Identification of the zebrafish homologues of IMPG2, a retinal proteoglycan.

Photoreceptor outer segments are surrounded by a carbohydrate-rich matrix, the interphotoreceptor matrix, necessary for physiological retinal function. Few roles for molecules characterizing the interphotoreceptor matrix have been clearly defined. Recent studies have found the presence of nonsense mutations in the interphotoreceptor matrix proteoglycan 2 (IMPG2) gene in patients affected by retinal dystrophies. IMPG2 encodes for a proteoglycan synthesized by photoreceptors and secreted in the interphotoreceptor matrix. Little is known about the structure and function of this protein, we thus decided to characterize zebrafish impg2. In zebrafish there are two Impg2 proteins, Impg2a and Impg2b. We generated a phylogenetic tree based on IMPG2 protein sequence similarity among vertebrates, showing a significant similarity between humans and teleosts. The human and zebrafish proteins share conserved domains, as also shown by homology models. Expression analyses of impg2a and impg2b show a continued expression in the photoreceptor layer starting from developmental stages and continuing through adulthood. Between 1 and 6 months post-fertilization, there is a significant shift of Impg2 expression toward the outer segment region, suggesting an increase in secretion. This raises intriguing hypotheses about its possible role(s) during retinal maturation, laying the groundwork for the generation of most needed models for the study of IMPG2-related inherited retinal dystrophies.

Plasma heavy metal levels correlate with deregulated gene expression of detoxifying enzymes in osteoporotic patients.

Heavy metal levels appear to be associated with low bone mineral density (BMD) and the consequent osteoporosis risk, but the relationship with the disease has not been clearly defined. The altered expression pattern of numerous genes, including detoxifying genes, seems to play a pivotal role in this context, leading to increased susceptibility to several diseases, including osteoporosis. The purpose of this study is to analyse circulating heavy metals levels and the expression of detoxifying genes in osteoporotic patients (OPs, n = 31), compared with healthy subjects (CTRs, n = 32). Heavy metals concentration in plasma samples was determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), and the subsequent expression analysis of NAD(P)H quinone dehydrogenase 1 (NQO1), Catalase (CAT), and Metallothionein 1E (MT1E) genes in Peripheral Blood Mononuclear Cells (PBMCs) was assessed by real-time polymerase chain reaction (qRT-PCR). Copper (Cu), mercury (Hg), molybdenum (Mo) and lead (Pb) were found to be significantly higher in the plasma of OPs compared to CTRs. Analysis of the expression levels of detoxifying genes showed a significant decrease in CAT and MT1E in OP group. In addition, Cu correlated positively with the expression levels of both CAT and MT1E in CTRs group and MT1E in OPs. This study shows an increased circulating concentration of certain metals combined with an altered expression pattern of detoxifying genes in OPs, highlighting a novel aspect to be investigated in order to better characterize the role of metals in the pathogenesis of osteoporosis.

Quantum Phase Transitions for an Integrable Quantum Rabi-like Model with Two Interacting Qubits.

A two-interacting-qubit quantum Rabi-like model with vanishing transverse fields on the qubit pair is studied. Independently of the coupling regime, this model can be exactly and unitarily reduced to two independent single-spin quantum Rabi models, where the spin-spin coupling plays the role of the transverse field. This transformation and the analytical treatment of the single-spin quantum Rabi model provide the key to prove the integrability of our model. The existence of different first-order quantum phase transitions, characterized by discontinuous two-spin magnetization, mean photon number, and concurrence, is brought to light.

68Ga-DOTATOC PET/MR imaging and radiomic parameters in predicting histopathological prognostic factors in patients with pancreatic neuroendocrine well-differentiated tumours.

