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Secondary acute myeloid leukemia (s-AML) is associated with inferior outcomes with conventional chemotherapy, and fludarabine combinations (FLAG-Ida) have been tested to improve results. More recently, CPX-351 resulted superior to conventional 3 + 7 in s-AML patients. In the UK NCRI AML19 trial, AML patients were randomized to receive either FLAG-Ida or CPX-351. Subgroup analysis revealed better overall survival (OS) with CPX-351 in patients with MDS-related gene mutations. Unfortunately, minimal residual disease (MRD) was evaluated only in a minority of patients. The aim of this study was to further disclose the mechanisms of higher efficacy of CPX-351 in s-AML, with a focus on MRD. We analyzed 183 consecutive s-AML elderly patients (median age 69, range 60-77) treated with CPX-351 (n = 82) or receiving FLAG-Ida (n = 101). Complete remission (CR) rate and MRD negativity probability were higher among patients receiving CPX-351 (MRD negative CR rate of 40/64, 62.5%, compared to 25/55, 45% in patients who received FLAG-Ida, p < 0.05). Extra-hematological toxicity was lower in CPX-351 arm, and 30 days mortality was 3.6% and 8% in patients receiving CPX-351 or FLAG-Ida, respectively. Notably, 21/64 (32.8%) CR patients treated with CPX 351 underwent allogeneic stem cell transplantation (HSCT), compared to 5/55 with FLAG-Ida (9%, p < 0.05). Overall, CPX-351 treatment resulted in higher OS (median OS 17.7 vs. 11.2 months with FLAG-Ida, p < 0.05). The better outcome of CPX-351 compared to FLAG-Ida in our cohort may be explained by a greater probability of MRD negativity, alongside with an improved tolerance, enabling more s-AML patients to undergo HSCT., (© 2024 John Wiley & Sons Ltd.)

Infectious disease surveillance systems, including wastewater surveillance, can alert communities to the threat of emerging pathogens. We need methods to infer understanding of transmission dynamics from non-detection. We estimate a sensitivity of detection of poliovirus in wastewater to inform the sensitivity of wastewater surveillance for poliovirus using both a clinical epidemiology and fecal shedding approach. We then apply freedom from disease to estimate the sensitivity of the wastewater surveillance network. Estimated sensitivity to detect a single poliovirus infection was low, <11% at most wastewater treatment plants and <3% in most counties. However, the maximum threshold for the number of infections when polio is not detected in wastewater was much lower. Prospective wastewater surveillance can confirm the absence of a polio threat and be escalated in the case of poliovirus detection. These methods can be applied to any emerging or re-emerging pathogen, and improve understanding from wastewater surveillance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Larsen et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Phosphodiesterase (PDE) inhibitors are gaining interest in the context of pulmonary pathologies. In particular, the PDE3 inhibitor enoximone (ENXM) has shown potential relative to the cure of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Despite its administration via inhalation being planned for use against COVID-19 related ARDS (C-ARDS), presently, no inhalable medicine containing ENXM is available., Objectives: This study aims to develop a new formulation suitable for pulmonary administration of ENXM., Methods: A solution for nebulization, based on the complex between ENXM and Hydroxypropyl-β-Cyclodextrin (HPβCD) (ENXM/HPβCD) is developed. The obtained solution is characterized in terms of aerodynamic distributions and biopharmaceutical features., Results: The evaluation of the aerosol droplets indicates a good bronchi-lung distribution of the drug. Biological evaluations of the air-liquid interface (ALI) in an in vitro lung cell model demonstrates that ENXM/HPβCD is capable of a local direct effect, increasing intracellular cyclic adenosine monophosphate (cAMP) levels and protecting from oxidative stress., Conclusions: This study offers a promising advance in the optimization of enoximone delivery to the lungs.

