botha Abrie
Published: September 2022

VIDEO DESCRIPTION: Our technique for large paraoesophageal hernia repair and gastropexy shown step by step. This approach takes components of a series of historical anti-reflux operations and can be seen as a hybrid of Hill, Toupet and Nissen with anterior and posterior hiatus repair.

1. Sac approached infero-posteriorly on the right crus after phreno-esophageal ligament identified and separated at the V.

2. Sac separated from the pleura in the mediastinum.

3. Sac dissected from right to left along the edge of the hiatus.

4. Short gastric taken, posterior component of the sac dissected.

5. Sac reduced and completely excised.

6. OGJ identified.

7. Hiatus repair: posterior and (mainly) anterior.

8. Mobilised fundus slid behind the oesophagus.

9. Angle of His reconstituted.

10. Lateral and posterior fundo-pexy (Toupet).

11. Mediastinal drain.

SEE DESCRIPTION: Esophago-Gastric Junction-plasty with anterior and posterior hiatal repair is an anatomical anti-reflux procedure which can be performed for large paraoesophageal hernias.
625. PROPENSITY SCORE-MATCHED COMPARISON OF OUTCOMES BETWEEN POSTERIOR MEDIASTINAL AND RETROSTERNAL ROUTES OF RECONSTRUCTION FOLLOWING THREE-PHASE ESOPHAGECTOMY
Authors: Wong Claudia , Zhang Rui Qi , Chan Desmond , Wong Ian , Law Betty , Chan Fion , Law Simon
Published: September 2022

The retrosternal (RS) and posterior mediastinal (PM) routes can be chosen for gastric conduit reconstruction following three-phase esophagectomy with cervical anastomosis. It is controversial if the choice of reconstruction route would affect the operative outcome. This study aims to evaluate the surgical outcome by comparing the routes of reconstruction.

Between 2002 and 2019, patients who underwent esophagectomy with cervical anastomosis and gastric conduit reconstruction via the retrosternal (RS) or posterior mediastinal (PM) route for esophageal squamous cell cancer were included. Clinicopathological data were analyzed from a prospectively managed database. Postoperative morbidity and mortality rates, presence of recurrent tumor invasion of the conduit and overall survival were compared between the two groups. Further analyses were made after propensity score matching (PSM).

There were 89 patients in the RS and 266 in PM groups. R0 resection rates were 47.2% and 89.1% in the RS and PM groups, respectively (p<0.01). Anastomotic leak occurred more frequently in RS group at 16.9% vs. 6.8%, (p=0.007) while cardiac complications were fewer; 19% vs. 32%, (p=0.02). 90-day mortality rates were <4% in both groups. Median survival was 20 and 64 months in RS and PM groups respectively (p<0.01). PSM yielded 60 patients in each group. Postoperative morbidities, and survival, were similar. Mediastinal tumor recurrences infiltrated the gastric conduit only in the PM group in 6.8% of patients.

When corrected for selection biases, RS and PM routes did not differ in post-operative morbidity and mortality rates. Placing the gastric conduit in the RS route could avoid invasion by mediastinal tumor recurrence. RS is the preferred route of reconstruction after a three-phase esophagectomy.
644. PREDICTORS OF ADVERSE CLINICAL EVENTS FOR CAUSTIC INGESTION IN ADULTS: A 20-YEAR CROSS-SECTIONAL STUDY
Authors: Tam Dick-Sang , Wong Ian Yu-Hong , Chan Kwan-Kit , Wong Claudia Lai-Yin , Law Tsz-Ting , Chan Fion Siu-Yin , Law Simon Ying-Kit
Published: September 2022

Caustic ingestion is an uncommon but potentially life-threatening condition. It can lead to various complications. There are limited epidemiological studies on caustic ingestion, especially in the Asian population. This study aims to review the clinical characteristics of corrosive ingestion in Hong Kong adults and look for predictors of adverse clinical events.

Patients admitted for caustic ingestion at a tertiary referral center in Hong Kong between January 2001 and December 2021 were studied. Patients’ demographic and clinical characteristics, types of caustic substances ingested, Zargar endoscopic grading and clinical outcomes were obtained. Adverse clinical events are defined as the presence of any of the following outcomes: intensive-care-unit (ICU) admission, gastrointestinal (GI) complications (including stricture, ischemia, gangrene, perforation and fistulation), need for surgical or endoscopic intervention, in-hospital mortality, or length of hospital stay (LOS) more than 14 days. Relationships between patients’ factors and different outcomes were then evaluated.

Among 69 patients, 45 (65.2%) were suicidal intent. Eight (11.6%) patients required emergency surgery (7 gastrectomies, and 1 esophagectomy). The most common GI complication was esophageal stricture (n=12, 17.4%). Eleven patients underwent endoscopic dilatation; 4 required elective esophagectomy. Patients with diabetes mellitus had a higher Zargar grading (OR=4.259, p=0.040). Adverse clinical events were associated with acid ingestion (OR=4.110, p=0.015) and suicidal intent (OR=3.635, p=0.027). Subgroup analysis showed that diabetes (OR=4.062, p=0.040), acid ingestion (OR=4.222, p=0.016) and suicidal intent (OR=15.932, p=0.009) had higher risks for ICU admission. The morbidity and mortality rates were 29.0% and 7.2% respectively.

