Discovery of a brain penetrant small molecule antagonist targeting LPA1 receptors to reduce neuroinflammation and promote remyelination in multiple sclerosis.

Multiple sclerosis (MS) is a chronic neurological disease characterized by inflammatory demyelination that disrupts neuronal transmission resulting in neurodegeneration progressive disability. While current treatments focus on immunosuppression to limit inflammation and further myelin loss, no approved therapies effectively promote remyelination to mitigate the progressive disability associated with chronic demyelination. Lysophosphatidic acid (LPA) is a pro-inflammatory lipid that is upregulated in MS patient plasma and cerebrospinal fluid (CSF). LPA activates the LPA1 receptor, resulting in elevated CNS cytokine and chemokine levels, infiltration of immune cells, and microglial/astrocyte activation. This results in a neuroinflammatory response leading to demyelination and suppressed remyelination. A medicinal chemistry effort identified PIPE-791, an oral, brain-penetrant, LPA1 antagonist. PIPE-791 was characterized in vitro and in vivo and was found to be a potent, selective LPA1 antagonist with slow receptor off-rate kinetics. In vitro, PIPE-791 induced OPC differentiation and promoted remyelination following a demyelinating insult. PIPE-791 further mitigated the macrophage-mediated inhibition of OPC differentiation and inhibited microglial and fibroblast activation. In vivo, the compound readily crossed the blood-brain barrier and blocked LPA1 in the CNS after oral dosing. Direct dosing of PIPE-791 in vivo increased oligodendrocyte number, and in the mouse experimental autoimmune encephalomyelitis (EAE) model of MS, we observed that PIPE-791 promoted myelination, reduced neuroinflammation, and restored visual evoked potential latencies (VEP). These findings support targeting LPA1 for remyelination and encourage development of PIPE-791 for treating MS patients with advantages not seen with current immunosuppressive disease modifying therapies.

Most Cited Articles in Body Contouring: A Bibliometric Analysis of the Past 45 Years.

Introduction: The purpose of this study is to produce a bibliometric review of the 30 most cited articles related to 6 major domains of body contouring-abdominoplasty, thighplasty, brachioplasty, gluteoplasty, body lift, and liposuction-for resident and fellow education. Methods: The authors utilized the Web of Science Citation Index to identify the 30 most cited articles related to surgery for body contouring published from 1975 to 2020. Articles were classified according to their level of evidence, type of study, and country of publication. Results: A total of 336 articles were reviewed to compile our list. The mean number of citations across the articles was 114.7 ± SD 86.1. The highest prevalence of the papers was published between 2000 and 2009 (n = 15, 50%). The country with the highest number of contributions was the United States (n = 22, 73%). Plastic and Reconstructive Surgery served as the main journal of publication for these papers (n = 22, 73.3%). The majority of articles were designated for clinical-type studies (n = 26, 86.7%). No basic science or prevalence study design papers were listed. In terms of level of evidence (LoE), most papers were assigned IV (n = 11, 36.7%) and III (n = 7, 23.3%). Conclusions: Our study reveals that the most cited papers in body contouring are of LoE III and IV. Although the LoE of plastic surgery research, in general, has improved, in the past decade, a call for higher quality papers remains. Overall, this analysis provides an easy, electronic starting point for residents and fellows interested in understanding the field's evolution.