Objective: Management of endometrial cancer is advancing, with accurate staging crucial for guiding treatment decisions. Understanding sentinel lymph node (SLN) involvement rates across molecular subgroups is essential. To evaluate SLN involvement in early-stage (International Federation of Gynecology and Obstetrics 2009 I-II) endometrial cancer, considering molecular subtypes and new European Society of Gynaecological Oncology (ESGO) risk classification., Methods: The SENECA study retrospectively reviewed data from 2139 women with stage I-II endometrial cancer across 66 centers in 16 countries. Patients underwent surgery with SLN assessment following ESGO guidelines between January 2021 and December 2022. Molecular analysis was performed on pre-operative biopsies or hysterectomy specimens., Results: Among the 2139 patients, the molecular subgroups were as follows: 272 (12.7%) p53 abnormal (p53abn, 1191 (55.7%) non-specific molecular profile (NSMP), 581 (27.2%) mismatch repair deficient (MMRd), 95 (4.4%) POLE mutated (POLE-mut). Tracer diffusion was detected in, at least one side, in 97.2% of the cases; with a bilateral diffusion observed in 82.7% of the cases. By ultrastaging (90.7% of the cases) or one-step nucleic acid amplification (198 (9.3%) of the cases), 205 patients were identified with affected sentinel lymph nodes, representing 9.6% of the sample. Of these, 139 (67.8%) had low-volume metastases (including micrometastases, 42.9%; and isolated tumor cells, 24.9%) while 66 (32.2%) had macrometastases. Significant differences in SLN involvement were observed between molecular subtypes, with p53abn and MMRd groups having the highest rates (12.50% and 12.40%, respectively) compared with NSMP (7.80%) and POLE-mut (6.30%), (p=0.004); (p53abn, OR=1.69 (95% CI 1.11 to 2.56), p=0.014; MMRd, OR=1.67 (95% CI 1.21 to 2.31), p=0.002). Differences were also noted among ESGO risk groups (2.84% for low-risk patients, 6.62% for intermediate-risk patients, 21.63% for high-intermediate risk patients, and 22.51% for high-risk patients; p<0.001)., Conclusions: Our study reveals significant differences in SLN involvement among patients with early-stage endometrial cancer based on molecular subtypes. This underscores the importance of considering molecular characteristics for accurate staging and optimal management decisions., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is little experience on the use of the WHO Standards for improving the quality of care (QOC) for children. We describe the use of four prioritised WHO Standard-based Quality Measures to assess the provision of care for children with pain in emergency departments (EDs)., Methods: In a multicentre observational study in 10 EDs with different characteristics in Italy, we collected data on 3355 children accessing the EDs between January 2019 and December 2020. The association between children and facility characteristics and quality measures was analysed through multivariate analyses., Results: The proportion of children whose pain was measured was 68.7% (n=2305), with extreme variations across different centres (from 0.0% to 99.8%, p<0.001). The proportion of children treated for pain was 28.9% (n=970) again with a wide range (5.3%-56.3%, p<0.001). The difference between the frequency of children with pain measured and pain treated varied widely between the facilities (ranging from -24.3 to 82). Children with moderate and severe pain were more frequently treated (48.9% and 62.9% of cases, respectively), although with large variations across centres (ranges: 0%-74.8% and 0%-100% respectively, p<0.001). After correction for children's characteristics, the variable more strongly associated with analysed outcomes was the facility which the child accessed for care. Being a facility in Northern Italy was associated with a higher rate of pain measurement (67.3%-95% CI: 39.9% to 94.6%, p<0.001) compared with facilities in South Italy (-22.1% lower (95% CI: -41.7% to -2.50%, p=0.03)., Conclusions: The use of few WHO Standard-based measures related to pain can help identifying priority gaps in QOC for children and in monitoring it over time. There is a need for more implementation research to establish which are the most sustainable and effective interventions to improve the QOC for acute pain in children., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Arterial blood gas (ABG) analysis is a simple and quick test that can provide multiple respiratory and metabolic parameters. The interpretation of ABG analysis and acid-base disorders represents one of the most complex chapters of clinical medicine. In this brief review, the authors propose a rational approach that sequentially analyzes the information offered by the ABG to allow a rapid classification of the respiratory, metabolic or mixed disorder. The patient's history and clinical-instrumental assessment are the framework in which to insert the information derived from the ABG analysis in order to characterize the critical heart patient.