Caustic ingestion remains an important clinical problem in daily practice, with potential risks of developing severe complications. Suicidal attempt, acid ingestions and history of diabetes are predictors of adverse clinical events.
652. EVOLUTION OF BARRETT’S ESOPHAGUS IN PATIENTS WHO UNDERWENT UPPER DIGESTIVE TRACT SURGERY: RETROSPECTIVE STUDY AT HIGH VOLUME CENTER
Authors: Szachnowicz Sergio , Dardin Felipe Augusto , Gallon Eduardo , Duarte André Fonseca , Sallum Rubens Antonio Aissar , Cecconello Ivan
Published: September 2022

Continuous episodes of Gastroesophageal reflux (GER) attack the esophageal mucosa and may lead to the unusual replacement of the squamous cell epithelium for the glandular columnar cell epithelium, with goblet cells. The intestinal metaplasia, in the esophageal mucosa characterizes Barrett's Esophagus (BE). BE occurs in 10 to 15% of chronic and long-term reflux patients. In addition, BE's epithelium is susceptible to chronic inflammation with risks for dysplasia and adenocarcinoma.

We analyzed the impact of unconventional techniques on the evolution of Barrett's esophagus extension, as: Antrectomy (n = 1), Roux-en-Y Bypass (n = 5), Cardiomyotomy (n = 6), Esophagectomy (n = 10), Gastrectomy (n = 12), Lind fundoplication (n = 12). For this purpose, a retrospective study with BE patients treated at our service was carried out, evaluating the extension of Barrett's epithelium between the first and the last endoscopy of each patient.

The greatest mean absolute regression of the BE extension was seen in esophagectomy, equivalent to 2.87 cm; esophagectomy combined with gastrectomy, 1.15 cm; and gastrectomy, with 0.97 cm. Antrectomy and procedures involving Roux-en-Y, in our series, did not reduce the extent of the columnar epithelium, actually showing progression or formation of Barrett's Esophagus. It is worth mentioning that Lind fundoplication, once the main treatment for GERD, obtained a mean regression of 0.37 cm in the BE extension, however it was not the treatment with the best result, and 17% of the evaluated patients showed lesion progression.

The majority of evaluated procedures as alternative procedures for the treatment of reflux in patients with BE can be effective in controlling the evolution and even contributing to its regression.
654. DO PATIENTS WITH "EARLY" ESOPHAGEAL CANCER NEED NEOADJUVANT THERAPY?
Authors: Venkataramani Karthik , Karimundackal George , Jiwnani Sabita , Niyogi Devayani , Tiwari Virendra Kumar , Pramesh CS
Published: September 2022

Surgery remains the treatment of choice for early esophageal carcinoma (T1/2&N0). However, the available staging modalities have variable accuracy for T&N stages, with considerable understaging of T3/N+ disease depriving them of neoadjuvant therapy (NAT) which has been shown to improve survival and is the standard of care. As adjuvant therapy is ineffective in esophageal cancers, it is critical to identify factors associated with under staging in early esophageal carcinoma and consider NAT in this subset.

We conducted a retrospective analysis of a prospectively maintained database of patients undergoing esophagectomy for esophageal cancer at a tertiary referral cancer center from 2011 to 2019. Patients with T1/2&N0, staged with EUS and PET-CT and undergoing upfront surgery were included in the analysis. Patients who underwent upfront surgery due to limited fitness for systemic therapy, non-invasive disease, non-epithelial histology and endoscopic resections were excluded from analysis. Data with respect to epidemiology, staging, perioperative outcomes and follow up was extracted and analyzed using SPSS 26.0

68/1496 patients (4.5%) who underwent esophagectomy had upfront surgery for T1/2&N0 disease. Squamous cancers (93%) of the middle third were the most common. EUS had an accuracy of 67% & 83% for T&N stage respectively with 10.2% & 17% upstaging to T3 & N+ respectively. 3-year overall survival (OS) of all patients undergoing upfront surgery was 75.2%, of the understaged subset was 48.2%, (95% CI 20%-71%) and patients with T3/N+ disease treated with NAT followed by surgery was 55.7%, (95% CI 52.9%-58.4%). Multivariate analysis showed T2 on EUS, tumor size >3.5cm and SUVmax >3.05 to be predictors of understaging

Current staging modalities are associated with 20% upstaging to T3 or N+ disease. T2 tumors with size greater than 3.5cm and SUV>3.05 are frequently associated with understaging and these tumors have poorer outcomes. Patients with these tumor characteristics may benefit from neoadjuvant therapy followed by surgery.
Incessant non-sustained ventricular tachycardia immediately after MitraClip placement: a case report
Authors: Funabashi Sayaka , Amaki Makoto , Yamagata Kenichiro , Izumi Chisato
Published: September 2022

Background

MitraClip therapy has become an alternative therapy for primary and secondary mitral regurgitation (MR) in patients at high surgical risk. However, this procedure is associated with several complications.

