Understanding the Elevated Lethality of COVID-19 in Liver Transplant Recipients: Does Immunosuppression Management Matter? Results from a Brazilian Multicentric Historical Cohort.

BACKGROUND: Infections by SARS-CoV-2 in liver transplant recipients (LT) patients are of particular concern, notably due to perceived added risks related to immunosuppression and comorbidity burden. Current literature on this topic often relies on small, non-standardized, and geographically limited studies. This manuscript describes COVID-19 presentations and causes for elevated mortality in a large cohort of LT recipients. METHODS: This study was designed as a multicentric historical cohort, including LT recipient patients with COVID-19 in 25 study centers, with the primary endpoint being COVID-related death. We also collected demographic, clinical, and laboratory data regarding presentation and disease progression. RESULTS: Two hundred and thirty-four cases were included. The study population was predominantly male and White and had a median age of 60 years. The median time from transplantation was 2.6 years (IQR 1-6). Most patients had at least one comorbidity (189, 80.8%). Patient age (P = .04), dyspnea (P < .001), intensive care unit admission (P < .001), and mechanical ventilation (P < .001) were associated with increased mortality. Modifications of immunosuppressive therapy (P < .001), specifically the suspension of tacrolimus, maintained significance in multivariable analysis. CONCLUSIONS: Attention to risk factors and the individualization of patient care, especially regarding immunosuppression management, is crucial for delivering more precise interventions to these individuals.

Incidence and Impact of COVID-19 Cases in Brazilian Liver Transplant Recipients: An Academic, Single-center Experience.

BACKGROUND: Current literature reports diverge on the impact of COVID-19 in liver transplant (LT) recipients. Literature findings often report conflicting results, relying on small sample sizes, limited ethnic variability, and nonstandardized methodologies. Notably, there are no studies on this topic regarding Latin American populations. This study seeks to report the impact of COVID-19, disease characteristics, and progression in LT recipients in a Latin American academic center environment. METHODS: The study design was a historic cohort, including adult LT recipient patients with suspected or confirmed COVID-19 who sought care between December 2019 to October 2021. The primary end point was defined as COVID-19-related death. Demographic, clinical, and laboratory data was also collected. RESULTS: Twenty-seven patients were included, representing a 3.5% incidence within 752 patients in the follow-up. The mean age and years from transplantation were 54 (SD ± 11) and 6.3 years (SD ± 5.4), respectively. Most patients were white (23 - 85.2%) and male (21 - 25.2%). The hospitalization rate was 55.6%, and 5 patients (18.5%), all of whom subsequently died, were admitted to the intensive care unit. Neither the presence of comorbidities nor advanced age were related to lethality. Patients with immunosuppression modifications (P = 0.039) or isolated tacrolimus suspension (P = 0.006) were associated with increased mortality. CONCLUSIONS: This study described COVID-19 infections in LT recipients in Latin American populations. This group was not affected by common factors associated with higher lethality, and displayed a tendency toward lower hospitalization rates. Our study concurred with previously reported evidence of a protective association of tacrolimus maintenance during treatment in LT recipients affected by COVID-19.

Autochthonous male urothelial carcinoma immune competent model: from induction to BCG transurethral treatment.

OBJECTIVE: To describe a new animal model of autochthonous urothelial cancer (UC) accessible by transurethral catheter in males, from induction to treatment. Seven-week-old male Fischer 344 rats were used. The first 10 animals were used to overcome and standardize the technical challenges of safe transurethral catheterization of male rats. The remaining 14 animals underwent intravesical N-Methyl-Nitrosourea (MNU) instillation for UC induction, of which six were randomized to undergo intravesical BCG treatment. The stretched male rat urethra travels 35 mm in a tortuous "S" shaped trajectory with a 180° angle behind the pubic bone, safely traversed by a 20G 36" 0.8 mm epidural catheter in a stretched, straightened urethra inserted after anterior dilation of the penile urethra with a 24G IV catheter. Histopathologic analysis of the urinary bladder demonstrated Stage pT1, pTa, and pTis lesions in the 8 controls, all with increased cell proliferation by Ki-67 expression and no pT1 or pTis in the animals 6 treated with BCG. This pioneering study describes an autochthonous, effective, and accessible transurethral animal model of immune-competent UC in males, and may help with understanding of the biology, immunology, and treatment of UC, which predominates in males.

Boosting bladder cancer treatment by intravesical nitazoxanide and bacillus calmette-guérin association.

