Immunostimulatory gene therapy targeting CD40, 4-1BB and IL-2R activates DCs and stimulates antigen-specific T-cell and NK-cell responses in melanoma models.

BACKGROUND: The activation of dendritic cells (DCs) is pivotal for generating antigen-specific T-cell responses to eradicate tumor cells. Hence, immunotherapies targeting this interplay are especially intriguing. Moreover, it is of interest to modulate the tumor microenvironment (TME), as this harsh milieu often impairs adaptive immune responses. Oncolytic viral therapy presents an opportunity to overcome the immunosuppression in tumors by destroying tumor cells and thereby releasing antigens and immunostimulatory factors. These effects can be further amplified by the introduction of transgenes expressed by the virus. METHODS: Lokon oncolytic adenoviruses (LOAd) belong to a platform of chimeric serotype Ad5/35 viruses that have their replication restricted to tumor cells, but the expression of transgenes is permitted in all infected cells. LOAd732 is a novel oncolytic adenovirus that expresses three essential immunostimulatory transgenes: trimerized membrane-bound CD40L, 4-1BBL and IL-2. Transgene expression was determined with flow cytometry and ELISA and the oncolytic function was evaluated with viability assays and xenograft models. The activation profiles of DCs were investigated in co-cultures with tumor cells or in an autologous antigen-specific T cell model by flow cytometry and multiplex proteomic analysis. Statistical differences were analyzed with Kruskal-Wallis test followed by Dunn's multiple comparison test. RESULTS: All three transgenes were expressed in infected melanoma cells and DCs and transgene expression did not impair the oncolytic activity in tumor cells. DCs were matured post LOAd732 infection and expressed a multitude of co-stimulatory molecules and pro-inflammatory cytokines crucial for T-cell responses. Furthermore, these DCs were capable of expanding and stimulating antigen-specific T cells in addition to natural killer (NK) cells. Strikingly, the addition of immunosuppressive cytokines TGF-ß1 and IL-10 did not affect the ability of LOAd732-matured DCs to expand antigen-specific T cells and these cells retained an enhanced activation profile. CONCLUSIONS: LOAd732 is a novel immunostimulatory gene therapy based on an oncolytic adenovirus that expresses three transgenes, which are essential for mediating an anti-tumor immune response by activating DCs and stimulating T and NK cells even under imunosuppressive conditions commonly present in the TME. These qualities make LOAd732 an appealing new immunotherapy approach.

Cyst formation and bony ingrowth inside coil-type open-architecture anchors used for arthroscopic remplissage: a volumetric computed tomographic study of 50 anchors.

BACKGROUND: The use of anchors in the proximal humerus during arthroscopic surgery can cause localized bone loss due to osteolysis and cyst formation. The purpose of this study was to use computed tomography (CT) to evaluate the incidence of implant-related bone loss and cyst formation after implantation of polyetheretherketone (PEEK) coil-type open-architecture anchors during remplissage for the management of Hill-Sachs defects (HSDs) in patients with shoulder instability. METHODS: This was a single-cohort, observational study with a minimum of 12 months of follow-up. Subjects undergoing arthroscopic instability surgery with HSD requiring remplissage were included. The volume of the bone defects and the degree of bony ingrowth into the anchor were measured on CT images. RESULTS: Thirty-one participants (28 males, 3 females; mean age 29.4 years, standard deviation [SD] 10.6) in whom 50 anchors (4.5-mm Healicoil PEEK double-loaded anchors) were used were evaluated with a CT performed at a mean of 14.1 (SD 3.74) months after surgery. Full bony ingrowth inside the anchor was found in 15 anchors (30%, range 17.8%-44.5%); clear ossification with a thin lucent rim was found in 10 anchors (20%, range 10.0%-33.7%); discontinuous ossification was found in 8 anchors (16%, range 7.2%-29.1%); and no ossification was observed inside 17 anchors (34%, range 21.2%-48.7%). Regarding bone defect size, no bone defect was identified in 15 anchors (30%, 95% CI 17.9%-44.6%), a partial bone defect was found in 17 anchors (34%, 95% CI 21.2%-48.7%), hole enlargement was found in 17 anchors (34%, 95% CI 21.2%-48.7%), and 1 anchor caused a cyst larger than twice the size of the hole made for anchor insertion (2%, 95% CI 0.1%-8.6%). At the 1-year evaluation, none of the participants presented recurrence or residual apprehension. CONCLUSION: The use of PEEK coil-type open-architecture anchors for remplissage during instability surgery caused large cystic lesions in less than 10% of anchors. There was full bony ingrowth in one-third of anchors, and partial cancellous bone ingrowth occurred in another third of anchors.

