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Lynch syndrome (LS) carriers develop mismatch repair–deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair–deficient cancers and precancers via transcriptomics analysis. Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers. This study provides the combined mutational and transcriptomic landscape along with a catalog of immunologically validated neoantigens in Lynch syndrome colonic precancers and tumors that will facilitate cancer immunoprevention strategies. [ABSTRACT FROM AUTHOR]

KRAS mutations, microsatellite instability, and tumor location have been found to be significant prognostic factors in colorectal cancer. The interaction between these variables and its effect on overall survival in nonmetastatic colon cancer has not been well elucidated. The National Cancer Database (2010–2016) was queried for patients with stage I–III colon cancer and known microsatellite instability and KRAS status undergoing curative resection. A total of 5,292 patients were identified: 60.4% had right-sided cancers, 36.4% had KRAS mutations, and 15.6% had microsatellite instability. Right-sided tumors were more likely to have microsatellite instability and KRAS mutations compared to left-sided tumors. On univariable analysis, KRAS mutations and microsatellite instability status were not associated with differences in survival, whereas right-sided cancers had worse overall survival compared to left-sided cancers (hazard ratio 1.32, 95% confidence interval: 1.18–1.47). On multivariable analysis, right-sided location, KRAS mutations, and microsatellite instability were not independent prognostic factors. However, a significant interaction between laterality and KRAS status was observed. In patients with mutated KRAS cancers, left-sided tumors were at increased risk of death compared to right-sided tumors (hazard ratio: 1.30, 95% confidence interval: 1.03–1.63), whereas in patients with wild-type KRAS cancers, left-sided tumors were at decreased risk of death (hazard ratio: 0.81, 95% confidence interval: 0.67–0.97). In patients with stage I–III colon cancer, laterality, KRAS mutation, and microsatellite instability status were not independently prognostic after curative resection. However, the effect of laterality was opposite based on KRAS status, with left-sided (compared to right-sided) tumors associated with worse overall survival in mutated KRAS patients and better overall survival in wild-type KRAS individuals. Laterality itself may not be an independent prognostic factor but a reflection of differing genetic profiles within the colon. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the practice and the associated outcomes of surgical treatment for young-onset colorectal cancer (YOCRC) patients presenting with synchronous liver metastases. The study cohort was divided into two groups according to surgery date: 131 patients in the early era (EE, 1998–2011) and 179 in the contemporary era (CE, 2012–2020). The CE had a higher rate of node-positive primary tumors, higher carcinoembryonic antigen level, and lower rate of RAS/BRAF mutations. The CE had higher rates of reverse or combined resection, multi-drug prehepatectomy chemotherapy, and two-stage hepatectomy. The median survival was 8.4 years in the CE and 4.3 years in the EE (p = 0.011). On multivariate analysis, hepatectomy in the CE was independently associated with improved overall survival (HR 0.48, p = 0.001). With a combination of perioperative systemic therapy, careful selection of treatment approach, and coordinated resections, durable cure can be achieved in YOCRC patients. [ABSTRACT FROM AUTHOR]

Parotid lymph node (PLN) metastasis greatly worsens the prognosis of patients with oral squamous cell carcinoma (OSCC) and poses a great challenge for further treatment of OSCC. The clinicopathological characteristics and treatment strategies for PLN metastasis from OSCC need to be comprehensively elucidated. A retrospective review of OSCC patients who experienced postoperative PLN metastasis in our department between 2000 and 2018 was performed in this study. A total of 47 OSCC patients with postoperative PLN metastasis were identified. PLN with metastasis were divided into three groups based on the location: parotid tail (PLN-t), superficial lobe (PLN-sl), and deep lobe (PLN-dl). Most of the patients experienced PLN metastasis within less than 12 months after the primary surgery for OSCC. Comparatively, patients with PLN-sl metastasis were more prone to have infiltration of the facial nerve. The tongue and buccal mucosa were the most frequent primary sites associated with PLN metastasis from OSCC. PLNs in the parotid tail were most commonly affected by the metastasized OSCC. Consequently, we recommend a series of strategies for the prevention and treatment of PLN metastasis for OSCC patients. In conclusion, PLNs should not be overlooked during preoperative evaluation and postoperative follow-up examinations for OSCC patients. [ABSTRACT FROM AUTHOR]

