Seroconversion in liver and intestine transplant patients after one, two or three doses of adenoviral vector vaccines against SARS-CoV-2. Single center experience in Argentina.

BACKGROUND: The capacity of different anti-SARS-CoV-2 vaccines to elicit immune response is not equivalent in the healthy population compared to chronically immunosuppressed patients. Most of the reports available to assess the effects of anti-SARS-CoV-2 vaccines on solid organ transplant recipients (SOTR) were performed using mRNA-based vaccines. OBJECTIVE: This study aims to assess the seroconversion rate in a cohort of liver and liver- intestinal transplant patients after vaccination with the non-replicative vector-based vaccines after transplantation used in our country, Argentina (rAd26-rAd5 (Sputnik V) and ChAdOx11 nCoV-19 (AZD1222) (Astra Zeneca-Oxford). METHODS: One hundred and three (103) liver and liver-intestinal transplant recipients were enrolled. Patients with previous PCR-confirmed COVID19 were excluded, therefore 77 were finally included for analysis; 75 were liver transplant recipients, 1 was a combined liver-intestine and 1 a multivisceral transplant. All received their first vaccine dose between March and June 2021; 66,2% males, and the mean age was 56,3 years. All patients have a post-transplant follow up longer than 1 year (mean 6.6 years, median 5 years, range 1-23 years). Immune response after first, second and third doses were determined using three different spike (S)-S commercial ELISA kits and an in-house made anti nucleocapsid-protein (N) ELISA. RESULTS: Following the three doses, 57.1 % (44/77) of the patients seroconverted, while 33/77 (42.9 %) did not present anti-SARS-CoV-2 antibodies. The seroconversion rate was different for each dose. We found that 5/27 (18.5 %) of transplant patients seroconverted after a single dose; 18/29 pts (62.0 %) had anti-SARS-Cov-2 antibodies after the second doses; and 18/21 pts (85.7 %) reached the seroconversion after the third doses. The proportion of seroconversion was significantly increased in the second doses regardless the response observed after the first doses (p = 0.012, Fisher's exact test), particularly when two doses of ChAdOx11 vaccine was administrated (p = 0.040, Chi-square). However, the comparisons of seroconversion rate between Sputnik V and ChAdOx11 vaccines showed no differences after the different vaccination doses. No significant statistical difference in patient́s gender, age, comorbidities, type of vaccine, post-transplant, or maintenance immunosuppressive therapy was found between responders and non-responders. CONCLUSION: Despite having a lower seroconversion rate compared to the general population, viral-vector vaccines benefit SOTR patients increasing the seroconversion rate using at least two doses of vaccine. These results support the concept of developing tailor-made vaccination guidelines for this specific population. This analysis provides further support to safety and efficacy of viral-vector vaccines in liver and liver-intestine transplant patients.

Periprosthetic Joint Infection After Total Knee Arthroplasty With or Without Antibiotic Bone Cement.

Importance: Despite increased use of antibiotic-loaded bone cement (ALBC) in joint arthroplasty over recent decades, current evidence for prophylactic use of ALBC to reduce risk of periprosthetic joint infection (PJI) is insufficient. Objective: To compare the rate of revision attributed to PJI following primary total knee arthroplasty (TKA) using ALBC vs plain bone cement. Design, Setting, and Participants: This international cohort study used data from 14 national or regional joint arthroplasty registries in Australia, Denmark, Finland, Germany, Italy, New Zealand, Norway, Romania, Sweden, Switzerland, the Netherlands, the UK, and the US. The study included primary TKAs for osteoarthritis registered from January 1, 2010, to December 31, 2020, and followed-up until December 31, 2021. Data analysis was performed from April to September 2023. Exposure: Primary TKA with ALBC vs plain bone cement. Main Outcomes and Measures: The primary outcome was risk of 1-year revision for PJI. Using a distributed data network analysis method, data were harmonized, and a cumulative revision rate was calculated (1 - Kaplan-Meier), and Cox regression analyses were performed within the 10 registries using both cement types. A meta-analysis was then performed to combine all aggregated data and evaluate the risk of 1-year revision for PJI and all causes. Results: Among 2 168 924 TKAs included, 93% were performed with ALBC. Most TKAs were performed in female patients (59.5%) and patients aged 65 to 74 years (39.9%), fully cemented (92.2%), and in the 2015 to 2020 period (62.5%). All participating registries reported a cumulative 1-year revision rate for PJI of less than 1% following primary TKA with ALBC (range, 0.21%-0.80%) and with plain bone cement (range, 0.23%-0.70%). The meta-analyses based on adjusted Cox regression for 1 917 190 TKAs showed no statistically significant difference at 1 year in risk of revision for PJI (hazard rate ratio, 1.16; 95% CI, 0.89-1.52) or for all causes (hazard rate ratio, 1.12; 95% CI, 0.89-1.40) among TKAs performed with ALBC vs plain bone cement. Conclusions and Relevance: In this study, the risk of revision for PJI was similar between ALBC and plain bone cement following primary TKA. Any additional costs of ALBC and its relative value in reducing revision risk should be considered in the context of the overall health care delivery system.

