In vitro CAR-T cell killing: validation of the potency assay.

For advanced therapy medicinal products, the development and validation of potency assays are required, in accordance with international guidelines, to characterise the product and obtain reliable and consistent data. Our purpose was to validate the killing assay for the evaluation of autologous anti-CD19 chimeric antigen receptor (CAR) T potency. We used CD4 + and CD8 + lymphocytes or anti-CD19 CAR-T cells as effector cells and REH (CD19 +) or MOLM-13 (CD19 -) cell lines as target cells. After co-culturing target and effector cells (1:1 ratio) for 24 h, samples were labelled with 7-AAD, anti-CD3 and anti-CD19 antibodies and the frequency of CD19 + dead cells was evaluated by flow cytometry. In order to verify the CAR-T specificity for the CD19 + target, the co-culture between CAR-T and REH or MOLM-13 at different effector-to-target ratios was scheduled. Moreover, not transduced CD4 + and CD8 + lymphocytes were tested in comparison with CAR-T from the same donor to demonstrate the assay specificity. Linearity and accuracy were evaluated, and established acceptance criteria were compiled for both parameters (r2 ≥ 0.97 for linearity and average relative error ≤ 10% for accuracy). Furthermore, the method was considered robust when performed between 23 and 25 h of co-culture, and the intra-assay, inter-assay and inter-day precision was obtained. Finally, in order to verify the inter-analyst precision, the test was executed by three different operators and the intra-class correlation coefficient was > 0.4 in both cases. In conclusion, we consider this CAR-T potency assay as validated and usable in all steps of product development and quality control.

Dendritic cell vaccines as cancer treatment: focus on 13 years of manufacturing and quality control experience in advanced therapy medicinal products.

BACKGROUND AIMS: Dendritic cells (DCs) are professional antigen-presenting cells of the mammalian immune system. Ex vivo differentiated DCs represent a unique Advanced Therapy Medicinal Product (ATMP), used in several clinical trials as personalized cancer immunotherapy. The therapy's reliability depends on its capacity to produce high-quality mature DCs (mDCs) in compliance with Good Manufacturing Practices. AIMS: From March 2010 to December 2023, 103 patients were enrolled in multiple clinical trials at the Immuno-Gene Therapy Factory at IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori". Six hundred forty-two doses were produced, and the manufacturing process was implemented to optimize production. Our study is a retrospective analysis focusing on the quality control results. METHODS: We retrospectively analyzed the results of the quality control tests carried out on each produced batch, evaluating viability, purity and phenotype of mDCs and their quality in terms of microbiological safety. The data obtained are given with median and interquartile range. RESULTS: The batches were found to be microbiologically safe in terms of sterility, mycoplasma, and endotoxins. An increase in DC maturation markers was found. The release criteria checks showed a high percentage of viability and purity was maintained during the production process. CONCLUSIONS: Our findings have confirmed that the measures implemented have ensured the safety of the products and have contributed to the establishing a robust "Pharmaceutical Quality System." This has enabled many safe mDCs to be produced for clinical trials.

Retrograde and semantic amnesia in a case of post-treatment Lyme disease syndrome: did something lead to a psychogenic memory loss? A single-case study.

OBJECTIVE: To describe a case of Post-Treatment Lyme Disease Syndrome (PTLDS) with an atypical cognitive profile. METHOD: A 41-year-old PTLDS patient underwent comprehensive neuropsychological testing and psychological assessment. RESULTS: The patient exhibited impaired intensive attention but preserved selective attention. Executive functions were normal. Short-term and anterograde memory were intact, while retrograde and semantic memory were significantly impaired. The patient also experienced identity loss, specific phobias, dissociative symptoms, and depressed mood. CONCLUSIONS: Severe episodic-autobiographical and retrograde semantic amnesia was consistent with some reports of dissociative amnesia. Loss of identity and phobias were also highly suggestive of a psychogenic mechanism underlying amnesia.

Lumbar braces and other assistive devices for treatment of chronic low back pain.

OBJECTIVES: This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To assess the benefits and harms of assistive technologies (i.e. non-rigid and rigid lumbar braces, belts, supports, and devices to assist mobility and gait) for improving pain and function (and consequently reducing disability) in adults with chronic low back pain.

Therapeutic exercises for idiopathic scoliosis in adolescents.

