challenges of running a gmp facility for regenerative medicine in a public hospital

Advanced therapy medicinal products represent a new generation of medicinal products for regenerative medicine. Since the implementation of the EU regulation for this innovative class of drugs, the academic and hospital institutions have played a central role in their development and manufacture. For these institutions that are not familiar with the industrial context, being in compliance with the pharmaceutical standards is extremely challenging. This report describes how we dealt with some specific issues during our hospital-based GMP experience. Furthermore, we identify as a future perspective the consistent stimulating contribution that a public entity can ensure for advanced therapy medicinal product development and licensing

La tutela cautelare tra giudice comunitario e giudice nazionale

L’eccessiva durata dei processi civili in molti ordinamenti processuali ha accentuato l’importanza della tutela cautelare quale componente essenziale di una tutela giurisdizionale effettiva. L’esigenza, in tale prospettiva, di una tutela cautelare autonoma da quella di merito ha influito sull’evoluzione della disciplina positiva in materia in alcuni sistemi giuridici verso il modello del référé francese ed è stata affermata anche e sopratutto da numerose decisioni della Corte di Giustizia comunitaria. Il procedimento cautelare così come disciplinato nel sistema delle azioni dirette dinanzi ai giudici comunitari presenta, tuttavia, alcune significative lacune, sovente ancora maggiori rispetto a quelle ancora esistenti in alcuni ordinamenti nazionali. La strumentalità della tutela cautelare, infatti, da un lato, è intesa in senso rigidamente strutturale e, da un altro, il giudice della cautela è munito di scarsi poteri a fronte dell’attività discrezionale delle istituzioni comunitarie lesiva dei diritti del cittadino europeo. Tali lacune appaiono, d’altra parte, tanto più gravi in ragione delle condizioni restrittive alle quali è subordinato, in generale, il diritto di accesso al giudice nel processo comunitario. Sorge, pertanto, un interrogativo: per la Corte di Giustizia del Lussemburgo l’effettività della tutela giurisdizionale è un valore da perseguire per meglio tutelare i diritti dei singoli o non costituisce, piuttosto, soltanto uno degli strumenti che la Corte utilizza per meglio ammonire gli Stati membri al rispetto degli obblighi derivanti dalla partecipazione alla Comunità europea? Il dubbio ora palesato è determinato anche dall’esame della giurisprudenza comunitaria in tema di tutela cautelare che i giudici nazionali possono concedere tutte le volte che venga in rilievo il diritto comunitario. Possono, infatti, verificarsi due situazioni pressoché speculari. In particolare, nell’ipotesi in cui il giudice interno è chiamato a concedere tutela cautelare per via di disapplicazione delle norme nazionali a favore di quelle comunitarie, la Corte di Giustizia si è limitata a sottolineare il dovere dei giudici di concedere tale tutela ove ricorrano le medesime condizioni alle quali nel diritto interno è possibile ottenere un provvedimento cautelare. Di contro, nell’ipotesi in cui i singoli domandino tutela cautelare al giudice nazionale a fronte di un atto comunitario che appare illegittimo, le condizioni cui la stessa Corte di Giustizia ha subordinato il diritto di ottenere tale tutela sono talmente restrittive da rendere in pratica impossibile che lo stesso si realizzi.The importance of interim relief is increased in last years as a result of civil proceedings excessive duration. Consequently, in many national systems there’s been an evolution in the direction of the autonomy of interim measures respect of final judgments. Also the EC Court of Justice has held the important role of the autonomy of interim relief for an effective judicial protection in the European Union. Although these judgments, the award of interim measures in proceedings before Community Courts is often more difficult than before national Courts. For example, it’s impossible to obtain interim measures ante causam because, under article 83 of the Rules of Procedure of the Court of Justice, an application to suspend the operation of any measure adopted by an institution shall be admissible only if the applicant is challenging the measure in proceedings before the Court. So in the community system interim measures are strictly ancillary to final judgment on the merit of claim. For these reasons we can ask ourselves if the real function of autonomy of interim relief in the Community Courts Case-Law is safeguard supremacy of community law rather than interests of private plaintiffs. Our doubt depends also on the EC Court of Justice Case-Law when, before national Courts, is relevant community law to decide an application for interim relief. There are, in fact, two different situations. In a first case national Courts could be faced with the question as to whether they are entitled to suspend a national legislation contrary to EC law. Since Factortame Case EC Court of Justice held that national judges must, pending a preliminary ruling procedure, set aside the national rule that is the sole obstacle which precludes the award of interim relief. In a second case national Courts could be faced with the question as to whether they are entitled to suspend a Community act pending a preliminary ruling on the validity of that act. Since Zuckerfabrik Case EC Court of Justice recognized the power of national judge to suspend in this situation a community act, but merely under conditions strictly defined in order to safeguard, as usual, supremacy and direct applicability of Community Law

