[Contribution of physical and rehabilitation medicine to primary care medicine]. / Apport de la médecine physique et de réadaptation à la médecine de premier recours.

Physical and rehabilitation medicine (PRM) is an independent medical specialty, little known in Switzerland. This specialty, strongly linked to the holistic approach of the International Classification of Functioning, will be increasingly solicited by the epidemiology of disability and the imperatives of "ageing better". Its skills in prescribing human and material resources for rehabilitation provide added value in terms of loss of autonomy. Based on a biopsychosocial model, PRM has a high role to play in prevention and primary healthcare, as well as in the management and prevention of the consequences of functionally limiting diseases. There are, however, financial (pricing) and demographic (lack of representation) obstacles to effective action on behalf of the population and the healthcare system.

La médecine physique et de réadaptation (MPR), discipline indépendante, est peu connue en Suisse. Cette spécialité, liée à l'approche holistique de la classification internationale du fonctionnement, sera de plus en plus sollicitée par l'épidémiologie du handicap et les impératifs du « vieillir mieux ¼. Ses compétences de prescription des moyens humains et matériels en réadaptation apportent une plus-value sur la perte d'autonomie. Basée sur un modèle biopsychosocial, la MPR trouve sa place dans la prévention et les soins de santé primaires ainsi que dans la prise en charge et la prévention des conséquences des maladies induisant une limitation fonctionnelle. Il existe toutefois des obstacles financiers (tarification) et démographiques (insuffisance de représentation) pour une action efficace au service de la population et du système de santé.

Post-stroke spasticity: follow-up and functional implications of chronic long-term treatment with botulinum toxin.

BACKGROUND: Around 40% of stroke survivor develop spasticity. Plantar flexors (PF) muscles are often affected, with severe functional impairment. The treatment of choice is botulinum toxin type A (BoNT-A) combined with adjuvant treatments. The temporary pharmacological effect implies periodic reassessment and reinjection. These long-term chronic programs require monitoring the functional impact of each cycle and the clinical evolution in relation to aging and repeated interventions. AIM: Evaluating changes of functional level in patients with post-stroke spasticity treated with BoNT-A by assessing the long-term maintenance of the therapeutic efficacy. DESIGN: Retrospective longitudinal observational study. SETTING: Outpatients. POPULATION: Chronic stroke survivors undergoing BoNT-A treatment and subsequent intensive rehabilitation (10 sessions in a day-hospital regime). METHODS: Medical records of the enrolled patients were consulted. The primary endpoint was the change in PF spasticity by at least 1 point on the Modified Ashworth Scale (MAS) at each cycle. Secondary endpoints were the assessment of possible trends in gait parameters (Six Minute Walking Test [6MWT]; Timed Up and Go [TUG], and 10 Meters Walking Test [10mWT]) pre- and post-injection and at each cycle. RESULTS: Thirty-six patients were enrolled. A reduction of at least one MAS point for PF was recorded after each cycle in all subjects. A time-dependent reduction in the proportion of patients reporting an improvement higher than the minimal clinically important difference (MCID) in 6MWT and 10mWT was observed. In the case of TUG, this data kept stable at all cycles. A one-point increase in the basal functional ambulation classification (FAC) score resulted in a reduction in the probability of having a TUG improvement greater than the MCID. The opposite correlation was found for 6MWT and 10mWT. CONCLUSIONS: With the proposed treatment, the clinical significance TUG improvement remains constant throughout repeated cycles and the proportion of patients with improvement in 6MWT and 10mWT tends to decline over time. The predictive value of basal FAC on the functional variables expected improvement may provide a potential treatment targeting tool. CLINICAL REHABILITATION IMPACT: These results may deliver prognostic indication allowing an optimized integration of different post-BoNT-A rehabilitation approaches, agreeing with current evidence. Adequate monitoring and treatment protocols are crucial for the stability of functional level and may prevent excessive fluctuations.

Chronic Pain in Patients with Spinal Muscular Atrophy in Switzerland: A Query to the Spinal Muscular Atrophy Registry.