BACKGROUND: Adolescent idiopathic scoliosis (AIS) is a pathology that changes the three-dimensional shape of the spine and trunk. While AIS can progress during growth and cause cosmetic issues, it is usually asymptomatic. However, a final spinal curvature above the critical threshold of 30° increases the risk of health problems and curve progression in adulthood. The use of therapeutic exercises (TEs) to reduce the progression of AIS and delay or avoid other, more invasive treatments is still controversial. OBJECTIVES: To evaluate the effectiveness of TE, including generic therapeutic exercises (GTE) and physiotherapeutic scoliosis-specific exercises (PSSE) in treating AIS, compared to no treatment, other non-surgical treatments, or between treatments. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, four other databases, and two clinical trials registers to 17 November 2022. We also screened reference lists of articles. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing TE with no treatment, other non-surgical treatments (braces, electrical stimulation, manual therapy), and different types of exercises. In the previous version of the review, we also included observational studies. We did not include observational studies in this update since we found sufficient RCTs to address our study aims. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. Our major outcomes were progression of scoliosis (measured by Cobb angle, trunk rotation, progression, bracing, surgery), cosmetic issues (measured by surface measurements and perception), and quality of life (QoL). Our minor outcomes were back pain, mental health, and adverse effects. MAIN RESULTS: We included 13 RCTs (583 participants). The percentage of females ranged from 50% to 100%; mean age ranged from 12 to 15 years. Studies included participants with Cobb angles from low to severe. We judged 61% of the studies at low risk for random sequence generation and 46% at low risk for allocation concealment. None of the studies could blind participants and personnel. We judged the subjective outcomes at high risk of performance and detection bias, and the objective outcomes at high risk of detection bias in six studies and at low risk of bias in the other six studies. One study did not assess any objective outcomes. Comparing TE versus no treatment, we are very uncertain whether TE reduces the Cobb angle (mean difference (MD) -3.6°, 95% confidence interval (CI) -5.6 to -1.7; 2 studies, 52 participants). Low-certainty evidence indicates PSSE makes little or no difference in the angle of trunk rotation (ATR) (MD -0.8°, 95% CI -3.8 to 2.1; 1 study, 45 participants), may reduce the waist asymmetry slightly (MD -0.5 cm, 95% CI -0.8 to -0.3; 1 study, 45 participants), and may result in little to no difference in the score of cosmetic issues measured by the Spinal Appearance Questionnaire (SAQ) General (MD 0.7 points, 95% CI -0.1 to 1.4; 1 study, 16 participants). PSSE may result in little to no difference in self-image measured by the Scoliosis Research Society - 22 Patient Questionnaire (SRS-22) (MD 0.3 points, 95% CI -0.3 to 0.9; 1 study, 16 participants) and improve QoL slightly measured by SRS-22 Total score (MD 0.3 points, 95% CI 0.1 to 0.4; 2 studies, 61 participants). Only Cobb angle results were clinically meaningful. Comparing PSSE plus bracing versus bracing, low-certainty evidence indicates PSSE plus bracing may reduce Cobb angle (-2.2°, 95% CI -3.8 to -0.7; 2 studies, 84 participants). Comparing GTE plus other non-surgical interventions versus other non-surgical interventions, low-certainty evidence indicates GTE plus other non-surgical interventions may reduce Cobb angle (MD -8.0°, 95% CI -11.5 to -4.5; 1 study, 80 participants). We are uncertain whether PSSE plus other non-surgical interventions versus other non-surgical interventions reduces Cobb angle (MD -7.8°, 95% CI -12.5 to -3.1; 1 study, 18 participants) and ATR (MD -8.0°, 95% CI -12.7 to -3.3; 1 study, 18 participants). PSSE plus bracing versus bracing alone may make little to no difference in subjective measurement of cosmetic issues as measured by SAQ General (-0.2 points, 95% CI -0.9 to 0.5; 1 study, 34 participants), self-image score as measured by SRS-22 Self-Image (MD 0.1 points, 95% CI -0.3 to 0.5; 1 study, 34 participants), and QoL measured by SRS-22 Total score (MD 0.2 points, 95% CI -0.1 to 0.5; 1 study, 34 participants). None of these results were clinically meaningful. Comparing TE versus bracing, we are very uncertain whether PSSE allows progression of Cobb angle (MD 2.7°, 95% CI 0.3 to 5.0; 1 study, 60 participants), changes self-image measured by SRS-22 Self-Image (MD 0.1 points, 95% CI -1.0 to 1.1; 1 study, 60 participants), and QoL measured by SRS-22 Total score (MD 3.2 points, 95% CI 2.1 to 4.2; 1 study, 60 participants). None of these results were clinically meaningful. Comparing PSSE with GTE, we are uncertain whether PSSE makes little or no difference in Cobb angle (MD -3.0°, 95% CI -8.2 to 2.1; 4 studies, 192 participants; very low-certainty evidence). PSSE probably reduces ATR (clinically meaningful) (MD -3.0°, 95% CI -3.4 to -2.5; 2 studies, 138 participants). We are uncertain about the effect of PSSE on QoL measured by SRS-22 Total score (MD 0.26 points, 95% CI 0.11 to 0.62; 3 studies, 168 participants) and on self-image measured by SRS-22 Self-Image and Walter Reed Visual Assessment Scale (standardised mean difference (SMD) 0.77, 95% CI -0.61 to 2.14; 3 studies, 168 participants). Further, low-certainty evidence indicates that 38/100 people receiving GTE may progress more than 5° Cobb versus 7/100 receiving PSSE (risk ratio (RR) 0.19, 95% CI -0.67 to 0.52; 1 study, 110 participants). None of the included studies assessed adverse effects. AUTHORS' CONCLUSIONS: The evidence on the efficacy of TE is currently sparse due to heterogeneity, small sample size, and many different comparisons. We found only one study following participants to the end of growth showing the efficacy of PSSE over TE. This result was weakened by adding studies with short-term results and unclear preparation of treating physiotherapists. More RCTs are needed to strengthen the current evidence and study other highly clinically relevant outcomes such as QoL, psychological and cosmetic issues, and back pain.