CD4+ T cell-derived IL-22 enhances liver metastasis by promoting angiogenesis.

Metastasis is a cancer-related systemic disease and is responsible for the greatest mortality rate among cancer patients. Interestingly, the interaction between the immune system and cancer cells seems to play a key role in metastasis formation in the target organ. However, this complex network is only partially understood. We previously found that IL-22 produced by tissue resident iNKT17 cells promotes cancer cell extravasation, the early step of metastasis. Based on these data, we aimed here to decipher the role of IL-22 in the last step of metastasis formation. We found that IL-22 levels were increased in established metastatic sites in both human and mouse. We also found that Th22 cells were the key source of IL-22 in established metastasis sites, and that deletion of IL-22 in CD4+ T cells was protective in liver metastasis formation. Accordingly, the administration of a murine IL-22 neutralizing antibody in the establishment of metastasis formation significantly reduced the metastatic burden in a mouse model. Mechanistically, IL-22-producing Th22 cells promoted angiogenesis in established metastasis sites. In conclusion, our findings highlight that IL-22 is equally as important in contributing to metastasis formation at late metastatic stages, and thus, identify it as a novel therapeutic target in established metastasis.

Diagnostic concordance between traditional and digital workflows. A study on 1427 prostate biopsies.

Objective: To evaluate intra-observer diagnostic reproducibility using traditional slides (TS) versus whole slide images (WSI). Methods: TS and WSI of 1427 prostatic biopsies (107 consecutive patients) were evaluated by a single pathologist. Agreement between readings was evaluated with Gwet's Agreement coefficient (AC) and Landis and Koch benchmark scale. Results: The positive/negative agreement between the readings was almost perfect (AC1= 0.962; 95% CI[0.949,0.974]), with method independent distribution of discrepancies. Among positive biopsies, 212 had identical Gleason score (GS) on TS and WSI and discordant GS in 69 cases (AC2 = 0.932; 95% CI[0.907, 0.956]). Concordant negative and positive patient classification was observed in 39 and 64 cases, respectively; two cases were assigned to the positive group on TS and 2 on WSI configuring an almost perfect agreement (AC1=0.929; 95% C1[0.860, 0.998]). ISUP Grade group (ISUP GG) agreement was evaluated in the 60 concordantly positive cases: in 45 cases it was identical on TS and WSI; in 10 biopsies the discrepancy implied a modification of the assigned ISUP GG of ≤ 1 class and in 5 the discrepancy implied a modification of 2 classes. Gwet's agreement coefficient was (95% CI [0.834, 0.962]), i.e.: almost perfect agreement. Conclusions: Our data show almost perfect agreement between digital and traditional diagnostic activity in a routine setting, confirming that digital pathology can be safely introduced into routine workflows.

Organisational models supported by technology for the management of diabetic disease and its complications in a diabetic clinic setting: study protocol for a randomised controlled trial targeting type 2 diabetes individuals with non-ideal glycaemic values (Telemechron study).

