Correlates of protection and determinants of SARS-CoV-2 breakthrough infections 1 year after third dose vaccination.

BACKGROUND: The emergence of new SARS-CoV-2 variants and the waning of immunity raise concerns about vaccine effectiveness and protection against COVID-19. While antibody response has been shown to correlate with the risk of infection with the original variant and earlier variants of concern, the effectiveness of antibody-mediated protection against Omicron and the factors associated with protection remain uncertain. METHODS: We evaluated antibody responses to SARS-CoV-2 spike (S) and nucleocapsid (N) antigens from Wuhan and variants of concern by Luminex and their role in preventing breakthrough infections 1 year after a third dose of mRNA vaccination, in a cohort of health care workers followed since the pandemic onset in Spain (N = 393). Data were analyzed in relation to COVID-19 history, demographic factors, comorbidities, vaccine doses, brand, and adverse events. RESULTS: Higher levels of anti-S IgG and IgA to Wuhan, Delta, and Omicron were associated with protection against vaccine breakthroughs (IgG against Omicron S antigen HR, 0.06, 95%CI, 0.26-0.01). Previous SARS-CoV-2 infection was positively associated with antibody levels and protection against breakthroughs, and a longer time since last infection was associated with lower protection. In addition, priming with BNT162b2 followed by mRNA-1273 booster was associated with higher antibody responses than homologous mRNA-1273 vaccination. CONCLUSIONS: Data show that IgG and IgA induced by vaccines against the original strain or by hybrid immunization are valid correlates of protection against Omicron BA.1 despite immune escape and support the benefits of heterologous vaccination regimens to enhance antibodies and the prioritization of booster vaccination in individuals without recent infections.

Co-hydrothermal carbonization of microalgae and digested sewage sludge: Assessing the impact of mixing ratios on the composition of primary and secondary char.

The role of microalgae cultivation in wastewater treatment and reclamation has been studied extensively, as has the potential utility of the resulting algal biomass. Most methods for processing such biomass generate solid residues that must be properly managed to comply with current sustainable resource utilization requirements. Hydrothermal carbonization (HTC) can be used to process both individual wet feedstocks and mixed feedstocks (i.e., co-HTC). Here, we investigate co-HTC using microalgae and digested sewage sludge as feedstocks. The objectives were to (i) study the material's partitioning into solid and liquid products, and (ii) characterize the products' physicochemical properties. Co-HTC experiments were conducted at 180-250°C using mixed microalgae/sewage sludge feedstocks with the proportion of sewage sludge ranging from 0 to 100 %. Analyses of the hydrochar composition and the formation and composition of secondary char revealed that the content of carbonized material in the product decreased as the proportion of sewage sludge in the feedstock increased under fixed carbonization conditions. The properties of the hydrochars and the partitioning of material between the liquid phase and the hydrochar correlated linearly with the proportion of microalgae in mixed feedstocks, indicating that adding sewage sludge to microalgae had weak or non-existent synergistic effects on co-HTC outcomes. However, the proportion of sewage sludge in the feedstock did affect the secondary char. For example, adding sewage sludge reduced the abundance of carboxylic acids and ketones as well as the concentrations of higher molecular weight cholesterols. Such changes may alter the viable applications of the hydrochar.

First molecular identification of the trematode Pulmonicola cochleotrema (Platyhelminthes: Opisthotrematidae) in West Indian manatees (Trichechus manatus, Sirenia: Trichechidae) from Puerto Rico and Florida.

