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BACKGROUND: β-cryptoxanthin (BCX), one of the major carotenoids detected in human circulation, can protect against the development of fatty liver disease. BCX can be metabolized through β-carotene-15,15'-oxygenase (BCO1) and β-carotene-9',10'-oxygenase (BCO2) cleavage pathways to produce both vitamin A and apo-carotenoids, respectively, which are considered important signaling molecules in a variety of biological processes. Recently, we have demonstrated that BCX treatment reduced hepatic steatosis severity and hepatic total cholesterol levels in both wide type and BCO1(–/–)/BCO2(–/–) double knock out (KO) mice. Whether the protective effect of BCX is seen in single BCO2(–/–) KO mice is unclear. METHODS: In the present study, male BCO2(–/–) KO mice at 1 and 5 months of age were assigned to two groups by age and weight-matching as follows: (I) –BCX control diet alone (AIN-93 purified diets); (II) +BCX 10 mg (supplemented with 10 mg of BCX/kg of diet) for 3 months. At 4 and 8 months of age, hepatic steatosis and inflammatory foci were evaluated by histopathology. Retinoids and BCX concentrations in liver tissue were analyzed by high-performance liquid chromatography (HPLC). Hepatic protein expressions of SIRT1, acetylated and total FoxO1, PGC1α, and PPARα were determined by the Western blot analysis. Real-time PCR for gene expressions (MCAD, SCD1, FAS, TNFα, and IL-1β gene expression relative to β-actin) was conducted in the liver. RESULTS: Steatosis was detected at 8 months but not at 4 months of age. Moreover, BCX supplementation significantly reduced the severity of steatosis in the livers of BCO2 KO mice, which was associated with changes in hepatic SIRT1 acetylation of FOXO1, PGC1α protein expression and PPARα protein expression in BCO2(–/–) KO mice. HPLC analysis showed that hepatic BCX was detected in BCX supplemented groups, but there were no differences in the hepatic levels of retinol and retinyl palmitate (RP) among all groups. CONCLUSIONS: The present study provided experimental evidence that BCX intervention can reduce liver steatosis independent of BCO2.

Major surgical societies advised using non-operative management of appendicitis and suggested against laparoscopy during the COVID-19 pandemic. The hypothesis is that a significant reduction in the number of emergent appendectomies was observed during the pandemic, restricted to complex cases. The study aimed to analyse emergent surgical appendectomies during pandemic on a national basis and compare it to the same period of the previous year. This is a multicentre, retrospective, observational study investigating the outcomes of patients undergoing emergent appendectomy in March–April 2019 vs March–April 2020. The primary outcome was the number of appendectomies performed, classified according to the American Association for the Surgery of Trauma (AAST) score. Secondary outcomes were the type of surgical technique employed (laparoscopic vs open) and the complication rates. One thousand five hundred forty one patients with acute appendicitis underwent surgery during the two study periods. 1337 (86.8%) patients met the inclusion criteria: 546 (40.8%) patients underwent surgery for acute appendicitis in 2020 and 791 (59.2%) in 2019. According to AAST, patients with complicated appendicitis operated in 2019 were 30.3% vs 39.9% in 2020 (p = 0.001). We observed an increase in the number of post-operative complications in 2020 (15.9%) compared to 2019 (9.6%) (p 24 h after admission (+ 58%), open surgery (+ 112%) and conversion to open surgery (+ 166%). In Italian hospitals, in March and April 2020, the number of appendectomies has drastically dropped. During the first pandemic wave, patients undergoing surgery were more frequently affected by more severe appendicitis than the previous year's timeframe and experienced a higher number of complications. Trial registration number and date: Research Registry ID 5789, May 7th, 2020

Rationale: Prone positioning as a complement to oxygen therapy to treat hypoxemia in coronavirus disease (COVID-19) pneumonia in spontaneously breathing patients has been widely adopted, despite a lack of evidence for its benefit. Objectives: To test the hypothesis that a simple incentive to self-prone for a maximum of 12 h per day would decrease oxygen needs in patients admitted to the ward for COVID-19 pneumonia on low-flow oxygen therapy. Methods: Twenty-seven patients with confirmed COVID-19 pneumonia admitted to Geneva University Hospitals were included in the study. Ten patients were randomised to self-prone positioning and 17 to usual care. Measurements and Main Results: Oxygen needs assessed by oxygen flow on nasal cannula at inclusion were similar between groups. Twenty-four hours after starting the intervention, the median oxygen flow was 1·0 L/min (interquartile range, 0·1-2·9) in the prone position group and 2·0 L/min (interquartile range, 0·5-3·0) in the control group (P = 0·507). Median oxygen saturation/fraction of inspired oxygen ratio was 390 (interquartile range, 300-432) in the prone position group and 336 (interquartile range, 294-422) in the control group (P = 0·633). One patient from the intervention group who did not self-prone was transferred to the high-dependency unit. Self-prone positioning was easy to implement. The intervention was well tolerated and only mild side-effects were reported. Conclusions: Self-prone positioning in patients with COVID-19 pneumonia requiring low-flow oxygen therapy resulted in a clinically meaningful reduction of oxygen flow, but without reaching statistical significance. Trial Registration: The study was registered on the Swiss National Clinical Trial portal (SNCTP000003718). Funding Statement: None. Declaration of Interests: None. Ethics Approval Statement: The institutional ethics review committee approved the trial (CCER 2020-00705). All participants provided written informed consent before screening.

We evaluated serologic responses of cattle, bison, elk, and swine representing negative control, early vaccination (4–8 wk), late vaccination (21–28 wk) or booster vaccination, early after-experimental challenge (2–4 wk), and late after-experimental challenge (8–21 wk), in a brucellosis fluorescence polarization assay (FPA; n = 10 sera per species per treatment) using negative control sera from cattle, bison, elk, and swine ( n = 5 per species). Sera from cattle shedding Brucella abortus strain RB51 in milk were also evaluated against the 20 negative control sera. The species of negative control sera used in the FPA could increase ( p < 0.05) delta millipolarization (mP; delta mP = sample mP − negative control mP) results. In general, the species of negative control sera did not alter the interpretation of FPA results in control, vaccinated, or infected animals. Even after repeated RB51 vaccinations in bison, cattle, or elk, or in cattle shedding RB51 in milk, serologic results from the FPA remained negative. Species differences in FPA results were noted; elk developed robust humoral responses very quickly after infection that resulted in strong positive FPA results. In cattle and bison, humoral responses appeared to develop over a longer period of time, and greater delta mP values were detected at later times after infection. Sensitivity of the FPA for detecting infected animals was greatest for elk in early challenge samples and bison in late challenge samples. Our data suggest that species of origin of negative control sera does not influence interpretation of the FPA in natural hosts of Brucella abortus.

Gingival hyperpigmentation is produced by excessive melanin deposit, generating a dark gum coloring. Although it does not constitute a health issue, in some cases it usually represents an aesthetic problem that can affect psychologically, for which there are currently several treatment alternatives such as: surgery with scalpel, laser therapy, abrasion, cryosurgery, electrosurgery, among others. The aim of this literature review was to analyze the available information about gingival melanosis and the therapeutics that can be applied to improve the appearance of patients with this condition. Articles in English and Spanish, published during the period 2000-2020 in the PubMed, Medline, Scielo, Cochrane and Lilacs databases, were reviewed. It was concluded that the selection of the technique will depend on each particular case, however, the laser is the most relevant. La hiperpigmentación gingival se produce por el depósito excesivo de melanina, generando una coloración oscura de la encía. Aunque no constituye un inconveniente para la salud, en algunos casos suele representar un problema estético que puede afectar psicológicamente, por lo cual, en la actualidad existen diversas alternativas de tratamiento como: cirugía con bisturí, terapia láser, abrasión, criocirugía, electrocirugía, entre otros. El objetivo de esta revisión de la literatura fue analizar la información disponible acerca de la melanosis gingival y la terapéutica que puede ser aplicada para mejorar el aspecto de los pacientes con esta condición. Se revisaron artículos en inglés y español, publicados durante el período 2000-2020 en las bases de datos PubMed, Medline, Scielo, Cochrane y Lilacs. Se concluyó que la elección de la técnica dependerá de cada caso en particular, sin embargo, el láser es el más destacado.

Objectives The current reference standard for diagnosing LAA thrombi is transesophageal echocardiography (TEE), a semi-invasive technique. We aimed to devise an optimal protocol for cardiac computed tomography (CCT) in diagnosing left atrial appendage (LAA) thrombus in patients with atrial fibrillation (AF), using TEE as reference standard. Methods Two hundred sixty consecutive patients referred for radiofrequency ablation for AF were prospectively enrolled. All patients underwent CCT and TEE within 2 hours. The CCT protocol included one standard angiographic phase and three delayed acquisitions at 1-, 3-, and 6-min after contrast injection. Thrombi were defined as persisting defects at 6-min delayed acquisition. Results TEE demonstrated spontaneous contrast in 52 (20%) patients and thrombus in 10 (4%). In 63 patients (24%), CCT demonstrated LAA early filling defects at angiographic phase. Among them, 15 (6%) had a persistent defect at 1-min, 12 (5%) at 3-min, and 10 (4%) at 6-min. All 10 thrombi diagnosed on TEE were correctly identified by delayed CCT, without any false positives. For all phases, sensitivity and negative predictive were 100%. Specificity increased from 79% for the angiographic phase to 100% at 6-min. Positive predictive value increased from 16% to 100%. Estimated radiation exposure was 2.08 ± 0.76 mSv (mean ± standard deviation) for the angiographic phase and 0.45 ± 0.23 mSv for each delayed phase. Conclusion A CCT protocol adding a 6-min delayed phase to the angiographic phase can be considered optimized for the diagnosis of LAA thrombi, with a low radiation dose. Key Points • In patients with persistent atrial fibrillation referred for ablation procedures, a cardiac CT examination comprising an angiographic-phase acquisition and, in case of filling defects, a 6-min delayed phase may help reduce the need for transesophageal echocardiography. • Cardiac CT would provide morphological and volumetric data, along with the potential to exclude the presence of thrombi in the left atrial appendage.

