Rilpivirine plus cobicistat-boosted darunavir as a two-drug switch regimen in HIV-infected, virologically suppressed subjects on steady standard three-drug therapy: a randomized, controlled, non-inferiority trial (PROBE 2).

BACKGROUND: We explored the combination of rilpivirine plus cobicistat-boosted darunavir [a two-drug regimen (2DR)] when switching from standard triple combined ART. METHODS: In this randomized, open-label, non-inferiority trial, participants had an HIV-RNA <50 copies/mL on a stable (>6 months) three-drug regimen. The primary endpoint was proportion with HIV-RNA <50 copies/mL at Week 24 (snapshot algorithm), with a -12% non-inferiority margin. ClinicalTrials.gov: NCT04064632. RESULTS: One hundred and sixty patients were allocated (1:1) to 2DR or to continue current ART (CAR). At Week 24, 72 (90.0%) of participants with 2DR and 75 (93.8%) with CAR maintained HIV-RNA <50 copies/mL [difference -3.75% (95% CI = -11.63 to 5.63)], confirming non-inferiority. Non-inferiority was confirmed considering an HIV-RNA >50 copies/mL (0% for 2DR; 3.7% for CAR; 95% CI = -0.4 to 7.9). Four patients reported adverse events not leading to treatment discontinuation (one patient in the 2DR group and three patients in the CAR group); eight subjects discontinued therapy in the 2DR group and three in the CAR group. With 2DR, lipid serum concentrations increased, but differences were statistically significant only for tenofovir disoproxil fumarate-containing CAR and in 2DR patients receiving a pre-switch regimen including tenofovir disoproxil fumarate. Median bone stiffness decreased in the CAR group from 86.1 g/cm2 (IQR = 74-98) to 83.2 g/cm2 (IQR = 74-97) and increased in the 2DR group from 84.9 g/cm2 (IQR = 74-103) to 85.5 g/cm2 (IQR = 74-101). The reduction within the CAR group was significant (P = 0.043). CONCLUSIONS: Once-daily rilpivirine plus cobicistat-boosted darunavir is an effective 2DR that combines a high virological efficacy with a potential to avoid major NRTI toxicities.

Tensor Network Annealing Algorithm for Two-Dimensional Thermal States.

Tensor network methods have become a powerful class of tools to capture strongly correlated matter, but methods to capture the experimentally ubiquitous family of models at finite temperature beyond one spatial dimension are largely lacking. We introduce a tensor network algorithm able to simulate thermal states of two-dimensional quantum lattice systems in the thermodynamic limit. The method develops instances of projected entangled pair states and projected entangled pair operators for this purpose. It is the key feature of this algorithm to resemble the cooling down of the system from an infinite temperature state until it reaches the desired finite-temperature regime. As a benchmark, we study the finite-temperature phase transition of the Ising model on an infinite square lattice, for which we obtain remarkable agreement with the exact solution. We then turn to study the finite-temperature Bose-Hubbard model in the limits of two (hard-core) and three bosonic modes per site. Our technique can be used to support the experimental study of actual effectively two-dimensional materials in the laboratory, as well as to benchmark optical lattice quantum simulators with ultracold atoms.

Restoration of vision after transplantation of photoreceptors.

Cell transplantation is a potential strategy for treating blindness caused by the loss of photoreceptors. Although transplanted rod-precursor cells are able to migrate into the adult retina and differentiate to acquire the specialized morphological features of mature photoreceptor cells, the fundamental question remains whether transplantation of photoreceptor cells can actually improve vision. Here we provide evidence of functional rod-mediated vision after photoreceptor transplantation in adult Gnat1−/− mice, which lack rod function and are a model of congenital stationary night blindness. We show that transplanted rod precursors form classic triad synaptic connections with second-order bipolar and horizontal cells in the recipient retina. The newly integrated photoreceptor cells are light-responsive with dim-flash kinetics similar to adult wild-type photoreceptors. By using intrinsic imaging under scotopic conditions we demonstrate that visual signals generated by transplanted rods are projected to higher visual areas, including V1. Moreover, these cells are capable of driving optokinetic head tracking and visually guided behaviour in the Gnat1−/− mouse under scotopic conditions. Together, these results demonstrate the feasibility of photoreceptor transplantation as a therapeutic strategy for restoring vision after retinal degeneration.

[Pathogenesis of systemic lupus erythematosus]. / Pathogenese des systemischen Lupus erythematodes.