PURPOSE: To explore the role of fully hybrid 68Ga-DOTATOC PET/MR imaging and radiomic parameters in predicting histopathological prognostic factors in patients with pancreatic neuroendocrine tumours (PanNETs) undergoing surgery. METHODS: One hundred eighty-seven consecutive 68Ga-DOTATOC PET/MRI scans (March 2018-June 2020) performed for gastroenteropancreatic neuroendocrine tumour were retrospectively evaluated; 16/187 patients met the eligibility criteria (68Ga-DOTATOC PET/MRI for preoperative staging of PanNET and availability of histological data). PET/MR scans were qualitatively and quantitatively interpreted, and the following imaging parameters were derived: PET-derived SUVmax, SUVmean, somatostatin receptor density (SRD), total lesion somatostatin receptor density (TLSRD), and MRI-derived apparent diffusion coefficient (ADC), arterial and late enhancement, necrosis, cystic degeneration, and maximum diameter. Additionally, first-, second-, and higher-order radiomic parameters were extracted from both PET and MRI scans. Correlations with several PanNETs' histopathological prognostic factors were evaluated using Spearman's coefficient, while the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to evaluate parameters' predictive performance. RESULTS: Primary tumour was detected in all 16 patients (15/16 by 68Ga-DOTATOC PET and 16/16 by MRI). SUVmax and SUVmean resulted good predictors of lymphnodal (LN) involvement (AUC of 0.850 and 0.783, respectively). Second-order radiomic parameters GrayLevelVariance and HighGrayLevelZoneEmphasis extracted from T2 MRI demonstrated significant correlations with LN involvement (adjusted p = 0.009), also showing good predictive performance (AUC = 0.992). CONCLUSION: This study demonstrates the role of the fully hybrid PET/MRI tool for the synergic function of imaging parameters extracted by the two modalities and highlights the potentiality of imaging and radiomic parameters in assessing histopathological features of PanNET aggressiveness.

Ten answers to key questions for fluid management in intensive care.

This review focuses on fluid management of critically ill patients. The topic is addressed based on 10 single questions with simplified answers that provide clinicians with the basic information needed at the point of care in treating patients in the Intensive Care Unit. The review has didactic purposes and may serve both as an update on fluid management and as an introduction to the subject for novices in critical care. There is an urgent need to increase awareness regarding the potential risks associated with fluid overload. Clinicians should be mindful not only of the indications for administering fluid loads and of the type of fluids administered, but also of the importance to set safety limits. Lastly, it is important to implement proactive strategies seeking to establish negative fluid balance as soon as the clinical conditions are considered to be stable and the risk of deterioration is low.

Ten answers to key questions for fluid management in intensive care.

This review focuses on fluid management of critically ill patients. The topic is addressed based on 10 single questions with simplified answers that provide clinicians with the basic information needed at the point of care in treating patients in the Intensive Care Unit. The review has didactic purposes and may serve both as an update on fluid management and as an introduction to the subject for novices in critical care. There is an urgent need to increase awareness regarding the potential risks associated with fluid overload. Clinicians should be mindful not only of the indications for administering fluid loads and of the type of fluids administered, but also of the importance to set safety limits. Lastly, it is important to implement proactive strategies seeking to establish negative fluid balance as soon as the clinical conditions are considered to be stable and the risk of deterioration is low.

Preliminary results in using Deep Learning to emulate BLOB, a nuclear interaction model.

PURPOSE: A reliable model to simulate nuclear interactions is fundamental for Ion-therapy. We already showed how BLOB ("Boltzmann-Langevin One Body"), a model developed to simulate heavy ion interactions up to few hundreds of MeV/u, could simulate also 12C reactions in the same energy domain. However, its computation time is too long for any medical application. For this reason we present the possibility of emulating it with a Deep Learning algorithm. METHODS: The BLOB final state is a Probability Density Function (PDF) of finding a nucleon in a position of the phase space. We discretised this PDF and trained a Variational Auto-Encoder (VAE) to reproduce such a discrete PDF. As a proof of concept, we developed and trained a VAE to emulate BLOB in simulating the interactions of 12C with 12C at 62 MeV/u. To have more control on the generation, we forced the VAE latent space to be organised with respect to the impact parameter (b) training a classifier of b jointly with the VAE. RESULTS: The distributions obtained from the VAE are similar to the input ones and the computation time needed to use the VAE as a generator is negligible. CONCLUSIONS: We show that it is possible to use a Deep Learning approach to emulate a model developed to simulate nuclear reactions in the energy range of interest for Ion-therapy. We foresee the implementation of the generation part in C++ and to interface it with the most used Monte Carlo toolkit: Geant4.

