A DROP-IN beta probe for robot-assisted 68Ga-PSMA radioguided surgery: first ex vivo technology evaluation using prostate cancer specimens

Background: Recently, a flexible DROP-IN gamma-probe was introduced for robot-assisted radioguided surgery, using traditional low-energy SPECT-isotopes. In parallel, a novel approach to achieve sensitive radioguidance using beta-emitting PET isotopes has been proposed. Integration of these two concepts would allow to exploit the use of PET tracers during robot-assisted tumor-receptor-targeted. In this study, we have engineered and validated the performance of a novel DROP-IN beta particle (DROP-INβ) detector. Methods: Seven prostate cancer patients with PSMA-PET positive tumors received an additional intraoperative injection of ~ 70 MBq 68Ga-PSMA-11, followed by robot-assisted prostatectomy and extended pelvic lymph node dissection. The surgical specimens from these procedures were used to validate the performance of our DROP-INβ probe prototype, which merged a scintillating detector with a housing optimized for a 12-mm trocar and prograsp instruments. Results: After optimization of the detector and probe housing via Monte Carlo simulations, the resulting DROP-INβ probe prototype was tested in a robotic setting. In the ex vivo setting, the probe—positioned by the robot—was able to identify 68Ga-PSMA-11 containing hot-spots in the surgical specimens: signal-to-background (S/B) was > 5 when pathology confirmed that the tumor was located < 1 mm below the specimen surface. 68Ga-PSMA-11 containing (and PET positive) lymph nodes, as found in two patients, were also confirmed with the DROP-INβ probe (S/B > 3). The rotational freedom of the DROP-IN design and the ability to manipulate the probe with the prograsp tool allowed the surgeon to perform autonomous beta-tracing. Conclusions: This study demonstrates the feasibility of beta-radioguided surgery in a robotic context by means of a DROP-INβ detector. When translated to an in vivo setting in the future, this technique could provide a valuable tool in detecting tumor remnants on the prostate surface and in confirmation of PSMA-PET positive lymph nodes. © 2020, The Author(s)

Cosmic shear from STIS Pure Parallels: I Data

Following the second HST servicing mission in 1997 when the STIS instrument was installed and the capability for parallel observations was enhanced, a substantial archive of non-proprietary parallel data has been accumulating. In this paper, we discuss the use of unfiltered STIS imaging data for a project that requires deep observations along as many independent lines-of-sight as possible. We have developed a technique to determine which datasets in the archive can safely be co-added together and have developed an iterative co-addition technique which enabled us to produce 498 high-quality, deep images. The principal motivation for this work is to measure the Cosmic Shear on small angular scales and a value derived from these data will be presented in a subsequent paper. A valuable by-product of this work is a set of high quality combined fields which can be used for other projects. The data are publicly available at http://www.stecf.org/projects/shear/Comment: 8 pages, 7 figures. accepted for publication in A&

Engineered neural tissue for peripheral nerve repair

A new combination of tissue engineering techniques provides a simple and effective method for building aligned cellular biomaterials. Self-alignment of Schwann cells within a tethered type-1 collagen matrix, followed by removal of interstitial fluid produces a stable tissue-like biomaterial that recreates the aligned cellular and extracellular matrix architecture associated with nerve grafts. Sheets of this engineered neural tissue supported and directed neuronal growth in a co-culture model, and initial in vivo tests showed that a device containing rods of rolled-up sheets could support neuronal growth during rat sciatic nerve repair (5 mm gap). Further testing of this device for repair of a critical-sized 15 mm gap showed that, at 8 weeks, engineered neural tissue had supported robust neuronal regeneration across the gap. This is, therefore, a useful new approach for generating anisotropic engineered tissues, and it can be used with Schwann cells to fabricate artificial neural tissue for peripheral nerve repair

Cytomegalovirus Viremia as a Risk Factor for Mortality Prior to Antiretroviral Therapy among HIV-Infected Gold Miners in South Africa

