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Coronavirus disease 2019 (COVID-19), which began in China, caused a global pandemic. Few studies have shown the benefit of hydroxychloroquine (HY) ± azithromycin (AZ) for treating COVID-19. Concerns of QT prolongation and increased risks of torsade’s de pointes (TdP) with this combination have been raised since each agent can individually prolong the QT interval. This retrospective, observational study included hospitalized patients treated with HY and AZ from March 2020 to May 2020 at a large community hospital. Serial assessments of the QT interval were performed. Our aim is to evaluate the safety and characterize the change in QTc interval and arrhythmic events in COVID-19 patients treated with HY/AZ. A total of 21 COVID patients who received at least four days of HY and AZ were included in this study. Mean baseline was QTc 403 ms, mean maximum QTc was 440 ms, mean change in QTc was 36 ms. Only one patient (4.8%) developed prolonged QTc > 500 ms. No patient had a change in QTc of 60 ms or more. No patient developed TdP. Fifteen patients (71.4%) had hypoxia on admission, with only two patients (9.5%) required oxygen of 1−2 L at discharge. 80.9% of patients have been discharged home or inpatient rehabilitation.

Multiple myeloma (MM) is twice as common in Black individuals compared with in White individuals, and diabetes mellitus (DM) disproportionately affects Black patients. Although numerous studies have shown a correlation between DM and MM, this has not been studied in the context of race and in vivo mechanisms. We conducted a retrospective clinical study of 5383 patients with MM of which 15% had DM (White, 12% and Black, 25%). Multivariable Cox models showed reduced overall survival (OS) for patients with DM (hazard ratio, 1.27; 95% confidence interval, 1.11-1.47; P < .001). This appeared to be driven by a marked difference in OS between White patients with and without DM but not in Black patients. In contrast, obesity was associated with better OS in Black patients but not in White patients. To complement this analysis, we assessed MM growth in a genetically engineered immunocompromised nonobese diabetic (Rag1-/-/muscle creatinine kinase promoter expression of a human IGF1R [M] with a lysine [K] to arginine [R] point mutation) mouse model to evaluate the mechanisms linking DM and MM. MM.1S xenografts grew in more Rag1-/-/MKR mice and grew more rapidly in the Rag1-/-/MKR mice compared with in controls. Western blot analysis found that MM1.S xenografts from Rag1-/-/MKR mice had higher phosphorylated S6 ribosomal protein (Ser235/236) levels, indicating greater activation of the mammalian target of rapamycin pathway. Our study is, to our knowledge, the first to evaluate racial differences in DM prevalence and survival in MM, as well as the effect of DM on tumor growth in mouse models. Our results suggest that DM may contribute to the higher incidence of MM in Black patients; and to improve survival in MM, DM management cannot be ignored.

Abstract The Druze are a distinct group known for their close community, traditions, and consanguineous marriages, dating back to the eleventh century. This practice has led to unique genetic variations, impacting both pathology and gene-associated phenotypes. Some Druze clans, particularly those with exceptional long-lived family heads (ELLI), attracted attention. Given that the bulk of these ELLI were men, the d3GHR polymorphism was the first obvious possibility. Among the 73 clan members, 8.2% carried the d3GHR isoform, with nearly 11% being males. There was a significant age-related increase (p = 0.04) in this isoform among males, leading to examination of potential environmental mediators affecting gene regulation among these carriers during life (namely epigenetic). We focused on DNA methylation due to its crucial role in gene regulation, development, and disease progression. We analyzed DNA samples from 14 clan members with different GHR genotypes, finding a significant (p