Background Noninvasive ventilation (NIV) is standard of care for chronic hypercapnic respiratory failure, but indications, devices, and ventilatory modes are in constant evolution. Research Question To describe changes in prevalence and indications for NIV over a 15-year period; to provide a comprehensive report of characteristics of the population treated (age, comorbidities, and anthropometric data), mode of implementation and follow-up, devices, modes and settings used, physiological data, compliance, and data from ventilator software. Study Design and Methods Cross-sectional observational study designed to include all subjects under NIV followed by all structures involved in NIV in the Cantons of Geneva and Vaud (1,288,378 inhabitants). Results A total of 489 patients under NIV were included. Prevalence increased 2.5-fold since 2000 reaching 38 per 100,000 inhabitants. Median age was 71 years, with 31% being > 75 years of age. Patients had been under NIV for a median of 39 months and had an average of 3 ± 1.8 comorbidities; 55% were obese. COPD (including overlap syndrome) was the most important patient group, followed by obesity hypoventilation syndrome (OHS) (26%). Daytime Pa co 2 was most often normalized. Adherence to treatment was satisfactory, with 8% only using their device Interpretation Use of NIV is increasing rapidly in this area, and the population treated is aging, comorbid, and frequently obese. COPD is presently the leading indication followed by OHS. Trial Registry ClinicalTrials.gov; No.: NCT04054570; URL: www.clinicaltrials.gov

Bone is the most common site of distant metastatic spread in prostate adenocarcinoma. Prostate-specific membrane antigen uptake has been described in both benign and malignant bone lesions, which can lead to false-positive findings on 68Ga-prostate-specific membrane antigen-11 positron emission tomography (68Ga-PSMA-11 PET). The purpose of this study was to evaluate the diagnostic accuracy of 68Ga-PSMA-11 PET for osseous prostate cancer metastases and improve bone uptake interpretation using semi-quantitative metrics. METHODS: 56 prostate cancer patients (18 pre-prostatectomy, 38 biochemical recurrence) who underwent 68Ga-PSMA-11 PET/MRI or PET/CT examinations with osseous PSMA-ligand uptake were included in the study. Medical records were reviewed retrospectively by board-certified nuclear radiologists to determine true or false positivity based on a composite endpoint. For each avid osseous lesion, biological volume, size, PSMA-RADS rating, maximum standardized uptake value (SUVmax), and ratio of lesion SUVmax to liver, blood pool, and background bone SUVmax were measured. Differences between benign and malignant lesions were evaluated for statistical significance, and cut-off values for these parameters were determined to maximize diagnostic accuracy. RESULTS: Among 56 participants, 13 patients (22.8%) had false-positive osseous 68Ga-PSMA-11 findings and 43 patients (76.8%) had true-positive osseous 68Ga-PSMA-11 findings. Twenty-two patients (39%) had 1 osseous lesion, 18 (32%) had 2-4 lesions, and 16 (29%) had 5 or more lesions. Cut-off values resulting in statistically significant (p

Leptospirosis is a global zoonosis causing significant economic losses for cattle production. Current cattle vaccines against leptospirosis need improvement to provide efficacy against multiple serovars, reduce shedding in urine, and to induce earlier and more robust immune responses. In this study, Leptospira borgpetersenii serovar Hardjo strain 203 antigen was combined with novel adjuvants (a biodegradable polyanhydride compressed rod implant (VPEAR), poly(diaminosulfide) microparticles, a water-oil-water emulsion adjuvant, and aluminum hydroxide) to develop novel vaccines. Cattle were immunized twice, at a 4 week interval, with inoculums containing adjuvants alone or leptospira antigens and immune responses were compared to responses of cattle receiving a commercial monovalent leptospirosis vaccine (Spirovac). All animals were inoculated with a single dose of Spirovac at 20 weeks to assess antigen recall responses. Serum antibody responses were increased (P 0.05) at 8 and 20 weeks after vaccination in cattle receiving inoculums containing leptospira antigens combined with water-oil-emulsion, poly(diaminosulfide) microparticles (PNSN-MP), or aluminum hydroxide and in cattle vaccinated with Spirovac. Humoral responses were predominantly IgG1 isotypes. Antigen-specific proliferative responses were detected after initial vaccination in cattle vaccinated with Spirovac, PNSN-MP and water-oil-water treatments. Most proliferative responses occurring within CD4+ and gamma delta T cell populations expressing CD45RO and CD25 markers, a response consistent with an effector memory phenotype. Antigen-specific immune responses were not detected in cattle vaccinated with VPEAR after initial inoculation, but were detected in the antigen recall responses. PBMCs from cattle vaccinated with Spirovac, oil-water-oil, or PNSN-MP treatments had increased (P 0.05) IL-17A release after in vitro stimulation with leptospirosis antigens, whereas all groups produced IFN-γ and IL-17A after in vitro stimulation during the antigen recall response. Our data demonstrates that combining leptospirosis antigens with these adjuvants enhances immunogenicity in cattle. Interpretative Summary: Vaccination of livestock is a key mechanism for minimizing transmission of leptospirosis, a zoonotic disease. Leptospirosis vaccines for cattle need to be improved to provide greater levels of protection from kidney colonization, better immune responses, and protection against multiple serovars. This could be accomplished using new vaccine adjuvants. In this study, several novel adjuvants were evaluated for their ability to induce effective immune responses in cattle to leptospira antigens as compared to currently available vaccines. Data suggested that vaccines containing biodegradable polymer microparticles and oil-emulsion adjuvants induced similar or greater immune responses as compared to a commercial vaccine. Our data suggest these new vaccine formulations warrant further investigation as new vaccine formulations for cattle and other livestock.

Background: Lung ultrasound (LUS) has a good performance with a high sensitivity and specificity for the diagnosis of pneumonia compared with chest X-ray, and it has been extensively used to assess patients during the COVID-19 pandemic. This study aims to evaluate the potential advantages of the regular use of LUS for the assessment of the severity and prognosis of COVID-19 pneumonia and to propose an adapted protocol with its inclusion in current local validated and published guidelines.Methods: This is a single-center prospective study conducted during the first (April–May 2020) and second (October 2020–January 2021) waves of the SARS-CoV2 pandemic in Switzerland. All adult patients presenting to dedicated test centers with a suspicion of mild-to-moderate COVID-19 pneumonia and not requiring hospitalization at the time of diagnosis were included. Patients with confirmed COVID-19 pneumonia were referred to an ambulatory follow-up unit at our institution for reassessment, with the inclusion of the use of LUS in a random selection. Descriptive statistics were calculated for demographics using percentages, means, and standard deviations according to the distribution of variables.Results: Eighty-eight ambulatory patients with a confirmed COVID-19 pneumonia were included (men = 57 [59%]; mean age, 52.1 ± 13.5 years). Among these, 19 (21%) were hospitalized and none died. Twenty-five lung assessments by ultrasound were performed during the follow-up consultation. All were consistent with the clinical examination and confirmed the clinician's opinion.Conclusion: The use of a standardized pleuro-pulmonary ultrasound protocol for ambulatory patients with COVID-19 could help to reduce the use of chest X-rays and improve overall management at the time of referral and eventual follow-up. However, a specific study including LUS in a systematic approach should be performed to evaluate the outcome of patients according to findings.

Objective The use of chlorine dioxide (ClO2) increased in the last year to prevent SARS-CoV-2 infection due to its use as disinfectant and therapeutic human treatments against viral infections. The absence of toxicological studies and sanitary regulation of this contaminant represents a serious threat to human and environmental health worldwide. The aim of this study was to evaluate the acute toxicity and sublethal efects of ClO2 on tadpoles of Trachycephalus typhonius, which is a common bioindicator species of contamination from aquatic ecosystems. Materials and methods Median lethal concentration (LC50), the lowest-observed efect concentration (LOEC), and the noobserved efect concentration (NOEC) were performed. Acetylcholinesterase (AChE) and glutathione-S-transferase (GST) activities, swimming behavior parameters, and cardiac rhythm were estimated on tadpoles of concentrations≤LOEC exposed at 24 and 96 h. ANOVA and Dunnett’s post-hoc comparisons were performed to defne treatments signifcance (p≤0.05). Results The LC50 of ClO2 was 4.17 mg L−1 (confdence limits: 3.73–4.66). In addition, NOEC and LOEC values were 1.56 and 3.12 mg L−1 ClO2, respectively, at 48 h. AChE and GST activities, swimming parameters, and heart rates increased in sublethal exposure of ClO2 (0.78–1.56 mg L−1) at 24 h. However, both enzyme activities and swimming parameters decreased, whereas heart rates increased at 96 h. Conclusion Overall, this study determined that sublethal concentrations of ClO2 produced alterations on antioxidant systems, neurotoxicity refected on swimming performances, and variations in cardiac rhythm on treated tadpoles. Thus, our fndings highlighted the need for urgent monitoring of this chemical in the aquatic ecosystems. Fil: Peltzer, Paola. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina Fil: Cuzziol Boccioni, Ana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina Fil: Attademo, Andres Maximiliano. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Martinuzzi, Candela Soledad. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina Fil: Colussi, Carlina Leila. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina Fil: Lajmanovich, Rafael Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina

Type 1 diabetes (T1D) is a chronic autoimmune disease resulting in progressive destruction of β-cells. Several factors affecting lymphocyte and antigen-presenting cells, including dendritic cells (DCs), contribute to defective maintenance of tolerance in T1D. DC-10 are a subset of human DCs involved in IL-10-mediated tolerance. A precise monitoring of DC-10 in the peripheral blood is possible thanks to the discovery of specific biomarkers. DC-10, being cells that naturally express HLA-G, may be used for the appropriate staging of the disease. By enumerating and phenotypically characterizing DC-10 in the peripheral blood of subjects at different stages of T1D development—first-degree relatives (FDRs) of T1D patients, without (Abneg) or with (Abpos) autoantibodies, T1D patients at onset, and age-matched healthy controls (HCs)—we showed that DC-10 contain a high proportion of HLA-G-expressing cells as compared with monocytes. We reported that a low frequency of DC-10 during disease development is paralleled with the increased proportion of pro-inflammatory cDC2 cells. Moreover, DC-10 number and phenotype differ from Abneg FDRs, Abpos FDRs, and T1D patients compared with HCs, and DC-10 from T1D patients express low levels of CD83. Finally, multiple regression analysis, considering DC-10 and HLA-G-related parameters, showed that Abneg FDRs are more similar to subjects with autoimmunity than to HCs. This is the first demonstration that impairment in DC-10 number and phenotype, specifically CD83 expression, is associated with risk of developing T1D, suggesting a possible use of CD83+ DC-10 to stratify individuals at risk of T1D in conjunction with classical prognostic factors.

