Technological prospecting of music therapy in Alzheimer's disease

Alzheimer's disease (AD) is characterized by cognitive impairment and progressive memory loss and drug treatments have limited efficacy. Thus, non-pharmacological interventions, such as music therapy, have shown to be promising as supporting pharmacological treatment and, therefore, may arouse commercial interest regarding the development of this type of product. Thus, this study aims to carry out a patentometric survey on patent registrations with music therapy in the treatment of AD. A systematic search was carried out from 2000 to 2020 on the Orbti-Questel website, searching for documents referring to music therapies in AD. The terms “Alzheimer music methodology active therapy” and “Alzheimer music methodology passive therapy” were used. After searching, reading, and excluding duplicate results, we found four patent families referring to music therapy in AD and all were selected as a result, which was considered little compared to the number of studies published on the subject.

Antibody Response after Vaccination for Sars-Cov-2 in Patients with AL Amyloidosis and the Impact of Therapy

Patients with lymphoproliferative disorders are at high risk for severe COVID-19. For patients with AL amyloidosis, in which there is also critical organ involvement, this risk may be even higher. Vaccination against SARS-CoV-2 is the best strategy to avoid severe COVID-19, but response to vaccines may be compromised in patients with B-cell lymphoproliferative or plasma cell malignancies, as in AL amyloidosis. Although modest in size, the plasma cell clone in AL may cause immunosuppression while anticlonal therapies further compromise immune responses. To evaluate immunization efficacy, we measured the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 after vaccination with BNT162b2 in patients with AL amyloidosis. As a control group we used volunteers, matched (ratio 1:2) for age and gender, who had no autoimmune or active malignant or infectious disease. Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement on (A) day 1 (D1; before the first dose of BNT162b2) (B) day 22 (D22; before the 2nd dose) and (C) day 50 (D50; ie 30 days after the 2nd dose). NAbs against SARS-CoV-2 were measured using FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA). According to the manufacturer of the assay, a titer ≥ 50% is considered a clinically relevant threshold for viral inhibition. The study included 144 patients with AL amyloidosis, of which 120 had NAbs titers assessed on all time points and were included in the final analysis (53% males; median age: 66, IQR: 57-72 years) and 240 matched controls (53% males; median age: 66, IQR: 57-72 years). 66 (55%) AL patients were on active therapy, 17.5% were on daratumumab (DARA)-based therapy, 52 (43%) had discontinued therapy >3 months from the date of the first shot, 19% had prior exposure to DARA and 94 (78%) were in hematologic remission (CR or VGPR). Prior to the 1st dose (D1), NAb titers were similar between patients and controls (median 14.9% (IQR 7.8-23.1%) vs 14% (IQR 6.8-22.9%), p=0.439); 6 AL patients had baseline NAbs >50%, of which 5 reported a history of COVID-19 infection. On D22, there was a significant increase of NAbs titers both in controls and AL patients (both p<0.001); however, median NAb titer was 23.6% (IQR 12.4-37.7%) in AL patients vs 47.5% (IQR 32.1-62.7%) in controls (p<0.001) and 20.5% of AL patients vs 46.7% of controls (p<0.001) developed NAb titers ≥50%. On D50, there was further increase in NAbs titers both in controls and AL patients (both p<0.001) and median NAb titer for AL patients was 83.1% (IQR 41.5-94.9%) vs 95.6% (IQR 91.7-97.2%) in controls (p<0.001); 71% of AL patients vs 98% of matched controls (p<0.001) developed NAb titers ≥50%. Among AL patients, factors associated with NAb titers on D50 included age (p<0.001), lymphocyte counts (p<0.001), serum albumin (p<0.001) and amount of proteinuria at the time of vaccination (p=0.047), renal involvement (p=0.047), use of steroids (p<0.001), active treatment (p<0.001), treatment-free interval (p=0.001), remission status (CR/VGPR) (p=0.018). There was no significant association with gender (p=0.092), BMI (p=0.198), IgG (0.099), IgA (p=0.789) or IgM levels (p=0.687), liver (p=0.521) or heart involvement (p=0.141). Patients on therapy had lower NAb titers at D50 (median 50.1% (IQR 25.3-84.1%) vs 91.6% (IQR 74.5-96.5%) for those not on treatment, p<0.001), so that 51% had a D50 NAb titer ≥50% vs 87% of those not on therapy. Current DARA therapy (median 52.1% vs 46.4% without DARA, p=0.486) or prior exposure to DARA (92.1% vs 91.2%, p=0.966) were not associated with D50 NAb titers. Generalized linear models were used for evaluation of multiple factors associated with D50 NAb titers: at least 3 months since the last dose of anticlonal therapy (p<0.001), lymphocyte counts (p=0.001) and serum albumin levels at the time of vaccination (p=0.020) were independent predictors of NAb titers on D50. When seroconversion was defined as a NAb titer ≥50% at D50, then >3 months of treatment-free interval (HR:7.75, p<0.001,) was the strongest factor associated with seconversion. In conclusion, patients with AL amyloidosis have an attenuated response to vaccination with BNT162b2 especially among those on active therapy or with less than 3 months since the last dose of treatment. For such patients, an anamnestic dosing strategy could be considered, especially after completion of anticlonal therapy. Figure 1 Figure 1. Disclosures Kastritis: Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Sanofi: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

