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Abstract Intestinal barrier is a first line of defense that prevents entry of various harmful substances from the lumen into the systemic environment. Impaired barrier function with consequent translocation of harmful substances into systemic circulation (“leaky gut”) is a central theme in many gastrointestinal, autoimmune, mental, and metabolic diseases. Probiotics have emerged as a promising strategy to maintain intestinal integrity and address “leaky gut”. Using in silico, in vitro and avian in vivo analyses, we previously showed that two novel L. reuteri strains, PTA-126787 (L. reuteri 3630) and PTA-126788 (L. reuteri 3632), isolated from broiler chickens possess favorable safety profiles. Consistent with a recent study, here we show that L. reuteri 3630 and 3632 are phylogenetically similar to human L. reuteri strains. Daily administration of high doses of L. reuteri 3630 and 3632 to Sprague Dawley rats for 28 days was found to be safe with no adverse effects. More importantly, administration of L. reuteri 3630 and 3632 significantly reduced markers associated with alcohol-induced leaky gut, by downregulating inflammatory cytokines and upregulating anti-inflammatory cytokines in an alcohol model of leaky gut in mice. While L. reuteri 3630 cells and supernatant showed no activation, L. reuteri 3632 cells but not supernatant showed activation of AhR, a key transcription factor that regulates gut and immune homeostasis. L. reuteri 3630 is creamish white in morphology typical of Lactobacillus species and L. reuteri 3632 displays a unique orange pigmentation, which was stable even after passaging for 480 generations. We identified a rare polyketide biosynthetic gene cluster in L. reuteri 3632 that likely encodes for the orange-pigmented secondary metabolite. Similar to L. reuteri 3632 cells, the purified orange metabolite activated AhR. All together, these data provide evidence on the phylogenetic relatedness, safety, efficacy, and one of the likely mechanisms of action of L. reuteri 3630 and 3632 for potential probiotic applications to address “leaky gut” and associated pathologies in humans.

The public transportation fare in a city is an important determinant of accessibility, equity, and quality of life for its citizens. This article makes a comparative quantitative analysis of the fare of the public transportation system in the city of Bogotá (Colombia), its evolution over time, and the impact on the poorest users. It compares with similar systems in Latin America and other cities in the world. The findings show that the fare has had high growth in US dollars (USD 0.38 in 2000 to 0.75 in 2024), but the purchasing capacity has increased with respect to the local minimum wage (10.84 tickets with a minimum daily wage, versus 14.69 in 2024). This rate is one of the highest in Latin America and has a high impact on lower-income citizens, since the purchase of 50 monthly tickets is equivalent to 15% of the local monthly minimum wage.

Abstract Introduction The aim of this German national guideline is to optimize the clinical care of patients with Parkinson's disease (PD) in terms of diagnostics, drug and surgical treatment and care. Summary or definition of the topic This guidance was prepared for the German Society of Neurology (DGN) in collaboration with the Austrian Society of Neurology (ÖGN) and the Swiss Neurological Society (SNG) for German-speaking countries. The guidelines for the diagnosis and treatment of PD have been revised by a national expert group and the guideline commission of the DGN at S2k level. The main objective of these guidelines is to optimize the clinical care of PD patients regarding diagnosis, including early detection, technical diagnostic examinations, and pharmacological as well as invasive treatment options. Recommendations The updated PD diagnosis and treatment guidelines are emphasizing optimized clinical care. Key revisions include preferring the name "Parkinson's disease" over previous terms and adopting International Parkinson and Movement Disorder Society (MDS) diagnostic criteria. Recommendations cover genetic and imaging diagnostics, initial pharmacotherapy considering efficacy and patient factors, and tailored pharmacological combinations for complications. Guidelines extend to managing cognitive, affective, psychotic, and autonomic symptoms, along with non-oral therapies like pump therapy and deep brain stimulation. Special situations like akinetic crisis, driving ability, and care concepts are addressed, ensuring comprehensive management for PD patients at various stages and conditions. Conclusions This guidance reflects the state of the art at the beginning of 2024.