Surface ruptures database related to the 26 December 2018, MW 4.9 Mt. Etna earthquake, southern Italy.

We provide a database of the surface ruptures produced by the 26 December 2018 Mw 4.9 earthquake that struck the eastern flank of Mt. Etna volcano in Sicily (southern Italy). Despite its relatively small magnitude, this shallow earthquake caused about 8 km of surface faulting, along the trace of the NNW-trending active Fiandaca Fault. Detailed field surveys have been performed in the epicentral area to map the ruptures and to characterize their kinematics. The surface ruptures show a dominant right-oblique sense of displacement with an average slip of about 0.09 m and a maximum value of 0.35 m. We have parsed and organized all observations in a concise database, with 932 homogeneous georeferenced records. The Fiandaca Fault is part of the complex active Timpe faults system affecting the eastern flank of Etna, and its seismic history indicates a prominent surface-faulting potential. Therefore, this database is essential for unravelling the seismotectonics of shallow earthquakes in volcanic areas, and contributes updating empirical scaling regressions that relate magnitude and extent of surface faulting.

Implementing a multi-faceted framework for proprietorship of hand hygiene compliance in a network of South African hospitals: leveraging the Ubuntu philosophy.

BACKGROUND: Given the lack of hospital-wide ownership and shortage of nurses, the ideal model for large-scale implementation of hand hygiene (HH) behaviour change in low- and middle-income countries is unknown. AIM: The aim of the multi-modal strategy was to engender hospital accountability for HH compliance. METHODS: The quasi-experimental study was conducted in 50 South African hospitals (November 2015 to July 2017) and involved five overlapping phases: executive governance and corporate behaviour change; group-wide systematic situational analysis; development of an electronic-assisted direct-observed data collection and analysis application; launch and implementation; and accountable governance. Measurement of intra- and inter-hospital variance to six HH opportunities was calculated and data compliance dashboards were e-mailed weekly to hospital leadership teams to provide feedback of recorded HH compliance and behaviour to frontline teams. Baseline comparison (July 2016) of compliance was compared versus post-implementation (July 2017). FINDINGS: Baseline HH compliance of ≤60% was documented for 16% (8/50) of hospitals, whereas overall, 48% (24/50) of hospitals demonstrated a significant improvement (P < 0.01). Over the 13-month observation period, 523,422 observations were recorded with a mean rate of 277 ± 223 observations per 1000 patient-days. The group mean composite compliance improved by 7.8% (P < 0.01) from 77.4% ± 12.8 to 85.2% ± 8.8 between July 2016 and July 2017, respectively. CONCLUSION: Implementation of a multi-faceted HH model in a large, diverse group of South African hospitals translated into changes in the organizational systems and accountability, standardized HH compliance management and feedback that led to HH proprietorship.

Aerobic exercise and Orexin A: role of sympathetic activity and redox system.

Aerobic exercise is associated with the sympathetic activation evoking adaptive responses to sustain muscle engagement. Physical exercise can cause alterations in the cardiovascular activity and cellular stress may occur which could be marked by either heart rate (HR), or galvanic skin response (GSR). Moderate plasma levels of reactive oxygen species (ROS) are considered as health markers, absolving to important roles such as adaptive cellular responses to exercise. Orexin A, a hypothalamic peptide, causes a widespread stimulation of the sympathetic nervous system, playing a role in many physiological functions.