Squamous cell carcinoma (SCC) of the parotid gland is a rare aggressive malignancy with a poor prognosis. The clinical behaviour, histopathological characteristics, and treatment strategies for parotid SCC still need to be comprehensively demonstrated. In this study, a retrospective review of patients diagnosed with parotid SCC was performed, covering the past two decades. Twenty-nine patients with primary parotid SCC and 10 patients with recurrent parotid SCC were identified. The clinicopathological characteristics of parotid SCC were summarized. Imaging records were used to determine the extent of invasion of the parotid SCC. Histopathological alterations in the parotid resulting from the infiltration of SCC were demonstrated. A set of treatment strategies was developed, involving parotidectomy, neck dissection, facial nerve treatment, defect repair, adjuvant radiotherapy, and chemotherapy/targeted therapy. The median patient survival was 24 months for those with primary parotid SCC and 14.5 months for those with recurrent parotid SCC. Comparatively, patients with a larger tumour size of primary parotid SCC experienced poorer overall survival (hazard ratio 8.986; P = 0.013). Great efforts have been made over the past two decades to identify and treat parotid SCC. Consensus regarding therapeutic options for parotid SCC has not been widely achieved and there is still a great need for well-designed prospective studies. [ABSTRACT FROM AUTHOR]

The objectives of this expert review are: (1) to prepare clinicians to recognize the presentation and evidence-based risk factors for young adult–onset colorectal cancer (CRC), defined as CRC diagnosed in individuals 18 - <50 years of age; (2) to improve management for patients with young onset CRC. This review will focus on the following topics relevant to young adult–onset CRC: epidemiology and risk factors; clinical presentation; diagnostic and therapeutic management including options for colorectal and extra-colonic surgical intervention, chemotherapy and immune-oncology therapies; genetic testing and its potential impact on preimplantation genetics; fertility preservation; and cancer surveillance recommendations for these individuals and their family members. The evidence reviewed in this manuscript is a summation of relevant scientific publications, expert opinion statements, and current practice guidelines. With the rising incidence of people developing CRC before 50 years of age, diagnostic evaluation of the colon and rectum is encouraged for all patients, irrespective of age, who present with symptoms that may be consistent with CRC, including but not limited to: rectal bleeding, weight loss, change in bowel habit, abdominal pain, iron deficiency anemia. Clinicians should obtain family history of colorectal and other cancers in first and second degree relatives of patients with young adult–onset CRC and discuss genetic evaluation with germline genetic testing either in targeted genes based on phenotypic presentation or in multiplex gene panels regardless of family history. Clinicians should present the role of fertility preservation prior to cancer-directed therapy including surgery, pelvic radiation, or chemotherapy Clinicians should counsel patients on the benefit of germline genetic testing and familial cancer panel testing in the pre-surgical period to inform which surgical options may be available to the patient with young adult–onset CRC Clinicians should consider utilizing germline and somatic genetic testing results to inform chemotherapeutic strategies Clinicians should offer hereditary CRC syndrome specific screening for CRC and extra-colonic cancers only to young adult–onset CRC patients who have a genetically or clinically diagnosed hereditary CRC syndrome. For patients with sporadic young adult–onset CRC, extra-colonic screening and CRC surveillance intervals are the same as for patients with older adult–onset CRC. [ABSTRACT FROM AUTHOR]

Despite the availability of effective colorectal cancer (CRC) screening strategies, up to 10% of CRC patients present with obstructive symptoms as the first sign of disease. For patients with acute or subacute malignant obstruction that requires urgent intervention, treatment options include endoscopic stenting as a bridge to surgery, one-stage surgical resection and anastomosis, or diverting ostomy which may or may not be followed by later tumor resection and stoma closure. However, to date, there is no consensus guideline for the optimal approach to manage malignant colorectal obstruction. This article aims to illustrate clinical scenarios in palliative, curative, and potentially curative settings, and delineate the key factors to be considered when making an individualized decision in order to determine the optimal treatment. [ABSTRACT FROM AUTHOR]

