Amedeo Avogadro University of Eastern Piedmont
Recent publications
Appropriate nomenclature for all pharmaceutical substances is important for clinical development, licensing, prescribing, pharmacovigilance, and identification of counterfeits. Nonproprietary names that are unique and globally recognized for all pharmaceutical substances are assigned by the International Nonproprietary Names (INN) Programme of the World Health Organization (WHO). In 1991, the INN Programme implemented the first nomenclature scheme for monoclonal antibodies. To accompany biotechnological development, this nomenclature scheme has evolved over the years; however, since the scheme was introduced, all pharmacological substances that contained an immunoglobulin variable domain were coined with the stem -mab. To date, there are 879 INN with the stem -mab. Owing to this high number of names ending in -mab, devising new and distinguishable INN has become a challenge. The WHO INN Expert Group therefore decided to revise the system to ease this situation. The revised system was approved and adopted by the WHO at the 73rd INN Consultation held in October 2021, and the radical decision was made to discontinue the use of the well-known stem -mab in naming new antibody-based drugs and going forward, to replace it with four new stems: -tug, -bart, -mig, and -ment.
Background Idiopathic intracranial hypertension is an infrequent condition of childhood, and is extremely rare in infants, with only 26 cases described. The etiology is still unknown. Typical clinical manifestations change with age, and symptoms are atypical in infants, thus the diagnosis could be late. This is based on increased opening pressure at lumbar puncture, papilloedema and normal cerebral MRI. The measurement of cerebrospinal fluid opening pressure in infants is an issue because many factors may affect it, and data about normal values are scanty. The mainstay of treatment is acetazolamide, which allows to relieve symptoms and to avoid permanent visual loss if promptly administered. Case presentation We report the case of an 8-month-old infant admitted because of vomit, loss of appetite and irritability; later, also bulging anterior fontanel was observed. Cerebral MRI and cerebrospinal fluid analysis resulted negative and after two lumbar punctures he experienced initial symptom relief. Once the diagnosis of idiopathic intracranial hypertension was made, he received oral acetazolamide, and corticosteroids, with progressive symptom resolution. Conclusions Infantile idiopathic intracranial hypertension is extremely rare, and not well described yet. Bulging anterior fontanel in otherwise healthy infants with normal neuroimaging should be always considered suggestive, but can be a late sign, while irritability and anorexia, especially if associated with vomiting, may represent an early sign. In such cases, lumbar puncture should be always done, hopefully with cerebrospinal fluid opening pressure measurement, which is among coded diagnostic criteria, but whose threshold is controversial in infants. Early diagnosis, timely treatment and strict follow-up help to prevent vision loss or death of affected infants.
In our third-level Neonatal Unit in Northern Italy, we recorded a high rate of neonatal hyperbilirubinemia requiring phototherapy in March-November 2020, during the first phase of COVID-19 pandemic, compared to the previous year (198/1348, 14.2%, vs 141/1432, 9.8%, p = 0.0004). Supposing it could be the result of neonatal polycythemia, we evaluated capillary hematocrit (Hct) and the rate of hyperbilirubinemia in all newborns ≥36 weeks gestational age born in December 2020. Out of 73 neonates, 37 had Hct ≥65% (50.7%). However, as capillary blood samples may overestimate Hct by 5-15%, even downsizing all values by 15%, Hct was still ≥65% in 9/73 neonates (12.3%), much higher than 0.4-5% prevalence of polycythemia reported in healthy newborns. All those newborns were singleton and healthy, with no clinical signs of hyperviscosity and no underlying factors predisposing to polycythemia. Out of 73 newborns, 13 (17.8%) developed hyperbilirubinemia requiring phototherapy. Their mean Hct value was 66.3 ± 8.2%. Since hyperbilirubinemia is common in the offspring of women with SARS-CoV-2 infection and we recorded increased rates of neonatal hyperbilirubinemia in the first phase of COVID-19 pandemic, it could be hypothesized that even asymptomatic Sars-CoV2 infection during pregnancy might cause placental vascular malperfusion, eliciting polycythemia in the fetus as a compensatory response, that could be the link between COVID-19 in the mothers and hyperbilirubinemia in the newborns.