Effectiveness of Rehabilitation Interventions on Adults With COVID-19 and Post-COVID-19 Condition. A Systematic Review With Meta-analysis.

OBJECTIVE: To evaluate the effectiveness of rehabilitation interventions for adults with COVID-19 and post COVID-19 condition (PCC) in all settings. DATA SOURCES: PubMed, EMBASE, CINAHL, Scopus, Web of Science, and Physiotherapy Evidence Database were searched from inception to December 31st, 2021. PROSPERO registration number: CRD42021258553. STUDY SELECTION: We included randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSI) according to the University of Alberta Evidence-based Practice Center. DATA EXTRACTION: One author extracted data using a predetermined Excel form. DATA SYNTHESIS: The meta-analysis indicates uncertain evidence about the effect of pulmonary rehabilitation and self-activities on exercise capacity (MD 65.06, 95% CI 42.87 to 87.25), respiratory function (forced expiratory volume in the first second [FEV1]: MD 0.16, 95% CI 0.05 to 0.28; FEV1/forced vital capacity [FVC]: MD 0.05, 95% CI 0.01 to 0.09; FVC: MD 0.19, 95% CI -0.03 to 0.42) and anxiety (MD -12.03, 95% CI -21.16 to -2.90) in mild COVID-19 and PCC patients. According to the narrative synthesis, including RCTs and NRSI, prone positioning seems to show improvements in vital parameters in severe COVID-19 post intensive care unit (ICU) discharge, pulmonary rehabilitation in activities of daily living, and qigong exercise and acupressure rehabilitation program, and "twist and raise" walking technique in reducing dyspnea and weakness in any degree of severity of COVID-19 and PCC. Functional electrical stimulation-cycling or early rehabilitation programs seem to support a faster recovery in patients with moderate COVID-19 after ICU discharge. Yoga and naturopathy, Mandala coloring, and respiratory exercise seem to reduce anxiety and depression in patients with moderate and mild COVID-19. Cognitive motor training seems to improve cognitive function in PCC patients. CONCLUSIONS: There is very uncertain evidence about the effect of pulmonary rehabilitation on exercise capacity and respiratory function in patients with mild COVID-19 and PCC. Further high-quality research is required to improve the certainty of evidence available to support rehabilitation's crucial role in managing COVID-19.

Overview of Cochrane Systematic Reviews for Rehabilitation Interventions in Individuals with Upper Limb Fractures: A Mapping Synthesis.

