Therapeutic Education and Physical Activity to Support Self-management of Cancer-related Fatigue in Hematologic Cancer Patients: Protocol of a Feasibility Randomized Controlled Trial

Introduction: Hematologic malignancies account for nearly 8% of new cancer diagnosis in Italy. Cancer-related fatigue (CRF) is one of the most distressing symptoms reported by patients with cancer. As CRF has a multifactorial etiology, physical activity and therapeutic education may be beneficial for managing CRF, both during and after cancer treatment. However, there is a lack of evidence specific to hematologic malignancies. This paper describes the protocol of a feasibility study on Therapeutic Education and Physical Activity (TEPA) intervention to support self-management of CRF in patients with hematologic malignancies. Methods: TEPA was addressed to newly diagnosed adult individuals with hematologic malignancy able to take part in a rehabilitation programme at the AUSL-IRCCS of Reggio Emilia. The protocol was developed in 2 phases. Phase I was an observational cohort study involving a convenience sample of 10 participants with the aim to evaluate the feasibility of the assessment schedule and to register longitudinal clinical data regarding CRF (FACIT-F), psychologic distress (NCCN Distress Thermometer), QoL (EORTC QLQ-C30), physical performance (TUG and 6MWT) and habitual level of physical activity during first months after diagnosis. Phase II (underway) is a feasibility randomized controlled trial (TEPA) involving a convenience sample of 40 participants and comparing 2 parallel active interventions (Therapeutic Education versus Therapeutic Education and Physical Activity) on top of usual care. The primary aim is to estimate the feasibility of TEPA, measured by the adherence rate to the intervention. Secondary aims are: to estimate the effect size of TEPA in terms of changes in CRF, psychological distress, QoL, physical performance and habitual level of physical activity (measured as in Phase I); to collect patient satisfaction, perception of usefulness of the TEPA intervention and data on long-term adherence to an active lifestyle. Data are collected in both phases at the time of diagnosis and then at 1-, 3- (completion of intervention) and 7-month follow-up. Discussion: Data on feasibility and effect size of TEPA will be analyzed upon completion of Phase II, allowing us to design a large, adequately powered RCT to verify the effectiveness of this intervention on CRF management in patients with hematologic cancer. Trial registration: clinicaltrials.gov; Trial registration number: NCT0340307

Therapeutic education and physical activity are feasible and safe in hematologic cancer patients referred to chemotherapy: results of a randomized controlled trial

Purpose: Although over 60% of patients with hematologic cancer report distressing fatigue, they often do not receive recommendations on fatigue management strategies. The aim of this pilot study was to estimate the feasibility of therapeutic education and physical activity (TEPA) by measuring the patients’ adherence to this multidimensional intervention. The secondary aim was to estimate the impact of TEPA on clinical outcomes. Methods: Patients with hematologic cancer participated in this single-center, open-label, randomized controlled trial. The control group (CG) received two educational group sessions on fatigue and physical activity. The experimental group (EG) received the two educational sessions plus six weekly individual sessions aimed at implementing a personalized physical exercise program. Follow-ups were at 1, 3, and 7 months. Results: Forty-six patients referred to chemotherapy were included, corresponding to 54% of recruitment rate. Adherence reached 90% in the EG and 68% in the CG. Most patients (65% in EG and 64% in CG) attended a minimum of 80% of the planned sessions. Overall retention rate was 87% (85% in EG and 91% in CG). No adverse events were registered. No between-group differences were detected in fatigue (FACIT-F), psychological distress (NCCN Distress Thermometer), QoL (EORTC QLQ-C30), or functional exercise capacity (TUG test and 6MWT). Adherence to an active lifestyle, measured by a semi-structured interview, increased from 56.5 to 84% in the EG at 7 months (p = 0.02), whereas it decreased slightly in the CG (from 47.8 to 42.9%). Conclusion: Multidimensional rehabilitation interventions are feasible and safe in this population, and larger trials should focus on the efficacy of such approaches on clinically relevant outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT03403075

Self-management in stroke survivors: Development and implementation of the look after yourself (lay) intervention

Objective: Self-management is recommended in stroke rehabilitation. This report aims to describe timing, contents, and setting of delivery of a patient-centered, self-management program for stroke survivors in their early hospital rehabilitation phase: the Look After Yourself (LAY) in-tervention. Methods: After extensive literature search, the LAY intervention was developed by in-tegrating the Chronic Disease Self-Management Program, based on the self-efficacy construct of social cognitive theory, with evidence-based key elements and input from stroke survivors. Results: the LAY intervention aims to implement self-management skills in stroke survivors, enabling them to be active in goal setting and problem solving using action plans and to facilitate the critical transition from hospital to community. It includes both group sessions to facilitate sharing of experi-ences, social comparison, vicarious learning, and increase motivation and one-to-one sessions fo-cused on setting feasible action plans and on teaching personalized strategies to prevent falls. Stand-ardization is ensured by manuals for facilitators and patients. Conclusion: The LAY intervention is the first Italian program to support early self-management in stroke rehabilitation; it has been ex-perimented and its efficacy proven in improving self-efficacy, mental health, and activities of daily living, and detailed results have been published. The LAY intervention is described according to the TIDieR checklist

An eleven-year history of Vanishing White Matter Disease in an adult patient with no cognitive decline and EIF2B5 mutations. A case report

Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy. The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions. We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5

Diagnosis and treatment of idiopathic premature ventricular contractions: A stepwise approach based on the site of origin