5-aminolevulinic acid fluorescence guided surgery for resection of cystic meningioma with bone invasion.

Meningiomas have a 5 year recurrence rate of 8%. Histological grade and extent of resection are the two main prognostic factors. Cystic meningiomas represent between 2 and 4% of meningiomas, and the complete resection rate in these cases is 62.7%. 5-ALA has been shown to be useful in detecting tumour remnants that could go unnoticed by the conventional microsurgical technique, thereby achieving more complete resections. We present the case of a 66-year-old patient with a frontal convexity meningioma, presenting with a cystic component and bone invasion, who was treated using 5-ALA fluorescence-guided surgery. Fluorescence emission from the tumour tissue allowed the areas of bone invasion and the cystic wall to be identified, achieving complete resection.

SWI/SNF Complex Alterations in Tumors with Rhabdoid Features: Novel Therapeutic Approaches and Opportunities for Adoptive Cell Therapy.

The SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin-remodeling complex is one of the most remarkably altered epigenetic regulators in cancer. Pathogenic mutations in genes encoding SWI/SNF-related proteins have been recently described in many solid tumors, including rare and aggressive malignancies with rhabdoid features with no standard therapies in advanced or metastatic settings. In recent years, clinical trials with targeted drugs aimed at restoring its function have shown discouraging results. However, preclinical data have found an association between these epigenetic alterations and response to immune therapy. Thus, the rationale for immunotherapy strategies in SWI/SNF complex alteration-related tumors is strong. Here, we review the SWI/SNF complex and how its dysfunction drives the oncogenesis of rhabdoid tumors and the proposed strategies to revert this alteration and promising novel therapeutic approaches, including immune checkpoint inhibition and adoptive cell therapy.

Analysis of the diagnostic accuracy of rapid antigenic tests for detection of SARS-CoV-2 in hospital outbreak situation.

The reverse transcriptase polymerase chain reaction (RT-PCR) continues to be the reference diagnostic method for the confirmation of COVID-19 cases; however, rapid antigen detection tests (RADT) have recently been developed. The purpose of the study is to assess the performance of rapid antigen-based COVID-19 testing in the context of hospital outbreaks. This was an observational, cross-sectional study. The study period was from October 2020 to January 2021. The "Panbio COVID-19 AG" RADT (Abbott) was performed and TaqPath COVID-19 test RT-PCR. The samples were obtained from hospitalised patients in suspected outbreak situations at the Ramón y Cajal Hospital. A hospital outbreak was defined as the presence of 3 or more epidemiologically linked cases. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the RADT were calculated using RT-PCR as a reference. A total of 17 hospital outbreaks were detected in 11 hospital units during the study period, in which 34 RT-PCR and RADT screenings were performed. We obtained 541 samples, which were analysed with RT-PCR and a further 541 analysed with RADT. Six RADT tests gave conflicting results with the RT-PCR, 5 of them with a negative RADT and positive RT-PCR and one with positive RADT and a negative RT-PCR. The sensitivity of the RADT was 83.3% (65.3-94.4%) and the specificity was 99.8% (98.9-100%). The PPV was 96.2% (80.4-99.9%) and the NPV was 99% (97.7-99.7%). The RADT shows good diagnostic performance in patients on non-COVID-19 hospital wards, in the context of an outbreak.

Assessment of isolated glenohumeral range of motion in patients with adhesive capsulitis can help predict failure of conservative treatment: a pilot study.