PURPOSE: Nitazoxanide (NTZ) has shown a promising antitumoral effect, the current study compared the anti-neoplastic effects of intravesical NTZ and BCG plus NTZ in NMIBC animal model. METHODS: 30 rats, Fisher 344 were instilled with 4 intravesical doses of 1.5 mg/kg of N-methyl-N-nitrosourea (MNU) every 15 days for BC induction. The animals were divided into 3 groups (Group BCG 106 UFC - 1 mg of BCG; Group NTZ - 300 mg/kg of NTZ; Group NTZ + BCG - simultaneous treatment of BCG and NTZ) and received weekly intravesical treatment for 6 consecutive weeks. Animals were submitted to ultrasound imaging and euthanasia, their bladders were collected and histopathological, immunohistochemical tests (ki67 e c-Myc) and Western Blotting (PI3K, mTOR, and p-4E-BP) were performed. RESULTS: Histopathological tests showed 66.67%, 62.5% and 37.5% incidence of BC in animals treated with BCG, NTZ, and NTZ + BCG, respectively. Nuclear positivity for ki-67 in BC animals were 12.4% (IC 10.1-14.6%), 13.2% (IC 10.5-15.9%) and 8.8% (IC 6.0-11.6%) in BCG, NTZ and NTZ + BCG group, respectively (p = 0.063). Between animals with carcinoma, c-Myc strong positive was 40.10% in NTZ, 32.2% in BCG and 19.90% in the NTZ + BCG group (p < 0.001). Blotting has shown mTOR (p = 0.0473) and PI3K inhibition (p = 0.0349) in the presence of BCG, added to 4-EBP inhibition in the presence of NTZ (p = 0.0004). CONCLUSIONS: Results show the possible synergy between the gold standard BC treatment BCG and NTZ, in which multiple targets inhibition such as c-Myc and downstream mTOR, p-4E-BP and PI3K might play a role.

Prevalence and Profile of Discarded Liver Donors in a Tertiary Health Service in Brazil From 2015 to 2018.

BACKGROUND: Little has changed in donor management and liver utilization rates in Brazil over the last decade. With a growing demand for liver donations, organ waste is an important obstacle toward better patient care. The study of discarded donors helps to shed light on the possibilities of increasing organ usage, including by using extended criteria donors. METHODS: We retrospectively analyzed all discarded liver donors in a high-volume Brazilian transplant center from January 2015 to December 2018. Pertinent clinical and laboratorial data were collected from the donors' electronic health records. RESULTS: In our study period, there were 248 liver harvests, of which 67 (27.0%) were discarded. Most discarded donors were male (65.7%). More than three-quarters of donors were Caucasian (79.1%). Median donor body mass index was 26.27 kg/m2, and most discarded donors presented no comorbidities. Donor liver injury tests were abnormal in 56 (83.5%) out of 67 discarded donors. Forty-three (64.1%) donors presented elevated transaminases. Alanine aminotransferase levels were elevated in 35 (52.2%) discarded donors, with a median value of 38 U/L. Half of all discarded livers were due to graft-related issues. Twenty-eight organs (41.79%) presented external pathologic alterations. Organ refusal due to donor clinical and laboratorial condition was reported in 24 cases. CONCLUSION: It is clear there is a considerable issue of organ waste in Brazil, with the subjective judgment of graft quality and inadequate interpretation of donor's laboratorial exams leading to excessive denial of organs that could be fitted into extended criteria for donation.

Age-independent secular testosterone populational trends among Brazilian males.

OBJECTIVES: Disruptions in testosterone levels are a cause of great morbidity to male patients, with effects ranging from impotence to increased cardiovascular risk. This study analyzes populational testosterone trends in South American males over a period of 8 years. METHODS: Between 2010 and 2017, Testosterone and Albumin measurements were performed in males over 19 years of age, in a routine male health program, and values outside laboratory normality ranges were excluded to reduce biases related to patients' pathologies. All data were collected on morning fasting and analyzed by tandem mass spectrometry. Data were compared by ANOVA tests with Tukey's post hoc analysis. RESULTS: A total of 2874 measurements were made in 8 years, mean participant age 56.18 years (19-84). The study found an age-independent testosterone decline of 10.68 ng/dL (1.6%) per year, displaying drops per year of 13.46 ng/dL (2.5%) in participants ≤ 40 years old, 7.12 ng/dL (1.4%) at the 41-60-year-old age group, and 11.4 ng/dL (2.4%) per year in participants > 60 years old. The values of albumin displayed significant variations along the study period, but without any clear upward or downward trends in post hoc analysis. CONCLUSION: The age-independent testosterone decline displays a worrying picture of possibly increasing rates of hypogonadism and its complications in the future. Further studies are needed to fully understand its etiology and impact in populations.

