Establishing a national HTA program for medical devices in Italy: Overhauling a fragmented system to ensure value and equal access to new medical technologies

Differing contexts have greatly influenced HTA development in various countries, with considerable effort recently made by international HTA networks (e.g., EUnetHTA) and the European Union (EU) to make HTA a more coherent, equal, and efficient process. Medical devices (MDs) present particular challenges for HTA because of frequent, rapid innovation, outcomes influenced by end-user competence, dynamic pricing and often low-quality scientific evidence. Our objective is to describe the development, structure and governance of a National HTA Program for MDs (PNHTADM) in Italy, a highly participatory, stakeholder-engaged, evidence-based process to reform a fragmented system of appraisal and approval. Based largely on EUnetHTA methods, the resulting process delineates a standardized system for proposing MDs by any stakeholders, accrediting HTA producers, setting criteria for prioritization and appraisals, and innovatively linking recommendations with coverage, reimbursement and procurement of MDs. Expected benefits include reduced disparities in pricing and reimbursement policies and improved access to new technologies across 21 regional healthcare systems in Italy's decentralized, universal system, complete with provisions to require additional evidence collection and centrally monitor diffusion. Though devised for Italy, the design, resources and underlying analysis provide a framework for other nations seeking to consolidate HTA initiatives, particularly in light of new EU regulation.     

Bulbectomy Enhances Neurogenesis and Cell Turnover of Primary Olfactory Neurons But Does Not Abolish Carnosine Expression

Primary olfactory neurons located in the olfactory neuroepithelium project to the ipsilateral olfactory bulb and undergo a continuous process of neurogenesis and differentiation. We describe, in the adult rat, the kinetics of proliferation, differentiation and survival of primary olfactory neurons either in the presence or absence of their target, the olfactory bulb. The experimental design included unilateral bulbectomy, coupled with a single bromodeoxyuridine pulse 35 days after surgery. The rate of proliferation and survival of olfactory neurons was then examined by immunohistochemistry for bromodeoxyuridine, and the differentiation status by in situ hybridization for calmodulin messenger RNA in immature and mature olfactory neurons and immunohistochemistry for the dipeptide carnosine in mature olfactory neurons. We show that primary olfactory neurons can synthesize carnosine in the absence of the olfactory bulb. However, the number of carnosine-immunopositive neurons in the absence of their target is dramatically reduced to less than one-fourth, whereas the number of olfactory neurons expressing calmodulin messenger RNA is only slightly reduced. The numeric reduction of camosine-positive neurons in the target-deprived neuroepithelium is correlated with a dramatic reduction in the survival rate of olfactory neurons, since newly generated olfactory neurons are completely lost 35 days after the bromodeoxyuridine pulse. In contrast, in the normal olfactory neuroepithelium almost one-third of newly generated olfactory neurons survive 35 days after the bromodeoxyuridine pulse. On the whole, these data indicate that most of the primary olfactory neurons have a short lifespan but that once they have connected with the olfactory bulb they may persist longer, and suggest that throughout adulthood olfactory neurons are overproduced, differentiate independently from their target, and then undergo a process of target-induced neuronal selection.     

Trastuzumab down-regulates Bcl-2 expression and potentiates apoptosis induction by Bcl-2/Bcl-XL bispecific antisense oligonucleotides in HER-2 gene--amplified breast cancer cells.

PURPOSE: To investigate the possible existence of an antiapoptotic cross-talk between HER-2 and antiapoptotic Bcl-2 family members. EXPERIMENTAL DESIGN: Bcl-2 and Bcl-XL expression and apoptosis induction were analyzed in HER-2 gene-amplified (BT474) and nonamplified (ZR 75-1) breast cancer cell lines exposed to trastuzumab, alone or in combination with either Bcl-2/Bcl-XL bispecific antisense oligonucleotides (AS-4625) or the small-molecule Bcl-2 antagonist HA14-1. RESULTS: In addition to HER-2 and epidermal growth factor receptor, trastuzumab down-regulated Bcl-2, but not Bcl-XL, protein, and mRNA expression in BT474 cells. Interestingly, trastuzumab-induced down-regulation of HER-2 and Bcl-2 was also observed in three of five and two of three breast cancer patients undergoing trastuzumab treatment, respectively. Despite Bcl-2 down-regulation, however, trastuzumab only marginally increased the rate of apoptosis (7.3 +/- 3.5%). We therefore investigated whether a combination of AS-4625 and trastuzumab might increase proapoptotic efficiency. AS-4625 treatment of BT474 cells decreased both Bcl-2 and Bcl-XL expression, resulting in a 21 +/- 7% net apoptosis induction; the combination of AS-4625 followed by trastuzumab resulted in a significantly stronger induction of apoptosis (37 +/- 6%, P <0.01) that was not observed with the reverse treatment sequence (trastuzumab followed by AS-4625). Similar results were obtained with the Bcl-2 antagonist HA14-1; indeed, exposure of BT474 cells to HA14-1 followed by trastuzumab resulted in a striking proapoptotic synergism (combination index=0.58 +/- 0.18), as assessed by isobologram analysis. CONCLUSIONS: Altogether our findings suggest that combined targeting of HER-2 and Bcl-2 may represent a novel, rational approach to more effective breast cancer therapy.     

Good response to the late treatment with ataluren in a boy with Duchenne muscular dystrophy: could the previous mild course of the disease have affected the outcome?

