Introduction to target trial emulation in rehabilitation: a systematic approach to emulate a randomized controlled trial using observational data.

Rehabilitation providers and policymakers need valid evidence to make informed decisions about the healthcare needs of the population. Whenever possible, these decisions should be informed by randomized controlled trials (RCTs). However, there are circumstances when evidence needs to be generated rapidly, or when RCTs are not ethical or feasible. These situations apply to studying the effects of complex interventions, including rehabilitation as defined by Cochrane Rehabilitation. Therefore, we explore using the target trial emulation framework by Hernán and colleagues to obtain valid estimates of the causal effects of rehabilitation when RCTs cannot be conducted. Target trial emulation is a framework guiding the design and analysis of non-randomized comparative effectiveness studies using observational data, by emulating a hypothetical RCT. In the context of rehabilitation, we outline steps for applying the target trial emulation framework using real world data, highlighting methodological considerations, limitations, potential mitigating strategies, and causal inference and counterfactual theory as foundational principles to estimating causal effects. Overall, we aim to strengthen methodological approaches used to estimate causal effects of rehabilitation when RCTs cannot be conducted.

Rehabilitation and COVID-19: systematic review by Cochrane Rehabilitation.

INTRODUCTION: Until the last update in February 2022, the Cochrane Rehabilitation COVID-19 Evidence-based Response (REH-COVER) action identified an increasing volume of evidence for the rehabilitation management of COVID-19. Therefore, our aim was to identify the best available evidence on the effectiveness of interventions for rehabilitation for COVID-19-related limitations of functioning of rehabilitation interest in adults with COVID-19 or post COVID-19 condition (PCC). EVIDENCE ACQUISITION: We ran the searches on February 17th, 2023, in the following databases: PubMed, EMBASE, CENTRAL, CINHAL, and the Cochrane COVID-19 Study Register, applying a publication date restriction to retrieve only papers published in 2022. To retrieve papers published before 2022, we screened the reference lists of previous publications included in the REH-COVER action, covering papers from early 2020 to the end of 2022. This current review includes only randomised controlled trials and concludes the rapid living systematic reviews of the Cochrane Rehabilitation REH-COVER action. The risk of bias and certainty of evidence were evaluated in all studies using the Cochrane Risk of Bias tool and GRADE, respectively. We conducted a narrative synthesis of the evidence. PROSPERO registration number: CRD42022374244. EVIDENCE SYNTHESIS: After duplicate removal, we identified 18,950 individual records and 53 RCTs met the inclusion criteria. Our findings suggest that the effect of breathing and strengthening exercise programs on dyspnea and physical exercise capacity compared to no treatment in non-severe COVID-19 patients is uncertain. Multicomponent telerehabilitation may slightly increase physical exercise capacity compared to educational intervention in adults with PCC. There is, however, uncertainty about its effect on lung function and physical exercise capacity when compared to no treatment. Finally, the effect of inspiratory muscle training on maximal inspiratory pressure compared to no treatment in adults with PCC is uncertain. CONCLUSIONS: Interventions that are part of comprehensive pulmonary rehabilitation approaches may benefit dyspnea and exercise tolerance in adults with COVID-19 and PCC. The available evidence has several methodological limitations that limit the certainty of evidence and the clinical relevance of findings. Therefore, we cannot provide robust suggestions for practice. While high-quality RCTs are being conducted, clinicians should consider using high-quality evidence from other pulmonary conditions to rehabilitate patients with COVID-19 or PCC using context-specific interventions.

Evidence-based position paper on physical and rehabilitation medicine professional practice for persons with COVID-19, including post COVID-19 condition: the European PRM position (UEMS PRM Section).

Although multiple factors still pose challenges to inpatient/outpatient rehabilitation for survivors of COVID-19, rehabilitation plays a key role for this patient population. This study aimed to improve Physical and Rehabilitation Medicine (PRM) physician's professional practice for persons with COVID-19-related functioning limitations, to promote functional recovery and reduce activity limitations and/or participation restrictions. A systematic review of the scientific literature was performed from December 2019 to August 2022, followed by production of recommendations through 5 Delphi rounds, by consensus among the delegates of all European countries represented in the Union of European Medical Specialists PRM Section. The systematic literature review is reported together with thirty-two recommendations resulting from the Delphi procedure. The PRM physician's role for persons with COVID-19-related limitations of functioning is to develop, foster, and monitor the implementation of an individual rehabilitation project tailored to the patient's age, previous medical and functional status, current comorbidities and complications, activity limitations and participation restrictions and personal and environmental factors. This is done by applying the concept of a multi-specialty integrated service model with multi-professional/interdisciplinary teams, providing care at all stages of COVID-19 illness. This evidence-based position paper represents the official position of the European Union through the UEMS PRM Section.

Trust/untrust is not the same as true/false. Lessons learned and ethical questions on the application of untrustworthiness scales to judge individuals.