West Indian manatees (Trichechus manatus) harbor a variety of endoparasites, including the nasal trematode Pulmonicola cochleotrema, which infects the respiratory tract, especially the nasal passages. Previous studies have described and identified this digenean using morphological data only. This study presents the first molecular identification of P. cochleotrema in West Indian manatees from Puerto Rico and Florida. Samples of the trematode were collected from seven manatees found stranded dead at both locations. The small subunit ribosomal DNA (18S rDNA) was amplified from each sample using universal primers for different regions of the gene, resulting in a consensus sequence of 1871 base pairs. The phylogenetic reconstruction was carried out using DNA sequences of other species of digenean parasites from other hosts, including a trematode of the same taxonomic family from another sirenian species. Specimens collected from both locations show the same molecular identity using SSU rDNA sequence data. The identity of P. cochleotrema was confirmed using the Basic Local Alignment Search Tool from the National Center for Biotechnology Information database, yielding a high similarity of 98.8 % with Opisthotrema dujonis and 98.2 % with Lankatrema mannarense located in the same clade in our analysis. The latter two digeneans belong to the Opisthotrematidae as does P. cochleotrema and previous studies reported them infecting the Eustachian tubes, esophagus, and digestive tract in dugongs (Dugong dugon). These findings evidence that the nasal trematode of manatees in Florida and Puerto Rico and the dugong, all inhabiting and feeding in marine environments, will have a marine mollusk as an intermediate host, probably a gastropod. The question remains, which species of nasal trematode are harbored by lotic-dwelling manatees in other parts of their distribution like South America.

Statistical Study of Low-Intensity Single-Molecule Recognition Events Using DeepTipTM Probes: Application to the Pru p 3-Phytosphingosine System.

The interaction between the plant lipid transfer protein Pru p 3 and phytosphingosine was assessed using an atomic force microscope. Phytosphingosine was covalently immobilized on DeepTipTM probes and Pru p 3 on MicroDeckTM functionalized substrates. Single-molecular interaction events between both molecules were retrieved and classified and the distribution for each one of the identified types was calculated. A success rate of over 70% was found by comparing the number of specific Pru p 3-phytosphingosine interaction events with the total number of recorded curves. The analysis of the distribution established among the various types of curves was further pursued to distinguish between those curves that can mainly be used for assessing the recognition between phytosphingosine (sensor molecule) and Pru p 3 (target molecule) in the context of affinity atomic force microscopy, and those that entail details of the interaction and might be employed in the context of force spectroscopy. The successful application of these functionalized probes and substrates to the characterization of the low-intensity hydrophobic interaction characteristic of this system is a clear indication of the potential of exploiting this approach with an extremely wide range of different biological molecules of interest. The possibility of characterizing molecular assembly events with single-molecule resolution offers an advantageous procedure to plough into the field of molecular biomimetics.

Comparative efficacy of remotely delivered mindfulness-based eating awareness training versus behavioral-weight loss counseling during COVID-19.

Introduction: Dysregulated eating (emotional eating, cue-elicited eating, and dietary restraint and restriction) has been linked to being overweight or obese. The present investigation used a random controlled trial (RCT) to test the differential efficacy of remotely delivered Mindfulness-Based Eating Awareness Training (MB-EAT) and Behavioral Weight Loss (BWL) counseling. Methods: The sample was recruited through advertisements that offered help to people "with problems controlling their eating" or "interested in improving their relationship with food" (n = 135). Results: Retention was low in both groups (42%), but not dissimilar to retention rates reported in related clinical trials delivered "in person." Among the participants who completed treatment, we found no between-group differences in any of the treatment outcomes, but participants in both groups experienced significant increases in eating-related mindfulness [Mindful Eating Questionnaire (MEQ) and awareness [Multidimensional Assessment of Interoceptive Awareness (MAIA), and significant decreases in unhealthy eating patterns [Dutch Eating Behavior Questionnaire (DEBQ); Binge Eating Scale (BES), and weight over the course of treatment. Participants in both groups also experienced increases in self-reported depression and anxiety symptoms [Hospital Anxiety and Depression Scale (HADS)], although these increases likely reflected normative changes observed in the population at large during COVID-19. Discussion: Overall, the results suggest that dysregulated eating and weight loss intervention delivered remotely via teleconference can be effective.

The rapid anxiety screening study-pilot data.

Anxiety disorders are the most common mental health condition in the United States. Medical providers often have many active issues when treating a patient, and do not always have time for a thorough psychiatric evaluation. The Patient Health Questionnaire 2, a two-question binary (yes/no) screening tool, has been developed to address these issues in the identification of unipolar depression. No similar binary screening tool has been developed to comprehensively screen for anxiety disorders. Our study seeks to develop a three-question, comprehensive, binary screening tool for anxiety and related disorders such that these patients can be easily identified and connected to treatment. Our pilot data shows promising results for our three-question binary Rapid Anxiety Screen (the RAS). Future studies will look to confirm these preliminary data and determine the sensitivities and specificities of the RAS with a larger data set.

