bluuebunny/crossref_metadata_2025 huggingface dataset:
Características clínicas y electroencefalográficas en pacientes con infección por SARS-CoV-2 atendidos en un hospital de alta complejidad de Bogotá (Colombia)
Authors: Bravo Guzmán Diana Judith , Millán Pérez Sonia , Fontanilla Diaz Luis , Martínez Reyes Andrea Estefanía
Published: August 2023

INTRODUCCIÓN: La pandemia de la enfermedad por coronavirus 2019 (COVID-19), ha sido un suceso desafiante sin precedentes para el sistema de salud en todo el mundo. OBJETIVO: Describir las características clínicas y electroencefalográficas de un grupo de pacientes diagnosticados con COVID-19. METODOLOGÍA: Se realizó un estudio observacional, descriptivo, transversal de pacientes con diagnóstico de COVID-19 atendidos en el Hospital Universitario Clínica San Rafael, de la ciudad de Bogotá, Colombia. RESULTADOS: Se identificaron 29 pacientes. La edad promedio fue 55,2 años (47,6-62,7); 58,6% fueron hombres. Las indicaciones del electroencefalograma (EEG) fueron: sospecha de estado epiléptico no convulsivo (31%), crisis epilépticas (27.6%), encefalopatía multifactorial (17.2%), encefalopatía hipóxico isquémica (13.8%) y demencia rápidamente progresiva, alteración de su estado de conciencia y antecedente de epilepsia (3.4% cada uno). El 80% de los EEG mostraron hallazgos anormales caracterizados en su mayoría por lentificación de la actividad de fondo generalizada en el 60% (uno de ellos con ondas trifásicas), seguida de actividad epiléptica, lentificación focal y ausencia de actividad electrocortical demostrable en el contexto clínico de muerte cerebral (10%, 6.7%, 3.3%. respectivamente).CONCLUSIÓN: El EEG no mostró un patrón típico en los pacientes con infección por COVID-19, sin embargo, si es posible identificar la presencia de compromiso encefalopático, muerte cerebral, lesiones focales y realizar diagnóstico diferencial con estado epiléptico no convulsivo.
Comparación de costos e indicadores de desempeño de dos inyectores de medios de contraste de doble cabezal en tomografías computarizadas con contraste
Authors: Upegui Daniel , Aldana Leal Juan Carlos , Vargas Emily
Published: August 2023

La adopción de tecnologías complejas para el diagnóstico médico, exige el análisis de sus ventajas económicas y técnicas. Se compararon dos inyectores de doble cabezal en términos de costos, tiempos y volumen de medio de contraste durante la tomografía computarizada, en un análisis prospectivo de 103 procedimientos. Dos observadores registraron consumibles e indicadores de desempaño durante el uso de (OptiVantage®) y (Medrad® Stellant combinado con el uso de Medrad Stellant Multi-Patient Kit; se determinaron los costos asociados al uso habitual y el uso recomendado en una institución de tercer nivel de atención en Colombia. Se evidenció un tiempo de preparación mayor de 23.3 segundos (p < 0.000) con OptiVantage® (52.2 segundos, IC95% 46.7 – 56.7) respecto del grupo del inyector Medrad® Stellant (28.9 segundos, IC95% 21.8 – 39.5). El volumen de medio de contraste inyectado fue mayor por 8.7 ml (p < 0.005) con OptiVantage® (68.4 ml, IC95% 63.4 – 73.3) versus el inyector Medrad® Stellant (59.7 ml, IC95% 56.7 – 62.7). El costo total por el uso de Medrad® Stellant es 8% más bajo en la modalidad habitual de uso. El Medrad® Stellant CT Injection System combinado con el uso del Medrad Stellant Multi-Patient Kit es más eficiente, ofrece seguridad y un menor costo total por procedimiento realizado.
Desenlaces tempranos del manejo de la asfixia perinatal con Cool-Cap® y manta
Authors: Ramírez-Corredor Ayelet , Devia-Neira Claudia , Vargas-Vacca Yaris Anzully , Bertolotto-Cepeda Ana María , Bohórquez-Peñaranda Adriana Patricia
Published: August 2023

Introducción: Los resultados a corto plazo obtenidos con el enfriamiento corporal mediante Cool-cap®️ y manta son controversiales. Se presentan los desenlaces de las dos modalidades de intervención bajo el mismo protocolo e institución.Pacientes y métodos: Estudio de cohortes ambidireccional de los neonatos con asfixia perinatal moderada o severa tratados con hipotermia controlada entre 2018 a 2020 atendidos en un hospital en Bogotá, Colombia.Resultados: 164 pacientes recibieron hipotermia terapéutica con los dispositivos mencionados (Cool-cap®️ 54,2 %; Manta 45,7%). La mortalidad fue de 11,2% y 16% respectivamente, con una mayor proporción de pacientes con Sarnat III en este último grupo (16 % vs. 6 %). El grupo de Cool-cap®️ presentó más trastornos cardiovasculares (60 %); la hipertensión pulmonar y los trastornos hematológicos tuvieron una proporción similar en ambos grupos. En ambas intervenciones, más de la mitad de los pacientes ingresaron fuera de periodo de ventana terapéutica y tuvieron una mortalidad global del 14,8 % (Cool-cap®️ n=7 y Manta n=7). Conclusiones: La mortalidad global fue 13,4%, menor a la reportada en la literatura que varia entre 14% y 20%, a pesar de que más de la mitad de los pacientes ingresaron fuera del periodo de ventana terapéutica. Siendo esta mayor en el grupo de manta, diferencia que se explica por la disparidad de la distribución de los factores pronósticos al ingreso de los dos grupos.
Fabrication of pyramid-shaped gold tip for adiabatic nanofocusing of surface plasmon polaritons
Authors: Khalaf Jamal Kheiro , Sadiq Diyar
Published: August 2023