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is a non-communicable disease representing one of the most serious public health challenges of the twenty-first century. Its incidence continues to rise in both developed and developing countries, causing the death of 1.5 million people every year. The use of technology (e.g. smartphone application-App) in the health field has progressively increased as it has been proved to be effective in helping individuals manage their long-term diseases. Therefore, it has the potential to reduce the use of health service and its related costs. The objective of this study is to evaluate the impact of using a digital platform called "TreC Diabete" embedded into a novel organisational asset targeting poorly controlled T2DM individuals in the Autonomous Province of Trento (PAT), Italy. METHODS: This trial was designed as a multi-centre, open-label, randomised, superiority study with two parallel groups and a 1:1 allocation ratio. Individuals regularly attending outpatient diabetes clinics, providing informed consent, are randomised to be prescribed TreC Diabete platform as part of their personalised care plan. Healthcare staff members will remotely assess the data shared by the participants through the App by using a dedicated online medical dashboard. The primary end-point is the evaluation of the Hb1Ac level at 12-month post-randomisation. Data will be analysed on an intention-to-treat (ITT) basis. DISCUSSION: This trial is the first conducted in the PAT area for the use of an App specifically designed for individuals with poorly controlled T2DM. If the effects of introducing this specific App within a new organisational asset are positive, the digital platform will represent a possible way for people diagnosed with T2DM to better manage their health in the future. Results will be disseminated through conferences and peer-reviewed journals once the study is completed. TRIAL REGISTRATION: ClinicalTrials.gov NCT05629221. Registered on November 29, 2022, prior start of inclusion.

IL-22BP controls the progression of liver metastasis in colorectal cancer.

Background: The immune system plays a pivotal role in cancer progression. Interleukin 22 binding protein (IL-22BP), a natural antagonist of the cytokine interleukin 22 (IL-22) has been shown to control the progression of colorectal cancer (CRC). However, the role of IL-22BP in the process of metastasis formation remains unknown. Methods: We used two different murine in vivo metastasis models using the MC38 and LLC cancer cell lines and studied lung and liver metastasis formation after intracaecal or intrasplenic injection of cancer cells. Furthermore, IL22BP expression was measured in a clinical cohort of CRC patients and correlated with metastatic tumor stages. Results: Our data indicate that low levels of IL-22BP are associated with advanced (metastatic) tumor stages in colorectal cancer. Using two different murine in vivo models we show that IL-22BP indeed controls the progression of liver but not lung metastasis in mice. Conclusions: We here demonstrate a crucial role of IL-22BP in controlling metastasis progression. Thus, IL-22 might represent a future therapeutic target against the progression of metastatic CRC.

Dynamic recycling of extracellular ATP in human epithelial intestinal cells.

Intestinal epithelial cells play important roles in the absorption of nutrients, secretion of electrolytes and food digestion. The function of these cells is strongly influenced by purinergic signalling activated by extracellular ATP (eATP) and other nucleotides. The activity of several ecto-enzymes determines the dynamic regulation of eATP. In pathological contexts, eATP may act as a danger signal controlling a variety of purinergic responses aimed at defending the organism from pathogens present in the intestinal lumen. In this study, we characterized the dynamics of eATP on polarized and non-polarized Caco-2 cells. eATP was quantified by luminometry using the luciferin-luciferase reaction. Results show that non-polarized Caco-2 cells triggered a strong but transient release of intracellular ATP after hypotonic stimuli, leading to low micromolar eATP accumulation. Subsequent eATP hydrolysis mainly determined eATP decay, though this effect could be counterbalanced by eATP synthesis by ecto-kinases kinetically characterized in this study. In polarized Caco-2 cells, eATP showed a faster turnover at the apical vs the basolateral side. To quantify the extent to which different processes contribute to eATP regulation, we created a data-driven mathematical model of the metabolism of extracellular nucleotides. Model simulations showed that eATP recycling by ecto-AK is more efficient a low micromolar eADP concentrations and is favored by the low eADPase activity of Caco-2 cells. Simulations also indicated that a transient eATP increase could be observed upon the addition of non-adenine nucleotides due the high ecto-NDPK activity in these cells. Model parameters showed that ecto-kinases are asymmetrically distributed upon polarization, with the apical side having activity levels generally greater in comparison with the basolateral side or the non-polarized cells. Finally, experiments using human intestinal epithelial cells confirmed the presence of functional ecto-kinases promoting eATP synthesis. The adaptive value of eATP regulation and purinergic signalling in the intestine is discussed.