Background and Objectives. This overview of Cochrane systematic reviews (CSRs) reports on current evidence on the effectiveness of rehabilitation interventions for persons with upper limb fractures (ULFs), and the quality of the evidence. Materials and Methods. Following the inclusion criteria defined by the World Health Organization, all CSRs tagged in the Cochrane Rehabilitation database that were relevant for persons with ULFs were included. A mapping synthesis was used to group outcomes and comparisons of included CSRs, indicating the effect of rehabilitation interventions and the certainty of evidence. Results. A total of three CSRs were included in the evidence map. The certainty of evidence was judged as low to very low. Early occupational and hand therapy, cyclic pneumatic soft tissue compression, and cross-education, when started during immobilization, may improve grip strength and wrist range of motion, with results maintained up to 12 weeks from the cast removal, compared to no intervention. Approaches such as occupational therapy and passive mobilisation, started post-immobilization, are probably safe in terms of secondary complications. However, the overall evidence of rehabilitative interventions related to proximal humeral fractures has been judged insufficient for all the outcomes considered. A paucity of primary studies and CSRs for elbow fractures was noted. Conclusions. This overview provided the effect and the certainty of evidence of rehabilitation interventions available after ULFs using a mapping synthesis. To date, there is a need to further the effectiveness and safety of these interventions for persons with ULFs, improving methodological quality of the research in the field.

Overview of Cochrane systematic reviews for rehabilitation interventions in individuals with cerebral palsy: A mapping synthesis.

AIM: This overview of Cochrane systematic reviews (CSRs) reports on current evidence on the effectiveness of rehabilitation interventions for individuals with cerebral palsy (CP) and the quality of the evidence. METHOD: Following the inclusion criteria defined by the World Health Organization, all CSRs tagged in the Cochrane Rehabilitation database that were relevant for individuals with CP were included. A mapping synthesis was used to group outcomes and comparisons of included CSRs indicating the effect of rehabilitation interventions and the certainty of evidence. RESULTS: A total of eight CSRs were included in the evidence map. The effect of interventions varied across comparisons and the certainty of evidence was inconsistent, ranging from high to very low. The best evidence was found for botulinum neurotoxin A (BoNT-A) combined with occupational therapy in the management of spasticity. However, the effect of BoNT-A on drooling and salivation remains unclear. A paucity of randomized controlled trials studying treatments for both dystonia and postural deformities was noted. INTERPRETATION: This review emphasizes the need to further investigate the effectiveness and cost-benefit of rehabilitation interventions for individuals with CP. WHAT THIS PAPER ADDS: The quality and quantity of evidence on rehabilitation interventions for cerebral palsy is limited worldwide. Botulinum neurotoxin A plus occupational therapy showed robust efficacy for the management of upper-limb spasticity. Evidence on sleep-positioning systems for hip migration and trihexyphenidyl for dystonia is scarce.

Overview of Cochrane Systematic Reviews for Rehabilitation Interventions in Persons With Spinal Cord Injury: A Mapping Synthesis.

OBJECTIVE: This article aims to describe the evidence on rehabilitation interventions for persons with spinal cord injury (SCI) identified in Cochrane Systematic Reviews (CSRs) selected for inclusion in the World Health Organization Rehabilitation Programme-Package of Interventions for Rehabilitation. DATA SOURCES: The CSRs search was led by the Cochrane Rehabilitation team, using the tagging process, using the terms "spinal cord injury" and "rehabilitation" in the Cochrane Library. STUDY SELECTION: We performed an overview of all the CSRs according to the inclusion criteria defined with the World Health Organization: rehabilitation interventions in persons with SCI. DATA EXTRACTION: The CSRs identified after the screening process were summarized using an evidence map, grouping outcomes, and comparisons of included CSRs indicating the effect and the quality of evidence to provide a comprehensive view of what is known. DATA SYNTHESIS: Out of 248 CSRs from the past 10 years tagged in the Cochrane Rehabilitation database, 3 were related to SCI. They provide data on 13 outcomes analyzed within 11 comparisons for a total of 64 primary studies, including 2024 participants with SCI. Of these, 7 outcomes and 1 comparison focused on people with cervical SCI. Rehabilitation interventions might improve respiratory outcomes and pain relief in people with SCI. There is uncertainty whether bodyweight-supported treadmill training, robotic-assisted training, and functional electrostimulation affect walking speed and capacity. CONCLUSIONS: The current evidence needs to be confirmed by better quality research. Therefore, future priorities are the improvement of methodological quality of the studies in people with SCI, particularly considering the complexity of this health condition. Further, there is a need for more CSRs in the field.