Objective: To investigate changes in depressive and suicidality status and their relationship with seizure outcomes after the addition or substitution of another antiseizure medication (ASM) in adults with drug-resistant focal epilepsy., Methods: Seven hundred seventy consecutively enrolled patients were assessed and followed prospectively for seizure outcome and depressive status over a 6-month period after starting treatment with a newly introduced ASM. The Neurological Disorders Depression Inventory for Epilepsy (NDDIE) was used to screen for depression and suicidality. Correlations of NDDIE results with clinical and treatment-related variables were assessed by using a stepwise logistic regression model., Results: At baseline, 50% of patients had a positive screening test result for depression and 13% had a positive screening test result for suicidal ideation. A psychiatric comorbidity at baseline was associated with a 2.3 times increased risk of an initially negative NDDIE screening result becoming positive at re-assessment after 6 months. In addition, the number of ASMs taken at baseline correlated with an increased risk of a change in depression screening test results from negative to positive during follow-up, whereas no association was identified with sociodemographic and epilepsy-related variables, including seizure outcomes. Approximately 6% of patients who were initially negative at screening for suicidal ideation became positive at the 6-month re-assessment. The risk of switch from a negative to a positive screening test result for suicidal ideation was increased more than two-fold in individuals who screened positive for depression at baseline, and was unrelated to the type of ASM introduced, sociodemographic variables, or seizure outcomes., Significance: Almost 1 in 5 adults with drug-resistant focal epilepsy who screen negative for depression become positive when re-assessed 6 months after a treatment change. At re-assessment 6 months later, 6.1% who screen initially negative for passive suicidal ideation become positive. These changes in screening status are independent of type of ASM introduced or seizure outcomes but correlate with psychiatric status at baseline., (© 2023 International League Against Epilepsy.)

Despite the results achieved with the evolution of conventional chemotherapy and the inclusion of targeted therapies in the treatment of acute myeloid leukemia (AML), survival is still not satisfying, in particular in the setting of relapsed/refractory (R/R) disease or elderly/unfit patients. Among the most innovative therapeutic options, cellular therapy has shown great results in different hematological malignancies such as acute lymphoblastic leukemia and lymphomas, with several products already approved for clinical use. However, despite the great interest in also expanding the application of these new treatments to R/R AML, no product has been approved yet for clinical application. Furthermore, cellular therapy could indeed represent a powerful tool and an appealing alternative to allogeneic hematopoietic stem cell transplantation for ineligible patients. In this review, we aim to provide an overview of the most recent clinical research exploring the effectiveness of cellular therapy in AML, moving from consolidated approaches such as post- transplant donor's lymphocytes infusion, to modern adoptive immunotherapies such as alloreactive NK cell infusions, engineered T and NK cells (CAR-T, CAR-NK) and novel platforms of T and NK cells engaging (i.e., BiTEs, DARTs and ANKET TM ).