The Flavonoid Cyanidin Shows Immunomodulatory and Broad-Spectrum Antiviral Properties, Including SARS-CoV-2.

New antiviral treatments are needed to deal with the unpredictable emergence of viruses. Furthermore, vaccines and antivirals are only available for just a few viral infections, and antiviral drug resistance is an increasing concern. Cyanidin (a natural product also called A18), a key flavonoid that is present in red berries and other fruits, attenuates the development of several diseases, through its anti-inflammatory effects. Regarding its mechanism of action, A18 was identified as an IL-17A inhibitor, resulting in the attenuation of IL-17A signaling and associated diseases in mice. Importantly, A18 also inhibits the NF-κB signaling pathway in different cell types and conditions in vitro and in vivo. In this study, we report that A18 restricts RSV, HSV-1, canine coronavirus, and SARS-CoV-2 multiplication, indicating a broad-spectrum antiviral activity. We also found that A18 can control cytokine and NF-κB induction in RSV-infected cells independently of its antiviral activity. Furthermore, in mice infected with RSV, A18 not only significantly reduces viral titers in the lungs, but also diminishes lung injury. Thus, these results provide evidence that A18 could be used as a broad-spectrum antiviral and may contribute to the development of novel therapeutic targets to control these viral infections and pathogenesis.

Native Spleen Preservation During Visceral Transplantation Inhibits Graft-Versus-Host-Disease Development: Clinical and Experimental Study.

OBJECTIVE: We aimed to assess whether native spleen preservation during visceral transplantation (VT) affects graft-versus-host-disease (GVHD) incidence. SUMMARY BACKGROUND DATA: GVHD is one of the most severe and frequently lethal hematological complications after VT procedures. Because there is no specific treatment for GVHD, it is imperative to develop a strategy to reduce donor lymphocyte engraftment and proliferation. METHODS: Our study included both clinical and experimental data. A total of 108 patients were divided into 3 groups: a native spleen preservation group, a native spleen removal with no donor spleen group, and a donor spleen included (allogeneic spleen) group. We also used an allogeneic VT rat model, in which recipients were divided into 2 groups: a native spleen preservation (+SP) group and a native spleen removal (-S) group. Skin rash appearance, histopathological changes, chimerism, and spleen effects on circulating allogeneic T-cells were assessed. RESULTS: The patients with native spleen preservation showed a lower rate of GVHD ( P <.001) and better survival ( P <.05) than those in the other groups. Skin and histological signs of GVHD were lower in the rats in the +SP group ( P <.05). The donor T-cell frequency in the bloodstream and skin was also significantly reduced when the native spleen was preserved ( P <.01 and P <.0001, respectively). CONCLUSIONS: The clinical and experimental data indicate that recipient spleen preservation protects against GVHD after VT, and donor cell clearance from the bloodstream by spleen macrophages could be the underlying mechanism. Therefore, spleen preservation should be considered in VT procedures, whenever possible.

Consensus among clinicians on referrals' priority and use of digital decision-making support systems.

The growing demand for referrals is a main policy concern in health systems. One approach involves the development of demand management tools in the form of clinical prioritization to regulate patient referrals from primary care to specialist care. For clinical prioritization to be effective, it is critical that general practitioners (GPs) assess patient priority in the same way as specialists. The progressive development of IT tools in clinical practice, in the form of electronic referrals support systems (e-RSS), can facilitate clinical prioritization. In this study, we tested if higher use of e-RSS or higher use of high-priority categories was associated with the degree of agreement and therefore consensus on clinical priority between GPs and specialists. We found that higher use by GPs of the e-RSS tool was positively associated with greater degree of priority agreement with specialists, while higher use of the high-priority categories was associated with lower degree of priority agreement with specialists. Furthermore, female GPs, GPs in association with others, and GPs using a specific electronic medical record showed higher agreement with specialists. Our study therefore supports the use of electronic referrals systems to improve clinical prioritization and manage the demand of specialist visits and diagnostic tests. It also shows that there is scope for reducing excessive use by GPs of high-priority categories.