Abstract Background In patients with stage IV colorectal cancer (CRC), minimally invasive surgery (MIS) may offer optimal oncologic outcome with low morbidity. However, the relative benefit of MIS compared to open surgery in patients requiring multistage resections has not been evaluated. Methods Patients who underwent totally minimally invasive (TMI) or totally open (TO) resections of CRC primary and liver metastases (CLM) in 2009–2016 were analyzed. Inverse probability of weighted adjustment by propensity score was performed before analyzing risk factors for complications and survival. Results The study included 43 TMI and 121 TO patients. Before and after adjustment, TMI patients had significantly less cumulated postoperative complications (41% vs. 59%, p = 0.001), blood loss (median 100 vs. 200 ml, p = 0.001) and shorter length of hospital stay (median 4.5 vs. 6.0 days, p < 0.001). Multivariate analysis identified TO approach vs. MIS (OR = 2.4, p < 0.001), major liver resection (OR = 4.4, p < 0.001), and multiple CLM (OR = 2.3, p = 0.001) as independent risk factors for complications. 5-year overall survival was comparable (81% vs 68%, p = 0.59). Conclusion In patients with CRC undergoing multistage surgical treatment, MIS resection contributes to optimal perioperative outcomes without compromise in oncologic outcomes. Synopsis: A coordinated preplanned approach to total laparoscopic multistage resection of stage IV colorectal cancer optimizes short-term outcomes. [ABSTRACT FROM AUTHOR]

Compared with single-stage latent heat storage, cascaded latent heat storage is considered as an effective way to store and utilize intermittent or fluctuant thermal energy due to an increased heat transfer rate, a uniform and lower HTF outlet temperature, faster charging/discharging processes and higher exergy efficiency. In this paper, an experimental three-stage latent heat storage system filled with three different phase change materials is established and its heat charging process is studied. Its temperature evolution in each stage during the heat charging process is measured and the corresponding thermodynamic performance is analyzed. Besides, the effects of stage number, HTF inlet temperature and HTF flow rates on the thermodynamic performance are discussed, respectively. The results show that the solid-liquid phase change in the three stages does not take place simultaneously due to the poor heat transfer and the large melting temperature difference. In addition, more stages could improve energy storage efficiency, exergy storage efficiency and entransy storage efficiency. Higher HTF inlet temperatures and larger HTF flow rates could increase transfer and storage rates of energy, exergy and entransy, but the storage efficiency of energy, exergy and entransy could only be obviously improved by higher HTF inlet temperatures. [ABSTRACT FROM AUTHOR]

Changes in the complexity of natural organic matter (NOM) have impacted the performance of direct filtration plants of water industries, resulting in reduced treatment capacity, and can lead to increased disinfection by-products. Hence, the need to identify new materials in future can be converted into more effective technologies and processes. We report a laboratory scale innovative use of graphene oxide membranes to remove NOMs from water that had been treated and still contained 5 mg/L DOC. Our study shows that graphene oxide based membranes can reject ∼100% of NOM while maintaining high water flux of 65 L m −2 h −1 bar −1 at atmospheric pressure. Our results indicate that it is possible to develop a graphene oxide-based water filtration technology. [ABSTRACT FROM AUTHOR]