Objectives: This study aimed to explore the practical organisational aspects and difficulties in the implementation of the molecular classification of endometrial carcinoma (EC), and to demonstrate its potential impact in prognostic risk group classification., Methods: We conducted a multicentre, retrospective cohort study of 230 patients with EC diagnosed between 2019 and 2022. Sample processing, clinicopathological, treatment and follow-up data were collected. Molecular classification was obtained by p53 and mismatch repair proteins immunohistochemistry, and POLE next-generation sequencing., Results: Implementation was achieved through centralization of molecular analysis. In practice, it was possible to optimise turnaround times of complete integrative reports for hysterectomy specimens to a median time of 18 workdays. If genetic study was started in endometrial biopsies before surgery, 82.0% were available at the time of multidisciplinary tumour board, compared to 8.4% if performed in hysterectomy. ECs were classified as follows: 37.8% no specific molecular profile, 31.7% p53 abnormal, 24.3% mismatch repair deficient, and 6.1% POLE mutant. Integration of these results with traditional clinicopathologic factors led to a change in prognostic risk group in 15 (6.5%) patients, most being initially allocated to high-intermediate (n = 8) and low (n = 5) risk groups. Eight patients changed to a higher risk, and 7 to a lower risk group, whereas 2 remained in the same group., Conclusions: Centralization of EC molecular classification is a feasible option for countries with limited resources. Optimization of workflows may be achieved by earlier analysis in biopsies and prioritisation of patients whose results imply changes in risk group classification., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Contraception in adolescence is essential to prevent unwanted pregnancies, abortion and sexually transmitted diseases. The use of longacting reversible contraceptive methods (LARCs) has been highly recommended due to their efficacy since they are user independent methods. The aim of this study was to evaluate the use of LARCs in adolescence in the population of a Childhood and Adolescence Gynecology clinic, and to describe the sociodemographic characteristics of the adolescents as well as previous contraceptive practices., Material and Methods: Retrospective analysis that included adolescents using LARCs, monitored in a Childhood and Adolescence Gynecology clinic of a Portuguese tertiary pediatric hospital, between June 2012 and June 2021., Results: A total of 122 adolescents were included, with a median age of 16 (11 - 18) years and 62.3% (n = 76) were sexually active. The preferred method was the subcutaneous implant, placed in 82.3% (n = 101), followed by the Levonorgestrel-Intrauterine System in 16.4% (n = 20) and the copper intrauterine device in 1.3% (n = 1). The main indications for LARCs were contraceptive needs 90.2% (n = 110), abnormal uterine bleeding during puberty in 14.8% (n = 18), dysmenorrhea in 10.7% (n = 13) and need for amenorrhea in 0.8% (n = 1). The median time of implant use was 20 (1 - 48) months and of the LNG-IUS it was 20 (1 - 36) months. The 12-month adherence rate for both was 76.2% (n = 93). The removal rate for reasons besides the expiration date was 9.8% (n = 12) in adolescents who had implants, and no LNG-IUS or copper intrauterine devices were removed. There were no pregnancies after insertion of LARCs., Conclusion: Contraceptive needs were the main reason for choosing LARCs, followed by abnormal uterine bleeding during puberty management and dysmenorrhea. All these factors may contribute to the high rate of satisfaction and continuity of these methods.

Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently available. ARDS involves severe respiratory failure, fibrin deposition in both airways and lung parenchyma, with the development of an obstructing hyaline membrane drastically limiting gas exchange. Moreover, hypercoagulation is related to deep lung inflammation, and a pharmacological action toward both aspects is expected to be beneficial. Plasminogen (PLG) is a main component of the fibrinolytic system playing key roles in various inflammation regulatory processes. The inhalation of PLG has been proposed in the form of the off-label administration of an eyedrop solution, namely, a plasminogen-based orphan medicinal product (PLG-OMP), by means of jet nebulisation. Being a protein, PLG is susceptible to partial inactivation under jet nebulisation. The aim of the present work is to demonstrate the efficacy of the mesh nebulisation of PLG-OMP in an in vitro simulation of clinical off-label administration, considering both the enzymatic and immunomodulating activities of PLG. Biopharmaceutical aspects are also investigated to corroborate the feasibility of PLG-OMP administration by inhalation. The nebulisation of the solution was performed using an Aerogen ® Solo TM vibrating-mesh nebuliser. Aerosolised PLG showed an optimal in vitro deposition profile, with 90% of the active ingredient impacting the lower portions of a glass impinger. The nebulised PLG remained in its monomeric form, with no alteration of glycoform composition and 94% of enzymatic activity maintenance. Activity loss was observed only when PLG-OMP nebulisation was performed under simulated clinical oxygen administration. In vitro investigations evidenced good penetration of aerosolised PLG through artificial airway mucus, as well as poor permeation across an Air-Liquid Interface model of pulmonary epithelium. The results suggest a good safety profile of inhalable PLG, excluding high systemic absorption but with good mucus diffusion. Most importantly, the aerosolised PLG was capable of reversing the effects of an LPS-activated macrophage RAW 264.7 cell line, demonstrating the immunomodulating activity of PLG in an already induced inflammatory state. All physical, biochemical and biopharmaceutical assessments of mesh aerosolised PLG-OMP provided evidence for its potential off-label administration as a treatment for ARDS patients.