Scattering-type scanning near-field optical microscopy based on adiabatic nanofocusing of surface plasmon polaritons (SPPs) is a powerful technique that can achieve free-background nanoscale optical resolution of material. However, the performance of the propagated confined modes strongly depends on the characteristic structure of the probe. Although the metallic pyramid structure provides excellent tightly confined modes, however, it is challenging to realize the required pyramid geometry. Here, we propose a simple method for fabricating a reproducible and controllable gold pyramid-shaped tip. The produced pyramid-shaped tips were made by electrochemical etching and by applying a pulse wave to the system. From a systematic study, we found that the key factor of fabrication of desired tip geometry is based on the platinum (Pt) wire shapes. Traditional circular-shaped platinum ring electrodes are used for gold tip fabrication in an electrochemical etching. In our method, we bent the Pt wire into a triangular shape as the electrode for the etching process. The influence of the geometrical ring shapes on the fabrication of the Au tip structure is investigated. The gold tip structure was optimized by controlling the Pt ring shape, and the desired pyramid-shaped gold tip was achieved with a yield of 70%. The obtained etched pyramid-shaped tips were then mounted along the side of one of the arms of a quartz tuning fork force sensor to test their performance for shear-force topographical image and for guiding SPPs along the pyramid wedge based on adiabatic nanofocusing microscopy. The result shows topographical images of indium tin oxide with a spatial resolution smaller than 20 nm. Furthermore, we experimentally demonstrate the generation of the SPPs that propagated adiabatically along the wedge of an appropriate fabricated pyramid-shaped tip toward a nanometer-size spot at the tip apex. The demonstration of this method strongly suggests that the obtained pyramid-shaped tip will enable new experiments probing the dynamics of optical excitations of individual metallic, semiconducting, and magnetic nanostructures.
Microbial-host-isozyme analyses reveal microbial DPP4 as a potential antidiabetic target
Authors: Wang Kai , Zhang Zhiwei , Hang Jing , Liu Jia , Guo Fusheng , Ding Yong , Li Meng , Nie Qixing , Lin Jun , Zhuo Yingying , Sun Lulu , Luo Xi , Zhong Qihang , Ye Chuan , Yun Chuyu , Zhang Yi , Wang Jue , Bao Rui , Pang Yanli , Wang Guang , Gonzalez Frank J. , Lei Xiaoguang , Qiao Jie , Jiang Changtao
Published: August 2023

A mechanistic understanding of how microbial proteins affect the host could yield deeper insights into gut microbiota–host cross-talk. We developed an enzyme activity–screening platform to investigate how gut microbiota–derived enzymes might influence host physiology. We discovered that dipeptidyl peptidase 4 (DPP4) is expressed by specific bacterial taxa of the microbiota. Microbial DPP4 was able to decrease the active glucagon like peptide-1 (GLP-1) and disrupt glucose metabolism in mice with a leaky gut. Furthermore, the current drugs targeting human DPP4, including sitagliptin, had little effect on microbial DPP4. Using high-throughput screening, we identified daurisoline-d4 (Dau-d4) as a selective microbial DPP4 inhibitor that improves glucose tolerance in diabetic mice.
Human STING is a proton channel
Authors: Liu Bingxu , Carlson Rebecca J. , Pires Ivan S. , Gentili Matteo , Feng Ellie , Hellier Quentin , Schwartz Marc A. , Blainey Paul C. , Irvine Darrell J. , Hacohen Nir
Published: August 2023

Proton leakage from organelles is a common signal for noncanonical light chain 3B (LC3B) lipidation and inflammasome activation, processes induced upon stimulator of interferon genes (STING) activation. On the basis of structural analysis, we hypothesized that human STING is a proton channel. Indeed, we found that STING activation induced a pH increase in the Golgi and that STING reconstituted in liposomes enabled transmembrane proton transport. Compound 53 (C53), a STING agonist that binds the putative channel interface, blocked STING-induced proton flux in the Golgi and in liposomes. STING-induced LC3B lipidation and inflammasome activation were also inhibited by C53, suggesting that STING’s channel activity is critical for these two processes. Thus, STING’s interferon-induction function can be decoupled from its roles in LC3B lipidation and inflammasome activation.
Cross-sectional study evaluating the impact of SARS-CoV-2 variants on Long COVID outcomes in UK hospital survivors
Authors: Saigal Anita , Nagoda Niklewicz Camila , Naidu Sindhu Bhaarrati , Bintalib Heba M , Shah Amar Jitu , Seligmann George , Hunter Alan Stewart , Wey Emmanuel , Abubakar Ibrahim , Mahungu Tabitha , Miller David , Barnett Joseph , Jain Neel Gautam , Brill Simon , Goldring James , Jarvis Hannah , Smith Colette , Ogbonnaya Chibueze , Hurst John R , Lipman Marc C I , Mandal Swapna
Published: August 2023

Objectives

COVID-19 studies report on hospital admission outcomes across SARS-CoV-2 waves of infection but knowledge of the impact of SARS-CoV-2 variants on the development of Long COVID in hospital survivors is limited. We sought to investigate Long COVID outcomes, aiming to compare outcomes in adult hospitalised survivors with known variants of concern during our first and second UK COVID-19 waves, prior to widespread vaccination.