Introduction : La présente étude vise à produire une analyse bibliométrique de 30 articles influents liés à six grands domaines du remodelage corporel (l'abdominoplastie, le redrapage des cuisses, la brachioplastie, la glutéoplastie, le redrapage du corps et la liposuccion) pour la formation des résidents et des étudiants en stage de perfectionnement postdoctoral. Méthodologie : Les auteurs ont utilisé l'index de citation de Web of Science pour extraire les 30 articles les plus cités sur les opérations de remodelage corporel publiés entre 1975 et 2020. Ils ont classé les articles d'après la qualité des preuves, le type d'étude et le pays de publication. Résultats : Au total, les auteurs ont analysé 336 articles pour compiler leur liste. Les articles contenaient un nombre moyen de 114,7± ÉT 86,1 citations. La plus forte prévalence d'articles a été publiée entre 2000 et 2009 (n = 15, 50 %). La majorité des articles provenaient des États-Unis d'Amérique (n = 22, 73 %), et c'est la revue Plastic and Reconstructive Surgery© qui en a publié le plus (n = 22, 73,3 %). La plupart des articles prenaient la forme d'études de type clinique (n = 26, 86,7 %). Aucun article de science fondamentale ni étude de prévalence n'a été répertorié. Pour ce qui est de la qualité des preuves, la plupart des articles ont obtenu un classement de IV (n = 11, 36,7 %) et de III (n = 7, 23,3 %). Conclusions : L'étude révèle que la qualité de preuve de la plupart des articles dans ce domaine était de III et IV. Même si la chirurgie plastique se prête moins bien aux études randomisées et contrôlées que la médecine, elle mérite des articles comportant une meilleure qualité de preuves. Grâce à la présente analyse, les résidents et les étudiants en stage de perfectionnement peuvent accéder rapidement et facilement à des concepts influents pour comprendre l'évolution du domaine par voie électronique. Termes MeSH : abdominoplastie, bibliométrie, chirurgie plastique, études transversales, liposuccion, remodelage corporel.

Identification and In Vivo Evaluation of Myelination Agent PIPE-3297, a Selective Kappa Opioid Receptor Agonist Devoid of ß-Arrestin-2 Recruitment Efficacy.

Structure-activity relationship studies led to the discovery of PIPE-3297, a fully efficacious and selective kappa opioid receptor (KOR) agonist. PIPE-3297, a potent activator of G-protein signaling (GTPγS EC50 = 1.1 nM, 91% Emax), did not elicit a ß-arrestin-2 recruitment functional response (Emax < 10%). Receptor occupancy experiments performed with the novel KOR radiotracer [3H]-PIPE-3113 revealed that subcutaneous (s.c.) administration of PIPE-3297 at 30 mg/kg in mice achieved 90% occupancy of the KOR in the CNS 1 h post dose. A single subcutaneous dose of PIPE-3297 in healthy mice produced a statistically significant increase of mature oligodendrocytes (P < 0.0001) in the KOR-enriched striatum, an effect that was not observed in animals predosed with the selective KOR antagonist norbinaltorphimine. An equivalent dose given to mice in an open-field activity-monitoring system revealed a small KOR-independent decrease in total locomotor activity versus vehicle measured between 60 and 75 min post dose. Daily doses of PIPE-3297 at both 3 and 30 mg/kg s.c. reduced the disease score in the mouse experimental autoimmune encephalomyelitis (EAE) model. Visually evoked potential (VEP) N1 latencies were also significantly improved versus vehicle in both dose groups, and latencies matched those of untreated animals. Taken together, these findings highlight the potential therapeutic value of functionally selective G-protein KOR agonists in demyelinating disease, which may avoid the sedating side effects typically associated with classical nonbiased KOR agonists.

Lymphatic Mapping with Contrast-enhanced Ultrasound for Lymphaticovenous Anastomosis Surgery: How We Do It.

Lymphaticovenous anastomosis (LVA) surgery is an effective surgery for the treatment of lymphedema in the extremities. Indocyanine green lymphography is the reference standard for visualizing lymphatics for LVA surgery, but it has several limitations; most notably, superficial dermal congestion can mask deeper lymphatic vessels. To overcome the limitations, we add contrast-enhanced ultrasound (CEUS) lymphography. We have previously reported that CEUS lymphography can identify lymphatic vessels for LVA surgery that indocyanine green lymphography does not. Here, we describe how we perform CEUS lymphography, including workflow, technique, and documentation. Before informed consent, the patient must be screened for possible adverse reactions to microbubbles. The procedure involves multiple intradermal injections of the microbubble agent at various sites along the extremity. After each injection, imaging for microbubble uptake by lymphatic vessels is performed using an ultrasound scanner with contrast-specific software. We use sulfur hexafluoride lipid-type A microspheres (Lumason/SonoVue; Bracco Suisse SA), but we are investigating the performance of other Food & Drug Administration-approved microbubble agents for CEUS lymphography. Having a systematic approach to marking the skin can mitigate the hindrance of marking over ultrasound coupling gel. Another benefit of CEUS lymphography is the rapid identification of neighboring veins compatible in size and location for anastomosis. We hold regular scheduled multidisciplinary meetings for coordination of care, discussion of outcomes, quality assurance, and ongoing innovation.