Endometrial carcinoma (EC) harboring POLE exonuclease domain mutations occurs in 5-15% of ECs and frequently affects young women with low body mass index (BMI). It presents at early stage as high grade endometrioid histotype with intense tumor infiltrating lymphocytes and has good clinical outcomes and favorable prognosis. In this article we report the case of a 32-year-old woman with endometriod EC (EEC) exhibiting a "ultramutated" molecular profile and an excellent prognosis despite tumor size and grading. Herein, to highlight the importance of defining POLE status in ECs for both clinical and therapeutic implications for patients., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Platinum-based chemotherapy is the standard chemotherapy for high grade serous ovarian cancer and primary peritoneal high-grade serous carcinoma. PARP inhibitors have changed the paradigm of the treatment in platinum-sensitive ovarian cancers and primary peritoneal high-grade serous carcinoma with BRCA1/2 mutation or homologous recombination deficiency (HRD). Platinum-resistant ovarian and primary peritoneal high-grade serous carcinoma have a lower chance to treat and have worse outcomes. We described a case of patient with a platinum resistant primary peritoneal high-grade serous carcinoma with a rare somatic BRCA2 amplification. There are no guidelines for the treatment of ovarian cancer or primary peritoneal high-grade serous carcinoma with BRCA2 amplification. BRCA2 amplification could result in extreme homologous recombination repair (HRR) pathway efficiency and in less platinum sensitivity, which could be a molecular signature for platinum resistance. Free platinum chemotherapy regimens could be more effective in cases with BRCA2 amplification. Further studies are necessary to establish better approaches and strategies for oncological management and treatment in BRCA2 amplification high grade ovarian cancer and primary peritoneal high-grade serous carcinoma., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Placental site trophoblastic tumor (PSTT), also known as atypical choriocarcinoma, syncytioma, chorioepitheliosis or trophoblastic pseudotumor, is a rare gestational trophoblastic disease (0.25-5% of all trophoblastic tumors) and it is composed by neoplastic proliferation of intermediate trophoblasts at placental implantation site. It consists of aggregates or sheets of large, polyhedral to round, predominantly mononucleated cells with a characteristic vascular and myometrial invasion. Main differential diagnoses are gestational choriocarcinoma (GC) and epitelioid trophoblastic tumor (ETT). We present a case of PSTT in a 25-year-old woman. Neoplastic cells showed moderate/high nuclear pleomorphism, abundant amphophilic, eosinophilic and clear cytoplasm, numerous mitotic figures (10 mitoses/10 HPF), and myometrial invasion. Other features are necrosis, vascular invasion with replacement of myometrial vessels by tumor cells and hemorrhage. The patient showed typical low serum β-hCG levels and high serum humane placental lactogen (hPL) levels., (Copyright © 2023 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: Venous thromboembolism represents the third most frequent acute cardiovascular syndrome worldwide. Its clinical manifestations are deep vein thrombosis and/or pulmonary embolism. Despite a considerable mortality, diagnosis is often missed.  CASE PRESENTATION: We report the management of a female patient with high-risk pulmonary thromboembolism treated initially with thromboaspiration, complicated by embolus jailing in a patent foramen ovale. In this situation, left cardiac chambers and systemic circulation were jeopardized by this floating embolus., Conclusions: High-risk pulmonary embolism requires reperfusion strategy but sometimes mechanical thromboaspiration may be not fully successful; transesophageal echocardiography led to a prompt diagnosis of this unexpected finding; in this very particular case, open surgery represented a bail-out procedure to avoid cerebral and systemic embolism., (© 2022. The Author(s).)