[A suspect cluster of childhood cancer in Valle di Ledro (Province of Trento, Northern Italy). Epidemiological evaluation, risk management, and communication activities, 2018-2020]. / Un sospetto cluster di tumori infantili in Valle di Ledro (provincia di Trento). Valutazione epidemiologica e attività di comunicazione e gestione del rischio. Anni 2018-2020.

BACKGROUND: leukaemia is the most prevalent form of childhood cancer, an overall rare condition in childhood. Even few cases occurring in a small community can cause considerable apprehension among the population. From 2014 to 2017, 4 cases of childhood cancer occurred in Valle di Ledro, a municipality of 5,300 inhabitants in Province of Trento (Northern Italy), and a group of concerned citizens asked provincial health authorities for an investigation. OBJECTIVES: to address the community's health needs by verifying the hypothesis of a cluster of childhood cancer and through effective risk communication activities. DESIGN: retrospective cohort analysis based on data from the Cancer registry of the Autonomous Province of Trento and data collected from hospital discharge records. The communication activities were carried out according to the recommendations published by Epidemiologia&Prevenzione in 2016 in a Supplement "Childhood cancers, risk factors and investigation models for the evaluation of spatio-temporal clusters". SETTING AND PARTICIPANTS: Valle di Ledro, a municipality of 5,300 inhabitants in the Province of Trento. The participants in risk communication process were: city council; grassroot committee of concerned parents; health workforce of different services (epidemiology, cancer registry, public health; environmental health; primary health care; personnel of the Environmental Protection Agency; journalists; general population. The participants in the statistical analyses were: children of 0-14 years of age who were diagnosed a cancer from 1998 to 2014 in the Province of Trento (N. 212); leukaemia (N. 84) and acute lymphoblastic leukaemia (N. 66) incident cases in the period 1998-2017 in Trento province. MAIN OUTCOME MEASURES: verification of the presence of a cluster of childhood cancers; degree of consensus and collaboration of the different community stakeholders to the survey procedures and acceptance of the final results; atmosphere in public assemblies and feedback in the local press. RESULTS: a total of 212 incident cancer cases in children 0-14 years have been registred in Province of Trento from 1998 to 2014, leukaemia in 35% (N. 74) cases. From 2015 to 2017, another 10 cases of leukaemia occurred, for a total of 84 cases of leukaemia from 1998 to 2017. In the years from 1998 to 2017, in Valle di Ledro, taking the Italian population as reference group, the standardized incidence ratios (SIRs) were the following: cancer, all types 1,47 (IC95% 0,40-3,76); leukaemia 3,39 (IC95% 0,70-9,90), LLA 2,81 (IC95% 0,34-10,16). No cluster emerged from the geographical analyses. From the very beginning of the risk management approach, a decision-making working group was set up applying a participatory approach. Group members included the city council and the local committee of concerned parents and experts from different services of the local health unit. Data analyses was delegated to a technical working group that reported back to the decision-making group. Members of the technical working group were supervised by external experts. Following this approach, it was possible to establish a climate of trust and credibility. The involvement of all stakeholders right from the start in a totally transparent process was a key element of success. CONCLUSIONS: the cluster hypothesis was rejected for both childhood cancer (all types) and leukaemia (all types and ALL). The implementation of the risk communication process recommended by the AIE guidelines was successful in establishing a climate of reciprocal trust that allowed to overcome inevitable moments of conflict in a productive manner. Thanks to this positive atmosphere, the communication of the results of the statistical analyses was effective in reassuring the population.

Induction Versus Maintenance Immunosuppression After Intestinal Transplant: Determining Which Treatment Most Impacts Long-Term Patient And Graft Survival.