Abstract The Caribbean‐South America subduction zone is a flat subduction zone, with Laramide‐style thick‐skinned uplifts occurring in the Merida Andes, Sierra de Perija Range, and Santa Marta Massif. Geodetic measurements and historical seismicity show this region is storing strain energy and is capable of a mega‐thrust earthquake (M ≥ 8.0). Previous seismic investigations of the lithosphere and upper mantle in this area are either very large scale, very local, or only peripheral to this area; therefore, details of the Caribbean plate subduction geometry beneath the Maracaibo block remain unclear. In this study, we used a new data set acquired by the Caribbean‐Merida Andes seismic experiment (CARMA), which comprised 65 temporary broadband stations and 44 permanent stations from the Colombian and Venezuelan national seismic networks. We jointly inverted ambient noise Rayleigh wave Z/H ratios, phase velocities in the 8–30 s band and ballistic Rayleigh wave phase velocities in 30–80 s band to construct a 3‐D S‐wave velocity model in the area between 75°–65°W and 5°–12°N. The 3‐D model reveals a general increase in crust thickness from the trench to the southeast. An anomalous area is the Lake Maracaibo, which is underlaid by the thinnest crystalline crust in the region. This observation may indicate that the Maracaibo block is experiencing a contortion deformation within the crust. We also identified a high velocity anomaly above the subducting Caribbean slab, likely representing a detached piece of eclogitized Caribbean large igneous province from the base of the Maracaibo block. Additionally, our Vs model clearly indicates a slab tear within the subducted Caribbean slab, approximately beneath the Oca‐Ancon Fault.

Abstract At many dormant volcanoes, magmatic gases are not channeled through preferential degassing routes as fumaroles and only percolate through the flanks of the volcano in a diffuse way. This type of volcanic gas emission provides valuable information, even though the soil matrix contains an important atmospheric component. This study aimed to demonstrate that chemical ratios such as He/CO2 in soil gases provide excellent information on the evolution of volcanic unrest episodes and help forecast the volcanic eruption onset. Before and during the occurrence of the October 2011–March 2012 submarine of El Hierro, Canary Islands, more than 8500 soil He analyses and diffuse CO2 emission measurements were performed. The results show that the soil He/CO2 emission ratio began increasing drastically one month before eruption onset, reaching the maximum value 10 days before. During the eruptive period, this ratio also showed a maximum value several days before the period with the highest magma emission rate. The He/CO2 ratio was also helpful in forecasting the eruption onset. We demonstrate that this tool can be applied in real-time during volcanic emergencies. Our results also encourage a reevaluation of the global He emission from the subaerial volcanism.

The SKY130 Process Design Kit (PDK) offers limited options for Static Random-Access Memory (SRAM) configurations, providing only three predefined memory sizes: $8\times 1024$ , $32\times 256$ , and $32\times 512$ , this poses a challenge for designers who require memories with different characteristics, as they must either design an entire memory architecture from scratch or resort to interleaving techniques with the available memory configurations. To address this issue, we present a novel framework that automates the generation of multiple memory arrays with custom floorplans, leveraging the concept of interleaving memory. Our framework enables designers to create various sizes and configurations memories by combining and interleaving the existing SKY130 PDK memories, additionally, the framework allows designers to easily specify their desired memory size, word length, floorplan, and other essential parameters. The framework then automatically generates multiple memory arrays that meet the specified requirements. Furthermore, it provides the files required by OpenLane, facilitating the seamless integration of these memories into the Register Transfer Level (RTL) to Graphic Data System II (GDSII) flow. The key advantage of our framework lies in its ability to streamline the creation of custom memories by automating the interleaving process and offering flexibility in floorplan design. This significantly reduces design time and effort, empowering designers to efficiently create memories with specific characteristics while adhering to the limitations of the SKY130 PDK. The framework thus serves as a valuable tool for memory design in the context of the SKY130 PDK, opening doors for more efficient and optimized chip designs.

This article introduces, models, and solves the time-dependent in-building delivery problem in last-mile logistics. It determines efficient travel sequences for a worker (e.g., delivery person, deliveryman, mailman, agent) who delivers goods or provides services directly to customers located within a building using its elevation system. We study, in detail, all the steps involved in a travel sequence inside a building: horizontal trips, unloading products to the customers, waiting for elevators, and vertical trips within elevators. The sequences and their total times vary depending on the building type, the elevation system, the moment of the day, and the arrival time because of the daily building traffic intensity variations. A mixed-integer linear programming model and a genetic algorithm-based metaheuristic are proposed to solve a set of instances in two office buildings. The results show that it is very important to determine the best time to visit a building because of its time dependency. The variation in delivery time between off-peak hours versus peak hours is between 15% and 30% for the set of solved instances. Moreover, the order of customer visits differs drastically depending on the arrival time to the building.