Outcomes of liver transplantation in non-alcoholic steatohepatitis (NASH) versus non-NASH associated hepatocellular carcinoma.

BACKGROUND: Non-alcoholic steatohepatitis (NASH)-associated hepatocellular carcinoma (HCC) is a rising indication for liver transplantation. This unique population, with multiple comorbidities, has potential for worse post-transplant outcomes. We compared post-transplant survival of NASH and non-NASH HCC patients using a large cohort. METHODS: Adults transplanted for HCC between 2008 and 2018, from United Network for Organ Sharing (UNOS) and University Health Network (UHN) databases were divided into two populations: NASH and non-NASH. Recipient characteristics and post-transplant survival were compared. Subgroup analyses were performed within and beyond Milan criteria. RESULTS: 2071 of 20,672 (10.0%) patients underwent transplantation for NASH HCC, with annual proportional increase of 1.2%UHN (p = 0.02) and 1.3%UNOS (p < 0.001). The 1-,3-,5-year post-transplant survival were 90.8%, 83.9%, 76.3% NASH HCC versus 91.9%, 82.1%, 74.9% non-NASH HCC (p = 0.94). No survival differences were observed in populations within or beyond Milan. Competing-risk analysis demonstrated no differences in risk for cardiovascular-related death (HR1.24, 95%CI 0.87-1.55, p = 0.16), or HCC recurrence-related death (HR1.21, 95%CI 0.89-1.65, p = 0.23). NASH HCC patients had lower risk of liver-related deaths (HR0.57, 95%CI 0.34-0.98, p = 0.04). DISCUSSION: NASH HCC is a rising indication for liver transplantation. Despite demographic differences, no post-transplantation survival differences were observed between NASH and non-NASH HCC. This justifies equivalent organ allocation, irrespective of NASH status.

Molecular Targets for Chalcones in Antileishmanial Drug Discovery.

Leishmaniases are infectious diseases caused by flagellated protozoan parasites belonging to the genus Leishmania that infect cells of the mononuclear phagocytic system. These parasites are transmitted to humans by biting an infected female sandfly belonging to the genera Phlebotomus in the Old World and Lutzomyia in the New World. Despite representing a major public health problem, the therapeutic options are old and have several disadvantages. Given this scenario, developing vaccines or drugs for oral administration is necessary. Therefore, integrating computational and experimental strategies into the studies on molecular targets essential for the survival and virulence of the parasite is fundamental in researching and developing new treatments for leishmaniasis. In the effort to develop new vaccines and drugs, molecular docking methods are widely used as they explore the adopted conformations of small molecules within the binding sites of macromolecular targets and estimate the free energy of target-ligand binding. Privileged structures have been widely used as an effective model in medicinal chemistry for drug discovery. Chalcones are a common simple scaffold found in many compounds of natural and synthetic origin, where studies demonstrate the great pharmacological potential in treating leishmaniasis. This review is based on scientific articles published in the last ten years on molecular docking of chalcone derivatives for essential molecular targets of Leishmania. Thus, this review emphasizes how versatile chalcone derivatives can be used in developing new inhibitors of important molecular targets involved in the survival, growth, cell differentiation, and infectivity of the parasites that cause leishmaniasis.

Geographical region and clinical outcomes of patients with primary biliary cholangitis from Western Europe.