OBJECTIVES: Immunosuppressive strategies for intestinal transplant have changed over time. However, specific intestinal transplant-oriented protocols and reports on long-term maintenance regimens are scarce. Our objective was to evaluate the impact of 2 different initial immunosuppressive protocols based on thymoglobulin (group A) and basiliximab (anti-interleukin 2 antibody) (group B) and of changes to maintenance immunosuppression over long-term follow-up in intestinal transplant recipients. MATERIALS AND METHODS: We performed a retrospective analysis of a prospectively established protocol for intestinal transplant immunosuppression, conducted between May 2006 and December 2020. We analyzed 51 intestinal transplant recipients, with 6 patients excluded because of early death or graft loss. Acute cellular rejection frequency and grade, number of acute cellular rejection episodes, time to the first acute cellular rejection episode, response to treatment, number of patients who progressed to chronic allograft rejection, kidney function, infections, incidence of posttransplant lymphoproliferative disorder and graft-versus-host disease, and patient and graft survival were analyzed. RESULTS: In the study groups, there were 87 acute cellular rejection episodes in 45 patients (33 in group A and 54 in group B). We found degree of acute cellular rejection to be mild in 45 patients, moderate in 18, and severe in 24 (not significant between groups). Our comparison of induction therapy (thymoglobulin [group A] vs interleukin 2 antibody [group B]) did not show any statistical difference during clinical followup. Long-term review showed that all patients were on tacrolimus. Five-year patient and graft survival rates were 62% and 45% for group A and 54% and 46% for group B, respectively (not significant). CONCLUSIONS: Long-term patient and graft outcomes reflected the use of an individualized follow-up with adjustments and changes in immunosuppressive medications according to the patient's clinical course and complications rather than based on the induction immunosuppressive protocol used.

Non-conventional vascular accesses for the management of superior vena cava syndrome in patients with Intestinal Failure. Case series and systematic review.

BACKGROUND: Type III Intestinal Failure (IF) is a devastating clinical condition.characterized by the inability of the gut to absorb necessary macronutrients, and/or water and electrolytes, requiring Parenteral Nutrition (PN) as chronic therapy. Long-term PN may lead to life-threatening complications; the loss of central venous access (LCVA) is the most frequent and challenging. To date, few studies in the literature have reported the relevance of Non-conventional Vascular Accesses (NCVA) in the management IF as part of the comprehensive multidisciplinary care. METHODS: A retrospective analysis of a database collected from January 2006 to December 2019 was performed using SPSS v25.0 for statistical analysis, followed by a systematic review, using the PRISMA.methodology RESULTS: From January 2006 to December 2019, 184 NCVA were placed in 71 patients with LCVA as IF-related complication; 173 were placed in 61 patients by interventional radiology (IR) and 11 NCVA were placed in 10 patients by the surgical team during the intestinal transplant (ITx) operation. From the 173 IR procedures 166 (95.9%) were successful with 3 ± 2.7 procedures/patient; average catheter permanence rate was 738.68 ± 997 days; complications related to the procedures occurred in 18/173 (10.4%), including two deaths. On the other hand, among the 11 NCVA implanted by the surgical team, 7 (64%) were successful and were safely withdrawn 30 days after ITx when were no longer needed; 2 (18%) catheters malfunctioned during the first week and could not be further used, and 1 was accidently removed; average catheter permanence rate was 26 ± 4 days. There was one complication (9%) requiring laparotomy; there was no mortality associated the procedure in this group. A systematic review was conducted to evaluate the success and safety of NCVA as part of the treatment of HPN-related complications; from 337,542 papers, 14 studies were included. A total of 28 HPN-patients with LCVA received NCVA; 34 procedures were successfully performed, while procedure-related complications were reported in 11.7%, as well as one death. CONCLUSIONS: The data analyzed show that NCVAs may be successfully placed by expert teams, allowing to sustain long-term PN, as well as increasing the Intestinal Transplantation applicability for candidates in the extreme need of vascular access.

Structure-Activity Relationship and Mode-Of-Action Studies Highlight 1-(4-Biphenylylmethyl)-1H-imidazole-Derived Small Molecules as Potent CYP121 Inhibitors.