PURPOSE: To prospectively evaluate a cohort of patients with adhesive capsulitis and identify predictors of failure of conservative treatment in the first 2 months of therapy. METHODS: This was a single-cohort, prospective observational study that included 20 participants (13 females/7 males; median age of 51.8 years [interquartile range: 8.65]) with primary adhesive capsulitis managed conservatively and evaluated clinically every month for at least 2 years of follow-up (29 [5] months). The evaluation included stage of the disease, treatment applied, radiological findings, pain levels and range of motion (active and passive ROM in the four planes and isolated glenohumeral passive ROM in abduction [GH-ABD], external rotation [GH-ER] and internal rotation). The main outcome assessed was failure of conservative treatment defined as the need for surgery and persistent pain or CMS below 70 points at the 1-year follow-up. RESULTS: Seven patients (7/20, 35%) were considered to have failed conservative treatment because they required arthroscopic capsular release 5.2 (2.1) months after the initial diagnosis. Of all the clinical and epidemiological variables, absence of improvement during the first 2 months in isolated glenohumeral ROM abduction and external rotation predicted failure of conservative treatment: improvement in GH-ABD (10° or more) occurred in 10/13 patients in the conservative treatment group and in 1/7 patients in the surgery group (p = 0.017). Improvement in GH-ER (10° or more) occurred in 9/13 patients in the conservative treatment group and in 0/7 patients in the surgery group (p = 0.005). CONCLUSIONS: Precise assessment of isolated glenohumeral ROM in patients with adhesive capsulitis can help identify patients in which conservative treatment might fail. In this study, patients who did not experience early improvements in isolated glenohumeral ROM often required surgery. LEVEL OF EVIDENCE: III (Prospective cohort study).

An m-Health telerehabilitation and health education program on physical performance in patients with hip fracture and their family caregivers: Study protocol for the ActiveHip+ randomized controlled trial.

Telerehabilitation interventions administered via a smartphone may provide new feasible and effective rehabilitation options at home for patients with hip fracture. However, to date, no such interventions have been shown to be effective in the recovery key health outcomes of these patients. The present multicentre randomized controlled trial (RCT) aims to test the effect of the ActiveHip+ m-Health system in the recovery of physical performance, functional level, quality of life, and other health-related outcomes in both patients with hip fracture and their family caregivers. A total of 104 patients older than 65 years, with hip fracture, and their family caregivers will be randomized into the ActiveHip+ rehabilitation (N = 52) or the control group (N = 52). ActiveHip+ is a 12-week smartphone-based rehabilitation program conducted in Granada and Cádiz (Spain) that includes: (1) 24 sessions of physical exercise and 12 sessions of occupational therapy; (2) seven educational modules for patients and for caregivers; and (3) general recommendations in activities of daily living. The control group will receive the usual rehabilitation protocol offered by the Andalusian Public Healthcare System. The primary outcome is the patient's physical performance, while the secondary outcomes are the patient's functional level, quality of life, pain, fear of falling, fitness perception, pre-fracture functional level, emotional status, and caregiver burden. The present project will substantially contribute to the existing knowledge by testing for the first time the efficacy and feasibility of a multidisciplinary m-Health system in the rehabilitation of patients with hip fracture.

Force and Torque Characterization in the Actuation of a Walking-Assistance, Cable-Driven Exosuit.

Soft exosuits stand out when it comes to the development of walking-assistance devices thanks to both their higher degree of wearability, lower weight, and price compared to the bulkier equivalent rigid exoskeletons. In cable-driven exosuits, the acting force is driven by cables from the actuation system to the anchor points; thus, the user's movement is not restricted by a rigid structure. In this paper, a 3D inverse dynamics model is proposed and integrated with a model for a cable-driven actuation to predict the required motor torque and traction force in cables for a walking-assistance exosuit during gait. Joint torques are to be shared between the user and the exosuit for different design configurations, focusing on both hip and ankle assistance. The model is expected to guide the design of the exosuit regarding aspects such as the location of the anchor points, the cable system design, and the actuation units. An inverse dynamics analysis is performed using gait kinematic data from a public dataset to predict the cable forces and position of the exosuit during gait. The obtained joint reactions and cable forces are compared with those in the literature, and prove the model to be accurate and ready to be implemented in an exosuit control scheme. The results obtained in this study are similar to those found in the literature regarding the walking study itself as well as the forces under which cables operate during gait and the cable position cycle.

Development of a new largely scalable in vitro prion propagation method for the production of infectious recombinant prions for high resolution structural studies.