Introduction Fluid challenges are widely adopted in critically ill patients to reverse haemodynamic instability. We reviewed the literature to appraise fluid challenge characteristics in intensive care unit (ICU) patients receiving haemodynamic monitoring and considered two decades: 2000–2010 and 2011–2021. Methods We assessed research studies and collected data regarding study setting, patient population, fluid challenge characteristics, and monitoring. MEDLINE, Embase, and Cochrane search engines were used. A fluid challenge was defined as an infusion of a definite quantity of fluid (expressed as a volume in mL or ml/kg) in a fixed time (expressed in minutes), whose outcome was defined as a change in predefined haemodynamic variables above a predetermined threshold. Results We included 124 studies, 32 (25.8%) published in 2000–2010 and 92 (74.2%) in 2011–2021, overall enrolling 6,086 patients, who presented sepsis/septic shock in 50.6% of cases. The fluid challenge usually consisted of 500 mL (76.6%) of crystalloids (56.6%) infused with a rate of 25 mL/min. Fluid responsiveness was usually defined by a cardiac output/index (CO/CI) increase ≥ 15% (70.9%). The infusion time was quicker (15 min vs 30 min), and crystalloids were more frequent in the 2011–2021 compared to the 2000–2010 period. Conclusions In the literature, fluid challenges are usually performed by infusing 500 mL of crystalloids bolus in less than 20 min. A positive fluid challenge response, reported in 52% of ICU patients, is generally defined by a CO/CI increase ≥ 15%. Compared to the 2000–2010 decade, in 2011–2021 the infusion time of the fluid challenge was shorter, and crystalloids were more frequently used.
Background: The prognostic value of extravascular lung water (EVLW) measured by transpulmonary thermodilution (TPTD) in critically ill patients is debated. We performed a systematic review and meta-analysis of studies assessing the effects of TPTD-estimated EVLW on mortality in critically ill patients. Methods: Cohort studies published in English from Embase, MEDLINE, and the Cochrane Database of Systematic Reviews from 1960 to 1 June 2021 were systematically searched. From eligible studies, the values of the odds ratio (OR) of EVLW as a risk factor for mortality, and the value of EVLW in survivors and non-survivors were extracted. Pooled OR were calculated from available studies. Mean differences and standard deviation of the EVLW between survivors and non-survivors were calculated. A random effects model was computed on the weighted mean differences across the two groups to estimate the pooled size effect. Subgroup analyses were performed to explore the possible sources of heterogeneity. Results: Of the 18 studies included (1296 patients), OR could be extracted from 11 studies including 905 patients (464 survivors vs. 441 non-survivors), and 17 studies reported EVLW values of survivors and non-survivors, including 1246 patients (680 survivors vs. 566 non-survivors). The pooled OR of EVLW for mortality from eleven studies was 1.69 (95% confidence interval (CI) [1.22; 2.34], p < 0.0015). EVLW was significantly lower in survivors than non-survivors, with a mean difference of -4.97 mL/kg (95% CI [-6.54; -3.41], p < 0.001). The results regarding OR and mean differences were consistent in subgroup analyses. Conclusions: The value of EVLW measured by TPTD is associated with mortality in critically ill patients and is significantly higher in non-survivors than in survivors. This finding may also be interpreted as an indirect confirmation of the reliability of TPTD for estimating EVLW at the bedside. Nevertheless, our results should be considered cautiously due to the high risk of bias of many studies included in the meta-analysis and the low rating of certainty of evidence. Trial registration the study protocol was prospectively registered on PROSPERO: CRD42019126985.