The causes of diseases and disorders of the immune system, which lead to the development of systemic lupus erythematosus (SLE), are not yet completely understood; however, it is known that there are various mechanisms, which can lead to SLE. The development of the disease is based on an underlying genetic disposition but is first triggered by exposure to environmental factors, such as sunburn, viral infections or vitamin D deficiency. Disease flares can also be triggered by environmental factors. Many disease manifestations are caused by pathogenic autoantibodies; hence, B­cells and plasma cells play a critical role in the pathogenesis of SLE. This review provides an overview of the most frequent factors leading to the development of SLE and describes the key mechanisms of its pathogenesis.

A 3-year interval is too short for re-screening women testing negative for human papillomavirus: a population-based cohort study.

OBJECTIVE: To compare the results from an initial negative human papillomavirus (HPV) test with re-screening after 3 years in women attending two HPV-based screening programmes. DESIGN: Population-based cohort study. SETTING: Two cervical service screening programmes in Italy. POPULATION: Women aged 25-64 years invited to screening from April 2009 to October 2015. METHODS: Eligible women were invited to undergo an HPV test. Those with a negative HPV test went on to the next screening round 3 years later. Cytology triage was performed for HPV+ (HPV by Hybrid Capture 2) samples, with immediate colposcopy (if abnormal) and HPV re-testing 1 year later (if negative). MAIN OUTCOME MEASURES: Participation rate, positivity at HPV and at triage, referral rate to colposcopy, positive predictive value for cervical intraepithelial neoplasia grade 2+ (CIN2+) at colposcopy, and detection rate for CIN2+. RESULTS: We present the results from 48 751 women at the first screening and 22 000 women at re-screening 3 years later. The response rate was slightly higher at the second screening (74.5 versus 72.1% at the first screening; referral rate, RR 1.11; 95% confidence interval, 95% CI, 1.07-1.14). Compared with the first screening, we observed a significant reduction at the second screening in terms of HPV positivity (RR 0.55, 95% CI 0.51-0.60), referral rate to colposcopy (RR 0.47, 95% CI 0.41-0.53), CIN2+ detection rate (RR 0.24, 95% CI 0.13-0.39), and positive predictive value (PPV) for CIN2+ at colposcopy (RR 0.51, 95% CI 0.29-0.87). CONCLUSIONS: The very low frequency of disease and inadequate PPV at colposcopy indicate that a 3-year interval after a negative HPV test is too short. TWEETABLE ABSTRACT: Three years after a negative HPV the frequency of cervical disease is so low that re-screening is inefficient.

Infective endocarditis in patients with hepatic diseases.

Few data have been published regarding the epidemiology and outcome of infective endocarditis (IE) in patients with chronic hepatic disease (CHD). A retrospective analysis of the Studio Endocarditi Italiano (SEI) database was performed to evaluate the epidemiology and outcome of CHD+ patients compared with CHD- patients. The diagnosis of IE was defined in accordance with the modified Duke criteria. Echocardiography, diagnosis, and treatment procedures were in accordance with current clinical practice. Among the 1722 observed episodes of IE, 300 (17.4 %) occurred in CHD+ patients. The cause of CHD mainly consisted of chronic viral infection. Staphylococcus aureus was the most common bacterial species in CHD+ patients; the frequency of other bacterial species (S. epidermidis, streptococci, and enterococci) were comparable among the two groups. The percentage of patients undergoing surgery for IE was 38.9 in CHD+ patients versus 43.7 in CHD- patients (p = 0.06). Complications were more common among CHD+ patients (77 % versus 65.3 %, p < 0.001); embolization (43.3 % versus 26.1 %, p < 0.001) and congestive heart failure (42 % versus 34.1 %, p = 0.01) were more frequent among CHD+ patients. Mortality was comparable (12.5 % in CHD- and 15 % in CHD+ patients). At multivariable analysis, factors associated with hospital-associated mortality were having an infection sustained by S. aureus, a prosthetic valve, diabetes and a neoplasia, and CHD. Being an intravenous drug user (IVDU) was a protective factor and was associated with a reduced death risk. CHD is a factor worsening the prognosis in patients with IE, in particular in patients for whom cardiac surgery was required.

Genitourinary infections in diabetic patients in the new era of diabetes therapy with sodium-glucose cotransporter-2 inhibitors.