Case summary

The patient was a 93-year-old male with severe MR caused by prolapse of the mid-posterior mitral leaflet (P2) and atrial enlargement. His heart failure (HF) continued to worsen, requiring hospitalization. Considering his high surgical risk, the heart team chose MitraClip treatment. After one clip was placed in the centre of the mitral valve (P2 lateral side), MR severity was reduced from severe to trivial. However, immediately after grasping, incessant non-sustained ventricular tachycardia (VT) with a heart rate of 150 beats/min occurred. Since there were no significant ST-T changes on electrocardiogram and no left ventricular (LV) wall motion abnormalities on echocardiography, ischaemic heart disease was ruled out, and pacing with a temporary pacemaker, potassium level correction, and intravenous amiodarone administration were performed. The frequency of VT decreased but it did not disappear. Diuretics were administered for HF, and VT disappeared within a few hours, with no recurrence, probably due to a decrease in the LV chamber size after diuresis.

Discussion

The VT waveform showed a right bundle branch block pattern with a superior axis. Furthermore, a negative lead I and a transition zone with an abrupt change from V4 to V5 indicated that PVC/VT arose from the posterior papillary muscle area. The probable cause was mechanical extension of the posterior medial papillary muscle as a result of leaflet grasping, with resolution following appropriate volume management.
Climate Change before the European Court of Human Rights: Capturing Risk, Ill-Treatment and Vulnerability
Authors: Heri Corina
Published: September 2022

Human rights law is increasingly being mobilized to litigate against the effects of anthropogenic climate change. This now includes proceedings before the European Court of Human Rights, which is currently considering its first five climate cases. The present article contends that an examination of climate change as a human rights issue by the Strasbourg Court, although requiring transformations of existing case law, is not only possible but also normatively desirable. It does so while examining two interlinked topics that could prove crucial to this type of case. The first is the assessment of risk – that is, the ability of the European Convention on Human Rights (ECHR) to capture impending harms through the doctrine of positive obligations. Second, the article frames climate claims as a matter for Article 3 of the ECHR (the prohibition of torture and inhuman and degrading treatment). This right has gone largely ignored in the relevant scholarship and the Court’s environmental cases to date. The resulting discussion of positive climatic obligations is interlinked with a discussion of climate-related vulnerabilities, which could potentially shape state obligations and lower the procedural and substantive hurdles that imperil the success of climate cases before the Court.
M2 Muscarinic Receptor-Dependent Contractions of Airway Smooth Muscle are Inhibited by Activation of β-Adrenoceptors
Authors: Alkawadri Tuleen , Wong Pei Yee , Fong Zhihui , Lundy Fionnuala T , McGarvey Lorcan P , Hollywood Mark A , Thornbury Keith D , Sergeant Gerard P
Published: September 2022

Beta-adrenoceptor (β-AR) agonists inhibit cholinergic contractions of airway smooth muscle (ASM), but the underlying mechanisms are unclear. ASM cells express M3 and M2 muscarinic receptors, but the bronchoconstrictor effects of acetylcholine are believed to result from activation of M3Rs, while the role of the M2Rs is confined to offsetting β-AR-dependent relaxations. However, a profound M2R-mediated hypersensitization of M3R-dependent contractions of ASM was recently reported, indicating an important role for M2Rs in cholinergic contractions of ASM. Here, we investigated if M2R-dependent contractions of murine bronchial rings were inhibited by activation of β-ARs. M2R-dependent contractions were apparent at low frequency (2Hz) electric field stimulation (EFS) and short (10s) stimulus  intervals. The β1-AR agonist, denopamine inhibited EFS-evoked contractions of ASM induced by reduction in stimulus interval from 100 to 10 s and was more effective at inhibiting contractions evoked by EFS at 2 than 20 Hz. Denopamine also abolished carbachol-evoked contractions that were resistant to the M3R antagonist 4-DAMP, similar to the effects of the M2R antagonists, methoctramine and AFDX-116. The inhibitory effects of denopamine on EFS-evoked contractions of ASM were smaller in preparations taken from M2R −/− mice, compared to wild-type (WT) controls. In contrast, inhibitory effects of the β3-AR agonist, BRL37344, on EFS-evoked contractions of detrusor strips taken from M2R −/− mice were greater than WT controls. These data suggest that M2R-dependent contractions of ASM were inhibited by activation of β1-ARs and that genetic ablation of M2Rs decreased the efficacy of β-AR agonists on cholinergic contractions.
A Chromosome-level Genome Assembly of the Highly Heterozygous Sea UrchinEchinometrasp. EZ Reveals Adaptation in the Regulatory Regions of Stress Response Genes
Authors: Ketchum Remi N , Davidson Phillip L , Smith Edward G , Wray Gregory A , Burt John A , Ryan Joseph F , Reitzel Adam M
Published: September 2022