Scoping review of rehabilitation care models for post COVID-19 condition.

Objective: To systematically map the current evidence about the characteristics of health systems, providers and patients to design rehabilitation care for post coronavirus disease 2019 (COVID-19) condition. Methods: We conducted a scoping review by searching the databases: MEDLINE®, Embase®, Web of Science, Cochrane COVID-19 Registry and Cochrane Central Register of Controlled Trials, from inception to 22 April 2022. The search strategy included terms related to (i) post COVID-19 condition and other currently known terminologies; (ii) care models and pathways; and (iii) rehabilitation. We applied no language or study design restrictions. Two pairs of researchers independently screened title, abstracts and full-text articles and extracted data. We charted the evidence according to five topics: (i) care model components and functions; (ii) safe delivery of rehabilitation; (iii) referral principles; (iv) service delivery settings; and (v) health-care professionals. Findings: We screened 13 753 titles and abstracts, read 154 full-text articles, and included 37 articles. The current evidence is conceptual and expert based. Care model components included multidisciplinary teams, continuity or coordination of care, people-centred care and shared decision-making between clinicians and patients. Care model functions included standardized symptoms assessment, telehealth and virtual care and follow-up system. Rehabilitation services were integrated at all levels of a health system from primary care to tertiary hospital-based care. Health-care workers delivering services within a multidisciplinary team included mostly physiotherapists, occupational therapists and psychologists. Conclusion: Key policy messages include implementing a multilevel and multiprofessional model; leveraging country health systems' strengths and learning from other conditions; financing rehabilitation research providing standardized outcomes; and guidance to increase patient safety.

Machine learning methods for functional recovery prediction and prognosis in post-stroke rehabilitation: a systematic review.

BACKGROUND: Rehabilitation medicine is facing a new development phase thanks to a recent wave of rigorous clinical trials aimed at improving the scientific evidence of protocols. This phenomenon, combined with new trends in personalised medical therapies, is expected to change clinical practice dramatically. The emerging field of Rehabilomics is only possible if methodologies are based on biomedical data collection and analysis. In this framework, the objective of this work is to develop a systematic review of machine learning algorithms as solutions to predict motor functional recovery of post-stroke patients after treatment. METHODS: We conducted a comprehensive search of five electronic databases using the Patient, Intervention, Comparison and Outcome (PICO) format. We extracted health conditions, population characteristics, outcome assessed, the method for feature extraction and selection, the algorithm used, and the validation approach. The methodological quality of included studies was assessed using the prediction model risk of bias assessment tool (PROBAST). A qualitative description of the characteristics of the included studies as well as a narrative data synthesis was performed. RESULTS: A total of 19 primary studies were included. The predictors most frequently used belonged to the areas of demographic characteristics and stroke assessment through clinical examination. Regarding the methods, linear and logistic regressions were the most frequently used and cross-validation was the preferred validation approach. CONCLUSIONS: We identified several methodological limitations: small sample sizes, a limited number of external validation approaches, and high heterogeneity among input and output variables. Although these elements prevented a quantitative comparison across models, we defined the most frequently used models given a specific outcome, providing useful indications for the application of more complex machine learning algorithms in rehabilitation medicine.

"Rehabilitation Research Framework for Patients With COVID-19" Defined by Cochrane Rehabilitation and the World Health Organization Rehabilitation Programme.

The coronavirus disease 2019 (COVID-19) pandemic resulted in a surge of research activity. Since its outset, efforts have been made to guide the rapid generation of research in medicine. There are gaps in some areas of rehabilitation research for patients with COVID-19. The development of a specific research framework might serve to help monitor the status of research (mapping), shape and strengthen research by pointing to under-investigated areas, and promote rehabilitation research in this context. This article introduces and discusses the COVID-19 Rehabilitation Research Framework (CRRF) and presents the methodology used for its development. The questions have been developed among the World Health Organization (WHO) Rehabilitation Programme, Cochrane Rehabilitation, and the experts of its Rehabilitation-COVID-19 Evidence-based Response Action International Multiprofessional Steering Committee. The framework is divided into 2 parts and includes 20 questions organized in 4 groups: epidemiology, and evidence at the micro- (individual), meso- (health services), and macro- (health systems) levels. The CRRF offers a comprehensive view of the research areas relevant to COVID-19 and rehabilitation that are necessary to inform best practice and ensure rehabilitation services and health systems can best serve the population with COVID-19. The collaboration between Cochrane Rehabilitation and the WHO Rehabilitation Programme in establishing the CRRF brought together perspectives from the health systems, health management, and clinical evidence. The authors encourage researchers to use the CRRF when planning studies on rehabilitation in the context of COVID-19.