Dual Blockade of EP2 and EP4 Signaling is Required for Optimal Immune Activation and Antitumor Activity Against Prostaglandin-Expressing Tumors.

While the role of prostaglandin E2 (PGE2) in promoting malignant progression is well established, how to optimally block the activity of PGE2 signaling remains to be demonstrated. Clinical trials with prostaglandin pathway targeted agents have shown activity but without sufficient significance or dose-limiting toxicities that have prevented approval. PGE2 signals through four receptors (EP1-4) to modulate tumor progression. EP2 and EP4 signaling exacerbates tumor pathology and is immunosuppressive through potentiating cAMP production. EP1 and EP3 signaling has the opposite effect through increasing IP3 and decreasing cAMP. Using available small-molecule antagonists of single EP receptors, the cyclooxygenase-2 (COX-2) inhibitor celecoxib, or a novel dual EP2/EP4 antagonist generated in this investigation, we tested which approach to block PGE2 signaling optimally restored immunologic activity in mouse and human immune cells and antitumor activity in syngeneic, spontaneous, and xenograft tumor models. We found that dual antagonism of EP2 and EP4 together significantly enhanced the activation of PGE2-suppressed mouse and human monocytes and CD8+ T cells in vitro as compared with single EP antagonists. CD8+ T-cell activation was dampened by single EP1 and EP3 antagonists. Dual EP2/EP4 PGE2 receptor antagonists increased tumor microenvironment lymphocyte infiltration and significantly reduced disease burden in multiple tumor models, including in the adenomatous polyposis coli (APC)min+/- spontaneous colorectal tumor model, compared with celecoxib. These results support a hypothesis that redundancy of EP2 and EP4 receptor signaling necessitates a therapeutic strategy of dual blockade of EP2 and EP4. Here we describe TPST-1495, a first-in-class orally available small-molecule dual EP2/EP4 antagonist. Significance: Prostaglandin (PGE2) drives tumor progression but the pathway has not been effectively drugged. We demonstrate significantly enhanced immunologic potency and antitumor activity through blockade of EP2 and EP4 PGE2 receptor signaling together with a single molecule.

Using Machine Learning and Deep Learning Algorithms to Predict Postoperative Outcomes Following Anterior Cervical Discectomy and Fusion.

STUDY DESIGN: A retrospective cohort study from a multisite academic medical center. OBJECTIVE: To construct, evaluate, and interpret a series of machine learning models to predict outcomes related to inpatient health care resource utilization for patients undergoing anterior cervical discectomy and fusion (ACDF). SUMMARY OF BACKGROUND DATA: Reducing postoperative health care utilization is an important goal for improving the delivery of surgical care and serves as a metric for quality assessment. Recent data has shown marked hospital resource utilization after ACDF surgery, including readmissions, and ED visits. The burden of postoperative health care use presents a potential application of machine learning techniques, which may be capable of accurately identifying at-risk patients using patient-specific predictors. METHODS: Patients 18-88 years old who underwent ACDF from 2011 to 2021 at a multisite academic center and had preoperative lab values within 3 months of surgery were included. Outcomes analyzed included 90-day readmissions, postoperative length of stay, and nonhome discharge. Four machine learning models-Extreme Gradient Boosted Trees, Balanced Random Forest, Elastic-Net Penalized Logistic Regression, and a Neural Network-were trained and evaluated through the Area Under the Curve estimates. Feature importance scores were computed for the highest-performing model per outcome through model-specific metrics. RESULTS: A total of 1026 cases were included in the analysis cohort. All machine learning models were predictive for outcomes of interest, with the Random Forest algorithm consistently demonstrating the strongest average area under the curve performance, with a peak performance of 0.84 for nonhome discharge. Important features varied per outcome, though age, body mass index, American Society of Anesthesiologists classification >2, and medical comorbidities were highly weighted in the studied outcomes. CONCLUSIONS: Machine learning models were successfully applied and predictive of postoperative health utilization after ACDF. Deployment of these tools can assist clinicians in determining high-risk patients. LEVEL OF EVIDENCE: III.

Evaluating the Impact of ACGME Resident Duty Hour Restrictions on Patient Outcomes for Bilateral Breast Reductions.