Objective: The objective of this study was to compare the use of pulmonary regurgitation volume (PRV) or indexed PRV (PRVi) with that of pulmonary regurgitation fraction (PRF) in the assessment of patients with pulmonary regurgitation (PR) undergoing cardiac magnetic resonance (CMR) imaging. Materials and Methods: CMR of 176 patients with PR were retrospectively evaluated. Their right ventricular diastolic (end-diastolic volume index [EDVi]) and systolic (end-systolic volume index) volume indexes, stroke volume, and ejection fraction were obtained from cine CMR sequences, whereas phase-contrast flow sequences were analyzed to obtain PRV, PRVi, and PRF. Patients were divided into subgroups, according to underlying pathology and according to PR severity. Correlations between PRV or PRF and RV parameters were studied through Spearman ρ, both in the main group and subgroups. Follow-up examinations were analyzed, and correlations between PRV or PRF from the first CMR examination and volume data from the second were calculated. Results: Tetralogy of Fallot was the main setting of PR (98/179). Overall, EDVi strongly correlates with PRV (ρ=0.592, P

The non-steroidal anti-inflammatory drug diclofenac (DCF) threatens the health of aquatic animals and ecosystems. In the present study, different biological endpoints (mortality, development and growth, abnormalities, cardiotoxicity, neurotoxicity and antioxidant system) were used to characterize the acute and chronic effects of DCF (at concentrations ranging between 125 and 4000 μg L−1) on two amphibian species from Argentina (Trachycephalus typhonius and Physalaemus albonotatus). Results showed that the larval developmental, growthrates, and body condition of DCF-exposed individuals of both species were significantly reduced. DCF-exposed individuals also showed several morphological abnormalities, including significantly altered body axis, chondrocraniumand hyobranchial skeleton, and organ and visceral abnormalities including cardiac hypoplasia, malrotated guts, asymmetrically inverted guts, and cholecystitis. DCF also had a significant effect on the swimmingperformance of both species: at low concentrations (125 and 250 μg L−1), swimming distance, velocity and global activity decreased, whereas, at high concentrations (1000 and 2000 μg L−1), these behavioral responsesincreased. Regarding cardiac function and rhythm, at DCF concentrations higher than 1000 μg L−1, the heart frequency and ventricular systole interval of both specieswere significantly reduced. Regarding the antioxidantsystem, the activity of acetylcholinesterase indicated that DCF is neurotoxic and thus related to the changes in behavioral performance. The DCF concentrations studied produced a biochemical imbalance between radicaloxygen species production and antioxidant systems. The sensitivities to sublethal and chronic DCF exposure in both anuran specieswere similar, thus indicating the inherent complexity involved in understanding the biotoxiceffects of DCF. Fil: Peltzer, Paola. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Saneamiento Ambiental. Cátedra de Ecotoxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Lajmanovich, Rafael Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Saneamiento Ambiental. Cátedra de Ecotoxicología; Argentina Fil: Martinuzzi, Candela Soledad. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Saneamiento Ambiental. Cátedra de Ecotoxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Attademo, Andres Maximiliano. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Saneamiento Ambiental. Cátedra de Ecotoxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Curi, Lucila Marilén. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas. Laboratorio de Saneamiento Ambiental. Cátedra de Ecotoxicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Santa Fe; Argentina Fil: Sandoval, María Teresa. Universidad Nacional del Nordeste. Facultad de Ciencias Exactas, Naturales y Agrimensura. Departamento de Biología; Argentina

The pathophysiology and management of primary spontaneous pneumothorax (PSP) are a subject of debate. Despite advances in the understanding of its etiopathogenesis and improvements in its management, implementation in clinical practice is suboptimal. In this manuscript, we review the recent literature with a focus on PSP pathophysiology and management. Blebs and emphysema-like changes (ELC) are thought to contribute to the pathophysiology of PSP but cannot explain all cases. Recent studies emphasize the role of a diffuse porosity of the visceral pleura. Others found a relationship between smoking, occurrence of a PSP and bronchiolitis, which could be the initial pathological process leading to ELC development. Recent or ongoing studies challenge the need to systematically remove air from the pleural cavity of stable patients, introducing conservative management as a valuable therapeutic option. Evidence is growing in favour of needle aspiration instead of chest tube insertion, when air evacuation is needed. In addition, ambulatory management is considered as a successful approach in meta-analyses and is under exploration in a large randomized study. Because of a high recurrence rate of PSP, the benefit of performing a pleurodesis at first occurrence is under evaluation with interesting but not generalizable results. Better identification of 'at risk patients' is needed to improve the investigation strategy. Finally, recent publications confirm the efficacy, security and cost-effectiveness of graded talc poudrage pleurodesis to prevent PSP recurrence. In conclusion, PSP pathophysiology and management are still under investigation. The results of recently published and ongoing studies should be more widely implemented in clinical practice.

Bison (Bison bison) heifer calves (n = 32) were randomly assigned to control or vaccination with 1010 colony-forming units of Brucella abortus strain RB51 (RB51) vaccine by single or boostered parenteral delivery, or by surgical implantation of a dry dart formulation (n = 8/trt). Serum and/or peripheral blood mononuclear cells (PBMC) were obtained at 0, 4, 8, 13, 16, 21, and 24 wks after initial vaccination and at 0, 4, 8, 12, 15, 22, and 27 wks after booster vaccination to characterize humoral and cellular immune responses to RB51. Bison in both RB51 vaccination treatments demonstrated greater (P < 0.0001) serum humoral responses when compared to non-vaccinates, with parenteral vaccinates demonstrating greater (P < 0.01) responses when compared to mean responses of bison inoculated with the dry dart. Only the booster vaccinated treatment demonstrated greater (P < 0.0001) humoral responses than control bison in samples collected after re-inoculation. At 4, 8, 12, 16, and 24 wks after initial vaccination, PBMC from parenteral RB51 vaccinates demonstrated greater proliferative responses to RB51 when compared to responses of control animals. In comparison, bison inoculated with the RB51 dry dart did not demonstrate greater (P > 0.05) proliferative responses when compared to responses of non-vaccinates. Bison were pasture bred and pregnant animals experimentally challenged in mid-gestation with 107 CFU of B. abortus strain 2,308. Bison in parenteral vaccination treatments had reduced (P < 0.05) abortions and infection in uterine and fetal samples as compared to non-vaccinated bison, with booster vaccinates tending to have the lowest colonization (CFU/gm) in tissues. In comparison, the dry dart formulation did reduce abortion (P < 0.05) but not infection (P > 0.05) in most tissues when compared to non-vaccinated bison. The results of this study reaffirm the efficacy of boostered parenteral vaccination of bison with RB51 in preventing brucellosis. Our data also suggests that the novel dry dart RB51 formulation does not induce sufficient efficacy in bison after a single inoculation.

Obesity has complex links to respiratory health. Mendelian randomization (MR) enables assessment of causality of body mass index (BMI) effects on airflow obstruction and mid-expiratory flow. In the adult SAPALDIA cohort, recruiting 9,651 population-representative samples aged 18–60 years at baseline (female 51%), BMI and the ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) as well as forced mid-expiratory flow (FEF25–75%) were measured three times over 20 follow-up years. The causal effects of BMI in childhood and adulthood on FEV1/FVC and FEF25–75% were assessed in predictive (BMI averaged over 1st and 2nd, lung function (LF) averaged over 2nd and 3rd follow-up; N = 2,850) and long-term cross-sectional models (BMI and LF averaged over all follow-ups; N = 2,728) by Mendelian Randomization analyses with the use of weighted BMI allele score as an instrument variable and two-stage least squares (2SLS) method. Three different BMI allele scores were applied to specifically capture the part of BMI in adulthood that likely reflects tracking of genetically determined BMI in childhood. The main causal effects were derived from models containing BMI (instrumented by BMI genetic score), age, sex, height, and packyears smoked as covariates. BMI interactions were instrumented by the product of the instrument (BMI genetic score) and the relevant concomitant variable. Causal effects of BMI on FEV1/FVC and FEF25–75% were observed in both the predictive and long-term cross-sectional models. The causal BMI- LF effects were negative and attenuated with increasing age, and stronger if instrumented by gene scores associated with childhood BMI. This non-standard MR approach interrogating causal effects of multiplicative interaction suggests that the genetically rooted part of BMI patterns in childhood may be of particular relevance for the level of small airway function and airflow obstruction later in life. The methodological relevance of the results is first to point to the importance of a life course perspective in studies on the etiological role of BMI in respiratory health, and second to point out novel methodological aspects to be considered in future MR studies on the causal effects of obesity related phenotypes.