Methodological Issues in Rehabilitation Research: A Scoping Review.

OBJECTIVE: To identify, synthesize, and categorize the methodological issues faced by the rehabilitation field. DATA SOURCES: A scoping review was conducted using studies identified in MEDLINE, the Cochrane Library, EMBASE, Web of Science, Scopus, Physiotherapy Evidence Database, and Google Scholar up to August 2018. STUDY SELECTION: We included all type of publications describing methodological issues in rehabilitation research where rehabilitation is described as a multimodal process. The methodological issues have been categorized and classified. DATA EXTRACTION: The synthesis included qualitative and quantitative analysis. To focus the attention on rehabilitation, we post hoc divided in "specific issues" (highly related to, even if not exclusive of, rehabilitation research) and "generic issues" (common in biomedical research). DATA SYNTHESIS: Seventy-one publications were included: 68% were narrative reviews, 15% systematic reviews, 7% editorials, 4% meta-epidemiologic studies, and 5% others. Specific methodological issues include the following: problematic application of randomized controlled trials (32%), absent definition of core outcome sets (28%), poor interventions description (22%), weak methodological (conducting) and reporting quality (21%), scarce clinical practice applicability (14%), lack of blinding assessor (10%), inadequate randomization methods or inadequate allocation concealment (8%), and inadequate participants description and recruitment (8%). "Generic" issues included the following: data and statistical description (31%), authors' methodological training (7%), peer review process (6%, n=4), funding declaration (6%), ethical statement (3%), protocol registration (3%), and conflict of interest declaration (1%). CONCLUSIONS: Methodological and reporting issues might influence the quality of the evidence produced in rehabilitation research. The next steps to move forward in the field of rehabilitation could be to evaluate the influence of all these issues on the validity of trial results through meta-epidemiologic studies and to develop specific checklists to provide guidance to authors to improve the reporting and conduct of trials in this field.

Effectiveness of Continuous Chest Wall Vibration With Concurrent Aerobic Training on Dyspnea and Functional Exercise Capacity in Patients With Chronic Obstructive Pulmonary Disease: A Randomized Controlled Trial.

OBJECTIVE: To investigate the effects of continuous chest wall vibration with concurrent aerobic training in addition to a 4-week pulmonary rehabilitation program on dyspnea and functional exercise capacity in patients with chronic obstructive pulmonary disease (COPD). DESIGN: Randomized, single-blind, placebo-controlled trial. SETTING: The Cardiopulmonary Rehabilitation Unit of a tertiary referral subacute rehabilitation center. PARTICIPANTS: A sample of 146 consecutive patients with COPD (Global Initiative for Chronic Obstructive Lung Disease II-III-IV) were assessed for eligibility. The final sample of 40 patients (N=40) was randomized into 3 groups (intervention, sham intervention, control). INTERVENTIONS: All groups carried out 5 sessions per week for 4 weeks of standard pulmonary rehabilitation treatment. The 2 daily 30-minute sessions included aerobic training and resistance training or airway clearance techniques. The intervention group performed the aerobic training with the addition of continuous chest wall vibration applied during cycling, whereas the sham intervention group received continuous chest wall vibration as a placebo during cycling. MAIN OUTCOME MEASURES: Six-minute walk distance (6MWD) and Barthel Index based on dyspnea (BID). RESULTS: A total of 36 participants completed the study (69±7 years; forced expiratory volume in 1 second percentage of predicted, 40.15%±15.97%). Intention to treat analysis showed no significant differences between groups for 6MWD and BID. However, the increase in 6MWD was a clinically important difference in the intervention group (42.57±43.87m, P=.003), with a moderate effect size (d=0.58). CONCLUSIONS: Continuous chest wall vibration with concurrent aerobic training in addition to a standard pulmonary rehabilitation program might improve functional exercise capacity compared with usual care, but there were no effects on dyspnea, respiratory muscle function, or quality of life in patients with COPD.