BACKGROUND AND AIMS: The are geographic variations in the incidence and prevalence of primary biliary cholangitis (PBC). The aim was to explore whether clinical outcomes of patients within Western Europe differ according to geographical region. METHODS: Ursodeoxycholic acid-treated patients from European centers from the Global PBC database diagnosed from 1990 onwards were included. Patients with a time lag > 1 year from diagnosis to start of follow-up were excluded. Differences in baseline characteristics were studied according to North/South and East/West, whereas outcomes (transplant-free survival and decompensation) were studied with center latitude and longitude. Cox regression analyses were adjusted for age, sex, diagnosis year, biochemical markers, and cirrhosis as a time-dependent covariate. RESULTS: One thousand eight hundred seventy-eight patients were included, and there were no geographical differences in age or sex, with a mean age of 54 years and 89% female patients. Those in North Europe were more often of a moderately advanced/advanced Rotterdam biochemical stage (28.4%) compared with South Europe (20.6%). Additionally, they exhibited higher median alkaline phosphatase (2.0 ×ULN vs. 1.4 ×ULN) and transaminases. In multivariable analysis, there was a significant interaction between center latitude and longitude for decompensation (P < 0.001) and a trend for transplant-free survival, in which the Northwestern area demonstrated an increased risk for poor outcomes as compared to the reference (Paris). CONCLUSION: We describe geographic variations in outcomes for patients across Europe from specialist centers in the Global PBC Study Group. Further study is important to explore the potential individual, environmental, and healthcare-related factors that may be contributors.

In silico approaches and in vitro assays identify a coumarin derivative as antiviral potential against SARS-CoV-2.

COVID-19, a disease caused by SARS-CoV-2, was declared a pandemic in 2020 and created a global crisis in health systems, with more than 545 million confirmed cases and 6.33 million deaths. In this sense, this work aims to identify possible inhibitors of the SARS-CoV-2 RdRp enzyme using in silico approaches. RdRp is a crucial enzyme in the replication and assembly cycle of new viral particles and a critical pharmacological target in the treatment of COVID-19. We performed a virtual screening based on molecular docking from our in-house chemical library, which contains a diversity of 313 structures from different chemical classes. Nine compounds were selected since they showed important interactions with the active site from RdRp. Next, the ADME-Tox in silico predictions served as a filter and selected the three most promising compounds: a coumarin LMed-052, a hydantoin LMed-087, and a guanidine LMed-250. Molecular dynamics simulations revealed details such as changes in the positions of ligands and catalytic residues during the simulations compared to the complex from molecular docking studies. Binding free energy analysis was performed using the MMGBSA method, demonstrating that LMed-052 and LMed-087 have better affinities for the RdRp by energetic contributions to the stability of the complexes when compared to LMed-250. Furthermore, LMed-052 showed significant in vitro inhibition against MHV-3, decreasing 99% of viral titers. Finally, these findings are useful to guide structural modifications aiming to improve the potential of these compounds to act as inhibitors of SARS-CoV-2.Communicated by Ramaswamy H. Sarma.

In silico approach identified benzoylguanidines as SARS-CoV-2 main protease (Mpro) potential inhibitors.

The coronavirus disease-2019 (COVID-19) pandemic, caused by the novel coronavirus severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), became the highest public health crisis nowadays. Although the use of approved vaccines for emergency immunization and the reuse of FDA-approved drugs remains at the forefront, the search for new, more selective, and potent drug candidates from synthetic compounds is also a viable alternative to combat this viral disease. In this context, the present study employed a computational virtual screening approach based on molecular docking and molecular dynamics (MD) simulation to identify possible inhibitors for SARS-CoV-2 Mpro (main protease), an important molecular target required for the maturation of the various polyproteins involved in viral replication. The virtual screening approach selected four potential inhibitors against SARS-CoV-2 Mpro. In addition, MD simulation studies revealed changes in the positions of the ligands during the simulations compared to the complex obtained in the molecular docking studies, showing the benzoylguanidines LMed-110 and LMed-136 have a higher affinity for the active site compared to the other structures that tended to leave the active site. Besides, there was a better understanding of the formation and stability of the existing H-bonds in the formed complexes and the energetic contributions to the stability of the target-ligand molecular complexes. Finally, the in silico prediction of the ADME profile suggested that LMed-136 has drug-like characteristics and good pharmacokinetic properties. Therefore, from the present study, it can be suggested that these structures can inhibit SARS-CoV-2 Mpro. Nevertheless, further studies are needed in vitro assays to investigate the antiviral properties of these structures against SARS-CoV-2.

Nanotherapeutics Plus Immunotherapy in Oncology: Who Brings What to the Table?

