Prognostic value of intrinsic subtypes in hormone-receptor-positive metastatic breast cancer: systematic review and meta-analysis.

BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.

Antibiotic therapy in dogs and cats in general practice in the United Kingdom before referral.

OBJECTIVES: To describe antibiotic prescription by veterinarians in general practices in the United Kingdom before referral and analyse if UK antibiotic stewardship guidelines were followed. MATERIALS AND METHODS: The clinical records from dogs and cats referred to the Internal Medicine and Oncology departments of two referral hospitals were retrospectively reviewed. RESULTS: There were 917 cases included, of which 486 (53.0%) had been prescribed antibiotics for the presentation they were subsequently referred for. Bacterial culture or cytology to guide antibiotic prescription had been performed in 43 of 486 (8.8%) and nine of 486 cases (1.8%) respectively. In four cases, both cytology and culture were performed. For those animals who had received antibiotics, 344 of 486 (70.8%) prescriptions did not comply with UK antibiotic stewardship guidelines. Following investigations at a referral centre, a bacterial aetiology was found or suspected in 17.9% of the cases that received antibiotics. CLINICAL SIGNIFICANCE: Use of diagnostics, including culture and cytology, to prove or determine the likelihood of a bacterial aetiology was infrequently performed before referral and may have contributed to overprescription of antibiotics. Encouraging veterinarians to undertake appropriate diagnostics, in combination with education around compliance with antibiotic stewardship guidelines, might reduce antibiotic prescription.

Malformaciones arteriovenosas pulmonares: presentación de un caso clínico pediátrico y revisión de la literatura / Pulmonary arteriovenous malformations: presentation of a pediatric case and review of the literature

Las malformaciones arteriovenosas pulmonares (MAVP) consisten en comunicaciones directas entre el sistema arterial y el sistema venoso pulmonar, sin paso de la sangre por el lecho capilar, produciéndose un cortocircuito de derecha a izquierda extracardíaco, pueden ser congénitas o adquiridas. Algunos casos pueden ser asintomáticos, en cambio en otros pueden ocasionar diversas manifestaciones clínicas y se pueden asociar a complicaciones severas. En niños se observa una baja incidencia y son más frecuentes las formas congénitas. La MAVP se debe sospechar por las manifestaciones clínicas y las imágenes de la radiografía de tórax (RxTx) y su confirmación se realiza mediante una AngioTomografía Computada (TC) de tórax. La embolización endovascular es actualmente el tratamiento de elección, con excelentes resultados, aunque requiere de un seguimiento posterior y de un operador experimentado. Reportamos el caso de una niña que ingresó con clínica muy sugerente, incluyendo: disnea, acropaquia, cianosis periférica, e hipoxemia refractaria. Sin embargo, inicialmente el cuadro clínico fue confundido con una crisis asmática. La Angio-TC de tórax confirmó el diagnóstico y el tratamiento mediante embolización endovascular resultó exitoso.

Pulmonary arteriovenous malformations (PAVM) are communications between the arterial and the pulmonary venous system, without passage of blood through the capillary bed, causing a left to right extracardiac shunt. Some cases may be asymptomatic, while others may cause various clinical manifestations and may be associated with severe complications. In children a low incidence is observed, and congenital forms are more frequent. PAVM should be suspected by clinical manifestations and chest x-ray imaging and confirmed by chest Computed Tomography Angiography (CTA). Endovascular embolization is currently the treatment of choice, with excellent results, although it requires subsequent follow-up. We report a patient who was admitted with a very suggestive clinical history, including: dyspnea, clubbing, peripheral cyanosis, and severe hypoxemia, refractory to oxygen therapy. However, initially the clinical picture was confounded with an asthmatic crisis. CTA confirmed the diagnosis and treatment by endovascular embolization was successful.