Echinometra is the most widespread genus of sea urchin and has been the focus of a wide range of studies in ecology, speciation, and reproduction. However, available genetic data for this genus are generally limited to a few select loci. Here, we present a chromosome-level genome assembly based on 10x Genomics, PacBio, and Hi-C sequencing for Echinometra sp. EZ from the Persian/Arabian Gulf. The genome is assembled into 210 scaffolds totaling 817.8 Mb with an N50 of 39.5 Mb. From this assembly, we determined that the E. sp. EZ genome consists of 2n = 42 chromosomes. BUSCO analysis showed that 95.3% of BUSCO genes were complete. Ab initio and transcript-informed gene modeling and annotation identified 29,405 genes, including a conserved Hox cluster. E. sp. EZ can be found in high-temperature and high-salinity environments, and we therefore compared E. sp. EZ gene families and transcription factors associated with environmental stress response (“defensome”) with other echinoid species with similar high-quality genomic resources. While the number of defensome genes was broadly similar for all species, we identified strong signatures of positive selection in E. sp. EZ noncoding elements near genes involved in environmental response pathways as well as losses of transcription factors important for environmental response. These data provide key insights into the biology of E. sp. EZ as well as the diversification of Echinometra more widely and will serve as a useful tool for the community to explore questions in this taxonomic group and beyond.
Closed loop simulations on recoverability of climate trends in next generation gravity missions
Authors: Schlaak M , Pail R , Jensen L , Eicker A
Published: September 2022

Gravity field satellite missions are unique observation systems to directly measure mass transport processes on Earth and to gather valuable information for climate research. Next Generation Gravity Missions (NGGMs) are expected to be launched within this decade, setting high anticipation for an enhanced monitoring capability that will improve the spatial and temporal resolutions of gravity observations significantly. They will allow for an evaluation of long-term trends in the Terrestrial Water Storage (TWS) signal. The results of this study are based on a time-series of global changes in soil moisture and snow obtained from future climate projections until the year 2100 of a coupled climate model taking part in the CMIP6 (Coupled Model Intercomparison Project Phase 6). For different mission concepts, namely in-line single-pair missions and a Bender double-pair mission, the recoverability of a time variable mass signal is evaluated, considering realistic noise assumptions, simulated over several decades. The results show that a single-pair mission can fulfill the target requirements for the long-term trend, set by the user community, after 70 yr while a double pair already achieves it after 30 yr of observation. After 100 yr of double-pair constellations the globally averaged RMS (polar areas excluded) improves, compared to a single-pair mission, by a factor of 5 for the linear trend, 2.5 for annual amplitude, and 1.8 for the phase observation. In addition, regional investigations indicate that the simple parameter model consisting of offset, linear trend, and annual signal coefficients, as it was used in this study, in several cases might not be able to capture the whole time-variable signal sufficiently, due to the presence of interannual signals. Hence, advanced, locally more adaptable parameter models need to be considered for a better parametrization of local effects in the future.
Deep-Tomography: iterative velocity model building with deep learning
Authors: Muller Ana P O , Bom Clecio R , Costa Jessé C , Klatt Matheus , Faria Elisangela L , Silva Bruno dos Santos , de Albuquerque Marcelo P , de Albuquerque Marcio P
Published: September 2022

The accurate and fast estimation of velocity models is crucial in seismic imaging. Conventional methods, such as tomography, stereotomography, migration velocity analysis and full-waveform inversion (FWI), obtain appropriate velocity models; however, they require intense and specialized human supervision and consume much time and computational resources. In recent years, some works investigated deep learning (DL) algorithms to obtain the velocity model directly from shots or migrated angle panels, obtaining encouraging predictions of synthetic models. This paper proposes a new flow to recover structurally complex velocity models with DL. Inspired by the conventional geophysical velocity model building methods, instead of predicting the entire model in one step, we predict the velocity model iteratively. We implement the iterative nature of the process when, at each iteration, we train the DL algorithm to determine the velocity model with a certain level of precision/resolution for the next iteration; we name this process as ‘Deep-Tomography’. Starting from an initial model, that is an ultrasmooth version of the true model, Deep-Tomography is able to predict an appropriate final model, even in complete unseen during the training data, like the Marmousi model. When used as the initial model for FWI, the models estimated by Deep-Tomography can also improve substantially the final results obtained with FWI.
Appraising community driven health research with Aboriginal and Torres Strait Islander communities: a scoping review using the Aboriginal and Torres Strait Islander Quality Appraisal Tool
Authors: Biles Brett , Biles Jessica , Friere Kate , Deravin Linda , Lawrence Jayne , Yashadhana Aryati
Published: September 2022

Most research involving Aboriginal and Torres Strait Islander peoples has been conducted by non-Indigenous people and has not been a positive experience for many Aboriginal and Torres Strait Islander communities. This scoping review maps approaches to health research involving Aboriginal and Torres Strait Islander peoples and communities in Australia from the last two decades. A literature search found 198 papers, of which 34 studies met the inclusion criteria. The Aboriginal and Torres Strait Islander Quality Appraisal Tool was then used to map the quality of the reported community driven research. The Quality Appraisal Tool privileges, Aboriginal and Torres Strait Islander people’s epistemologies and ethical research governance. The findings reported on strengths and identified areas for improvement in reporting community driven research.
Artificial Intelligence in Clinical Practice: Implementation Considerations and Barriers
Authors: Bahl Manisha
Published: September 2022