CYP121 of Mycobacterium tuberculosis (Mtb) is an essential target for the development of novel potent drugs against tuberculosis (TB). Besides known antifungal azoles, further compounds of the azole class were recently identified as CYP121 inhibitors with antimycobacterial activity. Herein, we report the screening of a similarity-oriented library based on the former hit compound, the evaluation of affinity toward CYP121, and activity against M. bovis BCG. The results enabled a comprehensive SAR study, which was extended through the synthesis of promising compounds and led to the identification of favorable features for affinity and/or activity and hit compounds with 2.7-fold improved potency. Mode of action studies show that the hit compounds inhibit substrate conversion and highlighted CYP121 as the main antimycobacterial target of our compounds. Exemplified complex crystal structures of CYP121 with three inhibitors reveal a common binding site. Engaging in both hydrophobic interactions as well as hydrogen bonding to the sixth iron ligand, our compounds block a solvent channel leading to the active site heme. Additionally, we report the first CYP inhibitors that are able to reduce the intracellular replication of M. bovis BCG in macrophages, emphasizing their potential as future drug candidates against TB.

COVID-19 hospitalizations in children in the Autonomous Province of Trento (Northern Italy), year 2020.

BACKGROUND: hospitalization rate of patients with SARS-CoV-2 infection can be considered as an indicator of severe COVID-19 burden. In children, however, hospital admissions may overestimate such burden. OBJECTIVES: to describe the hospitalizations with COVID-19-related discharge diagnoses in the population <18 years of age in the 545,000 inhabitants of the Autonomous Province of Trento (Trentino-Alto Adige Region, North-Eastern Italy) in year 2020. DESIGN: hospitalization characteristics and main and secondary discharge diagnosis codes were abstracted from anonymous hospital discharge records in all cases with at least one COVID-19-specific ICD-9-CM code. SETTING AND PARTICIPANTS: hospitalized patients 0-17 and >=18 years of age. MAIN OUTCOME MEASURES: in-hospital deaths, median length of stay and cost, frequency of main discharge diagnoses. RESULTS: from March to December 2020, 61 admissions with COVID-19-specific codes regarded patients 0-17 years and 3,811 patients >=18 years. No in-hospital deaths were observed in the younger group. Median hospital stay was not significantly different in the two groups, but cost was higher among patients >=18 years. In adult patients, more than 70% had a pneumonia or other lung or respiratory disease main discharge diagnosis; in children, they were only 6.5%. Almost half of the children admitted with SARS-CoV-2 infection had a main discharge diagnosis of either trauma or encounter with the health system for procedures and aftercare (ICD-9-CM V-codes). CONCLUSIONS: in the Province of Trento, a considerable proportion of hospitalizations of young patients with SARS-CoV-2 infection may be due to other underlying conditions requiring hospital care, supporting the hypothesis that hospitalization rate might overestimate the burden of serious COVID-19 in children.

Cellular and molecular changes and immune response in the intestinal mucosa during Trichinella spiralis early infection in rats.

BACKGROUND: The main targets of the host's immune system in Trichinella spiralis infection are the adult worms (AW), at the gut level, and the migrant or newborn larvae (NBL), at systemic and pulmonary levels. Most of the studies carried out in the gut mucosa have been performed on the Payer's patches and/or the mesenteric lymph nodes but not on the lamina propria, therefore, knowledge on the gut immune response against T. spiralis remains incomplete. METHODS: This study aimed at characterizing the early mucosal immune response against T. spiralis, particularly, the events taking place between 1 and 13 dpi. For this purpose, Wistar rats were orally infected with muscle larvae of T. spiralis and the humoral and cellular parameters of the gut immunity were analysed, including the evaluation of the ADCC mechanism exerted by lamina propria cells. RESULTS: A marked inflammation and structural alteration of the mucosa was found. The changes involved an increase in goblet cells, eosinophils and mast cells, and B and T lymphocytes, initially displaying a Th1 profile, characterised by the secretion of IFN-γ and IL-12, followed by a polarization towards a Th2 profile, with a marked increase in IgE, IgG1, IL-4, IL-5 and IL-13 levels, which occurred once the infection was established. In addition, the helminthotoxic activity of lamina propria cells demonstrated the role of the intestine as a place of migrant larvae destruction, indicating that not all the NBLs released in the gut will be able to reach the muscles. CONCLUSIONS: The characterization of the immune response triggered in the gut mucosa during T. spiralis infection showed that not only an effector mechanism is directed toward the AW but also towards the NBL as a cytotoxic activity was observed against NBL exerted by lamina propria cells.