Estado del arte de inteligencia artificial en ortodoncia. Revisión narrativa / State of the art on artificial intelligence in orthodontics. A narrative review

Introducción: Inteligencia artificial (IA) es la automatización de actividades vinculadas con procesos de pensamiento humano. En ortodoncia se han desarrollado sistemas que asistidos por IA pueden tomar decisiones terapéuticas y realizar análisis. No existe un compendio actualizado sobre el uso de IA en ortodoncia. Objetivos: Describir los usos de IA en ortodoncia de acuerdo con la literatura actual. Metodología: Se realizó una revisión narrativa en las bases Medline y SciELO mediante la búsqueda: (orthodont*) AND (“machine learning” OR “deep learning” OR “artificial intelligence” OR “neural network”). Resultados: Se obtuvieron 19 artículos que mostraron que IA se ha desarrollado en cinco áreas: 1) Cefalometría asistida por IA, donde la localización de puntos y análisis cefalométricos mostraron una precisión igual a ortodoncistas. 2) Localización de dientes no erupcionados en CBCT, con resultados similares entre IA y ortodoncistas. 3) Determinación de edad y maduración ósea de forma más eficiente apoyada por IA, que por métodos convencionales, 4) Análisis facial, donde la IA permite una evaluación objetiva del atractivo facial, con aplicaciones en diagnóstico y planificación quirúrgica. 5) Decisiones terapéuticas con IA, para determinar la necesidad de exodoncias y dientes que serán extraídos. Discusión: La IA se está incorporando aceleradamente en ortodoncia, por lo que debe conocerse conceptos y posibilidades que brinda. (AU)Conclusiones:Un número creciente de artículos sobre usos de IA en ortodoncia muestran resultados similares con IA a los obtenidos por especialistas. Sin embargo, la evidencia aún es poca y principalmente experimental, por lo que la IA debiera usarse cautelosamente en ortodoncia.

Introduction: Artificial Intelligence (AI) is the automation of activities related to human thought processes. In orthodontics, systems have been developed which, assisted by AI, can make therapeutic decisions and perform analyses. There is no updated compendium on the use of AI in orthodontics. Objectives: To describe the uses of AI in orthodontics according to the current literature. Methodology: A narrative review was performed in the Medline and SciELO bases by means of the following search: (orthodont*) AND (“machine learning” OR “deep learning” OR “artificial intelligence” OR “neural network”). Results: 19 articles were obtained, showing that AI has been developed in four areas: 1) IA assisted cephalometry, where localization of cephalometric points and cephalometric analysis showed equal accuracy than orthodontists. 2) Unerupted tooth localization with CBCT, with similar results between AI and orthodontists. 3) Determination of skeletal age, which is more efficient with AI than with conventional methods. 4) Facial analysis, where AI allows an objective evaluation of facial attractiveness with applications in diagnosis and surgical planning. 5) Therapeutic decisions with AI, to determine the need for exodontia and teeth to be extracted. Discussion: AI is being incorporated rapidly in orthodontics, so we must know concepts and possibilities that it gives us in orthodontics. Conclusions: An increasing number of articles refer to the uses of AI in orthodontics, with similar results to those obtained by specialists. However, the evidence is still scarce and mainly experimental, so AI should still be used with caution in orthodontics. (AU)

Targeted colonic release formulations of mesalazine - A clinical pharmaco-scintigraphic proof-of-concept study in healthy subjects and patients with mildly active ulcerative colitis.

Colonic targeting of orally applied therapeutic drugs remains a challenge. Tablet coatings relying on gastrointestinal pH and colonic bacterial enzymes as triggers in association with an inner alkaline layer are expected to improve targeting efficiency. Mesalazine release from three differently coated tablets labelled with 1 MBq 153Sm was characterised in a single centre, open-label, parallel group study in nineteen healthy subjects and seven patients with mildly active ulcerative colitis. Two semi-organic and one aqueous-based outer coating with different ratios of enteric polymer and resistant starch were tested. All coatings showed comparable release lagtimes in biorelevant dissolution media and were not affected by neutron-activation of the samarium tracer. Mesalazine pharmacokinetics and gamma scintigraphy were used to characterise drug release, anatomical site of tablet disintegration and gastrointestinal transit. Initial tablet disintegration occurred at the ileo-caecal junction or beyond in 92 % of the subjects. Time to initial tablet disintegration was inversely correlated with maximal plasma concentrations and systemic mesalazine exposure. Although high inter-subject variability precluded detection of differences between solvent types and different enteric polymer to polysaccharide ratios, the dual pH and enzymatic triggered release system in combination with an inner alkaline layer promoted mesalazine release at the target site with high accuracy.