While the number of oncology-related nanotherapeutics and immunotherapies is constantly increasing, cancer patients still suffer from a lack of efficacy and treatment resistance. Among the investigated strategies, patient selection and combinations appear to be of great hope. This review will focus on combining nanotherapeutics and immunotherapies together, how they can dually optimize each other to face such limits, bringing us into a new field called nano-immunotherapy. While looking at current clinical trials, we will expose how passive immunotherapies, such as antibodies and ADCs, can boost nanoparticle tumor uptake and tumor cell internalization. Conversely, we will study how immunotherapies can benefit from nanotherapeutics which can optimize their lipophilicity, permeability, and distribution (e.g., greater tumor uptake, BBB crossing, etc.), tumor, tumor microenvironment, and immune system targeting properties.

Trends in liver transplantation for autoimmune liver diseases: a Canadian study.

BACKGROUND: To our knowledge, no analysis of data from liver transplantation registries exists in Canada. We aimed to describe temporal trends in the number of liver transplantation procedures, patient characteristics and posttransplantation outcomes for autoimmune liver diseases (AILDs) in Canada. METHODS: We used administrative data from the Canadian Organ Replacement Register, which contains liver transplantation information from 6 centres in Canada. This study included transplantation information from 5 of the centres, as liver transplantation procedures in children were not included. We included adult (age ≥ 18 yr) patients with a diagnosis of primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH) or overlap syndrome (PBC-AIH or PSC-AIH) who received a liver transplant from 2000 to 2018. RESULTS: Of 5722 primary liver transplantation procedures performed over the study period, 1070 (18.7%) were for an AILD: 489 (45.7%) for PSC, 341 (31.9%) for PBC, 220 (20.6%) for AIH and 20 (1.9%) for overlap syndrome. There was a significant increase in the absolute number of procedures for PSC, with a yearly increase of 0.6 (95% confidence interval 0.1 to 1.2), whereas the absolute number of procedures for PBC and AIH remained stable. The proportion of transplantation procedures decreased for PBC and AIH but remained stable for PSC. Recipient age at transplantation increased over time for males with PBC (median 53 yr in 2000-2005 to 57 yr in 2012-2018, p = 0.03); whereas the median age among patients with AIH decreased, from 53 years in 2000-2005 to 44 years in 2006-2011 (p = 0.03). The Model for Endstage Liver Disease score at the time of transplantation increased over time for all AILDs, particularly AIH (median 16 in 2000-2005 v. 24 in 2012-2018, p < 0.001). There was a trend toward improved survival in the PBC group, with a 5-year survival rate of 81% in 2000-2005 and 90% in 2012-2018 (p = 0.06). CONCLUSION: Between 2000 and 2018, the absolute number of liver transplantation procedures in Canada increased for PSC but remained stable for PBC and AIH; proportionally, PBC and AIH decreased as indications for transplantation. Posttransplantation survival improved only for the PBC group. An improved understanding of trends and outcomes on a national scale among patients with AILD undergoing liver transplantation can identify disparities and areas for potential health care improvement.

Phosphorus release from hydrothermally carbonized digested sewage sludge using organic acids.

Hydrothermal carbonization (HTC) is a treatment technique with great potential for sanitizing digested sewage sludge (SS) and converting it into valuable products. In particular, phosphorus (P) recovery from hydrothermally carbonized SS has attracted special attention in recent years. This work aims to examine the leaching efficiency of P and the consequent release of metals and heavy metals from SS hydrochars (at 180, 215 and 250 °C) using organic acids (oxalate and citrate) over a range of pH values (0-4) and extraction times (5 min-24 h). Both organic acids triggered P extraction efficiencies exceeding 75 % at the lowest pH, but only oxalate reached a nearly complete P release from hydrochars at pH > 0 and for all carbonization temperatures. Low HTC temperature (180 °C) and short extraction time (5 min) were the optimal conditions treatment for P recovery when reacted in oxalate solutions of maximal pH buffering capacity (pH = 1.4). However, oxalate leaching also transferred metals/heavy metals into the P-leachate, with the exception of Ca being retained in the solid residue from HTC as Ca-oxalate precipitate. Different characterization methods confirmed the presence of this precipitate, and provided information about the surface and morphological changes of the SS hydrochars following acid treatment. The results suggest that HTC not only a promising technique to sanitize and reduce the volume of SS, but also an efficient means for P recovery using oxalic acid, thus contributing to the circular economy of P.