Abstract Acute respiratory distress syndrome (ARDS) is a devastating critical care syndrome with significant morbidity and mortality. The objective of this study was to evaluate the predictive values of dynamic clinical indices by developing machine-learning (ML) models for early and accurate clinical assessment of the disease prognosis of ARDS. We conducted a retrospective observational study by applying dynamic clinical data collected in the ARDSNet FACTT Trial (n = 1000) to ML-based algorithms for predicting mortality. In order to compare the significance of clinical features dynamically, we further applied the random forest (RF) model to nine selected clinical parameters acquired at baseline and day 3 independently. An RF model trained using clinical data collected at day 3 showed improved performance and prognostication efficacy (area under the curve [AUC]: 0.84, 95% CI: 0.78–0.89) compared to baseline with an AUC value of 0.72 (95% CI: 0.65–0.78). Mean airway pressure (MAP), bicarbonate, age, platelet count, albumin, heart rate, and glucose were the most significant clinical indicators associated with mortality at day 3. Thus, clinical features collected early (day 3) improved performance of integrative ML models with better prognostication for mortality. Among these, MAP represented the most important feature for ARDS patients’ early risk stratification.

Ahmed AK Hassoun,1 Md Faruque Pathan,2 Rita C Medlej,3,4 Monira Alarouj,5 Inass Shaltout,6 Manoj S Chawla,7 Ditte Knap,8 Julius A Vaz9 1Dubai Diabetes Centre, Dubai, UAE; 2Department of Endocrinology, BIRDEM Hospital, Dhaka, Bangladesh; 3Department of Endocrinology, Hotel Dieu de France Hospital, 4Chronic Care Centre, Saint Joseph University, Beirut, Lebanon; 5Dasman Diabetes Institute, Dasman, Kuwait; 6Faculty of Medicine, Cairo University, Cairo, Egypt; 7Lina Diabetes Care Centre, Mumbai, India; 8Novartis Pharma AG, Basel, Switzerland; 9Novartis Healthcare Private Limited, Hyderabad, India Background: VIRTUE was a prospective, observational study assessing the effectiveness and safety of vildagliptin vs sulfonylureas (SUs) (both as monotherapy and in combination with metformin) in patients with type 2 diabetes mellitus who fasted during Ramadan. A post hoc analysis was carried out to assess the effect of treatment with/without metformin and age (

This study examines the impact of conventional and sustainable olive oil production methods on export levels in ten Mediterranean countries from 2011 to 2022. Using panelcorrected standard errors (PCSE) and feasible generalized least squares (FGLS), the analysis explores relationships between export quantity, production volume, average annual rainfall, and export levels. The countries are divided into two sub-panels: conventional and sustainable practices. Results reveal a significant positive relationship between export quantity and export levels. In the sustainable sub-panel, the production volume and export relationship are positive but insignificant, while in the conventional sub-panel, it is negative and insignificant. Average annual rainfall positively influences export levels in the conventional panel but has an insignificant effect in the sustainable panel. The study recommends adopting sustainable practices to enhance export levels due to their positive economic and environmental outcomes.

Abstract Background Infections due to Citrobacter species are increasingly observed in hospitalized patients and are often multidrug-resistant. Yet, the magnitude and burden of Citrobacter spp. resistance in the hospital setting have not been reported. We aimed to evaluate the epidemiology of Citrobacter spp. infections among hospitalized patients, their main resistance patterns and Citrobacter spp. involvement in hospital outbreaks. Methods We conducted a systematic review and meta-analysis of published literature (PROSPERO registration Jan-2023, CRD42023390084). We searched Embase, Medline and grey literature for studies on hospitalized patients diagnosed with Citrobacter spp. infections, and nosocomial outbreaks due to Citrobacter spp. published during the years 2000–2022. We included observational, interventional, surveillance studies and outbreak reports. Outcomes of interest were the frequency of Citrobacter spp. infections among hospitalized patients and 3rd generation cephalosporin and/or carbapenem resistance percentages in these infections. We used random-effects models to generate pooled outcome estimates and evaluated risk of bias and quality of reporting of outbreaks. Results We screened 1609 deduplicated publications, assessed 148 full-texts, and included 41 studies (15 observational, 13 surveillance and 13 outbreak studies). Citrobacter spp. urinary tract- and bloodstream infections were most frequently reported, with Citrobacter freundii being the main causative species. Hospital-acquired infection occurred in 85% (838/990) of hospitalized patients with Citrobacter infection. After 2010, an increasing number of patients with Citrobacter spp. infections was reported in observational studies. Pooled frequency estimates for Citrobacter spp. infections could not be generated due to lack of data. The pooled prevalence of ESBL and carbapenemase producers among Citrobacter isolates were 22% (95%CI 4–50%, 7 studies) and 18% (95%CI 0–63%, 4 studies), respectively. An increased frequency of reported Citrobacter outbreaks was observed after 2016, with an infection/colonization ratio of 1:3 and a case-fatality ratio of 7% (6/89 patients). Common outbreak sources were sinks, toilets, contaminated food and injection material. Implemented preventive measures included environmental cleaning, isolation of positive patients and reinforcement of hand hygiene. Only seven out of 13 outbreaks (54%) were definitively controlled. Conclusion This review highlights the clinical importance of endemic and epidemic Citrobacter spp. in healthcare settings. As an emerging, multidrug‑resistant nosocomial pathogen it requires heightened awareness and further dedicated surveillance efforts.