Premature ventricular contractions in the absence of structural heart disease are among the most common arrhythmias in clinical practice, with well-defined sites of origin in the right and left ventricle. In this review, starting from the electrocardiographic localization of premature ventricular contractions, we investigated the mechanisms, prevalence in the general population, diagnostic work-up, prognosis and treatment of premature ventricular contractions, according to current scientific evidence

Usefulness of the maggic score in predicting the competing risk of non-sudden death in heart failure patients receiving an implantable cardioverter-defibrillator: A sub-analysis of the observo-icd registry

The role of prognostic risk scores in predicting the competing risk of non-sudden death in heart failure patients with reduced ejection fraction (HFrEF) receiving an implantable cardioverterdefibrillator (ICD) is unclear. To this goal, we evaluated the accuracy and usefulness of the MetaAnalysis Global Group in Chronic Heart Failure (MAGGIC) score. The present analysis included 1089 HFrEF ICD recipients enrolled in the OBSERVO-ICD registry (NCT02735811). During a median follow-up of 36 months (1st\u20133rd IQR 25\u201348 months), 193 patients (17.7%) experienced at least one appropriate ICD therapy, and 133 patients died (12.2%) without experiencing any ICD therapy. The frequency of patients receiving ICD therapies was stable around 17\u201319% across increasing tertiles of 3-year MAGGIC probability of death, whereas non-sudden mortality increased (6.4% to 9.8% to 20.8%, p < 0.0001). Accuracy of MAGGIC score was 0.60 (95% CI, 0.56\u20130.64) for the overall outcome, 0.53 (95% CI, 0.49\u20130.57) for ICD therapies and 0.65 (95% CI, 0.60\u20130.70) for non-sudden death. In patients with higher 3-year MAGGIC probability of death, the increase in the competing risk of non-sudden death during follow-up was greater than that of receiving an appropriate ICD therapy. Results were unaffected when analysis was limited to ICD shocks only. The MAGGIC risk score proved accurate and useful in predicting the competing risk of non-sudden death in HFrEF ICD recipients. Estimation of mortality risk should be taken into greater consideration at the time of ICD implantation

The practice of deep sedation in electrophysiology and cardiac pacing laboratories: Results of an italian survey promoted by the aiac (italian association of arrhythmology and cardiac pacing)

The aim of this survey, which was open to all Italian cardiologists involved in arrhythmia, was to assess common practice regarding sedation and analgesia in interventional electrophysiology procedures in Italy. The survey consisted of 28 questions regarding the approach to sedation used for elective direct-current cardioversion (DCC), subcutaneous implantable cardioverter-defibrillator (S-ICD) implantation, atrial fibrillation (AF) ablation, ventricular tachycardia (VT) ablation, and transvenous lead extraction procedures. A total of 105 cardiologists from 92 Italian centres took part in the survey. The rate of centres where DCC, S-ICD implantation, AF ablation, VT ablation and lead extraction procedures were performed without anaesthesiologic assistance was 60.9%, 23.6%, 51.2%, 37.3%, and 66.7%, respectively. When these procedures were performed without anaesthesiologic assistance, the drugs (in addition to local anaesthetics) commonly administered were benzodiazepines (from 64.3% to 79.6%), opioids (from 74.4% to 88.1%), and general anaesthetics (from 7.1% to 30.4%). Twenty-three (21.9%) of the 105 cardiologists declared that they routinely administered propofol, without the supervision of an anaesthesiologist, in at least one of the above-mentioned procedures. In current Italian clinical practice, there is a lack of uniformity in the sedation/analgesia approach used in interventional electrophysiology procedures

Loss of Wwox Perturbs Neuronal Migration and Impairs Early Cortical Development

Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species

Genotype–phenotype correlation in contactin-associated protein-like 2 (CNTNAP-2) developmental disorder

Contactin-associated protein-like 2 (CNTNAP2) gene encodes for CASPR2, a presynaptic type 1 transmembrane protein, involved in cell–cell adhesion and synaptic interactions. Biallelic CNTNAP2 loss has been associated with “Pitt-Hopkins-like syndrome-1” (MIM#610042), while the pathogenic role of heterozygous variants remains controversial. We report 22 novel patients harboring mono- (n = 2) and bi-allelic (n = 20) CNTNAP2 variants and carried out a literature review to characterize the genotype–phenotype correlation. Patients (M:F 14:8) were aged between 3 and 19 years and affected by global developmental delay (GDD) (n = 21), moderate to profound intellectual disability (n = 17) and epilepsy (n = 21). Seizures mainly started in the first two years of life (median 22.5 months). Antiseizure medications were successful in controlling the seizures in about two-thirds of the patients. Autism spectrum disorder (ASD) and/or other neuropsychiatric comorbidities were present in nine patients (40.9%). Nonspecific midline brain anomalies were noted in most patients while focal signal abnormalities in the temporal lobes were noted in three subjects. Genotype–phenotype correlation was performed by also including 50 previously published patients (15 mono- and 35 bi-allelic variants). Overall, GDD (p < 0.0001), epilepsy (p < 0.0001), hyporeflexia (p = 0.012), ASD (p = 0.009), language impairment (p = 0.020) and severe cognitive impairment (p = 0.031) were significantly associated with the presence of biallelic versus monoallelic variants. We have defined the main features associated with biallelic CNTNAP2 variants, as severe cognitive impairment, epilepsy and behavioral abnormalities. We propose CASPR2-deficiency neurodevelopmental disorder as an exclusively recessive disease while the contribution of heterozygous variants is less likely to follow an autosomal dominant inheritance pattern

Elucidating the clinical and molecular spectrum of SMARCC2-associated NDD in a cohort of 65 affected individuals

Purpose: Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort. Methods: Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays. Results: Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD. Conclusion: This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated