Treatment of the neck in residual/recurrent disease after chemoradiotherapy for advanced primary laryngeal cancer.

Concomitant chemoradiotherapy (CRT) is extensively used as primary organ preservation treatment for selected advanced laryngeal squamous cell carcinomas (LSCC). The oncologic outcomes of such regimens are comparable to those of total laryngectomy followed by adjuvant radiotherapy. However, the management of loco-regional recurrences after CRT remains a challenge, with salvage total laryngectomy being the only curative option. Furthermore, the decision whether to perform an elective neck dissection (END) in patients with rN0 necks, and the extent of the neck dissection in patients with rN + necks is still, a matter of debate. For rN0 patients, meta-analyses have reported occult metastasis rates ranging from 0 to 31 %, but no survival advantage for END. In addition, meta-analyses also showed a higher incidence of complications in patients who received an END. Therefore, END is not routinely recommended in addition to salvage laryngectomy. Although some evidence suggests a potential role of END for supraglottic and locally advanced cases, the decision to perform END should weigh benefits against potential complications. In rN + patients, several studies suggested that selective neck dissection (SND) is oncologically safe for patients with specific conditions: when lymph node metastases are not fixed and are absent at level IV or V. Super-selective neck dissection (SSND) may be an option when nodes are confined to one level. In conclusion, current evidence suggests that in rN0 necks routine END is not necessary and that in rN + necks with limited nodal recurrences SND or a SSND could be sufficient.

Inhibition of α-glucosidase activity by potential peptides derived from fermented spent coffee grounds.

The control of α-glucosidase activity has been associated with managing diabetes. We previously identified three peptides with high bioactive indices derived from protein hydrolysates of fermented spent coffee grounds. In this study, the peptides YGF, GMCC, and RMYRY were synthesized and tested in vitro for their α-glucosidase inhibition activity, complemented by in silico analyses. Two of the three peptides significantly inhibited α-glucosidase activity, with the more efficient peptides being YGF and GMCC (0.42 mg/mL), resulting in decreased enzymatic activity of 95.31% and 89.79%, respectively. These peptides exhibited binding free energies with the α-glucosidase complex of -8.5 and - 6.6 kcal/mol, respectively, through hydrogen bonds and van der Waals interactions with amino acids from the active site. Pharmacokinetic analysis indicated that YGF and GMCC profiles were unrelated to toxicity. These results underscore the importance of focusing on food waste bioprocessing products to expand the range of alternatives that could aid in diabetes treatment.

Secondary Prevention Therapies in Real-World Patients with Myocardial Infarction: Eligibility Based on Randomized Trials Supporting European and American Guidelines.

OBJECTIVE: We aimed to evaluate the applicability of the eligibility criteria of randomized controlled trials (RCTs) cited in guideline recommendations in a real-world cohort of patients receiving secondary prevention after acute myocardial infarction from the EPICOR registries. METHODS: Recommendations provided by American and European guidelines for acute myocardial infarction were classified into general (applying to all patients) and specific (applying to patients with left ventricular dysfunction or heart failure). Randomized controlled trials cited in these recommendations were selected, and their entry criteria were applied to our international cohort of 18,117 patients. RESULTS: There were 91.5% patients eligible for beta blockers (84.6% for general, and 5.9% for specific recommendations), 97.7% eligible for renin-angiotensin system inhibitor (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers [ACEI/ARB]) recommendations (69.9% for general, 27.9% for specific) and 4.1% eligible for mineralocorticoid receptor antagonists (only specific recommendations). The percentages of patients with eligibility criteria who were discharged with a prescription of the recommended therapies were 80%-85% for beta blockers, 70%-75% for ACEI/ARB, and 29% for mineralocorticoid receptor antagonists. There were large regional variations in the percentage of eligible patients and in those receiving the medications (eg, 95% in Northern Europe and 57% in Southeast Asia for beta blockers). CONCLUSION: Most real-world acute myocardial infarction patients are eligible for secondary prevention therapy in both general and specific guideline recommendations, and the percentage of those on beta blockers and ACEI/ARB at hospital discharge is high. There are large regional variations in the proportion of patients receiving recommended therapies. Local targeted interventions are needed for quality improvement.

Biostimulated-sesame sprout extracts as potential agents against Leishmania mexicana.