Background and Objectives: Chronic pain is a common symptom in various types of neuromuscular disorders. However, for patients with spinal muscular atrophy (SMA), the literature regarding chronic pain is scarce. Thus, this study assessed the prevalence of chronic pain in children, adolescents, and adults with SMA and investigated the influence of clinical characteristics on chronic pain. Materials and Methods: This study used data from 141 patients, which were collected by the Swiss Registry for Neuromuscular Disorders. Extracted data included information on pain (present yes/no, pain location, and pain medication) and clinical characteristics, such as SMA type, motor function, wheelchair use, scoliosis, and contractures. Results: The analyses revealed that the highest prevalence of chronic pain was observed in adolescents with 62%, followed by adults with 48%, children (6-12 years) with 39%, and children < 6 years with 10%. The legs, back, and hips were most frequently reported as pain locations. Sex (females), age (adolescents), and the presence of contractures and scoliosis (with surgery) were factors that were associated with chronic pain. Conclusions: These findings contribute to a better understanding of pain in SMA, shedding light on its prevalence and characteristics in different age groups, which underscores the importance of assessing and managing pain in patients with SMA.

Upper Limb Casting Application Post-Botulinum Toxin Injection for Elbow Spasticity: A Guided Casting Protocol.

ABSTRACT: Casting is an effective adjunctive treatment, which increases the effects of botulinum toxin on patients with spasticity. The evidence for casting as an adjunctive therapy post-botulinum toxin has been well documented in the literature. However, standardized casting protocols are lacking, with no published descriptions of upper limb casting application post-botulinum toxin injection for spasticity. In this article, we will describe our experience regarding the application of upper limb casting as an adjunctive therapy for elbow spasticity, detailing indications, contraindications, and description of our protocol (materials required and technique).

Botulinum Toxin for Pain Relief in Cancer Patients: A Systematic Review of Randomized Controlled Trials.

Cancer pain is one of the most disabling symptoms complained by cancer patients, with a crucial impact on physical and psychological well-being. Botulinum neurotoxins (BoNTs) type A and B have emerged as potential interventions for chronic pain; however, their role in these patients is still debated. Thus, this systematic review of randomized controlled trials aimed at assessing the effects of BoNT treatment for cancer pain to guide physicians in an evidence-based approach integrating BoNT in cancer care. Out of 5824 records, 10 RCTs satisfied our eligibility criteria and were included in the present work for a total of 413 subjects with several cancer types (breast, head and neck, esophageal, and thoracic/gastric cancers). While some studies demonstrated significant pain reduction and improved quality of life post-BoNT-A injections, outcomes across different cancer types were inconclusive. Additionally, several effects were observed in functioning, dysphagia, salivary outcomes, esophageal strictures, gastric emptying, and expansions. This review emphasizes the need for further standardized research to conclusively establish the efficacy of BoNT in comprehensive cancer pain management.

Selecting Goals and Target Muscles for Botulinum Toxin A Injection Using the Goal Oriented Facilitated Approach to Spasticity Treatment (GO-FAST) Tool.

The objective of this article is to introduce the GO-FAST Tool (developed by the Toxnet group) to clinicians working in the field of neurological rehabilitation, specifically post-stroke spasticity management. The concepts utilized in the Tool and described in this article can be broadly grouped into five topics: the principles of patient-centred goal-setting; an algorithm for setting SMART (specific, measurable, attainable, realistic, and timed) treatment goals; goal-related target muscles and botulinum toxin type A dose determinants; goal attainment follow-up, scoring, and interpretation; and the multimodal approach to spasticity management. The Tool can enhance clinical practice by providing guided assistance with goal-setting and target muscle selection for botulinum toxin type A treatment. It also provides support with the follow-up evaluation of goal attainment and calculation of treatment success. The Tool is designed to be used by clinicians with varying levels of expertise in the field of neurological rehabilitation and post-stroke spasticity management, from those who are new to the field to those with many years of experience. A case study is presented in the Results Section of the article to illustrate the utility of the Tool in setting SMART treatment goals in the management of patients with post-stroke spasticity.

Walking naturally after spinal cord injury using a brain-spine interface.