Imiquimod suppresses respiratory syncytial virus (RSV) replication via PKA pathway and reduces RSV induced-inflammation and viral load in mice lungs.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract disease and bronchiolitis in children, as well as an important cause of morbidity and mortality in elderly and immunocompromised individuals. However, there is no safe and efficacious RSV vaccine or antiviral treatment. Toll Like Receptors (TLR) are important molecular mediators linking innate and adaptive immunity, and their stimulation by cognate agonists has been explored as antiviral agents. Imiquimod is known as a TLR7 agonist, but additionally acts as an antagonist for adenosine receptors. In this study, we demonstrate that imiquimod, but not resiquimod, has direct anti-RSV activity via PKA pathway in HEp-2 and A549 cells, independently of an innate response. Imiquimod restricts RSV infection after viral entry into the host cell, interfering with viral RNA and protein synthesis. Probably as a consequence of these anti-RSV properties, imiquimod displays cytokine modulating activity in RSV infected epithelial cells. Moreover, in a murine model of RSV infection, imiquimod treatment improves the course of acute disease, evidenced by decreased weight loss, reduced RSV lung titers, and attenuated airway inflammation. Consequently, imiquimod represents a promising therapeutic alternative against RSV infection and may inform the development of novel therapeutic targets to control RSV pathogenesis.

Effect of implementing digital breast tomosynthesis (DBT) instead of mammography on population screening outcomes including interval cancer rates: Results of the Trento DBT pilot evaluation.

BACKGROUND/AIM: The Trento screening program transitioned to digital breast tomosynthesis (DBT) screening based on evidence that DBT improves breast cancer (BC) detection compared to mammography; an evaluation of the transition to DBT is reported in this pilot study. METHODS: Prospective implementation of DBT screening included women aged ≥50 years who attended the Trento program for biennial screening. DBT screening included DBT acquisitions with synthesized 2D-images. A historical cohort of women who attended the program (January 2013-October 2014) and received digital mammography (DM) provided a comparison group. Independent double-reading (with a third arbitrating read for discordance) was used for DBT and DM screening. Screening outcomes included cancer detection rate (CDR/1000 screens), percentage of screens recalled to assessment (recall%), interval cancer rate (ICR/1000 screens) at 2-year follow-up, and screening sensitivity. Rate ratios (RR) and 95% confidence interval (95%CI) examined outcomes for DBT versus DM screening. RESULTS: From women aged 50-69 years who accepted an invitation to screening (October 2014-October 2016) 46,343 comprised the DBT-screened group: amongst these 402 BCs (includes 50 ductal carcinoma in-situ (DCIS)) were detected (CDR 8.67/1000), whereas 205 BCs (includes 33 DCIS) were detected amongst 37,436 DM screens (CDR 5.48/1000) [RR for CDR:1.58 (1.34-1.87)]. Recall% was lower for DBT (2.55%) than DM (3.21%) [RR:0.79 (0.73-0.86)]. Compared to DM, DBT screening increased CDR for stage I-II BC, for all tumour size and grade categories, and for node-negative BC, but did not increase CDR for DCIS. Estimated ICR for DBT was 1.1/1000 whereas ICR for DM was 1.36/1000 [RR:0.81 (0.55-1.19)]. Screening sensitivity was 88.74% for DBT versus 80.08% for DM [RR:1.11 (0.94-1.31)]. CONCLUSION: DBT significantly improved early-detection measures but did not significantly reduce ICR (relative to DM screening), suggesting that it could add benefit as well as adding over-detection in population BC screening.