Leishmania mexicana is one of the causal agents of cutaneous leishmaniasis. Current antileishmanial chemotherapeutics have demonstrated adverse side effects; thus, alternative treatments are needed. In this study, we performed in silico and in vitro analyses of the leishmanicidal potential of the most abundant phenolic compounds identified in black sesame sprouts biostimulated with Bacillus clausii. The molecular docking analysis showed strong interactions (binding free energies between -6.5 and -9.5 kcal/mol) of sesaminol 2-O-triglucoside, pinoresinol dihexoside, isoverbascoside, and apigenin with the arginase, leishmanolysin, cysteine peptidase B, and pyruvate kinase leishmanial enzymes. Furthermore, almost all phenolic compounds interacted with the active site residues of L. mexicana enzymes. In vitro, the B. clausii-biostimulated sprout phenolic extracts and apigenin inhibited the growth of promastigotes with IC50 values of 0.08 mg gallic acid equivalent/mL and 6.42 µM (0.0017 mg/mL), respectively. Additionally, in the macrophage infection model, cells treated with B. clausii-biostimulated sprout phenolic extracts and infected with L. mexicana exhibited significantly (P < 0.05) reduced nitric oxide production and decreased parasite burden. Altogether, our study provides important data related to high efficacy and less toxic natural antileishmanial candidates against promastigotes of L. mexicana.

Considerations when planning and conducting large global observational studies: Experience from the DISCOVER study of patients with type 2 diabetes.

DISCOVER is a global programme of observational research that includes patients with type 2 diabetes initiating second-line glucose-lowering therapy from 38 countries worldwide, including many with little or no previous epidemiological data available. More than 15,000 patients were followed-up for 3 years, and comprehensive data were collected using a standardized electronic case report form at enrolment, and 6, 12, 24 and 36 months. The study has formed the basis for a long-term registry that is intended to expand the geographic and clinical scope of the study and allow data collection beyond 3 years. In this review, critical aspects of study planning and implementation are summarized, along with challenges that were faced, to provide a resource for researchers planning similar studies. In particular, it is essential to set realistic expectations regarding the degree of study representativeness that can be achieved, allow for sufficient time to obtain ethics committee approval, develop tools to help recruit patients effectively, ensure that data collection systems are robust, user-friendly and adaptable, plan adequate remote and on-site monitoring, maximize patient retention through continuous engagement with study sites and ensure that everyone involved in the study forms a friendly and effective team. Observational studies such as DISCOVER are crucial for understanding disease epidemiology and management in real-world settings. They are also increasingly used by governmental, regulatory and payor agencies for post-marketing surveillance and when considering new drug submissions. The development of future studies of similar scope and ambition to DISCOVER is encouraged.

Impact of standard modifiable cardiovascular risk factors on 2-year all-cause mortality: Insights from an international cohort of 23,489 patients with acute coronary syndrome.

BACKGROUND: Controversial findings have been reported in the literature regarding the impact of the absence of standard modifiable cardiovascular risk factors (SMuRFs) on long-term mortality risk in patients with acute coronary syndrome (ACS). While the prognostic additive value of SMuRFs has been well described, the prognostic role of prior cardiovascular disease (CVD) by sex is less well-known in patients with and without SMuRFs. METHODS: EPICOR and EPICOR Asia are prospective, observational registries conducted between 2010 and 2014, which enrolled ACS patients in 28 countries across Europe, Latin America, and Asia. Association between SMuRFs (diabetes, dyslipidaemia, hypertension, and smoking) and 2-year postdischarge mortality was evaluated using adjusted Cox models stratified by geographical region. RESULTS: Among 23,489 patients, the mean age was 60.9 ± 11.9 years, 24.3% were women, 4,582 (20.1%) presented without SMuRFs, and 16,055 (69.5%) without prior CVD. Patients with SMuRFs had a higher crude 2-year postdischarge mortality (HR 1.86; 95% CI, 1.56-2.22; P < .001), compared to those without SMuRFs. After adjustment for potential confounding, the association between SMuRFs and 2-year mortality risk was substantially attenuated (HR 1.17, 95% CI 0.98-1.41; P = .087), regardless of the type of ACS. The risk conferred by prior CVD was added to the underlying risk of SMuRFs to provide risk-specific phenotypes (eg, women with SMuRFs and with prior CVD were at higher risk of dying than women without SMuRFs and without CVD; HR 1.67, 95% CI 1.34-2.06). CONCLUSIONS: In this large-scale international ACS cohort the absence of SMuRFs was not associated with a lower adjusted 2-year postdischarge mortality risk. Patients with both SMuRFs and prior CVD had a higher mortality irrespective of their sex.