A number of innovative drugs, developed for precision medicine, have shown impressive activity in neoplastic patients with rare molecular targets, independently from the site and type of tumor. This gave rise to the concept of agnostic treatments in oncology. The detection of such rare targets is a prerequisite for these treatments and is nowadays one of the main challenges in diagnostic molecular pathology. Various algorithms, new diagnostic strategies and pathological workflows have been suggested to help pathologists in the detection of these rare molecular alterations. An emblematic example of biological targets for agnostic treatments is represented by genetic rearrangements affecting members of the Neurotrophic Tyrosine Receptor Kinase (NTRK) gene family. These gene rearrangements have an unusual dual mode of distribution: the first, at high frequency in some very rare neoplasms, and the second with extremely lower frequencies in more common tumors. Even in the context of an agnostic approach, knowledge of site, histotype and prevalence of the tumors carrying these genetic lesions may be helpful to guide the pathologist in the daily effort in search of these molecular alterations. This review examines the prevalence of NTRK gene fusions in different forms of solid tumors, based on the largest studies to date, reports a comprehensive diagnostic algorithm and an innovative pathological workflow for rapid screening., (Copyright © 2022 Società Italiana di Anatomia Patologica e Citopatologia Diagnostica, Divisione Italiana della International Academy of Pathology.)

Background: The pathological involvement of the heart is frequent in SARS-Coronavirus-2 infection (COVID-19) with various clinical and echocardiographic manifestations during the course of the disease., Case Summary: A 69-year-old female patient with severe COVID-19-related acute respiratory distress syndrome undergoing mechanical ventilation developed acute left ventricular dysfunction, that successfully improved with vasoactive therapy. After 5 days, she suddenly developed hemodynamic instability due to acute onset of pericardial effusion, which required emergency pericardiocentesis. Ultrasound-guided parasternal pericardiocentesis with high-frequency linear probe and lateral-to-medial in-plane approach was performed by inserting a central venous catheter using a Seldinger technique. 700 mL of serous fluid was drained resolving the acute critical state., Discussion: Pericardial effusion with cardiac tamponade is a rare manifestation of Covid-19. Despite the diffusion of echocardiography, emergency cardiac procedures could be particularly difficult to be performed in a pandemic scenario of limited resources and the heterogeneous skills of the professional figures involved in the management of COVID-19 patients. The spread of expertise in ultrasound-guided vascular cannulation makes this approach attractive for anesthesiologists, emergency medicine and critical care specialists too. Furthermore in this pericardiocentesis' technique, the high-frequency linear probe adds optimal spatial resolution to maintain a close control of the needle's direction. However the need of a good parasternal view and a deep ultrasound knowledge are crucial to avoid iatrogenic complications. In conclusion, ultrasound-guided lateral-to-medial parasternal pericardiocentesis with high-frequency linear probe is an alternative to treat potential lethal acute haemodynamic instability due to cardiac tamponade., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Increased levels of alkaline phosphatase (ALP) should alert us to changes in the liver, kidney, bone and malignancy. However, there is a physiological increase in pregnancy up to twice the upper limit. There has been a paucity of cases reporting extreme elevations of ALP in pregnancy. This is a case of an incidental pregnancy finding of a 24-fold increase in ALP in the third trimester (2877 U/L). The patient was kept under surveillance and ALP levels were monitored during the postpartum period. Literature suggests a correlation between ALP elevation and several perinatal complications, proposing it could represent an important tool in monitoring high-risk pregnancies and underlying placental damage. We report a case with no perinatal complications and normal labor at term, with a placenta showing lesions of chronic villitis. We should not rely exclusively on an isolated, marked rise in ALP to dictate the approach in the absence of other fetomaternal considerations., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, Ferro et al.)

The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars. Plasminogen is considered a key player in fibrinolysis processes, and in view of a bench-to-bedside translation, we focused on the aerosolization of an orphan medicinal product (OMP) for ligneous conjunctivitis: human plasminogen (PLG-OMP) eye drops. As such, the sterile and preservative-free solution guarantees the pharmaceutical quality of GMP production and meets the Ph. Eur. requirements of liquid preparations for nebulization. PLG-OMP aerosolization was evaluated both from technological and stability viewpoints, after being submitted to either jet or ultrasonic nebulization. Jet nebulization resulted in a more efficient delivery of an aerosol suitable for pulmonary deposition. The biochemical investigation highlighted substantial protein integrity maintenance with the percentage of native plasminogen band > 90%, in accordance with the quality specifications of PLG-OMP. In a coherent way, the specific activity of plasminogen is maintained within the range 4.8-5.6 IU/mg (PLG-OMP pre-nebulization: 5.0 IU/mg). This is the first study that focuses on the technological and biochemical aspects of aerosolized plasminogen, which could affect both treatment efficacy and clinical dosage delivery. Increasing evidence for the need of local fibrinolytic therapy could merge with the availability of PLG-OMP as an easy handling solution, readily aerosolizable for a fast translation into an extended clinical efficacy assessment in COVID-19 patients.