Mycobacterium bovis is the cause of tuberculosis in most animals, most notably cattle. The stereotypical lesion of bovine tuberculosis is the granuloma; a distinct morphological lesion where host and pathogen interact and disease outcome (i.e., dissemination, confinement, or resolution) is determined. Accordingly, it is critical to understand host-pathogen interactions at the granuloma level. Host-pathogen interactions within individual granulomas at different stages of disease have not been examined in cattle. We examined bacterial burden and cytokine expression in individual pulmonary granulomas from steers at 30, 90, 180, and 270 days after experimental aerosol infection with M. bovis. Bacterial burdens within individual granulomas examined 30 days after infection were greater and more heterogenous (variable) than those examined 90 to 270 days after infection. Bacterial burdens did not correlate with expression of IFN-γ, TNF-α, TGF-β, granuloma stage, or lung lesion score, although there was a modest positive correlation with IL-10 expression. Granuloma stage did have modest positive and negative correlations with TNF-α and IL-10, respectively. Heterogeneity and mean expression of IFN-γ, IL-10 and TNF-α did not differ significantly over time, however, expression of TGF-β at 90 days was significantly greater than that seen at 30 days after infection.

Aquagenic wrinkling of the palms (AWP), also known as aquagenic palmoplantar keratoderma, is an uncommon dermatosis characterized by transient translucent whitish papules, edema, and hyper-wrinkling of the palms and soles shortly after water immersion. Approximately up to 80% of cases reported are associated with cystic fibrosis (CF) patients and up to 25% with CF carriers. We present the case of a 16-year-old male who complains of new-onset symmetrical edematous wrinkling on his palms associated with brief water exposure. After evaluation and genetic testing, the patient was diagnosed with CF and AWP. While there are numerous theories regarding the pathogenesis of AWP, no consensus has been reached regarding its etiology or relationship with CF. However, given the high prevalence of AWP associated with the genetic disease, physicians should have a high index of suspicion of CF or cystic fibrosis transmembrane regulator (CFTR)-related disease in pediatric patients with this presentation. The presence of AWP as part of the physical examination may help recognize challenging CF cases with uncommon genetic variants. Prompt recognition of CF disease leads to timely initiation of CFTR-modulating therapy, improving the patient's health outcomes and quality of life. In this case, we also present the patient's response to CFTR-modulating therapy and compare with baseline status.

Cattle are natural hosts of the intracellular pathogen, Brucella abortus, which inflicts a significant burden on the health and reproduction of these important livestock. The primary routes of infection in field settings have been described, but it is not known how the bovine host shapes the structure of B. abortus populations during infection. We utilized a library of approximately 106 uniquely barcoded B. abortus strains to temporally and spatially quantify population structure at the strain level during colonization of cattle through a natural route of infection. Introducing 108 bacteria from this barcoded library to the conjunctival mucosa resulted in expected levels of local lymph node colonization at a one-week timepoint. We leveraged variance in strain abundance in the library to demonstrate that only 1 in 10,000 brucellae introduced at the site of infection reached the parotid lymph nodes. Thus, cattle restrict the overwhelming majority of B. abortus introduced via the ocular conjunctiva at this dose. Individual strains were spatially restricted within the host tissue, and the total B. abortus census was dominated by a small number of distinct strains in each lymph node. These results define a bottleneck that B. abortus must traverse to colonize local lymph nodes from the conjunctival mucosa. The data further support a model in which a small number of spatially isolated granulomas founded by unique strains are present one-week post infection. These experiments demonstrate the power of barcoded transposon tools to quantify infection bottlenecks and to define pathogen population structure in host tissues.Significance statementUnderstanding microbial population dynamics during infection has important implications for disease management, transmission and pathogen evolution. A quantitative analysis of microbial population structure requires the ability to track individual strains. We used a pool of individually barcoded strains to measure changes in Brucella abortus population structure during infection of bovine hosts via the ocular conjunctiva, a natural route of entry. Cattle exert a severe bottleneck on the bacterial population entering through the conjunctival mucosa such that individual cells have a 0.0001 probability of colonizing a local draining lymph node. The populations in lymph nodes, even on different sides of the same animal, are distinct and dominated by a small number of highly abundant, spatially distinct clones.

Background: An international collaborative study was conducted to determine the demographic and clinical profiles of Hispanic/Latinx endometriosis patients from Latin America and Spain using the Minimal Clinical Questionnaire developed by the World Endometriosis Research Foundation (WERF) Endometriosis Phenome and Biobanking Harmonization Project (EPHect).Methods: This is a cross-sectional study to collect self-reported data on demographics, lifestyle, and endometriosis symptoms of Hispanic/Latinx endometriosis patients from April 2019 to February 2020. The EPHect Minimal Clinical Questionnaire (EPQ-M) was translated into Spanish. Comprehension and length of the translated survey were assessed by Spanish-speaking women. An electronic link was distributed via social media of endometriosis patient associations from 11 Latin American countries and Spain. Descriptive statistics (frequency, means and SD, percentages, and proportions) and correlations were conducted using SPSSv26.Results: The questionnaire was completed by 1,378 participants from 23 countries; 94.6% had self-reported diagnosis of endometriosis. Diagnostic delay was 6.6 years. Most participants had higher education, private health insurance, and were employed. The most common symptoms were back/leg pain (85.4%) and fatigue (80.7%). The mean number of children was 1.5; 34.4% had miscarriages; the mean length of infertility was 3.7 years; 47.2% reported pregnancy complications. The most common hormone treatment was oral contraceptives (47.0%). The most common comorbidities were migraines (24.1%), polycystic ovary syndrome (PCOS) (22.2%), and irritable bowel syndrome (21.1%). Most participants (97.0%) experienced pelvic pain during menses; for 78.7%, pain was severe; 86.4% reported dyspareunia. The mean age of dysmenorrhea onset was 16.2 years (SD ± 6.1). Hormone treatments were underutilized, while impact was substantial. Pain catastrophizing scores were significantly correlated with pain intensity (p < 0.001).Conclusion: This is the first comprehensive effort to generate a clinical–demographic profile of Hispanic/Latinx endometriosis patients. Differences in clinical presentation compared to other cohorts included higher prevalence and severity of dysmenorrhea and dyspareunia and high levels of pain catastrophizing. Though future studies are needed to dissect the impact of race and ethnicity on pain and impact, this profile is the first step to facilitate the recognition of risk factors and diagnostic features and promote improved clinical management of this patient population. The EPHect questionnaire is an efficient tool to capture data to allow comparisons across ethnicities and geographic regions and tackle disparities in endometriosis research.

Introduction and Objectives Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pneumonia is associated with severe hypoxemic respiratory failure requiring treatment in intensive care units (ICUs) in approximately 5-10% of hospitalized patients Lung protective mechanical ventilation and intermittent prone positioning are standard care and evidence-based strategies in the management of severe acute respiratory distress syndrome These strategies are presented in Surviving Sepsis Campaign guidelines for the management of critically-ill adults with coronavirus disease (COVID-19) Prone positioning as a complement to oxygen therapy to treat hypoxemia in COVID-19 pneumonia in spontaneously breathing patients has been widely adopted, despite a lack of evidence for its benefit The objective of this single-center, cluster-randomised controlled trial is to test the hypothesis that a simple incentive to self-prone would decrease oxygen needs in patients admitted to the ward for COVID-19 pneumonia on low-flow oxygen therapy Methods Twenty-seven patients with confirmed COVID-19 pneumonia admitted to our University Hospital medical ward were included in the study Ten patients were randomised to self-prone positioning and 17 to usual care Main Results Oxygen needs assessed by oxygen flow on nasal cannula at inclusion were similar between groups Twenty-four hours after starting the intervention, the median oxygen flow was 1 0 L/min (interquartile range, 0 1-2 9) in the prone position group and 2 0 L/min (interquartile range, 0 5-3 0) in the control group (P = 0 507) (figure 1) Median oxygen saturation/fraction of inspired oxygen ratio was 390 (interquartile range, 300-432) in the prone position group and 336 (interquartile range, 294-422) in the control group (P = 0 633) No serious adverse events were observed Conclusions Self-prone positioning in patients with COVID-19 pneumonia requiring low-flow oxygen therapy resulted in a clinically meaningful reduction of oxygen flow, without reaching statistical significance Early interruption of the trial after the first wave most probably resulted in underpower of our study Self-prone positioning was easy to implement and well tolerated Given the rapid increase of cases during the COVID-19 pandemic, any simple intervention to limit the progression of hypoxemia and avoid transfers of patients to ICUs may be of benefit for the management of hospital resources

Background The symptomatic response to continuous positive airway pressure (CPAP) therapy in COPD-obstructive sleep apnea overlap syndrome (OVS) compared to OSA syndrome (OSA) alone has not been well studied so far. The aim of this study is to explore main differences in the clinical response to CPAP treatment in OVS compared to OSA alone. Study design and methods Using prospective data from the French National Sleep Apnea Registry, we conducted an observational study among 6320 patients with moderate-to-severe OSA, available spirometry, and at least one follow-up visit under CPAP therapy. Results CPAP efficacy measured on the residual apnea-hypopnea index and median adherence were similar between OVS and OSA patients. In both groups, the overall burden of symptoms related to sleep apnea improved with CPAP treatment. In a multivariable model adjusted for age, gender, body mass index, adherence to treatment and residual apnea-hypopnea index, OVS was associated with higher odds for persistent morning headaches (OR: 1.37 [95% CI; 1.04; 1.79]; P = 0.02), morning tiredness (OR: 1.33 [95% CI: 1.12; 1.59]; P Interpretation CPAP therapy was effective in normalizing the apnea-hypopnea index and significantly improved OSA-related symptoms, regardless of COPD status. CPAP should be offered to patients with OVS on a trial basis as a significant improvement in OSA-related symptoms can be expected, although the range of response may be less dramatic than in OSA alone.