A spinal cord injury interrupts the communication between the brain and the region of the spinal cord that produces walking, leading to paralysis1,2. Here, we restored this communication with a digital bridge between the brain and spinal cord that enabled an individual with chronic tetraplegia to stand and walk naturally in community settings. This brain-spine interface (BSI) consists of fully implanted recording and stimulation systems that establish a direct link between cortical signals3 and the analogue modulation of epidural electrical stimulation targeting the spinal cord regions involved in the production of walking4-6. A highly reliable BSI is calibrated within a few minutes. This reliability has remained stable over one year, including during independent use at home. The participant reports that the BSI enables natural control over the movements of his legs to stand, walk, climb stairs and even traverse complex terrains. Moreover, neurorehabilitation supported by the BSI improved neurological recovery. The participant regained the ability to walk with crutches overground even when the BSI was switched off. This digital bridge establishes a framework to restore natural control of movement after paralysis.

International Recommendations to Manage Poststroke Equinovarus Foot Deformity Validated by a Panel of Experts Using Delphi.

OBJECTIVE: To establish international recommendations for the management of spastic equinovarus foot deformity. DESIGN: Delphi method. SETTING: International study. PARTICIPANTS: A total of 24 international experts (N=24) in neuro-orthopedic deformities, from different specialties (Physical and Rehabilitation Medicine physicians, neurologists, geriatricians, orthopedic surgeons, neurosurgeons, plastic surgeons). INTERVENTIONS: Experts answered 3 rounds of questions related to important aspects of diagnosis, assessment, and treatment of spastic equinovarus foot deformity. MAIN OUTCOME MEASURES: A consensus was established when at least 80% of experts agreed on a statement RESULTS: A total of 52 items reached consensus. Experts recommend assessing effect of the deformity on functional activities before treatment. Before treatment, it is crucial to differentiate spastic muscle overactivity from soft tissue contractures, identify which muscles are involved in the deformity, and evaluate the activity of antagonist muscles. Motor nerve blocks, 2-dimensional video analysis, and radiologic examinations are often required to complement a clinical examination. The treatment of equinovarus foot depends on the correctability of the deformity and the patient's ability to stand or walk. The preoperative assessment should include an interdisciplinary consultation that must finalize a formal agreement between physicians and the patient, which will define personalized attainable goals before surgery. CONCLUSION: The establishment of guidelines on managing equinovarus foot will help physicians and surgeons, specialists, and nonspecialists to diagnoses and assess the deformity and direct patients to a network of experts to optimize patient functional recovery and improve their autonomy.

A practical guide to botulinum neurotoxin treatment of shoulder spasticity 2: Injection techniques, outcome measurement scales, and case studies.

Introduction: Botulinum neurotoxin type A (BoNT-A) is a first-line treatment option for post-stroke spasticity, reducing pain and involuntary movements and helping to restore function. BoNT-A is frequently injected into the arm, the wrist, the hand, and/or the finger muscles but less often into the shoulder muscles, despite clinical trials demonstrating improvements in pain and function after shoulder BoNT-A injection. Methods: In part 2 of this two-part practical guide, we present an experts' consensus on the choice of outcome measurement scales and goal-setting recommendations for BoNT-A in the treatment of shoulder spasticity to increase awareness of shoulder muscle injection with BoNT-A, alongside the more commonly injected upper limb muscles. Expert consensus was obtained from five European experts with a cumulative experience of more than 100 years of BoNT-A use in post-stroke spasticity. Case studies are included as examples of approaches taken in the treatment of shoulder spasticity. Results: Although the velocity-dependent increase in muscle tone is often a focus of patient assessment, it is only one component of spasticity and should be assessed as part of a wider range of measurements. For outcome measurement following BoNT-A injection in shoulder muscles, shoulder-specific scales are recommended. Other scales to be considered include Pain Numerical Rating and/or global functioning, as well as the quality of life and global perception of benefit scores.Goal setting is an essential part of the multidisciplinary management process for spasticity; goals should be patient-centric, realistic, and achievable; functional-focused goal statements and a mixture of short- (3-6 month) and long-term (9-18 month) goals are recommended. These can be grouped into symptomatic, passive function, active function, involuntary movement, and global mobility.Clinical evaluation tools, goal setting, and outcome expectations for the multipattern treatment of shoulder spasticity with BoNT-A should be defined by the whole multidisciplinary team, ensuring patient and caregiver involvement. Discussion: These recommendations will be of benefit to clinicians who may not be experienced in evaluating and treating spastic shoulders.

A practical guide to botulinum neurotoxin treatment of shoulder spasticity 1: Anatomy, physiology, and goal setting.