Mechanism of translation control of the alternative Drosophila melanogaster Voltage Dependent Anion-selective Channel 1 mRNAs.

The eukaryotic porin, also called the Voltage Dependent Anion-selective Channel (VDAC), is the main pore-forming protein of the outer mitochondrial membrane. In Drosophila melanogaster, a cluster of genes evolutionarily linked to VDAC is present on chromosome 2L. The main VDAC isoform, called VDAC1 (Porin1), is expressed from the first gene of the cluster. The porin1 gene produces two splice variants, 1A-VDAC and 1B-VDAC, with the same coding sequence but different 5' untranslated regions (UTRs). Here, we studied the influence of the two 5' UTRs, 1A-5' UTR and 1B-5' UTR, on transcription and translation of VDAC1 mRNAs. In porin-less yeast cells, transformation with a construct carrying 1A-VDAC results in the expression of the corresponding protein and in complementation of a defective cell phenotype, whereas the 1B-VDAC sequence actively represses VDAC expression. Identical results were obtained using constructs containing the two 5' UTRs upstream of the GFP reporter. A short region of 15 nucleotides in the 1B-5' UTR should be able to pair with an exposed helix of 18S ribosomal RNA (rRNA), and this interaction could be involved in the translational repression. Our data suggest that contacts between the 5' UTR and 18S rRNA sequences could modulate the translation of Drosophila 1B-VDAC mRNA. The evolutionary significance of this finding is discussed.

Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit

Background. Colistin is an old antibiotic that has been reintroduced as salvage therapy in hospitalised patients because it is frequently the only agent active against Gram-negative bacteria. Various guidelines for colistin administration have led to confusion in establishing the appropriate dose, which has potential for adverse consequences including treatment failure or toxicity. The emergence and spread of colistin resistance has been documented in South Africa (SA), but no local information exists on how and why colistin is used in hospitals, and similarly, compliance with current dosing guidelines is unknown.Objectives. To evaluate the current utilisation of colistin in SA hospitals, in order to identify stewardship opportunities that could enhance the appropriate use of this antibiotic.Methods. Electronic patient records of adult patients on intravenous (IV) colistin therapy for >72 hours in four private hospitals were retrospectively audited over a 10-month period (1 September 2015 - 30 June 2016). The following data were recorded: patient demographics, culture and susceptibility profiles, diagnosis, and indication for use. Compliance with six colistin process measures was audited: obtaining a culture prior to initiation, administration of a loading dose, administration of the correct loading dose, adjustments to maintenance dose according to renal function, whether colistin was administered in combination with another antibiotic, and whether de-escalation following culture and sensitivity results occurred. Outcome measures included effects on renal function, overall hospital mortality, intensive care unit length of stay (LoS), and hospital LoS.Results. Records of 199 patients on IV colistin were reviewed. There was 99.0% compliance with obtaining a culture prior to antibiotic therapy, 93.5% compliance with prescription of a loading dose, and 98.5% compliance regarding prescription of colistin in combination with another agent. However, overall composite compliance with the six colistin stewardship process measures was 82.0%. Non-compliance related to inappropriate loading and maintenance doses, lack of adjustment according to renal function and lack of de-escalation following culture sensitivity was evident. Significantly shorter durations of treatment were noted in patients who received higher loading doses (p=0.040) and in those who received maintenance doses of 4.5 MU twice daily v. 3 MU three times daily (p=0.0027). In addition, compared with patients who survived, more patients who died received the 3 MU three times daily maintenance dose (p=0.0037; phi coefficient 0.26).Conclusions. The study identified multiple stewardship opportunities to optimise colistin therapy in hospitalised patients. Urgent implementation of a stewardship bundle to improve colistin utilisation is warranted

Opportunities to optimise colistin stewardship in hospitalised patients in South Africa: Results of a multisite utilisation audit.