Organoids are 3D structures grown from pluripotent stem cells derived from human tissue and serve as in vitro miniature models of human organs. Organoids are expected to revolutionize biomedical research and clinical care. However, organoids are not seen as morally neutral. For instance, tissue donors may perceive enduring personal connections with their organoids, setting higher bars for informed consent and patient participation. Also, several organoid sub-types, e.g., brain organoids and human–animal chimeric organoids, have raised controversy. This systematic review provides an overview of ethical discussions as conducted in the scientific literature on organoids. The review covers both research and clinical applications of organoid technology and discusses the topics informed consent, commercialization, personalized medicine, transplantation, brain organoids, chimeras, and gastruloids. It shows that further ethical research is needed especially on organoid transplantation, to help ensure the responsible development and clinical implementation of this technology in this field.
Background IMbrave150 has established the superiority of atezolizumab plus bevacizumab over sorafenib in patients with unresectable hepatocellular carcinoma (HCC). Methods We generated a prospectively maintained database including patients treated with atezolizumab plus bevacizumab for unresectable HCC across Europe, Asia and USA. Clinico-pathologic characteristics were assessed for their prognostic influence on overall survival (OS) and progression-free survival (PFS) in univariable and multivariate analyses. Overall response rate by RECIST v1.1 and treatment-related adverse events (TRAEs) per CTCAE v.5.0 were reported. Results Out of 433 patients, 296 Child-Pugh A and ECOG performance status01 patients received atezolizumab plus bevacizumab in first line and were included. Patients were mostly male (82.7%), cirrhotic (75%) with history of viral hepatitis (65.9%). Overall, 68.9% had Barcelona Clinic Liver Cancer C-stage HCC with portal vein tumour thrombosis (PVTT, 35%) and extrahepatic spread (EHS, 51.7%). After a median follow-up of 10.0 months (95% confidence interval (CI): 9.4–10.4), median OS and PFS were 15.7 (95% CI: 14.5-NE) and 6.9 months (95% CI: 6.1–8.3), respectively. In the response-evaluable patients (n = 273), overall response rate was 30.8%. Overall, 221 patients (74.6%) developed TRAEs, with 70 (23.6%) reporting grade 3 or higher TRAEs; 25 (8.4%) patients had bleeding events. OS was independently associated with baseline Albumin-bilirubin (ALBI) grade and PVTT. Shorter PFS was associated with AFP≥ 400 ng/ml, worse ALBI and presence of EHS. Conclusion This global observational study confirms the reproducible safety and efficacy of atezolizumab plus bevacizumab in routine clinical practice. Within Child-Pugh-A criteria, the presence of PVTT and higher ALBI grade identify patients with poorer survival.
Glioblastoma (GBM) is the most common and mortal primary brain tumor in human. After standard therapies, that include surgical resection followed by radiotherapy and chemotherapy, it is difficult to completely remove the tumor and the development of relapses and resistance is almost inevitable. The chemotherapy now available also show important side effects, to overcame those limitation, new platinum-based drugs are being synthetized, Pt(IV)Ac-POA, (OC-6–44)-acetate-diamine-chloride(2-(2-propynyl)octanoato)platinum(IV), a prodrug having an Histone-3-DeAcetylase-Inhibitor as axial ligands, is one of them. Moreover, new compounds of plant origin are increasingly seen as potential sources of benefits in oncological treatments. The aim of the study is to investigate the possible contribution of micotherapy in the fight against GBM, its role in the metabolism of reactive oxygen species (ROS) and its synergic effect with a new platinum-based compound, Pt(IV)Ac-POA, on human glioblastoma U251 cells. Through cytofluorimetric and immunofluorescence analysis, the ability of the micotherapy in study to regulate the cell cycle was assessed, and its importance in controlling the cellular redox state was also revealed, opening to the possibility of a new therapy in which micotherapy can support the activity of new chemotherapy while reducing its side effects controlling inflammatory conditions in the microenvironment. Additionally, the combined therapy appeared able to induce regulated form of necrosis, such as ferroptosis, and to hinder the establishment of resistance mechanisms.