Abstract The vast majority of Parkinson’s disease cases are idiopathic. Unclear etiology and multifactorial nature complicate the comprehension of disease pathogenesis. Identification of early transcriptomic and metabolic alterations consistent across different idiopathic Parkinson’s disease (IPD) patients might reveal the potential basis of increased dopaminergic neuron vulnerability and primary disease mechanisms. In this study, we combine systems biology and data integration approaches to identify differences in transcriptomic and metabolic signatures between IPD patient and healthy individual-derived midbrain neural precursor cells. Characterization of gene expression and metabolic modeling reveal pyruvate, several amino acid and lipid metabolism as the most dysregulated metabolic pathways in IPD neural precursors. Furthermore, we show that IPD neural precursors endure mitochondrial metabolism impairment and a reduced total NAD pool. Accordingly, we show that treatment with NAD precursors increases ATP yield hence demonstrating a potential to rescue early IPD-associated metabolic changes.

This summarizes and updates an article originally published as Anderson and Nelgen (2021) which is based on a freely available revised global database and ebook (Anderson and Nelgen, 2020a; Anderson and Nelgen, 2020b).

Anemia affects humans throughout life, and is linked to higher morbidity and mortality. Unclear is whether hemoglobin values are equivalent between women and men. This study evaluates the association of preoperative hemoglobin levels with in-hospital mortality and estimates thresholds for survival equity between men and women. All adult patients undergoing surgery between 2010 and 2019 from 14 German hospitals were included in the study. Thresholds for survival equity were determined with generalized additive models. In total, 842,130 patients with a median in-hospital follow-up time of 7 days were analyzed. During follow-up 20,370 deaths occurred. Preoperative hemoglobin stratified in-hospital mortality (log-rank test p

This article summarizes and updates an article originally published as Anderson and Puga (2023a). The aim of this note is to summarise key insights from a recently compiled and updated annual database on Australia’s winegrape and wine production (Anderson and Puga, 2023b). This database, with its 189 tables, is freely available from the website of the University of Adelaide’s Wine Economics Research Centre (for a lengthier analysis and a detailed description of the assumptions behind this database, see Anderson and Puga, 2023a).

Background: This review addresses the emerging field of automated packing cells, which lies at the intersection of robotics and packing problems. Integrating these two fields is critical for optimizing logistics and e-commerce operations. The current literature focuses on packing problems or specific robotic applications without addressing their integration. Methods: To bridge this gap, we conducted a comprehensive review of 46 relevant studies, analyzing various dimensions, including the components of robotic packing cells, the types of packing problems, the solution approaches, and performance comparisons. Results: Our review reveals a significant trend towards addressing online packing problems, which reflects the dynamic nature of logistics operations where item information is often incomplete. We also identify several research gaps, such as the need for standardized terminologies, comprehensive methodologies, and the consideration of real-world constraints in robotic algorithms. Conclusions: This review uniquely integrates insights from robotics and packing problems, providing a structured framework for future research. It highlights the importance of considering practical robotic constraints. It proposes a research structure that enhances the reproducibility and comparability of results in real-world scenarios. By doing so, we aim to guide future research efforts and facilitate the development of more robust and practical automated packing systems.