Design

Prospective observational cross-sectional study.

Setting

Secondary care tertiary hospital in the UK.

Participants

This study investigated Long COVID in 673 adults with laboratory-positive SARS-CoV-2 infection or clinically suspected COVID-19, 6 weeks after hospital discharge. We compared adults with wave 1 (wildtype variant, admitted from February to April 2020) and wave 2 patients (confirmed Alpha variant on viral sequencing (B.1.1.7), admitted from December 2020 to February 2021).

Outcome measures

Associations of Long COVID presence (one or more of 14 symptoms) and total number of Long COVID symptoms with SARS-CoV-2 variant were analysed using multiple logistic and Poisson regression, respectively.

Results

322/400 (wave 1) and 248/273 (wave 2) patients completed follow-up. Predictors of increased total number of Long COVID symptoms included: pre-existing lung disease (adjusted count ratio (aCR)=1.26, 95% CI 1.07, 1.48) and more COVID-19 admission symptoms (aCR=1.07, 95% CI 1.02, 1.12). Weaker associations included increased length of inpatient stay (aCR=1.02, 95% CI 1.00, 1.03) and later review after discharge (aCR=1.00, 95% CI 1.00, 1.01). SARS-CoV-2 variant was not associated with Long COVID presence (OR=0.99, 95% CI 0.24, 4.20) or total number of symptoms (aCR=1.09, 95% CI 0.82, 1.44).

Conclusions

Patients with chronic lung disease or greater COVID-19 admission symptoms have higher Long COVID risk. SARS-CoV-2 variant was not predictive of Long COVID though in wave 2 we identified fewer admission symptoms, improved clinical trajectory and outcomes. Addressing modifiable factors such as length of stay and timepoint of clinical review following discharge may enable clinicians to move from Long COVID risk stratification towards improving its outcome.
Molecular diagnosis of tuberous sclerosis complex in fetuses and infants: an institutional case series
Authors: Bolshakova Anna S , Maslennikov Dmitry N , Shubina Jekaterina , Bystritskiy Andrey A , Tolmacheva Ekaterina R , Mukosey Irina S , Kochetkova Taisiya O , Vasiliev Grigory S , Atapina Ekaterina E , Sadelov Igor O , Zaretskaya Nadezhda V , Barkov Ilya Yu , Degtyarev Dmitry N , Trofimov Dmitry Yu
Published: August 2023

Objective

We describe the clinical and genetic characteristics of fetuses and infants diagnosed with tuberous sclerosis complex (TSC) in our centre, prenatally or neonatally, for a better understanding of the benefits of early screening.

Methods

In this retrospective study, we analysed the data on one fetus and nine infants with a definitive TSC diagnosis by genetic criteria (five patients carryingTSC1variants and 5 patients carryingTSC2variants). We explored the differences between phenotypes of patients carryingTSC1andTSC2pathogenic variants.

Results

The most common initial presenting features of TSC were cardiac rhabdomyomas (CRs) that were observed in nine out of ten patients. The most common postnatal features, besides CR, were presented with subependymal nodules—in five patients, and hypomelanotic macules—in four patients. In total, 10 variants causing TSC were detected in this study, including 5 novel variants. We demonstrated that patients withTSC2variants had earlier onset and more severe clinical manifestations compared with patients carryingTSC1variants.

Conclusion

Early diagnosis of TSC improves genetic counselling and perinatal management.
Nivolumab and ipilimumab in combination with radiotherapy in patients with high-risk locally advanced squamous cell carcinoma of the head and neck
Authors: Johnson Jennifer M , Vathiotis Ioannis A , Harshyne Larry A , Ali Ayesha , Bar Ad Voichita , Axelrod Rita , Lorber Emily , Curry Joseph , Cognetti David M , Luginbuhl Adam J , Tuluc Madalina , Keith Scott , Mahoney Mỹ G , Argiris Athanassios
Published: August 2023

Background

The combination of nivolumab and ipilimumab has been approved for the treatment of multiple solid tumors. This was a phase I study investigating definitive radioimmunotherapy (RIT) with nivolumab and ipilimumab for the treatment of locally advanced (LA) squamous cell carcinoma of the head and neck (SCCHN).

Methods

Patients with newly diagnosed, stage IVA–IVB SCCHN eligible for cisplatin-based chemotherapy received nivolumab (3 mg/kg every 2 weeks for a total of 17 doses) and ipilimumab (1 mg/kg every 6 weeks for a total of 6 doses) starting 2 weeks prior to radiotherapy. The primary endpoint was safety of definitive RIT. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Exploratory endpoints included the association of baseline programmed death-ligand 1 (PD-L1) expression as well as on-treatment changes in immune bias with treatment outcomes.

Results

Twenty-four patients were enrolled. With a median follow-up of 36.1 months, grade 3 or higher treatment-related adverse events were reported in 21 individuals (88%); 5 individuals developed in-field soft tissue ulceration during consolidation immunotherapy, resulting in one fatality. The 3-year PFS and OS rates were 74% (95% CI 58% to 94%) and 96% (95% CI 88% to 100%), respectively. PD-L1 combined positive score (CPS) did not correlate with death or disease progression. Decreases in extracellular vesicle PD-L1 within the concurrent RIT phase were associated with prolonged PFS (p=0.006). Also, interval decreases in circulating interleukin (IL)4, IL9, IL12, and IL17a during concurrent RIT were associated with subsequent ulceration.