Tryptophan-enriched diet or 5-hydroxytryptophan supplementation given in a randomized controlled trial impacts social cognition on a neural and behavioral level.

Understanding of emotions and intentions are key processes in social cognition at which serotonin is an important neuromodulator. Its precursor is the essential amino acid tryptophan (TRP). Reduced TRP availability leads to weaker impulse control ability and higher aggression, while TRP supplementation promotes confidence. In a double-blind placebo-controlled fMRI study with 77 healthy adults, we investigated the influence of a 4 week TRP enriched diet and an acute 5-hydroxytryptophan (5-HTP) intake on two social-cognitive tasks, a moral evaluation and an emotion recognition task. With 5-HTP, immoral behavior without negative consequences was rated as more reprehensible. Additionally, during story reading, activation in insula and supramarginal gyrus was increased after TRP intake. No significant effects of TRP on emotion recognition were identified for the whole sample. Importantly, emotion recognition ability decreased with age which was for positive emotions compensated by TRP. Since the supramarginal gyrus is associated with empathy, pain and related information integration results could be interpreted as reflecting stricter evaluation of negative behavior due to better integration of information. Improved recognition of positive emotions with TRP in older participants supports the use of a TRP-rich diet to compensate for age related decline in social-cognitive processes.

The impact of fluorescence angiography on anastomotic leak rate following transanal total mesorectal excision for rectal cancer: a comparative study.

BACKGROUND: Anastomotic leak (AL) is the most feared complication in colorectal surgery. Indocyanine green (ICG) fluorescence angiography allows for real-time intraoperative evaluation of bowel perfusion. This study aimed to assess the impact of ICG on perioperative outcomes in patients treated with transanal total mesorectal excision (TaTME) for rectal cancer. METHODS: Comparative study based on a retrospective analysis of prospectively collected data, to validate the use of ICG assessment (ICGA) during TaTME (November/2011-June/2018). The primary outcome was the clinical AL rate. The secondary outcomes included modification of proximal colonic transection, anastomotic redo, additional surgical maneuvers and surgical morbidity. RESULTS: Two hundred and eighty-four patients were included, 204 (71.8%) in non-ICG group and 80 (28.2%) in ICG group. No significant differences were found in patient and tumor features. Mean anastomotic height was 4.85 cm vs. 5.04 cm (p = 0.500), diverting stoma was constructed in 205 patients (72.1% vs. 72.5%; p = 0.941). Fluorescence angiography modified the surgical plan in 23 patients (28.7%). AL was diagnosed in 23 patients (11.3%) in the non-ICG group and in two patients (2.5%) in the ICG group (p = 0.020). Postoperative intraabdominal collection was diagnosed in 19 patients (7.4% vs. 5.1%; p = 0.490), and reintervention was needed in 24 patients (10.8% vs. 7.6%; p = 0.420). Median length of hospital stay was 6.0 (IQR 5.0-9) vs. 4.0 (IQR 3.0-8.5) (p = 0.005). ICGA was found as independent protective factor for AL in the multivariate analysis of the whole cohort (n = 284) (OR 0.142; 95% CI 0.032-0.633; p = 0.010). CONCLUSION: ICG fluorescence angiography modified the proximal colonic transection in more than one-quarter of patients, leading to a significant decrease of AL rate.

"Influence of diet on mood and social cognition: a pilot study".