BACKGROUND: Colistin is an old antibiotic that has been reintroduced as salvage therapy in hospitalised patients because it is frequently the only agent active against Gram-negative bacteria. Various guidelines for colistin administration have led to confusion in establishing the appropriate dose, which has potential for adverse consequences including treatment failure or toxicity. The emergence and spread of colistin resistance has been documented in South Africa (SA), but no local information exists on how and why colistin is used in hospitals, and similarly, compliance with current dosing guidelines is unknown. OBJECTIVES: To evaluate the current utilisation of colistin in SA hospitals, in order to identify stewardship opportunities that could enhance the appropriate use of this antibiotic. METHODS:  Electronic patient records of adult patients on intravenous (IV) colistin therapy for >72 hours in four private hospitals were retrospectively audited over a 10-month period (1 September 2015 - 30 June 2016). The following data were recorded: patient demographics, culture and susceptibility profiles, diagnosis, and indication for use. Compliance with six colistin process measures was audited: obtaining a culture prior to initiation, administration of a loading dose, administration of the correct loading dose, adjustments to maintenance dose according to renal function, whether colistin was administered in combination with another antibiotic, and whether de-escalation following culture and sensitivity results occurred. Outcome measures included effects on renal function, overall hospital mortality, intensive care unit length of stay (LoS), and hospital LoS. RESULTS: Records of 199 patients on IV colistin were reviewed. There was 99.0% compliance with obtaining a culture prior to antibiotic therapy, 93.5% compliance with prescription of a loading dose, and 98.5% compliance regarding prescription of colistin in combination with another agent. However, overall composite compliance with the six colistin stewardship process measures was 82.0%. Non-compliance related to inappropriate loading and maintenance doses, lack of adjustment according to renal function and lack of de-escalation following culture sensitivity was evident. Significantly shorter durations of treatment were noted in patients who received higher loading doses (p=0.040) and in those who received maintenance doses of 4.5 MU twice daily v. 3 MU three times daily (p=0.0027). In addition, compared with patients who survived, more patients who died received the 3 MU three times daily maintenance dose (p=0.0037; phi coefficient 0.26). CONCLUSIONS:  The study identified multiple stewardship opportunities to optimise colistin therapy in hospitalised patients. Urgent implementation of a stewardship bundle to improve colistin utilisation is warranted.

Italian survey on benign paroxysmal positional vertigo.

Benign paroxysmal positional vertigo (BPPV) is the most common type of peripheral vertigo. BPPV often relapses after the first episode, with a recurrence rate between 15% and 50%. To date both the aetiopathogenetic processes that lead to otoconia detachment and the factors that make BPPV a relapsing disease are still unclear, but recent epidemiological studies have shown a possible association with cardiovascular risk factors. The aim of the present study (Sesto Senso Survey) was to evaluate in the Italian population through an observational survey, the main demographic and clinical characteristics of patients with BPPV (first episode or recurrent) with particular focus on the potential cardiovascular risk factors. The survey was conducted in 158 vestibology centres across Italy on 2,682 patients (mean age 59.3 ± 15.0 years; 39.1% males and 60.9% females) suffering from BPPV, from January 2013 to December 2014. The results showed a high prevalence of cardiovascular risk factors such as high blood pressure (55.8%), hypercholesterolaemia (38.6%) and diabetes (17.7%), as well as a family history of cardiovascular disease (49.4%). A high percentage of patients also had hearing loss (42.9%), tinnitus (41.2%), or both (26.8%). The presence of hypertension, dyslipidaemia and pre-existing cardiovascular comorbidities were significantly related to recurrent BPPV episodes (OR range between 1.84 and 2.31). In addition, the association with diabetes and thyroid/autoimmune disease (OR range between 1.73 and 1.89) was relevant. The survey results confirm the significant association between cardiovascular comorbidities and recurrent BPPV and identify them as a potential important risk factor for recurrence of BPPV in the Italian population, paving the way for the evaluation of new therapeutic strategies in the treatment of this disease.