Feral swine (Sus scrofa) are a destructive invasive species widespread throughout the United States that disrupt ecosystems, damage crops, and carry pathogens of concern for the health of domestic stock and humans includingBrucella suis—the causative organism for swine brucellosis. In domestic swine, brucellosis results in reproductive failure due to abortions and infertility. Contact with infected feral swine poses spillover risks to domestic pigs as well as humans, companion animals, wildlife, and other livestock. Genetic factors influence the outcome of infectious diseases; therefore, genome wide association studies (GWAS) of differential immune responses among feral swine can provide an understanding of disease dynamics and inform management to prevent the spillover of brucellosis from feral swine to domestic pigs. We sought to identify loci associated with differential antibody responses among feral swine naturally infected withB. suisusing a case-control GWAS. Tissue, serum, and genotype data (68,516 bi-allelic single nucleotide polymorphisms) collected from 47 feral swine were analyzed in this study. The 47 feral swine were culture positive forBrucellaspp. Of these 47, 16 were antibody positive (cases) whereas 31 were antibody negative (controls). Single-locus GWAS were performed using efficient mixed-model association eXpedited (EMMAX) methodology with three genetic models: additive, dominant, and recessive. Eight loci associated with seroconversion were identified on chromosome 4, 8, 9, 10, 12, and 18. Subsequent bioinformatic analyses revealed nine putative candidate genes related to immune function, most notably phagocytosis and induction of an inflammatory response. Identified loci and putative candidate genes may play an important role in host immune responses toB. suisinfection, characterized by a detectable bacterial presence yet a differential antibody response. Given that antibody tests are used to evaluate brucellosis infection in domestic pigs and for disease surveillance in invasive feral swine, additional studies are needed to fully understand the genetic component of the response toB. suisinfection and to more effectively translate estimates ofBrucellaspp. antibody prevalence among feral swine to disease control management action.

Objective Intraventricular hemorrhage (IVH) is the most common central nervous system pathology in preterm infants. No consensus has been reached over the best indication for intervention in patients with posthemorrhagic hydrocephalus (PHH). The authors present the neurological outcome of infants with IVH and an early treatment approach, defined as an intervention when ventricular dilation is less than 4-mm over the 97th-percentile of Levene’s index. Methods We performed a retrospective case-series study of 12 infants who had IVH and an early intervention, their neurological development was evaluated after 18-months of corrected age using the Bayley-III Scales. Measures of central tendency and Pearson’s correlation were used for data analysis. Results In a 15-month period, twelve patients were diagnosed with IVH and underwent an early intervention. At the time of diagnosis, 2 patients had grade II IVH, 7 grade III, and 3 grade IV. Subgaleal shunt was the first intervention. 9 (75 %) ultimately required a ventriculoperitoneal shunt. A total of 9 (75 %) patients had normal cognitive scores, 7 (58.3 %) for the language-composite, and 8 (66.7 %) for the motor-composite. 6 (50 %) patients had normal scores in all composites. The average scores reported normal results (CC:98.33 ± 22.59; LC:98.25 ± 23.93; MC:88.58 ± 21.47). There was a significant correlation between antenatal steroids and the LC-score (p = 0.044). Conclusions Half of the patients with PHH and early neurosurgical interventions had an average or above average neurodevelopmental score in all three areas. Current literature and undergoing clinical trials have shown promising results on the implementation of this type of intervention.

The tumour microenvironment (TME) is an important mediator of breast cancer progression. Cancer-associated fibroblasts (CAFs) constitute a major component of the TME and may originate from tissue-associated fibroblasts or infiltrating mesenchymal stromal cells (MSCs). The mechanisms by which cancer cells activate fibroblasts and recruit MSCs to the TME are largely unknown, but likely include deposition of a pro-tumourigenic secretome. The secreted embryonic protein NODAL is clinically associated with breast cancer stage and promotes tumour growth, metastasis, and vascularization. Herein, we show that NODAL expression correlates with the presence of activated fibroblasts in human triple negative breast cancers and that it directly induces CAF phenotypes. We further show that NODAL reprograms cancer cell secretomes by simultaneously altering levels of chemokines (e.g. CXCL1), cytokines (e.g. IL-6) and growth factors (e.g. PDGFRA), leading to alterations in MSC chemotaxis. We therefore demonstrate a hitherto unappreciated mechanism underlying the dynamic regulation of the TME.

BackgroundMore advanced knowledge is needed on how COPD alters the clinical presentation of obstructive sleep apnea (OSA) and how the association of both diseases, known as 'overlap syndrome' (OVS), impacts on cardiovascular health.ObjectiveTo investigate differences between patients with OVS and those with moderate-to-severe OSA alone.MethodsA cross-sectional study conducted in the French National Sleep Apnea Registry between January 1997 and January 2017. Univariable and multivariable logistic regression models were used to compare OVS versus OSA alone on symptoms and cardiovascular health.Results46,786 patients had moderate-to-severe OSA. Valid spirometry was available for 16,466 patients: 14,368 (87%) had moderate-to-severe OSA alone and 2098 (13%) had OVS. A lower proportion of OVS patients complained of snoring, morning headaches and excessive daytime sleepiness compared to OSA alone (median Epworth Sleepiness Scale score: 9 [interquartile range (IQR) 6-13] versus 10 (IQR 6-13), respectively; P ConclusionsIn adults with moderate-to-severe OSA, OVS was minimally symptomatic, but exhibited higher odds for prevalent coronary heart disease, heart failure and peripheral arteriopathy.

Prior studies suggest that a combination of physical activity and mind–body exercises, often seen in martial arts, may attenuate negative behaviors in youth with Autism Spectrum Disorder (ASD). Therefore, the aim of this study was to examine the effects of an 8-week judo program on behavioral factors in children with ASD, using a mixed-methods approach. A total of 25 children (ages 8–17), diagnosed with ASD, participated in an 8-week judo program (1 × week). Parents of participants were given the Aberrant Behavior Checklist (ABC) to compare the severity of ASD-related behavior at baseline and at the end of the program. A subset of parents (n = 9) participated in semi-structured interviews that focused on their child’s behaviors during the judo program. Non-parametric paired t-tests were conducted to compare differences in the ABC scores from at baseline and at the end of the program. Interviews were coded independently by two trained researchers and categorized into behavioral themes. Participants attended an average of 7.04 ± 1.06 classes (out of 8 sessions). There were no significant changes in ABC scores, however, parent interviews revealed that 78% of parents observed improvements in both social skills and self-esteem as a result of the judo program. Despite no significant differences in ABC scores pre and post-judo, data from parent interviews indicate improvements in self-esteem and social skills. Future studies should further examine the effects of judo in a larger sample of youth with ASD, and include control conditions (e.g. no-exercise group) for comparison purposes.

We present a case of a 61-year-old man with history of prostate cancer and rising PSA levels referred for restaging. Ga-PSMA-11 PET/CT identified 2 lung nodules with low and moderate PSMA uptake. Subsequent F-FDG PET/CT showed high hypermetabolism in the nodule with low PSMA uptake, and low hypermetabolism in the nodule with moderate PSMA uptake. The isolated pulmonary findings and metabolic appearance is an atypical presentation of prostate cancer metastases and raised concern for a second primary malignancy. Fine-needle aspiration of the F-FDG active lung nodule confirmed metastatic prostatic adenocarcinoma that subsequently responded to androgen deprivation therapy and abiraterone acetate.

Background: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome driven by ectopic production of fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting, hypophosphatemia, and bone demineralization. Successful therapy requires complete resection of the tumor, which is often challenging to localize. Clinical Case: A bedridden 37-year-old woman presented to Endocrine Clinic after 9 years of progressive pain and weakness in her back, hips, and extremities. She had previously been diagnosed with a neurodegenerative disease, though an MRI from 5 years ago showed bilateral subacute sacral ala fractures. CT scan on presentation showed generalized osteopenia and numerous subacute to chronic atraumatic fractures (involving ribs, scapula, pubic rami, and right femoral shaft) concerning for osteomalacia. On exam, she had profound lower extremity weakness. Laboratory testing was notable for serum phosphorus 0.6 mg/dL (normal (nl) 2.5-4.9), calcium 8.4 mg/dL (nl 8.5-10.5), PTH 216 pg/mL (nl 13-85), 25-OH vitamin D 26 ng/mL (nl 30-100), alkaline phosphatase 345 U/L (nl 45-130), 1,25-(OH)2 vitamin D 28 pg/mL (nl 18-72), renal tubular phosphorus reabsorption TmP/GFR 0.53 mg/dL (nl 2.97-4.45), and inappropriately normal FGF23 level 170 RU/mL (nl

Introduction: A composite pheochromocytoma (PC) is an adrenal tumor that is often diagnosed post-operatively on histopathology. PCs are unique in that it is a combination of typicalpheochromocytoma and neural crest derived tumors. The incidence is reported to be less than 3%of adrenal neoplasms. The most common co-existing tumor within a PC is a ganglioneuroma. Wepresent a rare case of PC containing ganglioneuroblastoma (PC-GNBL) in a woman withoutsignificant biochemical manifestation of excess catecholamine production. Case Report: A 63-year-old woman with a prolonged history of uncontrolled hypertension on 4 oral anti-hypertensive medications (Amilodipine 10mg daily, Valsartan/HCTZ 320/25mg daily andClonidine 0.1mg/24h patch) and uncontrolled type 2 diabetes on insulin was diagnosed with a1.5x1.8x1.5cm right adrenal incidentaloma 2 years prior on CT imaging for abdominal pain. Hormonal evaluation was notable for plasma free metanephrine of 66 (

To evaluate ascending aortic strain (AAS) with cardiac magnetic resonance (CMR) in a large consecutive series of patients with different types of cardiovascular disease (CVD).Two-dimensional phase-contrast gradient-echo sequences of the ascending aorta were retrospectively reviewed in 1027 patients (726 males, 301 females). Aortic lumen area was segmented using a semi-automatic approach to calculate AAS values. Subgroup analysis was performed for patients with normal CMR, tetralogy of Fallot (ToF), and ischemic heart disease (IHD). Multivariate and post-hoc analyses were performed to evaluate the effect of age, gender, and CVD on AAS values. Shapiro-Wilk, three- and two-way ANOVA, Mann-Whitney U, and Spearman correlation statistics were used.Multivariate analysis showed significant differences in AAS among decades of age (p0.001), genders (p=0.006) and CVD subgroups (p0.001) without interaction among these factors. A gender-related difference (higher AAS in females) was significant in ToF (p=0.008), while an AAS reduction during aging was observed in all CVD subgroups. Post-hoc analysis showed a significantly lower AAS in ToF and IHD patients compared to subjects with normal CMR (p0.001).Differences in age, gender, and CVD independently affect AAS. The lower AAS observed in ToF fosters its assessment during follow-up in adulthood. Future studies on causes and clinical implications of a higher AAS in females affected by ToF are warranted.