AIMS: To review prevalence and significance of urinary tract (UTI) and genital infections (GI) in diabetes and the effects of sodium glucose cotransporter 2 (SGLT-2) inhibitors on these complications. DATA SYNTHESIS: The prevalence of asymptomatic bacteriuria (ASB) is 2-3 times higher in diabetic than in non-diabetic women. The treatment of ASB has no impact on the development of UTIs and/or a decline in renal function. Therefore, there is no indication for screening for and/or treatment of ASB. The incidence of UTI is higher and frequently complicated in diabetic patients, particularly in those with longer duration of disease and of older age. There is no consistent evidence of an association between A1c levels, glycosuria and the risk of ASB and/or UTIs. Diabetes is a known risk factor for Candida colonization and GI, and a poor glycemic control is associated with a higher risk. While patients treated with SGLT-2 inhibitors may have a non-significant increased risk of UTI, they have a clearly increased risk of GI; most of these infections are mild, easy to treat, and the rate of recurrence is low. CONCLUSION: Diabetic patients are at high risk of UTIs and of GI. Only GI are associated with poor glycemic control. Although patients treated with SGLT-2 inhibitors have an increased 3-5 fold risk of GI, proper medical education can reduce this risk.

Evaluation of serum myostatin and sclerostin levels in chronic spinal cord injured patients.

STUDY DESIGN: Case-control study. OBJECTIVES: To assess serum myostatin levels, bone mineral density (BMD), appendicular skeletal muscle mass (ASMM) and serum sclerostin levels in chronic spinal cord injured (SCI) patients and healthy controls. SETTING: SCI centre in Italy. METHODS: Blood samples, whole-body bioelectrical impedance analysis and BMD measurement with the ultrasound technique at the calcaneus level were taken from patients suffering from chronic SCI (both motor complete and incomplete) and healthy control subjects. RESULTS: A total of 28 SCI patients and 15 healthy controls were enrolled. Serum myostatin levels were statistically higher (P<0.01) in SCI patients compared with healthy controls. Similar results were found comparing both the motor complete and the motor incomplete SCI subgroups to healthy controls. Serum sclerostin was significantly higher in patients with SCI compared with healthy controls (P<0.01). BMD, stiffness and mean T-score values in SCI patients were significantly lower than those in healthy controls. Serum myostatin concentrations in the motor complete SCI subgroups correlated only with serum sclerostin levels (r(2)=0.42; P=0.001) and ASMM (r(2)=0.70; P=0.002) but not in healthy controls. DISCUSSION: Serum myostatin and serum sclerostin are significantly higher in chronic SCI patients compared with healthy controls. They are potential biomarkers of muscle and bone modifications after SCI. This is the first study reporting an increase in serum myostatin in patients suffering from chronic SCI and a correlation with ASMM.

X-linked agammaglobulinemia in community-acquired pneumonia cases revealed by immunoglobulin level screening at hospital admission.

In children with primary immunodeficiencies, the onset of symptoms precedes the diagnosis and the initiation of appropriate treatment by months or years. This delay in diagnosis is due to the fact that while these disorders are rare, some of the infections seen in immunodeficient patients are common. Defective antibody production represents the largest group among these disorders, with otitis, sinusitis and pneumonia as the most frequent initial manifestation. We performed a prospective study of humoral immunity in children hospitalized due to community-acquired pneumonia in tertiary care hospital. Out of 254 patients (131 boys, 123 girls, median age 4.5 years) recruited over 3 years, we found 2 boys (age 11 and 21 months) lacking serum immunoglobulins and circulating B cells. Subsequent genetic analysis confirmed diagnosis of X-linked agammaglobulinemia. Despite their immunodeficiency, the pneumonia was uncomplicated in both patients and did not call for immunological evaluation. However, the immunoglobulin screening at admission allowed for an early diagnosis of the immunodeficiency and timely initiation of immunoglobulin substitution, the key prerequisite for a favorable course of the disease.Simple and inexpensive immuno-globulin measurement during the manage-ment of hospitalized children with community-acquired pneumonia may help in early identification of patients with compromised humoral immunity and prevent serious complications.

Clinical variables associated with late-onset thrombotic and cardiovascular events, after SARS-CoV-2 infection, in a cohort of patients from the first epidemic wave: an 18-month analysis on the "Surviving-COVID" cohort from Bergamo, Italy.