Riluzole (RLZ), a sodium channel-blocking benzothiazole anticonvulsant BCS class II drug, is very slightly soluble in aqueous medium. To improve aqueous solubility and modulate dissolution rate and membrane permeability, complex formation of RLZ with two cyclodextrin, α-cyclodextrin (α-CD) and sulfobutylether-β-cyclodextrin (SBE-β-CD), was studied. The stability constants demonstrated a greater affinity of SBE-β-CD towards RLZ compared to α-CD. A solubility growth of 1.7-fold and 3.7-fold with α-CD and SBE-β-CD, respectively, was detected in the solutions of 1% cyclodextrins and accompanied by the permeability reduction. For 1% CD solutions, several biopolymers (1% w/v) were tested for the membrane permeability under static conditions. The synergistic positive effect of α-CD and polymer on the solubility accompanied by unchanged permeability was revealed in RLZ/α-CD/PG, RLZ/α-CD/PEG400, and RLZ/α-CD/PEG1000 systems. Solid RLZ/CD complexes were prepared. Dynamic dissolution/permeation experiments for the solid samples disclosed the characteristic features of the release processes and permeation rate through different artificial membranes. The maximal permeation rate was determined across the hydrophilic semi-permeable cellulose membrane followed by the lipophilic PermeaPad barrier (model of intestinal and buccal absorption) and polydimethylsiloxane-polycarbonate membrane (simulating transdermal delivery way). Different mode of the permeation between the membranes was estimated and discussed.

Traffic congestion is a major source of discomfort and economic losses in urban environments. Recently, the proliferation of traffic detectors and the advances in algorithms to efficiently process data have enabled taking a data-driven approach to mitigate congestion. In this context, this work proposes a reinforcement learning (RL) based distributed control scheme that exploits cooperation among intersections. Specifically, a RL controller is synthesized, which manipulates traffic signals using information from neighboring intersections in the form of an embedding obtained from a traffic prediction application. Simulation results using SUMO show that the proposed scheme outperforms classical techniques in terms of waiting time and other key performance indices.

Precipitation patterns are projected to change in different directions across wine regions in Australia, but temperatures are projected to increase in all wine regions, making them less prone to frosts but more prone to heatwaves and more arid. This research aims to estimate how climate change could affect grape yields in Australia. This is, to our knowledge, the first study using a panel data framework to estimate the potential impact of climate change on grape yields. This framework involves a two-step approach in which the first step consists of estimating the impact of weather on grape yields using a fixed effects panel data model, and the second step involves estimating the potential impact of climate change projections using the estimates from the first step. We also estimate a novel hybrid model that interacts weather with climate, potentially accounting for long-run adaptation. The results suggest that climate change by 2050 may lead to higher yields in most regions but lower yields in some of the country’s largest regions. Put differently, an increase in yields may be expected in the coolest regions, while a decrease may be expected in the hottest regions. Consequently, the average yield in Australia may change very little.

The present study reports the effects of two pharmaceutical excipients of differing natures—non-ionic surfactant pluronic F127 (F127) and anionic sulfobutylether-β-cyclodextrin (SBE-β-CD)—on the permeation of the model compound, carbamazepine (CBZ). The permeability coefficients of CBZ at three concentrations of the excipients were measured through two different artificial barriers: hydrophilic cellulose membrane (RC) and lipophilic polydimethylsiloxane–polycarbonate membrane (PDS). The equilibrium solubility of CBZ in F127 and SBE-β-CD solutions was determined. The micellization, complexation, and aggregation tendencies were investigated. Systemically increasing the solubility and the reduction of permeation upon the excipients’ concentration growth was revealed. The quantitative evaluation of the permeability tendencies was carried out using a Pratio parameter, a quasi-equilibrium mathematical mass transport model, and a correction of permeability coefficients for the free drug concentration (“true” permeability values). The results revealed the mutual influence of the excipient properties and the membrane nature on the permeability variations.

In the original publication [...]

Abstract The main objective of this work is to develop and evaluate an artificial intelligence system based on deep learning capable of automatically identifying, quantifying, and characterizing COVID-19 pneumonia patterns in order to assess disease severity and predict clinical outcomes, and to compare the prediction performance with respect to human reader severity assessment and whole lung radiomics. We propose a deep learning based scheme to automatically segment the different lesion subtypes in nonenhanced CT scans. The automatic lesion quantification was used to predict clinical outcomes. The proposed technique has been independently tested in a multicentric cohort of 103 patients, retrospectively collected between March and July of 2020. Segmentation of lesion subtypes was evaluated using both overlapping (Dice) and distance-based (Hausdorff and average surface) metrics, while the proposed system to predict clinically relevant outcomes was assessed using the area under the curve (AUC). Additionally, other metrics including sensitivity, specificity, positive predictive value and negative predictive value were estimated. 95% confidence intervals were properly calculated. The agreement between the automatic estimate of parenchymal damage (%) and the radiologists’ severity scoring was strong, with a Spearman correlation coefficient (R) of 0.83. The automatic quantification of lesion subtypes was able to predict patient mortality, admission to the Intensive Care Units (ICU) and need for mechanical ventilation with an AUC of 0.87, 0.73 and 0.68 respectively. The proposed artificial intelligence system enabled a better prediction of those clinically relevant outcomes when compared to the radiologists’ interpretation and to whole lung radiomics. In conclusion, deep learning lesion subtyping in COVID-19 pneumonia from noncontrast chest CT enables quantitative assessment of disease severity and better prediction of clinical outcomes with respect to whole lung radiomics or radiologists’ severity score.