The resolution of the three-dimensional structure of infectious prions at the atomic level is pivotal to understand the pathobiology of Transmissible Spongiform Encephalopathies (TSE), but has been long hindered due to certain particularities of these proteinaceous pathogens. Difficulties related to their purification from brain homogenates of disease-affected animals were resolved almost a decade ago by the development of in vitro recombinant prion propagation systems giving rise to highly infectious recombinant prions. However, lack of knowledge about the molecular mechanisms of the misfolding event and the complexity of systems such as the Protein Misfolding Cyclic Amplification (PMCA), have limited generating the large amounts of homogeneous recombinant prion preparations required for high-resolution techniques such as solid state Nuclear Magnetic Resonance (ssNMR) imaging. Herein, we present a novel recombinant prion propagation system based on PMCA that substitutes sonication with shaking thereby allowing the production of unprecedented amounts of multi-labeled, infectious recombinant prions. The use of specific cofactors, such as dextran sulfate, limit the structural heterogeneity of the in vitro propagated prions and makes possible, for the first time, the generation of infectious and likely homogeneous samples in sufficient quantities for studies with high-resolution structural techniques as demonstrated by the preliminary ssNMR spectrum presented here. Overall, we consider that this new method named Protein Misfolding Shaking Amplification (PMSA), opens new avenues to finally elucidate the three-dimensional structure of infectious prions.

Effect of childhood pneumococcal vaccination and beta-lactam antibiotic use on the incidence of invasive pneumococcal disease in the adult population.

Describe the incidence of invasive pneumococcal disease (IPD) in serotypes with reduced antibiotic sensitivity to penicillin (RAS-Pen) in adults over 59 years of age and its association with childhood anti-pneumococcal vaccination coverage (CVC) and community consumption of beta-lactam. We selected IPD cases in adults over 59 years of age reported in the Community of Madrid between 2007 and 2016. We estimated the incidence of cases caused by serotypes included in the 13-valent pneumococcal conjugate vaccine (PCV13), those not included (non-PCV13) and the six serotypes additional to the 7-valent (PCV13-no7). We compared the incidences of serotypes from the pre-vaccine period (2007-2009) and the vaccine period (2011-2016) by analysing the incidence trend (JointPoint Trend Analysis) and its association with the CVC and community consumption of beta-lactam (Poisson model). We identified 1936 cases of IPD, 29.2% (n = 565) in serotypes with RAS-Pen. The incidence decreased for PCV13 cases (annual percentage of change, APC: -12.2, p < 0.05) and increased for non-PCV13 (APC: 15.4, p < 0.05). The incidence of IPD due to non-PCV13 was associated with community beta-lactam consumption (IRR 1.156; CI95% 1.025-1.304) and that of cases of PCV13-no7 with CVC (IRR 0.574; 95% CI95% 0.413-0.797). The non-PCV13 strains that increased the most at the end of the period were 6C, 11A and 15A. The incidence of IPD due to PCV13 with RAS-Pen at > 59 years was decreasing and was associated with CVC. The incidence of cases due to non-PCV13 was increasing and was associated with community consumption of beta-lactam.

IL-6 Signaling Blockade during CD40-Mediated Immune Activation Favors Antitumor Factors by Reducing TGF-ß, Collagen Type I, and PD-L1/PD-1.

IL-6 plays a role in cancer pathogenesis via its connection to proteins involved in the formation of desmoplastic stroma and to immunosuppression by driving differentiation of myeloid suppressor cells together with TGF-ß. Inhibition of IL-6 signaling in the tumor microenvironment may, thus, limit desmoplasia and myeloid suppressor cell differentiation. CD40 signaling can further revert myeloid cell differentiation toward antitumor active phenotypes. Hence, the simultaneous use of IL-6 blockade with CD40 stimuli may tilt the tumor microenvironment to promote antitumor immune responses. In this paper, we evaluated the mechanisms of LOAd713, an oncolytic adenovirus designed to block IL-6R signaling and to provide myeloid cell activation via a trimerized membrane-bound isoleucine zipper (TMZ) CD40L. LOAd713-infected pancreatic cancer cells were killed by oncolysis, whereas infection of stellate cells reduced factors involved in stroma formation, including TGF-ß-1 and collagen type I. Virus infection prevented IL-6/GM-CSF-mediated differentiation of myeloid suppressors, but not CD163 macrophages, whereas infection of dendritic cells led to upregulation of maturation markers, including CD83, CD86, IL-12p70, and IFN-γ. Further, IL-6R blockade prevented upregulation of programed death ligand 1 (PD-L1) and PD-1 on the stimulated dendritic cells. These results suggest that LOAd713 can kill infected tumor cells and has the capacity to affect the tumor microenvironment by stimulating stellate cells and myeloid suppressors with TMZ-CD40L and IL-6R blockade. Gene transfer of murine TMZ-CD40L prolonged survival in an animal model. LOAd713 may be an interesting therapeutic option for cancers connected to IL-6 signaling, such as pancreatic cancer.