This special paper reflects on trustworthiness and its implications for scientific medical journals and all the communities they serve: health professionals, policymakers, the public, and a specific discipline, in our case, Physical and Rehabilitation Medicine. We start from a recent episode: a paper claimed the untrustworthiness of two randomised controlled trials (RCTs) published in the European Journal of Physical and Rehabilitation Medicine based on a newly developed trustworthiness scale, used until now only in systematic reviews. This likely represents the first case of applying such a scale focusing on a single leading author. Developing a proper answer to this case led us to present some insights from the perspective of a Journal editor. We discuss the impact of false research results, why trust is needed in science and medicine, the difference between untrust and false results, the problems in judging trustworthiness, the unfortunately weak capacity of the peer review system in preventing these issues, the problems of "post-hoc" judgements and the emerging ethical issues. We conclude with some suggestions for the future based on prevention at the system level.

Effects of Levodopa-Carbidopa Intestinal Gel Compared with Optimized Medical Treatment on Nonmotor Symptoms in Advanced Parkinson's Disease: INSIGHTS Study.

Background: Nonmotor symptoms (NMS) are common in advanced Parkinson's disease (APD) and reduce health-related quality of life. Objective: The aim of the study was to evaluate levodopa-carbidopa intestinal gel (LCIG) versus optimized medical treatment (OMT) on NMS in APD. Methods: INSIGHTS was a phase 3b, open-label, randomized, multicenter study in patients with APD (LCIG or OMT, 26 weeks) (NCT02549092). Primary outcomes assessed were total NMS (NMS scale (NMSS) and PD sleep scale (PDSS-2)). Key secondary outcomes included the Unified PD Rating Scale (UPDRS) Part II, Clinical Global Impression of Change (CGI-C), and PD Questionnaire-8 (PDQ-8). Additional secondary measures of Patient Global Impression of Change (PGIC), King's PD Pain Scale (KPPS), and Parkinson Anxiety Scale (PAS) also were evaluated. Finally, safety was assessed. Results: Out of 89 patients randomized, 87 were included in the analysis (LCIG, n = 43; OMT, n = 44). There were no significant differences in NMSS or PDSS-2 total score changes (baseline to Week 26) between LCIG and OMT; within-group changes were significant for NMSS (LCIG, p < 0.001; OMT, p = 0.005) and PDSS-2 (LCIG, p < 0.001; OMT, p < 0.001). Between-group treatment differences were nominally significant for UPDRS Part II (p = 0.006) and CGI-C (p < 0.001) at Week 26 in favor of LCIG; however, statistical significance could not be claimed in light of primary efficacy outcomes. PGIC (Week 26) and KPPS (Week 12) scores were nominally significantly reduced with LCIG versus OMT (p < 0.001; p < 0.05). There were no significant differences in PDQ-8 or PAS. Adverse events (AEs) were mostly mild to moderate; common serious AEs were pneumoperitoneum (n = 2) and stoma-site infection (n = 2) (LCIG). Conclusions: There were no significant differences between LCIG versus OMT in NMSS or PDSS-2; both LCIG and OMT groups significantly improved from baseline. AEs were consistent with the known safety profile.

Evidence-based position paper on Physical and Rehabilitation Medicine practice for people with amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease that affects both upper and lower motor neurons and is fatal in its course. This evidence-based position paper represents the official position of the UEMS PRM Section. The aim of the paper is to define the role of the physical and rehabilitation medicine (PRM) physician and PRM professional practice for people with ALS. A systematic review of the literature and a consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with thirty-two recommendations resulting from the Delphi procedure. The responsibility of the PRM physician is functional assessment of persons with ALS and delivering the optimal and most effective PRM program of care. The rehabilitation program of patients with ALS should be delivered and monitored by the multiprofessional team, with the PRM physician as principal coordinator.

Evidence based position paper on Physical and Rehabilitation Medicine practice for people with muscular dystrophies.

Muscular dystrophies present a group of inherited degenerative disorder that are characterized by progressive muscular weakness. This evidence-based position paper represents the official position of the European Union through the UEMS PRM Section. The aim of the paper is to evaluate the role of the physical and rehabilitation medicine (PRM) physician and PRM practice for people with muscular dystrophies. A systematic review of the literature and a consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with thirty-three recommendations resulting from the Delphi procedure. The role of the PRM physician is to assess the functional status of persons with muscular dystrophy and to plan, monitor and lead PRM program in an interdisciplinary setting within a multiprofessional team.

Rehabilitation and COVID-19: rapid living systematic review by Cochrane Rehabilitation Field - third edition. Update as of June 30th, 2021.