Background Dual programmed cell death-1 and vascular endothelial growth factor pathway inhibition is the novel standard of care for patients with unresectable hepatocellular carcinoma. Direct comparisons between first-line treatments are lacking. Method We conducted a literature search in MEDLINE (, the Cochrane library ( and Embase ( between January 2007 and February 2022. We included phase III randomised controlled trials that tested immune-checkpoint inhibitors or tyrosine kinase inhibitors, including sorafenib, lenvatinib and donafenib, and evaluated as primary end-point overall survival (OS) or progression-free survival (PFS). Studies testing loco-regional therapies were excluded. The primary end-point was to compare the efficacy of first-line options in terms of OS and PFS. We extracted Hazard ratios (HR) and 95% confidence intervals (95% CI) for OS and PFS and performed a frequentist network meta-analysis with fixed effect multivariable meta-regression models. The research protocol was registered in PROSPERO, an international prospective register of systematic reviews (registration code CRD42022312489). Findings Literature review yielded 13709 results, after duplicates removal and exclusion of not relevant studies, 70 papers were available for screening. After full-text review, 9 studies were eligible for analysis. Atezolizumab plus bevacizumab reduced the risk of death compared to placebo (HR 0·40; 95% CI 0·28-0·57), sorafenib (HR 0·58; 95% CI 0·42-0·80), lenvatinib (HR 0·63; 95% CI 0·44-0·89), atezolizumab plus cabozantinib (HR 0·64; 95% CI 0·43-0·97), nivolumab (HR 0·68; 95% CI 0·48-0·98) and donafenib (HR 0·69; 95% CI 0·48-0·99). Atezolizumab plus bevacizumab was not statistically superior to durvalumab plus tremelimumab (HR 0·74; 95% CI 0·52-1·06) and sintilimab plus IBI305 (HR 1·02; 95% CI 0·67-1·55) in reducing the risk of death. Efficacy was associated with a higher risk of grade 3 adverse events.
Previous studies have shown, although not consistently, that first generation antipsychotics (FGA) are associated with a prevalence of extrapyramidal symptoms (EPS) higher than second generation antipsychotics (SGA). We assessed the prevalence and the incidence of antipsychotic-induced EPS in a large sample of community-dwelling Italian persons with schizophrenia before and after a 4-year naturalistic treatment, to shed light on their natural evolution and to identify possible predicting factors. EPS and psychopathology were assessed in 571 subjects with schizophrenia before (baseline) and after 4-year follow-up. Patients underwent treatment with SGA and/or FGA according to the referring clinicians' judgment. Relationships between EPS and psychopathology were assessed by network analysis, while a linear multiple regression investigated factors correlated to the presence of EPS at follow-up. EPS were significantly more frequent in the FGA- than in the SGA-treated group, and patients with EPS presented a more severe psychopathology. Parkinsonism was directly and positively connected with poor emotional expression at baseline and with poor emotional expression and disorganization at follow-up. Over the 4-year follow-up, emergent EPS were more frequent in FGA-treated patients, while relieved EPS occurred more frequently in SGA-treated persons. The presence of EPS at follow-up was significantly associated with EPS at baseline, illness duration, antipsychotic generation and the daily dose of antipsychotic medications. After a 4-year naturalistic treatment, EPS disappeared more frequently in SGA-treated patients, while they emerged more frequently in FGA-treated individuals. Therefore, although SGA did not eliminate the risk of EPS, these drugs seem to be associated to a more favorable EPS natural evolution.