Recently, a relationship has been observed between nutrition and social cognition. In this aspect, several dietary patterns, or even some probiotics, have been reported as social cognition modulators. However, to date, no studies have reported the effects of specific nutrients. Our aim was to evaluate the relationship between dietary macronutrients and the processing of social and affective information. Participants were undergraduates from the University of Extremadura (Badajoz, Spain) aged 21.3 ± 2.9 years., with a BMI of 22.8 ± 3.9 (kg m-2). The students' social cognition and diet were analysed through questionnaires and a dietary record. The diets were analysed with DIAL v.1.18® software (Alce Ingeniería®). The participants filled out the WHO-5 well-being index, Beck's anxiety inventory, Beck's depression inventory, ruminative response scale (RSS), Leiden index of depression sensitivity (LEIDS-r), empathy quotient (EQ), and interpersonal reactivity index (IRI). To analyse the data, nutrients were grouped through principal component analysis (PCA) into lipids, carbohydrates and proteins. Additionally, we assayed if these principal components were associated with psychological questionnaire scores using multiple linear regression analyses. The dietary pattern differed from the traditional Mediterranean diet due to high intake of proteins and saturated fatty acids. Regarding social cognition and macronutrients, we found a positive association between lipids, specifically cholesterol, and the Perspective-Taking Scale (an IRI component). Carbohydrates influenced the RSS, indicating that complex carbohydrates may be a risk factor for depression. Moreover, the brooding factor, a component of the RRS, was negatively affected by dietary carbohydrates and proteins, specifically by fiber and aspartate. Diet may influence several variables related to social cognition and mood. Particularly, a low-cholesterol diet rich in fiber, complex carbohydrates, and aspartate apparently provides benefits, improving the processing of social and affective information and psychic well-being.

Three-year outcome after transanal versus laparoscopic total mesorectal excision in locally advanced rectal cancer: a multicenter comparative analysis.

BACKGROUND: For patients with mid and distal rectal cancer, robust evidence on long-term outcome and causal treatment effects of transanal total mesorectal excision (TaTME) is lacking. This multicentre retrospective cohort study aimed to assess whether TaTME reduces locoregional recurrence rate compared to laparoscopic total mesorectal excision (LapTME). METHODS: Consecutive patients with rectal cancer within 12 cm from the anal verge and clinical stage II-III were selected from three institutional databases. Outcome after TaTME (Nov 2011 - Feb 2018) was compared to a historical cohort of patients treated with LapTME (Jan 2000 - Feb 2018) using the inverse probability of treatment weights method. The primary endpoint was three-year locoregional recurrence. RESULTS: A total of 710 patients were analysed, 344 in the TaTME group and 366 in the LapTME group. At 3 years, cumulative locoregional recurrence rates were 3.6% (95% CI, 1.1-6.1) in the TaTME group and 9.6% (95% CI, 6.5-12.7) in the LapTME group (HR = 0.4; 95% CI, 0.23-0.69; p = 0.001). Three-year cumulative disease-free survival rates were 74.3% (95% CI, 68.8-79.8) and 68.6% (95% CI, 63.7-73.5) (HR = 0.82; 95% CI, 0.65-1.02; p = 0.078) and three-year overall survival 87.2% (95% CI, 82.7-91.7) and 82.2% (95% CI, 78.0-86.2) (HR = 0.74; 95% CI, 0.53-1.03; p = 0.077), respectively. In patients who underwent sphincter preservation procedures, TaTME was associated with a significantly better disease-free survival (HR = 0.78; 95% CI, 0.62-0.98; p = 0.033). CONCLUSIONS: These findings suggest that TaTME may improve locoregional recurrence and disease-free survival rates among patients with mid and distal locally advanced rectal cancer.

[Mediation in public healthcare: opportunities for improvement]. / Mediación en el sistema público de salud: oportunidades para mejorar.