Thoracic aorta: anatomy and pathology

The aorta is the largest elastic artery in the human body and is classically divided into two ana-tomical segments, the thoracic and the abdominal aorta, separated by the diaphragm. The thoracic aorta includes the aortic root, the ascending aorta, the arch, and the descending aorta. The aorta's elastic properties depend on its wall structure, composed of three distinct histologic layers: intima, media, and adventitia. The different aortic segments show different embryological and anatomical features, which account for their different physiological properties and impact the occurrence and natural history of congenital and acquired diseases that develop herein. Diseases of the thoracic aorta may present either as a chronic, often asymptomatic disorder or as acute life-threatening conditions, i.e., acute aortic syndromes, and are usually associated with states that increase wall stress and alter the structure of the aortic wall. This review aims to provide an update on the dis-ease of the thoracic aorta, focusing on the morphological substrates and clinicopathological cor-relations. Information on anatomy and embryology will also be provided

COVID-19 lockdown: impact on online gambling, online shopping, web navigation and online pornography

Background: The COVID-19 pandemic and control measures may have had an impact on unpleasant emotions experimented during the lockdown (LD). This may have increased the number of hours spent online and could have impacted the quality of the enacted behavior, in terms of loss of control of Internet use. In this online survey, we were interested in measure how much loss of control was perceived regarding online gambling, online shopping, the fruition of online pornographic content and web navigation.Design and methods: The online survey was carried out during the COVID-19 pandemic in the post-lockdown and 1232 subjects participated in the survey. In the participating sample, healthcare workers (HW) were 43.1% of the sample, of which 18.7% were directly involved in the Coronavirus emergency, and 52.3% of the sample is not a HW. Only 0.6% of the sample gambled online and 37.5% of those reported losing control of their gambling mode. Most of the sample shopped online during the LD (70.1%), but only 7.2% of those lost control by buying and/or spending more than what they had set themselves.Results: Significant data emerged showing that those who lost control while online shopping also lost control regarding the amount of time spent online (p<0.001); 21.6% of the sample, reported making use of online pornographic material during LD, 4.7% of them stated that the frequency increased and 5.1% reported losing control by having spent more money or more time than what was intended. Finally, 44.7% of the sample have experienced loss of control during the web navigation. Furthermore, during the LD 67.8% of the sample reports having experienced unpleasant emotions. Of these, 8.4% state that they enacted behaviors such as online gambling, online shopping, online pornographic material viewing and web navigation to counter their negative emotions. Interestingly, we found a correlation between loss of control during web navigation and online shopping and the emotional states “upset”, “scared” and “restless” (p<0.05).Conclusion: To conclude, there was no significant increase in potentially addictive behaviors, nor an increase in loss of control of these behaviors when enacted online. However, the loss of control in online shopping and web navigation was significantly correlated to the unpleasant emotional states of nervousness, fear and restlessness, whereas those who reported feeling strong and able to handle the situation experienced a lower loss of control in their web navigation. These correlations may suggest that these online behaviors may act as modulators of unpleasant emotional states

Nonischemic left ventricular scar and cardiac sudden death in the young

Nonischemic Left Ventricular Scar (NLVS) is a pattern of myocardial injury characterized by midventricular and/or subepicardial gadolinium hyper enhancement at cardiac magnetic resonance, in absence of significant coronary artery disease. We aimed to evaluate the prevalence of NLVS in juvenile sudden cardiac death and to ascertain its aetiology at autopsy. We examined 281 consecutive cases of sudden death of subjects aged 1 to 35 years of age. NLVS was defined as a thin, grey rim of subepicardial and/or midmyocardial scar in the left ventricular free wall and/or the septum, in absence of significant stenosis of coronary arteries. NLVS was the most frequent finding (25%) in sudden deaths occurring during sports. Myocardial scar was localized most frequently within the left ventricular posterior wall, and affected the subepicardial myocardium, often extending to the midventricular layer. On histology it consisted of fibrous or fibro-adipose tissue. Right ventricular involvement was always present. Patchy lymphocytic infiltrates were frequent. Genetic and molecular analyses clarified the aetiology of NLVS in a subset of cases. ECG recordings were available in over half of subjects. The most frequent abnormality was the presence of low QRS voltages (< 0,5 mV) in limb leads. In serial ECG tracings, the decrease in QRS voltages appeared, in some way progressive. NLVS is the most frequent morphologic substrate of juvenile cardiac sudden death in sports. It can be suspected based on ECG findings. Autopsy study and clinical screening of family members are required to differentiate between Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia and chronic acquired myocarditis

The puzzling situation of hospital exemption for advanced therapy medicinal products in Europe and stakeholders' concerns