Background: Emergency treatment of perforated colon cancer has traditionally been linked with dismal outcomes due to the double jeopardy of a septic insult combined with a malignant disease, leaving unclear how aggressive emergency surgical procedures should be. We aimed to define short- and long-term outcomes in the current era of critical care support and oncologic advances, to provide updated data for decision making.Study Design: Patients with perforations associated with a primary colon cancer were identified. Peri-operative and long-term survival were compared among free (FP; n = 41) and contained perforations (CP; n = 45) and to age-, stage-, and resection status case-matched, non-perforated (NP; n = 85), controls.Results: Tumors were completely resected in 67% of FP but fewer lymph nodes were harvested (median, 11 vs. 11 and 16 in CP and NP; p = 0.21 and p < 0.001). Peri-operative mortality was highest in FP: 19% vs. 0% and 5% in CP and NP (p = 0.038), respectively. After adjusting for peri-operative mortality, 5-year overall survival was comparable: 55%, 59%, and 54% for FP, CP, and NP, respectively. Advanced age, higher ASA class, presence of residual disease, and advanced stage, but not perforation, were independent predictors of poorer long-term overall survival.Conclusions: Patients with malignant colonic perforation face high risk of peri-operative death, making septic source control the priority in the acute setting. Pursuit of an oncologically oriented resection and long-term cancer-directed treatments, however, may lead to improved long-term outcomes. [ABSTRACT FROM AUTHOR]

Advances in molecular biology have enabled identification of tumor biomarkers that allow for individualized risk assessment for patients with cancer. Molecular predictors of clinical outcome can help inform discussion regarding the role of adjuvant chemotherapy in patients with resected colon cancer, such as those with stage II colon cancer in which the benefit of adjuvant therapy is controversial or those with stage III colon cancer who may have a lower risk of recurrence and less absolute benefit from oxaliplatin therapy. This article summarizes the data surrounding the development, validation, and clinical and economic utility of the Oncotype DX® colon cancer assay, a multigene expression assay validated to independently predict recurrence risk in patients with stage II and III colon cancer beyond traditional factors. [ABSTRACT FROM AUTHOR]

Taro ( Colocasia esculenta ) is an important crop in Africa, Southeast Asia and the subtropics, as it is used for food and medicine. The aims of this study were to access a large expression datasets of taro and reveal the candidate genes of starch synthesis. As a result, approximately 2.2 Gb sequence data of taro transcriptome were obtained by using Illumina HiSeq 2000 platform and assembled into 52,935 contigs with an average length of 588.5 bp. Sequence similarity analyses against four public databases (NR, GO, KEGG, KOG) found 17,047 contigs that could be annotated with gene descriptions, conserved protein domains, or gene ontology terms. Among the important metabolic pathways, 26 genes related to starch synthesis were validated by RT-PCR. This transcriptome dataset can serve as an important public information platform for further studies in gene expression, genomics, and functional genomic studies in C. esculenta . [ABSTRACT FROM AUTHOR]

Background: With advances in multimodality therapy, colorectal cancer survivors are living longer. However, little is known about the quality of their long-term survival. We investigated the functional outcomes and symptoms among long-term survivors. Methods: A cross-sectional study of 1,215 long-term (>5 years) colorectal cancer survivors was conducted using a validated disease-specific questionnaire. Younger onset survivors (18-50 years) were matched 1:2 to later onset survivors (>50 years). Standardized mean scores were compared using one-way ANOVA. Key patient and treatment factors that impact function and symptoms were assessed by multivariate linear regression. Results: Eight hundred thirty survivors responded at an interval of 10.8 ± 3 years from diagnosis (68 % response rate). Younger onset survivors underwent more surgery (97.9 vs. 93.6 %, P < 0.001) and received more chemotherapy (86.1 vs. 77.7 %, P = 0.004). Anxiety, body image, sexual dysfunction, embarrassment by bowel movements, micturition problems, and impotence were significant concerns. Younger onset survivors reported worse anxiety, body image, and embarrassment with bowel movements, whereas later onset survivors highlighted sexual dysfunction, micturition problems, and impotence. Age at diagnosis was a key independent determinant of long-term function and symptoms. Conclusion: Long-term survivors of CRC face ongoing functional deficits and symptoms, and their survivorship experience differs by age. Age at diagnosis should serve as a basis for tailored, personalized survivorship care plans. [ABSTRACT FROM AUTHOR]