Introduction: Daratumumab (DARA)-based regimens are effective and well tolerated in both newly diagnosed and relapsed/refractory multiple myeloma (RRMM) patients. However, the prognosis for patients who have become refractory to proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs) and DARA is poor. A better understanding of determinants of response and mechanisms of resistance to DARA may lead to new rationally designed treatment strategies. We therefore characterized the effect of DARA on the immune system in MM patients treated with DARA monotherapy in part A of the DARA-ATRA study (ClinicalTrials.gov NCT02751255). Methods: In part A of this prospective multicenter phase 2 trial, 63 DARA-naïve patients were treated with DARA monotherapy (16 mg/kg; approved schedule). Median number of prior lines of treatment was 4 (range 2-11), all patients were previously exposed to lenalidomide and a PI; 89% was refractory to an IMiD, 71% to a PI and 67% to both IMiD and PI. Bone marrow (BM) aspirates obtained at baseline (BL) and at progression (PD; primary refractory, or acquired resistance after prior response) were subjected to deep immune profiling using 28 surface- and intracellular proteins measured by flow cytometry (BL n=51, PD n=47). In a subset of these patients (BL n=39, PD n=33) mass cytometry (CyTOF) was also performed profiling 39 proteins. In addition, peripheral blood (PB) samples obtained at BL (n=44) and PD (n=37) were analyzed using CyTOF. Computational analyses of flow data were performed using UMAP and FlowSOM; CyTOF data were analyzed using SPADE and Freeviz. Statistical analyses included Wilcoxon rank-sum and signed-rank tests, Generalized Linear Mixed Models and ANOVA. Results: A partial response or better was achieved in 41% of patients treated with DARA monotherapy. We compared immune profiles of responding and non-responding (primary-refractory) patients. At BL, the percentages of MM-, T-, B- and NK cells in BM were similar between both groups. However, NK cells of non-responding patients had a lower proportion of CD16 + (P=0.029), and a higher proportion of TIM-3 + (P=0.010) and HLA-DR + (P=0.043) NK cells, suggesting an exhausted phenotype. Non-responders also had a higher proportion of TIM-3 + CD4 + (P=0.022) and TIM-3 + CD8 + T-cells (P=0.004), and a higher proportion of TIM-3 + regulatory T-cells (Tregs) (P=0.042). A higher proportion of TIM-3 + -NK cells, -T-cells, or -Tregs in BM was also associated with poor progression-free and overall survival (PFS; OS). In addition, clinical characteristics associated with poor PFS such as LDH (P=0.016), extramedullary disease (P=0.001) and (R-)ISS stage III (P=0.015) were associated with an increased number of phenotypically exhausted NK- and T-cells. Similar to prior studies, DARA treatment resulted in reduced levels of CD38 on all immune cell subsets and a marked decrease in Tregs, regulatory B cells (Bregs) and NK cells in both BM and PB. Upon acquired resistance, remaining NK cells displayed higher proportions of TIM-3 + (P=0.022), HLA-DR + (P=0.0007) and LAG-3 + (P=0.011), and lower proportions of CD16 + (P=0.002) (Figure 1), compatible with an exhausted phenotype. Furthermore, disease progression was associated with an increase in CD4 + and CD8 + terminally differentiated effector memory T-cells and a decrease in CD4 + and CD8 + central memory T-cells in BM. There was no significant change in the proportion of T-cells expressing immune checkpoint molecules. CyTOF analysis of BM and PB samples confirmed flow cytometric findings. Furthermore, data-driven analysis identified immune profiles specific to progression, including a significant decrease in the fraction of Granzyme B + NK cells, and increase in the fraction of Granzyme B + Bregs at the time of progression. Based on NK cell depletion and -exhaustion observed at PD, we hypothesized that NK cell repletion may restore DARA sensitivity. Indeed, in ex vivo experiments we show that DARA-resistance can be overcome by addition of healthy donor derived NK cells to MM cells obtained from DARA-refractory patients. Conclusion: Here we show that an increased proportion of NK cells with an exhausted phenotype is associated with primary and acquired DARA-resistance, which is in line with the important role of NK cells in DARA-mediated tumor cell elimination ex vivo. Future DARA-based treatment strategies may benefit from reinvigorating NK cells and restoring their cytotoxic capacities. Figure 1 Figure 1. Disclosures Zweegman: Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Minnema: Celgene: Other: Travel expenses; Alnylam: Consultancy; Cilag: Consultancy; Janssen: Consultancy; Kite/Gilead: Consultancy; BMS: Consultancy. Broyl: Celgene/BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Levin: Roche, Janssen, Abbvie: Other: Travel Expenses, Ad-Board. Kersten: Kite/Gilead: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Roche: Honoraria; Takeda: Consultancy; BMS/Celgene: Consultancy; Miltenyi Biotech: Consultancy. Krevvata: Janssen: Current Employment. Casneuf: Janssen: Current Employment. Abraham: Janssen: Current Employment. Verona: Janssen: Current Employment. Smets: Janssen: Current Employment. Vanhoof: Janssen: Current Employment. Cortes-Selva: Janssen: Current Employment. van Steenbergen: Biolizard working for Janssen: Current Employment. Vieyra: Janssen: Current Employment. Sonneveld: Karyopharm: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Mutis: Janssen: Honoraria; Genmab: Research Funding; Takeda: Research Funding; Novartis: Research Funding; ONK Therapeutics: Research Funding. van de Donk: Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Bone marrow fat is a functionally distinct adipose tissue that may contribute to systemic metabolism. This study aimed at evaluating a possible association between bone marrow fat and insulin sensitivity indices. Fifty obese (n = 23) and non-obese (n = 27) premenopausal women underwent proton magnetic resonance spectroscopy to measure vertebral bone marrow fat content and unsaturation index at L4 level. Abdominal visceral, subcutaneous fat, and epicardial fat were also measured using magnetic resonance imaging. Bone mineral density was measured by dual-energy X-ray absorptiometry. Body composition was assessed by bioelectrical impedance analysis. Fasting serum glucose, insulin, lipids, adiponectin were measured; the insulin resistance index HOMA (HOMA-IR) was calculated. Bone marrow fat content and unsaturation index were similar in obese and non-obese women (38.5 ± 0.1 vs. 38.6 ± 0.1%, p = 0.994; 0.162 ± 0.065 vs. 0.175 ± 0.048, p = 0.473, respectively). Bone marrow fat content negatively correlated with insulin and HOMA-IR (r = −0.342, r = −0.352, respectively, p = 0.01) and positively with high density lipoprotein cholesterol (r = 0.270, p = 0.043). From a multivariate regression model including lnHOMA-IR as a dependent variable and visceral, subcutaneous, epicardial fat, and bone marrow fat as independent variables, lnHOMA-IR was significantly associated with bone marrow fat (β = −0.008 ± 0.004, p = 0.04) and subcutaneous fat (β = 0.003 ± 0.001, p = 0.04). Bone marrow fat, among the other adipose depots, was a significant predictor of circulating adiponectin (β = 0.147 ± 0.060, p = 0.021). Bone marrow fat unsaturation index negatively correlated with visceral fat (r = −0.316, p = 0.026). There is a relationship between bone marrow fat content and insulin sensitivity in obese and non-obese premenopausal women, possibly mediated by adiponectin secretion. Visceral fat does not seem to regulate bone marrow fat content while it may affect bone marrow fat composition.

BACKGROUND Barriers and motives towards physical activity (PA) in lung transplant (LTx) recipients with cystic fibrosis (CF) are largely unknown. We aimed to explore perceptions towards PA in LTx recipients with CF to better understand individuals' needs and preferences. METHODS Participants completed an online survey at two Swiss LTx and one follow-up shared care centre between June and December 2018. RESULTS One hundred and eleven individuals completed the survey (87.4% response rate). Overall, survey participants perceive PA as important for their daily life and health. Perceived motives of PA were improving muscle strength, endurance and quality of life (QoL), to feel better, fun, to achieve personal goals and having more energy for everyday life. Fatigue was the most common perceived barrier to PA and associated with poorer QoL (r = -0.43, p

Background. Pulmonary alveolar proteinosis (PAP) is a pulmonary disease characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. PAP is classically classified into three categories (Table 1): 1/primary (or autoimmune) with antibodies targeting the GM-CSF pathway, 2/secondary to another disease, typically a hematologic malignancy, and 3/genetic. Case-report. A 30 year-old woman received an allogenic hematopoietic stem cell transplantation (HSCT) after treatment for acute myeloid leukemia (AML). Within the first 6 months post HSCT, she developed an ocular, oral, digestive and hepatic graft-versus-host disease associated with a mixed ventilatory defect with a very severe obstructive syndrome and a severe CO diffusion impairment. High resolution computed tomography showed a classical “crazy paving” pattern. Aspect and differential cell count of BAL were normal. All microbiological samples remained culture negative. Histo-pathological analysis of transbronchial biopsies was unremarkable. Because of the severity of the respiratory insufficiency, open-lung biopsy (OBL) could not be performed. Despite multiple immunosuppressive therapies, lung function deteriorated rapidly; the patient also developed an excavated fungal lesion unresponsive to treatment. She underwent a bilateral lung transplant 48 months after HSCT. Histo-pathological analysis of explanted lungs showed obliterative bronchiolitis (OB), diffuse PAP and invasive cavitary pulmonary aspergillosis. Conclusions. This case illustrates the simultaneous occurrence of OB, PAP and a fungal infection in a 30-year old female patient who underwent HSCT for acute myeloid leukemia (AML). To our knowledge this is the only documented case of PAP associated with OB treated by lung transplantation., Highlights • PAP is characterized by disruption of surfactant homeostasis resulting in its accumulation in the alveoli. • Secondary PAP represent less than 10 % of all cases, hematologic disorders account for the majority of them. • Bronchoalveolar-lavage can establish diagnosis in 75% of cases however lung biopsy remains thegold standard. • There is no specific treatment, whole-lung lavage remains the standard of care. • This case illustrates the simultaneous occurrence of OB, PAP and invasive pulmonary aspergillosis treated by BLT.