N/AIn Europe, advanced therapy medicinal products (ATMPs), including cell and gene medicinal products , tissue-engineered products and combined ATMPs, are governed by Directive 2001/ 83/EC and Regulation 726/2004, amended by Regulation 1394/2007, which sets specific rules concerning their centralized marketing authorization (MA), supervision and pharmacovigilance. Nevertheless, ATMPs not intended to be marketed and not industrially prepared are beyond the scope of Directive 2001/83/EC, according to article 28 of Regulation 1394/2007. This is commonly called “hospital exemption” (HE) and is restricted to any ATMP “which is prepared on a non-routine basis according to specific quality standards, and used within the same Member State in a hospital under the exclusive professional responsibility of amedical practitioner, in order to comply with an individual medical prescription for a custom-made product for an individual patient.” Member States must ensure that the manufacture of ATMPs under HE is authorized by the competent national authority and that traceability, pharmacovigilance and specific quality standards are equivalent to those applying to ATMPs granted centralized MA

ASRS Questionnaire and Tobacco Use: Not Just a Cigarette. A Screening Study in an Italian Young Adult Sample

Young adults exhibit greater sensitivity than adults to nicotine reinforcement, and Attention Deficit Hyperactivity Disorder (ADHD) increases the risk for early-onset smoking. We investigated the correlation between ADHD Self-Report Scale (ASRS) scores and smoking, evaluated the prevalence of ADHD symptomatology (not diagnoses) in smokers and non-smokers and its comorbidity with benzodiazepine and gambling addictions. A total of 389 young adults from 14 schools in Northern Italy fill out a survey and the Adult ADHD Self-Report Scale (ASRS). A total of 15.2% of subjects tested positive at the ASRS, which correlated with smoking; moreover, smokers had twice the probability of testing positive at the ASRS. ADHD symptomatology, especially when comorbid with tobacco abuse, is an important condition to monitor because early nicotine exposure could be a gateway for other addictive behaviors

Disc Regeneration Using MSC Transplanted via the Endplate Route

IntroductionStem cell based intervertebral disc (IVD) regeneration is quickly moving toward clinical applications.1 However, many aspects need to be investigated to routinely translate this therapy..

A Chemically Defined Medium-Based Strategy to Efficiently Generate Clinically Relevant Cord Blood Mesenchymal Stromal Colonies.

During the last decade it has been demonstrated that mesenchymal progenitors are present and can be isolated also from cord blood (CB). Recently, we managed to set up a standard protocol allowing the isolation of mesenchymal stromal cells (MSCs) with high proliferative potential and multiple differentiation capabilities, whereas the generation rate of MSC-initiating colonies could still be further improved. Herein, we strikingly succeeded in defining some simple and basic culture conditions based on the use of a chemically defined medium that increased the colony isolation efficiency up to almost 80% of processed CB units. Importantly, this result was achieved irrespective of CB unit white blood cell content and time elapsed from delivery, two limiting parameters involved with processing CB units. Thus, this high efficiency is guaranteed without strict selection of the starting material. In addition, since we are profoundly concerned about how different culture conditions can influence cell behavior, we devoted part of this study to in-depth characterization of the established CB-MSC populations to confirm their stemness features in this novel isolation and culture system. Therefore, an extended study of their immunophenotype, including classical pericytic markers, and a detailed molecular analysis addressing telomere length and also stemness-related microRNA contribution were performed. In summary, we propose a straightforward, extremely efficient, and reliable approach to isolate and expand thoroughly characterized CB-MSCs, even when poor-quality CB units are the only available source, or there is no space for an isolation to fail

Factors associated with a change in smoking habit during the first COVID-19 lockdown: an Italian cross-sectional study among ever-smokers

Background: The COVID-19 pandemic and the lockdown period lasted from March to May 2020, resulted in a highly stressful situation yielding different negative health consequences, including the worsening of smoking habit. Methods: A web-based cross-sectional study on a convenient sample of 1013 Italian ever smokers aged 18 years or more was conducted. Data were derived from surveys compiled by three different groups of people: subjects belonging to Smoking Cessation Services, Healthcare Providers and Nursing Sciences' students. All institutions were from Northern Italy. The primary outcome self-reported worsening (relapse or increase) or improvement (quit or reduce) of smoking habit during lockdown period. Multiple unconditional (for worsening) and multinomial (for improving) logistic regressions were carried out. Results: Among 962 participants, 56.0% were ex-smokers. Overall, 13.2% of ex-smokers before lockdown reported relapsing and 32.7% of current smokers increasing cigarette intake. Among current smokers before lockdown, 10.1% quit smoking and 13.5% decreased cigarette intake. Out of 7 selected stressors related to COVID-19, four were significantly related to relapse (OR for the highest vs. the lowest tertile ranging between 2.24 and 3.62): fear of being infected and getting sick; fear of dying due to the virus; anxiety in listening to news of the epidemic; sense of powerlessness in protecting oneself from contagion. In addition to these stressors, even the other 3 stressors were related with increasing cigarette intensity (OR ranging between 1.90 and 4.18): sense of powerlessness in protecting loved ones from contagion; fear of losing loved ones due to virus; fear of infecting other. Conclusion: The lockdown during the COVID-19 pandemic was associated with both self-reported relapse or increase smoking habit and also quitting or reduction of it