Abstract Background Abnormal remodeling of distal pulmonary arteries in patients with pulmonary arterial hypertension (PAH) leads to progressively increased pulmonary vascular resistance, followed by right ventricular hypertrophy and failure. Despite considerable advancements in PAH treatment prognosis remains poor. We aim to evaluate the potential for using the cytokine resistin as a genetic and biological marker for disease severity and survival in a large cohort of patients with PAH. Methods Biospecimens, clinical, and genetic data for 1121 adults with PAH, including 808 with idiopathic PAH (IPAH) and 313 with scleroderma-associated PAH (SSc-PAH), were obtained from a national repository. Serum resistin levels were measured by ELISA, and associations between resistin levels, clinical variables, and single nucleotide polymorphism genotypes were examined with multivariable regression models. Machine-learning (ML) algorithms were applied to develop and compare risk models for mortality prediction. Results Resistin levels were significantly higher in all PAH samples and PAH subtype (IPAH and SSc-PAH) samples than in controls (P

Abstract Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017–March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36–1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Abstract B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25−0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31−3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05–3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21−0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17–0.59, P

Abstract Despite significant advances in reconstructing genome-scale metabolic networks, the understanding of cellular metabolism remains incomplete for many organisms. A promising approach for elucidating cellular metabolism is analysing the full scope of enzyme promiscuity, which exploits the capacity of enzymes to bind to non-annotated substrates and generate novel reactions. To guide time-consuming costly experimentation, different computational methods have been proposed for exploring enzyme promiscuity. One relevant algorithm is PROXIMAL, which strongly relies on KEGG to define generic reaction rules and link specific molecular substructures with associated chemical transformations. Here, we present a completely new pipeline, PROXIMAL2, which overcomes the dependency on KEGG data. In addition, PROXIMAL2 introduces two relevant improvements with respect to the former version: i) correct treatment of multi-step reactions and ii) tracking of electric charges in the transformations. We compare PROXIMAL and PROXIMAL2 in recovering annotated products from substrates in KEGG reactions, finding a highly significant improvement in the level of accuracy. We then applied PROXIMAL2 to predict degradation reactions of phenolic compounds in the human gut microbiota. The results were compared to RetroPath RL, a different and relevant enzyme promiscuity method. We found a significant overlap between these two methods but also complementary results, which open new research directions into this relevant question in nutrition.

Abstract Anaesthetics are used daily in human and veterinary medicine as well as in scientific research. Anaesthetics have an impact on cell homeostasis especially through modulation of protein post-translational modifications. O-GlcNAcylation, a ubiquitous post-translational modification, plays a role in many biological processes. The aims of this study were to evaluate whether (1) anaesthesia influences O-GlcNAcylation and (2) its stimulation affects physiological parameters. Male Wistar rats (n = 38) were anaesthetized with ketamine-xylazine or isoflurane. They randomly received either an intravenous injection of Ringer's lactate or NButGT (10mg/kg) in order to increase O-GlcNAcylation levels. One hour after induction of anaesthesia, haemodynamic parameters and plasmatic markers were evaluated. Heart, brain and lungs were harvested and O-GlcNAcylation levels and O-GlcNAc-related enzymes were evaluated by western blot. Cardiac and pulmonary O-GlcNAcylation levels and cardiac, cerebral and pulmonary O-GlcNAc associated enzyme expression were not impacted with anaesthesia. Compared with ketamine-xylazine, isoflurane had a lower impact on blood pressure, heart rate and glycaemia. Pharmacological stimulation of O-GlcNAcylation by NButGT did not affect the physiological parameters. This study offers unprecedented insights into the regulation of O-GlcNAcylation and O-GlcNAc related enzymes during anaesthesia. Pharmacological stimulation of O-GlcNAcylation over a 1-h period did not disrupt the physiological balance in healthy anaesthetized rats.