Duchenne muscular dystrophy (DMD) is a severe, progressive X-linked recessive disorder, caused by the absence of the dystrophin protein. A resolutive therapy for DMD is not yet available. The first approved drug for DMD patients with nonsense mutations is ataluren, approved for the treatment of children aged ≥ 2 yrs, that seems effective in slowing the disease progression. An earlier introduction of ataluren seems to give better results.We report the case of a 14-year-old DMD patient with a nonsense mutation in exon 70, still ambulant, who started taking ataluren at 12 years and remained stable for the following two years. The patient was on steroid since the age of 6, with beneficial effects. At two-years follow-up, an optimal disease evolution was observed, associated with a constant decrease of creatine kinase blood levels. Despite the late start of the treatment, ataluren seems to have significantly contributed to the stabilization of the functional status in this patient though it cannot be excluded that the result may have been influenced by the previous favorable course of the disease. However, further studies should be planned in patients with similar age treated with ataluren to better evaluate the treatment’s results compared to the natural course of the disease.Key words: Duchenne muscular dystrophy, target therapy, nonsense mutation, ataluren, time function tests     

Safety and Efficacy of Eucaloric Very Low-Carb Diet (EVLCD) in Type 1 Diabetes: A One-Year Real-Life Retrospective Experience

A eucaloric very low carbohydrate diet (EVLCD) is a diet with a daily caloric intake equal to the total daily energy expenditure (TDEE) with a carbohydrate content of <50 g/day. The literature on very low carbohydrate diets (VLCD) in type 1 diabetes (DM 1) is limited, although recently published scientific studies have highlighted their safety and efficacy in managing DM 1. In this retrospective analysis, we report the clinical data of 33 patients affected by DM 1 carrying out insulin therapy who switched voluntarily from their usual diet (high carb, low fat) to an EVLCD. Our aim is to evaluate the glycemic control, the amount of insulin needed in order to maintain glycemic control and safety of EVLCD. The switch improved glycemic control (mean glycated hemoglobin decreased from 8.3% to 6.8% (p < 0.01). The number of patients who reached a glycated hemoglobin value of <7% increased statistically from 12% to 57% (p < 0.01), and there was a statistically significant decrease (p < 0.01) in the units of daily insulin (from 36.7± 14.9 IU to 28.9 ±9.1 IU) A reduction from 54% to 24% in clinical level 2 hypoglycemia episodes was reported. No cases of severe hypoglycemia or ketoacidosis were observed. The results of the study support that EVLCD in DM 1 seems safe and effective when adopted under tight medical supervision.     

Multisystem Inflammatory Syndrome in Neonates Born to Mothers with SARS-CoV-2 Infection (MIS-N) and in Neonates and Infants Younger Than 6 Months with Acquired COVID-19 (MIS-C): A Systematic Review

(1) Introduction: There is an increasing literature describing neonates born to mothers with SARS-CoV-2 infection (MIS-N) and infants infected with SARS-CoV-2 who presented with a severe disease (MIS-C). (2) Methods: To investigate clinical features of multisystem inflammatory syndrome in neonates and infants under six months of age, we used a systematic search to retrieve all relevant publications in the field. We screened in PubMed, EMBASE and Scopus for data published until 10 October 2021. (3) Results: Forty-eight articles were considered, including 29 case reports, six case series and 13 cohort studies. Regarding clinical features, only 18.2% of MIS-N neonates presented with fever; differently from older children with MIS-C, in which gastrointestinal symptoms were the most common manifestation, we displayed that cardiovascular dysfunction and respiratory distress are the prevalent findings both in neonates with MIS-N and in neonates/infants with MIS-C. (4) Conclusions: We suggest that all infants with suspected inflammatory disease should undergo echocardiography, due to the possibility of myocardial dysfunction and damage to the coronary arteries observed both in neonates with MIS-N and in neonates/infants with MIS-C. Moreover, we also summarize how they were treated and provide a therapeutic algorithm to suggest best management of these fragile infants.     

Impact of direct acting antivirals (DAAs) on cardiovascular events in HCV cohort with pre-diabetes

Background and aimsBeyond type 2 diabetes, even a condition of prediabetes is associated with an increased cardiovascular (CV) risk, and HCV infection coexistence represents an exacerbating factor. CV prognosis improvement in prediabetes represents a challenge, due to the increasing prevalence of this metabolic condition worldwide. Hence, we aimed to prospectively assess how direct acting antivirals (DAAs) could affect major cardiovascular events (MACE) in a prediabetic HCV positive cohort.Methods and resultsIn this prospective multicenter study, we enrolled HCV patients with overt prediabetes. We compared a subgroup of patients treated with DAAs with untreated prediabetic controls. We recorded all CV events occurred during an overall median follow-up of 24 months (IQR 19–34). 770 HCV positive prediabetic patients were enrolled, 398 untreated controls and 372 DAAs treated patients. Overall, the CV events annual incidence was much higher among prediabetic treated patients (1.77 vs. 0.62, p < 0.001), and HCV clearance demonstrated to significantly reduce CV events (RR: 0.411, 95%CI 0.148–1.143; p < 0.001), with an estimated NNT for one additional patient to benefit of 52.1. Moreover, an independent association between a lower rate of CV events and HCV clearance after DAAs was observed (OR 4.67; 95%CI 0.44–53.95; p = 0.016).ConclusionsHCV eradication by DAAs allows a significant reduction of MACEs in the prediabetic population, and therefore represents a primary objective, regardless of the severity of liver disease and CV risk factors.