Conclusions

Definitive RIT with nivolumab and ipilimumab has sufficient clinical activity to support further development. Early changes in circulating biomarkers appear able to predict treatment outcomes as well as ensuing in-field soft tissue ulceration.

Trial registration number

NCT03162731.
Global health context for the military in Defence Engagement (Health)
Authors: Foley Sue , Falconer Hall T , Bates D , Attridge K
Published: August 2023

Global health practice is becoming a key enabler within UK Defence and foreign policy. The definition of global health remains debated, though some important themes have been identified including: the multidisciplinary nature of global health, its ethical foundation and the political nature of global health. This paper contributes to the ongoing rational discourse that this important discipline deserves and recommends a framework and principles to apply to military health and care system strengthening in the Defence Engagement (Health) (DE(H)) practitioner role. DE(H) involves complex multiorganisational relationships and processes, and while practitioners should be mindful of the political nature of their role, the broad aims of preventing conflict and building stability mean DE(H) should contribute positively to global health.

This paper forms part of a special issue ofBMJ Military Healthdedicated to Defence Engagement.
Analysing delay factors in construction projects using Z-number approach: insights from Pakistan
Authors: Nadeem Muhammad , Jiskani Izhar Mithal , Urwat Muhammad Salman , Uddin Salah , Akhtar Kamran , Khokhar Nadar Hussain
Published: August 2023

Delays are a pervasive challenge in the global construction industry, requiring more consideration to address project failure. This research proposes an improved methodology for analysing delays in the construction industry. Through a literature review, a set of 85 delay factors was identified and classified into five categories aligned with the various project phases: initiation, design, procurement, execution, and closeout. A method based on the Z-number theory was developed for the evaluation and prioritization of delay factors in the context of Pakistan. This approach incorporates expert judgment, confidence level, and experience to enhance the reliability of the evaluation. The research findings underscore the substantial influence of several critical factors on project delays. Specifically, factors such as cost inflation, contractor financial issues, inadequate project supervision and management, adverse weather conditions, insufficient skilled labour, delays in government document approvals, and unforeseen cost escalations during construction emerged as the foremost contributors to project delays.
Agata detector technology: recent progress and future developments
Authors: Eberth J. , Hess H. , Reiter P. , Bertoldo S. , Carraro C. , Maggioni G. , Napoli D. R. , Raniero W. , De Salvador D.
Published: August 2023

$$\gamma $$γ-ray tracking is based on a new generation of position sensitive high-purity germanium (HPGe) detectors. A novel type of cluster detector was successfully developed and assembled for the high-resolution$$\gamma $$γ-ray spectrometer Advanced Gamma Tracking Array AGATA. The core part of the detector consists of three encapsulated, 36-fold segmented HPGe detectors which are operated in a common cryostat. The Ge crystal is hermetically sealed inside an aluminium can. All energy channels provide best energy resolution of core and segment signals for an extended energy range well above 50 MeV. A low cross-talk level was determined for the HPGe detectors and its preamplifier circuitry. Related cross-talk corrections are essential for highest energy resolution and improved position dependent pulse shape information. Recently a new encapsulation technology was put into operation which is based on a renewable metal elastic seal. HPGe detector developments are concerned with technologies for the production of p+ and n+ contacts, the segmentation and passivation of encapsulated HPGe crystals. Semiconductor processing research specifically aimed to develop a stable, thin and easy to segment n+ contact. A novel process, based on pulsed laser melting PLM, was successfully employed to produce very thin n+ and p+ contacts preserving the Ge purity. The contacts were segmented using a photolithographic process and then the intrinsic surface between contacts was passivated to assure the electrical insulation between them. A small detector prototype with three segments was made using these new techniques and then successfully tested.
Machine Learning and Physics: A Survey of Integrated Models
Authors: Seyyedi Azra , Bohlouli Mahdi , Oskoee Seyedehsan Nedaaee
Published: August 2023

Predictive modeling of various systems around the world is extremely essential from the physics and engineering perspectives. The recognition of different systems and the capacity to predict their future behavior can lead to numerous significant applications. For the most part, physics is frequently used to model different systems. Using physical modeling can also very well help the resolution of complexity and achieve superior performance with the emerging field of novel artificial intelligence and the challenges associated with it. Physical modeling provides data and knowledge that offer a meaningful and complementary understanding about the system. So, by using enriched data and training phases, the overall general integrated model achieves enhanced accuracy. The effectiveness of hybrid physics-guided or machine learning-guided models has been validated by experimental results of diverse use cases. Increased accuracy, interpretability, and transparency are the results of such hybrid models. In this article, we provide a detailed overview of how machine learning and physics can be integrated into an interactive approach. Regarding this, we propose a classification of possible interactions between physical modeling and machine learning techniques. Our classification includes three types of approaches: (1) physics-guided machine learning (2) machine learning-guided physics, and (3) mutually-guided physics and ML. We studied the models and specifications for each of these three approaches in-depth for this survey.
Exploring progressive mental model representation of core physiology concepts in physician assistant students through word frequency and association analyses
Authors: Murphy Michelle Pauley , Hung Woei
Published: August 2023