Abstract: Carbon and nitrogen are the most frequent foreign interstitial atoms in α-Fe. The presence of even a little amount of these impurities in interstitial positions has a drastic influence on the properties of steels. However, the physics of the C–N interaction remains unclear. Here we perform first-principles calculations based on the density functional theory to study the interactions of C–N and those with vacancy (□) in α-Fe. When C and N atoms are in neighbor octahedral sites, a hybridization around −8eV of C 2p states with the N 2p states is observed. C and N atoms lie as far away from one another as possible. When a vacancy is introduced, it can attract two C atoms and a N atom, and a C–C–N–□ complex is formed. When the C and N atoms are the first nearest neighbors of the vacancy and stay in two neighbor octahedral sites, a covalent C–N bond is formed. And the peak of 2p states of the C atom’s density of states shifts to around −8eV, where the peak of the N atom’s 2p states lies. [Copyright &y& Elsevier]

Local excision (LE) was historically developed to palliate patients with rectal adenocarcinoma who either are medically unfit or have adamantly refused to undergo transabdominal standard resection (SR) procedures. Over the years, the tradeoffs between the oncologic benefit and adverse functional sequelae associated with SR procedures have been increasingly recognized. In parallel, there has been growing interest in considering LE as an alternative to SR in select patients with early-stage disease. However, concerns regarding its oncologic adequacy remain. These concerns relate to the adequacy of tumor resection, the removal of mesorectal disease, the accuracy of preoperative selection, and the use of adjunctive treatment modalities. Evolving strategies that aim at improving the oncologic outcomes of LE for stage I T1/T2 rectal cancers include adoption of transanal endoscopic microsurgery and the addition of non-surgical modalities. Current evidence surrounding these approaches is examined to provide a basis for an informed discussion with patients. Key factors to be considered in formulating the treatment plan for an individual patient with T1/T2 rectal cancer are summarized. [Copyright &y& Elsevier]

Abstract: In this letter, an improved sampling frequency offset (SFO) estimation scheme is proposed for an orthogonal frequency division multiplexing based digital radio mondiale (DRM) system. An analytical closed-form expression of the mean square error is derived for the proposed SFO synchronization scheme. The new scheme is demonstrated and verified under simulations carried out within the framework of DRM systems. [Copyright &y& Elsevier]

OBJECTIVE: To evaluate the effects of a single transrectal ultrasound (TRUS)-guided transperineal injection of botulinum toxin A (BTX-A) to the external urethral sphincter (EUS) for treating detrusor external sphincter dyssynergia (DESD). DESIGN: Descriptive study. SETTING: Rehabilitation hospital affiliated with a medical university. PARTICIPANTS: Patients (N=18) with suprasacral spinal cord injury who had DESD confirmed on video-urodynamic study. INTERVENTIONS: A single dose of 100U BTX-A was applied into the EUS via TRUS-guided transperineal route injection. MAIN OUTCOME MEASURES: Maximal detrusor pressure, detrusor leak-point pressure, integrated electromyography (iEMG), maximal pressure on static urethral pressure profilometry, and postvoiding residuals. RESULTS: There were significant reductions in iEMG (P=.008) and static (P=.012) and dynamic urethral pressure (P=.023), but not in detrusor pressure and detrusor leak-point pressure after treatment. Postvoiding residuals also significantly decreased in the first and second month after treatment (P<.012). CONCLUSIONS: TRUS-guided transperineal injection of BTX-A has beneficial effects in treating DESD. Copyright © 2010 by the American Congree of Rehabilitation Medicine [ABSTRACT FROM AUTHOR]

Background: Chemotherapy is highly effective for metastatic germ cell tumor (GCT), but experience with resection of hepatic metastases from GCT is limited.Methods: Fifteen patients with GCT metastatic to the liver underwent 16 hepatic operations (1975-2002). Pre-resection therapy, surgical pathology, and operative outcomes were reviewed. All patients were followed to death or last contact for survival and disease status.Results: Patients underwent biopsy (three), wedge resection (nine), bisegmentectomy (two), and major lobectomy (two). Hepatic histology included: necrosis (33%), viable tumor (27%), mature teratoma (13%), and benign histology (27%). Concomitant resection of extrahepatic disease (14 patients, 93%) found necrosis (53%), mature teratoma (27%), and viable tumor (13%). Operative mortality was 0% and morbidity was 40%. At 8.2 years (mean) from resection, 11 patients (73%) were alive: five with no evidence of disease, two with elevated tumor marker only, and four with gross disease. Four patients (27%) died. The 10-year overall survival was 62% from diagnosis.Conclusion: Resection of post-chemotherapy hepatic disease is safe, even when combined with resection of extrahepatic residual disease. The varied histologic findings, lack of reliable predictors, and prolonged survival achieved support a multidisciplinary approach which includes surgical resection of hepatic metastases. [ABSTRACT FROM AUTHOR]