The Accreditation Council for Graduate Medical Education (ACGME) implemented duty-hour restrictions limiting residents to 80 hours per week in 2003 and further extended restrictions in 2011 to improve resident and patient well-being. Numerous studies have examined the effects of these restrictions on patient outcomes with inconclusive results. Few efforts have been made to examine the impact of this reform on the safety of common plastic surgery procedures. This study seeks to assess the influence of ACGME duty-hour restrictions on patient outcomes, using bilateral breast reduction mammoplasty as a marker for resident involvement and operative autonomy. Methods: Bilateral breast reductions performed in the 3 years before and after each reform were collected from the National Inpatient Sample database: pre-duty hours (2000-2002), duty hours (2006-2008), and extended duty hours (2012-2014). Multivariable logistic regression models were constructed to investigate the association between ACGME duty hour restrictions on medical and surgical complications. Results: Overall, 19,423 bilateral breast reductions were identified. Medical and surgical complication rates in these patients increased with each successive iteration of duty hour restrictions (P < 0.001). The 2003 duty-hour restriction independently associated with increased surgical (OR = 1.51, P < 0.001) and medical complications (OR = 1.85, P < 0.001). The 2011 extended duty-hour restriction was independently associated with increased surgical complications (OR = 1.39, P < 0.001). Conclusions: ACGME duty-hour restrictions do not seem associated with better patient outcomes for bilateral breast reduction although there are multiple factors involved. These considerations and consequences should be considered in decisions that affect resident quality of life, education, and patient safety.

Environmentally Responsive Materials for Building Envelopes: A Review on Manufacturing and Biomimicry-Based Approaches.

Buildings must adapt and respond dynamically to their environment to reduce their energy loads and mitigate environmental impacts. Several approaches have addressed responsive behavior in buildings, such as adaptive and biomimetic envelopes. However, biomimetic approaches lack sustainability consideration, as conducted in biomimicry approaches. This study provides a comprehensive review of biomimicry approaches to develop responsive envelopes, aiming to understand the connection between material selection and manufacturing. This review of the last five years of building construction and architecture-related studies consisted of a two-phase search query, including keywords that answered three research questions relating to the biomimicry and biomimetic-based building envelopes and their materials and manufacturing and excluding other non-related industrial sectors. The first phase focused on understanding biomimicry approaches implemented in building envelopes by reviewing the mechanisms, species, functions, strategies, materials, and morphology. The second concerned the case studies relating to biomimicry approaches and envelopes. Results highlighted that most of the existing responsive envelope characteristics are achievable with complex materials requiring manufacturing processes with no environmentally friendly techniques. Additive and controlled subtractive manufacturing processes may improve sustainability, but there is still some challenge to developing materials that fully adapt to large-scale and sustainability needs, leaving a significant gap in this field.

#MadelungDeformity: Insights Into a Rare Congenital Difference Using Social Media.

BACKGROUND: Madelung deformity is a rare congenital hand difference with little known regarding the patient perspective. In this cross-sectional survey study, we harnessed the global reach of social media to understand the clinical spectrum of Madelung deformity and its impact on physical, mental, and social health. METHODS: A survey was developed based on a previously published protocol and multiple Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. The survey was distributed on several Madelung deformity communities on Facebook and Instagram. T-scores were calculated, interpreted, and compared between patients who underwent surgery and those who did not. Correlations between scores were calculated using the Spearman rank correlation coefficient. RESULTS: Mean PROMIS scores for adults were as follows: pain intensity, 4.9 ± 2.8; pain interference, 57.6 ± 10.0; upper extremity, 35.2 ± 8.1; depression, 53.8 ± 11.1; anxiety, 55.4 ± 11.4; and ability to participate in social roles and activities, 42.5 ± 7.7. Mean scores for children were as follows: pain intensity, 5.0 ± 2.8; pain interference, 55.7 ± 11.3; upper extremity function, 24.6 ± 10.4; depressive symptoms, 57.7 ± 11.3; anxiety, 57.3 ± 11.9; and peer relationships, 42.2 ± 10.3. CONCLUSIONS: Madelung deformity has significant effects on patients' physical, mental, and social well-being, even after surgical treatment. Using social media, we were able to compensate for Madelung deformity's rarity by engaging an international audience, demonstrating the feasibility to conduct research through it, and providing a global perspective of the disease entity.