This study applies text mining, an artificial intelligence form of natural language processing, to evaluate a series of physiology student-written prompt completions. Text mining of student writing in physiology has not yet been reported in the literature. Through the application of this technique, longitudinal trends in student development of mental models of core concepts were identified and visualized through word frequency distributions and cluster dendrograms.
Validation of a Cost-Effective RP-HPLC Method for Quantitative Investigation of Daclatasvir Dihydrochloride in Pharmaceutical Formulations
Authors: Sarfraz Sadaf , Saeed Muhammad , Javed Mohsin , Hussain Nadia , Iqbal Shahid , Amin Shahid , Bahadur Ali , Jawhari Ahmed Hussain , Althobiti Randa A. , Alzahrani Eman , Farouk Abd-ElAziem , Aljazzar Samar O. , Elkaeed Eslam B.
Published: August 2023

A well-known direct-acting antiviral (DAA) drug called daclatasvir may be used to treat chronic hepatitis C virus (HCV) infection. Herein, we reported a selective, precise, and a cost-effective analytical method for the measurement of an active pharmaceutical ingredient (API) of daclatasvir dihydrochloride in drug substances as well as drug products via the reversed-phase RP-HPLC technique. To obtain greater separation, the majority of the chromatographic conditions were improved. Best separation findings were achieved under chromatographic conditions with an HPLC column of USP L1 (150 × 4.6 mm, 5 μm) by utilizing a combination of acetonitrile and buffer solution of KH2PO4 (30 : 70, v/v) as a mobile phase at a stream rate of 1 mL.min−1 with a finding at 300 nm and a column temperature of 40°C. Linearity was examined in the range of 90–210 ppm (R2 = 0.999) for daclatasvir dihydrochloride. The new technique has been verified using industry-recognized criteria, including applicability, system precision, accuracy, robustness, specificity, range, linearity, quantification limit, reagent stability, and detection limit. All the measured metrics were determined to be within acceptable limits using the criteria of the Worldwide Council for Harmonisation (ICH). In pharmaceutical labs, daclatasvir dihydrochloride may be analyzed qualitatively and quantitatively using the well-established RP-HPLC technique. Our study also highlights the need to evaluate the greenness of the method developed using a recognized tool ,i.e., Analytical Greenness Metrics (AGREE).
Effects of pH, Total Soluble Solids, and Pectin Concentration on Color, Texture, Vitamin C, and Sensory Quality of Mango Fruit Bar
Authors: Vu Ngoc Duc , Nguyen Van Muoi , Tran Thanh Truc
Published: August 2023

Mango purée is a byproduct of the current production processes (such as freeze-drying, dehydration) after the product shaping stage or grades II and III mangoes. Currently, fruit bar is a convenient and highly nutritious snack made from fruit. The objective of this study is to utilize mango byproduct in order to develop a fruit bar processing technology, which is based on evaluating the quality (color, break force, vitamin C content, and sensory) when varying the pH of mango purée and the concentration of added pectin. Additionally, total soluble solids (TSS) after blending at 80°C were also investigated. The increase in pH, pectin concentration of mango purée, and TSS after blending showed that vitamin C content in fruit bars tended to decrease. TSS results revealed that at

TSS
=
63

°Bx, pH 3.3, and a pectin concentration of 1.3%, the product received a high rating of 6.3. Additionally, the vitamin C content of the product reached 7.82 mg/100 gDW. The results of this study are expected on the diversification of products from mango. Solving the situation that grades II and III mangoes are difficult to be commercialized and making the most of the byproduct mango flesh after certain production processes.
Analysis of Household Daily Water Consumption Dynamics in the Tropical Environment
Authors: Ogunbode Timothy O. , Oyebamiji Victor O. , Oluwole Olumide A. , Akande John A.
Published: August 2023

Understanding daily water use determinants is critical to sustainable water access and its efficient use at household level. To pursue this objective, primary data were generated through a survey of 276 respondents across the 5 quarters into which the city of Iwo is divided. 67.5% of the respondents were between 19 and 45 years old while 35.5% were between 46 and 65 years old and the remaining 3.9% comprised of those above 65 years. The results of factor analysis (FA) showed that 12 of the 40 factors analyzed were significant determinants of daily water use in homes. The 12 factors explained 85.794% of the observed variation in household daily water use. The factors in descending order were (i) closeness to water source; (ii) night time baths; (iii) household cooking; (iv) Sunday activities; (v) water demands of the dry season; (vi) morning time water use; (vii) household size; (viii) respondents’ attitude; (ix) water availability in the dry season; (x) break in water flow; (xi) social events; and (xii) source of water. Further evaluation condensed the results into four categories, namely, (i) season-associated information; (ii) household-related information; (iii) time of the day; and (iv) water source-related information. The result of correlation analysis showed weak associations among 83.33% of the variables, indicating that each variable should be treated separately from others in the matter relating to daily variation in home water use. The study concluded that household-related information and time of the day (contributing 62.02% of the absolute explanation) are most significant to daily variation in water use at the household level and should be considered when prioritizing effective policies for water use and management.
A Phase II Trial of the CD40 Agonistic Antibody Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Confirmed Disease Progression on Anti-PD-1 Therapy
Authors: Weiss Sarah A. , Sznol Mario , Shaheen Montaser , Berciano-Guerrero Miguel-Ángel , Couselo Eva Muñoz , Rodríguez-Abreu Delvys , Boni Valentina , Schuchter Lynn M. , Gonzalez-Cao Maria , Arance Ana , Wei Wei , Ganti Apar Kishor , Hauke Ralph J. , Berrocal Alfonso , Iannotti Nicholas O. , Hsu Frank J. , Kluger Harriet M.
Published: August 2023

Purpose:

Disease progression during or after anti-PD-1-based treatment is common in advanced melanoma. Sotigalimab is a CD40 agonist antibody with a unique epitope specificity and Fc receptor binding profile optimized for activation of CD40-expressing antigen-presenting cells. Preclinical data indicated that CD40 agonists combined with anti-PD1 could overcome resistance to anti-PD-1.