Longitudinal changes in co-involved drugs, comorbidities, and demographics of methamphetamine-related deaths in Los Angeles County.

INTRODUCTION: We conducted a population-based observational study of all medical examiner cases in Los Angeles County from January 2012 through June 2021 in which methamphetamine was listed as a cause of or contributing factor to death (n = 6125). We aimed to characterize demographics, comorbidities, and co-involved substances in methamphetamine-related deaths longitudinally in Los Angeles County, California. METHODS: We used detailed death record data to manually classify fatalities by involvement of each organ system, opioids, alcohol, cocaine, other drugs or medications, and external/traumatic causes. Primary outcomes included: the number of methamphetamine-involved deaths, demographics of decedents, percentage of methamphetamine deaths also involving other drugs, and percentage of methamphetamine deaths involving different organ systems. We performed Mann Kendall tests of trends to identify statistically significant longitudinal changes. RESULTS: During the study period, the percentage of methamphetamine-related deaths involving opioids significantly increased from 16 % in 2012 to 54 % in 2021 (p < 0.001). Concurrently, the percentage involving cardiovascular causes significantly decreased from 47 % to 26 % (p < 0.05). Methamphetamine-related deaths in LAC increasingly affected people experiencing homelessness, for whom the percentage tripled from 13 % in 2012 to 35 % in 2021. The share of decedents under 40 years old increased from 33 % to 41 %. The percentage of Black or African American decedents increased over five-fold from 3 % to 17 %. CONCLUSIONS: Methamphetamine-related deaths involving opioids more than tripled in Los Angeles County from 2012 to 2021, reflecting the drug supply's shift to illicit fentanyl. More than a quarter involved cardiovascular causes. These findings have implications for treatment and prevention, including scaling up contingency management, distributing naloxone to people who primarily use stimulants, and including cardiovascular care alongside these interventions directly targeted to reduce harms of methamphetamine use.

Design and synthesis of aminopyridine containing biaryls reducing c-MYC protein levels in cells.

The c-MYC oncogene transcription factor has been implicated in cell cycle regulation controlling cell growth and proliferation. It is tightly regulated in normal cells, but has been shown to be deregulated in cancer cells, and is thus an attractive target for oncogenic therapies. Building upon previous SAR, a series of analogues containing benzimidazole core replacements were prepared and evaluated, leading to the identification of imidazopyridazine compounds that were shown to possess equivalent or improved c-MYC HTRF pEC50 values, lipophilicity, solubility, and rat pharmacokinetics. The imidazopyridazine core was therefore determined to be superior to the original benzimidazole core and a viable alternate for continued lead optimization and medicinal chemistry campaigns.

Biochemical and Physiological Responses in Sedentary Subjects During the Evaluation of Maximum Oxygen Uptake / Respuestas funcionales durante una prueba de consumo máximo de oxígeno en sujetos sedentarios / Respostas funcionais durante um teste de absorção máxima de oxigênio em indivíduos sedentários

Abstract: Introduction: The use of incremental exercise tests (IET) to evaluate the individual's acute responses is an essential tool in Physical Activity Science. Objective: This paper aims to analyze the behavior between biochemical and physiological variables as aerobic-anaerobic transition indicators during two incremental exercise tests, which measure the maximum oxygen uptake in healthy subjects. Methodology: The sample consisted of two individuals, who were thirty-three and twenty-five years old, respectively. During the execution of the tests, the following materials and tools were used: a portable glucometer, a portable lactometer, reactive tapes, a treadmill, a stationary Cycle Ergometer Monark®, a heart rate monitor Polar®, a gas analyzer, software Breeze®, a computer, tools for recording data, and a pencil. Results: the high inverse correlation between the Glycemic index and VO2 (r: -0,853) and the Glycemic and CO2 (r: -0,851) are notable. Moreover, the detection of thresholds for each subject through blood lactate invasive and non-invasive methods, such as heart rate (HR), is also shown. Conclusion: A clear explanation of Respiratory Quotient (RQ) behavior is given during the Cycle-ergometer test, concluding that this type of protocol is safe for the group under study and that the validity of the results is in accordance with theoretical expectations.