Importance: Population studies have recorded an increased, unexplained risk of post-acute cardiovascular and thrombotic events, up to 1 year after acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objectives: To search for clinical variables and biomarkers associated with late post-acute thrombotic and cardiovascular events after SARS-CoV-2 infection. Design: Retrospective cohort study. Setting: Third-level referral hospital in Bergamo (Italy). Participants: Analysis of an existing database of adult patients, who received care for SARS-CoV-2 infection at our institution between 20 February and 30 September 2020, followed up on a single date ("entry date") at 3-6 months. Exposure: Initial infection by SARS-CoV-2. Main outcomes and measures: Primary outcome: occurrence, in the 18 months after entry date, of a composite endpoint, defined by the International Classification of Diseases-9th edition (ICD-9) codes for at least one of: cerebral/cardiac ischemia, venous/arterial thrombosis (any site), pulmonary embolism, cardiac arrhythmia, heart failure. Measures (as recorded on entry date): history of initial infection, symptoms, current medications, pulmonary function test, blood tests results, and semi-quantitative radiographic lung damage (BRIXIA score). Individual clinical data were matched to hospitalizations, voluntary vaccination against SARS-CoV-2 (according to regulations and product availability), and documented reinfections in the following 18 months, as recorded in the provincial Health Authority database. A multivariable Cox proportional hazard model (including vaccine doses as a time-dependent variable) was fitted, adjusting for potential confounders. We report associations as hazard ratios (HR) and 95% confidence intervals (CI). Results: Among 1,515 patients (948 men, 62.6%, median age 59; interquartile range: 50-69), we identified 84 endpoint events, occurring to 75 patients (5%): 30 arterial thromboses, 11 venous thromboses, 28 arrhythmic and 24 heart failure events. From a multivariable Cox model, we found the following significant associations with the outcome: previous occurrence of any outcome event, in the 18 months before infection (HR: 2.38; 95% CI: 1.23-4.62); BRIXIA score ≥ 3 (HR: 2.43; 95% CI: 1.30-4.55); neutrophils-to-lymphocytes ratio ≥ 3.3 (HR: 2.60; 95% CI: 1.43-4.72), and estimated glomerular filtration rate < 45 ml/min/1.73 m2 (HR: 3.84; 95% CI: 1.49-9.91). Conclusions and relevance: We identified four clinical variables, associated with the occurrence of post-acute thrombotic and cardiovascular events, after SARS-CoV-2 infection. Further research is needed, to confirm these results.

Expression of nogo-a is decreased with increasing gestational age in the human fetal brain.

Nogo is a member of the reticulon family. Our understanding of the physiological functions of the Nogo-A protein has grown over the last few years, and this molecule is now recognized as one of the most important axonal regrowth inhibitors present in central nervous system (CNS) myelin. Nogo-A plays other important roles in nervous system development, epilepsy, vascular physiology, muscle pathology, stroke, inflammation, and CNS tumors. Since the exact role of Nogo-A protein in human brain development is still poorly understood, we studied its cellular and regional distribution by immunohistochemistry in the frontal lobe of 30 human fetal brains. Nogo-A was expressed in the following cortical zones: ependyma, ventricular zone, subventricular zone, intermediate zone, subplate, cortical plate, and marginal zone. The number of positive cells decreased significantly with increasing gestational age in the subplate and marginal zone. Using different antibodies, changes in isoform expression and dimerization states could be shown between various cortical zones. The results demonstrate a significant change in the expression of Nogo-A during the development of the human brain. The effects of its time- and region-specific regulation have to be further studied in detail.

Quantum memory assisted probing of dynamical spin correlations.

We propose a method to probe time-dependent correlations of nontrivial observables in many-body ultracold lattice gases. The scheme uses a quantum nondemolition matter-light interface, first to map the observable of interest on the many-body system into the light and then to store coherently such information into an external system acting as a quantum memory. Correlations of the observable at two (or more) instances of time are retrieved with a single final measurement that includes the readout of the quantum memory. Such a method brings to reach the study of dynamics of many-body systems in and out of equilibrium by means of quantum memories in the field of quantum simulators.

Epidemiology, characteristics, and outcome of infective endocarditis in Italy: the Italian Study on Endocarditis.

BACKGROUND: The characteristics of patients with infective endocarditis (IE) vary significantly by region of the world. The aim of this study was to evaluate the contemporary epidemiology, characteristics, and outcome of IE in a large, nationwide cohort of Italian patients. METHODS: We conducted a prospective, observational study at 24 medical centers in Italy, including all the consecutive patients with a definite or possible diagnosis of IE (modified Duke criteria) admitted from January 2004 through December 2009. A number of clinical variables were collected through an electronic case report form and analyzed to comprehensively delineate the features of IE. We report the data on patients with definite IE. RESULTS: A total of 1,082 patients with definite IE were included. Of these, 753 (69.6%) patients had infection on a native valve, 277 (25.6%) on a prosthetic valve, and 52 (4.8%) on an implantable electronic device. Overall, community-acquired (69.2%) was more common than nosocomial (6.2%) or non-nosocomial (24.6%) health care-associated IE. Staphylococcus aureus was the most common pathogen (22.0%). In-hospital mortality was 15.1%. From the multivariate analysis, congestive heart failure (CHF), stroke, prosthetic valve infection, S. aureus, and health care-associated acquisition were independently associated with increased in-hospital mortality, while surgery was associated with decreased mortality. CONCLUSIONS: The current mortality of IE remains high, and is mainly due to its complications, such as CHF and stroke.