Development of a novel radiofluorinated riboflavin probe for riboflavin receptor-targeting PET imaging.

Riboflavin receptor 3 (RFVT3) is a key protein in energetic metabolism reprogramming and is overexpressed in multiple cancers involved in malignant proliferation, angiogenesis, chemotherapy resistance, and immunosuppression. To enable non-invasive real-time quantification of RFVT3 in tumors, we sought to develop a suitable PET probe that would allow specific and selective RFVT3 imaging in vivo. A novel radiofluorinated riboflavin probe (18F-RFTA) based on riboflavin was synthesized and characterized in terms of radiochemical purity, hydrophilicity, binding affinity, and stability. Positron emission tomography (PET) imaging of 18F-RFTA was performed in U87MG tumor-bearing mice. Immunohistochemistry staining was carried out to determine the expression of RFVT3 in U87MG tumors. 18F-RFTA was characterized by high radiochemical purity and RFVT3 binding affinity, and remarkable stability in vitro and in vivo. Small-animal PET imaging with 18F-RFTA revealed significantly higher uptake in RFVT3-expressing U87MG tumors than in muscle. In conclusion, we have developed the first radiofluorinated riboflavin-based PET probe that is suitable for imaging RFVT3-positive tumors. The new target/probe system can be leveraged for extensive use in the diagnosis and treatment of RFVT3 overexpressing diseases, such as oncologic, cardiovascular, and neurodegenerative diseases.

Meta-Analysis of Point-of-Care Lung Ultrasonography Versus Chest Radiography in Adults With Symptoms of Acute Decompensated Heart Failure.

Acute decompensated heart failure (ADHF) is a primary cause of older adults presenting to the emergency department with acute dyspnea. Point-of-care lung ultrasound (LUS) has shown comparable or superior diagnostic accuracy in comparison with a chest x-ray (CXR) in patients presenting with symptoms of ADHF. The systematic review and meta-analysis aimed to elucidate the sensitivity and specificity of LUS in comparison with CXR for diagnosing ADHF and summarize the rapidly growing body of evidence in this domain. A total of 5 databases were searched through February 18, 2021, to identify observational studies that reported on the use of LUS compared with CXR in diagnosing ADHF in patients presenting with shortness of breath. Meta-analysis was conducted on the sensitivities and specificities of each diagnostic method. A total of 8 studies reporting on 2,787 patients were included in this meta-analysis. For patients presenting with signs and symptoms of ADHF, LUS was found to be more sensitive than CXR (91.8% vs 76.5%) and more specific than CXR (92.3% vs 87.0%) for the detection of cardiogenic pulmonary edema. In conclusion, LUS is more sensitive and specific than CXR in detecting pulmonary edema. This highlights the importance of sonographic B-lines, along with the accurate interpretation of clinical data, in the diagnosis of ADHF. In addition to its convenience, reduced costs, and reduced radiation exposure, LUS should be considered an effective alternative to CXR for evaluating patients with dyspnea in the setting of ADHF.

Numerical Assessment of Zebra-Stripes-Based Strategies in Buildings Energy Performance: A Case Study under Tropical Climate.

Urban growth has increased the risk of over-heating both in the microclimate and inside buildings, affecting thermal comfort and energy efficiency. That is why this research aims to evaluate the energy performance of buildings in terms of thermal comfort (operative temperature (OP) levels, satisfied hours of natural ventilation SHNV, thermal lag), and energy efficiency (roof heat gains and surface temperatures) in an urban area in Panama City, using superficial-heat-dissipation biomimetic strategies. Two case studies, a base case and a proposed case, were evaluated using the Designbuilder software through dynamic simulation. The proposed case is based on a combined biomimetic strategy; the reflective characteristics of the Saharan ant applied as a coating on the roofs through a segmented pattern such as the Zebra's stripes (one section with coating, and another without). Results showed that the OP decreased from 8 to 10 °C for the entire urban zone throughout the year. A reduction of 3.13% corresponding to 8790 kWh per year was achieved for cooling energy consumption. A difference of 5 °C in external surface temperature was obtained, having a lower temperature in which the biomimetic strategy was applied. Besides, it was evidenced that a contrasted-reflectivity-stripes pitched roof performed better than a fully reflective roof. Thus, the functionality of Zebra stripes, together with the reflective characteristics of the Saharan ant, provide better performance for buildings' thermal regulation and energy needs for cooling.