Resumen: Introducción: La ejecución de pruebas físicas incrementales para evaluar las respuestas agudas del individuo, representa una herramienta fundamental en el área de las ciencias de la actividad física. Objetivo: En este sentido, el presente trabajo tiene como objetivo el análisis del comportamiento entre variables bioquímicas y fisiológicas como indicadores de la transición aerobio-anaeróbica en la ejecución de dos test incrementales que miden el consumo máximo de oxígeno, en sujetos sedentarios. Metodología: La muestra se conformó por dos individuos, los cuales presentan edades de treinta y tres y veinticinco años, respectivamente. En el desarrollo de la prueba se utilizaron los siguientes materiales e instrumentos: un glucómetro portátil, un lactómetro portátil, cintas reactivas, treadmill, cicloergomertro Monark ®, pulsometro marca polar ®, analizador de gases, software Breeze ®, computador, instrumentos de registro de datos y lápiz. Resultados: destacan la alta correlación inversa presente entre los valores de glicemia y VO2 (r: -0,853), así como Glicemia y CO2 (r: -0,851) del mismo modo se muestra la detección de los Umbrales para cada sujeto mediante métodos invasivos del lactacidemia y no invasivos como la frecuencia cardíaca. Conclusión: También se ejecuta una explicación clara del comportamiento del cociente respiratorio en la prueba ejecutada con el cicloergómetro, concluyendo que este tipo de protocolos son seguros para el grupo en estudio y la validez de los resultados es acorde con las expectativas teóricas.

Resumo: Introdução: A execução de testes físicos incrementais para avaliar as respostas agudas do indivíduo representa uma ferramenta fundamental na área das ciências da atividade física. Objetivo: Neste sentido, o presente trabalho visa analisar o comportamento entre as variáveis bioquímicas e fisiológicas como indicadores da transição aeróbico-anaeróbica na execução de dois testes incrementais que medem o consumo máximo de oxigênio em sujeitos sedentários. Metodologia: A amostra consistiu de dois indivíduos, com trinta e três e vinte e cinco anos de idade, respectivamente. Os seguintes materiais e instrumentos foram utilizados no desenvolvimento do teste: um glicosímetro portátil, um lactômetro portátil, tiras de teste, esteira, cicloergômetro Monark®, pulsômetro polar®, analisador de gás, software Breeze®, computador, instrumentos de registro de dados e lápis. Resultados: A alta correlação inversa entre glicemia e VO2 (r: -0,853), assim como glicemia e CO2 (r: #0,851) e a detecção dos limiares para cada sujeito usando métodos invasivos como lactacidemia e métodos não-invasivos como a frequência cardíaca. Conclusão: Uma explicação clara do comportamento do quociente respiratório no teste executado com o cicloergômetro também é executada, concluindo que este tipo de protocolos são seguros para o grupo em estudo e a validade dos resultados está de acordo com as expectativas teóricas.

Necesidades de atención domiciliaria en el paciente paliativo pediátrico percibidas por los profesionales: Una teoría fundamentada / Home care needs of paediatric palliative patients perceived by professionals: A grounded theory

Objetivo: Explorar los elementos que intervienen en el proceso de los cuidados paliativos pediátricos domiciliarios en el contexto de España según la opinión de los profesionales. Método: Estudio cualitativo sustentado en la Teoría Fundamentada, ajustado a normas COREQ, mediante muestreo teórico con entrevistas en profundidad (junio 2021 - febrero 2022) a pediatras, enfermeras pediátricas y trabajadores sociales de unidades de cuidados paliativos infantiles en España, excluyendo profesionales con experiencia inferior a 1 año. Las entrevistas han sido grabadas y transcritas literalmente para su codificación y categorización mediante un proceso comparativo constante a través de coocurrencias de códigos hasta la saturación de datos usando Atlas-Ti®. Se ha garantizado el anonimato de los informantes empleando pseudónimos tras la aprobación por el Comité de Ética de la Investigación del Hospital Universitario de Gran Canaria Doctor Negrín (Las Palmas, Islas Canarias) con número de registro 2021-403-1. Resultados: Se realizaron 18 entrevistas que expusieron 990 citas agrupadas en 22 categorías de análisis y estructuradas en cuatro grupos temáticos (cuidados, entorno, paciente y familia y profesionales). Los hallazgos mostraron una visión holística que enfatiza la necesidad de organizar e integrar los factores que intervienen en el abordaje domiciliario a los cuidados paliativos domiciliarios en pediatría. Conclusiones: En nuestro contexto, el entorno domiciliario reúne unas condiciones apropiadas para desarrollar los cuidados paliativos pediátricos. Las categorías de análisis identificadas establecen un punto de partida para seguir profundizando en el abordaje desde las esferas temáticas implicadas: los cuidados, el entorno, el paciente y la familia y los profesionales.(AU)