To examine the preliminary efficacy of an 8-week judo program to promote moderate-to-vigorous physical activity (MVPA) and reduce sedentary behavior (SB) in youth with Autism Spectrum Disorder (ASD). Fourteen children diagnosed with ASD participated in a weekly judo program over a period of 8 weeks. Participants wore an Actigraph accelerometer to measure activity levels at baseline and post-judo. All 14 children attended at least 75% of the 8 judo classes. Percentage of time spent in daily MVPA (8% vs 4%, p = .05) increased following the intervention. A high rate of participation and an increase in time spent in MVPA was observed following the 8-week program. Further research to examine causal mechanisms is warranted.

Oculomotor synkinesis is the involuntary movement of the eyes or eyelids with a voluntary attempt at a different movement. The chemokine receptor CXCR4 and its ligand CXCL12 regulate oculomotor nerve development; mice with loss of either molecule have oculomotor synkinesis. In a consanguineous family with congenital ptosis and elevation of the ptotic eyelid with ipsilateral abduction, we identified a co-segregating homozygous missense variant (c.772G>A) in ACKR3, which encodes an atypical chemokine receptor that binds CXCL12 and functions as a scavenger receptor, regulating levels of CXCL12 available for CXCR4 signaling. The mutant protein (p.V258M) is expressed and traffics to the cell surface but has a lower binding affinity for CXCL12. Mice with loss of Ackr3 have variable phenotypes that include misrouting of the oculomotor and abducens nerves. All embryos show oculomotor nerve misrouting, ranging from complete misprojection in the midbrain, to aberrant peripheral branching, to a thin nerve, which aberrantly innervates the lateral rectus (as seen in Duane syndrome). The abducens nerve phenotype ranges from complete absence, to aberrant projections within the orbit, to a normal trajectory. Loss of ACKR3 in the midbrain leads to downregulation of CXCR4 protein, consistent with reports that excess CXCL12 causes ligand-induced degradation of CXCR4. Correspondingly, excess CXCL12 applied to ex vivo oculomotor slices causes axon misrouting, similar to inhibition of CXCR4. Thus, ACKR3, through its regulation of CXCL12 levels, is an important regulator of axon guidance in the oculomotor system; complete loss causes oculomotor synkinesis in mice, while reduced function causes oculomotor synkinesis in humans.

El cáncer de mama es el segundo tipo de cáncer más frecuente entre las mujeres de los Estados Unidos y Puerto Rico. La mastectomía es uno de los diversos tratamientos para el cáncer de mama. En Puerto Rico, son escasas las investigaciones en el estudio del impacto de la mastectomía en la satisfacción sexual y en la relación de pareja. Los objetivos de este estudio fueron: (a) evaluar si la cirugía de mastectomía impacta significativamente la satisfacción sexual de las participantes, (b) evaluar si la cirugía de mastectomía impacta la relación de pareja de las participantes, (c) evaluar si la cirugía de mastectomía impacta los síntomas de depresión de las participantes. Se llevó a cabo un estudio de método cuantitativo de tipo exploratorio con una muestra de 29 mujeres con cáncer del mama y 30 mujeres sin cáncer como grupo comparativo. Se utilizó un cuestionario sociodemográfico y sexual, el ESSS, el ESP-10 y el PHQ-8. Se llevó a cabo un análisis de prueba U de Mann-Whitney de muestras independientes para la comparación de los grupos. Los resultados sugieren que la muestra de mujeres con cáncer de seno sometidas a mastectomía reportó significativamente menor satisfacción sexual y satisfacción en la relación de pareja, que las participantes del grupo comparativo. No se encontró diferencias significativas en los síntomas de depresión. Además, se encontraron diferencias significativas para las variables de edad y tiempo en la relación. Estos resultados exponen la importancia de que el tratamiento para las mujeres con cáncer de seno y sometidas a mastectomía sea integrado desde un enfoque interdisciplinario.

Mental health disorders are a burgeoning global public health challenge, and disproportionately affect the poor. Low- and middle-income countries (LMICs) bear 80 % of the mental health disease burden. Stigma associated with mental health results in delayed help seeking, reduced access to health services, suboptimal treatment, poor outcomes and an increased risk of individuals' human rights violations. Moreover, widespread co-occurrence of physical comorbidities such as noncommunicable diseases with mental health disorders makes the treatment of both conditions challenging and worsens prognosis. This paper explores various aspects of stigma towards mental health with a focus on LMICs and assesses measures to increase help-seeking and access to and uptake of mental health services. Stigma impacts persons living with mental illness, their families and caregivers and healthcare professionals (mental health professionals, non-psychiatric specialists and general practitioners) imparting mental health care. Cultural, socio-economic and religious factors determine various aspects of mental health in LMICs, ranging from perceptions of health and illness, health seeking behavior, attitudes of the individuals and health practitioners and mental health systems. Addressing stigma requires comprehensive and inclusive mental health policies and legislations; sustainable and culturally-adapted awareness programs; capacity building of mental health workforce through task-shifting and interprofessional approaches; and improved access to mental health services by integration with primary healthcare and utilizing existing pathways of care. Future strategies targeting stigma reduction must consider the enormous physical comorbidity burden associated with mental health, prioritize workplace interventions and importantly, address the deterioration of population mental health from the COVID-19 pandemic.

The tumour microenvironment (TME), consisting of stromal cell types including fibroblasts, endothelial, immune and mesenchymal stromal cells (MSCs), is an important mediator of breast cancer (BCa) progression. BCa cells regulate the composition of the TME by secreting a myriad of factors; however, mechanisms governing the dynamic reciprocity between BCa and TME components are largely unknown. Cancer-associated fibroblasts (CAFs) are a major stromal component in many BCa and have been shown to be activated by BCa cells. MSCs recruited to the TME are an important source of CAFs in many cancers; therefore, characterizing the factors involved in MSC recruitment could provide additional avenues for therapeutic intervention by disrupting the TME in BCa. NODAL, an embryonic morphogen belonging to the TGF-beta superfamily, is clinically associated with BCa progression, and has been shown to sustain BCa stem cells and to promote tumour growth, metastasis, and vascularization. Herein, we report that NODAL expression positively correlates with the presence of CAFs in the stroma of triple-negative human BCa tissues, as determined by NODAL and a-smooth muscle Actin (SMA) staining. Further, our in vitro studies show that NODAL directly induces primary fibroblast activation and chemotaxis. Proteomic analysis of the conditioned media of NODAL-overexpressing MDA-MB-231 and SUM149 BCa cells by mass spectrometry reveal that NODAL reprograms BCa secretomes by simultaneously altering levels of chemokines (e.g. CXCL1), growth factors (e.g. PDGFRA) and cytokines (e.g. IL-6), and that the NODAL-regulated secretome, but not NODAL directly, impacts the ability of BCa cells to affect MSC chemotaxis. We provide evidence that IL-6 promotes MSC chemotaxis, and further discuss the context-dependent effects of NODAL in BCa cell lines. Collectively, our results suggest that factors present in NODAL-regulated secretomes may induce MSC recruitment to the breast TME, where they may contribute to CAF population, therefore demonstrating a hitherto unappreciated role of NODAL as a dynamic regulator of breast TME components. Citation Format: Dylan Dieters-Castator, Paola M. Dantonio, Matt Piaseczny, Guihua Zhang, Jiahui Liu, Miljan Kuljanin, Stephen Sherman, Michael Jewer, Katherine Quesnel, Eun-Young Kang, Martin Köbel, Gabrielle M. Siegers, Andrew Leask, David Hess, Gilles Lajoie, Lynne-Marie Postovit. Embryonic protein NODAL as a potential modulator of the tumour microenvironment: Breast cancer secretome reprogramming and fibroblast activation [abstract]. In: Proceedings of the AACR Virtual Special Conference on the Evolving Tumor Microenvironment in Cancer Progression: Mechanisms and Emerging Therapeutic Opportunities; in association with the Tumor Microenvironment (TME) Working Group; 2021 Jan 11-12. Philadelphia (PA): AACR; Cancer Res 2021;81(5 Suppl):Abstract nr PO028.

Rationale and Objectives To evaluate the diagnostic accuracy of semiautomated global quantification of left ventricular myocardial perfusion derived from stress dynamic computed tomography myocardial perfusion imaging (CTMPI) for detection of territorial perfusion deficits (PD). Materials and Methods Dynamic CTMPI datasets of 71 patients were analyzed using semiautomated volume-based software to calculate global myocardial blood flow (MBF), myocardial blood volume, and volume transfer constant. Optimal cutoff values to assess the diagnostic accuracy of these parameters for detection of one- to three-vessel territories with PD in comparison to visual analysis were calculated. Results Nonsignificant differences ( P = 0.694) were found for average global MBF in patients without PD and single-territorial PD. Significant differences were found for mean global MBF in patients with PD in two ( P P Conclusions Semiautomated global quantification of left ventricular MBF during stress dynamic CTMPI shows high diagnostic accuracy for detection of ≥2 vessel territories with PD, facilitating identification of patients with multi-territorial myocardial PD.