The rapid growth of artificial intelligence (AI) in radiology has led to Food and Drug Administration clearance of more than 20 AI algorithms for breast imaging. The steps involved in the clinical implementation of an AI product include identifying all stakeholders, selecting the appropriate product to purchase, evaluating it with a local data set, integrating it into the workflow, and monitoring its performance over time. Despite the potential benefits of improved quality and increased efficiency with AI, several barriers, such as high costs and liability concerns, may limit its widespread implementation. This article lists currently available AI products for breast imaging, describes the key elements of clinical implementation, and discusses barriers to clinical implementation.
Stars versus Bars: How the Aesthetics of Product Ratings “Shape” Product Preference
Authors: Jia He (Michael) , Wan Echo Wen , Zheng Wanyi
Published: September 2022

Websites commonly use visual formats to display numerical product ratings. Highlighting the overlooked notion of the “aesthetics” of product ratings, the current research examines how the shape of basic visual rating units (rectangular vs. non-rectangular) influences product preference. Seven experiments (and 23 supplementary experiments; N = 17,994) demonstrate a visual rounding effect. Specifically, compared to the rectangular rating format (e.g., bar ratings), the non-rectangular rating format (e.g., star ratings) increases product preference when product ratings (e.g., 3.7, 3.8, 3.9) are below the nearest integer. In contrast, the non-rectangular rating format decreases product preference when product ratings (e.g., 4.1, 4.2, 4.3) are above the nearest integer. Occurring for both the overall rating and by-attribute ratings of a product, the visual rounding effect results from a visual completeness restoration process, wherein consumers perceive non-rectangular rating units to be incomplete after vertical cutting. This research contributes to the product rating and visual marketing literatures and provides actionable implications by demonstrating what visual rating format should be adopted based on rating distribution, how the visual rounding effect can be prevented if needed, and who are even more susceptible to the visual rounding effect.
Survival and clinicopathological significance of blood vessel invasion in operable breast cancer: a systematic review and meta-analysis
Authors: Lin Yingxin , Zhang Yuehua , Fang Huiqiong , Hu Qian , Duan Haibo , Zhang Liangyun , Pang Danmei
Published: September 2022

Background

Lymphovascular invasion, including lymphatic-vessel invasion and blood-vessel invasion, plays an important role in distant metastases. The metastatic pattern of blood-vessel invasion may differ from that of lymphatic-vessel invasion. However, its prognostic significance in breast cancer remains controversial. We evaluated the role of blood-vessel invasion in the prognosis of operable breast-cancer patients and its association with clinicopathological characteristics.

Methods

We systematically searched EMBASE, PubMed, the Cochrane Library and Web of Science for studies in English through December 2020. Disease-free survival, overall survival and cancer-specific survival were the primary outcomes. Pooled hazard ratios and 95% confidence intervals were assessed using a random-effects model.

Results

Twenty-seven studies involving 7954 patients were included. Blood-vessel invasion occurred in 20.4% of tumor samples. Pooled results showed significant associations of blood-vessel invasion with worse disease-free survival (hazard ratio = 1.82; 95% confidence interval = 1.43–2.31) and overall survival (hazard ratio = 1.86; 95% confidence interval = 1.16–2.99) in multivariate analyses. The results of the univariate analyses were similar. Among the clinicopathological factors, blood-vessel invasion was associated with larger tumor size, lymph-node metastasis, nonspecific invasive type, higher histological grade, estrogen receptor-negative breast cancer, human epidermal growth factor receptor 2-positive breast cancer and lymphatic-vessel invasion. In the lymph-node-negative subgroup analyses, the presence of blood-vessel invasion led to poorer disease-free survival (hazard ratio = 2.46; 95%confidence interval = 1.64–3.70) and overall survival (hazard ratio = 2.94; 95%confidence interval = 1.80–4.80).

Conclusions

We concluded that blood-vessel invasion is an independent predictor of poor prognosis in operable breast cancer and is associated with aggressive clinicopathological features. Breast-cancer patients with blood-vessel invasion require more aggressive treatments after surgery.
Augmenting randomized clinical trial data with historical control data: Precision medicine applications
Authors: Freidlin Boris , Korn Edward L
Published: September 2022