Objective: To explore the elements involved in the process of paediatric palliative home care in the Spanish context according to the opinion of professionals. Method: Qualitative study based on Grounded Theory, adjusted to COREQ standards, using theoretical sampling with in-depth interviews (June 2021 - February 2022) with paediatricians, paediatric nurses and social workers from paediatric palliative care units in Spain, excluding professionals with less than 1 year's experience. Interviews were recorded and transcribed literally for coding and categorisation through a constant comparative process of code co-occurrence until data saturation using Atlas-Ti®. The anonymity of the informants has been guaranteed by using pseudonyms after approval by the Research Ethics Committee of the Hospital Universitario de Gran Canaria Doctor Negrín (Las Palmas, Canary Islands) with registration number 2021-403-1. Results: 18 interviews were conducted and 990 quotes were grouped into 22 categories of analysis and structured into four thematic groups (care, environment, patient and family, and professionals). The findings showed a holistic view emphasising the need to organise and integrate the factors involved in the home-based approach to paediatric palliative home care. Conclusions: In our context, the home environment meets appropriate conditions for the development of paediatric palliative care. The categories of analysis identified establish a starting point for further deepening the approach from the thematic areas involved: care, the environment, the patient and family, and professionals.(AU)

Anaerobic performance in prepubertal girls practicing racing skating / Rendimiento anaeróbico en niñas prepúberes que practican patinaje de carreras

A high anaerobic demand in skating is a determining factor in the possibilities of success, however, it has been little studied in younger categories. the present study aimed to analyze the anaerobic performance in prepubertal girls who practice roller skating. through a random sampling, 44 girls between 7 and 10 years old, who practice roller speed skating in the Department of Sucre-Colombia, all with tanner stage 1 for sexual maturation, were evaluated. The RAST test adapted to pediatric population and the Abalakov bipodal jumps (ABK) and right unipodal jumps (RUJ) and left unipodal jumps (LuJ) measured by the myjump2 © application were applied. In the statistical analysis, the SPSS © version 25.0 program was used to perform the analysis of variance and the correlation between the power and height of jumps between ages. It can be observed that girls of 7 and 8 years old, present better power production in comparison with the other groups, differences p<.05 were found in the fatigue index between girls of 8 and 10 years old. Correlations p<.05 were found between absolute power (W) and relative power (W/kg) with ABK, RUJ and with LuJ. It is concluded that the improvement of the mechanical power produced in jumps increases the probabilities of improvement of the anaerobic power in the group of prepubertal girls evaluated who practice racing skating. (AU)

Una alta demanda anaeróbica en el patinaje es un factor determinante en las posibilidades de éxito, sin embargo, ha sido poco estudiado en categorías menores. el presente estudio tuvo como objetivo analizar el rendimiento anaeróbico en niñas prepúberes que practican patinaje sobre ruedas. a través de un muestreo aleatorio, se evaluaron 44 niñas entre 7 y 10 años de edad, que practican patinaje de velocidad sobre ruedas en el departamento de Sucre-Colombia, todas con estadio tanner 1 de maduración sexual. Se aplicó el test RAST adaptado a población pediátrica y los saltos bipodales de Abalakov (ABK) y saltos unipodales derecho (RUJ) e izquierdo (LuJ) medidos por la aplicación myjump2 ©. En el análisis estadístico se utilizó el programa SPSS © versión 25.0 para realizar el análisis de varianza y la correlación entre la potencia y la altura de los saltos entre edades. Se puede observar que las niñas de 7 y 8 años, presentan mejor producción de potencia en comparación con los otros grupos, se encontraron diferencias p<.05 en el índice de fatiga entre las niñas de 8 y 10 años. Se encontraron correlaciones p<.05 entre la potencia absoluta (W) y la potencia relativa (W/kg) con ABK, RUJ y con LuJ. Se concluye que la mejora de la potencia mecánica producida en los saltos aumenta las probabilidades de mejora de la potencia anaeróbica en el grupo de niñas prepúberes evaluadas que practican patinaje de carreras. (AU)

Home care needs of paediatric palliative patients perceived by professionals: A grounded theory.