Pulmonary hypertension (PH) is a haemodynamic syndrome defined by a mean pulmonary arterial pressure (mPAP) >25 mmHg determined by right heart catheterisation (RHC) [1, 2]. A lot of ­diseases fulfil this definition, but they differ widely between each other in respect to their pathophysiology, their haemodynamic characteristics, their clinical presentation, their natural prognosis and their potential therapeutic strategies. The current guidelines on PH diagnosis and management make the distinction between five groups of more than 200 causes of PH [2], but these diseases are very different from one another. In the current classification, the first group (group 1) represents a progressive vasculopathy leading to pre-capillary PH called pulmonary arterial hypertension (PAH), characterised by a characteristic small-calibre pulmonary artery remodelling, as a result of proliferation of endothelial and smooth muscle cells as well as medial hypertrophy. So, if we compare PAH (for example idiopathic PAH) from PH due to valvular disease like mitral insufficiency (group 2.3) it is easy to understand that apart from the fact that mean pulmonary arterial pressure (mPAP) exceeds 25 mmHg in both cases, these two entities have very different pathophysiological pathways. In the first case, there is a true pulmonary vasculopathy. In the second, PH is mainly related to the consequences of an increased hydrostatic pressure in the left atrium ­transmitted to the venous compartment of the pulmonary circulation and then back through the capillary bed. If the pathophysiology of these entities is different, the targets of their treatments are too. The main goal of PAH treatment consists in reducing pulmonary vascular resistance (PVR) with specific medication and, when appropriate, with specific treatment of the underlying disease as it is the case for associated-PAH (group 1.4). Alternatively, the management of PH related to a mitral regurgitation would be to improve the ventricular preload, diminish the ventricular afterload and, if necessary, to correct the anatomical anomaly., The distinction between PH in the elderly and normal ageing might make diagnosis difficult http://ow.ly/YYF1Q

To assess the effects of challenge dose and stage of gestation on infection and abortion, 35 elk were conjunctivally challenged with virulent Brucella abortus strain 2308 (S2308) during pregnancy. Seventeen elk were experimentally challenged early in the second trimester of gestation (December) with high (approximately 108 CFU) or low challenge (approximately 107 CFU) treatments having 8 and 9 pregnant elk, respectively. Other pregnant elk were experimentally challenged at a later challenge time (approximately early third trimester, February), with high and low challenge treatments having 8 and 10 elk, respectively. Conjunctival swabs from all animals were culture positive for the S2308 strain at 7 days after experimental challenge. All animals seroconverted on a B. abortus ELISA but optical density readings were not influenced (P > 0.05) by time of challenge or by challenge dosage. In the early challenge group, abortions occurred in 2 of 9 (22%) in the low challenge treatment and 3 of 8 (37%) in the high challenge treatment, whereas in the later challenge group, 1 of 8 (12.5%) in the low challenge treatment and 2 of 10 (20%) in the high challenge treatment aborted. The ability to recover B. abortus from samples obtained at necropsy did not differ (P > 0.05) between early and late challenges or between high and low challenge treatments. Despite the lack of abortions observed after experimental challenge, recovery from maternal tissues ranged from 50% (low dose, late challenge) to 77% (low dose, early challenge). Our data suggests that naive elk do not abort as frequently after experimental infection with B. abortus strain 2308 as compared to similar data in cattle and bison.

Brucellosis is a bacterial zoonosis and a significant source of economic loss and a major public health concern, worldwide. Bovine brucellosis, as caused primarily by Brucella abortus, is an important cause of reproductive loss in cattle. Vaccination has been the most effective way to reduce disease prevalence contributing to the success of control and eradication programs. Currently, there are no human vaccines available, and despite the success of commercial vaccines for livestock, such as B. abortus strain RB51 (RB51), there is need for development of novel and safer vaccines against brucellosis. In the current study, we report the fabrication of and immune responses to an implantable single dose polyanhydride-based, methanol-killed RB51 antigen containing delivery platform (VPEAR) in cattle. In contrast to animals vaccinated with RB51, we did not observe measurable RB51-specific IFN-γ or IgG responses in the peripheral blood, following initial vaccination with VPEAR. However, following a subsequent booster vaccination with RB51, we observed an anamnestic response in both vaccination treatments (VPEAR and live RB51). The magnitude and kinetics of CD4+ IFN-γ-mediated responses and circulating memory T cell subpopulations were comparable between the two vaccination treatments. Additionally, IgG titers were significantly increased in animals vaccinated with VPEAR as compared to live RB51- vaccinated animals. These data demonstrate that killed antigen may be utilized to generate and sustain memory, IFN-γ-mediated, CD4+ T cell and humoral responses against Brucella in a natural host. To our knowledge, this novel approach to vaccination against intracellular bacteria, such as Brucella, has not been reported before.

We present the case of an 87-year-old man with a history of melanoma metastatic to the lungs found to have an FDG-negative liver lesion that was initially thought to be benign. Follow-up CT revealed growth of the liver lesion despite excellent response to nivolumab therapy of the pulmonary melanoma metastases. Biopsy of the lesion confirmed primary hepatocellular carcinoma. Follow-up F-FDG PET/CT showed minimal FDG uptake, slightly above liver background, and subsequent Ga-PSMA-11 PET/MR showed focal, intense uptake of radiotracer in a different region of the tumor. These imaging findings support intratumor metabolic heterogeneity with radiotracer uptake in different tumor locations.

Purpose: Systemic androgen-signaling inhibition added to ongoing androgen-deprivation therapy (ADT) improved clinical outcomes in patients with nonmetastatic castration-resistant prostate cancer without detectable metastases by conventional imaging (nmCRPC). Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) detects prostate cancer with superior sensitivity to conventional imaging, but its performance in nmCRPC remains largely unknown. We characterized cancer burden in high-risk patients with nmCRPC using PSMA-PET. Experimental Design: We retrospectively included 200 patients with nmCRPC, prostate-specific antigen (PSA) >2 ng/mL, and high risk for metastatic disease [PSA doubling time (PSADT) of ≤10 months and/or Gleason score of ≥8] from six high-volume PET centers. We centrally reviewed PSMA-PET detection rate for pelvic disease and distant metastases (M1). We further evaluated SPARTAN patients stratified by risk factors for PSMA-PET-detected M1 disease. Results: PSMA-PET was positive in 196 of 200 patients. Overall, 44% had pelvic diseases, including 24% with local prostate bed recurrence, and 55% had M1 disease despite negative conventional imaging. Interobserver agreement was very high (κ: 0.81–0.91). PSA ≥ 5.5 ng/mL, locoregional nodal involvement determined by pathology (pN1), prior primary radiation, and prior salvage radiotherapy independently predicted M1 disease (all P < 0.05). Conclusions: PSMA-PET detected any disease in nearly all patients and M1 disease in 55% of patients previously diagnosed with nmCRPC, including subgroups with PSADT of ≤10 months and Gleason score of ≥8. The value of PSMA-PET imaging for treatment guidance should be tested in future studies.

New Onset Diabetes after Transplantation (NODAT) is a frequent complication after solid organ transplantation, with higher incidence during the first year. Several clinical and genetic factors have been described as risk factors of Type 2 Diabetes (T2DM). Additionally, T2DM shares some genetic factors with NODAT. We investigated if three genetic risk scores (w-GRS) and clinical factors were associated with NODAT and how they predicted NODAT development 1 year after transplantation. In both main (n = 725) and replication (n = 156) samples the clinical risk score was significantly associated with NODAT (ORmain: 1.60 [1.36-1.90], p = 3.72*10-8 and ORreplication: 2.14 [1.39-3.41], p = 0.0008, respectively). Two w-GRS were significantly associated with NODAT in the main sample (ORw-GRS 2:1.09 [1.04-1.15], p = 0.001 and ORw-GRS 3:1.14 [1.01-1.29], p = 0.03) and a similar ORw-GRS 2 was found in the replication sample, although it did not reach significance probably due to a power issue. Despite the low OR of w-GRS on NODAT compared to clinical covariates, when integrating w-GRS 2 and w-GRS 3 in the clinical model, the Area under the Receiver Operating Characteristics curve (AUROC), specificity, sensitivity and accuracy were 0.69, 0.71, 0.58 and 0.68, respectively, with significant Likelihood Ratio test discrimination index (p-value 0.0004), performing better in NODAT discrimination than the clinical model alone. Twenty-five patients needed to be genotyped in order to detect one misclassified case that would have developed NODAT 1 year after transplantation if using only clinical covariates. To our knowledge, this is the first study extensively examining genetic risk scores contributing to NODAT development.

Although most melanoma cases may be treated by surgical intervention upon early diagnosis, a significant portion of patients can still be refractory, presenting low survival rates within 5 years after the discovery of the illness. As a hallmark, melanomas are highly prone to evolve into metastatic sites. Moreover, melanoma tumors are highly resistant to most available drug therapies and their incidence have increased over the years, therefore leading to public health concerns about the development of novel therapies. Therefore, researches are getting deeper in unveiling the mechanisms by which melanoma initiation can be triggered and sustained. In this context, important progress has been achieved regarding the roles and the impact of cellular signaling pathways in melanoma. This knowledge has provided tools for the development of therapies based on the intervention of signal(s) promoted by these cascades. In this review, we summarize the importance of major signaling pathways (mitogen-activated protein kinase (MAPK), phosphoinositide 3-kinase (PI3K)-Akt, Wnt, nuclear factor κ-light-chain-enhancer of activated B cell (NF-κB), Janus kinase (JAK)-signal transducer and activator of transcription (STAT), transforming growth factor β (TGF-β) and Notch) in skin homeostasis and melanoma progression. Available and developing melanoma therapies interfering with these signaling cascades are further discussed.