Tools to Assess the Risk of Bias and Reporting Quality of Randomized Controlled Trials in Rehabilitation.

OBJECTIVES: (1) To determine whether new tools and items have been developed to evaluate the risk of bias (RoB) and reporting of randomized controlled trials (RCTs) in rehabilitation; (2) to determine which items are included in the existing reporting guidelines, and to create a matrix of items to report and conduct trials in rehabilitation as the first step for a starting a rigorous validation process. DATA SOURCES: Searches were conducted in MEDLINE, EMBASE, and Cumulative Index to Nursing and Allied Health databases. STUDY SELECTION: Studies should describe a newly developed tool to evaluate the RoB or quality of reporting for RCTs in the area of rehabilitation. DATA EXTRACTION: (1) First, we extracted items from new tools identified by the electronic search strategies and then (2) we looked at the items provided by the Consolidated Standards of Reporting Trials statement and its relevant extensions. We determined whether these items were already included in our matrix of items. Items were classified based on methodological domains they accomplish, biases they were able to target, and whether they guide reporting or conduct. DATA SYNTHESIS: Among the 1596 citations found, 23 articles were potentially relevant. From these, only 3 new scales (National Institute for Complementary Medicine Acupuncture Network, Quality of reports on spa and balneotherapy [SPAC], Assessment of Study Quality and Reporting in Exercise) were found. In addition, the newly updated Cochrane RoB tool (RoB 2.0) was included. Our matrix contained 122 unique items for any rehabilitation area, 46 items (37.7%) were related to conduct, and 58 (47.5%) were related to the reporting; 18 (14.8%) were related to both. Overall, 76 new items were added among all domains. CONCLUSIONS: Many individual and diverse items have been used to guide the reporting and conduct of rehabilitation trials. This indicates a great variability in number of items and an apparent lack of consensus on a core set of items to be used in rehabilitation. Future research should look into developing a core set of items for the rehabilitation field.

Density Distribution Maps: A Novel Tool for Subcellular Distribution Analysis and Quantitative Biomedical Imaging.

Subcellular spatial location is an essential descriptor of molecules biological function. Presently, super-resolution microscopy techniques enable quantification of subcellular objects distribution in fluorescence images, but they rely on instrumentation, tools and expertise not constituting a default for most of laboratories. We propose a method that allows resolving subcellular structures location by reinforcing each single pixel position with the information from surroundings. Although designed for entry-level laboratory equipment with common resolution powers, our method is independent from imaging device resolution, and thus can benefit also super-resolution microscopy. The approach permits to generate density distribution maps (DDMs) informative of both objects' absolute location and self-relative displacement, thus practically reducing location uncertainty and increasing the accuracy of signal mapping. This work proves the capability of the DDMs to: (a) improve the informativeness of spatial distributions; (b) empower subcellular molecules distributions analysis; (c) extend their applicability beyond mere spatial object mapping. Finally, the possibility of enhancing or even disclosing latent distributions can concretely speed-up routine, large-scale and follow-up experiments, besides representing a benefit for all spatial distribution studies, independently of the image acquisition resolution. DDMaker, a Software endowed with a user-friendly Graphical User Interface (GUI), is also provided to support users in DDMs creation.

Wearable Devices for Biofeedback Rehabilitation: A Systematic Review and Meta-Analysis to Design Application Rules and Estimate the Effectiveness on Balance and Gait Outcomes in Neurological Diseases.

Wearable devices are used in rehabilitation to provide biofeedback about biomechanical or physiological body parameters to improve outcomes in people with neurological diseases. This is a promising approach that influences motor learning and patients' engagement. Nevertheless, it is not yet clear what the most commonly used sensor configurations are, and it is also not clear which biofeedback components are used for which pathology. To explore these aspects and estimate the effectiveness of wearable device biofeedback rehabilitation on balance and gait, we conducted a systematic review by electronic search on MEDLINE, PubMed, Web of Science, PEDro, and the Cochrane CENTRAL from inception to January 2020. Nineteen randomized controlled trials were included (Parkinson's n = 6; stroke n = 13; mild cognitive impairment n = 1). Wearable devices mostly provided real-time biofeedback during exercise, using biomechanical sensors and a positive reinforcement feedback strategy through auditory or visual modes. Some notable points that could be improved were identified in the included studies; these were helpful in providing practical design rules to maximize the prospective of wearable device biofeedback rehabilitation. Due to the current quality of the literature, it was not possible to achieve firm conclusions about the effectiveness of wearable device biofeedback rehabilitation. However, wearable device biofeedback rehabilitation seems to provide positive effects on dynamic balance and gait for PwND, but higher-quality RCTs with larger sample sizes are needed for stronger conclusions.