OBJECTIVE: To explore the elements involved in the process of paediatric palliative home care in the Spanish context according to the opinion of professionals. METHOD: Qualitative study based on Grounded Theory, adjusted to COREQ standards, using theoretical sampling with in-depth interviews (June 2021-February 2022) with paediatricians, paediatric nurses and social workers from paediatric palliative care units in Spain, excluding professionals with less than 1 years' experience. Interviews were recorded and transcribed literally for coding and categorisation through a constant comparative process of code co-occurrence until data saturation using Atlas-Ti®. The anonymity of the informants has been guaranteed by using pseudonyms after approval by the Research Ethics Committee of the Hospital Universitario de Gran Canaria Doctor Negrín (Las Palmas, Canary Islands) with registration number 2021-403-1. RESULTS: 18 interviews were conducted and 990 quotes were grouped into 22 categories of analysis and structured into four thematic groups (care, environment, patient and family, and professionals). The findings showed a holistic view emphasising the need to organise and integrate the factors involved in the home-based approach to paediatric palliative home care. CONCLUSIONS: In our context, the home environment meets appropriate conditions for the development of paediatric palliative care. The categories of analysis identified establish a starting point for further deepening the approach from the thematic areas involved: care, the environment, the patient and family, and professionals.

Activity of plant essential oils against clinically and environmentally isolated Salmonella enterica serotypes: in vitro assays and molecular docking.

This research aimed to evaluate the antimicrobial activity of essential oils (EOs) against clinically and environmentally isolated Salmonella serotypes. Oregano, thyme, and grapefruit EO compounds were identified, and the antimicrobial activity was evaluated against the S. Saintpaul, Oranienburg, and Infantis serotypes. In addition, molecular docking was performed to explore the possible mechanisms between compounds of EOs with microbial enzymes. Thymol was the main compound identified in oregano (44.0%) and thyme (31%) EOs, while d-limonene was present in a greater proportion in grapefruit EO. Oregano EO had the highest antimicrobial activity, followed by thyme and grapefruit EOs. Oregano and thyme EOs illustrated a greater inhibitory capacity to all serotypes, particularly with the environmental S. Saintpaul. Oregano EO presented values of minimum inhibitory concentration (MIC) and minimum bactericidal concentration of 0.1 µL/mL for all serotypes, while thyme and grapefruit EOs presented MIC values of 0.1 µL/mL for the clinical serotypes S. Infantis and S. Oranienburg, respectively. Molecular docking analysis showed the optimal binding free energies for thymol and carvacrol with glucokinase, ATP-dependent-6-fructokinase, outer membrane porin C, and topoisomerase IV. Our results indicate that these EOs can inhibit clinically and environmentally isolated Salmonella serotypes and can be used as alternatives for developing natural food preservatives.

HbA1c trajectories over 3 years in people with type 2 diabetes starting second-line glucose-lowering therapy: The prospective global DISCOVER study.

AIM: To identify distinct HbA1c trajectories in people with type 2 diabetes (T2D) starting second-line glucose-lowering therapy. MATERIALS AND METHODS: DISCOVER was a 3-year observational study of individuals with T2D beginning second-line glucose-lowering therapy. Data were collected at initiation of second-line treatment (baseline) and at 6, 12, 24 and 36 months. Latent class growth modelling was used to identify groups with distinct HbA1c trajectories. RESULTS: After exclusions, 9295 participants were assessed. Four distinct HbA1c trajectories were identified. Mean HbA1c levels decreased between baseline and 6 months in all groups; 72.4% of participants showed stable good levels of glycaemic control over the remainder of follow-up, 18.0% showed stable moderate levels of glycaemic control and 2.9% showed stable poor levels of glycaemic control. Only 6.7% of participants showed highly improved glycaemic control at month 6 and stable control over the rest of follow-up. For all groups, dual oral therapy use decreased over time, compensated for by the increasing use of other treatment regimens. Use of injectable agents increased over time in groups with moderate and poor glycaemic control. Logistic regression models suggested that participants from high-income countries were more probable to be in the stable good trajectory group. CONCLUSIONS: Most people receiving second-line glucose-lowering treatment in this global cohort achieved stable good or highly improved long-term glycaemic control. One-fifth of participants showed moderate or poor glycaemic control during follow-up. Further large-scale studies are required to characterize possible factors associated with patterns of glycaemic control to inform personalized diabetes treatment.