A Clue to Better Select Chronic Lymphocytic Leukemia Patients with Optimal Response to BNT162b2 mRNA COVID-19 Vaccine

Given the immunosuppression of chronic lymphocytic leukemia (CLL), this disease represents a challenging model for assessing the extent of serologic response to mRNA vaccination against severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). In this perspective, we assessed the efficacy of the BNT162b2 mRNA COVID-19 vaccine in 70 CLL pts followed up at single hematological institution. The study was approved by the Institutional Review Board. Serologic testing for SARS Cov2 IgG was performed using the LIAISON® SARS-CoV-2 S1/S2 IgG test (DiaSorin; Saluggia, Italy), a chemiluminescence immunoassay for the quantitative determination of anti-S1 and anti-S2 specific IgG antibodies to SARS-CoV-2. Clinical sensitivity and specificity of assay were 98.7% and 99.5% respectively. Samples were considered negative for antibody titers below 13 AU/ml. Results were compared with those of an age-matched group of subjects with no hematological malignancy (n=57). Patient samples for serology testing were obtained after median time of 14 days (range, 14-28) from the second vaccine dose. Median age of CLL pts was 72 years (range, 63-88) and 71.4% were males. The median time from CLL diagnosis to vaccination was 82.5 mo. (range, 1-280). Twenty-three pts (32.9%) were treatment naïve (TN), 36 (51.4%) on active therapy (i.e., BTKi, 22; anti-BCL2 12; PI3Ki,1; cyclophosphamide,1) and 11 (15.7%) off-therapy (i.e., 8 in complete [CR] or partial remission [PR], and 3 in CLL relapse). Of note, 9 (25.7%) of 35 pts on therapy with a pathway inhibitor (PI) at the time of vaccination had been given an anti-CD20 antibody. The vaccine elicited an antibody-mediated response in 41 (58.5%) of the 70 CLL pts. An inferior response rate [RR] (58.5% vs 100%, OR, 0.012 [0.0007-0.206];P=0.02) and a lower antibody titers (median, 58 AU/ml; range, 1.8-800 vs. 284 AU/ml; range, 14-800; P< 0.0001) were observed in CLL pts in comparison to age-matched subjects with no hematological malignancy. The RR was higher in TN (87%) or off-therapy pts with sustained clinical response (87.5%) in comparison to pts on therapy at the time of vaccination (41.7%)(<0.0001). Similar results were observed when comparison was performed in terms of antibody titers (P=0.02;Kruskall-Wallis test; Fig 1). In comparison to pts treated with a PI as monotherapy, those who received an anti-CD20 antibody in association to PI had a lower antibody response to SARS-CoV-2 vaccine (11.1% vs 53.8%; OR,0.107 [0.011-0.984];P=0.04). In univariate analysis, the following variables were significantly associated with serological response to SARS-CoV-2 vaccination: early Rai stage (i.e.,0-I) (OR, 0.36 [0.13-0.97];P=0.04), mutated IGHV status (OR,0.30 [0.10-0.88]; P=0.02), lack of active therapy - which comprised TN and off-therapy pts with sustained response - (OR,0.09 [0.03-0.32];P<0.0001), and no anti-CD20 antibody exposure preceding vaccination (OR, 013 [0.01-1.23];P=0.04). Levels of immunoglobulins or absolute values of CD3,CD4,CD8, and CD16/CD56 cells measured before the first COVID-19 vaccination were not associated to vaccine response. Of note, in pts who experienced a serological response a concomitant increase of the absolute of CD16/CD56 positive cells was observed (P=0.02). Finally, Rai stage (OR, 0.19 [0.05-0.79]; P=0.02) and treatment status (OR, 0.06 [0.02-0.27]; P<0.0001) were independent predictors of response in multivariate analysis. We used these factors to build a score that identified pts with different pattern of response to vaccine. Serologic response to SARS-CoV-2 vaccination was 100% in pts with no factor (n=21), 45% in pts. with one factor (n=38) and 36% in pts with two factors (n=11) (P<0.0001). In agreement with results of recent studies (Herishanu et al, Blood 2021; Roeker et al, Leukemia 2021;Perry et al, Blood Cancer J. 2021; Benjamini O et al, Haematologica 2021 ) our findings suggest that antibody-mediated response to COVID-19 vaccination is significantly reduced in CLL and influenced by disease activity and treatment status. The serological response to SARS-CoV-2 vaccination observed in pts. with early disease with no need of therapy may help to identify CLL pts who are expected to achieve an optimal response to COVID-19 vaccine similarly to age- and sex-matched controls. Figure 1 Figure 1. Disclosures Molica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Antimicrobial Activity of Aztreonam in Combination with Old and New β-Lactamase Inhibitors against MBL and ESBL Co-Producing Gram-Negative Clinical Isolates: Possible Options for the Treatment of Complicated Infections