As precision medicine becomes more precise, the sizes of the molecularly targeted subpopulations become increasingly smaller. This can make it challenging to conduct randomized clinical trials of the targeted therapies in a timely manner. To help with this problem of a small patient subpopulation, a study design that is frequently proposed is to conduct a small randomized clinical trial (RCT) with the intent of augmenting the RCT control arm data with historical data from a set of patients who have received the control treatment outside the RCT (historical control data). In particular, strategies have been developed that compare the treatment outcomes across the cohorts of patients treated with the standard (control) treatment to guide the use of the historical data in the analysis; this can lessen the potential well-known biases of using historical controls without any randomization. Using some simple examples and completed studies, we demonstrate in this commentary that these strategies are unlikely to be useful in precision medicine applications.
Identifying the Boundaries of a Sales Contract
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter notes the boundaries of a sales contract. A contract of sale usually implies that the seller is obligated to deliver the goods and transfer property, while the buyer, on the other hand, has to pay the price. The implication changes in many countries as some elements specify the need for money as payment. The distinction is made between an agreement to sell and sale to the contract of sale in terms of common law. The chapter then discusses the framework agreements which remain pertinent to the realms of uniform law. It explores sales by auction, other supply of goods contracts, and mixed contracts.
Agency
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter discusses the authority and liability of agencies. Agents act on behalf of people taking part in modern commercial transactions. The general law of agency is still primarily governed by case law with the exception of India, Pakistan, and Malaysia. Special rules exist for the agency in commercial environments, especially for countries with distinctions between civil law and commercial code. The chapter explains how the law could establish authority and the intent of the principal. It also notes that an agent’s liability is dependent whether it is towards the principal or the third party.
Capacity to Contract
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter cites the capacity to contract legal persons and natural persons. Legal capacity in this work is concerned only with a person or party’s legal ability to contract. Some jurisdictions distinguish between the capacity to have legal rights and the capacity to make legal decisions and contract in line with applicable law. Generally, all jurisdictions recognize that natural persons have the legal authority to enter into contracts except for those limitations of age, mental capacity, and office they hold. Meanwhile, corporations gain their capacity to contract from the statute. The chapter notes the ultra vires doctrine is the most significant issue in the context of legal capacity.
Fraud and Duress
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter expounds on the concept of fraud and duress. Laws concerning fraud and duress in the context of contracts are designed to protect parties rather than society as a whole. Consent is significant when it comes to fraud or duress contracts as obligations of the contract do not reflect the real intentions of the party. The chapter defines fraud as a statement, act, or omission which deceives another party to induce that party to act or refrain from acting in a particular manner, while duress is the illegitimate pressure that may lead a party to conclude a contract when it might not have otherwise done so.
Documents and Costs
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter looks into documents and costs. The respective characteristic obligations under a sales contract include the procurement of licenses and documents and the payment of certain costs and expenses. Documents can be classified into three broadly defined categories: goods, the right to claim physical possession and contract which do not affect title or possession. These documents could be used by the seller as evidence of conformity of the goods at the time of delivery. Moreover, the chapter tackles the contractual terms and default rules of handling licenses, transportation, and insurance.
Third Party Property Rights
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter explicates third-party property rights. A general principle of sales law indicates that the seller is liable to the buyer when delivering goods not free from third-party rights. Sellers can only escape liability when the buyer is aware of the encumbrance with third-party rights. Meanwhile, the rules on third-party rights in terms of non-conformity always relate to the physical properties of the goods. Legal systems differ with the legal regime applied to goods encumbered with third-party property rights. The circumstances in which third-party rights may affect the goods can be categorized into three groups: ownership rights, third party encumbered with goods, and the impact of public law.
Payment
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter cites the significance of payment. The payment of the purchase price is the reciprocal counterpart of the seller’s obligation to deliver the goods and transfer title. In common law jurisdictions, the seller’s willingness to accept a lesser sum instead of the original contract price is in line with a modification of the contract and thus requires consideration. The chapter highlights the importance of identifying the place for payment as it determines the mode of payment, especially for international transactions. Moreover, the place of payment of the purchase price is primarily a matter of substantive law. Default rules should be consulted if no negotiation was reached.
Transfer of Title
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter expounds on the concept of transferring titles. The transfer of title is ultimately the obligation of the buyer in a sales contract. The transfer of title in the goods sold under a sales contract is central to the parties and their creditors’ interests. The chapter notes the importance of distinguishing legal systems following a unitary approach or a functional approach. It explains the applicable law used in default provisions. The mode of transferring title is also considered on a jurisdiction basis. The chapter also differentiates the buyer’s obligation of transferring titles and the seller’s obligation of delivering goods.
Suspension of Performance
Authors: Schwenzer Ingeborg , Muñoz Edgardo
Published: September 2022

This chapter explores the suspension of performance which often happens where there is a loss of confidence between both parties. Under the general principle of the freedom of contract, the parties may contractually agree on a right to withhold performance. The Convention expressly provides the possibility to establish such a right in the contract for specific circumstances of withholding performance at the international level. The chapter lists the default pre-requisites to withhold performance such as performance due, concurrent obligations, non-performance by the co-contractant, and readiness to perform. Moreover, it notes the possibility of the uncertainty of obligor’s economic position.
Lightning-induced chemistry on tidally-locked Earth-like exoplanets
Authors: Braam Marrick , Palmer Paul I , Decin Leen , Ridgway Robert J , Zamyatina Maria , Mayne Nathan J , Sergeev Denis E , Abraham N Luke
Published: September 2022