BACKGROUND: Mediation in healthcare is a non-adversarial process to resolve a dispute risen between patients and health providers during medical attention Aim: To characterize the mediation process taking place in the public health system in Chile, from its start until 2017. MATERIAL AND METHODS: Cross-sectional descriptive study. Under the Transparency Law, information about mediation processes between 2005 and 2017 was requested to the State Defense Council (CDE in its Spanish acronym). This data was complemented with the information available on the website of this agency. RESULTS: Ninety four percent of the complaints filed at the CDE were deemed eligible for mediation. Only 19% of the concluded cases led to an agreement between the disputing parties. The agreements reached were mostly monetary compensation, medical assistance, and apologies/explanation of the facts. The average amount of compensation reached $14,862,088 (Chilean pesos). The most commonly claimed damage resulting from medical care was partial disability. The medical specialties more often claimed were Obstetrics and Gynecology, General Surgery, and Internal Medicine. CONCLUSIONS: The analysis of conducted mediations is a source of feedback for healthcare staff and health institutions. It would greatly contribute to prevent possible damage and medical conflicts, specially within the specialties with the most complaints. Improvements to the existing legislation are required to ensure free access for all the population.

Mediación en el sistema público de salud: oportunidades para mejorar / Mediation in public healthcare: opportunities for improvement

Background: Mediation in healthcare is a non-adversarial process to resolve a dispute risen between patients and health providers during medical attention Aim: To characterize the mediation process taking place in the public health system in Chile, from its start until 2017. Material and Methods: Cross-sectional descriptive study. Under the Transparency Law, information about mediation processes between 2005 and 2017 was requested to the State Defense Council (CDE in its Spanish acronym). This data was complemented with the information available on the website of this agency. Results: Ninety four percent of the complaints filed at the CDE were deemed eligible for mediation. Only 19% of the concluded cases led to an agreement between the disputing parties. The agreements reached were mostly monetary compensation, medical assistance, and apologies/explanation of the facts. The average amount of compensation reached $14,862,088 (Chilean pesos). The most commonly claimed damage resulting from medical care was partial disability. The medical specialties more often claimed were Obstetrics and Gynecology, General Surgery, and Internal Medicine. Conclusions: The analysis of conducted mediations is a source of feedback for healthcare staff and health institutions. It would greatly contribute to prevent possible damage and medical conflicts, specially within the specialties with the most complaints. Improvements to the existing legislation are required to ensure free access for all the population.

5G-assisted telementored surgery.

Safe and effective implementation of remote surgery and telementoring can have significant limitations. Fifth-generation (5G) wireless networks could be useful in overcoming these drawbacks. As a proof of concept, the authors present technical and clinical details of two procedures assisted by telementoring using 5G that were also broadcast live. Secure remote access advice.

Elaboración del Informe Médico Legal de Lesiones Odontológico: Recomendaciones para el Odontólogo / Elaboration of the Dental Legal Report of Dental Injuries: Recommendations for the Dentist

RESUMEN: El odontólogo juega un papel relevante en la acreditación o constatación de lesiones, especialmente si cumple labores en servicios de urgencia. Esta primera evaluación es fundamental para que el perito en lesionología forense del Servicio Médico Legal (SML) se pronuncie posteriormente respecto del pronóstico médico legal de las lesiones, señalando el tiempo que demorarán en sanar o la incapacidad laboral que generan, además de vincularlas causalmente con los hechos delictivos investigados. Se presenta información actualizada sobre el proceso de constatación de lesiones, el informe de lesiones en la legislación chilena y la participación que le cabe al cirujano dentista. La preparación de un correcto informe médicolegal de lesiones es un acto médico que no se puede delegar a otro miembro del personal de salud que no sea el profesional médico tratante. Todo cirujano dentista debe tener la capacidad de generar un primer informe de lesiones apropiado a las exigencias legales y éticas que la sociedad exige. La ley expresa la posibilidad de citar a un juicio oral, en calidad de testigo, al profesional que haya confeccionado un informe médicolegal de lesiones (constatación de lesiones), con el propósito de dar testimonio de manera directa, explicando desde un punto de vista profesional lo registrado.