Metallo-β-lactamases (MBLs) are among the most challenging bacterial enzymes to overcome. Aztreonam (ATM) is the only β-lactam not hydrolyzed by MBLs but is often inactivated by co-produced extended-spectrum β-lactamases (ESBL). We assessed the activity of the combination of ATM with old and new β-lactamases inhibitors (BLIs) against MBL and ESBL co-producing Gram-negative clinical isolates. Six Enterobacterales and three non-fermenting bacilli co-producing MBL and ESBL determinants were selected as difficult-to-treat pathogens. ESBLs and MBLs genes were characterized by PCR and sequencing. The activity of ATM in combination with seven different BLIs (clavulanate, sulbactam, tazobactam, vaborbactam, avibactam, relebactam, zidebactam) was assessed by microdilution assay and time–kill curve. ATM plus avibactam was the most effective combination, able to restore ATM susceptibility in four out of nine tested isolates, reaching in some cases a 128-fold reduction of the MIC of ATM. In addition, relebactam and zidebactam showed to be effective, but with lesser reduction of the MIC of ATM. E. meningoseptica and C. indologenes were not inhibited by any ATM–BLI combination. ATM–BLI combinations demonstrated to be promising against MBL and ESBL co-producers, hence providing multiple options for treatment of related infections. However, no effective combination was found for some non-fermentative bacilli, suggesting the presence of additional resistance mechanisms that complicate the choice of an active therapy.

INTEGRATING PLACEBO IN CONVENTIONAL HEARING AID PRESCRIPTION PRACTICES FOR BETTER ACCEPTANCE

The placebo effect is the reduction of a symptom or a change in the psychological parameters when an inert treatment is administered to a subject who is told that it is an active therapy with specific properties. The use of placebo is not equivalent to the absence of treatment, for example, placebo could be used in addition to standard care. In all cases, its use should be associated with measures to minimize exposure and avoid irreversible harm. (Placebo in clinical trials U. Gupta and M. Verma , 2013)

Unknown fatal encephalomyelopolyradiculoneuritis in a child. A case report

In childhood, various infectious, autoimmune, genetic diseases can manifest. We present a case of fatal encephalomyelopolyradiculoneuritis of unknown etiology in a 9-year-old child. Patient N.K. in February 2019, noted an increase in temperature to subfebrile values, received symptomatic and antibiotic therapy without effect. An increase in protein and lymphocytes was found in the cerebrospinal fluid. According to MRI data, the emergence of more and more foci of the pathological signal in the brain and spinal cord, cranial nerves and nerve roots of the lumbar plexus was noted. Known infectious and autoimmune diseases were excluded. Despite active therapy with glucocorticoids, antibiotics, antiviral drugs, immunoglobulin, the disease continued to progress, and the patient died in April 2020.