Patients and Methods:

We conducted a multicenter, open-label, phase II trial to evaluate the combination of sotigalimab 0.3 mg/kg and nivolumab 360 mg every 3 weeks in patients with advanced melanoma following confirmed disease progression on a PD-1 inhibitor. The primary objective was to determine the objective response rate (ORR).

Results:

Thirty-eight subjects were enrolled and evaluable for safety. Thirty-three were evaluable for activity. Five confirmed partial responses (PR) were observed for an ORR of 15%. Two PRs are ongoing at 45.9+ and 26+ months, whereas the other three responders relapsed at 41.1, 18.7, and 18.4 months. The median duration of response was at least 26 months. Two additional patients had stable disease for >6 months. Thirty-four patients (89%) experienced at least one adverse event (AE), and 13% experienced a grade 3 AE related to sotigalimab. The most common AEs were pyrexia, chills, nausea, fatigue, pruritus, elevated liver function, rash, vomiting, headache, arthralgia, asthenia, myalgia, and diarrhea. There were no treatment-related SAEs, deaths, or discontinuation of sotigalimab due to AEs.

Conclusions:

Sotigalimab plus nivolumab had a favorable safety profile consistent with the toxicity profiles of each agent. The combination resulted in durable and prolonged responses in a subset of patients with anti-PD-1-resistant melanoma, warranting further evaluation in this setting.

See related commentary by Wu and Luke, p. 9
Treatment Response in First-Line Metastatic Pancreatic Ductal Adenocarcinoma Is Stratified By a Composite Index of Tumor Proliferation and CD8 T-Cell Infiltration
Authors: Beatty Gregory L. , Delman Devora , Yu Jiayi , Liu Mingen , Li Joey H. , Zhang Liti , Lee Jae W. , Chang Renee B. , Bahary Nathan , Kennedy Eugene P. , Wang-Gillam Andrea , Rossi Gabriela R. , Garrido-Laguna Ignacio
Published: August 2023

Purpose:

Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting.

Experimental Design:

Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing.

Results:

Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome.

Conclusions:

Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.
Data from Granulocyte–Macrophage Colony-Stimulating Factor Influence on Soluble and Membrane-Bound ICOS in Combination with Immune Checkpoint Blockade
Authors: Li Xiaoyu , Li Jingjing , Zheng Yue , Lee Sandra J. , Zhou Jun , Giobbie-Hurder Anita , Butterfield Lisa H. , Dranoff Glenn , Hodi F. Stephen
Published: August 2023

Abstract
With the successful development of immune checkpoint blockade, there remains the continued need to improve efficacy and decrease toxicities. The addition of granulocyte–macrophage colony-stimulating factor (GM-CSF) to ipilimumab has previously demonstrated both an improvement in efficacy and decrease in the incidence of high-grade adverse events. ICOS+CD4+ or ICOS+CD8+ peripheral blood T cells are significantly greater in the patients treated with ipilimumab plus GM-CSF than in the patients treated with ipilimumab alone. To better understand the effects of GM-CSF on inducible T-cell costimulator (ICOS) and clinical outcomes, the relative roles of identified soluble ICOS and membrane-bound ICOS were evaluated. The ICOS splice variant was secreted and found to have immunologic suppressive effects. Changes in soluble ICOS splice variant levels in treated patients correlated with clinical outcomes. GM-CSF enhanced membrane-bound ICOS in an IL12-dependent manner but did not increase soluble ICOS levels. Whereas soluble ICOS plays a role in immune suppression, GM-CSF efficacy involves increasing membrane-bound ICOS and induction of dendritic cell development. Thus, soluble ICOS splice variants may be used as a biomarker for GM-CSF and immune checkpoint blockade–based therapies.
Data from Small Gene Networks Delineate Immune Cell States and Characterize Immunotherapy Response in Melanoma
Authors: Egan Donagh , Kreileder Martina , Nabhan Myriam , Iglesias-Martinez Luis F. , Dovedi Simon J. , Valge-Archer Viia , Grover Amit , Wilkinson Robert W. , Slidel Timothy , Bendtsen Claus , Barrett Ian P. , Brennan Donal J. , Kolch Walter , Zhernovkov Vadim
Published: August 2023

Abstract
Single-cell technologies have elucidated mechanisms responsible for immune checkpoint inhibitor (ICI) response, but are not amenable to a clinical diagnostic setting. In contrast, bulk RNA sequencing (RNA-seq) is now routine for research and clinical applications. Our workflow uses transcription factor (TF)–directed coexpression networks (regulons) inferred from single-cell RNA-seq data to deconvolute immune functional states from bulk RNA-seq data. Regulons preserve the phenotypic variation in CD45+ immune cells from metastatic melanoma samples (n = 19, discovery dataset) treated with ICIs, despite reducing dimensionality by >100-fold. Four cell states, termed exhausted T cells, monocyte lineage cells, memory T cells, and B cells were associated with therapy response, and were characterized by differentially active and cell state–specific regulons. Clustering of bulk RNA-seq melanoma samples from four independent studies (n = 209, validation dataset) according to regulon-inferred scores identified four groups with significantly different response outcomes (P < 0.001). An intercellular link was established between exhausted T cells and monocyte lineage cells, whereby their cell numbers were correlated, and exhausted T cells predicted prognosis as a function of monocyte lineage cell number. The ligand–receptor expression analysis suggested that monocyte lineage cells drive exhausted T cells into terminal exhaustion through programs that regulate antigen presentation, chronic inflammation, and negative costimulation. Together, our results demonstrate how regulon-based characterization of cell states provide robust and functionally informative markers that can deconvolve bulk RNA-seq data to identify ICI responders.
Tusamitamab Ravtansine in Patients with Advanced Solid Tumors: Phase I Study of Safety, Pharmacokinetics, and Antitumor Activity Using Alternative Dosing Regimens
Authors: Tabernero Josep , Bedard Philippe L. , Bang Yung-Jue , Vieito Maria , Ryu Min-Hee , Fagniez Nathalie , Chadjaa Mustapha , Soufflet Christine , Masson Nina , Gazzah Anas
Published: August 2023