Context: Classic Hodgkin lymphoma (cHL) is a phenotypically heterogeneous disease with enigmatic biology and pathogenesis. By leveraging ctDNA analysis, here we identify molecular groups of cHL with phenotype- and outcome-associated signatures. Objective: Identification and biological characterization of novel cHL subgroups. Methods: We sequenced 202 cHL patients targeting ~344 kb of genomic space. The length of ctDNA mapped reads was extracted, and unsupervised clustering was performed. PET/CT scan and 71 plasma cytokines were obtained for clinical correlation. Single-cell RNA sequencing was performed for 8 patients. Results: To identify molecular subgroups within cHL, we focused on the fragmentation profile of cfDNA, a non-genetic way of detecting tumor-derived DNA in the cfDNA samples. We identified two distinct clusters, one with a fragmentation profile close to healthy (N=135), named mono-nucleosomal, and a submono-nucleosomal cluster characterized by a global shift toward shorter fragments, whose length was less than the typical wrap around the nucleosome (N=67). We explored whether cHL subtypes defined by the cfDNA fragmentation profile are clinically and biologically validated. Patients with the submono-nucleosomal fragmentome showed more frequent advanced-stage B symptoms and elevated ESR at the clinical level, higher tumor volume (TMTV and TLG) at the radiomic level, and lower PFS in terms of outcome. Tumor mutations and immune microenvironment are pathophysiologic features of cHL. The submono-nucleosomal cluster carried a higher tumor mutation burden because of heavier aberrant somatic hypermutation (ASHM). The submono-nucleosomal cluster had an immune-suppressive microenvironment enriched of T-regs and higher plasmatic levels of T-regs chemoattractants and inducers of PD1 expression (IL6, CCL2, CCL4). Conversely, mono-nucleosomal cHL had a microenvironment enriched of TFH cells and cytotoxic CD8 TEM cells and associated with cytokines and chemokines that are known for being attractants and activators of effector T cells (IL-1a, CCL21, CXCL12, IL-17A). Conclusions: Our observations indicate that cHL subgroups belonging to the submono-nucleosomal cluster have a more aggressive disease, a higher mutation load and more neoantigens likely due to denser ASHM, and an immune-suppressive microenvironment. Instead, cHL subgroups belonging to the mono-nucleosomal cluster have a less aggressive disease, a lower mutation load and lower neoantigens likely due to lighter ASHM, and a tumor-suppressive microenvironment.
Context: Pivekimab sunirine (PVEK, IMGN632) is a first-in-class ADC comprising a CD123 high-affinity antibody, a cleavable linker, and an IGN (indolinobenzodiazepine pseudodimer) payload. PVEK with azacitidine (AZA) and venetoclax (VEN) is a novel triplet that has demonstrated anti-leukemia activity in relapsed/refractory AML patients. Objective: Evaluate the anti-leukemia activity in genetic subgroups of AML and safety of the triplet. Intervention: Patients with relapsed/refractory AML received PVEK+AZA+VEN in a three-drug escalation over a 28-day cycle: PVEK 0.015 or 0.045 mg/kg day 7, AZA 50 or 75 mg/m2 days 1-7, and VEN 400 mg for 8, 14, or 21 days. Results: Twenty-nine patients (median age 67 y, ELN adverse 62%, prior VEN 48%) were in higher-intensity cohorts (PVEK 0.045 mg/kg and/or VEN for 14 or 21 days). The overall response rate (ORR) was 59% (4 CR, 6 CRh, 1 CRp, 6 MLFS) and the composite complete remission rate (CCR, CR+CRh+CRp+CRi) was 38%. Higher rates are seen in patients with FLT3-ITD (n=9, ORR 89%, CCR 78%), IDH2 (n=4, ORR 75%, CCR 75%), and WT1 (n=7, ORR 57%, CCR 43%) mutations. Lower rates are seen in patients with monosomy 7/abn7q (n=6, ORR 17%, CCR 17%), TP53 (n=4, ORR 25%, CCR 25%), and ASXL1 (n=6, ORR 67%, CCR 17%) deletions or mutations. The safety profile for the PVEK triplet is similar to AZA+VEN. No VOD, TLS, or CRS was reported. IRRs were reported in 33% (n=17, one grade 4) of patients given 1 dose of dexamethasone (8 mg) as premedication (n=51); these IRRs were most frequently tachycardia and chills, with no anaphylactic reactions reported. Following the data cut-off, there was a second grade 4 IRR, and the prophylactic regimen was increased with two additional doses of dexamethasone on the day prior to the PVEK dose. The IRR rate has dropped to 8% (3 of 38), with no grade 3+; all were grades 1-2 that resolved with limited intervention (P<0.01). Conclusions: The PVEK triplet with AZA+VEN demonstrates anti-leukemic activity across multiple high-risk genetic subsets of relapsed/refractory AML. Prophylactic steroids added on day -1 have significantly reduced IRRs. Expansion cohorts are now enrolling for untreated and relapsed AML patients (NCT04086264).