Outcomes associated with antithrombotic strategies in heart failure with reduced ejection fraction and sinus rhythm following acute ischemic stroke.

Purpose: Insufficient data exist regarding the benefit of long-term antiplatelet vs. anticoagulant therapy in the prevention of recurrent ischemic stroke in patients with ischemic stroke and heart failure with reduced ejection fraction (HFrEF). Therefore, this study aimed to compare longitudinal outcomes associated with antiplatelet vs. anticoagulant use in a cohort of patients with stroke and with an ejection fraction of ≤40%. Methods: We retrospectively analyzed single-center registry data (2015-2021) of patients with ischemic stroke, HFrEF, and sinus rhythm. Time to the primary outcome of recurrent ischemic stroke, major bleeding, or death was assessed using the adjusted Cox proportional hazards model and was compared between patients treated using anticoagulation (±antiplatelet) vs. antiplatelet therapy alone after propensity score matching using an intention-to-treat (ITT) approach, with adjustment for residual measurable confounders. Sensitivity analyses included the multivariable Cox proportional hazards model using ITT and as-treated approaches without propensity score matching. Results: Of 2,974 screened patients, 217 were included in the secondary analyses, with 130 patients matched according to the propensity score for receiving anticoagulation treatment for the primary analysis, spanning 143 patient-years of follow-up. After propensity score matching, there was no significant association between anticoagulation and the primary outcome [hazard ratio (HR) 1.10, 95% confidence interval (CI): 0.56-2.17]. Non-White race (HR 2.26, 95% CI: 1.16-4.41) and the presence of intracranial occlusion (HR 2.86, 95% CI: 1.40-5.83) were independently associated with the primary outcome, while hypertension was inversely associated (HR 0.42, 95% CI: 0.21-0.84). There remained no significant association between anticoagulation and the primary outcome in sensitivity analyses. Conclusion: In HFrEF patients with an acute stroke, there was no difference in outcomes of antithrombotic strategies. While this study was limited by non-randomized treatment allocation, the results support future trials of stroke patients with HFrEF which may randomize patients to anticoagulation or antiplatelet.

Recent advances and applications of microspheres and nanoparticles in transarterial chemoembolization for hepatocellular carcinoma.

Transarterial chemoembolization (TACE) is a recommended treatment for patients suffering from intermediate and advanced hepatocellular carcinoma (HCC). As compared to the conventional TACE, drug-eluting bead TACE demonstrates several advantages in terms of survival, treatment response, and adverse effects. The selection of embolic agents is critical to the success of TACE. Many studies have been performed on the modification of the structure, size, homogeneity, biocompatibility, and biodegradability of embolic agents. Continuing efforts are focused on efficient loading of versatile chemotherapeutics, controlled sizes for sufficient occlusion, real-time detection intra- and post-procedure, and multimodality imaging-guided precise treatment. Here, we summarize recent advances and applications of microspheres and nanoparticles in TACE for HCC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Molecular Imaging of Tumor Microenvironment to Assess the Effects of Locoregional Treatment for Hepatocellular Carcinoma.

Liver cancer is one of the leading causes of cancer deaths worldwide. Among all primary liver cancers, hepatocellular carcinoma (HCC) is the most common type, representing 75%-85% of all primary liver cancer cases. Median survival following diagnosis of HCC is approximately 6 to 20 months due to late diagnosis in its course and few effective treatment options. Interventional therapy with minimal invasiveness is recognized as a promising treatment for HCC. However, due to the heterogeneity of HCC and the complexity of the tumor microenvironment, the long-term efficacy of treatment for HCC remains a challenge in the clinic. Tumor microenvironment, including factors such as hypoxia, angiogenesis, low extracellular pH, interstitial fluid pressure, aerobic glycolysis, and various immune responses, has emerged as a key contributor to tumor residual and progression after locoregional treatment for HCC. New approaches to noninvasively assess the treatment response and assist in the clinical decision-making process are therefore urgently needed. Molecular imaging tools enabling such an assessment may significantly advance clinical practice by allowing real-time optimization of treatment protocols for the individual patient. This review discusses recent advances in the application of molecular imaging technologies for noninvasively assessing changes occurring in the microenvironment of HCC after locoregional treatment.