Purpose:

Tusamitamab ravtansine is an antibody–drug conjugate that targets carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) and delivers a cytotoxic maytansinoid payload. In a phase I dose-escalation study, the maximum tolerated dose (MTD) was 100 mg/m2 every 2 weeks (Q2W). Here we report results for two alternative schedules.

Experimental Design:

Adults ages ≥18 years (range, 34–73) with locally advanced/metastatic solid tumors (N = 43; colon/rectum, 29; stomach, 7; pancreas, 4; other, 3) expressing/likely to express CEACAM5 received intravenous tusamitamab ravtansine 120–170 mg/m2 [loading dose (LD)], then 100 mg/m2 Q2W (Q2W-LD, n = 28), or 120–190 mg/m2 fixed dose [every 3 weeks (Q3W), n = 15]. The primary endpoint was dose-limiting toxicities (DLTs) during cycles 1–2 (Q2W-LD) and cycle 1 (Q3W).

Results:

Reversible DLTs were observed in 2 of 9 patients (grade 2 keratopathy; grade 2 keratitis) with 170 mg/m2 in Q2W-LD and in 2 of 3 patients (grade 2 keratopathy; grade 3 transaminase elevation) with 190 mg/m2 in Q3W. Nineteen (67.9%) patients in Q2W-LD and 13 (86.7%) patients in Q3W experienced treatment-related adverse events (AE); 3 of 43 patients discontinued treatment because of AEs. The most common AEs were asthenia, gastrointestinal complaints, keratopathy, keratitis, and peripheral sensory neuropathy. In this small, heavily pretreated population, no confirmed responses were observed; however, stable disease occurred in 35.7% of patients in Q2W-LD and 40.0% of patients in Q3W.

Conclusions:

Tusamitamab ravtansine had a favorable safety profile with both alternative administration schedules; MTDs were 170 mg/m2 (LD) followed by 100 mg/m2 Q2W, and 170 mg/m2 Q3W as a fixed dose. (NCT02187848).

Significance:

The collective results of this phase I dose-escalation study will inform further studies of tusamitamab ravtansine in patients with solid tumors with CEACAM5 expression, including patients with non–small cell lung cancer.
An effective gossip routing based wireless sensor network framework for forest fire detection
Authors: Alagarsamy Manjunathan , Selvaraj Sinnasamy Sathya , Gopal Indhumathi , Kuppusamy Radhika , Haffishthullah Anwar Basha , Suriyan Kannadhasan
Published: August 2023

This research looks about a counsel structure that uses degree-supervised snitch to consider allocated sensor networks. Level managed snitch is a proposed process that combines evening out and invading together. This strategy reduces the number of possible messages by delivering them via the base station mechanism, hence increasing the sensor neighborhood’s presence time. The sensor district, which contains numerous sensor centers, is dynamically assigned into phases of extended clear by the use of various energy ranges at the base station. The game design divides the entire sensor neighborhood into distinct concentric zones based on distance from the base station, with the group being routed from high-capacity center to center locations within the lower-capacity zone. The transmission of information proximity of the forest fire to the base station will increase the opportunity. The primary benefit of the display is that it sends a basic event with a higher probability while also conserving the presence time of the neighborhood destiny noticing.
Experimental study on the effects of injection timing using reuse of waste energy as a fuel on a diesel engine
Authors: Subrahmanyam Dvsrbm , Manikandan Jagadeesh
Published: August 2023

In the course of this study, an eco-friendly alternative fuel was manufactured by transesterifying waste oils with the help of alcohol and a catalyst. As required by the American society for testing and materials (ASTM) requirements, we conducted an analysis on the acquired waste cooking oil biofuel (WOB) to determine its most important properties. We were successful in producing three separate fuel mixes, which we will refer to as BF100WOB0 (100% diesel), BF80WOB20 (80% diesel and 20% biofuel), and BF0WOB100 (100% biofuel) respectively. This research used a diesel engine with direct injection; the engine had a single cylinder, and the computer that operated it was located in the cabin. The results showed that the BF80WOB20 had a 3.8% increase in fuel consumption and a 1.4% loss in thermal efficiency while it was at a temperature of 26.5° b top dead center (TDC) conditions with low injection time led to decreased levels of both nitrogen oxides (NOx) and hartridge smoke level (HSL) emissions. The addition of 20% WOB to the fundamental fuel improved the engine combustion characteristics at 26.5° b TDC. This improvement occurred at the same time.
Suplicy de Lacerda e Vieira Netto: dois modelos de intervenção intelectual (Paraná, 1940-1970)
Authors: Costa Regis Clemente da , Souza Eliezer Felix de , Campos Névio de
Published: August 2023