Characterization of novel papillomavirus from free-ranging Antillean manatee Trichechus manatus manatus with genital papillomatosis.

The Antillean manatee Trichechus manatus manatus is an Endangered species living along the Atlantic coasts of the Americas from Florida (USA), throughout the Caribbean, to Brazil. In July 2020, a manatee with multiple wounds due to boat-inflicted trauma was rescued from the coast east of Cayo Mata, Salinas, Puerto Rico. This manatee had neutropenia, leukopenia, and monocytosis associated with immunosuppression and nutritional deficiency anemia, as well as bacteria and fungi within the lesions. The manatee had genital lesions which included papules and linear plaques, microscopically characterized by mucosal hyperplasia with cytopathic changes typical of papillomavirus infection. Superficial epithelial cells had strong nuclear immunolabeling when examined using a monoclonal antibody specific to papillomavirus. The sequencing data of PCR products with papillomavirus-specific degenerative primers indicated that these lesions contained a novel manatee papillomavirus (Trichechus manatus papillomavirus, TmPV). The genomic DNA was amplified using a rolling circle amplification, and fully sequenced to be 7586 bp (GenBank accession no. OK073977). Other TmPVs were previously isolated from Florida manatees T. manatus latirostris. This novel virus was designated TmPV type 5 (TmPV5) based on its genomic characterization and sequence comparison. The TmPV5 genome shared 50.7, 48.9, 69.4, and 62.1% similarities with TmPV1, TmPV2, TmPV3, and TmPV4, respectively. TmPV5 is classified in the genus Rhopapillomavirus together with other manatee papillomaviruses. After 2.5 mo of veterinary treatment and rehabilitation, the manatee recovered and was released. This is the first report of papillomatosis in a free-ranging Antillean manatee.

Outcomes of Adult Liver Retransplantation: A Canadian National Database Analysis.

Background: Liver retransplantation remains as the only treatment for graft failure. This investigation aims to assess the incidence, post-transplant outcomes, and risk factors in liver retransplantation recipients in Canada. Materials and Methods: The Canadian Organ Replacement Register was used to obtain and analyse data on all adult liver retransplant recipients, matched donors, transplant-specific variables, and post-transplant outcomes from January 2000 to December 2018. Results: 377 (6.5%) patients underwent liver retransplantation. Autoimmune liver disease and hepatitis C virus (HCV) were the most common underlying diagnoses. Graft failure was 7.9% and 12.5%, and overall survival was 77.1% and 65.6% at 1 year and 5 years, respectively. In contrast to recipients receiving their first graft transplant, the retransplantation group had a significantly higher incidence of graft failure (p < 0.001) and lower overall survival (p < 0.001). The graft failure and patient survival rates were comparable between second transplant and repeat retransplant recipients. Furthermore, there were no differences in graft failure and patient survival when stratified according to time to retransplantation. Recipient and donor age (HR = 1.12, p=0.011; HR = 1.09, p=0.008), recipient HCV status (HR = 1.81, p=0.014), and donor cytomegalovirus status (HR = 4.10, p=0.006) were predictors of patient mortality. Conclusion: This analysis of liver retransplantation demonstrates that this is a safe treatment for early and late graft failure. Furthermore, even in patients requiring more than two grafts, similar outcomes to initial retransplantation can be achieved with careful selection.

Relationship between lymphedema after breast cancer treatment and biophysical characteristics of the affected tissue.