An Inspection of the Life Cycle of Sustainable Construction Projects: Towards a Biomimicry-Based Road Map Integrating Circular Economy.

According to the National Energy Plan in Panama, the construction sector is one of the most prosperous and impactful sectors in the economy and it is expected to expand due to population growth by almost 300% by 2050. However, this sector must work on the transition towards sustainability and resilience in the face of climate change, since its growth implies a high consumption of resources and the contribution of greenhouse gases. The need to establish practices and strategies that embrace the dimension of sustainability and a circular economy is imminent. Currently, there is little guidance in the reference framework beyond certifications in planning, management and evaluation tools for its implementation. Different studies vary in the number of phases and considerations for projects. Therefore, the present work proposes the development of a unified road map, with defined phases, practices and indicators based on principles inspired by nature, such as biomimicry (Greek words: "bio" means life and "mimesis", imitation), and focuses on a circular economy, validated by construction professionals, where strengths, opportunities, skills and threats are identified with a high level of acceptance. This contributes to strengthening the field of sustainable construction project management and a precedent for Panama.

Sustainability Assessment of the Anthropogenic System in Panama City: Application of Biomimetic Strategies towards Regenerative Cities.

To understand the sustainability problem for Panama's metropolitan area, its urban metabolism was investigated. A way to evaluate its current state was obtained by estimating a sustainable indicator based on the Green City Index. With the abstraction of the identified problems, the biomimetic strategy "problem-based approach" was carried out, where different pinnacles of nature were selected as a reference for the design of regenerative solutions. These were inspired by the understanding of the living world and how to include ecosystems in urban designs. Therefore, a framework was proposed for positive generation and natural solutions in cities to take advantage of the regenerative potential in Panama City. Using ecosystem services, a set of indicators were developed to measure regeneration over the years at the city scale. The results indicate that from the 11 selected pinnacles, 17 solutions inspired in nature were proposed to regenerate cities. Consequently, a SWOT analysis was realized along with a questionnaire by experts from different fields. The findings obtained show that the feasible solutions were: arborization, green facades, solar roofs, e-mobility, green corridors, bicycle lanes, sidewalks, and biofilters. This research represents a step towards creating and developing regenerative cities, thus improving the quality of life of living beings and ecosystems present in society.

Effect of famotidine on hospitalized patients with COVID-19: A systematic review and meta-analysis.

INTRODUCTION: Famotidine is a competitive histamine H2-receptor antagonist most commonly used for gastric acid suppression but thought to have potential efficacy in treating patients with Coronavirus disease 2019 (COVID-19). The aims of this systematic review and meta-analysis are to summarize the current literature and report clinical outcomes on the use of famotidine for treatment of hospitalized patients with COVID-19. METHODS: Five databases were searched through February 12, 2021 to identify observational studies that reported on associations of famotidine use with outcomes in COVID-19. Meta-analysis was conducted for composite primary clinical outcome (e.g. rate of death, intubation, or intensive care unit admissions) and death separately, where either aggregate odds ratio (OR) or hazard ratio (HR) was calculated. RESULTS: Four studies, reporting on 46,435 total patients and 3,110 patients treated with famotidine, were included in this meta-analysis. There was no significant association between famotidine use and composite outcomes in patients with COVID-19: HR 0.63 (95% CI: 0.35, 1.16). Across the three studies that reported mortality separated from other endpoints, there was no association between famotidine use during hospitalization and risk of death-HR 0.67 (95% CI: 0.26, 1.73) and OR 0.79 (95% CI: 0.19, 3.34). Heterogeneity ranged from 83.69% to 88.07%. CONCLUSION: Based on the existing observational studies, famotidine use is not associated with a reduced risk of mortality or combined outcome of mortality, intubation, and/or intensive care services in hospitalized individuals with COVID-19, though heterogeneity was high, and point estimates suggested a possible protective effect for the composite outcome that may not have been observed due to lack of power. Further randomized controlled trials (RCTs) may help determine the efficacy and safety of famotidine as a treatment for COVID-19 patients in various care settings of the disease.