INTRODUCTION: This paper updates and summarizes the current evidence informing rehabilitation of patients with COVID-19 and/or describing the consequences of the disease and its treatment. EVIDENCE ACQUISITION: Studies published from May 1st to June 30th, 2021 were selected, excluding descriptive studies and expert opinions. Papers were categorized according to study design, research question, COVID-19 phase, limitations of functioning of rehabilitation interest, and type of rehabilitation service involved. From this edition, we improved the quality assessment using the Joanna Briggs Institute checklists for observational studies and the Cochrane Risk of Bias Tool for randomized-controlled clinical trials (RCTs). EVIDENCE SYNTHESIS: Twenty-five, out of 3699 papers, were included. They were three RCTs, 13 cross-sectional studies and nine cohort studies. Twenty studies reported data on symptom prevalence (N.=13) or disease natural history (N.=7); and five studies reported intervention effectiveness at the individual level. All study participants were COVID survivors and 48% of studies collected information on participants 6 months or longer after COVID-19 onset. The most frequent risks of bias for RCTs concerned weaknesses in allocation concealment, blinding of therapists, and lack of intention-to-treat analysis. Most analytical studies failed to identify or deal with confounders, describe or deal with dropouts or eventually perform an appropriate statistical analysis. CONCLUSIONS: Most studies in this updated review targeted the prevalence of limitations of functioning of rehabilitation interest in COVID-19 survivors. This is similar to past review findings; however, data in the new studies was collected at longer follow-up periods (up to one year after symptom onset) and in larger samples of participants. More RCTs and analytical observational studies are available, but the methodological quality of recently published studies is low. There is a need for good quality intervention efficacy and effectiveness studies to complement the rapidly expanding evidence from observational studies.

Rehabilitation and COVID-19: a rapid living systematic review by Cochrane Rehabilitation Field updated as of December 31st, 2020 and synthesis of the scientific literature of 2020.

INTRODUCTION: COVID-19 infection significantly increased mortality risk and the burden of disability in most survivors, regardless of symptom severity at onset. The rehabilitation needs of people infected are receiving growing attention, as evidenced by the increasing number of publications, including those addressing the chronic consequences of infection. This rapid living systematic review reports the evidence published in November and December 2020 and summarises the entire body of literature on rehabilitation in COVID-19 patients published in 2020. EVIDENCE ACQUISITION: This update was performed using the methodology reported by the second edition conducted by Cochrane Rehabilitation REH-COVER Action. We searched PubMed, Embase, CINAHL, Scopus, Web of Science, and Pedro databases. Papers related to COVID-19 and rehabilitation were retrieved and summarised descriptively. EVIDENCE SYNTHESIS: The search retrieved 4441 studies. After the removal of duplicates and the screening for title and abstract, we retained 105 studies. Of these, we included 54 in the qualitative synthesis of this update. According to OCEBM 2011 levels of evidence table, most studies (64.8%) fall within the category of level 4 evidence. Up to 40.7% of papers included COVID-19 patients in the postacute phase. In 2020, our rapid living systematic review included 230 studies; most of these (73.9%) were level 4 studies, 25.7% were level 3, and only one study was level 2. The evidence level improved over time. While most studies (44.8%) included patients with acute COVID-19, we observed a gradual increase in the number of reports about chronic symptoms and the long-term consequences of the infection. CONCLUSIONS: The update of the rapid living systematic review by Cochrane Rehabilitation Field demonstrates an increase in the level of evidence of studies addressing the rehabilitation needs associated with COVID-19 infection. Although most studies are still case reports/series, there is a trend towards conducting prospective investigations of the early natural history of the disease (first months post onset). High-quality-level studies on the efficacy of rehabilitation, and long-term monitoring of the disease and its sequelae are yet to emerge.

Rehabilitation and COVID-19: a rapid living systematic review 2020 by Cochrane Rehabilitation Field. Update as of October 31st, 2020.

INTRODUCTION: This living systematic review presents the monthly update of the second edition of the rapid living systematic review 2020 conducted by Cochrane Rehabilitation REH-COVER Action Steering Committee. The aim of this study was to update the monthly COVID-19 and rehabilitation literature research up to October 31st, 2020. EVIDENCE ACQUISITION: Methodology described in the second edition of the rapid living systematic review 2020 conducted by Cochrane Rehabilitation REH-COVER action was applied. PubMed, Embase, CINAHL, Scopus, Web of Science, and PEDro databases were searched, and papers related to COVID-19 and rehabilitation were retrieved and summarized descriptively. EVIDENCE SYNTHESIS: The database search retrieved 2704 publications. Duplicates were removed, and 1185 unique records were screened for inclusion. After screening titles, abstracts and full-texts, 22 papers were included in the present review. According to OCEBM 2011 Levels of Evidence table, 17 studies (77%) fall within the level of evidence 4 category, while the remainder (23%) are categorized as level of evidence 3. Most studies (N.=19; 86%) provided epidemiological data about the disease natural history/determining factor or the clinical presentation of COVID-19 infection, while only two studies focused on health service organization and intervention efficacy. CONCLUSIONS: The most recent published COVID-19 research relevant to rehabilitation primarily provides data on the clinical course and the clinical presentation of the pathology, rather than on rehabilitation interventions or service delivery. Studies with high levels of evidence regarding the efficacy of interventions, long-term monitoring, or new health service organization models are lacking.