The Sergushkin-3 ground cemetery (Northern Angara region), studied in 1974-2011, included 24 burials of the Bronze Age, Early Iron Age and the Middle Ages. The cultural and chronological attribution of some complexes is polemical. The purpose of this article is to introduce into scientific discourse materials from burials 8 and 9, including the results of contextual and comparative study of funeral and commemorative practices of these assemblages, as well as paleo-anthropological data and radiocarbon dates. Burial 8 contains macerated, broken and partly burned bones of a 25–30 year old woman and represents an oval pit oriented along the river. According to the grave contents, the remains of the dead woman were burnt in the burial pit. She was accompanied with two sickle type bronze blades, a stone arrowhead and two bone plates. The burnt tree samples provided the radiocarbon ages of 3165 ± 130 BP (SPb_147) and 2945 ± 130 BP (SPb_148). Burial 9 contains macerated, partly broken and burnt bones of a young 18–20 year old man and a young 16–20 year old woman in a ground pit oriented along the river. The partial cremation of the remains was performed outside. The deceased were accompanied with a piercing tool made of moose splint bone, one stone and four bone arrowheads, four horn arrowhead sockets and a hollow horn collar. The burnt tree samples were radiocarbon dated to 2790 ± 100 BP (SPb_381) and 2750 ± 100 BP (SPb_382). The grave goods of both burials are similar to those of the Tsepan Culture of the Early Iron Age (8th–2nd c. BC), while the calibrated calendar interval of their radiocarbon ages is within 15th-10th c. BC. It agrees with the dates of the same “early” Tsepan burial 4 on the Pashina settlement (late 2nd — early 1st mil. BC). The recorded details of funeral rites of these burials are typical for earlier assemblages in the Baikal-Angara region. The sickle type bronze blades and horn sockets are unique for the Bronze Age materials in Angara and Baikal regions, but they impressively resemble the curved knives and bone sockets of the pre-Scythian period from Yakutia and Trans-Baikal region. Based on the above, a suggestion has been made regarding the initial stage of formation of the Tsepan Culture as having been the result of migration processes in the region in the second half of the 2nd mil. BC.

Summary: Developing drugs for treating Alzheimer’s disease has been extremely challenging and costly due to limited knowledge of underlying mechanisms and therapeutic targets. To address the challenge in AD drug development, we developed a multi-task deep learning pipeline that learns biological interactions and AD risk genes, then utilizes multi-level evidence on drug efficacy to identify repurposable drug candidates. Using the embedding derived from the model, we ranked drug candidates based on evidence from post-treatment transcriptomic patterns, efficacy in preclinical models, population-based treatment effects, and clinical trials. We mechanistically validated the top-ranked candidates in neuronal cells, identifying drug combinations with efficacy in reducing oxidative stress and safety in maintaining neuronal viability and morphology. Our neuronal response experiments confirmed several biologically efficacious drug combinations. This pipeline showed that harmonizing heterogeneous and complementary data/knowledge, including human interactome, transcriptome patterns, experimental efficacy, and real-world patient data shed light on the drug development of complex diseases.