ABSTRACT: The general dentist plays a major role in ascertaining and verifying injuries, especially if he or she, works in an emergency department. The initial evaluation is fundamental for the forensic dentist in order to subsequently state a prognosis of the injuries sustained, indicating how long they will take to heal, and the disability related to time away from employment. Further, it is the forensic dentist´s responsibility to evaluate and relate cause of injuries with the criminal offenses being investigated. In this study, updated information about the process is presented of medical injury verification, the injuries report in the Chilean legislation, and the participation of the dentist. The correct preparation of a forensic report of injuries is a medical responsibility that cannot be delegated to another member of the healthcare staff. All dentists must have the ability to generate a first report of injuries, according to society's legal and ethical requirements. The law states that the professional who completes a forensic report of injuries, can be summoned to trial as a witness, with the purpose of providing direct testimony, and objectively explain what he/she observed in that specific case.

Responsabilidad Médica en Chile: Fallos de la Corte Suprema de Justicia 2017 / Medical Malpractice in Chile: Rulings of the Supreme Court of Justice 2017

RESUMEN: El objetivo de este trabajo fue analizar los datos epidemiológicos y jurídicos de los casos por responsabilidad médica fallados por la Corte Suprema de Justicia chilena (CSJ) el año 2017, para relevar los escenarios de alto riesgo, aportando a su prevención. Se realizó un estudio retrospectivo, revisando los fallos de la CSJ en la base de datos electrónica del Poder Judicial chileno. Se seleccionaron y analizaron los fallos por responsabilidad médica. Se detectó un total de 61 casos por responsabilidad médica que alcanzaron la CSJ en 2017. Todos correspondieron a causas civiles. La duración promedio de los juicios fue 41,9 meses. La especialidad más demandada y condenada fue ginecología. La mayoría de las demandas y condenas afectó al Sistema Público de salud. Los casos que dan origen a las demandas son, en su mayoría, de atención de urgencias por sobre las programadas, y de tratamiento por sobre procedimientos quirúrgicos. El 54,8 % de los casos resultaron en la muerte del paciente. La mitad de los fallos condenatorios involucraba el fallecimiento del usuario afectado. Se deben investigar los factores de riesgo no sólo de la ocurrencia de mal-praxis, si no de la judicialización de los conflictos médico-paciente, especialmente en el área gineco-obstétrica, incluyendo los casos de instancias anteriores a la CSJ. Se debe investigar así mismo los factores de riesgo para la mayor propensión de los profesionales de sexo masculino de ser demandados y condenados por malpraxis médica.

ABSTRACT: The objective of the present study is to characterize the epidemiologic and juridical data for medical malpractice cases ruled by the Chilean Supreme Court (CSC) in 2017, to highlight the high risk scenarios, as a contribution to their prevention. A search of the CSC electronic database was conducted to identify and analyze CSC rulings for medical malpractice cases. In this study 61 malpractice cases ruled by CSC were identified. The CSC received only civil cases of medical malpractices during the studied period. The average duration of the trial was 41.9 months. Gynecologists faced suits and received sentences more frequently than any other type of specialist. The majority of prosecuted cases and convictions were associated with the public health system. A greater number of claims were related to emergency care than with scheduled procedures. Likewise, more claims were associated with non-surgical treatment than with surgical procedures. 54.8 % of all cases resulted in the patient's death. Half of the cases that lead to conviction, were related to the death of a patient. Risk factors should be investigated, not only of the occurrence of malpractice, but also of the judicial process of doctor-patient conflicts, especially in the obstetrics and gynecology area, including the analysis of cases of prior judicial instances. The risk factors for the higher propensity of male professionals to be prosecuted and convicted for medical malpractice should also be investigated.

Author Correction: Combination of KIR2DS4 and FcγRIIa polymorphisms predicts the response to cetuximab in KRAS mutant metastatic colorectal cancer.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.