The fourth industrial revolution (Industry 4.0) is driving significant changes across multiple sectors, including the food industry. This review examines how Industry 4.0 technologies, such as smart sensors, artificial intelligence, robotics, and blockchain, among others, are transforming unit operations within the food sector. These operations, which include preparation, processing/transformation, preservation/stabilization, and packaging and transportation, are crucial for converting raw materials into high-quality food products. By incorporating advanced digital, physical, and biological innovations, Industry 4.0 technologies are enhancing precision, productivity, and environmental responsibility in food production. The review highlights innovative applications and key findings that showcase how these technologies can streamline processes, minimize waste, and improve food product quality. The adoption of Industry 4.0 innovations is increasingly reshaping the way food is prepared, transformed, preserved, packaged, and transported to the final consumer. The work provides a valuable roadmap for various sectors within agriculture and food industries, promoting the adoption of Industry 4.0 solutions to enhance efficiency, quality, and sustainability throughout the entire food supply chain.

The EU funded project EuroSea brought together key actors of the European ocean observing and forecasting communities with key users of the ocean observing products and services in order to better integrate existing ocean observation systems and tools, and to improve the delivery of ocean information to users. EuroSea was constructed around the ocean observing value chain that connects observations to users of ocean information, and, just as intended, the value chain concept was a useful prism to improve the system. In this article, we summarize some of the main take-home messages from EuroSea on the needs for developing the European Ocean Observing System and its links with modeling and forecasting systems. During the project, the challenges and gaps in the design and coordination of the European ocean observing and forecasting system were identified and mapped. Many gaps and challenges related to the observations of physical, chemical and biological Essential Ocean Variables were identified. Some of these gaps are related to technological developments, while others are caused by insufficient and short-term funding leading to a not sustainable system, management, and cooperation between different entities, as well as limitations in foresight activities, policies and decisions. This article represents a compilation of the broader needs for advancing the observing and forecasting system, and is meant as a guide for the community, and to funders and investors to advance ocean observing and the delivery of ocean information in Europe. To enhance the sustainability of ocean observations, which is paramount for a reliable provision of quality oceanographic data and services, several recommendations were compiled for ocean observing networks, frameworks, initiatives, as well as the ocean observing funders within the European nations, and the European Commission.

Not available.

Although the rapid growth in the efficiency of medical imaging is undeniable, the expansion of health information technology (HIT) into medical imaging has not been as seamless or well-integrated as it was thought to be. The socio-technical complexities in medical imaging associated with HIT systems can cause risks to patient harm and inconvenience, both individually and collectively, often in new, unforeseen, and unexpected ways. This study reflects a retrospectively collected single incident report related to medical imaging HIT systems, aiming to develop a set of preventive and corrective strategies. A combination of multiple deductive approaches (existing frameworks), i.e., HIT Classification Systems and 18-step medical imaging process workflow and inductive method (content analysis), were used to analyze the incident. The incident was identified as a “system configuration”-related software issue, contributed by system upgrade– changes in hardware and software. The incident was determined to occur during steps 10–12, i.e., “study selection and retrieval,” “calling up of patient's referral,” and “image review and interpretation,” causing severe disruptions in the clinical workflow for several weeks. We propose 16 preventive and corrective strategies grouped under four key areas based on the socio-technical aspects associated with HIT systems. The key areas are (i) preparation and integration for upgraded systems, (ii) training for medical imaging specialists, (iii) contingency planning/immediate backup system, and (iv) system design and configuration. These strategies are expected to help healthcare staff, analysts, reporters, researchers, and relevant stakeholders improve care delivery and patient safety in medical imaging in the context of any system upgrades.