Botulinum neurotoxin type A (BoNT-A) is a first-line treatment option for post-stroke spasticity, reducing pain and involuntary movements and helping to restore function. BoNT-A is frequently injected into the arm, wrist, hand and/or finger muscles, but less often into the shoulder muscles, despite clinical trials demonstrating improvements in pain and function after shoulder BoNT-A injection. In part 1 of this two-part practical guide, we present an experts' consensus on the use of BoNT-A injections in the multi-pattern treatment of shoulder spasticity to increase awareness of shoulder muscle injection with BoNT-A, alongside the more commonly injected upper limb muscles. Expert consensus was obtained from five European experts with a cumulative experience of more than 100 years of BoNT-A use in post-stroke spasticity. A patient-centered approach was proposed by the expert consensus: to identify which activities are limited by the spastic shoulder and consider treating the muscles that are involved in hindering those activities. Two patterns of shoulder spasticity were identified: for Pattern A (adduction, elevation, flexion and internal rotation of the shoulder), the expert panel recommended injecting the pectoralis major, teres major and subscapularis muscles; in most cases injecting only the pectoralis major and the teres major is sufficient for the first injection cycle; for Pattern B (abduction or adduction, extension and internal rotation of the shoulder), the panel recommended injecting the posterior part of the deltoid, the teres major and the latissimus dorsi in most cases. It is important to consider the local guidelines and product labels, as well as discussions within the multidisciplinary, multiprofessional team when deciding to inject shoulder muscles with BoNT-A. The choice of shoulder muscles for BoNT-A injection can be based on spastic pattern, but ideally should also firstly consider the functional limitation and patient expectations in order to establish better patient-centered treatment goals. These recommendations will be of benefit for clinicians who may not be experienced in evaluating and treating spastic shoulders.

The Lack of Systemic and Subclinical Side Effects of Botulinum Neurotoxin Type-A in Patients Affected by Post-Stroke Spasticity: A Longitudinal Cohort Study.

Botulinum Neurotoxin type-A (BoNT-A) is the treatment of choice for focal post-stroke spasticity (PSS). Due to its mechanism of action and the administration method, some authors raised concern about its possible systemic diffusion leading to contralateral muscle weakness and autonomic nervous system (ANS) alterations. Stroke itself is a cause of motor disability and ANS impairment; therefore, it is mandatory to prevent any source of additional loss of strength and adjunctive ANS disturbance. We enrolled 15 hemiparetic stroke survivors affected by PSS already addressed to BoNT-A treatment. Contralateral handgrip strength and ANS parameters, such as heart rate variability, impedance cardiography values, and respiratory sinus arrythmia, were measured 24 h before (T0) and 10 days after (T1) the ultrasound (US)-guided BoNT-A injection. At T1, neither strength loss nor modification of the basal ANS patterns were found. These findings support recent literature about the safety profile of BoNT-A, endorsing the importance of the US guide for a precise targeting and the sparing of "critical" structures as vessels and nerves.

Multidimensional Effectiveness of Botulinum Toxin in Neuropathic Pain: A Systematic Review of Randomized Clinical Trials.

Although botulinum toxin (BoNT) has been suggested as a treatment to counter neuropathic pain, no previous systematic reviews investigated the multidimensional effects of BoNT on pain relief and Health-Related Quality of Life (HR-QoL). The aim of this systematic review is to summarize the current evidence on the effectiveness of BoNT treatment for neuropathic pain, and to characterize its multidimensional effectiveness in order to guide physicians in clinical practice. Five databases were systematically searched up to 4 April 2022, to identify randomized controlled trials satisfying the following criteria: adults suffering from neuropathic pain, BoNT administration, any comparator, multidimensional assessment of pain as primary outcome, HR-QoL, physical function, anxiety and depression, and sleep quality as secondary outcomes. Twelve studies were included. The multidimensional pain scales used were short-form McGill Pain Questionnaire, Neuropathic pain scale, Neuropathic Pain Symptom Inventory, International SCI Pain Basic Data Set, West Haven-Yale Multidimensional Pain Inventory, Brief Pain Inventory, and Douleur Neuropathique 4. These scales highlighted the positive effects of BoNT administration. According to the Jadad scale, all the RCTs included were high-quality studies. BoNT administration might be effectively introduced in the comprehensive management of neuropathic pain. Further research should focus on optimal and cost-effective therapeutic protocols.