Manganese dioxide coating reduces bacterial adhesion and infection in silicon implants in animal model.

PURPOSE: To propose a new coating to silicone implants using Manganese dioxide. We present bacterial adhesion and proliferation when implants are challenged with Escherichia coli. METHODS: Coated and control silicon implants were placed in two independent subcutaneous pouches in the dorsum of Wistar rats. After skin closure, 0.5 ml of E. coli solution was injected in each incision. The animals were euthanized at 7 and 28 days. Extracted material was cultured and analyzed by confocal microscopy. RESULTS: At 1 week, uncoated implants had a 17-fold higher infection rate (p < 0.001). Coated samples showed a mean bacterial count of 28,700 CFU/ml, while the control ones 503,000 CFU/ml, with a significant mean difference of 474,300 CFU/ml (95% CI 165,900-782,600). At 4 weeks, the mean bacterial growth in coated group was 7600; while in control one was 53,890. The mean difference between groups was 46,200 (95% CI 21,100-71,400). Confocal microscopy presented the percentage of implant's surface with attached bacteria: at 7 days, coated implants had 6.85% and controls 10.9% and the difference was not significant (p =0.32). At 4 weeks, the coated group showed 0.98% of the surface with attached bacteria, while control group showed 7.64%, which resulted in a significant 11-fold difference (p = 0.004). CONCLUSIONS: Manganese dioxide coating inhibits bacterial proliferation and adhesion in subcutaneous silicon implants in an animal model. These findings can be useful to improve development of biomaterials.

The effectiveness of current informative material in improving awareness and opinion of undergraduate students towards organ donation: a comparative, randomized survey study.

OBJECTIVES: Despite the contribution of awareness campaigns to the rise of organ donation rates in Brazil, younger folks are subject to few awareness actions. Records on the effect of informative campaigns at improving opinion and knowledge of undergraduates about organ donation are scarce. This study aimed to assess the effect of informative material about organ donation on changes in the trend of answers to a questionnaire compared to the answers of a control group. METHODS: Two randomized groups were compared, receiving the same standardized questionnaire. One group was supplied informative material on the subject, while the other was not. The questionnaire was sent to undergraduate students from two Brazilian universities. Statistical analysis was performed using Student's t-test, Chi-square test and multinomial regression tests. Adopted significance was 5%. RESULTS: There were 739 responses to the questionnaire. Mean age was 22 years, with a majority of women. Six of 14 questions displayed a change in the answer pattern of the experimental group compared to controls (p<0.05). Opinion on organ donation had changes in 2 of 7 analyzed questions (p<0.05). Knowledge on the subject had a shift in answer patterns in 4 of 7 questions. Regression demonstrated 3 items that were not influenced by respondents' age. CONCLUSION: There is controversy regarding the benefit of exposure to informative material. Negative changes were noted in the trust in transplantation as a safe treatment. Positive results regarding technical knowledge were obtained. Better results may be obtained by designing informative material tailored towards the student's specific concerns.

The effectiveness of current informative material in improving awareness and opinion of undergraduate students towards organ donation: a comparative, randomized survey study

OBJECTIVES: Despite the contribution of awareness campaigns to the rise of organ donation rates in Brazil, younger folks are subject to few awareness actions. Records on the effect of informative campaigns at improving opinion and knowledge of undergraduates about organ donation are scarce. This study aimed to assess the effect of informative material about organ donation on changes in the trend of answers to a questionnaire compared to the answers of a control group. METHODS: Two randomized groups were compared, receiving the same standardized questionnaire. One group was supplied informative material on the subject, while the other was not. The questionnaire was sent to undergraduate students from two Brazilian universities. Statistical analysis was performed using Student's t-test, Chi-square test and multinomial regression tests. Adopted significance was 5%. RESULTS: There were 739 responses to the questionnaire. Mean age was 22 years, with a majority of women. Six of 14 questions displayed a change in the answer pattern of the experimental group compared to controls (p<0.05). Opinion on organ donation had changes in 2 of 7 analyzed questions (p<0.05). Knowledge on the subject had a shift in answer patterns in 4 of 7 questions. Regression demonstrated 3 items that were not influenced by respondents' age. CONCLUSION: There is controversy regarding the benefit of exposure to informative material. Negative changes were noted in the trust in transplantation as a safe treatment. Positive results regarding technical knowledge were obtained. Better results may be obtained by designing informative material tailored towards the student's specific concerns.