Role of nicergoline in corneal wound healing in diabetic rats.

BACKGROUND: To investigate the effect of nicergoline on the rate of complete corneal ulcer reepithelialization (CCUR) in diabetic rats with diabetic keratopathy. METHODS: Forty-eight streptozotocin-induced diabetic rats were randomly divided into two groups. The experimental group (n = 24) received nicergoline (10 mg.kg- 1.day- 1), while the control group (n = 24) received a placebo. A corneal epithelial defect was induced using a corneal diamond burr, and defect area was compared at time points of 0, 12, 24, 48 and 72 h after the injury using image analysis software. The probability of CCUR within 72 h was assessed using the Kaplan-Meier survival analysis log-rank test. RESULTS: When compared, 4 of the 24 rats (17%) in the placebo group and 12 of the 24 rats (50%) in the nicergoline group were found to have CCUR within 72 h (log-rank = 0.027). Cox regression analysis found no effect of the covariates blood glucose (P = 0.601) or weight (P = 0.322) on the corneal reepithelialization (survival) curve. CONCLUSIONS: Nicergoline increased wound healing rates relative to placebo and may therefore be investigated as a treatment option in diabetic keratopathy.

Data Protection by Design in the Context of Smart Cities: A Consent and Access Control Proposal.

The growing availability of mobile devices has lead to an arising development of smart cities services that share a huge amount of (personal) information and data. Without accurate and verified management, they could become severe back-doors for security and privacy. In this paper, we propose a smart city infrastructure able to integrate a distributed privacy-preserving identity management solution based on attribute-based credentials (p-ABC), a user-centric Consent Manager, and a GDPR-based Access Control mechanism so as to guarantee the enforcement of the GDPR's provisions. Thus, the infrastructure supports the definition of specific purpose, collection of data, regulation of access to personal data, and users' consents, while ensuring selective and minimal disclosure of personal information as well as user's unlinkability across service and identity providers. The proposal has been implemented, integrated, and evaluated in a fully-fledged environment consisting of MiMurcia, the Smart City project for the city of Murcia, CaPe, an industrial consent management system, and GENERAL_D, an academic GDPR-based access control system, showing the feasibility.

The OLYMPUS Architecture-Oblivious Identity Management for Private User-Friendly Services.

Privacy enhancing technologies (PETs) allow to achieve user's transactions unlinkability across different online Service Providers. However, current PETs fail to guarantee unlinkability against the Identity Provider (IdP), which becomes a single point of failure in terms of privacy and security, and therefore, might impersonate its users. To address this issue, OLYMPUS EU project establishes an interoperable framework of technologies for a distributed privacy-preserving identity management based on cryptographic techniques that can be applied both to online and offline scenarios. Namely, distributed cryptographic techniques based on threshold cryptography are used to split up the role of the Identity Provider (IdP) into several authorities so that a single entity is not able to impersonate or track its users. The architecture leverages PET technologies, such as distributed threshold-based signatures and privacy attribute-based credentials (p-ABC), so that the signed tokens and the ABC credentials are managed in a distributed way by several IdPs. This paper describes the Olympus architecture, including its associated requirements, the main building blocks and processes, as well as the associated use cases. In addition, the paper shows how the Olympus oblivious architecture can be used to achieve privacy-preserving M2M offline transactions between IoT devices.