Introduction Bladder cancer assessment with non-invasive gene expression signatures facilitates the detection of patients at risk and surveillance of their status, bypassing the discomforts given by cystoscopy. To achieve accurate cancer estimation, analysis pipelines for gene expression data (GED) may integrate a sequence of several machine learning and bio-statistical techniques to model complex characteristics of pathological patterns. Methods Numerical experiments tested the combination of GED preprocessing by discretization with tree ensemble embeddings and nonlinear dimensionality reductions to categorize oncological patients comprehensively. Modeling aimed to identify tumor stage and distinguish survival outcomes in two situations: complete and partial data embedding. This latter experimental condition simulates the addition of new patients to an existing model for rapid monitoring of disease progression. Machine learning procedures were employed to identify the most relevant genes involved in patient prognosis and test the performance of preprocessed GED compared to untransformed data in predicting patient conditions. Results Data embedding paired with dimensionality reduction produced prognostic maps with well-defined clusters of patients, suitable for medical decision support. A second experiment simulated the addition of new patients to an existing model (partial data embedding): Uniform Manifold Approximation and Projection (UMAP) methodology with uniform data discretization led to better outcomes than other analyzed pipelines. Further exploration of parameter space for UMAP and t-distributed stochastic neighbor embedding (t-SNE) underlined the importance of tuning a higher number of parameters for UMAP rather than t-SNE. Moreover, two different machine learning experiments identified a group of genes valuable for partitioning patients (gene relevance analysis) and showed the higher precision obtained by preprocessed data in predicting tumor outcomes for cancer stage and survival rate (six classes prediction). Conclusions The present investigation proposed new analysis pipelines for disease outcome modeling from bladder cancer-related biomarkers. Complete and partial data embedding experiments suggested that pipelines employing UMAP had a more accurate predictive ability, supporting the recent literature trends on this methodology. However, it was also found that several UMAP parameters influence experimental results, therefore deriving a recommendation for researchers to pay attention to this aspect of the UMAP technique. Machine learning procedures further demonstrated the effectiveness of the proposed preprocessing in predicting patients’ conditions and determined a sub-group of biomarkers significant for forecasting bladder cancer prognosis.
The reaction between the binuclear cobalt complex, [Co2(Et2dtc)5]⁺, and Me2pipdt and Ph2pipdt ligands has provided almost quantitatively the cobalt tris-chelate heteroleptic complexes [Co(Et2dtc)2(R2pipdt)]BF4 (1 and 2). The molecular structure of 2 shows the metal in a distorted octahedral geometry. The nature of the bonding in these complexes has been elucidated with the support of DFT TD-DFT calculations. Both chelating S,S donors work as weak-field ligands. The comparison of the chemical reactivity for the homoleptic dithiocarbamate complex [Co(Et2dtc)3] and the heteroleptic [Co(Et2dtc)2(Ph2pipdt)]⁺ derivative shows that the global softness σ is significantly higher in [Co(Et2dtc)2(Ph2pipdt)]⁺ than in the homoleptic dithiocarbamate complex, due to a reduction of nephelauxetic effect induced by the dithioxamide ligand. The kinetics for the reaction between the reagents in CH2Cl2 has been followed spectrophotometrically as a function of temperature in pseudo-first order conditions with respect to R2pipdt ligands. Kinetic results further support a reaction mechanism involving a one-end reversible dissociation of the [Co2(Et2dtc)5]⁺ dimer forming a reactive cobalt(III)dithiocarbamato center susceptible to attack by nucleophiles. The effectiveness and versatility of the above reaction is an easy and clean method to provide heteroleptic-dithiocarbamates with a variety of suitable ligands of interest for applicative purposes.