The treatment of breast cancer is often complicated by lymphedema of the upper limbs. Standard lymphedema evaluation methodologies are not able to measure tissue fibrosis. The ultrasound aspects related to tissue microstructures of lymphedema are neglected in clinical evaluations. The objective of this study was to identify and measure the degree of impairment, topography, and biophysical alterations of subcutaneous lymphedema tissue secondary to the treatment of breast cancer by ultrasonography. Forty-two women at a mean age of 58 (±9.7) years, with unilateral lymphedema due to breast cancer treatment, were evaluated. The upper limbs were divided into affected (affected by lymphedema) and control (contralateral limb). Each limb was subdivided into seven areas, defined by perimetry, evaluated in pairs. The biophysical characteristics thickness, entropy, and echogenicity were evaluated by ultrasonography. The results showed a significant difference in the echogenicity and thickness variables between the affected and unaffected upper limb, in all the extent of the upper limb, while entropy showed no significant difference. The findings indicate that the data presented were consistent both in identifying and measuring the degree of impairment and biophysical changes in the subcutaneous tissue of lymphedema secondary to the treatment of breast cancer.

Medical management and resolution of perinatal bilateral exophthalmia and secondary corneal ulcers in an Antillean manatee (Trichechus manatus manatus) neonate from Puerto Rico.

OBJECTIVE: To present a novel case of perinatal bilateral exophthalmos and corneal ulcers in a neonate Antillean manatee and describe the medical treatment that led to the resolution of the observed clinical signs and vision restoration. ANIMAL STUDIED: A manatee stranded alone in Puerto Rico on July 5, 2020. RESULTS: The manatee was found in critical condition with pronounced exophthalmos, lagophthalmos, and corneal opacification of both eyes (OU). Vision impairment was evident due to the lack of ocular menace reflex and bumping into the tank's walls. Biomicroscopy revealed conjunctival hyperemia and chemosis, limited third eyelid movement, but had viscous tears present OU. Dense, full-thickness, white to cream-colored cellular infiltrates affected 70% of the cornea with peripheral active vascularization OU. Rubeosis iridis was also present OU. Treatment consisted of supportive medical management, including nutritional support and topical treatment for ulcerative keratitis. Resolution of the corneal ulcers and functional vision were achieved after 6 weeks of therapy. Currently, bilateral, mild, intermittent exophthalmos is observed with no adverse clinical signs, and the calf is in good health. CONCLUSIONS: The extent of bilateral corneal disease on a neonatal calf may be a result of an intrauterine infection or possible trauma at or right after birth. While the latter may have led to exophthalmia and consequent corneal disease, the exact cause could not be determined. Supportive therapy and medical management of infectious keratitis were successful and led to vision recovery. This is the first report of ocular pathology in a neonatal manatee.

Dynamic risk profiling of HCC recurrence after curative intent liver resection.

BACKGROUND AND AIMS: Following liver resection (LR) for HCC, the likelihood of survival is dynamic, in that multiple recurrences and/or metastases are possible, each having variable impacts on outcomes. We sought to evaluate the natural progression, pattern, and timing of various disease states after LR for HCC using multistate modeling and to create a practical calculator to provide prognostic information for patients and clinicians. APPROACH AND RESULTS: Adult patients undergoing LR for HCC between January 2000 and December 2018 were retrospectively identified at a single center. Multistate analysis modeled post-LR tumor progression by describing transitions between distinct disease states. In this model, the states included surgery, intrahepatic recurrence (first, second, third, fourth, fifth), distant metastasis with or without intrahepatic recurrence, and death. Of the 486 patients included, 169 (34.8%) remained recurrence-free, 205 (42.2%) developed intrahepatic recurrence, 80 (16.5%) developed distant metastasis, and 32 (7%) died. For an average patient having undergone LR, there was a 33.1% chance of remaining disease-free, a 31.0% chance of at least one intrahepatic recurrence, a 16.3% chance of distant metastasis, and a 19.8% chance of death within the first 60 months post-LR. The transition probability from surgery to first intrahepatic recurrence, without a subsequent state transition, increased from 3% (3 months) to 17.4% (30 months) and 17.2% (60 months). Factors that could modify these probabilities included tumor size, satellite lesions, and microvascular invasion. The online multistate model calculator can be found on https://multistatehcc.shinyapps.io/home/. CONCLUSIONS: In contrast to standard single time-to-event estimates, multistate modeling provides more realistic prognostication of outcomes after LR for HCC by taking into account many postoperative disease states and transitions between them. Our multistate modeling calculator can provide meaningful data to guide the management of patients undergoing postoperative surveillance and therapy.