Determining the habitability and interpreting atmospheric spectra of exoplanets requires understanding their atmospheric physics and chemistry. We use a 3-D coupled climate-chemistry model, the Met Office Unified Model with the UK Chemistry and Aerosols framework, to study the emergence of lightning and its chemical impact on tidally-locked Earth-like exoplanets. We simulate the atmosphere of Proxima Centauri b orbiting in the Habitable Zone of its M-dwarf star, but the results apply to similar M-dwarf orbiting planets. Our chemical network includes the Chapman ozone reactions and hydrogen oxide (HOx = H + OH + HO2) and nitrogen oxide (NOx = NO + NO2) catalytic cycles. We find that photochemistry driven by stellar radiation (177–850 nm) supports a global ozone layer between 20–50 km. We parametrize lightning flashes as a function of cloud-top height and the resulting production of nitric oxide (NO) from the thermal decomposition of N2 and O2. Rapid dayside convection over and around the substellar point results in lightning flash rates of up to 0.16 flashes km−2 yr−1, enriching the dayside atmosphere below altitudes of 20 km in NOx. Changes in dayside ozone are determined mainly by UV irradiance and the HOx catalytic cycle. ∼45 per cent of the planetary dayside surface remains at habitable temperatures (Tsurf > 273.15K), and the ozone layer reduces surface UV radiation levels to 15 per cent. Dayside–nightside thermal gradients result in strong winds that subsequently advect NOx towards the nightside, where the absence of photochemistry allows NOx chemistry to involve reservoir species. Our study also emphasizes the need for accurate UV stellar spectra to understand the atmospheric chemistry of exoplanets.
Model of abasic site DNA cross-link repair; from the architecture of NEIL3 DNA binding domains to the X-structure model
Authors: Huskova Andrea , Dinesh Dhurvas Chandrasekaran , Srb Pavel , Boura Evzen , Veverka Vaclav , Silhan Jan
Published: September 2022

Covalent DNA interstrand crosslinks are toxic DNA damage lesions that block the replication machinery that can cause a genomic instability. Ubiquitous abasic DNA sites are particularly susceptible to spontaneous cross-linking with a base from the opposite DNA strand. Detection of a crosslink induces the DNA helicase ubiquitination that recruits NEIL3, a DNA glycosylase responsible for the lesion removal. NEIL3 utilizes several zinc finger domains indispensable for its catalytic NEI domain repairing activity. They recruit NEIL3 to the repair site and bind the single-stranded DNA. However, the molecular mechanism underlying their roles in the repair process is unknown. Here, we report the structure of the tandem zinc-finger GRF domain of NEIL3 and reveal the molecular details of its interaction with DNA. Our biochemical data indicate the preferential binding of the GRF domain to the replication fork. In addition, we obtained a structure for the catalytic NEI domain in complex with the DNA reaction intermediate that allowed us to construct and validate a model for the interplay between the NEI and GRF domains in the recognition of an interstrand cross-link. Our results suggest a mechanism for recognition of the DNA replication X-structure by NEIL3, a key step in the interstrand cross-link repair.
Phosphorylation of the auxin signaling transcriptional repressor IAA15 by MPKs is required for the suppression of root development under drought stress in Arabidopsis
Authors: Kim Sun Ho , Bahk Sunghwa , Nguyen Nhan Thi , Pham Minh Le Anh , Kadam Ulhas Sopanrao , Hong Jong Chan , Chung Woo Sik
Published: September 2022

Since plants are sessile organisms, developmental plasticity in response to environmental stresses is essential for their survival. Upon exposure to drought, lateral root development is suppressed to induce drought tolerance. However, the molecular mechanism by which the development of lateral roots is inhibited by drought is largely unknown. In this study, the auxin signaling repressor IAA15 was identified as a novel substrate of mitogen-activated protein kinases (MPKs) and was shown to suppress lateral root development in response to drought through stabilization by phosphorylation. Both MPK3 and MPK6 directly phosphorylated IAA15 at the Ser-2 and Thr-28 residues. Transgenic plants overexpressing a phospho-mimicking mutant of IAA15 (IAA15DD OX) showed reduced lateral root development due to a higher accumulation of IAA15. In addition, MPK-mediated phosphorylation strongly increased the stability of IAA15 through the inhibition of polyubiquitination. Furthermore, IAA15DD OX plants showed the transcriptional downregulation of two key transcription factors LBD16 and LBD29, responsible for lateral root development. Overall, this study provides the molecular mechanism that explains the significance of the MPK-Aux/IAA module in suppressing lateral root development in response to drought.
Single-cell gene regulation network inference by large-scale data integration
Authors: Dong Xin , Tang Ke , Xu Yunfan , Wei Hailin , Han Tong , Wang Chenfei
Published: September 2022