BACKGROUND: Cytomegalovirus (CMV) viremia has been shown to be an independent risk factor for increased mortality among HIV-infected individuals in the developing world. While CMV infection is nearly ubiquitous in resource-poor settings, few data are available on the role of subclinical CMV reactivation on HIV. METHODS: Using a cohort of mineworkers with stored plasma samples, we investigated the association between CMV DNA concentration and mortality prior to antiretroviral therapy availability. RESULTS: Among 1341 individuals (median CD4 count 345 cells/µl, 70% WHO stage 1 or 2, median follow-up 0.9 years), 70 (5.2%) had CMV viremia at baseline; 71 deaths occurred. In univariable analysis CMV viremia at baseline was associated with a three-fold increase in mortality (hazard ratio [HR] 3.37; 95% confidence intervals [CI] 1.60, 7.10). After adjustment for CD4 count, WHO stage and HIV viral load (N = 429 with complete data), the association was attenuated (HR 2.27; 95%CI 0.88, 5.83). Mortality increased with higher CMV viremia (≥1,000 copies/ml vs. no viremia, adjusted HR 3.65, 95%CI: 1.29, 10.41). Results were similar using time-updated CMV viremia. CONCLUSIONS: High copy number, subclinical CMV viremia was an independent risk factor for mortality among male HIV-infected adults in South Africa with relatively early HIV disease. Studies to determine whether anti-CMV therapy to mitigate high copy number viremia would increase lifespan are warranted

The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008

Primary immunodeficiencies (PID) are rare diseases; therefore transnational studies are essential to maximize the scientific outcome and to improve diagnosis and therapy. In order to estimate the prevalence of PID in Europe as well as to establish and evaluate harmonized guidelines for the diagnosis and treatment of PID, the European Society for Immunodeficiencies (ESID) has developed an internet-based database for clinical and research data on patients with PID. This database is a platform for epidemiological analyses as well as the development of new diagnostic and therapeutic strategies and the identification of novel disease-associated genes. Within 4 years, 7430 patients from 39 countries have been documented in the ESID database. Common variable immunodeficiency (CVID) represents the most common entity, with 1540 patients or 20.7% of all entries, followed by isolated immunoglobulin (Ig)G subclass deficiency (546 patients, 7.4%). Evaluations show that the average life expectancy for PID patients varies from 1 to 49 years (median), depending on the type of PID. The prevalence and incidence of PID remains a key question to be answered. As the registration progress is far from finished we can only calculate minimum values for PID, with e.g. France currently showing a minimum prevalence of 3.72 patients per 100,000 inhabitants. The most frequently documented permanent treatment is immunoglobulin replacement; 2819 patients (42% of all patients alive) currently receive this form of treatment

The 2021 EULAR/American College of Rheumatology Points to Consider for Diagnosis, Management and Monitoring of the Interleukin-1 Mediated Autoinflammatory Diseases: Cryopyrin-Associated Periodic Syndromes, Tumour Necrosis Factor Receptor-Associated Periodic Syndrome, Mevalonate Kinase Deficiency, and Deficiency of the Interleukin-1 Receptor Antagonist

BACKGROUND: The interleukin-1 (IL-1) mediated systemic autoinflammatory diseases, including the cryopyrin- associated periodic syndromes (CAPS), tumour necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD) and deficiency of the IL-1 receptor antagonist (DIRA), belong to a group of rare immunodysregulatory diseases that primarily present in early childhood with variable multiorgan involvement. When untreated, patients with severe clinical phenotypes have a poor prognosis, and diagnosis and management of these patients can be challenging. However, approved treatments targeting the proinflammatory cytokine IL-1 have been life changing and have significantly improved patient outcomes. OBJECTIVE: To establish evidence-based recommendations for diagnosis, treatment and monitoring of patients with IL-1 mediated autoinflammatory diseases to standardise their management. METHODS: A multinational, multidisciplinary task force consisting of physician experts, including rheumatologists, patients or caregivers and allied healthcare professionals, was established. Evidence synthesis, including systematic literature review and expert consensus (Delphi) via surveys, was conducted. Consensus methodology was used to formulate and vote on statements to guide optimal patient care. RESULTS: The task force devised five overarching principles, 14 statements related to diagnosis, 10 on therapy, and nine focused on long-term monitoring that were evidence and/or consensus-based for patients with IL-1 mediated diseases. An outline was developed for disease-specific monitoring of inflammation-induced organ damage progression and reported treatments of CAPS, TRAPS, MKD and DIRA. CONCLUSION: The 2021 EULAR/American College of Rheumatology points to consider represent state-of-the-art knowledge based on published data and expert opinion to guide diagnostic evaluation, treatment and monitoring of patients with CAPS, TRAPS, MKD and DIRA, and to standardise and improve care, quality of life and disease outcomes