Management of Recurrent Well-Differentiated Thyroid Carcinoma in the Neck: A Comprehensive Review.

Surgery has been historically the preferred primary treatment for patients with well-differentiated thyroid carcinoma and for selected locoregional recurrences. Adjuvant therapy with radioactive iodine is typically recommended for patients with an intermediate to high risk of recurrence. Despite these treatments, locally advanced disease and locoregional relapses are not infrequent. These patients have a prolonged overall survival that may result in long periods of active disease and the possibility of requiring subsequent treatments. Recently, many new options have emerged as salvage therapies. This review offers a comprehensive discussion and considerations regarding surgery, active surveillance, radioactive iodine therapy, ultrasonography-guided percutaneous ablation, external beam radiotherapy, and systemic therapy for well-differentiated thyroid cancer based on relevant publications and current reference guidelines. We feel that the surgical member of the thyroid cancer management team is empowered by being aware and facile with all management options.

Treatment patterns and glycated haemoglobin levels over 36 months in individuals with type 2 diabetes initiating second-line glucose-lowering therapy: The global DISCOVER study.

AIMS: To describe glucose-lowering treatment regimens and glycated haemoglobin (HbA1c) trajectories in individuals with type 2 diabetes (T2D) over 36 months of follow-up from the start of second-line therapy. MATERIALS AND METHODS: This data analysis from the 3-year, observational DISCOVER study programme included 14 687 participants from 37 countries with T2D initiating second-line glucose-lowering therapy. Treatment and HbA1c data were collected at baseline (start of second-line therapy) and at 6, 12, 24 and 36 months. Treatment regimen changes over follow-up were analysed using the McNemar test, with carry-forward imputation for intermediate missing values. RESULTS: A total of 11 592 participants had treatment data at baseline and 36 months, and 11 882 had HbA1c data at baseline. At baseline and 36 months, respectively, rates of oral monotherapy use were 12.1% and 12.4% (P = 0.22), rates of dual oral therapy use were 63.4% and 47.6% (P < 0.0001), rates of ≥ triple oral therapy use were 17.5% and 25.4% (P < 0.0001), and rates of injectable treatment use were 7.0% and 13.7% (P < 0.0001). Use of injectable drugs was most common among participants with an HbA1c level ≥64 mmol/mol (≥8.0%). Overall, 42.9% of participants changed treatment during follow-up. Mean HbA1c levels at baseline and 6 months were 67 mmol/mol (8.3%) and 55 mmol/mol (7.2%), respectively, remaining stable thereafter. CONCLUSIONS: Dual oral therapy was the most common treatment regimen at the start of second-line treatment, and over half of the participants remained on the same treatment during follow-up.

Structural, Optical, and Arsenic Removal Properties of Sol-Gel Synthesized Fe-Doped TiO2 Nanoparticles.

Pure and Fe-doped TiO2 nanoparticles were synthesized by the sol-gel method. The samples were characterized by X-ray diffraction, Raman spectroscopy, BET, UV-vis diffuse reflectance spectroscopy, and scanning electron microscopy. The results show a dependence between the crystallite size and the amount of dopant, which decreases from 13.02 to 12.81 nm. The same behavior was observed in the optical properties, where the band gap decreased from 3.2 to 2.86 eV. The arsenic (V) adsorption was tested in aqueous solution containing 5 mg/L of arsenic and 0.5 g/L of adsorbent at pH 7 and in dark conditions. The results indicate that the TiO2-B sample shows a higher arsenic removal, reaching 88% arsenic removal from the water at pH 7. Thus, it is also shown that the best performance occurs at pH 5, where it reaches an arsenic removal of 94%. Ion competition studies show that arsenic removal capacity is slightly affected by chloride, carbonate, nitrate, and sulfate ions. According to the results, the synthesized samples are a promising material for treating arsenic-contaminated water.