Background: Pancreatoduodenal (PD) neoplasms represent the principal disease-specific lethality in multiple endocrine neoplasia type 1 (MEN1). Potential oncologic benefits of PD resection must be weighed against operative morbidities, compromised pancreatic function, and quality of life (QOL). Methods: Fifty MEN1 patients underwent PD resections during 1984-2004. Postoperative pancreatic function and QOL were assessed by EORTC QLQ-C30 and a disease-specific questionnaire (response rate, 78%). Results: Twelve patients (24%) had asymptomatic disease detected by screening; 38 patients (76%) were symptomatic. All gross neoplasm was resected in 80% of patients. No patients died; 21 patients (42%) had complications. At 5 years postoperatively, 60% of patients were alive without disease, 24% of patients were with disease, 10% of patients died of PD neoplasms, 4% of patients died of other malignancies, and 2% of patients died of an unknown cause. Diabetes that requires insulin or oral hypoglycemics developed in 20% of patients. Frequent steatorrhea (>once/week) occurred in 25% of patients, early dumping occurred in 25% of patients, bloating occurred in 25% of patients, late dumping occurred in 7% of patients, hypoglycemia occurred in 7% of patients, and vomiting occurred in 4% of patients. Global QOL did not differ from that of the reference population (72.8 vs 75.3; P = .58). Conclusion: PD resections in MEN1 are associated with perioperative risks and altered pancreatic function. The moderate compromise in patient-perceived QOL suggests that most patients accept and adapt to these trade-offs for the potential of prolonged survival. [Copyright &y& Elsevier]

The results of colectomy and ileorectal anastomosis (IRA) in patients diagnosed by physiologic testing as having slow transit constipation (STC) have been reported. The durability of functional results and long-term quality of life (QoL) in these patients, however, has not been established. Between 1987 and 2002, 3670 patients were evaluated for constipation at our institution; 110 (3%) fulfilled the criteria for STC and underwent an IRA. Patients were prospectively followed and functional outcomes assessed annually by standardized questionnaires. After a median follow-up of 11 years, 104 eligible patients were mailed validated questionnaires to assess functional outcomes and QoL (Knowles-Eccersley-Scott Symptom [KESS] score, the Irritable Bowel Syndrome Quality of Life [IBS-QOL], and the SF-12 health survey). Prospectively assessed functional data was available on 85 of 104 (82%) eligible patients. At last follow-up, improvement of constipation and satisfaction with bowel function was reported by 98% and 85% of patients, respectively. Performance measures including social activity, household work, sexual life, and family relationships were reported to have improved or were not affected as a result of surgery by 75%, 86%, 81%, and 86% of the patients respectively. Fifty-nine patients (57%) responded to the study questionnaires. All 59 patients reported their constipation to be better since IRA, 83% did not require any medication, and 85% reported being satisfied with bowel function. The KESS scores of patients undergoing IRA for STC (median 6, range 0−35) were lower than reported scores of STC patients not operated upon (median 21, range 11−35, P < 0.001) indicating symptomatic improvement after surgery. Mean IBS-QOL scores were similar to reported scores of patients undergoing IRA for other conditions [80 (23) versus 84 (16)], P = 0.7). Mean SF-12 physical and mental summary scores were similar to reported SF-12 scores of the normal population (49.5 versus 50 and P = 0.70, 48.7 versus 50, P = 0.42, respectively). Ileorectal anastomosis in appropriately selected patients with slow transit constipation results in durable symptomatic relief and a long-term quality of life indistinguishable from the general population. [Copyright &y& Elsevier]