From 2010 to 2015, young (13-24 years) Hispanic/Latino gay, bisexual and other men who have sex with men (MSM) experienced the largest increase (18%) in numbers of HIV diagnoses among all racial/ethnic groups. In 2016, the Centers for Disease Control and Prevention (CDC) assembled a team of scientists and public health analysts to develop a programmatic approach for addressing the increasing HIV diagnosis among Hispanic/Latino MSM. The team used a data driven review process, i.e., comprehensive review of surveillance, epidemiologic, and programmatic data, to explore key questions from the literature on factors associated with HIV diagnoses among Hispanic/Latino MSM and to inform the approach. This paper describes key findings from the review and discusses the approach. The approach includes the following activities: increase awareness and support testing by expanding existing campaigns targeting Hispanic/Latino MSM to jurisdictions where diagnoses are increasing; strengthen existing efforts that support treatment as prevention and increase engagement in care and viral suppression among Hispanic/Latino MSM living with HIV and promote prevention, e.g., PrEP uptake and condom use, among Hispanic/Latino MSM who are at high-risk for HIV infection., (Published by Elsevier Inc.)

Background: Certolizumab pegol, a PEGylated tumour necrosis factor (TNF)-inhibitor, improves the clinical signs and symptoms of rheumatoid arthritis (RA) when used in combination with methotrexate or as monotherapy. This study evaluatedthe cost-utility of certolizumab pegol versusTNF-inhibitors plus methotrexate in the treatment of moderate-to-severe RA in Spain., Methods: A Markov cohort health state transition model was developed to evaluate the cost-utility (costs and quality-adjusted life years [QALYs]) of certolizumab pegol versus other TNF-inhibitors licensed in Spain in 2009. Efficacy was measured using the American College of Rheumatology (ACR) responses at 6 months, based on adjusted indirect comparisons from published clinical trials. Utilities were derived from EQ-5D data from certolizumab pegol RA clinical trials. Clinical history and resource use data came from published literature. Unit costs were taken from Spanish databases or published data (cost year 2009). Base case analyses were conducted from the payer perspective, with a lifetime horizon, 3.5 % annual discounting rates for costs and outcomes, and 3 % inflation rate for 2009 onwards. One-way sensitivity analyses were conducted., Results: The average lifetime costs for certolizumab pegol, etanercept, adalimumab (every 2 weeks and weekly) and infliximab (3 mg/kg and 5 mg/kg) in combination with methotrexate were €140,971, €141,197, €139,148, €164,741, €136,961 and €152,561, respectively. The QALYs gained were 6.578, 6.462, 6.430 (for both adalimumab doses), 6.430, and 6.318 (for both infliximab doses), respectively. At a €30,000/QALY willingness-to-pay threshold, certolizumab pegol plus methotrexate dominated adalimumab weekly, etanercept, and infliximab 5 mg/kg, and was cost-effective versus adalimumab every 2 weeks and infliximab 3 mg/kg (all with methotrexate), with estimated ICERs of €12,346/QALY and €15,414/QALY, respectively. Certolizumab pegol monotherapy was more cost-effective versus adalimumab, and less expensive with similar health gains versus etanercept (6.416 QALYs vs 6.492). Univariate analysis showed ICERs to be sensitive to changes in time horizon, ACR response time point, baseline Heath Assessment Questionnaire (HAQ) score, and rate of HAQ-disability index deterioration after discontinuing treatment., Conclusions: This analysis shows that certolizumab pegol is cost-effective compared with other TNF-inhibitors recommended in Spain for the treatment of RA.