Introduction: cancer is a disease of multifactorial origin, related to genetic and environmental risk factors. Aging is a phenomenon that occurs in the world and in Cuba. Objective: to evaluate the risk factors associated with some types of cancer in the older adult belonging to the medical office 12 of the Ernesto Guevara de la Serna polyclinic, Sandino in the period September 2018 to May 2019. Method: a longitudinal and prospective analytical study was carried out, the universe was constituted by 332 older adults, a simple random sample of 90 older adults was selected, the variables used gave them output to the research objectives, theoretical, empirical and descriptive statistics methods were used, given absolute and percentage frequency. Results: 32,2 % belonged to the age group 65-69 years, 64,4 % were female, 66,7 % were white, with pre-university school level, had other occupations, 40 % were married, normal weight (50 %) and overweight (33,3 %), 40 % were sedentary, had up to 3 risk factors associated with 45,5 %, such as family pathological history of hypertension and personal history of hypertension, and breast cancer. Conclusions: risk factors such as sedentary lifestyle, bad eating habits and smoking predominated; the combination of several of these factors favors the appearance of breast, endometrial and colorectal cancer in women and lung, colorectal and prostate cancer in men.

Cyclodextrin-based delivery systems have been intensively used to improve the bioavailability of drugs through the modification of their pharmaceutically relevant properties, such as solubility, distribution and membrane permeation. The present work aimed to disclose the influence of HP-β-CD and SBE-β-CD on the distribution and permeability of nortriptyline hydrochloride (NTT•HCl), a tricyclic antidepressant drug. To this end, the distribution coefficients in the 1-octanol/buffer and n-hexane/buffer model systems and the coefficients of permeability through the cellulose membrane and lipophilic PermeaPad barrier were determined at several cyclodextrin concentrations. The results demonstrated a dramatic decrease in both the distribution and the permeability coefficients as the cyclodextrin concentration rose, with the decrease being more pronounced in SBE-β-CD due to the charge–charge attraction and electrostatic interactions between NTT and SBE-β-CD. It is these interactions that were shown to be responsible for the greater value of the constant of NTT’s association with SBE-β-CD than that with HP-β-CD. The findings of this study revealed similar trends in the 1-octanol/buffer 6.8 pH distribution and permeability through the PermeaPad barrier in the presence of CDs. These results were attributed to the determinative role of the distribution coefficient (serving as a descriptor) in permeation through the PermeaPad barrier modeling the lipophilic nature of biological barriers.

The main aims of the study were to disclose the influence of the structure on the solubility, distribution and permeability of the parent substances, iproniazid (IPN), isoniazid (INZ) and isonicotinamide (iNCT), at 310.2 K and to evaluate how the presence of cyclodextrins (2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and methylated β-cyclodextrin (M-β-CD)) affects the distribution behavior and diffusion properties of a model pyridinecarboxamide derivative, iproniazid (IPN). The following order of decreasing the distribution and permeability coefficients was estimated: IPN > INZ > iNAM. A slight reduction of the distribution coefficients in the 1-octanol/buffer pH 7.4 and n-hexane/buffer pH 7.4 systems (more pronounced in the first system) was revealed. The extremely weak IPN/cyclodextrins complexes were estimated from the distribution experiments: KC(IPN/HP-β-CD) > KC(IPN/M-β-CD). The permeability coefficients of IPN through the lipophilic membrane—the PermeaPad barrier—were also measured with and without cyclodextrins in buffer solution. Permeability of iproniazid was increased in the presence of M-β-CD and reduced by HP-β-CD.

Antibodies have become the Swiss Army tool for molecular biology and nanotechnology. Their outstanding ability to specifically recognise molecular antigens allows their use in many different applications from medicine to the industry. Moreover, the improvement of conventional structural biology techniques (e.g., X-ray, NMR) as well as the emergence of new ones (e.g., Cryo-EM), have permitted in the last years a notable increase of resolved antibody-antigen structures. This offers a unique opportunity to perform an exhaustive structural analysis of antibody-antigen interfaces by employing the large amount of data available nowadays. To leverage this factor, different geometric as well as chemical descriptors were evaluated to perform a comprehensive characterization.