Arming Oncolytic Adenoviruses: Effect of Insertion Site and Splice Acceptor on Transgene Expression and Viral Fitness.

Oncolytic adenoviruses (OAds) present limited efficacy in clinics. The insertion of therapeutic transgenes into OAds genomes, known as "arming OAds", has been the main strategy to improve their therapeutic potential. Different approaches were published in the decade of the 2000s, but with few comparisons. Most armed OAds have complete or partial E3 deletions, leading to a shorter half-life in vivo. We generated E3+ OAds using two insertion sites, After-fiber and After-E4, and two different splice acceptors linked to the major late promoter, either the Ad5 protein IIIa acceptor (IIIaSA) or the Ad40 long fiber acceptor (40SA). The highest transgene levels were obtained with the After-fiber location and 40SA. However, the set of codons of the transgene affected viral fitness, highlighting the relevance of transgene codon usage when arming OAds using the major late promoter.

Mouse corticospinal system comprises different functional neuronal ensembles depending on their hodology.

BACKGROUND: Movement performance depends on the synaptic interactions generated by coherent parallel sensorimotor cortical outputs to different downstream targets. The major outputs of the neocortex to subcortical structures are driven by pyramidal tract neurons (PTNs) located in layer 5B. One of the main targets of PTNs is the spinal cord through the corticospinal (CS) system, which is formed by a complex collection of distinct CS circuits. However, little is known about intracortical synaptic interactions that originate CS commands and how different populations of CS neurons are functionally organized. To further understand the functional organization of the CS system, we analyzed the activity of unambiguously identified CS neurons projecting to different zones of the same spinal cord segment using two-photon calcium imaging and retrograde neuronal tracers. RESULTS: Sensorimotor cortex slices obtained from transgenic mice expressing GCaMP6 funder the Thy1 promoter were used to analyze the spontaneous calcium transients in layer 5 pyramidal neurons. Distinct subgroups of CS neurons projecting to dorsal horn and ventral areas of the same segment show more synchronous activity between them than with other subgroups. CONCLUSIONS: The results indicate that CS neurons projecting to different spinal cord zones segregated into functional ensembles depending on their hodology, suggesting that a modular organization of CS outputs controls sensorimotor behaviors in a coordinated manner.

Antitumor virotherapy using syngeneic or allogeneic mesenchymal stem cell carriers induces systemic immune response and intratumoral leukocyte infiltration in mice.

Oncolytic virotherapy uses oncolytic viruses that selectively replicate in cancer cells. The use of cellular vehicles with migration ability to tumors has been considered to increase their delivery to target sites. Following this approach, the antitumor efficacy of the treatment Celyvir (mesenchymal stem cells infected with the oncolytic adenovirus ICOVIR-5) has been demonstrated in patients with neuroblastoma. However, the better efficacy of syngeneic or allogeneic mesenchymal stem cells as cell carriers and the specific role of the immune system in this therapy are still unknown. In this study we use our virotherapy Celyvir with syngeneic and allogeneic mouse mesenchymal stem cells to determine their antitumor efficacy in a C57BL/6 murine adenocarcinoma model. Adoptive transfer of splenocytes from treated mice to new tumor-bearing mice followed by a secondary adoptive transfer to a third group was performed. Similar reduction of tumor growth and systemic activation of the innate and adaptive immune system was observed in groups treated with syngeneic or allogeneic mesenchymal stem cells loaded with ICOVIR-5. Moreover, a different pattern of infiltration was observed by immunofluorescence in Celyvir-treated groups. While non-treated tumors presented higher density of infiltrating immune cells in the periphery of the tumor, both syngeneic and allogeneic Celyvir-treated groups presented higher infiltration of CD45+ cells in the core of the tumor. Therefore, these results suggest that syngeneic and allogeneic Celyvir induce systemic activation of the immune system, similar antitumor effect and a higher intratumoral infiltration of leukocytes.

Cofactors influence the biological properties of infectious recombinant prions.