Lateral gain is impaired in macular degeneration and can be targeted to restore vision in mice.

Macular degeneration is a leading cause of blindness. Treatments to rescue vision are currently limited. Here, we study how loss of central vision affects lateral feedback to spared areas of the human retina. We identify a cone-driven gain control mechanism that reduces visual function beyond the atrophic area in macular degeneration. This finding provides an insight into the negative effects of geographic atrophy on vision. Therefore, we develop a strategy to restore this feedback mechanism, through activation of laterally projecting cells. This results in improved vision in Cnga3-/- mice, which lack cone function, as well as a mouse model of geographic atrophy. Our work shows that a loss of lateral gain control contributes to the vision deficit in macular degeneration. Furthermore, in mouse models we show that lateral feedback can be harnessed to improve vision following retinal degeneration.

In vitro activity effects of twelve antibiotics alone and in association against twenty-seven Enterococcus faecalis strains isolated from Italian patients with infective endocarditis: high in vitro synergistic effect of the association ceftriaxone-fosfomycin.

BACKGROUND: In 2004-2008, the epidemiological and clinical Infective Endocarditis Study Group (SEI) evaluated 852 cases of infective endocarditis. Staphylococcus aureus was the main involved pathogen (24.5%) and Enterococcus faecalis etiology was described in 11% of the cases. The aim of this study was to evaluate the in vitro activity of 12 antibiotics alone and in association against 27 strains of E. faecalis isolated from blood cultures of patients with infective endocarditis. RESULTS: The results showed high in vitro activity of tigecycline, daptomycin and linezolid. A high synergistic effect was obtained with the association ceftriaxone-fosfomycin [fractional inhibitory concentration (FIC)(50) = 0.34, FIC(90) = 0.78]. Furthermore, ceftriaxone plus ampicillin presented additive results (FIC(50) = 0.66, FIC(90) = 1.00), and ceftriaxone plus fosfomycin and ceftriaxone plus ampicillin were significantly more active in vitro than each drug alone. The efficacy of ceftriaxone plus fosfomycin was confirmed by the association testing using the broth dilution technique. CONCLUSION: Fosfomycin seems particularly significant and its association with ceftriaxone could be considered as a useful therapeutic option in medical treatment of E. faecalis infective endocarditis.

An apparatus for the continuous measurement of thickness during the electropolishing of superconducting cavities.

An apparatus allowing continuous acquisition of thickness measurements during electropolishing of superconducting cavities is described. The instrument is based on the ultrasound thickness measurement technique and allows the connection of up to six probes. The apparatus has been employed to monitor the surface treatment of PIP-II low beta single cell prototypes developed and manufactured by LASA-INFN and specifically to measure surface removal at different points of interest on the cavity surface. The apparatus facilitated the development and optimization of electropolishing parameters for incorporation into the cavity manufacturing process.

Pfaffian state generation by strong three-body dissipation.

We propose a scheme for preparing and stabilizing the Pfaffian state with high fidelity in rapidly rotating 2D traps containing a small number of bosons. The goal is achieved by strongly increasing three-body loss processes, which suppress superpositions of three particles while permitting pairing. This filtering mechanism gives rise to reasonably small losses if the system is initialized with the right angular momentum. We discuss some methods for tuning independently two- and three-body interactions.

Wilson fermions and axion electrodynamics in optical lattices.

We show that ultracold Fermi gases in optical superlattices can be used as quantum simulators of relativistic lattice fermions in 3+1 dimensions. By exploiting laser-assisted tunneling, we find an analogue of the so-called naive Dirac fermions, and thus provide a realization of the fermion doubling problem. Moreover, we show how to implement Wilson fermions, and discuss how their mass can be inverted by tuning the laser intensities. In this regime, our atomic gas corresponds to a phase of matter where Maxwell electrodynamics is replaced by axion electrodynamics: a 3D topological insulator.