Development and psychometric properties of the “Suicidality: Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales” in adolescents

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity—the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test–retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS—the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = − 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents

Development and psychometric properties of the “Suicidality:Treatment Occurring in Paediatrics (STOP) Risk and Resilience Factors Scales” in adolescents

Suicidality in the child and adolescent population is a major public health concern. There is, however, a lack of developmentally sensitive valid and reliable instruments that can capture data on risk, and clinical and psychosocial mediators of suicidality in young people. In this study, we aimed to develop and assess the validity of instruments evaluating the psychosocial risk and protective factors for suicidal behaviours in the adolescent population. In Phase 1, based on a systematic literature review of suicidality, focus groups, and expert panel advice, the risk factors and protective factors (resilience factors) were identified and the adolescent, parent, and clinician versions of the STOP-Suicidality Risk Factors Scale (STOP-SRiFS) and the Resilience Factors Scale (STOP-SReFS) were developed. Phase 2 involved instrument validation and comprised of two samples (Sample 1 and 2). Sample 1 consisted of 87 adolescents, their parents/carers, and clinicians from the various participating centres, and Sample 2 consisted of three sub-samples: adolescents (n = 259) who completed STOP-SRiFS and/or the STOP-SReFS scales, parents (n = 213) who completed one or both of the scales, and the clinicians who completed the scales (n = 254). The STOP-SRiFS demonstrated a good construct validity—the Cronbach Alpha for the adolescent (α = 0.864), parent (α = 0.842), and clinician (α = 0.722) versions of the scale. Test–retest reliability, inter-rater reliability, and content validity were good for all three versions of the STOP-SRiFS. The sub-scales generated using Exploratory Factor Analysis (EFA) were the (1) anxiety and depression risk, (2) substance misuse risk, (3) interpersonal risk, (4) chronic risk, and (5) risk due to life events. For the STOP-SRiFS, statistically significant correlations were found between the Columbia-Suicide Severity Rating Scale (C-SSRS) total score and the adolescent, parent, and clinical versions of the STOP-SRiFS sub-scale scores. The STOP-SRiFS showed good psychometric properties. This study demonstrated a good construct validity for the STOP-SReFS—the Cronbach Alpha for the three versions were good (adolescent: α = 0.775; parent: α = 0.808; α = clinician: 0.808). EFA for the adolescent version of the STOP-SReFS, which consists of 9 resilience factors domains, generated two factors (1) interpersonal resilience and (2) cognitive resilience. The STOP-SReFS Cognitive Resilience sub-scale for the adolescent was negatively correlated (r = − 0.275) with the C-SSRS total score, showing that there was lower suicidality in those with greater Cognitive Resilience. The STOP-SReFS Interpersonal resilience sub-scale correlations were all negative, but none of them were significantly different to the C-SSRS total scores for either the adolescent, parent, or clinician versions of the scales. This is not surprising, because the items in this sub-scale capture a much larger time-scale, compared to the C-SSRS rating period. The STOP-SReFS showed good psychometric properties. The STOP-SRiFS and STOP-SReFS are instruments that can be used in future studies about suicidality in children and adolescents

Antagomir-17-5p Abolishes the Growth of Therapy-Resistant Neuroblastoma through p21 and BIM

We identified a key oncogenic pathway underlying neuroblastoma progression: specifically, MYCN, expressed at elevated level, transactivates the miRNA 17-5p-92 cluster, which inhibits p21 and BIM translation by interaction with their mRNA 3′ UTRs. Overexpression of miRNA 17-5p-92 cluster in MYCN-not-amplified neuroblastoma cells strongly augments their in vitro and in vivo tumorigenesis. In vitro or in vivo treatment with antagomir-17-5p abolishes the growth of MYCN-amplified and therapy-resistant neuroblastoma through p21 and BIM upmodulation, leading to cell cycling blockade and activation of apoptosis, respectively. In primary neuroblastoma, the majority of cases show a rise of miR-17-5p level leading to p21 downmodulation, which is particularly severe in patients with MYCN amplification and poor prognosis. Altogether, our studies demonstrate for the first time that antagomir treatment can abolish tumor growth in vivo, specifically in therapy-resistant neuroblastoma