Roller Compacted Concrete (RCC) exhibits many characteristics of both asphalt and rigid pavements, but their use is restricted. Many reasons led to this decision, including the fact that RCC is a type of concrete mixture that requires a specific consistency. It should be firm enough to be compacted by a roller compactor but also have enough moisture to ensure even distribution. The lab-field performance difference of RCC is another reason for decreasing its use. The laboratory RCC mixes are prepared using the modified Proctor compaction method. Subsequently, specimens are fabricated utilizing a vibratory hammer (VH) to evaluate their strength properties. Nevertheless, in the construction industry, pavement is built utilizing static, pneumatic, and vibratory rollers. Consequently, quality control is carried out by acquiring pavement samples and comparing them to laboratory samples. Each of these procedures employs different processes and energies, resulting in variations in field and laboratory behavior. In this investigation, some studies will be discussed about the RCC behavior under field and lab conditions using various design methods, such as the vibrating table (VH), vibratory table (VT), gyratory compactor (GC), and modified proctor (MP). These studies showed a difference in RCC mechanical and macroscale properties between laboratory compaction methods. For instance, VH specimens led to a higher evaluation, while GY specimens produced a less favorable estimation of the hardened properties observed in the field. While the MP and VT compacted specimens had a comparable structural arrangement to the field, they exhibited notable differences in terms of porosity and strength. Other studies revealed the essence of the curing stage in terms of RCC mechanical properties and indicated that some curing processes, like compound curing, may improve RCC performance.

عاث المحتلون الاجانب بالأرض العراقية وعبثوا بذلك الارث الحضاري الكبير ، وتعرض الاحفاد العراقيين الى الكثير من الازمات والحروب والكوارث ، وترسخ ذلك في طبيعة الشخصية العراقية ، ولذلك فقد شابت العلاقة بين الحكام الاجانب والسكان المحليين فتور وتوترات عصيبة أثرت على مختلف مفاصل الحياة ، وكانت سياسة الحكم الاجنبي غير ملائمة للتعامل مع افراد الشعب العراقي الذي يضم خليطا من القوميات والمعتقدات المختلفة ، اذ ظهرت الغاية الاساسية للحكم الاجنبي المتمثلة في السيطرة على الموارد الاقتصادية والبشرية المهمة واستغلالها في ادامة مخططاتهم ، وبرزت معارضة شعبية حقيقية على الرغم من قوة وبطش السلطات الاجنبية الحاكمة ، ولقد شهدت السماوة لاسيما مدة الاحتلال العثماني للعراق أحداثا عديدة سجلتها وثائق الارشيف العثماني والتي بينت مدى سوء الحكومة المحلية وتخبطها في طريقة ادارتها للمنطقة وتعاملها مع السكان .

We study a newsvendor problem with greenhouse gas (GHG) emissions at the disposal stage regulated by a cap-and-trade policy. We first consider a synchronous version of the problem where the replenishment period and the emission assessment period are the same. For this problem, we propose simple algorithms to derive the optimal quantity and cost for both continuous and discrete demand distributions. We show that ignoring the carbon tax may lead to large overcost, especially when the GHG quota is small. For a normally distributed demand, we also show that the demand standard deviation has a non-linear and non-monotonic effect on the order quantity. We then investigate an asynchronous version of the problem where replenishment decisions occur at a higher frequency than the quota allocation. We formulate this lot sizing problem as a Markov decision process and solve it with a dynamic programming algorithm whose complexity is assessed. Through a numerical experimentation and theoretical results, we demonstrate how and when the flexibility of the optimal dynamic replenishment decisions allows to reduce costs. When approaching the end of the time horizon, the uncertainty reduction allows the decision maker to adopt a riskier policy and order larger quantities. [ABSTRACT FROM AUTHOR]