Quality of Life Interventions in Breast Cancer Survivors: State of the Art in Targeted Rehabilitation Strategies.

Breast cancer is the most common malignant tumor and the most prevalent cause of mortality in women. Advances in early diagnosis and more effective adjuvant therapies have improved the long-term survival of these patients. Pharmacotherapies and intrinsic tumor-related factors may lead to a wide spectrum of treatment-related disabling complications, such as breast cancer-related lymphedema, axillary web syndrome, persistent pain, bone loss, arthralgia, and fatigue. These conditions have a detrimental impact on the health-related quality of life of survivors. Here, we sought to provide a portrait of the role that rehabilitation plays in breast cancer survivors. Particular emphasis has been put in terms of recovering function, improving independence in activities of daily living, and reducing disability. This complex scenario requires a precision medicine approach to provide more effective decision-making and adequate treatment compliance.

Ergonomic Recommendations in Ultrasound-Guided Botulinum Neurotoxin Chemodenervation for Spasticity: An International Expert Group Opinion.

Ultrasound (US)-guided botulinum neurotoxin (BoNT) injections are becoming a mainstay in the treatment of muscle spasticity in upper motor neuron syndromes. As a result, there has been a commensurate increase in US-guided BoNT injection for spasticity training courses. However, many of these courses do not emphasize the importance of ergonomics. This paper aims to highlight the importance of ultrasound ergonomics and presents ergonomic recommendations to optimize US-guided BoNT injection techniques in spasticity management. Expert consensus opinion of 11 physicians (4 different continents; representing 8 countries, with an average of 12.6 years of practice using US guidance for BoNT chemodenervation (range 3 to 22 years)). A search using PubMed, College of Physicians and Surgeons of British Columbia database, EMbase was conducted and found no publications relating the importance of ergonomics in US-guided chemodenervation. Therefore, recommendations and consensus discussions were generated from the distribution of a 20-question survey to a panel of 11 ultrasound experts. All 11 surveyed physicians considered ergonomics to be important in reducing physician injury. There was complete agreement that physician positioning was important; 91% agreement that patient positioning was important; and 82% that ultrasound machine positioning was important. Factors that did not reach our 80% threshold for consensus were further discussed. Four categories were identified as being important when implementing ultrasound ergonomics for BoNT chemodenervation for spasticity; workstation, physician, patient and visual ergonomics. Optimizing ergonomics is paramount when performing US-guided BoNT chemodenervation for spasticity management. This includes proper preparation of the workspace and allowing for sufficient pre-injection time to optimally position both the patient and the physician. Lack of awareness of ergonomics for US-guided BoNT chemodenervation for spasticity may lead to suboptimal patient outcomes, increase work-related injuries, and patient discomfort. We propose key elements for optimal positioning of physicians and patients, as well as the optimal setup of the workspace and provide clinical pearls in visual identification of spastic muscles for chemodenervation.

[Neurorehabilitation in the acute and post-acute phase: what did we learn from the first wave of COVID-19?] / Neurorééducation en phases aiguë et postaiguë : qu'avons-nous appris de la première vague de Covid-19 ?

The majority of patients with Coronavirus disease 2019 (COVID-19) present mild to moderate illness and recover without hospitalization. Nevertheless, 5 % of cases require hospitalization in the intensive care unit, with 15 % of them showing severe central and peripheral nervous system manifestations. These patients should be considered high risk patients and their management must include prevention of a potential accompanying cascade of negative factors. In order to optimize care, it is essential that signs of neurological damage are searched for as early as in intensive care so that appropriate neurorehabilitation can be started immediately and continued in a specific unit for patients with neurological sequelae at post-acute and outpatient phases.

La majorité des patients atteints par la maladie due au coronavirus 2019 (Covid-19) présente une évolution plutôt favorable. Cependant 5 % nécessitent une hospitalisation aux soins intensifs, dont 15 % présentent des atteintes sévères des systèmes nerveux central et périphérique. Ces patients doivent être considérés comme des personnes à haut risque de développer des séquelles graves et leur plan de traitement doit nécessairement impliquer la prévention d'une potentielle cascade de facteurs négatifs concomitants. Afin d'optimiser une telle prise en charge, il est primordial que les premiers signes d'atteintes neurologiques soient détectés dès les soins intensifs et qu'une neurorééducation puisse être débutée précocement et poursuivie dans une filière de patients neuro-lésés en phase postaiguë, puis en ambulatoire.