Stepwise introduction of the 'Best Care Always' central-line-associated bloodstream infection prevention bundle in a network of South African hospitals.

BACKGROUND: Healthcare-associated infection (HCAI) remains a major international problem. AIM: The 'Best Care Always!' (BCA) campaign was launched in South Africa to reduce preventable HCAI, including central-line-associated bloodstream infection (CLABSI). METHODS: The intervention took place in 43 Netcare Private Hospitals, increasing later to 49 with 958 intensive care units (ICUs) and 439 high-care (HC) beds and 1207 ICUs and 493 HC beds, respectively. Phase 1, April 2010 to March 2011, ICU infection prevention and control (IPC) nurse-driven change: commitment from management and doctors and training of IPC nurses. Bundle compliance and infections per 1000 central-line-days were incorporated as standard IPC measures and captured monthly. Phase 2, April 2011 to March 2012, breakthrough collaborative method: multiple regional learning sessions for nursing leaders, IPC nurses and unit managers. Phase 3, April 2012 to May 2016: sustained goal-setting, benchmarks, ongoing audits. FINDINGS: A total of 1,119,558 central-line-days were recorded. Bundle compliance improved significantly from a mean of 73.1% [standard deviation (SD): 11.2; range: 40.6-81.7%] in Phase 1 to a mean of 90.5% (SD: 4.7; range: 76.5-97.2%) in Phase 3 (P = 0.0004). The CLABSI rate declined significantly from a mean of 3.55 (SD: 0.82; range: 2.54-5.78) per 1000 central-line-days in Phase 1 to a mean of 0.13 (SD: 0.09; range: 0-0.33) (P < 0.0001). CONCLUSION: This intervention, the first of its kind in South Africa, through considerable motivation and education, and through competition between hospitals resulted in significant decreases in CLABSI.

Short, full-dose adjuvant chemotherapy (CT) in high-risk adult soft tissue sarcomas (STS): long-term follow-up of a randomized clinical trial from the Italian Sarcoma Group and the Spanish Sarcoma Group.

BACKGROUND: To report on long-term results of a phase 3 trial comparing three versus five cycles of adjuvant chemotherapy (CT) with full-dose epirubicin+ifosfamide in high-risk soft tissue sarcomas (STS). METHODS: Patients (pts) were randomized to receive three preoperative cycles of epirubicin 120 mg/m2 and ifosfamide 9 g/m2 (Arm A) or to receive the same three preoperative cycles plus two postoperative cycles (Arm B). Radiotherapy could be either delivered in the preoperative or in the postoperative setting. Non-inferiority of the primary end point, OS, was assessed by the confidence interval of the hazard ratio (HR; Arm A/Arm B) derived from Cox model. RESULTS: Between January 2002 and April 2007, 164 pts were assigned to arm A and 164 to arm B. At a median follow-up (FU) of 117 months (IQ range 103-135 months), 123 deaths were recorded: 58 in Arm A and 65 in Arm B. Ten-year OS was 61% for the entire group of patients: 64% in Arm A and 59% in Arm B. The intention-to-treat analysis confirmed that three cycles were not inferior to five cycles (one-sided 95% upper confidence limit was 1.24). A per protocol analysis was consistent with these results. Pts with leiomyosarcoma and undifferentiated pleomorphic sarcoma (UPS) had the lowest, and the highest response rates, respectively. Consistently, Leiomyosarcoma and UPS had the worse and the best prognosis, respectively. CONCLUSIONS: At a longer FU, the non-inferiority of three cycles of a full-dose conventional CT in comparison to five is confirmed. Response to therapy is also confirmed to be associated with better survival. This regimen is currently tested within an ongoing international trial against three cycles of a neoadjuvant histology-tailored CT (ClinicalTrials.gov Identifier: NCT01710176).