Using a dataset with 16 climate variables for locations representing 813 wine regions that cover 99 % of the world’s winegrape area, we employ principal component analysis (PCA) for data reduction and cluster analysis for grouping similar regions. The PCA resulted in three components explaining 89 % of the variation in the data, with loadings that differentiate between locations that are warm/dry from cool/wet, low from high diurnal temperature ranges, low from high nighttime temperatures during ripening, and low from high vapour pressure deficits. The cluster analysis, based on these three principal components, resulted in three clusters defining wine regions globally, with the results showing that premium wine regions can be found across each of the climate types. This is, to our knowledge, the first such classification of virtually all of the world’s wine regions. However, with both climate change and an increasing preference for premium relative to non-premium wines, many of the world’s winegrowers may need to change their mixes of varieties, or source more of their grapes from more appropriate climates.

This study examined the links between COVID-19 psychosocial stressors, ethnic discrimination, COVID-19 fears, and their combined effects on mental health outcomes among U.S.-based Latinx college students (N = 148; M[subscript age] = 20.68, SD = 2.53). Findings showed that sleep and eating disturbances, emotional distress, and work disruptions were linked with fear of contamination, fear of social distancing, and fear of pandemic impact. Further, ethnic discrimination was found to uniquely contribute to COVID-19 fears above and beyond COVID-19 psychosocial stressors. Finally, COVID-19 emotional distress and COVID fear of pandemic impact were significantly linked to anxiety and depression symptomatology. Recommendations for practice and future research are provided.

ObjectiveClinical practice guidelines (CPGs) serve as frameworks to unify diagnostic criteria and guide clinical decision-making. There is a paucity of literature surrounding the uptake of CPGs in urology practice settings with varied levels of resources worldwide. This study aims to evaluate reported use of CPGs within the context of international urology practice, identify local barriers to uptake, and evaluate the role of stakeholders in the CPG-development process. MethodsThis was an international, multi-center, cross-sectional study. An online survey collecting variables pertaining to the use of CPGs was distributed to attending/consultant urologists in Latin America, Africa, and China. Statistical analysis was conducted using R software. ResultA total of 249 practicing urologists from 28 countries completed the survey. The majority of participants were males, aged 36 to 45, and practiced in a non-academic setting. Ninety-three percent of urologists used CPGs in their everyday clinical practice, and 43% believed CPGs were very important to medical decision-making. However, barriers such as the lack of adaptability or applicability of CPGs to local settings were mentioned by 29% and 24% of participants, respectively. Urologists believed scientific associations (81%), national urology boards (68%), and ministries of health (56%), were important stakeholders to consult to foster the development of local CPGs. ConclusionsGlobally, CPGs are widely used tools for clinical practice. However, there are concerns about the adaptability and applicability of CPGs to settings that may lack the resources to implement their recommendations. Efforts should be directed towards incorporating scientific and medical stakeholders into the review and adaptation of urology CPGs to suit the unique features of local health care systems

While macrophage heterogeneity during metabolic dysfunction-associated steatohepatitis (MASH) has been described, the fate of these macrophages during MASH regression is poorly understood. Comparing macrophage heterogeneity during MASH progression vs regression, we identified specific macrophage subpopulations that are critical for MASH/fibrosis resolution. We elucidated the restorative pathways and gene signatures that define regression-associated macrophages and establish the importance of TREM2+ macrophages during MASH regression. Liver-resident Kupffer cells are lost during MASH and are replaced by four distinct monocyte-derived macrophage subpopulations. Trem2 is expressed in two macrophage subpopulations: i) monocyte-derived macrophages occupying the Kupffer cell niche (MoKC) and ii) lipid-associated macrophages (LAM). In regression livers, no new transcriptionally distinct macrophage subpopulation emerged. However, the relative macrophage composition changed during regression compared to MASH. While MoKC was the major macrophage subpopulation during MASH, they decreased during regression. LAM was the dominant macrophage subtype during MASH regression and maintained Trem2 expression. Both MoKC and LAM were enriched in disease-resolving pathways. Absence of TREM2 restricted the emergence of LAMs and formation of hepatic crown-like structures. TREM2+ macrophages are functionally important not only for restricting MASH-fibrosis progression but also for effective regression of inflammation and fibrosis. TREM2+ macrophages are superior collagen degraders. Lack of TREM2+ macrophages also prevented elimination of hepatic steatosis and inactivation of HSC during regression, indicating their significance in metabolic coordination with other cell types in the liver. TREM2 imparts this protective effect through multifactorial mechanisms, including improved phagocytosis, lipid handling, and collagen degradation.