Mortality and characteristics of older people dying with COVID-19 in Lombardy nursing homes, Italy: An observational cohort study.

BACKGROUND: The aim of the study was to describe the epidemiological characteristics of Nursing Homes (NHs) residents infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and to compute the related case-fatality rate. MATERIALS AND METHODS: The outcomes were mortality and case-fatality rate with related epidemiological characteristics (age, sex, comorbidity, and frailty). RESULTS: During the COVID-19 outbreak lasted from March 1 to May 7, 2020, 330 residents died in Fondazione Don Gnocchi NHs bringing the mortality rate to 27% with a dramatic increase compared to the same period of 2019, when it was 7.5%. Naso/oropharyngeal swabs resulted positive for COVID-19 in 315 (71%) of the 441of the symptomatic/exposed residents tested. The COVID-19 population was 75% female, with a 17% overall fatality rate and sex-specific fatality rates of 19% and 13% for females and males, respectively. Fifty-six percent of deaths presented SARS-CoV-2-associated pneumonia, 15% cardiovascular, and 29% miscellaneous pathologies. CONCLUSION: Patients' complexity and frailty might influence SARS-CoV-2 infection case-fatality rate estimates. A COVID-19 register is needed to study COVID-19 frail patients' epidemiology and characteristics.

Pan-Sigma Receptor Modulator RC-106 Induces Terminal Unfolded Protein Response In In Vitro Pancreatic Cancer Model.

Pancreatic cancer (PC) remains one of the most lethal cancers worldwide. Sigma receptors (SRs) have been proposed as cancer therapeutic targets. Their main localization suggests they play a potential role in ER stress and in the triggering of the unfolded protein response (UPR). Here, we investigated the mechanisms of action of RC-106, a novel pan-SR modulator, to characterize therapeutically exploitable role of SRs in tumors. Two PC cell lines were used in all the experiments. Terminal UPR activation was evaluated by quantifying BiP, ATF4 and CHOP by Real-Time qRT-PCR, Western Blot, immunofluorescence and confocal microscopy. Cell death was studied by flow cytometry. Post-transcriptional gene silencing was performed to study the interactions between SRs and UPR key proteins. RC-106 activated ER stress sensors in a dose- and time-dependent manner. It also induced ROS production accordingly with ATF4 upregulation at the same time reducing cell viability of both cell lines tested. Moreover, RC-106 exerted its effect through the induction of the terminal UPR, as shown by the activation of some of the main transducers of this pathway. Post-transcriptional silencing studies confirmed the connection between SRs and these key proteins. Overall, our data highlighted a key role of SRs in the activation of the terminal UPR pathway, thus indicating pan-SR ligands as candidates for targeting the UPR in pancreatic cancer.

Investigating the Benefit of Combined Androgen Modulation and Hypofractionation in Prostate Cancer.

Hypofractionation is currently considered a valid alternative to conventional radiotherapy for the treatment of patients with organ-confined prostate cancer. Recent data have demonstrated that extreme hypofractionation, which involves the use of a high radiation dose per delivered fraction and concomitant reduction of sessions, is a safe and effective treatment, even though its radiobiological rationale is still lacking. The present work aims to investigate the biological basis sustaining this approach and to evaluate the potential of a hypofractionated regimen in combination with androgen deprivation therapy, one of the major standards of care for prostate cancer. Findings show that androgen receptor (AR) modulation, by use of androgens and antiandrogens, has a significant impact on cell survival, especially in hypoxic conditions (4% O2). Subsequent experiments have revealed that AR activity as a transcription factor is involved in the onset of malignant senescence-associated secretory phenotype (SASP) and activation of DNA repair cascade. In particular, we found that AR stimulation in hypoxic conditions promotes the enhanced transcription of ATM gene, the cornerstone kinase of the DNA damage repair genes. Together, these data provide new potential insights to justify the use of androgen deprivation therapy, in particular with second-generation anti-androgens such as enzalutamide, in combination with radiotherapy.