Single-cell ATAC-seq (scATAC-seq) has proven to be a state-of-art approach to investigating gene regulation at the single-cell level. However, existing methods cannot precisely uncover cell-type-specific binding of transcription regulators (TRs) and construct gene regulation networks (GRNs) in single-cell. ChIP-seq has been widely used to profile TR binding sites in the past decades. Here, we developed SCRIP, an integrative method to infer single-cell TR activity and targets based on the integration of scATAC-seq and a large-scale TR ChIP-seq reference. Our method showed improved performance in evaluating TR binding activity compared to the existing motif-based methods and reached a higher consistency with matched TR expressions. Besides, our method enables identifying TR target genes as well as building GRNs at the single-cell resolution based on a regulatory potential model. We demonstrate SCRIP’s utility in accurate cell-type clustering, lineage tracing, and inferring cell-type-specific GRNs in multiple biological systems. SCRIP is freely available at https://github.com/wanglabtongji/SCRIP.
Manipulation of Menthol and Nicotine Content in Cigarettes: Effects on Smoking Behavior and Toxicant Exposure in Women Menthol Smokers
Authors: Oncken Cheryl , Litt Mark D , Thurlow Sheila , Mead-Morse Erin L , Wang Lanqing , Hatsukami Dorothy K
Published: September 2022

Background

The purpose of this study was to determine the effects of smoking and other outcomes of assigning cigarettes with reduced nicotine and/or no menthol to female menthol smokers.

Aims and Methods

Nontreatment-seeking female menthol smokers (N = 263) participated in a randomized controlled trial in which levels of menthol and nicotine in cigarettes were manipulated using experimental cigarettes. After a baseline period, participants were assigned to the following conditions for 6 weeks: (1) their own brand of cigarette (conventional nicotine with menthol), (2) a conventional nicotine cigarette with no menthol, (3) a cigarette with reduced nicotine (RNC) with menthol, or (4) a RNC cigarette and no menthol. Participants then returned to using their own brand and were followed for another 6 weeks. Outcomes included cigarettes smoked, biomarkers of exposure, and dependence measures.

Results

Results indicated that, after an initial increase, rates of smoking of all three experimental cigarettes were at or below baseline rates of smoking of one’s own brand. Levels of biomarkers also decreased during the experimental phase but rebounded somewhat after participants resumed smoking their own brand. There was evidence that the overall amount of smoking decreased similarly among women who switched to non-menthol and/or RNC cigarettes.

Conclusions

These results suggest that no detrimental effect will occur in nicotine or toxicant exposure levels with a ban on characterizing menthol and/or a product standard on nicotine content in cigarettes.

Implications

The implication of this work is that there would be no risk to women menthol smokers associated with regulations restricting nicotine and eliminating menthol in cigarettes.
Screening and validation of nickel ion cytotoxicity biomarkers based on transcriptomic and proteomic technology
Authors: Zhang Fudan , Huang Yan , Zhang Yajing , Lü Xiaoying
Published: September 2022

The aim of this study was to screen cytotoxicity biomarkers of nickel ions (Ni2+) using transcriptomic and proteomic approaches combined with molecular biology validation. First, the MTT method was used to evaluate cytotoxicity in L929 cells treated with Ni2+ at different concentrations. Ni2+ at both 100 μM and 200 μM affected cell proliferation. Then, transcriptomic and proteomic technology was used to study the effects of Ni2+ on the expression of genes/proteins in cells. It was found that 1490, 789, 652 and 729 genes (12, 24, 48 and 72 h, respectively) and 177, 2191 and 2095 proteins (12, 24 and 48 h, respectively) were differentially expressed after treatment with 100 μM Ni2+. In total, 1403, 963, 916 and 1230 genes (12, 24, 48 and 72 h, respectively) and 83, 1681 and 2398 proteins (12, 24 and 48 h, respectively) were differentially expressed after treatment with 200 μM Ni2+. Then, four target gene/protein biomarkers were filtered by combined screening using gene/proteomic experimental data and biological pathway analyses. Further expression level validation of all these target biomarkers and functional validation of selected gene/protein biomarkers were carried out, and a final gene/protein biomarker (UQCRB) was identified.
DEVELOPMENT AND ESTIMATION OF HUMAN DOSIMETRY OF A NEW 47SC-RISEDRONATE FOR RADIOPHARMACEUTICAL APPLICATION
Authors: Moghaddam-Banaem Leila , Deilami-nezhad Leila , Sadeghi Mahdi , Jalilifar Mostafa
Published: September 2022

Bisphosphonate risedronate (2-(3-pyridinyl)-1-hydroxyethane diphosphonic acid) was radiolabeled with scandium-47 (47Sc) as potential therapeutic radiopharmaceutical for skeletal metastases. Its time-dependent biodistribution in mice was measured and its human dosimetry was derived. The labelling process was performed at 95 °C for 30 min. The stability of the radio-conjugate was tested in human serum at 37 °C and its biodistribution was studied in balb/c mice. The radiochemical yield of ≥90% was obtained corresponding to a specific activity of 277 MBq/mg. The radio-conjugate showed good stability in human serum up to 48 h. A high bone uptake by 48 h post-injection was achieved, which suggests that 47Sc-risedronate may be therapeutically beneficial for the palliation of painful bone metastasis. The estimated absorbed dose coefficient and the time-integrated activity coefficient (ã (rs, TD)) in the bone were 1.35 mGy/MBq and 31.04 (Bq-h/Bq), respectively. The absorbed doses to non-osseous normal organs were much lower than that to the bone.