The role of chemistry and strut porosity and the influence of serum proteins in modulating cellular response to bone graft substitutes

The objective of this thesis was to investigate the role of hydroxyapatite and silicate-substituted hydroxyapatite synthetic bone graft substitute (SBG) material properties in modulating the processes of protein adsorption and desorption, and their combined role in the subsequent regulation of cell attachment, proliferation and differentiation on the surfaces of these materials in vitro. As a result of their purported role in promoting osteogenic behaviour in vivo the materials parameters selected for investigation were chemistry (stoichiometric hydroxyapatite (HA) versus 0.8wt% silicate-substituted hydroxyapatite (SA)) and strut porosity (20% versus 30% strut porosity). Cell attachment and response to different SBG was assessed to samples in the ‘as received’ condition as well as after a series of sequentially varied pre-treatments with solutions of phosphate buffered saline or cell culture media either unsupplemented or in combination with mixed serum proteins and/or Fibronectin (Fn). This enabled investigation of the effect of sample chemistry and strut porosity on mixed serum protein interactions and Fn adsorption under both competitive and non-competitive conditions, and the study of subsequent regulation of cell attachment and response as a consequence of pre-treatment. Results showed that serum protein interactions were key to modulation of cell response to chemistry, and there was evidence that for Fn this may be related to conformational changes in the adsorbed protein rather than its level of enrichment in the protein interlayer. In terms of the materials properties investigated strut porosity was found to be the most dominant factor in the regulation of cell response, where SBG with 30% strut porosity promoted human mesenchymal stem cell (hMSC) osteoblastic differentiation. Moreover hMSC response to SBG with 30% strut porosity seemed to be less sensitive to pre-treatment. In conclusion, the results of these experiments indicate that strut porosity more directly influences the cellular response to HA and SA BGS than chemistry in vitro. Moreover, the role that Fn and other serum proteins have in regulating this response is dependent on the physiological environment and BG

Proarrhythmia assessment in treatment with hydroxychloroquine and azithromycin hospitalized elderly COVID-19 patients - our experience

The aim of our study was to characterize the repolarization disorders propensity induced by drug-drug interaction. In this observational retrospective study, we report our experience on all elderly patients with ascertained diagnosis of coronavirus disease 2019 through nasopharyngeal swab with real time-polymerase chain reaction at our Pugliese-Ciaccio hospital in Catanzaro, who received hydroxychloroquine (HCQ), with or without azithromycin (AZY). 33 hospitalized patients were examined. We calculated QT value, cQT, QT dispersion, and cQT dispersion and examined possible progression on the basal electrocardiogram (T0) and after the insertion of the drug (T1). The QT value is increased by T0 vs T1 (370±40.74 vs 420±36.91 ms; P=0.000), as well as the cQT value (408±25.40 vs 451.54±58.81; P=0.003), the QT dispersion (QTd: 36.36±14.53 vs 50.90±13.12 ms; P=0.000); the dispersion of cQTc (cQTd 46.27±18.72 vs 63.18±21.93 ms; P=0.001). The ΔQT was 37.44±44.09 while the ΔcQT was 32.01±56.47). The main determinant of QTc prolongation is the number of drug at risk of prolongation of the QT that could influence the ventricular repolarization phase. The use of HCQ in combination with AZY, in patients suffering from severe acute respiratory syndrome-related coronavirus-2, can favor the onset of serious side effects, even potentially fatal. Finally, the measures of QTd and cQTd confirmed additional electrocardiographic parameters useful in identifying patients being treated with drugs at risk of potential adverse arrhythmic events following drug interaction

Hydroxychloroquine and QTc: beyond COVID-19

Hydroxychloroquine is an antimalarial drug also known for its anti-inflammatory and antiviral effects, which have raised the interest of many researchers for its potential use in COVID-19 patients. It is known that this drug, being able to influence the cardiac repolarization phase with QTc interval prolongation, can be potentially harmful, chiefly in elderly subjects with frailty syndrome, several comorbidities and polypharmacotherapy. Therefore, although electrocardiogram monitoring of QTc prolongation is the focal point for reducing the arrhythmic risk of these patients, in order to identify the most exposed patients, the traditional Comprehensive Geriatric Assessment should be combined with a multiparametric risk score for QTc prolongation

Experimental Protocol to Test Explicit Motor Learning–Cerebellar Theta Burst Stimulation

Implicit and explicit motor learning processes work interactively in everyday life to promote the creation of highly automatized motor behaviors. The cerebellum is crucial for motor sequence learning and adaptation, as it contributes to the error correction and to sensorimotor integration of on-going actions. A non-invasive cerebellar stimulation has been demonstrated to modulate implicit motor learning and adaptation. The present study aimed to explore the potential role of cerebellar theta burst stimulation (TBS) in modulating explicit motor learning and adaptation, in healthy subjects. Cerebellar TBS will be applied immediately before the learning phase of a computerized task based on a modified Serial Reaction Time Task (SRTT) paradigm. Here, we present a study protocol aimed at evaluating the behavioral effects of continuous (cTBS), intermittent TBS (iTBS), or sham Theta Burst Stimulation (TBS) on four different conditions: learning, adaptation, delayed recall and re-adaptation of SRTT. We are confident to find modulation of SRTT performance induced by cerebellar TBS, in particular, processing acceleration and reduction of error in all the conditions induced by cerebellar iTBS, as already known for implicit processes. On the other hand, we expect that cerebellar cTBS could induce opposite effects. Results from this protocol are supposed to advance the knowledge about the role of non-invasive cerebellar modulation in neurorehabilitation, providing clinicians with useful data for further exploiting this technique in different clinical conditions

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

The Role of Attitudes Toward Medication and Treatment Adherence in the Clinical Response to LAIs: Findings From the STAR Network Depot Study

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time. Methods: The STAR Network \u201cDepot Study\u201d was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS 65 41). Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions\u2014conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently\u2014showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline. Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p < .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p < .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Osteopathic Manipulative Treatment Limits Chronic Constipation in a Child with Pitt-Hopkins Syndrome

Pitt-Hopkins Syndrome (PTHS) is a rare genetic disorder caused by insufficient expression of the TCF4 gene. Children with PTHS typically present with gastrointestinal disorders and early severe chronic constipation is frequently found (75%). Here we describe the case of a PTHS male 10-year-old patient with chronic constipation in whom Osteopathic Manipulative Treatment (OMT) resulted in improved bowel functions, as assessed by the diary, the QPGS-Form A Section C questionnaire, and the Paediatric Bristol Stool Form Scale. The authors suggested that OMT may be a valid tool to improve the defecation frequency and reduce enema administration in PTHS patients