Discovery of Proline-Based p300/CBP Inhibitors Using DNA-Encoded Library Technology in Combination with High-Throughput Screening.

E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of 22 led to not only reduced clearance but also improved cMyc cellular potency.

Development and Validation of Machine Models Using Natural Language Processing to Classify Substances Involved in Overdose Deaths.

Importance: Overdose is one of the leading causes of death in the US; however, surveillance data lag considerably from medical examiner determination of the death to reporting in national surveillance reports. Objective: To automate the classification of deaths related to substances in medical examiner data using natural language processing (NLP) and machine learning (ML). Design, Setting, and Participants: Diagnostic study comparing different natural language processing and machine learning algorithms to identify substances related to overdose in 10 health jurisdictions in the US from January 1, 2020, to December 31, 2020. Unstructured text from 35 433 medical examiner and coroners' death records was examined. Exposures: Text from each case was manually classified to a substance that was related to the death. Three feature representation methods were used and compared: text frequency-inverse document frequency (TF-IDF), global vectors for word representations (GloVe), and concept unique identifier (CUI) embeddings. Several ML algorithms were trained and best models were selected based on F-scores. The best models were tested on a hold-out test set and results were reported with 95% CIs. Main Outcomes and Measures: Text data from death certificates were classified as any opioid, fentanyl, alcohol, cocaine, methamphetamine, heroin, prescription opioid, and an aggregate of other substances. Diagnostic metrics and 95% CIs were calculated for each combination of feature extraction method and machine learning classifier. Results: Of 35 433 death records analyzed (decedent median age, 58 years [IQR, 41-72 years]; 24 449 [69%] were male), the most common substances related to deaths included any opioid (5739 [16%]), fentanyl (4758 [13%]), alcohol (2866 [8%]), cocaine (2247 [6%]), methamphetamine (1876 [5%]), heroin (1613 [5%]), prescription opioids (1197 [3%]), and any benzodiazepine (1076 [3%]). The CUI embeddings had similar or better diagnostic metrics compared with word embeddings and TF-IDF for all substances except alcohol. ML classifiers had perfect or near perfect performance in classifying deaths related to any opioids, heroin, fentanyl, prescription opioids, methamphetamine, cocaine, and alcohol. Classification of benzodiazepines was suboptimal using all 3 feature extraction methods. Conclusions and Relevance: In this diagnostic study, NLP/ML algorithms demonstrated excellent diagnostic performance at classifying substances related to overdoses. These algorithms should be integrated into workflows to decrease the lag time in reporting overdose surveillance data.

Spectroscopic study of terrestrial analogues to support rover missions to Mars - A Raman-centred review.

The 2020s could be called, with little doubt, the "Mars decade". No other period in space exploration history has experienced such interest in placing orbiters, rovers and landers on the Red Planet. In 2021 alone, the Emirates' first Mars Mission (the Hope orbiter), the Chinese Tianwen-1 mission (orbiter, lander and rover), and NASA's Mars 2020 Perseverance rover reached Mars. The ExoMars mission Rosalind Franklin rover is scheduled for launch in 2022. Beyond that, several other missions are proposed or under development. Among these, MMX to Phobos and the very important Mars Sample Return can be cited. One of the key mission objectives of the Mars 2020 and ExoMars 2022 missions is the detection of traces of potential past or present life. This detection relies to a great extent on the analytical results provided by complementary spectroscopic techniques. The development of these novel instruments has been carried out in step with the analytical study of terrestrial analogue sites and materials, which serve to test the scientific capabilities of spectroscopic prototypes while providing crucial information to better understand the geological processes that could have occurred on Mars. Being directly involved in the development of three of the first Raman spectrometers to be validated for space exploration missions (Mars 2020/SuperCam, ExoMars/RLS and RAX/MMX), the present review summarizes some of the most relevant spectroscopy-based analyses of terrestrial analogues carried out over the past two decades. Therefore, the present work describes the analytical results gathered from the study of some of the most distinctive terrestrial analogues of Martian geological contexts, as well as the lessons learned mainly from ExoMars mission simulations conducted at representative analogue sites. Learning from the experience gained in the described studies, a general overview of the scientific outcome expected from the spectroscopic system developed for current and forthcoming planetary missions is provided.