Prion diseases are caused by a misfolding of the cellular prion protein (PrP) to a pathogenic isoform named PrPSc. Prions exist as strains, which are characterized by specific pathological and biochemical properties likely encoded in the three-dimensional structure of PrPSc. However, whether cofactors determine these different PrPSc conformations and how this relates to their specific biological properties is largely unknown. To understand how different cofactors modulate prion strain generation and selection, Protein Misfolding Cyclic Amplification was used to create a diversity of infectious recombinant prion strains by propagation in the presence of brain homogenate. Brain homogenate is known to contain these mentioned cofactors, whose identity is only partially known, and which facilitate conversion of PrPC to PrPSc. We thus obtained a mix of distinguishable infectious prion strains. Subsequently, we replaced brain homogenate, by different polyanionic cofactors that were able to drive the evolution of mixed prion populations toward specific strains. Thus, our results show that a variety of infectious recombinant prions can be generated in vitro and that their specific type of conformation, i.e., the strain, is dependent on the cofactors available during the propagation process. These observations have significant implications for understanding the pathogenesis of prion diseases and their ability to replicate in different tissues and hosts. Importantly, these considerations might apply to other neurodegenerative diseases for which different conformations of misfolded proteins have been described.

Drug-Coated Balloons: Hope or Hot Air: Update on the Role of Coronary DCB.

PURPOSE OF REVIEW: The present manuscript reviews the mechanism of action of drug-coated balloons (DCBs), offering a brief summary of the main clinical evidence on these devices. RECENT FINDINGS: DCBs are regular semi-compliant balloons coated with antiproliferative agents that are rapidly released on contact with the vessel intima, exerting an anti-restenotic effect. This technology may offer some benefits of drug-eluting stents, in particular for the treatment of restenotic lesions, small vessels, and in patients at high-bleeding risk, when the prolonged dual antiplatelet regimen should be avoided. Most recent data have pointed to a possible benefit of these devices in treating bare metal stents (BMS) or drug-eluting stents in-stent restenosis (DES ISR), effectively reducing the recurrence of restenosis and avoiding additional layers of metal in the same coronary segment. In other clinical scenarios such as bifurcations, small vessels, and de novo lesions, data is more scarce and the benefits are still unclear. There are potential benefits related to the use of DCB in selected populations. However, larger clinical trials with longer follow-up are still needed to confirm the enthusiastic initial results.

The absorbable subacromial spacer for irreparable posterosuperior cuff tears has inconsistent results.

PURPOSE: To evaluate the 2-year results of an absorbable subacromial spacer in patients with irreparable posterosuperior rotator cuff tears. METHODS: Prospective longitudinal study of a consecutive case series of 16 subjects with irreparable tears of the posterosuperior rotator cuff in which the InSpace® subacromial spacer was arthroscopically implanted. A full clinical evaluation that included the Constant test, Simple Shoulder Test (SST) and the QuickDash questionnaire was performed preoperatively and at 12 and 24 months follow-up. The primary outcome for assessing the success of the procedure was a variable composed of a clinically relevant variation of the Constant (established in an improvement greater than 10 points) and the absence of surgical reintervention. RESULTS: Fifteen subjects (11 women/4 men, median age = 69.4 years [interquartile range 7.50], range 60-80 years) completed the 2-year of follow-up. According to the main evaluation criteria, only 6 patients (40%) had a successful outcome. Five subjects required reconversion to a reverse shoulder arthroplasty (at a median of 9.8 months postoperatively) due to absence of clinical improvement or worsening of symptoms. Of the ten remaining subjects, only 6 had improvements greater than 10 points in the Constant score. Despite of this, these 10 subjects had, on average, some improvement in the Constant test (preoperative Constant: median 35.0 [27.0-52.5] vs Constant at 24 months: 53.5 [55.0-84.0], significant differences p = 0.02), in the SST (3.0 [2.0-4.0] vs 6.0 [3.25-7.75], p = 0.039) and in the QuickDASH test (37.0 [33.25-40.0] vs 27.5 [20.5-32.75], p = 0.012). CONCLUSIONS: The outcomes of the implantation of the subacromial biodegradable spacer at 2-year follow-up are not satisfactory. In this small case series only 40% of patients seem to clearly benefit from surgery. One in three required revision to a reverse shoulder arthroplasty. The described technique does not seem a reasonable alternative for the management of the majority of patients with irreparable ruptures of the rotator cuff. The indications of this device should be more clearly defined. LEVEL OF EVIDENCE: IV.