Este artigo discute a intervenção política de Suplicy de Lacerda e Vieira Netto, no contexto paranaense entre as décadas de 1940 e 1970. Apoia-se em fontes históricas e nos conceitos de intelectual guardião da ordem moralizador ou de instituição e intelectual orgânico para problematizar os modos de atuação política dessas desses dois professores da Universidade Federal do Paraná. Assim, de um lado pode-se dizer que Suplicy de Lacerda personifica o modelo de intelectual que defende a universidade em nome de valores que ele considerava de ordem suprema (nação), cujo resultado foi a submissão dos interesses acadêmicos à lógica do campo político. De outro que Vieira Netto simboliza o intelectual orgânico, cuja preocupação é mostrar que conhecimento e interesse social são indissociáveis, evidenciando uma crítica à ideia de existência de neutralidade dos valores e a dessacralização da autorrepresentação do intelectual guardião da ordem moralizador.
Historia intelectual, entre alcances y límites. El accionar de los sujetos para la determinación de lo político.
Authors: Sánchez Eduardo Nazareno
Published: August 2023

Uno de los aportes más relevantes del pensamiento posfundacional y de la historia intelectual ha sido reflexionar sobre la construcción de todo orden político, en los términos de Carl Schmitt, el cual es resultado del accionar de los sujetos históricos; especialmente de los intelectuales ya que son los encargados de elaborar determinados discursos, siempre en circunstancias concretas y delimitadas, que dan forma al entramado político y social que ellos mismos integran. Por lo tanto, siempre existe una fisura en lo político que es necesaria para su funcionamiento porque permite la actuación de hombres y mujeres, pero, al mismo tiempo, es la que se intenta resolver a la hora de elaborar un orden que permita la vida en comunidad. En resumidas cuentas, lo político siempre es contingente y son los sujetos los encargados de actuar en dichas circunstancias.
Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: The CAMEO-DAPA Trial
Authors: Borlaug Barry A. , Reddy Yogesh N.V. , Braun Amanda , Sorimachi Hidemi , Omar Massar , Popovic Dejana , Alogna Alessio , Jensen Michael D. , Carter Rickey
Published: August 2023

BACKGROUND:

Sodium-glucose cotransporter-2 inhibitors reduce risk of hospitalization for heart failure in patients who have heart failure with preserved ejection fraction (HFpEF), but the hemodynamic mechanisms underlying these benefits remain unclear. This study sought to determine whether treatment with dapagliflozin affects pulmonary capillary wedge pressure (PCWP) at rest and during exercise in patients with HFpEF.

METHODS:

This was a single-center, double-blinded, randomized, placebo-controlled trial testing the effects of 10 mg of dapagliflozin once daily in patients with HFpEF. Patients with New York Heart Association class II or III heart failure, ejection fraction ≥50%, and elevated PCWP during exercise were recruited. Cardiac hemodynamics were measured at rest and during exercise using high-fidelity micromanometers at baseline and after 24 weeks of treatment. The primary end point was a change from baseline in rest and peak exercise PCWPs that incorporated both measurements, and was compared using a mixed-model likelihood ratio test. Key secondary end points included body weight and directly measured blood and plasma volumes. Expired gas analysis was performed evaluate oxygen transport in tandem with arterial lactate sampling.

RESULTS:

Among 38 patients completing baseline assessments (median age 68 years; 66% women; 71% obese), 37 completed the trial. Treatment with dapagliflozin resulted in reduction in the primary end point of change in PCWP at rest and during exercise at 24 weeks relative to treatment with placebo (likelihood ratio test for overall changes in PCWP;
P
<0.001), with lower PCWP at rest (estimated treatment difference [ETD], −3.5 mm Hg [95% CI, −6.6 to −0.4];
P
=0.029) and maximal exercise (ETD, −5.7 mm Hg [95% CI, −10.8 to −0.7];
P
=0.027). Body weight was reduced with dapagliflozin (ETD, −3.5 kg [95% CI, −5.9 to −1.1];
P
=0.006), as was plasma volume (ETD, −285 mL [95% CI, −510 to −60];
P
=0.014), but there was no significant effect on red blood cell volume. There were no differences in oxygen consumption at 20-W or peak exercise, but dapagliflozin decreased arterial lactate at 20 W (−0.70 ± 0.77 versus 0.37 ± 1.29 mM;
P
=0.006).

CONCLUSIONS:

In patients with HFpEF, treatment with dapagliflozin reduces resting and exercise PCWP, along with the favorable effects on plasma volume and body weight. These findings provide new insight into the hemodynamic mechanisms of benefit with sodium-glucose cotransporter-2 inhibitors in HFpEF.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04730947.
Behaviors and Attitudes Towards Companion Animals During COVID-19: An Exploratory Study in Portugal
Authors: Duarte Vera , Costa Susana , Cardoso Catarina , Soares Mariana
Published: August 2023

The COVID-19 pandemic declared by the World Health Organization in March 2020 caused many uncertainties. Threatening the wellbeing of both people and their companion animals, the pandemic raised many questions about the role of the interactions and relationships between humans and companion animals in the context of social distancing and all the restrictions it imposes. It was in this setting that an online questionnaire about the behaviors and attitudes toward companion animals during the first lockdown of the coronavirus pandemic in Portugal was developed. The questionnaire received 2,198 validated responses. Four main behaviors and attitudes toward companion animals were identified, comparing the periods before and during the first lockdown: 1) a greater human-animal proximity; 2) a greater confinement of humans and companion animals; 3) the “other” as a threat and the depletion of the support network/system; and 4) increased hygiene practices/decreased healthcare.