A practical guide to optimizing the benefits of post-stroke spasticity interventions with botulinum toxin A: An international group consensus.

This consensus paper is derived from a meeting of an international group of 19 neurological rehabilitation specialists with a combined experience of more than 250 years (range 4-25 years; mean 14.1 years) in treating post-stroke spasticity with botulinum toxin A. The group undertook critical assessments of some recurring practical challenges, not yet addressed in guidelines, through an exten-sive literature search. They then discussed the results in the light of their individual clinical experience and developed consensus statements to present to the wider community who treat such patients. The analysis provides a comprehensive overview of treatment with botulinum toxin A, including the use of adjunctive therapies, within a multidisciplinary context, and is aimed at practicing clinicians who treat patients with post-stroke spasticity and require further practical guidance on the use of botulinum toxin A. This paper does not replicate information published elsewhere, but instead aims to provide practical advice to help optimize the use of botulinum toxin A and maximize clinical outcomes. The recommendations for each topic are summarized in a series of statements. Where published high-quality evidence exists, the recommendations reflect this. However, where evidence is not yet conclusive, the group members issued statements and, in some cas-es, made recommendations based on their clinical experience.

Bone Muscle Crosstalk in Spinal Cord Injuries: Pathophysiology and Implications for Patients' Quality of Life.

PURPOSE OF REVIEW: The goal of this review is to provide a comprehensive overview of (i) bone and muscle tissue modifications pathophysiology in spinal cord injury (SCI), (ii) experimental data on the physiopathological mechanisms underpinning these modifications and their similarities with the aging process, and (iii) potential clinical implications in the management of the disabling sequelae of SCI. RECENT FINDINGS: Several studies attempted to describe the biology underpinning the links between bone and muscle tissues in the setting of highly disabling conditions, such as osteoporosis, sarcopenia, and neurodegenerative disorders, although these bidirectional connections remain still unclear. SCI could be considered an in vivo paradigmatic model of the bone muscle interactions in unloading conditions that might be expanded in the field of neurodegenerative disorders or cancer studies. Future studies should take into consideration the newer insights into bone muscle crosstalk in order to develop multitargeted and therapeutic interventions.

[Spasticity management: an interprofessional evaluation]. / Prise en charge de la spasticité : une évaluation interprofessionnelle.

Spasticity is a common sign of central nervous system lesions and its management is difficult because it is usually associated with other symptoms of upper motoneuron syndrome (paresis, spastic dystonia, contractures, …). We propose an interprofessional evaluation, which demonstrates that a standardized evaluation, a common approach and a gait analysis improve the therapeutic decision.

La spasticité est très fréquente après une lésion du système nerveux central, et sa prise en charge demeure difficile, car elle se combine avec d'autres symptômes caractéristiques du syndrome du motoneurone supérieur (parésie, dystonie spastique, contractures…). Afin de faciliter le choix thérapeutique, nous présentons le modèle d'une évaluation interprofessionnelle, qui démontre qu'une évaluation standardisée, une approche commune et une analyse de la marche permettent une meilleure prise en charge thérapeutique.

Spinal Cord Injury as a Model of Bone-Muscle Interactions: Therapeutic Implications From in vitro and in vivo Studies.

Spinal cord injuries (SCIs) represent a variety of conditions related to the damage of the spinal cord with consequent musculoskeletal repercussions. The bone and muscle tissues share several catabolic pathways that lead to variable degrees of disability in SCI patients. In this review article, we provide a comprehensive characterization of the available treatment options targeting the skeleton and the bone in the setting of SCI. Among the pharmacological intervention, bisphosphonates, anti-sclerostin monoclonal antibodies, hydrogen sulfide, parathyroid hormone, and RANKL pathway inhibitors represent valuable options for treating bone alterations. Loss phenomena at the level of the muscle can be counteracted with testosterone, anabolic-androgenic steroids, and selective androgen receptor modulators. Exercise and physical therapy are valuable strategies to increase bone and muscle mass. Nutritional interventions could enhance SCI treatment, particularly in the setting of synergistic and multidisciplinary interventions, but there are no specific guidelines available to date. The development of multidisciplinary recommendations is required for a proper clinical management of SCI patients.