Background: Few studies have investigated the long-term effects of COVID-19 on cancer patients. Materials & methods: The authors conducted a telephone survey on the long-term symptoms of cancer patients from Guy's Cancer Centre. They compared patients whose symptoms occurred/got worse over 4 weeks after COVID-19 diagnosis (classified as long COVID) with patients who did not develop symptoms or whose symptoms occurred/got worse in the first 4 weeks after diagnosis. Results: The authors analyzed responses from 80 patients with a previous COVID-19 diagnosis; 51.3% (n = 41) developed long COVID. The most common symptoms were fatigue, breathlessness and cognitive impairment. Conclusion: Findings suggest that over half of the cancer population will experience long-term effects after their initial COVID-19 diagnosis. Further studies are required to validate the findings of this study.
Regenerative medicine (RM) is changing how we think and practice transplant medicine. In regenerative medicine, the aim is to develop and employ methods to regenerate, restore or replace damaged/diseased tissues or organs. Regenerative medicine investigates using tools such as novel technologies or techniques, extracellular vesicles, cell-based therapies, and tissue-engineered constructs to design effective patient-specific treatments. This review illustrates current advancements in regenerative medicine that may pertain to transplant medicine. We highlight progress made and various tools designed and employed specifically for each tissue or organ, such as the kidney, heart, liver, lung, vasculature, gastrointestinal tract, and pancreas. By combing both fields of transplant and regenerative medicine, we can harbor a successful collaboration that would be beneficial and efficacious for the repair and design of de novo engineered whole organs for transplantations.
Introduction: In recent years, growing attention is rising to virtual reality (VR) tools and exergaming in rehabilitation management of patients with Parkinson disease (PD). However, no strong evidence supports the effectiveness of these cutting-edge technologies on cognitive function and the integration of these promising tool in the rehabilitation framework of PD patients is still challenging. Therefore, the present systematic review of randomized controlled trials (RCTs) aimed at assessing the effects of VR and exergames/telerehabilitation in the cognitive rehabilitation management of patients with PD. Evidence acquisition: PubMed, Scopus and Web of Science databases were systematically searched up to February 14th, 2022, to identify RCTs assessing patients with PD undergoing cognitive rehabilitation including VR or exergames/telerehabilitation. The intervention was compared to conventional rehabilitation protocols. The primary outcome was cognitive function. The quality assessment was performed following the Version 2 of the Cochrane risk-of-bias tool for randomized trials (RoB 2). PROSPERO registration code: CRD42022319788. Evidence synthesis: Out of 1419 identified studies, 66 articles were assessed for eligibility, and, at the end of the screening process, 10 studies were included in the present systematic review. Five RCTs (50%) assessed the exergaming devices, reporting significant positive results on cognitive outcomes scales (Trail Making test scale, Digit Span backward, MoCA, and MyCQ score). The other 5 RTCs (50%) assessed VR approaches, reporting significant improvement in executive functions. The RoB 2 showed an overall high risk of bias for the 40% of studies included. Conclusions: Exergaming and VR might be considered promising rehabilitation interventions in the cognitive rehabilitation framework of PD patients. Further high-quality studies are needed to define the role of exergames and VR in a comprehensive rehabilitation approach aiming at improving the multilevel cognitive impairment characterizing patients with PD.
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Marco Milanesio
  • Dipartimento di Scienze e Innovazione Tecnologica DISIT
Katia Sparnacci
  • Dipartimento di Scienze e Innovazione Tecnologica DISIT
Silvio Aprile
  • Department of Pharmaceutical Sciences
Elena Grossini
  • Dipartimento di Medicina Traslazionale
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